Education and Career

Academic & Professional Experience

•   1998 04 ,  - 現在, Faculty of Medicine, Kindai University

Research Activities

Research Areas

• Life sciences, Medical systems
• Life sciences, Tumor diagnostics and therapeutics

Research Interests

• nodule-in-nodule HCC, Coded phase inversion harmonic, Pure arterial phase imaging, dysplastic nodule, nodule-in-nodule, Sonazoid

Published Papers

• Hepatic arterial infusion chemotherapy versus sorafenib in patients with advanced hepatocellular carcinoma, Ueshima K, Ogasawara S, Ikeda M, Yasui Y, Terashima T, Yamashita T, Obi S, Sato S, Aikata H, Ohmura T, Kuroda H, Ohki T, Nagashima K, Ooka Y, Takita M, Kurosaki M, Chayama K, Kaneko S, Izumi N, Kato N, Kudo M, Omata M, Liver Cancer, Liver Cancer, In press, Jun. 2020 , Refereed
• Promising anticancer therapy: combination of immune checkpoint inhibitors and molecular-targeted agents, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, HepatoBiliary Surg Nutr, HepatoBiliary Surg Nutr, 2020 , Refereed
• Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1, Naoshi Nishida, Kazuko Sakai, Masahiro Morita, Tomoko Aoki, Masahiro Takita, Satoru Hagiwara, Yoriaki Komeda, Mamoru Takenaka, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Kazuto Nishio, Masatoshi Kudo, Liver Cancer, Liver Cancer, 2020 , Refereed
• Multiple Gastrointestinal Stromal Tumors of the Duodenum Associated with Neurofibromatosis Type, Shigenaga Matsui, Hiroshi Kashida, Kenji Nomura, Yoriaki Komeda, Masatoshi Kudo, Adv Res Gastroentero Hepatol Volume 14 Issue 3 - January 2020, Adv Res Gastroentero Hepatol Volume 14 Issue 3 - January 2020, Jan. 2020 , Refereed
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• Significance of the surgical hepatic resection margin in patients with a single hepatocellular carcinoma., T Aoki, K Kubota, K Hasegawa, S Kubo, N Izumi, N Kokudo, M Sakamoto, S Shiina, T Takayama, O Nakashima, Y Matsuyama, T Murakami, M Kudo, The British journal of surgery, The British journal of surgery, 107(1), 113 - 120, Jan. 2020 , Refereed
  Summary:BACKGROUND: The impact of a wide surgical margin on the outcome of patients with hepatocellular carcinoma (HCC) has not been evaluated in relation to the type of liver resection performed, anatomical or non-anatomical. The aim of this study was to evaluate the impact of surgical margin status on outcomes in patients undergoing anatomical or non-anatomical resection for solitary HCC. METHODS: Data from patients with solitary HCC who had undergone non-anatomical partial resection (Hr0 group) or anatomical resection of one Couinaud segment (HrS group) between 2000 and 2007 were extracted from a nationwide survey database in Japan. Overall and recurrence-free survival associated with the surgical margin status and width were evaluated in the two groups. RESULTS: A total of 4457 patients were included in the Hr0 group and 3507 in the HrS group. A microscopically positive surgical margin was associated with poor overall survival in both groups. A negative but 0-mm surgical margin was associated with poorer overall and recurrence-free survival than a wider margin only in the Hr0 group. In the HrS group, the width of the surgical margin was not associated with patient outcome. CONCLUSION: Anatomical resection with a negative 0-mm surgical margin may be acceptable. Non-anatomical resection with a negative 0-mm margin was associated with a less favourable survival outcome.
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• Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma, Cheng AL, Hsu C, Chan SL, Choo SP, Kudo M, J Hepatol, J Hepatol, 72, 307 - 319, 2020 , Refereed
• Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial., Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL, KEYNOTE, investigators, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, JCO1901307, Dec. 2019 , Refereed
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• Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial., Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Yasui K, Aino H, Ido A, Kawabe N, Nakao K, Wada Y, Yokosuka O, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Johnson PJ, Arai Y, TACTICS study group, Gut, Gut, Dec. 2019 , Refereed
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• Prediction of Survival Among Patients Receiving Transarterial Chemoembolization for Hepatocellular Carcinoma: A Response-Based Approach., Han G, Berhane S, Toyoda H, Bettinger D, Elshaarawy O, Chan AWH, Kirstein M, Mosconi C, Hucke F, Palmer D, Pinato DJ, Sharma R, Ottaviani D, Jang JW, Labeur TA, van Delden OM, Pirisi M, Stern N, Sangro B, Meyer T, Fateen W, García-Fiñana M, Gomaa A, Waked I, Rewisha E, Aithal GP, Travis S, Kudo M, Cucchetti A, Peck-Radosavljevic M, Takkenberg RB, Chan SL, Vogel A, Johnson PJ, Hepatology (Baltimore, Md.), Hepatology (Baltimore, Md.), Nov. 2019 , Refereed
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• Novel concept of bared type metallic stent for endoscopic bilateral stent-in-stent placement in patients with hilar malignant biliary obstruction (with video)., Takenaka M, Nakai A, Kudo M, Journal of hepato-biliary-pancreatic sciences, Journal of hepato-biliary-pancreatic sciences, Nov. 2019 , Refereed
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• REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset., Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, Aikata H, Kawaguchi Y, Wada Y, Numata K, Inaba Y, Kuromatsu R, Kobayashi M, Okusaka T, Tamai T, Kitamura C, Saito K, Haruna K, Okita K, Kumada H, Journal of gastroenterology, Journal of gastroenterology, Nov. 2019 , Refereed
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• Response to the letter to the editor 'Reply to "Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study" by Dr. Peng Chen'., Yamao K, Watanabe T, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), Nov. 2019 , Refereed
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• The chances of hepatic resection curing hepatocellular carcinoma., Cucchetti A, Zhong J, Berhane S, Toyoda H, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Ercolani G, Mazzaferro V, Kudo M, Cescon M, Pinna AD, Kumada T, Johnson PJ, Journal of hepatology, Journal of hepatology, Nov. 2019 , Refereed
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• Objective Response by mRECIST Is an Independent Prognostic Factor for Overall Survival in Hepatocellular Carcinoma Treated with Sorafenib in the SILIUS Trial., Kudo M, Ueshima K, Chiba Y, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Arai Y, Liver cancer, Liver cancer, 8(6), 505 - 519, Nov. 2019 , Refereed
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• Can Localized Stenosis of the Main Pancreatic Duct be a Predictive Factor for Early Detection of Pancreatic Cancer?, Takenaka M, Yamao K, Kudo M, Clinical endoscopy, Clinical endoscopy, 52(6), 523 - 524, Nov. 2019 , Refereed
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• Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update., Kokudo N, Takemura N, Hasegawa K, Takayama T, Kubo S, Shimada M, Nagano H, Hatano E, Izumi N, Kaneko S, Kudo M, Iijima H, Genda T, Tateishi R, Torimura T, Igaki H, Kobayashi S, Sakurai H, Murakami T, Watadani T, Matsuyama Y, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 49(10), 1109 - 1113, Oct. 2019 , Refereed
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• Correction: Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma., Evans TRJ, Kudo M, Finn RS, Han KH, Cheng AL, Ikeda M, Kraljevic S, Ren M, Dutcus CE, Piscaglia F, Sung MW, British journal of cancer, British journal of cancer, 121(7), 625, Oct. 2019 , Refereed
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• Corrigendum to "Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis" [J Hepatol 71 (2019) 543-552]., Yau T, Hsu C, Kim TY, Choo SP, Kang YK, Hou MM, Numata K, Yeo W, Chopra A, Ikeda M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Dela Cruz C, Kudo M, Journal of hepatology, Journal of hepatology, Oct. 2019 , Refereed
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• LENVATINIB AS AN INITIAL TREATMENT IN PATIENTS WITH INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA BEYOND UP-TO-SEVEN CRITERIA AND CHILD-PUGH A LIVER FUNCTION: A MULTICENTER PROPENSITY-SCORE MATCHED STUDY, Kudo Masatoshi, Ueshima Kazuomi, Chan Stephen L, Minami Tomohiro, Chishina Hirokazu, Aoki Tomoko, Takita Masahiro, Hagiwara Satoru, Minami Yasunori, Ida Hiroshi, Takenaka Mamoru, Sakurai Toshiharu, Watanabe Tomohiro, Morita Masahiro, Ogawa Chikara, Wada Yoshiyuki, Ikeda Masafumi, Ishii Hiroshi, Izumi Namiki, Nishida Naoshi, HEPATOLOGY, HEPATOLOGY, 70, 133A - 134A, Oct. 2019 , Refereed
• A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE., Kudo M, Liver cancer, Liver cancer, 8(5), 299 - 311, Oct. 2019 , Refereed
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• Newly Proposed ALBI Grade and ALBI-T Score as Tools for Assessment of Hepatic Function and Prognosis in Hepatocellular Carcinoma Patients., Hiraoka A, Kumada T, Michitaka K, Kudo M, Liver cancer, Liver cancer, 8(5), 312 - 325, Oct. 2019 , Refereed
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• Long-term outcomes of EUS-guided transluminal stent deployment for benign biliary disease: Multicenter clinical experience (with videos)., Ogura T, Takenaka M, Shiomi H, Goto D, Tamura T, Hisa T, Kato H, Nishioka N, Minaga K, Masuda A, Onoyama T, Kudo M, Higuchi K, Kitano M, Endoscopic ultrasound, Endoscopic ultrasound, 8(6), 398 - 403, Sep. 2019 , Refereed
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• Effective use of the Japan Narrow Band Imaging Expert Team classification based on diagnostic performance and confidence level., Hirata D, Kashida H, Iwatate M, Tochio T, Teramoto A, Sano Y, Kudo M, World journal of clinical cases, World journal of clinical cases, 7(18), 2658 - 2665, Sep. 2019 , Refereed
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• Comparison of the efficacy and safety of endoscopic ultrasound-guided choledochoduodenostomy and hepaticogastrostomy for malignant distal biliary obstruction: Multicenter, randomized, clinical trial., Minaga K, Ogura T, Shiomi H, Imai H, Hoki N, Takenaka M, Nishikiori H, Yamashita Y, Hisa T, Kato H, Kamada H, Okuda A, Sagami R, Hashimoto H, Higuchi K, Chiba Y, Kudo M, Kitano M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(5), 575 - 582, Sep. 2019 , Refereed
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• Adjuvant therapy after radical surgery for hepatocellular carcinoma: still an unmet need., Minami Y, Kudo M, Hepatobiliary surgery and nutrition, Hepatobiliary surgery and nutrition, 8(4), 414 - 416, Aug. 2019 , Refereed
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• Real-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan, Takaguchi, Koichi, Toyoda, Hidenori, Tsutsui, Akemi, Suzuki, Yoshiyuki, Nakamuta, Makoto, Imamura, Michio, Senoh, Tomonori, Nagano, Takuya, Tada, Toshifumi, Tachi, Yoshihiko, Hiraoka, Atsushi, Michitaka, Kojiro, Shibata, Hiroshi, Joko, Kouji, Okubo, Hironao, Tsuji, Kunihiko, Takaki, Shintaro, Watanabe, Tsunamasa, Ogawa, Chikara, Chayama, Kazuaki, Kumada, Takashi, Kudo, Masatoshi, Kumada, Hiromitsu, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 54(8), 742 - 751, Aug. 2019 , Refereed
  Summary:BackgroundThe virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings.MethodsIn a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics.ResultsMore than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%.ConclusionsMany patients tre
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• Biology and Significance of Alpha-Fetoprotein in Hepatocellular Carcinoma., Galle PR, Foerster F, Kudo M, Chan SL, Llovet JM, Qin S, Schelman W, Chintharlapalli S, Abada P, Sherman M, Zhu AX, Liver international : official journal of the International Association for the Study of the Liver, Liver international : official journal of the International Association for the Study of the Liver, Aug. 2019 , Refereed
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• Immuno-Oncology Therapy for Hepatocellular Carcinoma: Current Status and Ongoing Trials., Kudo M, Liver cancer, Liver cancer, 8(4), 221 - 238, Jul. 2019 , Refereed
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• B-Mode Ultrasonography versus Contrast-Enhanced Ultrasonography for Surveillance of Hepatocellular Carcinoma: A Prospective Multicenter Randomized Controlled Trial., Kudo M, Ueshima K, Osaki Y, Hirooka M, Imai Y, Aso K, Numata K, Kitano M, Kumada T, Izumi N, Sumino Y, Ogawa C, Akazawa K, Liver cancer, Liver cancer, 8(4), 271 - 280, Jul. 2019 , Refereed
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• Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis., Bettinger D, Pinato DJ, Schultheiss M, Sharma R, Rimassa L, Pressiani T, Burlone ME, Pirisi M, Kudo M, Park JW, Buettner N, Neumann-Haefelin C, Boettler T, Abbasi-Senger N, Alheit H, Baus W, Blanck O, Gerum S, Guckenberger M, Habermehl D, Ostheimer C, Riesterer O, Tamihardja J, Grosu AL, Thimme R, Brunner TB, Gkika E, Liver cancer, Liver cancer, 8(4), 281 - 294, Jul. 2019 , Refereed
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• Novel concept using a plastic stent for endoscopic ultrasound-guided hepaticogastrostomy adjusting the length according to the patient's anatomy., Takenaka M, Minaga K, Yoshikawa T, Okamoto A, Nakai A, Omoto S, Kudo M, Endoscopy, Endoscopy, Jul. 2019 , Refereed
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• Conversion of percutaneous transhepatic gallbladder drainage to endoscopic ultrasound-guided hepaticogastrostomy by the intentional expansion method., Takenaka M, Kamata K, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(6), 718, Jul. 2019 , Refereed
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• Large balloon expansion method for re-intervention after endoscopic ultrasound-guided hepaticogastrostomy for stent obstruction., Takenaka M, Nakai A, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(5), e99 - e100, Jul. 2019 , Refereed
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• Important Clinical Factors in Sequential Therapy Including Lenvatinib against Unresectable Hepatocellular Carcinoma., Hiraoka A, Kumada T, Atsukawa M, Hirooka M, Tsuji K, Ishikawa T, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Tada T, Toyoda H, Nouso K, Tsutsui A, Nagano T, Itokawa N, Hayama K, Imai M, Joko K, Tanaka H, Tamai T, Koizumi Y, Hiasa Y, Michitaka K, Kudo M, Real-life Practice Experts for HCC, RELPEC) Study Group., HC, Group (hepatocellular carcinoma exper, s, fr, clinics in Ja, Oncology, Oncology, 97(5), 1 - 9, Jul. 2019 , Refereed
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• CLINICAL UTILITY OF ENDOSCOPIC ULTRASOUND-GUIDED DRAINAGE USING CONTRAST-ENHANCED HARMONIC IMAGING IN CASES WITH DIFFICULTIES, Minaga Kosuke, Takenaka Mamoru, Yoshikawa Tomoe, Okamoto Ayana, Ishikawa Rei, Yamazaki Tomohiro, Nakai Atsushi, Omoto Shunsuke, Kamata Ken, Yamao Kentaro, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB299, Jun. 2019 , Refereed
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• ENDOSCOPIC UTRASOUND-GUDED CHOLEDOCHODUODENOSTOMY USING A THIN STENT DELIVERY SYSTEM IN PATIENTS WITH UNRESECTABLE MALIGNANT DISTAL BILIARY OBSTRUCTION: A PROSPECTIVE MYLTICENTER STUDY, Itonaga Masahiro, Kitano Masayuki, Hatamaru Keiichi, Tamura Takashi, Nuta Junya, Kawaji Yuki, Takenaka Mamoru, Minaga Kosuke, Kudo Masatoshi, Ogura Takeshi, Higuchi Kazuhide, Chiba Yasutaka, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB315, Jun. 2019 , Refereed
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• LONG-TERM OUTCOMES OF EUS-GUIDED TRANSLUMINAL STENT DEPLOYEMNT FOR BENIGN BILIARY DISEASE: MULTICENTER CLINICAL EXPERIENCE, Ogura Takeshi, Takenaka Mamoru, Shiomi Hideyuki, Goto Daisuke, Hisa Takeshi, Tamura Takashi, Kato Hironari, Nishioka Nobu, Minaga Kosuke, Kudo Masatoshi, Higuchi Kazuhide, Kitano Masayuki, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB297, Jun. 2019 , Refereed
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• VALUE OF THE BISPECTRAL INDEX MONITOR DURING ENDOSCOPIC ULTRASONOGRAPHY UNDER SEDATION WITH PROPOFOL AND MIDAZOLAM, Okamoto Ayana, Kamata Ken, Takenaka Mamoru, Yoshikawa Tomoe, Ishikawa Rei, Yamazaki Tomohiro, Nakai Atsushi, Omoto Shunsuke, Minaga Kosuke, Yamao Kentaro, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB602 - AB603, Jun. 2019 , Refereed
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• LINEAR EUS TRAINING BY USING SYSTEMATIC SCREENING PROTCOL FOR THE PANCREATOBILIARY SYSTEM, Omoto Shunsuke, Takenaka Mamoru, Ishikawa Rei, Okamoto Ayana, Nakai Atsushi, Yamazaki Tomohiro, Minaga Kosuke, Kamata Ken, Yamao Kentaro, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB584, Jun. 2019 , Refereed
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• THE USEFULNESS OF NOVEL CANNULATION METHOD USING A UNIQUE, DOUBLE LUMENS CATHETER (UNEVEN METHOD) FOR THE PATIENTS WITH SURGICALLY ALTERED GASTROINTESTINAL ANATOMY, Takenaka Mamoru, Yoshikawa Tomoe, Ishikawa Rei, Okamoto Ayana, Yamazaki Tomohiro, Nakai Atsushi, Omoto Shunsuke, Minaga Kosuke, Kamata Ken, Yamao Kentaro, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB223, Jun. 2019 , Refereed
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• EXAMINATION OF ACTUAL RADIATION EXPOSURE DOSE OF THE PATIENTS WHO PERFORMED EUS-GUIDED DRAINAGE (EUS-BD/EUS-PD/EUS-CD), Takenaka Mamoru, Hayashi Shiro, Nishida Tsutomu, Hosono Makoto, Yoshikawa Tomoe, Ishikawa Rei, Okamoto Ayana, Yamazaki Tomohiro, Nakai Atsushi, Omoto Shunsuke, Minaga Kosuke, Kamata Ken, Yamao Kentaro, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 89(6), AB444 - AB445, Jun. 2019 , Refereed
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• Response Evaluation Criteria in Cancer of the Liver (Version 5) (RECICL 2019 revised version)., Kudo M, Ikeda M, Ueshima K, Sakamoto M, Shiina S, Tateishi R, Hasegawa K, Furuse J, Miyayama S, Murakami T, Yamashita T, Kokudo N, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, Jun. 2019 , Refereed
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• Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma., Evans TRJ, Kudo M, Finn RS, Han KH, Cheng AL, Ikeda M, Kraljevic S, Ren M, Dutcus CE, Piscaglia F, Sung MW, British journal of cancer, British journal of cancer, 121(3), 218 - 221, Jun. 2019 , Refereed
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• Recent Updates on the Relationship between Cancer and Autoimmune Pancreatitis., Okamoto A, Watanabe T, Kamata K, Minaga K, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 58(11), 1533 - 1539, Jun. 2019 , Refereed
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• Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan., Kobayashi M, Kudo M, Izumi N, Kaneko S, Azuma M, Copher R, Meier G, Pan J, Ishii M, Ikeda S, Journal of gastroenterology, Journal of gastroenterology, 54(6), 558 - 570, Jun. 2019 , Refereed
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• Novel sphincterotomy device that orientates blade along the axis of the bile duct in patients with Roux-en-Y anastomosis., Takenaka M, Yoshikawa T, Okamoto A, Nakai A, Minaga K, Yamao K, Kudo M, Endoscopy, Endoscopy, 51(6), E132 - E134, Jun. 2019 , Refereed
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• The IFN-α-IL-33 Axis as Possible Biomarkers in IgG4-Related Disease., Minaga K, Watanabe T, Kamata K, Takenaka M, Yasukawa S, Kudo M, The American journal of gastroenterology, The American journal of gastroenterology, 114(6), 1002 - 1003, Jun. 2019 , Refereed
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• Endoscopic submucosal dissection of duodenal adenocarcinoma arising from Brunner's gland., Tanaka H, Matsui S, Kashida H, Kudo M, Annals of gastroenterology, Annals of gastroenterology, 32(3), 316, May 2019 , Refereed
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• A novel technique for stent dysfunction after endoscopic ultrasound-guided hepaticogastrostomy with antegrade stenting., Okamoto A, Minaga K, Takenaka M, Yoshikawa T, Kamata K, Yamao K, Kudo M, Endoscopy, Endoscopy, May 2019 , Refereed
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• Hemorrhage from metastasis of a 5-mm renal cell carcinoma lesion to the gallbladder detected by contrast-enhanced endoscopic ultrasonography., Takenaka M, Okabe Y, Kudo M, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 51(5), 743, May 2019 , Refereed
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• Autoimmune hepatitis and IgG4-related disease., Minaga K, Watanabe T, Chung H, Kudo M, World journal of gastroenterology, World journal of gastroenterology, 25(19), 2308 - 2314, May 2019 , Refereed
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• Pembrolizumab for the Treatment of Hepatocellular Carcinoma., Kudo M, Liver cancer, Liver cancer, 8(3), 143 - 154, May 2019 , Refereed
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• Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures., Hidaka H, Kurosaki M, Tanaka H, Kudo M, Abiru S, Igura T, Ishikawa T, Seike M, Katsube T, Ochiai T, Kimura K, Fukuhara T, Kano T, Nagata T, Tanaka K, Kurokawa M, Yamamoto K, Osaki Y, Izumi N, Imawari M, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 17(6), 1192 - 1200, May 2019 , Refereed
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• Endoscopic ultrasound-guided choledochoduodenostomy using a thin stent delivery system in patients with unresectable malignant distal biliary obstruction: A prospective multicenter study., Itonaga M, Kitano M, Hatamaru K, Tamura T, Nuta J, Kawaji Y, Takenaka M, Minaga K, Kudo M, Ogura T, Higuchi K, Chiba Y, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(3), 291 - 298, May 2019 , Refereed
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• Radiofrequency ablation of liver metastasis: potential impact on immune checkpoint inhibitor therapy., Minami Y, Nishida N, Kudo M, European radiology, European radiology, 29(9), 5045 - 5051, Apr. 2019 , Refereed
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• Current status and perspectives for computer-aided ultrasonic diagnosis of liver lesions using deep learning technology., Nishida N, Yamakawa M, Shiina T, Kudo M, Hepatol Int, Hepatol Int, Feb 21. doi: 10.1007/s12072-01, Feb. 2019 , Refereed
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• Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial., Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M, REACH, study investigators, The Lancet. Oncology, The Lancet. Oncology, 20(2), 282 - 296, Feb. 2019 , Refereed
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• Hepatic portal venous gas associated with Klebsiella oxytoca infection in the absence of preceding antibiotic treatment, Tanaka H, Watanabe T, Nagai T, Minaga K, Kamata K, Komeda Y, Kudo M, Clin J Gastroenterol, Clin J Gastroenterol, 12(4), 316 - 319, 2019 , Refereed
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• RICK/RIP2 is a NOD2-independent nodal point of gut inflammation, Watanabe T, Minaga K, Kamata K, Sakurai T, Komeda Y, Nagai T, Kitani A, Tajima M, Fuss IJ, Kudo M, Strober W, Int Immunol, Int Immunol, 31(10), 669 - 683, 2019 , Refereed
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• 膵管内乳頭粘液性腫瘍術後フォローアップにおけるEUSの有用性, 鎌田 研, 竹中 完, 三長 孝輔, 大本 俊介, 宮田 剛, 山雄 健太郎, 今井 元, 中井 敦史, 田中 秀和, 千葉 康敬, 渡邉 智裕, 櫻井 俊治, 西田 直生志, 筑後 考章, 松本 逸平, 竹山 宜典, 北野 雅之, 工藤 正俊, 61(4), 417 - 426, 2019 , Refereed
• Verrucous antral gastritis in relation to Helicobacter pylori infection, nutrition, and gastric atrophy, Tsuji N, Umehara Y, Takenaka M, Minami Y, Watanabe T, Nishida N, Kudo M, 2019 , Refereed
• Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer. Digestion, Sakurai T, Komeda Y, Nagai T, Kamata K, Minaga K, Yamao K, Takenaka M, Hagiwara S, Watanabe T, Nishida N, Kashida H, Nakagawa K, Kudo M, Digestion, Digestion, 100(3), 192 - 200, 2019 , Refereed
  DOI
• Comparison of the Diagnostic Performance of Newly Designed 21-Gauge and Standard 22-Gauge Aspiration Needles in Patients with Solid Pancreatic Masses, Minaga K, Yoshikawa T, Yamashita Y, Akamatsu H, Ikenouchi M, Ishii T, Matsumoto H, Iwagami H, Nakatani Y, Hatamaru K, Takenaka M, Akamatsu T, Uenoyama Y, Watanabe T, Ono K, Chiba Y, Kudo M, Dig Dis Sci, Dig Dis Sci, 64(10), 2982 - 2991, 2019 , Refereed
  DOI
• Efficacy and Safety of Chemotherapy Following Anti-PD-1 Antibody Therapy for Gastric Cancer: A Case of Sclerosing Cholangitis, Kono M, Sakurai T, Okamoto K, Masaki S, Nagai T, Komeda Y, Kamata K, Minaga K, Yamao K, Takenaka M, Watanabe T, Nishida N, Kudo M, Intern Med, Intern Med, 58(9), 1263 - 1266, 2019 , Refereed
  DOI
• Risk factors for local recurrence and appropriate surveillance interval after endoscopic resection, Komeda Y, Watanabe T, Sakurai T, Kono M, Okamoto K, Nagai T, Takenaka M, Hagiwara S, Matsui S, Nishida N, Tsuji N, Kashida H, Kudo M, World J Gastroenterol, World J Gastroenterol, 25, 1502 - 1512, 2019 , Refereed
• Targeted and immune therapy for hepatocellular carcinoma: predictions for 2019 and beyond, Masatoshi Kudo, World J Gastroenterol, World J Gastroenterol, 25, 789 - 807, 2019 , Refereed
• [Systemic therapy for hepatocellular carcinoma:recent advances and future perspective]., Kudo M, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, 116(1), 8 - 17, 2019 , Refereed
  DOI
• Liver damage related to immune checkpoint inhibitors., Nishida N, Kudo M, Hepatology international, Hepatology international, 13(3), 248 - 252, Jan. 2019 , Refereed
  DOI
• Rendezvous within biloma technique combining percutaneous and endoscopic approaches: a novel biliary recanalization method., Okamoto A, Minaga K, Takenaka M, Yoshikawa T, Iwasaki T, Tsurusaki M, Kudo M, Endoscopy, Endoscopy, Dec. 2018 , Refereed
  DOI
• Nivolumab-Induced Hemophilia A Presenting as Gastric Ulcer Bleeding in a Patient With NSCLC., Kato R, Hayashi H, Sano K, Handa K, Kumode T, Ueda H, Okuno T, Kawakami H, Matsumura I, Kudo M, Nakagawa K, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 13(12), e239 - e241, Dec. 2018 , Refereed
  DOI
• Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients., Tak WY, Ryoo BY, Lim HY, Kim DY, Okusaka T, Ikeda M, Hidaka H, Yeon JE, Mizukoshi E, Morimoto M, Lee MA, Yasui K, Kawaguchi Y, Heo J, Morita S, Kim TY, Furuse J, Katayama K, Aramaki T, Hara R, Kimura T, Nakamura O, Kudo M, Investigational new drugs, Investigational new drugs, 36(6), 1072 - 1084, Dec. 2018 , Refereed
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• Liver Ultrasound Elastography: An Update to the World Federation for Ultrasound in Medicine and Biology Guidelines and Recommendations., Ferraioli G, Wong VW, Castera L, Berzigotti A, Sporea I, Dietrich CF, Choi BI, Wilson SR, Kudo M, Barr RG, Ultrasound in medicine & biology, Ultrasound in medicine & biology, 44(12), 2419 - 2440, Dec. 2018 , Refereed
  DOI
• Dual-energy computed tomography for non-invasive staging of liver fibrosis: Accuracy of iodine density measurements from contrast-enhanced data., Sofue K, Tsurusaki M, Mileto A, Hyodo T, Sasaki K, Nishii T, Chikugo T, Yada N, Kudo M, Sugimura K, Murakami T, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 48(12), 1008 - 1019, Nov. 2018 , Refereed
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• Acute Pancreatitis with Disturbed Consciousness Caused by Hyperparathyroidism., Otsuka Y, Kamata K, Minaga K, Takenaka M, Watanabe T, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 57(21), 3075 - 3078, Nov. 2018 , Refereed
  DOI
• Novel metallic stent designed for endoscopic bilateral stent-in-stent placement in patients with hilar malignant biliary obstruction., Takenaka M, Yamao K, Minaga K, Nakai A, Omoto S, Kamata K, Kudo M, Endoscopy, Endoscopy, Nov. 2018 , Refereed
  DOI
• Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease., Watanabe T, Minaga K, Kamata K, Kudo M, Strober W, Trends in immunology, Trends in immunology, 39(11), 874 - 889, Nov. 2018 , Refereed
  DOI
• New Diagnostic Method for Hepatic Steatosis Using Attenuation Measurement By Ultrasound B Mode: Comparison with Controlled Attenuation Parameter., Koizumi Yohei, Hirooka Masashi, Yada Norihisa, Tamaki Nobuharu, Izumi Namiki, Kudo Masatoshi, Hiasa Yoichi, HEPATOLOGY, HEPATOLOGY, 68, 1311A, Oct. 2018 , Refereed
• Systemic Therapy for Hepatocellular Carcinoma: Latest Advances., Kudo M, Cancers, Cancers, 10(11), Oct. 2018 , Refereed
  DOI
• Ramucirumab as Second-Line Systemic Therapy in Hepatocellular Carcinoma., Kudo M, Liver cancer, Liver cancer, 7(4), 305 - 311, Oct. 2018 , Refereed
  DOI
• A case of EUS-guided pancreatic duct rendezvous stenting in which initial contrast medium injection was useful for the second puncture., Omoto S, Takenaka M, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(1), e20 - e21, Oct. 2018 , Refereed
  DOI
• Cytokines produced by innate immune cells in IgG4-related disease., Yoshikawa T, Watanabe T, Minaga K, Kamata K, Kudo M, Modern rheumatology, Modern rheumatology, 29(2), 1 - 18, Oct. 2018 , Refereed
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• Value of contrast-enhanced harmonic EUS with enhancement pattern for diagnosis of pancreatic cancer: a meta-analysis., Yamashita Y, Shimokawa T, Napoléon B, Fusaroli P, Gincul R, Kudo M, Kitano M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(2), 125 - 133, Oct. 2018 , Refereed
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• Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions, Ken Kamata, Mamoru Takenaka, Masayuki Kitano, Shunsuke Omoto, Takeshi Miyata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Tosiharu Sakurai, Naoshi Nishida, Hiroshi Kashida, Takaaki Chikugo, Yasutaka Chiba, Takuya Nakai, Yoshifumi Takeyama, Andrea Lisotti, Pietro Fusaroli, Masatoshi Kudo, Gastroenterological Endoscopy, Gastroenterological Endoscopy, 60, 1611 - 1620, Sep. 01 2018
  Summary:Copyright© 2018 Japan Gastroenterological Endoscopy Society. All rights reserved. Background and Aim: Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for diagnosis of localized gallbladder lesions. Methods: One hundred and twenty-five patients with localized gallbladder lesions were evaluated by CH-EUS between March 2007 and February 2014. This was a single-center retrospective study. Utilities of fundamental B-mode EUS (FB-EUS) and CH-EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images. Results: In the differentiation between gallbladder lesions and sludge plug, FB-EUS had a sensitivity, specificity, and accuracy of 82％, 100％, and 95％, respectively, whereas CH-EUS had a sensitivity, specificity, and accuracy of 100％, 99％, and 99％, respectively. FB-EUS-based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61-87％, 71-88％, and 74-86％, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH-EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90％, 98 ％, and 96％, respectively. There was a significant difference between FB-EUS and CH-EUS in terms of carcinoma diagnosis. Conclusion: CH-EUS was useful for the evaluation of localized gallbladder lesions.
  DOI
• Corrigendum to 'Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study' [Eur J Canc 81 (2017) 17-25]., Chau I, Peck-Radosavljevic M, Borg C, Malfertheiner P, Seitz JF, Park JO, Ryoo BY, Yen CJ, Kudo M, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Okusaka T, Bowman L, Cui ZL, Girvan AC, Abada PB, Yang L, Zhu AX, European journal of cancer (Oxford, England : 1990), European journal of cancer (Oxford, England : 1990), 100, 135 - 136, Sep. 2018 , Refereed
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• Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy., Nishida N, Nishimura T, Kaido T, Minaga K, Yamao K, Kamata K, Takenaka M, Ida H, Hagiwara S, Minami Y, Sakurai T, Watanabe T, Kudo M, Cancers, Cancers, 10(10), Sep. 2018 , Refereed
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• Cannulation method for intradiverticular papilla with long oral protrusion using biopsy forceps for axis alignment., Takenaka M, Minaga K, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 30(5), 700 - 701, Sep. 2018 , Refereed
  DOI
• Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection., Chan AWH, Zhong J, Berhane S, Toyoda H, Cucchetti A, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Mazzaferro V, García-Fiñana M, Kudo M, Kumada T, Roayaie S, Johnson PJ, Journal of hepatology, Journal of hepatology, Sep. 2018 , Refereed
  DOI
• Extremely High Objective Response Rate of Lenvatinib: Its Clinical Relevance and Changing the Treatment Paradigm in Hepatocellular Carcinoma., Kudo M, Liver cancer, Liver cancer, 7(3), 215 - 224, Sep. 2018 , Refereed
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• Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial., Kudo M, Liver cancer, Liver cancer, 7(3), 225 - 234, Sep. 2018 , Refereed
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• ENBD tube guided scope insertion technique for internal drainage in a case of difficult selective biliary duct guiding., Takenaka M, Minaga K, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(1), e1 - e2, Aug. 2018 , Refereed
  DOI
• A novel method of biliary cannulation for patients with Roux-en-Y anastomosis using a unique, uneven, double lumen cannula (Uneven method)., Takenaka M, Yamao K, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 30(6), 808 - 809, Aug. 2018 , Refereed
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• Neurilemmoma Mimicking a Multilocular Cystic Lesion of the Liver: A Case Report., Yoshida A, Yamao K, Takenaka M, Nakai A, Omoto S, Kamata K, Minaga K, Miyata T, Imai H, Matsumoto I, Takeyama Y, Chikugo T, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 57(23), 3377 - 3380, Aug. 2018 , Refereed
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• A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation., Tateishi R, Seike M, Kudo M, Tamai H, Kawazoe S, Katsube T, Ochiai T, Fukuhara T, Kano T, Tanaka K, Kurokawa M, Yamamoto K, Osaki Y, Izumi N, Imawari M, Journal of gastroenterology, Journal of gastroenterology, 54(2), 171 - 181, Aug. 2018 , Refereed
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• Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial., Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M, KEYNOTE, investigators, The Lancet. Oncology, The Lancet. Oncology, 19(7), 940 - 952, Jul. 2018 , Refereed
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• Clinical Efficacy and Safety of EUS-guided Gallbladder Drainage Replacement of Percutaneous Drainage: A Multicenter Retrospective Study., Minaga K, Yamashita Y, Ogura T, Takenaka M, Shimokawa Y, Hisa T, Itonaga M, Kato H, Nishikiori H, Okuda A, Matsumoto H, Uenoyama Y, Watanabe T, Chiba Y, Higuchi K, Kudo M, Kitano M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 31(2), 180 - 187, Jul. 2018 , Refereed
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• Ramucirumab Safety in East Asian Patients: A Meta-Analysis of Six Global, Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Trials., Yen CJ, Muro K, Kim TW, Kudo M, Shih JY, Lee KW, Chao Y, Kim SW, Yamazaki K, Sohn J, Cheng R, Zhang Y, Binder P, Mi G, Orlando M, Chung HC, Journal of global oncology, Journal of global oncology, (4), 1 - 12, Jul. 2018 , Refereed
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• SIMILAR EFFICACY AND SAFETY OF ENDOSCOPIC ULTRASOUND-GUIDED BILIARY DRAINAGE VIA HEPATICOGASTROSTOMY AND CHOLEDOCHODUODENOSTOMY APPROACHES FOR MALIGNANT DISTAL BILIARY OBSTRUCTION: A MULTICENTER, PROSPECTIVE, RANDOMIZED TRIAL, Minaga Kosuke, Kitano Masayuki, Ogura Takeshi, Shiomi Hideyuki, Hoki Noriyuki, Nishikiori Hidefumi, Yamashita Yukitaka, Hisa Takeshi, Kato Hironari, Kamada Hideki, Takenaka Mamoru, Higuchi Kazuhide, Chiba Yasutaka, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 87(6), AB147, Jun. 2018 , Refereed
• NEW METHOD FOR DIFFICULT BILIARY CANNULATION USING THE NOVEL UNEVEN DOUBLE LUMEN CANNULA (DLC METHOD), Takenaka Mamoru, Nakai Atsushi, Omoto Shunsuke, Miyata Takeshi, Minaga Kosuke, Kamata Ken, Yamao Kentaro, Imai Hajime, Kudo Masatoshi, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 87(6), AB209 - AB210, Jun. 2018 , Refereed
• Ultrasound-ultrasound image overlay fusion improves real-time control of radiofrequency ablation margin in the treatment of hepatocellular carcinoma, Minami Y, Minami T, Hagiwara S, Ida H, Ueshima K, Nishida N, Murakami T, Kudo M, Eur Radiol, Eur Radiol, 28(5), 1986 - 1993, May 2018 , Refereed
• Immune checkpoint blockade for the treatment of human hepatocellular carcinoma., Nishida N, Kudo M, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 48(8), 622 - 634, May 2018 , Refereed
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• Contrast-enhanced Harmonic EUS Imaging of Pancreatic Mucinous Cystadenocarcinoma., Tanaka H, Kamata K, Takenaka M, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), May 2018 , Refereed
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• Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond., Raoul JL, Kudo M, Finn RS, Edeline J, Reig M, Galle PR, Cancer treatment reviews, Cancer treatment reviews, 68, 16 - 24, May 2018 , Refereed
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• Cystic duct antegrade stenting for cholangitis after the long-term deployment of lumen-apposing metal stents for calculous cholecystitis., Kamata K, Takenaka M, Minaga K, Nakai A, Omoto S, Miyata T, Yamao K, Imai H, Sakurai T, Watanabe T, Nishida N, Kudo M, Endoscopic ultrasound, Endoscopic ultrasound, 7(5), 349 - 350, May 2018 , Refereed
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• Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study., Chau I, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Kudo M, Pfiffer T, Hatano E, Chung HC, Kopeckova K, Phelip JM, Brandi G, Ohkawa S, Li CP, Okusaka T, Hsu Y, Abada PB, Zhu AX, British journal of cancer, British journal of cancer, 119(1), 19 - 26, May 2018 , Refereed
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• Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: A review., Minaga K, Watanabe T, Kamata K, Asano N, Kudo M, World journal of gastroenterology, World journal of gastroenterology, 24(16), 1725 - 1733, Apr. 2018 , Refereed
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• Value of additional endoscopic ultrasonography for surveillance after surgical removal of intraductal papillary mucinous neoplasms., Kamata K, Takenaka M, Minaga K, Omoto S, Miyata T, Yamao K, Imai H, Nakai A, Tanaka H, Chiba Y, Watanabe T, Sakurai T, Nishida N, Chikugo T, Matsumoto I, Takeyama Y, Kitano M, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Apr. 2018 , Refereed
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• Gastric Inverted Hyperplastic Polyp Mimicking a Papilla., Matsui S, Kashida H, Kudo M, The American journal of gastroenterology, The American journal of gastroenterology, 113(4), 462, Apr. 2018 , Refereed
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• Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial., Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Akazawa K, Yoshimura KI, Johnson P, Arai Y, SILIUS study group, The lancet. Gastroenterology & hepatology, The lancet. Gastroenterology & hepatology, Apr. 2018 , Refereed
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• Reintervention for stent occlusion after endoscopic ultrasound-guided hepaticogastrostomy with novel use of a precut needle-knife., Minaga K, Takenaka M, Okamoto A, Omoto S, Miyata T, Imai H, Kudo M, Endoscopy, Endoscopy, 50(7), E153 - 154, Apr. 2018 , Refereed
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• Lenvatinib May Drastically Change the Treatment Landscape of Hepatocellular Carcinoma., Kudo M, Liver cancer, Liver cancer, 7(1), 1 - 19, Mar. 2018 , Refereed
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• Combination Cancer Immunotherapy in Hepatocellular Carcinoma., Kudo M, Liver cancer, Liver cancer, 7(1), 20 - 27, Mar. 2018 , Refereed
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• Treatment Optimization for Hepatocellular Carcinoma in Elderly Patients in a Japanese Nationwide Cohort., Kaibori M, Yoshii K, Hasegawa K, Ogawa A, Kubo S, Tateishi R, Izumi N, Kadoya M, Kudo M, Kumada T, Sakamoto M, Nakashima O, Matsuyama Y, Takayama T, Kokudo N, Liver Cancer Study, Group of Japan, Annals of surgery, Annals of surgery, Mar. 2018 , Refereed
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• Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting., Kenichi Takayasu, Shigeki Arii, Michiie Sakamoto, Yutaka Matsuyama, Masatoshi Kudo, Shuichi Kaneko, Osamu Nakashima, Masumi Kadoya, Namiki Izumi, Tadatoshi Takayama, Yonson Ku, Takashi Kumada, Shoji Kubo, Takashi Kokudo, Yasuhiro Hagiwara, Norihiro Kokudo, Liver international : official journal of the International Association for the Study of the Liver, Liver international : official journal of the International Association for the Study of the Liver, 38(3), 484 - 493, Mar. 2018 , Refereed
  Summary:BACKGROUND AND AIMS: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. METHODS: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. RESULTS: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. CONCLUSIONS: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA.
  DOI
• [Hepatitis C Virus-Induced Cryoglobulinemic Vasculitis]., Minami Y, Kudo M, Brain and nerve = Shinkei kenkyu no shinpo, Brain and nerve = Shinkei kenkyu no shinpo, 70(2), 133 - 137, Feb. 2018 , Refereed
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• Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial., Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL, Lancet (London, England), Lancet (London, England), 391(10126), 1163 - 1173, Feb. 2018 , Refereed
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• Autoimmune Pancreatitis Mouse Model., Kamata K, Watanabe T, Minaga K, Strober W, Kudo M, Current protocols in immunology, Current protocols in immunology, 120, 15.31.1 - 15.31.8, Feb. 2018 , Refereed
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• Alleviating Pancreatic Cancer-Associated Pain Using Endoscopic Ultrasound-Guided Neurolysis., Minaga K, Takenaka M, Kamata K, Yoshikawa T, Nakai A, Omoto S, Miyata T, Yamao K, Imai H, Sakamoto H, Kitano M, Kudo M, Cancers, Cancers, 10(2), Feb. 2018 , Refereed
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• Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B., Hagiwara S, Nishida N, Watanabe T, Ida H, Sakurai T, Ueshima K, Takita M, Komeda Y, Nishijima N, Osaki Y, Kudo M, Antiviral therapy, Antiviral therapy, 23(6), 513 - 521, Feb. 2018 , Refereed
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• Dysbiosis-Associated Polyposis of the Colon-Cap Polyposis., Okamoto K, Watanabe T, Komeda Y, Okamoto A, Minaga K, Kamata K, Yamao K, Takenaka M, Hagiwara S, Sakurai T, Tanaka T, Sakamoto H, Fujimoto K, Nishida N, Kudo M, Frontiers in immunology, Frontiers in immunology, 9, 918, 2018 , Refereed
  DOI
• Utility of endoscopic ultrasound in hemorrhage from recurrent duodenal varices, Matsui S, Kashida H, Kudo M, Ann Gastroenterol, Ann Gastroenterol, 31, 636, 2018 , Refereed
• Management of hepatocellular carcinoma in Japan as a world-leading model, Masatoshi Kudo, Liver Cancer, Liver Cancer, 7, 134 - 147, 2018 , Refereed
• Cabozantinib as a second-line agent in advanced hepatocellular carcinoma, Masatoshi Kudo, Liver Cancer, Liver Cancer, 7, 123 - 133, 2018 , Refereed
• Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: A review., Minaga K, Watanabe T, Kamata K, Asano N, Kudo M, World J Gastroenterol, World J Gastroenterol, 2018 , Refereed
• How to perform Contrast-Enhanced Ultrasound (CEUS)., Dietrich CF, Averkiou M, Nielsen MB, Barr RG, Burns PN, Calliada F, Cantisani V, Choi B, Chammas MC, Clevert DA, Claudon M, Correas JM, Cui XW, Cosgrove D, D'Onofrio M, Dong Y, Eisenbrey J, Fontanilla T, Gilja OH, Ignee A, Jenssen C, Kono Y, Kudo M, Lassau N, Lyshchik A, Franca Meloni M, Moriyasu F, Nolsøe C, Piscaglia F, Radzina M, Saftoiu A, Sidhu PS, Sporea I, Schreiber-Dietrich D, Sirlin CB, Stanczak M, Weskott HP, Wilson SR, Willmann JK, Kim TK, Jang HJ, Vezeridis A, Westerway S, Ultrasound international open, Ultrasound international open, 4(1), E2 - E15, Jan. 2018 , Refereed
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• Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in west Japan., Yamao K, Kitano M, Takenaka M, Minaga K, Sakurai T, Watanabe T, Kayahara T, Yoshikawa T, Yamashita Y, Asada M, Okabe Y, Hanada K, Chiba Y, Kudo M, Gastrointestinal endoscopy, Gastrointestinal endoscopy, 88(1), 66 - 75.e2, Jan. 2018 , Refereed
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• Cabozantinib for advanced hepatocellular carcinoma, Masatoshi Kudo, Hepatobil Surg Nutr, Hepatobil Surg Nutr, 2018 , Refereed
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• Erythropoietic Protoporphyria-related Hepatopathy Successfully Treated with Phlebotomy., Yoshida A, Hagiwara S, Watanabe T, Nishida N, Ida H, Sakurai T, Komeda Y, Yamao K, Takenaka M, Enoki E, Kimura M, Miyake M, Kawada A, Kudo M, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 57(17), 2505 - 2509, 2018 , Refereed
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• 香川県下におけるSorafenibの使用とその傾向, 小川 力, 筒井 朱美, 妹尾 知典, 永野 拓也, 高口 浩一, 谷 丈二, 森下 朝洋, 米山 弘人, 正木 勉, 守屋 昭男, 安東 正晴, 出口 章広, 國土 泰孝, 工藤 正俊, The Liver Cancer Journal, The Liver Cancer Journal, 9(2), 160 - 161, Dec. 2017
• Induction of complete remission by azacitidine in a patient with myelodysplastic syndrome-associated inflammatory bowel disease., Kono M, Komeda Y, Sakurai T, Okamoto A, Minaga K, Kamata K, Hagiwara S, Inoue H, Enoki E, Matsumura I, Watanabe T, Kudo M, Journal of Crohn's & colitis, Journal of Crohn's & colitis, Dec. 2017 , Refereed
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• Endoscopic ultrasound-guided biliary drainage using a newly designed metal stent with a thin delivery system: a preclinical study in phantom and porcine models., Minaga K, Kitano M, Itonaga M, Imai H, Miyata T, Yamao K, Tamura T, Nuta J, Warigaya K, Kudo M, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 45(3), 391 - 397, Dec. 2017 , Refereed
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• A case of small invasive gastric cancer arising from Helicobacter pylori-negative gastric mucosa: Fundic gland-type adenocarcinoma., Komeda Y, Watanabe T, Matsui S, Kashida H, Sakurai T, Kono M, Minaga K, Nagai T, Hagiwara S, Enoki E, Kudo M, JGH open : an open access journal of gastroenterology and hepatology, JGH open : an open access journal of gastroenterology and hepatology, 1(2), 74 - 75, Oct. 2017 , Refereed
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• Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice., Nishiyama H, Nagai T, Kudo M, Okazaki Y, Azuma Y, Watanabe T, Goto S, Ogata H, Sakurai T, Biochemical and biophysical research communications, Biochemical and biophysical research communications, 495(1), 273 - 279, Oct. 2017 , Refereed
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• Transrectal endoscopic ultrasound-guided paracentesis for diagnosis of malignant ascites in the pelvis., Minaga K, Takenaka M, Kamata K, Kudo M, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Oct. 2017 , Refereed
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• Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study., Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, Izumi N, Heo J, Lee YJ, Sheen IS, Chiu CF, Arioka H, Morita S, Arai Y, The lancet. Gastroenterology & hepatology, The lancet. Gastroenterology & hepatology, 3(1), 37 - 46, Oct. 2017 , Refereed
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• EUS-guided approaches for bile duct stones: A single-center experience, Minaga Kosuke, Takenaka Mamoru, Kamata Ken, Miyata Takeshi, Yamao Kentaro, Imai Hajime, Omoto Shunsuke, Nakai Atsushi, Yoshikawa Tomoe, Watanabe Tomohiro, Kudo Masatoshi, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 32, 240, Sep. 2017 , Refereed
• Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2012: General v, Yanagihara K, Watanabe A, Aoki N, Matsumoto T, Yoshida M, Sato J, Wakamura T, Sunakawa K, Kadota J, Kiyota H, Iwata S, Kaku M, Hanaki H, Ohsaki Y, Fujiuchi S, Takahashi M, Takeuchi K, Takeda H, Ikeda H, Miki M, Nakanowatari S, Takahashi H, Utagawa M, Nishiya H, Kawakami S, Morino E, Takasaki J, Mezaki K, Chonabayashi N, Tanaka C, Sugiura H, Goto H, Saraya T, Kurai D, Katono Y, Inose R, Niki Y, Takuma T, Kudo M, Ehara S, Sato Y, Tsukada H, Watabe N, Honma Y, Mikamo H, Yamagishi Y, Nakamura A, Ohashi M, Seki M, Hamaguchi S, Toyokawa M, Fujikawa Y, Mitsuno N, Ukimura A, Miyara T, Nakamura T, Mikasa K, Kasahara K, Ui K, Fukuda S, Nakamura A, Morimura M, Yamashita M, Takesue Y, Wada Y, Sugimoto K, Kusano N, Nose M, Mihara E, Kuwabara M, Doi M, Watanabe Y, Tokuyasu H, Hino S, Negayama K, Mukae H, Kawanami T, Ota T, Fujita M, Honda J, Hiramatsu K, Aoki Y, Fukuoka M, Magarifuchi H, Nagasawa Z, Kaku N, Fujita J, Higa F, Tateyama M, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 23(9), 587 - 597, Sep. 2017 , Refereed
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• Impact of Advanced Age on Survival in Patients Undergoing Resection of Hepatocellular Carcinoma: Report of a Japanese Nationwide Survey., Kaibori M, Yoshii K, Yokota I, Hasegawa K, Nagashima F, Kubo S, Kon M, Izumi N, Kadoya M, Kudo M, Kumada T, Sakamoto M, Nakashima O, Matsuyama Y, Takayama T, Kokudo N, Liver Cancer Study, Group of Japan, Annals of surgery, Annals of surgery, 269(4), 692 - 699, Sep. 2017 , Refereed
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• Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial., Ikeda M, Kudo M, Aikata H, Nagamatsu H, Ishii H, Yokosuka O, Torimura T, Morimoto M, Ikeda K, Kumada H, Sato T, Kawai I, Yamashita T, Horio H, Okusaka T, Miriplatin TACE, Study Group, Journal of gastroenterology, Journal of gastroenterology, Aug. 2017 , Refereed
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• Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma., Sakurai T, Yada N, Hagiwara S, Arizumi T, Minaga K, Kamata K, Takenaka M, Minami Y, Watanabe T, Nishida N, Kudo M, Cancer science, Cancer science, 108(10), 1996 - 2003, Aug. 2017 , Refereed
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• Utility of contrast-enhanced harmonic EUS for evaluating the effects of steroid therapy in a case of immunoglobulin G4-negative focal autoimmune pancreatitis., Kamata K, Takenaka M, Minaga K, Kudo M, Gastrointestinal endoscopy, Gastrointestinal endoscopy, Jul. 2017 , Refereed
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• Fatal liver gas gangrene after biliary surgery., Miyata Y, Kashiwagi H, Koizumi K, Kawachi J, Kudo M, Teshima S, Isogai N, Miyake K, Shimoyama R, Fukai R, Ogino H, International journal of surgery case reports, International journal of surgery case reports, 39, 5 - 8, Jul. 2017 , Refereed
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• Achievement of long-term stent patency in endoscopic ultrasonography-guided right bile duct drainage after left hepatic lobectomy (with video), Minaga K, Takenaka M, Miyata T, Yamao K, Kitano M, Kudo M, Endosc Ultrasound, Endosc Ultrasound, in press, Jul. 2017 , Refereed
• 肝動脈化学塞栓療法(TACE)の適応の再考 (1)BCLC-Bの亜分類とTACEの適応, Tadaaki Arizumi, Masatoshi Kudo, The Liver Cancer Journal, The Liver Cancer Journal, 9(1), 26 - 29, Jun. 2017 , Refereed
• Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions., Kamata K, Takenaka M, Kitano M, Omoto S, Miyata T, Minaga K, Yamao K, Imai H, Sakurai T, Nishida N, Kashida H, Chikugo T, Chiba Y, Nakai T, Takeyama Y, Lisotti A, Fusaroli P, Kudo M, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, Jun. 2017 , Refereed
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• S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial., Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, Kawazoe S, Ohkawa S, Sato Y, Kaneko S, Furuse J, Takeuchi M, Fang X, Date Y, Takeuchi M, Okusaka T, The lancet. Gastroenterology & hepatology, The lancet. Gastroenterology & hepatology, 2(6), 407 - 417, Jun. 2017 , Refereed
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• Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan., Suda G, Furusyo N, Toyoda H, Kawakami Y, Ikeda H, Suzuki M, Arataki K, Mori N, Tsuji K, Katamura Y, Takaguchi K, Ishikawa T, Tsuji K, Shimada N, Hiraoka A, Yamsaki S, Nakai M, Sho T, Morikawa K, Ogawa K, Kudo M, Nagasaka A, Furuya K, Yamamoto Y, Kato K, Ueno Y, Iio E, Tanaka Y, Kurosaki M, Kumada T, Chayama K, Sakamoto N, Journal of gastroenterology, Journal of gastroenterology, 53(1), 119 - 128, May 2017 , Refereed
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• Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-alpha and IL-33 Produced by Plasmacytoid Dendritic Cells, Tomohiro Watanabe, Kouhei Yamashita, Yasuyuki Arai, Kosuke Minaga, Ken Kamata, Tomoyuki Nagai, Yoriaki Komeda, Mamoru Takenaka, Satoru Hagiwara, Hiroshi Ida, Toshiharu Sakurai, Naoshi Nishida, Warren Strober, Masatoshi Kudo, JOURNAL OF IMMUNOLOGY, JOURNAL OF IMMUNOLOGY, 198(10), 3886 - 3896, May 2017 , Refereed
  Summary:In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-alpha. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-beta 1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-alpha and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.
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• A case of successful transluminal drainage of walled-off necrosis under contrast-enhanced harmonic endoscopic ultrasonography guidance., Minaga K, Takenaka M, Omoto S, Miyata T, Kamata K, Yamao K, Imai H, Watanabe T, Kitano M, Kudo M, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 45(1), 161 - 165, Mar. 2017 , Refereed
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• Serum microRNA profile that predict initial effect of sorafenib in patients with advanced hepatocellular carcinoma, Nishida N, Arizumi T, Hagiwara S, Ida H, Sakurai T, Kudo M, Liver Cancer, Liver Cancer, 6, 113 - 125, 2017 , Refereed
• The usefulness of endoscopic ultrasonography in the diagnosis of "Early-Stage" chronic pancreatitis, Mamoru Takenaka, Masayuki Kitano, Masatoshi Kudo, Gastroenterological Endoscopy, Gastroenterological Endoscopy, 59, 255 - 264, Jan. 01 2017
  Summary:Chronic pancreatitis is one of the risk factors for pancreatic cancer and is considered to be an irreversible and progressive disease. However, the conventional diagnostic criteria of chronic pancreatitis had the problem of being able to diagnose only advanced chronic pancreatitis. Based on the hypothesis that the early stage of chronic pancreatitis is a reversible disease, the diagnostic criteria of "early-stage" chronic pancreatitis were developed in Japan for early detection and early treatment of chronic pancreatitis. Endoscopic ultrasonography (EUS) plays an important role in detecting "early-stage" chronic pancreatitis. Many EUS image findings of "early-stage" chronic pancreatitis are mentioned in the Rosemont criteria for the EUS diagnosis of chronic pancreatitis.
• Malignant Transformation of Hepatocellular Adenoma, Kwok WY, Hagiwara S, Nishida N, Watanabe T, Sakurai T, Ida H, Minami Y, Takita M, Minami T, Iwanishi M, Chishina H, Kono M, Ueshima K, Komeda Y, Arizumi T, Enoki E, Nakai T, Kumabe T, Nakashima O, Kondo F, Kudo M, Oncology, Oncology, 92(Suppl 1), 16 - 28, 2017
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• Characterization of Pancreatic Tumors with Quantitative Perfusion Analysis in Contrast-Enhanced Harmonic Endoscopic Ultrasonography., Omoto S, Takenaka M, Kitano M, Miyata T, Kamata K, Minaga K, Arizumi T, Yamao K, Imai H, Sakamoto H, Harwani Y, Sakurai T, Watanabe T, Nishida N, Takeyama Y, Chiba Y, Kudo M, Oncology, Oncology, 93 Suppl 1, 55 - 60, 2017 , Refereed
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• Risk Factors for Postoperative Bleeding in Endoscopic Submucosal Dissection of Colorectal Tumors., Okamoto K, Watanabe T, Komeda Y, Kono T, Takashima K, Okamoto A, Kono M, Yamada M, Arizumi T, Kamata K, Minaga K, Yamao K, Nagai T, Asakuma Y, Takenaka M, Sakurai T, Matsui S, Nishida N, Chikugo T, Kashida H, Kudo M, Oncology, Oncology, 93 Suppl 1, 35 - 42, 2017 , Refereed
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• Detection of High-Grade Pancreatic Intraepithelial Neoplasia without Morphological Changes of the Main Pancreatic Duct over a Long Period: Importance for Close Follow-Up for Confirmation., Yamao K, Takenaka M, Nakai A, Omoto S, Kamata K, Minaga K, Miyata T, Imai H, Sakurai T, Watanabe T, Nishida N, Matsumoto I, Takeyama Y, Chikugo T, Kudo M, Oncology, Oncology, 93 Suppl 1, 81 - 86, 2017 , Refereed
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• Computer-Aided Diagnosis Based on Convolutional Neural Network System for Colorectal Polyp Classification: Preliminary Experience., Komeda Y, Handa H, Watanabe T, Nomura T, Kitahashi M, Sakurai T, Okamoto A, Minami T, Kono M, Arizumi T, Takenaka M, Hagiwara S, Matsui S, Nishida N, Kashida H, Kudo M, Oncology, Oncology, 93 Suppl 1, 30 - 34, 2017 , Refereed
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• Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)., Kudo M, Arizumi T, Oncology, Oncology, 93 Suppl 1, 127 - 134, 2017 , Refereed
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• Clinical Analysis of Esophageal Stricture in Patients Treated with Intralesional Triamcinolone Injection after Endoscopic Submucosal Dissection for Superficial Esophageal Cancer., Okamoto K, Matsui S, Watanabe T, Asakuma Y, Komeda Y, Okamoto A, Rei I, Kono M, Yamada M, Nagai T, Arizumi T, Minaga K, Kamata K, Yamao K, Takenaka M, Sakurai T, Nishida N, Kashida H, Chikugo T, Kudo M, Oncology, Oncology, 93 Suppl 1, 9 - 14, 2017 , Refereed
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• New Paradigm in Gastrointestinal Cancer Treatment., Kudo M, Oncology, Oncology, 93 Suppl 1, 1 - 8, 2017 , Refereed
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• A Social Program for the Early Detection of Pancreatic Cancer: The Kishiwada Katsuragi Project., Sakamoto H, Harada S, Nishioka N, Maeda K, Kurihara T, Sakamoto T, Higuchi K, Kitano M, Takeyama Y, Kogire M, Kudo M, Oncology, Oncology, 93 Suppl 1, 89 - 97, 2017 , Refereed
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• Comparative Study of Clarithromycin- versus Metronidazole-Based Triple Therapy as First-Line Eradication for Helicobacter pylori., Adachi T, Matsui S, Watanabe T, Okamoto K, Okamoto A, Kono M, Yamada M, Nagai T, Komeda Y, Minaga K, Kamata K, Yamao K, Takenaka M, Asakuma Y, Sakurai T, Nishida N, Kashida H, Kudo M, Oncology, Oncology, 93 Suppl 1, 15 - 19, 2017 , Refereed
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• Serum IFN-lambda 3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C, Susumu Imoto, Soo Ryang Kim, Keisuke Amano, Etsuko Iio, Seitetsu Yoon, Shigeya Hirohata, Yoshihiko Yano, Toru Ishikawa, Shinji Katsushima, Toshiki Komeda, Toyokazu Fukunaga, Hobyung Chung, Hiroyuki Kokuryu, Yutaka Horie, Takashi Hatae, Aya Fujinami, Soo Ki Kim, Masatoshi Kudo, Yasuhito Tanaka, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 531 - 540, 2017 , Refereed
  Summary:Background: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-lambda (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. Aim: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. Materials and Methods: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an inhouse, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-alpha, IFN-alpha, and IFN-beta induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. Results: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-alpha and IFN-beta were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). Conclusion: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC. (C) 2017 S. Karger AG, Basel
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• THE REGULATION OF AIRWAY SMOOTH MUSCLE CONTRACTION., Kudo M, Arerugi = [Allergy], Arerugi = [Allergy], 66(6), 798 - 803, 2017 , Refereed
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• Evidence and topics of chemotherapy for hepatocellular carcinoma., Ueshima K, Kudo M, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, 114(9), 1621 - 1628, 2017 , Refereed
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• Oncogenic signal and tumor microenvironment in hepatocellular carcinoma., Naoshi Nishida, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 160 - 164, 2017 , Refereed
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• Immuno-Oncology in Hepatocellular Carcinoma: 2017 Update, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 147 - 159, 2017 , Refereed
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• Systemic Therapy for Hepatocellular Carcinoma: 2017 Update, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 135 - 146, 2017 , Refereed
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• Transarterial Chemoembolization in Combination with Molecular Targeted Agent: Lessons from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2), Masatoshi Kudo, Tadaaki Arizumi, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• Validation of newly proposed time to TACE progression (TTTP) in intermediate stage hepatocellular carcinoma cases, Hirofumi Izumoto, Atsushi Hiraoka, Yoshihiro Ishimaru, Tadashi Murakami, Shogo Kitahata, Hidetaro Ueki, Toshihiko Aibiki, Tomonari Okudaira, Yuji Miyamoto, Hiroka Yamago, Ryuichiro Iwasaki, Hideomi Tomida, Kenichiro Mori, Masato Kishida, Eiji Tsubouchi, Hideki Miyata, Tomoyuki Ninomiya, Hideki Kawasaki, Masashi Hirooka, Bunzo Matsuura, Masanori Abe, Yoichi Hiasa, Kojiro Michitaka, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• A case of pancreatic carcinoma in situ diagnosed by repeated pancreatic juice cytology, Takeshi Miyata, Mamoru Takenaka, Shunsuke Omoto, Ken Kamata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 98 - 101, 2017 , Refereed
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• A social program for the early detection of pancreatic cancer, the Kishiwada project: A multi-center study, Hiroki Sakamoto, Satoshi Harada, Nobu Nishioka, Kazuo Maeda, Takamasa Kurihara, Tateki Sakamoto, Kazuhide Higuchi, Masayuki Kitano, Yoshifumi Takeyama, Masafumi Kogire, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• EUS-guided pancreatic duct drainage for repeat pancreatitis in a patient with pancreatic cancer., Ken Kamata, Mamoru Takenaka, Kosuke Minaga, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 87 - 88, 2017 , Refereed
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• Detection of High-grade pancreatic intraepithelial neoplasia without morphological changes of the main pancreatic duct over long period: Importance for close follow-up for confirmation., Kentaro Yamao, Mamoru Takenaka, Atsushi Nakai, Shunske Omoto, Ken Kamata, Kosuke Minaga, Takeshi Miyata, Hajime Imai, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Ippei Matsumoto, Yosihumi Takeyama, Takaaki Chikugo, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• Primary hepatic adenosquamous carcinoma associated with primary sclerosing cholangitis., Kentaro Yamao, Mamoru Takenaka, Hajime Imai, Atsushi Nakai, Shunske Omoto, Ken Kamata, Kosuke Minaga, Takeshi Miyata, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Ippei Matsumoto, Yosihumi Takeyama, Takaaki Chikugo, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 76 - 80, 2017 , Refereed
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• Needle tract seeding: an overlooked rare complication of endoscopic ultrasound-guided fine-needle aspiration, Kosuke Minaga, Mamoru Takenaka, Akio Katanuma, Masayuki Kitano, Yukitaka Yamashita, Ken Kamata, Kentaro Yamao, Tomohiro Watanabe, Hiroyuki Maguchi, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 107 - 112, 2017 , Refereed
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• Association between the risk factors for pancreatic ductal adenocarcinoma and those for malignant intraductal papillary mucinous neoplasm, Ken Kamata, Mamoru Takenaka, Atsushi Nakai, Shunsuke Omoto, Takeshi Miyata, Kosuke Minaga, Tomohiro Matsuda, Kentaro Yamao, Hajime Imai, Yasutaka Chiba, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Takaaki Chikugo, Ippei Matsumoto, Yoshifumi Takeyama, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 102 - 106, 2017 , Refereed
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• Utility of endoscopic ultrasound-guided hepaticogastrostomy with antegrade stenting for malignant biliary obstruction after failed endoscopic retrograde cholangiopancreatography., Hajime Imai, Mamoru Takenaka, Shunsuke Omoto, Ken Kamata, Takeshi Miyata, Kosuke Minaga, Kentaro Yamao, Toshihiko Sakurai, Naoshi Nishida, Tomohiro Watanabe, Masayuki Kitano, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 69 - 75, 2017 , Refereed
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• Chronic Pancreatitis finding by Endoscopic Ultrasonography in the Pancreatic Parenchyma of IPMNs is Associated with Invasive IPMC, Mamoru Takenaka, Atsuhiro Masuda, Hideyuki Shiomi, Yosuke Yagi, Yoh Zen, Arata Sakai, Takashi Kobayashi, Yoshifumi Arisaka, Yoshihiro Okabe, Hiromu Kutsumi, Hirochika Toyama, Takumi Fukumoto, Yonson Ku, Masatoshi Kudo, Takeshi Azuma, Oncology, Oncology, Supple(in press), 2017 , Refereed
• Characterization of pancreatic tumors with quantitative perfusion analysis in contrast-enhanced harmonic EUS., Shunsuke Omoto, Mamoru Takenaka, Masayuki Kitano, Takeshi Miyata, Ken Kamata, Kosuke Minaga, Tadaaki Arizumi, Kentaro Yamao, Hajime Imai, Hiroki Sakamoto, Yogesh Harwani, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Yoshifumi Takeyama, Yasutaka Chiba, Masatoshi Kudo, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• The feasibility of 18-mm diameter colonic stents for obstructive colorectal cancers, Ogawa S, Ishii T, Minaga K, Nakatani Y, Hatamaru K, Akamatsu T, Seta T, Urai S, Uenoyama Y, Yamashita Y, Kudo M, Oncology, Oncology, Suppl(in press), 43 - 48, 2017 , Refereed
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• Magnifying narrow band imaging (NBI) for the diagnosis of localized colorectal lesions using the Japan NBI Expert Team (JNET) classification., Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, George Tribonias, Tomoyuki Nagai, Masashi Kono, Kosuke Minaga, Mamoru Takenaka, Tadaaki Arizumi, Satoru Hagiwara, Shigenaga Matsui, Tomohiro Watanabe, Naoshi Nishida, Takaaki Chikugo, Yasutaka Chiba, Masatoshi Kudo, Oncology, Oncology, Supple(in press), 49 - 54, 2017 , Refereed
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• Risk factors for post-operative bleeding in endoscopic submucosal dissection for colorectal tumors., Okamoto K, Watanabe T, Komeda Y, Kono T, Takashima K, Okamoto A, Kono M, Yamada MArizumi T, Kamata K, Minaga K, Yamao K, Nagai T, Asakuma Y, Takenaka M, Sakurai T, Matsui S, Nishida N, Chikugo T, Kashida H, Kudo M, Oncology, Oncology, in press, 2017 , Refereed
• Computer-aided diagnosis based on convolutional neural network system for colorectal polyp classification:, Komeda Y, Handa H, Watanabe T, Nomura T, Kitahashi M, Sakurai T, Okamoto A, Minami T, Kono M, Arizumi T, Takenaka M, Hagiwara S, Matsui S, Nishida N, Kashida H, Kudo M, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• Prophylactic Suturing Closure is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy., Sakurai T, Adachi T, Kono M, Arizumi T, Kamata K, Minaga K, Yamao K, Komeda Y, Takenaka M, Hagiwara S, Watanabe T, Nishida N, Kashida H, Kudo M, Oncology, Oncology, Suppl(in press), 27 - 29, 2017 , Refereed
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• Clinical significance of Bmi1 expression in inflammatory bowel disease., Yamada M, Sakurai T, Komeda Y, Nagai T, Kamata K, Minaga K, Watanave T, Nishida N, Kashida H, Kudo M, Oncology, Oncology, Suppl(in press), 20 - 26, 2017 , Refereed
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• Comparative study of clarithromycin vs. metronidazole-based triple therapy as first-line eradication for Helicobacter pylori., Adachi T, Matsui S, Watanabe T, Okamoto K, Okamoto A, Kono M, Yamada M, Nagai T, Komeda Y, Minaga K, Kamata K, Yamao K, Takenaka M, Asakuma Y, Sakurai T, Nishida N, Kashida H, Kudo M, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• linical analysis of esophageal stricture in patients treated with intra-lesional triamcinolone injection post endoscopic submucosal dissection for superficial esophageal cancer., Okamoto K, Matsui S, Watanabe T, Asakuma Y, Komeda Y, Okamoto A, Ishikawa R, Kono M, Yamada M, Nagai T, Arizumi T, Minaga, K, Kamata K, Yamao K, Takenaka M, Sakurai T, Nishida N, Kashida H, Chikugo T, Kudo M, Oncology, Oncology, Suppl(in press), 2017 , Refereed
• Preface: New Paradigm in Gastrointestinal Cancer Treatment, Masatoshi Kudo, Oncology, Oncology, Supple(in press), 2017 , Refereed
• Non-hypervascular hypointense hepatic nodules during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI as a risk factor of intrahepatic distant recurrence after radiofrequency ablation of hepatocellular carcinoma., Iwamoto T, Imai Y, Igura T, Kogita S, Sawai Y, Fukuda K, Yamaguchi Y, Matsumoto Y, Nakahara M, Morimoto O, Ohashi H, Fujita N, Kudo M, Takehara T, Digest Dis, Digest Dis, 35(6), 574 - 582, 2017 , Refereed
• Serum IFN-lambda 3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C, Susumu Imoto, Soo Ryang Kim, Keisuke Amano, Etsuko Iio, Seitetsu Yoon, Shigeya Hirohata, Yoshihiko Yano, Toru Ishikawa, Shinji Katsushima, Toshiki Komeda, Toyokazu Fukunaga, Hobyung Chung, Hiroyuki Kokuryu, Yutaka Horie, Takashi Hatae, Aya Fujinami, Soo Ki Kim, Masatoshi Kudo, Yasuhito Tanaka, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 531 - 540, 2017 , Refereed
  Summary:Background: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-lambda (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. Aim: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. Materials and Methods: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an inhouse, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-alpha, IFN-alpha, and IFN-beta induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. Results: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-alpha and IFN-beta were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). Conclusion: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC. (C) 2017 S. Karger AG, Basel
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• Impact of age on survival in patients undergoing resection of hepatocellular carcinoma: report of a Japanese nationwide survey., Kaibori M, Yoshii K, Yokota I, Hasegwa K, Nagashima F, Kubo S, Kon M, Izumi N, Kadoya M, Kudo M, Kumada T, Sakamoto M, Nakashima O, Matsuyama Y, Takayama T, Kokudo N, J Hepatol, J Hepatol, in press, 2017 , Refereed
• Identification of a HBx mutation that enhances human hepatocarcinogenesis through the activation of the JNK and Wnt pathways., Hagiwara S, Nishida N, Sakurai T, Park AM, Komeda Y, Kitano M, Kudo M, BMC Cancer, BMC Cancer, in press, 2017 , Refereed
• Treatment response and tolerability in elderly patients with chronic hepatitis C: subgroup analysis in ReGIT-J study., Nishikawa H, Enomoto H, Saito M, Aizawa N, Tsuda Y, Higuchi K, Okazaki K, Seki K, Seki T, Kim SR, Hongo Y, Jyomura H, Nishida N, Kudo M, Osaki Y, Nishiguchi S, Acta Gastro-Ent Belg, Acta Gastro-Ent Belg, in press, 2017 , Refereed
• Second IA of the GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) non-interventional study, Lencioni R, Kudo M, Venook A, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, Guevara LL, Papandreou C, Sanyal AJ, Takayama T, Yoon SK, Nakajima K, Lehr R, Heldner S, Marrero JA, Liver Int, Liver Int, in press, 2017 , Refereed
• New Era in the Treatment of Chronic Liver Diseases and Liver Cancer: State-of-the Art Progress in 2017, Masatoshi Kudo, Digest Dis, Digest Dis, 35(6), 493 - 497, 2017 , Refereed
• Endoscopic Treatment of Tracheoesophageal Fistula using the Over-The-Scope-Clip System., Matsui S, Kashida H, Asakuma Y, Kudo M, Ann Gastol, Ann Gastol, 30(30), 578 - 578, 2017 , Refereed
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• New endoscopic ultrasonography techniques for pancreaticobiliary diseases, Kamata K, Kitano M, Omoto S, Kadosaka K, Miyata T, Minaga K, Yamao K, Imai H, Kudo M, Ultrasonography, Ultrasonography, 35(3), 169 - 179, Jul. 2016 , Refereed
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• Response, Kitano M, Imai H, Kamata K, Kudo M, Gastrointest Endosc, Gastrointest Endosc, 83(6), 1303, Jun. 2016 , Refereed
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• Epigenetic regulation and development of hepatocellular carcinoma., Nishida N, Kudo M, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, 113(5), 775 - 784, May 2016 , Refereed
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• Reply: Hepatocyte damage due to protoporphyrin deposition, Hagiwara S, Nishida N, Kudo M, Hepatology, Hepatology, 64, 306, 2016 , Refereed
• Defect Reperfusion Imaging with Sonazoid (R): A Breakthrough in Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 5(1), 1 - 7, 2016 , Refereed
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• Inclusion of Journal of Medical Ultrasonics in MEDLINE., Kudo M, Kanai H, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 43(1), 163, Jan. 2016 , Refereed
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• Plasmacytoid Dendritic Cell Activation and IFN-alpha Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis, Yasuyuki Arai, Kouhei Yamashita, Katsutoshi Kuriyama, Masahiro Shiokawa, Yuzo Kodama, Toshiharu Sakurai, Kiyomi Mizugishi, Kazushige Uchida, Norimitsu Kadowaki, Akifumi Takaori-Kondo, Masatoshi Kudo, Kazuichi Okazaki, Warren Strober, Tsutomu Chiba, Tomohiro Watanabe, JOURNAL OF IMMUNOLOGY, JOURNAL OF IMMUNOLOGY, 195(7), 3033 - 3044, Oct. 2015 , Refereed
  Summary:The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-alpha production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-alpha, and with pDC depletion and IFN-alpha-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-alpha. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-alpha-expressing pDCs and had significantly higher serum IFN-alpha levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-alpha and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-alpha is a major cause of murine AIP; in addition, the increased pDC production of IFN-alpha and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.
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• Antiviral therapy for chronic hepatitis B: combination of nucleoside analogs and interferon, Hagiwara S, Nishida N, Kudo M, World J Hepatol, World J Hepatol, 7(23), 2427 - 2431, Oct. 2015 , Refereed
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• Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study, Cheng AL, Kang YK, He AR, Lim HY, Ryoo BY, Hung CH, Sheen IS, Izumi N, Austin T, Wang Q, Greenberg J, Shiratori S, Beckman RA, Kudo M, he investigators’study group, J Hepatol, J Hepatol, 63(4), 896 - 904, Oct. 2015 , Refereed
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• Primary leiomyosarcoma of the colon, Kono M, Tsuji N, Ozaki N, Matsumoto N, Takaba T, Okumura N, Kawasaki M, Tomita T, Umehara Y, Taniike S, Hatabe S, Funai S, Ono Y, Ochiai K, Maekura S, Kudo M, Clin J Gastroenterol, Clin J Gastroenterol, 8(4), 217 - 222, Aug. 2015 , Refereed
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• [Gastric ulcer, duodenal ulcer]., Matsui S, Kashida H, Asakuma Y, Sakurai T, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 73(7), 1116 - 1122, Jul. 2015 , Refereed
• High-range-resolution imaging using frequency domain interferometry with stabilization techniques for real-time vascular ultrasound, H. Taki, K. Taki, M. Yamakawa, T. Shiina, M. Kudo, T. Sato, Jpn. J. Appl. Phys., Jpn. J. Appl. Phys., 54(07HF05), 1 - 10, May 2015 , Refereed
• [US]., Kitano M, Imai H, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 73 Suppl 3, 50 - 54, Mar. 2015 , Refereed
• [US]., Kitano M, Kamata K, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 73 Suppl 3, 491 - 494, Mar. 2015 , Refereed
• A bridge between multi-omics data and the management of hepatocellular carcinoma, Nishida N, Kudo M, Ann Transl Med, Ann Transl Med, 3(1), 1, Jan. 2015 , Refereed
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• Prospective Multicenter Randomized Controlled Trial of Histological Diagnostic Yield Comparing 25G EUS-FNA Needles With and Without a Core Trap in Patients With Solid Pancreatic Masses, Ashida R, Yasukawa S, Yanagisawa A, Kamata K, Kudo M, Ogura T, Higuchi K, Fukutake N, Nebiki H, Hirose S, Hoki N, Asada M, Yazumi S, Takaoka M, Okazaki K, Matsuda F, Okabe Y, Kitano M, Gastrointest Endosc, Gastrointest Endosc, 79, AB111, May 2014 , Refereed
• Reply to Kadayifci and brugge, Kitano K, Kamata K, Kudo M, Endoscopy, Endoscopy, 46(4), 358 - 358, Apr. 2014 , Refereed
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• Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a +/- A ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial, ReGIT-J study, Shuhei Nishiguchi, Hirayuki Enomoto, Nobuhiro Aizawa, Hiroki Nishikawa, Yukio Osaki, Yasuhiro Tsuda, Kazuhide Higuchi, Kazuichi Okazaki, Toshihito Seki, Soo Ryang Kim, Yasushi Hongo, Hisato Jyomura, Naoshi Nishida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 49(3), 492 - 501, Mar. 2014 , Refereed
  Summary:We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high). The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFN alpha-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFN alpha-2a (group A) or PEG-IFN alpha-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFN alpha-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFN alpha-2a/RBV (group E) or PEG-IFN alpha-2a/RBV/fluvastatin (group F). Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation. In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy.
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• Virtual Sonography for Novice Sonographers: Usefulness of SYNAPSE VINCENT (R) with Pre-Check Imaging of Tumor Location, Chikara Ogawa, Yasunori Minami, Yumiko Morioka, Akiyo Noda, Soichi Arasawa, Masako Izuta, Atsushi Kubo, Toshihiro Matsunaka, Noriyuki Tamaki, Mitsushige Shibatouge, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 50 - 54, 2014 , Refereed
  Summary:Purpose: To evaluate the usefulness of a virtual ultrasound (US) imaging device as a tool to assist novice sonographers. Materials and Methods: A prospective blinded pilot study was conducted involving patients with liver lesions. Two sonographers and 2 medical doctors with less than 5 years of experience performed US examinations. The time needed to detect liver lesions on US and the success rate for detecting liver lesions with and without using the virtual US imaging device SYNAPSE VINCENT (R) (Fujifilm Medical Co., Tokyo, Japan) before US examination were evaluated. Results: Thirty-two patients with the following 42 liver lesions were included: liver cyst (n = 24), hemangioma (n = 8), hepatocellular carcinoma (n = 6), and liver metastasis (n = 4). The maximal diameter of these lesions ranged from 0.3 to 1.5 cm (mean +/- SD, 0.8 +/- 0.4). The average time for detecting liver lesions on US was 47.8 s (range, 7-113) with VINCENT and 112.9 s (range, 14-313) without VINCENT before US examination. There were significant differences in the duration of US examination with and without VINCENT (p = 0.0002, Student's t test). The rates for accurately detecting liver lesions were 100 and 76.2% (16/21) in US beginners with and without VINCENT, respectively. Significantly higher detection rates were found in the US beginners who used VINCENT compared to those who did not use VINCENT (p = 0.047, Fisher's exact test). Conclusion: Before US examination, a reference with VINCENT could contribute to the successful detection of liver lesions and could be time-saving for US beginners. (C) 2014 S. Karger AG, Basel
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• Stabilization technique for real-time high-resolution vascular ultrasound using frequency domain interferometry, Taki H, Taki K, Yamakawa M, Shiina T, Kudo M, Sato T, Conf Proc IEEE Eng Med Biol Soc, Conf Proc IEEE Eng Med Biol Soc, 2014, 5085 - 5088, 2014 , Refereed
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• [Recurrent hepatocellular carcinoma]., Ueshima K, Kudo M, Gan to kagaku ryoho. Cancer & chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 40(8), 995 - 997, Aug. 2013 , Refereed
• ミニオーラル105：肝 その他2 P-105-2 本邦における多発肝嚢胞症治療の実態, 小川光一, 福永 潔, 竹内朋代, 川岸直樹, 乳原善文, 工藤正俊, 大河内,信弘, 第68回日本消化外科学会総会抄録集, 第68回日本消化外科学会総会抄録集, Jul. 2013
• Impact of peginterferon alpha-2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B., Hagiwara S, Kudo M, Osaki Y, Matsuo H, Inuzuka T, Matsumoto A, Tanaka E, Sakurai T, Ueshima K, Inoue T, Yada N, Nishida N, Journal of medical virology, Journal of medical virology, 85(6), 987 - 995, Jun. 2013 , Refereed
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• [Recent advances in EUS-guided biliary drainage]., Kitano M, Kudo M, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, 110(4), 557 - 567, Apr. 2013 , Refereed
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• p38 alpha Inhibits Liver Fibrogenesis and Consequent Hepatocarcinogenesis by Curtailing Accumulation of Reactive Oxygen Species, Toshiharu Sakurai, Masatoshi Kudo, Atsushi Umemura, Guobin He, Ahmed M. Elsharkawy, Ekihiro Seki, Michael Karin, CANCER RESEARCH, CANCER RESEARCH, 73(1), 215 - 224, Jan. 2013 , Refereed
  Summary:Most hepatocellular carcinomas (HCC) develop in the context of severe liver fibrosis and cirrhosis caused by chronic liver inflammation, which also results in accumulation of reactive oxygen species (ROS). In this study, we examined whether the stress-activated protein kinase p38 alpha (Mapk14) controls ROS metabolism and development of fibrosis and cancer in mice given thioacetamide to induce chronic liver injury. Liver-specific p38 alpha ablation was found to enhance ROS accumulation, which appears to be exerted through the reduced expression of antioxidant protein HSP25 (Hspb1), a mouse homolog of HSP27. Its reexpression in p38 alpha-deficient liver prevents ROS accumulation and thioacetamide-induced fibrosis. p38 alpha deficiency increased expression of SOX2, a marker for cancer stem cells and the liver oncoproteins c-Jun (Jun) and Gankyrin (Psmd10) and led to enhanced thioacetamide-induced hepatocarcinogenesis. The upregulation of SOX2 and c-Jun was prevented by administration of the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with ROS accumulation in liver. Thus, p38 alpha and its target HSP25/HSP27 appear to play a conserved and critical hepatoprotective function by curtailing ROS accumulation in liver parenchymal cells engaged in oxidative metabolism of exogenous chemicals. Augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis. Cancer Res; 73(1); 215-24. (C) 2012 AACR.
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• Unique association between global DNA hypomethylation and chromosomal alterations in human hepatocellular carcinoma., Nishida N, Kudo M, Nishimura T, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Yokomichi N, Nagasaka T, Goel A, PloS one, PloS one, 8(9), e72312, 2013 , Refereed
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• Hypovascular hepatic nodules showing hypointense on the hepatobiliary-phase image of Gd-EOB-DTPA-enhanced MRI to develop a hypervascular hepatocellular carcinoma: a nationwide retrospective study on their natural course and risk factors., Inoue T, Hyodo T, Murakami T, Takayama Y, Nishie A, Higaki A, Korenaga K, Sakamoto A, Osaki Y, Aikata H, Chayama K, Suda T, Takano T, Miyoshi K, Koda M, Numata K, Tanaka H, Iijima H, Ochi H, Hirooka M, Imai Y, Kudo M, Digestive diseases (Basel, Switzerland), Digestive diseases (Basel, Switzerland), 31(5-6), 472 - 479, 2013 , Refereed
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• [Molecular targeted agent for hepatocellular carcinoma]., Ueshima K, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 70 Suppl 8, 457 - 462, Nov. 2012 , Refereed
• Treatment of advanced hepatocellular carcinoma, KUDO Masatoshi, Nihon Shokakibyo Gakkai Zasshi, Nihon Shokakibyo Gakkai Zasshi, 109(8), 1327 - 1334, Aug. 05 2012
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• Long duration of stable disease may improve overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib, ARIZUMI Tadaaki, UESHIMA Kazuomi, HAYAISHI Sousuke, TAKITA Masahiro, KITAI Satoshi, INOUE Tatsuo, YADA Norihisa, HAGIWARA Satoru, MINAMI Yasunori, SAKURAI Toshiharu, NISHIDA Naoshi, KUDO Masatoshi, Kanzo, Kanzo, 53(6), 348 - 350, Jun. 2012
  Summary:【PURPOSE】 Sorafenib is a molecularly-targeted drug, which have been proven survival benefit for advanced hepatocellular carcinoma (HCC). Because of the unique side effects of sorafenib such as hand-foot skin reaction (HFSR), the administration of sorafenib is often discontinued. We compared the efficacy of overall survival (OS) in the view of the duration of stable disease (SD). 【METHODS】 112 patients with advanced HCC have been treated with sorafenib in our hospital. They were evaluated the antitumor response according to the modified Response Evaluation Criteria in Solid Tumor. We compared the relationship between the duration of SD and OS. 【RESULTS】 Complete response (CR) was observed in 2 patients, partial response (PR) in 16 patients, SD in 36 patients and progression disease (PD) in 27 patients, respectively. CR+PR patients (CR+PR group) had Child-Pugh A/B=18/0, BCLC stage A/B/C=3/6/9 and HBV/HCV/NBNC=6/8/4. SD patients (SD group) had Child-Pugh A/B=30/6, BCLC stage A/B/C=16/6/14 and HBV/HCV/NBNC=5/20/11. In the SD group the median duration of SD was 3.3 months. The SD group was divided into two groups; less than three months defined as Short SD and more than three months defined as Long SD. We compared the relationship of overall survival between the group of PR, Long SD, and Short SD. In the Short SD group, the median OS was 6.2 months (95%C.I. 4.7-7.3). In the Long SD group, the median OS was 17.6 months (95%C.I. 10.4-23.6). In the CR+PR Group, the median OS was 19.1 months (95%C.I. 14.2-23.8). There was not statistically significant difference between the OS of CR+PR group and the OS of Long SD group, however, there was statistically significant difference between the OS of Long SD group and the OS of Short SD group. 【CONCLUSION】 In the treatment of sorafenib for advanced HCC, long duration of SD improves the OS as same as CR+PR. Controlling the unique side effects of sorafenib such as HFSR is important to obtain the longer treatment duration.
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• Comparison of tumor response in patients treated with sorafenib for hepatocellular carcinoma, ARIZUMI Tadaaki, UESHIMA Kazuomi, TAKEDA Haruhiko, OSAKI Yukio, HAGIWARA Satoru, INOUE Tatsuo, KITAI Satoshi, YADA Norihisa, SAKURAI Toshiharu, NISHIDA Naoshi, KUDO Masatoshi, Kanzo, Kanzo, 53(6), 344 - 347, Jun. 2012
  Summary:Response Evaluation Criteria In Solid Tumor version 1.1 (RECIST1.1), modified RECIST (mRECIST) and Response Evaluation Criteria In Cancer of the Liver (RECICL) are frequently used as a response evaluation criteria for hepatocellular carcinoma. The overall survival (OS) of the patients treated with sorafenib was evaluated among these criteria respectively. In patients treated with sorafenib over 30 days, OS was stratified by RECICL and mRECIST, but not stratified by RECIST1.1. There was a statistically significant difference in RECICL (p=0.0133). In patients treated with sorafenib over 60 days, OS was also stratified by RECICL and mRECIST, but not stratified by RECIST1.1. There was also a statistically significant difference in the RECICL (p=0.0173). In patients with advanced hepatocellular carcinoma treated with sorafenib, evaluation of the tumor necrosis is considered very important and bidimensional measurement is necessary to measure viable area more precisely. RECICL which evaluates the tumor necrosis and includes bidimensional measurement may be considered the most useful criteria to predict the prognosis in the evaluation of treatment with sorafenib.
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• Brivanib, 64(5), 669 - 675, May 2012
• A case of chronic hepatitis B which achieved hepatitis B surface antigen seroclearance during combination therapy with peginterferon alfa-2b and entecavir, INUZUKA Tadashi, OSAKI Yukio, MATSUDA Fumihiro, SAKAMOTO Azusa, HATAMARU Keiichi, HENMI Shinichiro, ISHIKAWA Tetsuro, SAITO Sumio, NISHIKAWA Hiroki, KITA Ryuichi, OKABE Yoshihiro, KIMURA Toru, WAKASA Tomoko, HAGIWARA Satoru, KUDO Masatoshi, Kanzo, Kanzo, 53(1), 42 - 47, Jan. 25 2012
  Summary:A 65-year-old Japanese male with chronic hepatitis B (CH-B) diagnosed in December 2008 was referred to our department in July 2009. He started combination therapy with peginterferon alfa-2b (80 μg/week) and entecavir (0.5 mg/day) for 48 weeks from December 2009. At the initiation of therapy, his significant laboratory test results were as follows: alanine aminotransferase (ALT) 55 IU/l, aspartate aminotransferase (AST) 37 IU/l, hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) positive, hepatitis B virus (HBV) DNA levels 7.9 Log copies/ml. HBV DNA, HBsAg and HBeAg levels decreased progressively with therapy. After 36 weeks, HBV DNA, AST and ALT levels flared up, but after 44 weeks, HBV DNA levels decreased below 2.1 Log copies/ml and HBeAg seroconversion and HBsAg seroclearance were achieved. After 72 weeks he maintained HBsAg seroclearance and achieved a sustained viral response. Cases of spontaneous HBsAg seroclearance have been reported previously, but HBsAg seroclearance caused by combination therapy with peginterferon alfa-2b and entecavir has not been reported. Pre- and post-treatment cccDNA load in liver tissue, hepatitis B virus core-related antigen (HBcrAg) concentration in serum and expression of hepatitis B core antigen (HBcAg) in hepatocyte were compared, and it was found that all were drastically decreased. The present study suggests that these reduction appeared to contribute to the successful outcome of this therapy.
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• Retreatment with Peginterferon alpha-2a+Ribavirin in Patients Who Failed Previous Peginterferon alpha-2b+Ribavirin Combination Therapy, Taisuke Ued, Kaoru Tsuchiya, Satoru Hashimot, Taisuke Inoue, Nobuyuki Enomoto, Mie Inao, Atsushi Tanaka, Masahiko Kaito, Fumio Imazeki, Shuhei Nishiguchi, Satoshi Mochida, Osamu Yokosuka, Hiroshi Yatsuhashi, Namiki Izumi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 30(6), 554 - 560, 2012 , Refereed
  Summary:Background/Aims: Peginterferon (PEG-IFN) + ribavirin (RBV) combination therapy is the current standard of care for chronic hepatitis C. However, more than half of the patients cannot achieve sustained viral response (SVR). In Japan, the clinical benefit of retreatment with PEG-IFN + RBV combination retreatment is still unknown. Methods: We collected clinical data in 106 chronic hepatitis C patients who failed to achieve SVR with PEG-IFN alpha-2b + RBV combination therapy and were retreated with PEG-IFN alpha-2a + RBV. This retrospective study examined the efficacy of retreatment with PEG-IFN alpha-2a + RBV by evaluating the time to eradication of hepatitis C virus RNA, early virological response (EVR), and SVR. We compared the results of the previous therapy and retreatment in terms of efficacy and analyzed the factors influencing SVR. Results: The SVR rates in the non-responders and relapsers were 11 and 53%, respectively. EVR and prolonged treatment duration were associated with SVR. We also found that a prior response to PEG-IFN + RBV therapy was more important than the Interleukin-28B genotype for predicting the response to retreatment. Conclusions: Retreatment with PEG-IFN alpha-2a + RBV should be considered for relapsers and partial responders. Our results suggest that prolonged administration is also favorable for EVR cases to attain a higher SVR. Copyright (C) 2012 S. Karger AG, Basel
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• Risk of Hepatocellular Carcinoma Development in Cases of Hepatitis C Treated by Long-Term, Low-Dose PEG-IFN alpha-2a, Satoru Hagiwara, Toshiharu Sakurai, Masahiro Takita, Kazuomi Ueshima, Yasunori Minami, Tatsuo Inoue, Norihisa Yada, Satoshi Kitai, Tomoyuki Nagai, Sousuke Hayaishi, Tadaaki Arizumi, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 30(6), 561 - 567, 2012 , Refereed
  Summary:Objective: Increasing evidence suggests the efficacy of maintenance therapy with interferon (IFN) for chronic hepatitis C (CHC) in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to determine clinical characteristics on the risk of occurrence of HCC in CHC patients receiving maintenance IFN therapy. Methods: A total of 55 patients were treated in a single center with PEG-IFN alpha-2a monotherapy for CHC and evaluated for variables predictive of the occurrence of HCC. Results: The cumulative incidences of HCC were 0.092, 0.117 and 0.161 at 3, 5 and 7 years, respectively. Serum ALT level (>40 IU/l) in the 6th month after commencement of IFN therapy and BMI >25 were associated with shorter time-to-HCC emergence using multivariate analysis (relative risk 16.034, p = 0.01 for ALT >40 IU/I; relative risk 6.020, p = 0.026 for BMI >25, respectively). The IL28B SNP was extracted as a significant factor for the occurrence of HCC. Conclusions: Maintenance therapy with the use of long-term low-dose PEG-IFN alpha-2a is effective for preventing HCC occurrence irrespective of the IL28B SNP, at least for a subset of CHC patients. The initial response of serum ALT levels and BMI provides a prognostic value for determining the risk of developing HCC later in life. Copyright (C) 2012 S. Karger AG, Basel
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• [Effects of interferon treatment on recurrence and survival after curative treatment of hepatitis C virus-related hepatocellular carcinoma]., Ueda T, Chung H, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 4, 319 - 324, May 2011 , Refereed
• [Efficacy of adjuvant treatment after curative treatment in patients with HBV related hepatocellular carcinoma]., Hagiwara S, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 4, 546 - 550, May 2011 , Refereed
• The prognosis of patients with pancreatic cancer is extremely poor. Preface., Kudo M, Yamao K, Shimosegawa T, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 11 Suppl 2, 1 - 2, 2011 , Refereed
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• Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma., Kudo M, Digestive diseases (Basel, Switzerland), Digestive diseases (Basel, Switzerland), 29(3), 289 - 302, 2011 , Refereed
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• Des-gamma-Carboxyprothrombin May Be a Promising Biomarker to Determine the Therapeutic Efficacy of Sorafenib for Hepatocellular Carcinoma, Kazuomi Ueshima, Masatoshi Kudo, Masahiro Takita, Tomoyuki Nagai, Chie Tatsumi, Taisuke Ueda, Satoshi Kitai, Emi Ishikawa, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Yasunori Minami, Hobyung Chung, Toshiharu Sakurai, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 29(3), 321 - 325, 2011 , Refereed
  Summary:Objective: The purpose of this study was to evaluate the role of des-gamma-carboxyprothrombin (DCP) as a marker for the efficacy of sorafenib therapy for hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC treated with sorafenib were retrospectively evaluated, focusing on DCP levels and clinical characteristics. Results: 50 patients with advanced HCC were treated with sorafenib alone. In 25 of these patients, the serum levels of DCP were evaluated twice (pretreatment and within 2 weeks after starting therapy). The time to progression was significantly longer in patients in whom the DCP level at 2 weeks after starting sorafenib was 6 2-fold higher than the pretreatment levels, as compared with patients without an increase in DCP (p = 0.0296). Conclusions: The serum level of DCP is a surrogate marker for tissue hypoxia and can be a predictive marker to assess the tumor response to sorafenib therapy. Copyright (C) 2011 S. Karger AG, Basel
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• Searching for biological markers of molecular targeting treatment of liver cancer., Arao T, Kudo M, Nishio K, Gan to kagaku ryoho. Cancer & chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 37(10), 1879 - 1882, Oct. 2010 , Refereed
• Estimation of Liver Function Using T1 Mapping on Gadolinium Ethoxybenzyl Diethylenetriamine Pentaacetic Acid-enhanced Magnetic Resonance Imaging., Katsube T, Okada M, Kumano S, Hori M, Imaoka I, Ishii K, Kudo M, Kitagaki H, Murakami T, Invest Radiol, Invest Radiol, 46, 277 - 283, Aug. 28 2010 , Refereed
• Diagnosis of subepithelial tumors in the upper gastrointestinal tract by endoscopic ultrasonography., Sakamoto H, Kitano M, Kudo M, World journal of radiology, World journal of radiology, 2(8), 289 - 297, Aug. 2010 , Refereed
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• Endoscopic findings of intestinal Behcet's disease complicated with toxic megacolon, Y. Umehara, M. Kudo, M. Kawasaki, ENDOSCOPY, ENDOSCOPY, 42, E173 - E174, Jul. 2010 , Refereed
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• Management of hepatocellular carcinoma: from prevention to molecular targeted therapy., Kudo M, Oncology, Oncology, 78 Suppl 1, 1 - 6, Jul. 2010 , Refereed
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• Contrast-enhanced harmonic ultrasound imaging in ablation therapy for primary hepatocellular carcinoma., Minami Y, Kudo M, World journal of radiology, World journal of radiology, 1(1), 86 - 91, Dec. 2009 , Refereed
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• [Radio frequency ablation for metastatic liver cancer]., Inoue T, Kudo M, Gan to kagaku ryoho. Cancer & chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 36(8), 1253 - 1255, Aug. 2009 , Refereed
• Utility of Gd-EOB-DTPA-Enhanced MRI in Diagnosing Small Hepatocellular Carcinoma., Kim SR, Imoto S, Nakajima T, Ando K, Mita K, Fukuda K, Nishikawa R, Koma YI, Matsuoka T, Kudo M, Hayashi Y, Case reports in gastroenterology, Case reports in gastroenterology, 3(2), 187 - 192, Jul. 2009 , Refereed
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• [Prevention of recurrence of liver cancer]., Kudo M, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 97(7), 1681 - 1689, Jul. 2008 , Refereed
• Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy., Kudo M, Oncology, Oncology, 75 Suppl 1, 1 - 12, 2008 , Refereed
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• Epidemiology of hepatocellular carcinoma in Japan and Korea. A review., Kim SR, Kudo M, Hino O, Han KH, Chung YH, Lee HS, Organizing Committee of Japan-Korea Liver, Symposium, Oncology, Oncology, 75 Suppl 1, 13 - 16, 2008 , Refereed
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• Impact of interferon therapy after curative treatment of hepatocellular carcinoma., Kudo M, Oncology, Oncology, 75 Suppl 1, 30 - 41, 2008 , Refereed
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• Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignancies: comparison with contrast-enhanced CT., Hatanaka K, Kudo M, Minami Y, Maekawa K, Oncology, Oncology, 75 Suppl 1, 42 - 47, 2008 , Refereed
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• Imaging of hepatocellular carcinoma: qualitative and quantitative analysis of postvascular phase contrast-enhanced ultrasonography with sonazoid. Comparison with superparamagnetic iron oxide magnetic resonance images., Inoue T, Kudo M, Hatanaka K, Takahashi S, Kitai S, Ueda T, Ishikawa E, Hagiwara S, Minami Y, Chung H, Ueshima K, Maekawa K, Oncology, Oncology, 75 Suppl 1, 48 - 54, 2008 , Refereed
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• Intranodular blood supply correlates well with biological malignancy grade determined by tumor growth rate in pathologically proven hepatocellular carcinoma., Kudo M, Tochio H, Oncology, Oncology, 75 Suppl 1, 55 - 64, 2008 , Refereed
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• Validation of a new prognostic staging system for hepatocellular carcinoma: a comparison of the biomarker-combined Japan Integrated Staging Score, the conventional Japan Integrated Staging Score and the BALAD Score., Kitai S, Kudo M, Minami Y, Haji S, Osaki Y, Oka H, Seki T, Kasugai H, Sasaki Y, Matsunaga T, Oncology, Oncology, 75 Suppl 1, 83 - 90, 2008 , Refereed
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• PIVKA-II is the best prognostic predictor in patients with hepatocellular carcinoma after radiofrequency ablation therapy., Takahashi S, Kudo M, Chung H, Inoue T, Ishikawa E, Kitai S, Tatsumi C, Ueda T, Nagai T, Minami Y, Ueshima K, Oncology, Oncology, 75 Suppl 1, 91 - 98, 2008 , Refereed
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• Response evaluation of transcatheter arterial chemoembolization in hepatocellular carcinomas: the usefulness of sonazoid-enhanced harmonic sonography., Xia Y, Kudo M, Minami Y, Hatanaka K, Ueshima K, Chung H, Hagiwara S, Inoue T, Ishikawa E, Kitai S, Takahashi S, Tatsumi C, Ueda T, Hayaishi S, Maekawa K, Oncology, Oncology, 75 Suppl 1, 99 - 105, 2008 , Refereed
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• Combination therapy with S-1 and pegylated interferon alpha for advanced hepatocellular carcinoma., Ueshima K, Kudo M, Nagai T, Tatsumi C, Ueda T, Takahashi S, Hatanaka K, Kitai S, Ishikawa E, Inoue T, Hagiwara S, Minami Y, Chung H, Oncology, Oncology, 75 Suppl 1, 106 - 113, 2008 , Refereed
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• Review of 4th Single Topic Conference on HCC. Hepatocellular carcinoma: International consensus and controversies., Kudo M, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 37 Suppl 2, S83 - 7, Sep. 2007 , Refereed
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• Hepatic angiomyolipoma: identification of an efferent vessel as a hepatic vein by contrast-enhanced harmonic sonography., Zheng RQ, Kudo M, Ishikawa E, Chung H, Minami Y, Ogawa C, Sakaguchi Y, Kitano M, Kawasaki T, Maekawa K, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 32(4), 191 - 196, Dec. 2005 , Refereed
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• Hemodynamic and morphologic changes of peripheral hepatic vasculature in chronic liver disease: a preliminary study by contrast-enhanced coded phase-inversion harmonic sonography., Sakaguchi Y, Kudo M, Zheng RQ, Chung H, Minami Y, Ogawa C, Kitano M, Kawasaki T, Maekawa K, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 32(4), 197 - 204, Dec. 2005 , Refereed
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• Prospective respiratory-triggered multidetector row CT (MDCT) for abdominal examinations: initial experience with a prototype., Fahrni M, Murakami T, Hori M, Kim T, Matsumura T, Kudo M, Sase S, Tomoda K, Nakamura H, Radiation medicine, Radiation medicine, 23, 528 - 531, Nov. 2005 , Refereed
• Quantitative tissue blood flow evaluation of pancreatic tumor: comparison between xenon CT technique and perfusion CT technique based on deconvolution analysis., Abe H, Murakami T, Kubota M, Kim T, Hori M, Kudo M, Hashimoto K, Nakamori S, Dono K, Tomoda K, Monden M, Nakamura H, Radiation medicine, Radiation medicine, 23, 364 - 370, Aug. 2005 , Refereed
• [Current topics on therapy of hepatocellular carcinoma]., Kudo M, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 94(3), 464 - 472, Mar. 2005 , Refereed
• [Comparison of treatment methods for hepatocellular carcinoma--based on JIS score]., Kudo M, Chung H, Osaki Y, Kasugai H, Oka H, Seki T, Gan to kagaku ryoho. Cancer & chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 31(13), 2100 - 2104, Dec. 2004 , Refereed
• [Efficacy of short-duration interferon administration to prevent HCV transmission to medical personnel]., Chung H, Kudo M, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 62 Suppl 7(Pt 1), 315 - 318, Jul. 2004 , Refereed
• Diagnosis of acute cholecystitis in patients with liver cirrhosis: waveform analysis of the cystic artery by color Doppler imaging., Tochio H, Nishiuma S, Okabe Y, Orino A, Kudo M, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 31(1), 21 - 28, Mar. 2004 , Refereed
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• Contrast-enhanced agent detection imaging: Early experience in hepatocellular carcinoma., Wen YL, Kudo M, Minami Y, Chung H, Suetomi Y, Onda H, Kitano M, Kawasaki T, Maekawa K, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 30(2), 77 - 84, Jun. 2003 , Refereed
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• Assessment of image quality of contrast-enhanced power doppler imaging in hepatocellular carcinoma with the personal ultrasound imager: Comparison with the conventional machine., Wen YL, Kudo M, Minami Y, Chung H, Suetomi Y, Onda H, Kitano M, Kawasaki T, Maekawa K, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 30(1), 31 - 38, Mar. 2003 , Refereed
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• Contrast advanced dynamic flow imaging and contrast pulse subtraction imaging: Preliminary results in hepatic tumors., Wen YL, Kudo M, Maekawa K, Minami Y, Chung H, Suetomi Y, Onda H, Kitano M, Kawasaki T, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 29(4), 195 - 204, Dec. 2002 , Refereed
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• Proximal bifurcation of hepatic artery: Novel findings on hepatic arteries demonstrated by ultrasound Doppler imaging, B-flow, and US angiography., Tochio H, Iwasaki N, Nakamura H, Nakayama K, Soga T, Nishiuma S, Fukunaga T, Okabe Y, Kashida H, Hirasa M, Ibuki Y, Fujimoto T, Morimoto Y, Kudo M, Tomita S, Konishi Y, Orino A, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 29(1), 11 - 17, Mar. 2002 , Refereed
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• A Randomised Phase 3 Trial of Lenvatinib vs. Sorafenib in First-line Treatment of Patients With Unresectable Hepatocellular Carcinoma, Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron AD, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL, Lancet, Lancet, in press, Refereed
• Deficiency of Gankyrin in the small intestine is associated with augmented colitis accompanied by altered bacterial composition of intestinal microbiota, Toshiharu Sakurai, Hiroki Nishiyama, Tomoyuki Nagai, Susumu Goto, Hiroyuki Ogata, Masatoshi Kudo, BMC Gastroenterology, BMC Gastroenterology, 20(1), Dec. 2020 , Refereed
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• A Randomized, Double-Blind, Placebo-Controlled, Phase 3 of Tivantinib in Japanese Patients with MET-high Hepatocellular Carcinoma., Masatoshi Kudo, Manabu Morimoto, Michihisa Moriguchi, Namiki Izumi, Tetsuji Takayama, Hitoshi Yoshiji, Keisuke Hino, Takayoshi Oikawa, Tetsuhiro Chiba, Kenta Motomura, Junko Kato, Kentaro Yasuchika, Akio Ido, Takashi Sato, Daisuke Nakashima, Kazuomi Ueshima, Masafumi Ikeda, Takuji Okusaka, Kazuo Tamura, Junji Furuse, Cancer science, Cancer science, Jul. 27 2020 , Refereed
  Summary:A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c-Met inhibitor tivantinib as second-line treatment significantly prolonged progression-free survival in a subpopulation whose tumor samples highly expressed c-Met (MET-high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. This randomized, double-blind, placebo-controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET-high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice-a-day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression-free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n=134) or placebo (n=61) group. Median progression-free survival was 2.8 (95% confidence interval: 2.7-2.9) and 2.3 (1.5-2.8) months in the tivantinib and placebo groups, respectively (hazard ratio=0.74, 95% confidence interval: 0.52-1.04, p=0.082). Median overall survival was 10.3 (95% confidence interval: 8.1-11.6) and 8.5 (6.2-11.4) months in the tivantinib and placebo group, respectively (hazard ratio=0.82, 95% confidence interval: 0.58-1.15). The most common tivantinib-related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma.
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• Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma., Richard S Finn, Masafumi Ikeda, Andrew X Zhu, Max W Sung, Ari D Baron, Masatoshi Kudo, Takuji Okusaka, Masahiro Kobayashi, Hiromitsu Kumada, Shuichi Kaneko, Marc Pracht, Konstantin Mamontov, Tim Meyer, Tomoki Kubota, Corina E Dutcus, Kenichi Saito, Abby B Siegel, Leonid Dubrovsky, Kalgi Mody, Josep M Llovet, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, JCO2000808, Jul. 27 2020 , Refereed
  Summary:PURPOSE: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.
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• Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2020 - WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS., Christoph F Dietrich, Christian Pállson Nolsøe, Richard G Barr, Annalisa Berzigotti, Peter N Burns, Vito Cantisani, Maria Cristina Chammas, Nitin Chaubal, Byung Ihn Choi, Dirk-André Clevert, Xinwu Cui, Yi Dong, Mirko D'Onofrio, J Brian Fowlkes, Odd Helge Gilja, Pintong Huang, Andre Ignee, Christian Jenssen, Yuko Kono, Masatoshi Kudo, Nathalie Lassau, Won Jae Lee, Jae Young Lee, Ping Liang, Adrian Lim, Andrej Lyshchik, Maria Franca Meloni, Jean Michel Correas, Yasunori Minami, Fuminori Moriyasu, Carlos Nicolau, Fabio Piscaglia, Adrian Saftoiu, Paul S Sidhu, Ioan Sporea, Guido Torzilli, Xiaoyan Xie, Rongqin Zheng, Ultraschall in der Medizin (Stuttgart, Germany : 1980), Ultraschall in der Medizin (Stuttgart, Germany : 1980), Jul. 24 2020 , Refereed
  Summary:The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications.The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.
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• Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS., Christoph F Dietrich, Christian Pállson Nolsøe, Richard G Barr, Annalisa Berzigotti, Peter N Burns, Vito Cantisani, Maria Cristina Chammas, Nitin Chaubal, Byung Ihn Choi, Dirk-André Clevert, Xinwu Cui, Yi Dong, Mirko D'Onofrio, J Brian Fowlkes, Odd Helge Gilja, Pintong Huang, Andre Ignee, Christian Jenssen, Yuko Kono, Masatoshi Kudo, Nathalie Lassau, Won Jae Lee, Jae Young Lee, Ping Liang, Adrian Lim, Andrej Lyshchik, Maria Franca Meloni, Jean Michel Correas, Yasunori Minami, Fuminori Moriyasu, Carlos Nicolau, Fabio Piscaglia, Adrian Saftoiu, Paul S Sidhu, Ioan Sporea, Guido Torzilli, Xiaoyan Xie, Rongqin Zheng, Ultrasound in medicine & biology, Ultrasound in medicine & biology, Jul. 22 2020 , Refereed
  Summary:The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.
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• Purpura-free small intestinal IgA vasculitis complicated by cytomegalovirus reactivation., Mariko Matsumura, Yoriaki Komeda, Tomohiro Watanabe, Masatoshi Kudo, BMJ case reports, BMJ case reports, 13(7), Jul. 06 2020 , Refereed
  Summary:IgA vasculitis (Henoch-Schönlein purpura) affects various organs, including the skin, gastrointestinal (GI) tract, joints and kidneys. Its clinical course typically consists of two phases: initial appearance of purpura and delayed onset of arthralgia, GI symptoms and haematuria. We report the case of an adult patient with IgA vasculitis of the small bowel, without skin involvement, complicated by cytomegalovirus (CMV) enteritis following prednisolone administration. Single-balloon enteroscopy revealed mucosal oedema, redness, erosions and transverse ulcers of the duodenum and jejunum. Jejunal biopsy specimens showed IgA deposition in the capillary walls. CMV reactivation was confirmed by PCR and immunostaining using jejunal biopsy specimens. This case report strongly suggests that adult patients with IgA vasculitis can present with isolated GI involvement, without characteristic skin purpura. Furthermore, CMV reactivation needs to be considered in patients with IgA vasculitis showing poor response to glucocorticoids.
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• Partial Pancreatic Parenchymal Atrophy Is a New Specific Finding to Diagnose Small Pancreatic Cancer (≤10 mm) Including Carcinoma in Situ: Comparison with Localized Benign Main Pancreatic Duct Stenosis Patients., Kentaro Yamao, Mamoru Takenaka, Rei Ishikawa, Ayana Okamoto, Tomohiro Yamazaki, Atsushi Nakai, Shunsuke Omoto, Ken Kamata, Kosuke Minaga, Ippei Matsumoto, Yoshifumi Takeyama, Isao Numoto, Masakatsu Tsurusaki, Takaaki Chikugo, Yasutaka Chiba, Tomohiro Watanabe, Masatoshi Kudo, Diagnostics (Basel, Switzerland), Diagnostics (Basel, Switzerland), 10(7), Jul. 01 2020 , Refereed
  Summary:BACKGROUND: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). METHODS: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. RESULTS: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. CONCLUSIONS: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS.
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• The AFSUMB Consensus Statements and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound using Sonazoid., Jae Young Lee, Yasunori Minami, Byung Ihn Choi, Won Jae Lee, Yi-Hong Chou, Woo Kyoung Jeong, Mi-Suk Park, Nobuki Kudo, Min Woo Lee, Ken Kamata, Hiroko Iijima, So Yeon Kim, Kazushi Numata, Katsutoshi Sugimoto, Hitoshi Maruyama, Yasukiyo Sumino, Chikara Ogawa, Masayuki Kitano, Ijin Joo, Junichi Arita, Ja-Der Liang, Hsi-Ming Lin, Christian Nolsoe, Odd Helge Gilja, Masatoshi Kudo, Ultrasonography (Seoul, Korea), Ultrasonography (Seoul, Korea), 39(3), 191 - 220, Jul. 2020 , Refereed
  Summary:The first edition of the guidelines for the use of ultrasound contrast agents was published in 2004, dealing with liver applications. The second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some nonliver applications. The third edition of the contrast-enhanced ultrasound (CEUS) guidelines was the joint World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology (WFUMB-EFSUMB) venture in conjunction with other regional US societies such as Asian Federation of Societies for Ultrasound in Medicine and Biology, resulting in a simultaneous duplicate on liver CEUS in the official journals of both WFUMB and EFSUMB in 2013. However, no guidelines were described mainly for Sonazoid due to limited clinical experience only in Japan and Korea. The new proposed consensus statements and recommendations provide general advice on the use of Sonazoid and are intended to create standard protocols for the use and administration of Sonazoid in hepatic and pancreatobiliary applications in Asian patients and to improve patient management.
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• Treatment of Hepatocellular Carcinoma (HCC) during the COVID-19 Outbreak: The Working Group Report of JAMTT-HCC., Masatoshi Kudo, Masayuki Kurosaki, Masafumi Ikeda, Hiroshi Aikata, Atsushi Hiraoka, Takuji Torimura, Naoya Sakamoto, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, Jun. 24 2020 , Refereed
  Summary:This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the COVID-19 pandemic. Measures required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID-19 and the availability of resources, including personal protective equipment and inpatient beds). Also, models suggest that second and third waves of COVID-19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2-3 years). This guide should serve as a good reference for best practices in the management of HCC in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID-19 infections.
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• Improved liver metastasis detection using Kupffer-phase imaging in contrast-enhanced harmonic EUS in patients with pancreatic cancer (with video)., Kosuke Minaga, Masayuki Kitano, Atsushi Nakai, Shunsuke Omoto, Ken Kamata, Kentaro Yamao, Mamoru Takenaka, Masakatsu Tsurusaki, Takaaki Chikugo, Ippei Matsumoto, Yasutaka Chiba, Tomohiro Watanabe, Masatoshi Kudo, Gastrointestinal endoscopy, Gastrointestinal endoscopy, Jun. 24 2020 , Refereed
  Summary:BACKGROUND AND AIMS: Kupffer-phase imaging visualized by Sonazoid distribution into normal liver tissues upon phagocytosis by Kupffer cells, potentially aids in improving liver metastasis detection compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for left-lobe liver metastasis was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. RESULTS: We enrolled 426 patients with pancreatic cancer. The left-lobe liver metastasis was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for left-lobe liver metastasis were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P < 0.001). In 2.1% patients, only CH-EUS could detect a single distant metastasis of the left-lobe liver, thereby upgrading the tumor staging and altering the clinical management. CONCLUSIONS: CH-EUS-based Kupffer-phase imaging increased the detectability of left-lobe liver metastasis. This technique could be a reliable pretreatment imaging modality for clinical decision-making in pancreatic cancer patients.
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• A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements., Masatoshi Kudo, Kwang-Hyub Han, Sheng-Long Ye, Jian Zhou, Yi-Hsiang Huang, Shi-Ming Lin, Chung-Kwe Wang, Masafumi Ikeda, Stephen Lam Chan, Su Pin Choo, Shiro Miyayama, Ann Lii Cheng, Liver cancer, Liver cancer, 9(3), 245 - 260, Jun. 2020 , Refereed
  Summary:The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.
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• Trial Design and Endpoints in hepatocellular carcinoma: AASLD Consensus Conference., Josep M Llovet, Augusto Villanueva, Jorge A Marrero, Myron Schwartz, Tim Meyer, Peter R Galle, Riccardo Lencioni, Tim F Greten, Masatoshi Kudo, Sumithra J Mandrekar, Andrew X Zhu, Richard S Finn, Lewis R Roberts, Hepatology (Baltimore, Md.), Hepatology (Baltimore, Md.), May 20 2020 , Refereed
  Summary:Proper trial design is critical for the success of clinical investigations. Hepatocellular carcinoma (HCC) is a complex disease that has several unique properties. In 2008, after the approval of sorafenib, a panel of experts proposed guidelines for trial design and endpoints in HCC that have been instrumental during the last decade and provided a framework to allow an homogeneous analysis of reported investigations. Since then, several phase III studies have been reported and novel challenges have emerged. A panel of experts conveyed by AASLD organized a Special Topic Conference on trial design and endpoints to address those emerging challenges. This review summarizes the analysis and conclusions of those discussions and provides novel recommendations on the selection endpoints, stratification variables and targeted populations in the complex arena of HCC. We have covered the full spectrum of the disease, from surveillance/ chemoprevention, to neoadjuvant and adjuvant trials after curative therapies, and trials in intermediate and advanced stages of HCC. We explore the prospects for incorporating biomarkers and liquid biopsy into conventional clinical trials. In addition, we address the need for obtaining tissue and blood samples in all investigations and propose novel primary endpoints such as progression free survival with restrictive rules and patient reported outcomes. This up-dated set of recommendations is timely considering the advent of more potent combination therapies in all areas of HCC management, the increase in adverse events associated with those combinations, and the evidence that several lines of effective treatments will benefit a given patient. We herein articulate a framework to facilitate capturing the efficacy of novel therapeutic strategies with the goal of improving the outcomes of patients suffering from this disease.
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• Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma., Naoshi Nishida, Masatoshi Kudo, Cancers, Cancers, 12(5), May 18 2020 , Refereed
  Summary:Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers to predict outcome and develop novel combination therapies that enhance the efficacy of ICIs. Recently, several attempts have been made to classify HCC based on genome, epigenome, and transcriptome analyses. These molecular classifications are characterized by unique clinical and histological features of HCC, as well immune phenotype. For example, HCCs exhibiting gene expression patterns with proliferation signals and stem cell markers are associated with the enrichment of immune infiltrates in tumors, suggesting immune-proficient characteristics for this type of HCC. However, the presence of activating mutations in β-catenin represents a lack of immune infiltrates and refractoriness to ICIs. Although the precise mechanism that links the immunological phenotype with molecular features remains controversial, it is conceivable that alterations of oncogenic cellular signaling in cancer may lead to the expression of immune-regulatory molecules and result in the acquisition of specific immunological microenvironments for each case of HCC. Therefore, these molecular and immune characteristics should be considered for the management of HCC using immunotherapy.
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• Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma., Richard S Finn, Shukui Qin, Masafumi Ikeda, Peter R Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, Valeriy Breder, Philippe Merle, Ahmed O Kaseb, Daneng Li, Wendy Verret, Derek-Zhen Xu, Sairy Hernandez, Juan Liu, Chen Huang, Sohail Mulla, Yulei Wang, Ho Yeong Lim, Andrew X Zhu, Ann-Lii Cheng, The New England journal of medicine, The New England journal of medicine, 382(20), 1894 - 1905, May 14 2020 , Refereed
  Summary:BACKGROUND: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. METHODS: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. CONCLUSIONS: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).
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• Serum Levels of Alpha Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma., David M Hughes, Sarah Berhane, C A Emily de Groot, Hidenori Toyoda, Toshifumi Tada, Takashi Kumada, Shinji Satomura, Naoshi Nishida, Masatoshi Kudo, Toru Kimura, Yukio Osaki, Ruwanthi Kolamunage-Dona, Ruben Amoros Salvador, Tom Bird, Marta Garcίa-Fiñana, Philip Johnson, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, May 07 2020 , Refereed
  Summary:BACKGROUND & AIMS: Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular Carcinoma (HCC). US analysis is, however, limited in patients who are obese or have small tumors. Addition of measurement of serum level of alpha-fetoprotein (AFP) to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. METHODS: We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014 and followed for a median 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximate every 3 months) to develop a model to determine risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). RESULTS: HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development dataset, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were correctly classified. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). Similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. CONCLUSIONS: We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum level of AFP over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.
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• Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer., Changhoon Yoo, Do-Youn Oh, Hye Jin Choi, Masatoshi Kudo, Makoto Ueno, Shunsuke Kondo, Li-Tzong Chen, Motonobu Osada, Christoph Helwig, Isabelle Dussault, Masafumi Ikeda, Journal for immunotherapy of cancer, Journal for immunotherapy of cancer, 8(1), May 2020 , Refereed
  Summary:BACKGROUND: Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β 'trap') fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors. METHODS: In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7-32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatment-related adverse events (TRAEs), most commonly rash (17%), maculopapular rash and fever (13% each), and increased lipase (10%). Eleven (37%) patients had grade ≥3 TRAEs; three patients had grade 5 events (septic shock due to bacteremia, n=1; interstitial lung disease (reported term: interstitial pneumonitis), n=2). The objective response rate was 20% (95% CI 8 to 39) per independent review committee (IRC), with five of six responses ongoing (12.5+ to 14.5+ months) at data cut-off. Two additional patients with durable stable disease had a partial response per investigator. Median progression-free survival assessed by IRC and overall survival were 2.5 months (95% CI 1.3 to 5.6) and 12.7 months (95% CI 6.7 to 15.7), respectively. Clinical activity was observed irrespective of PD-L1 expression and microsatellite instability-high status. CONCLUSIONS: Bintrafusp alfa had clinical activity in Asian patients with pretreated BTC, with durable responses. Based on these results, bintrafusp alfa is under further investigation in patients with BTC (NCT03833661 and NCT04066491). TRIAL REGISTRATION NUMBER: NCT02699515.
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• IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation., Stephen P Hack, Jessica Spahn, Minshan Chen, Ann-Lii Cheng, Ahmed Kaseb, Masatoshi Kudo, Han Chu Lee, Adam Yopp, Pierce Chow, Shukui Qin, Future oncology (London, England), Future oncology (London, England), 16(15), 975 - 989, May 2020 , Refereed
  Summary:Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. Clinical Trial Registration: NCT04102098.
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• Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma., Masatoshi Kudo, Cancers, Cancers, 12(5), Apr. 27 2020 , Refereed
  Summary:A successful phase III trial for the combination of atezolizumab and bevacizumab (the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been reported. This is groundbreaking because nivolumab and pembrolizumab, both programmed cell death-1 (PD-1) antibodies, have failed to show efficacy as first- and second-line therapeutics, respectively, in phase III clinical trials. Immunotherapy with a combination of atezolizumab and bevacizumab resulted in better survival than treatment with sorafenib for the first time since sorafenib was approved in 2007. The high efficacy of the combination of PD-1/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) antibodies is not only due to their additive effects on tumor growth, but also to their reprogramming of the immunosuppressive microenvironment into an immunostimulatory microenvironment. These results were confirmed in a phase Ib trial that showed significantly longer progression-free survival in the atezolizumab plus bevacizumab group than in patients that received atezolizumab alone. These results demonstrate that immunotherapy with a combination of PD-1/PD-L1 and VEGF inhibitors is effective and may result in a reprogramming of the tumor microenvironment. The results of an ongoing phase III trial of a PD-1 antibody in combination with the VEGF receptor tyrosine kinase inhibitor (TKI) are highly anticipated.
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• Phase I Study of the Bifunctional Fusion Protein Bintrafusp Alfa in Asian Patients with Advanced Solid Tumors, Including a Hepatocellular Carcinoma Safety-Assessment Cohort., Toshihiko Doi, Yutaka Fujiwara, Takafumi Koyama, Masafumi Ikeda, Christoph Helwig, Morihiro Watanabe, Yulia Vugmeyster, Masatoshi Kudo, The oncologist, The oncologist, Apr. 23 2020 , Refereed
  Summary:LESSONS LEARNED: Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types. BACKGROUND: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor-β (TGF-β) RII receptor (a TGF-β "trap") fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death-ligand 1 (PD-L1). Bintrafusp alfa is designed to neutralize TGF-β signaling by "trapping" and sequestering all TGF-β isoforms, and this trap function is physically linked to PD-L1 blockade in the tumor microenvironment. METHODS: NCT02699515 was a phase I, open-label, dose-escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety-assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response. RESULTS: As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment-related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment-related deaths occurred. In the dose-escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose-proportional pharmacokinetics profile was observed at doses of >3 mg/kg. CONCLUSION: Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC.
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• Endoscopic ultrasound-guided radiofrequency ablation of porcine liver., Shuya Maeshima, Yoshiyuki Ida, Ryo Shimizu, Yuki Kawaji, Takashi Tamura, Junya Nuta, Keiichi Hatamaru, Masahiro Itonaga, Masatoshi Kudo, Masayuki Kitano, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), Apr. 16 2020 , Refereed
  Summary:PURPOSE: Animal studies of endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) of the liver have rarely been reported. We assessed the effectiveness and safety of EUS-RFA in pigs. METHODS: We conducted four experiments using newly designed RFA electrodes. In the first experiment, we ablated excised liver using 19 G electrodes with active electrode tips with lengths of 1, 1.5, and 2 cm. The second experiment was performed with the same electrodes as those used in the first experiment, but with the electrodes inserted into the livers of live pigs under EUS. In the third experiment, we tested the electrodes for water permeability. In the fourth experiment, we performed EUS-RFA on live pigs, using 19 G electrodes in 7/12 pigs and 18 G electrodes in 5/12 pigs. Complications were evaluated after 7 days of survival. RESULTS: The newly designed RFA electrodes achieved ablation of the liver. In the first experiment, the maximal sizes of the ablation areas were 27, 26, 24, and 25 mm at 10, 20, 30, and 40 W, respectively, with the 2-cm electrode. In the second experiment, the maximal vertical sizes were 22, 23, 22, and 23 mm at 10, 20, 30, and 40 W, respectively, with the 2-cm electrode. In the third experiment, the 18 G electrode had better water permeability than the 19 G electrode. In the fourth experiment, all pigs survived. Complications occurred in 1/5 (18 G electrode) and 4/7 (19 G electrode) pigs. CONCLUSION: We performed EUS-RFA in pigs and concluded that it may be feasible to perform RFA of lesions near the stomach.
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• Benefits, Open questions and Challenges of the use of Ultrasound in the COVID-19 pandemic era. The views of a panel of worldwide international experts., Fabio Piscaglia, Federico Stefanini, Vito Cantisani, Paul S Sidhu, Richard Barr, Annalisa Berzigotti, Maria Cristina Chammas, Jean-Michel Correas, Christoph Frank Dietrich, Steven Feinstein, Pintong Huang, Christian Jenssen, Yuko Kono, Masatoshi Kudo, Ping Liang, Andrej Lyshchik, Christian Nolsøe, Xyaoyan Xie, Francesco Tovoli, Ultraschall in der Medizin (Stuttgart, Germany : 1980), Ultraschall in der Medizin (Stuttgart, Germany : 1980), Apr. 15 2020 , Refereed
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• Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2., Masatoshi Kudo, Peter R Galle, Josep M Llovet, Richard S Finn, Arndt Vogel, Kenta Motomura, Eric Assenat, Philippe Merle, Giovanni Brandi, Bruno Daniele, Takuji Okusaka, Jiří Tomášek, Christophe Borg, Vincenzo Dadduzio, Manabu Morimoto, Marc Pracht, Min-Hua Jen, Nora Drove Ubreva, Ryan C Widau, Kenta Shinozaki, Reigetsu Yoshikawa, Andrew X Zhu, Liver international : official journal of the International Association for the Study of the Liver, Liver international : official journal of the International Association for the Study of the Liver, Apr. 12 2020 , Refereed
  Summary:BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.
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• Dual-frequency MR elastography to differentiate between inflammation and fibrosis of the liver: Comparison with histopathology., Keitaro Sofue, Minori Onoda, Masakatsu Tsurusaki, Daisuke Morimoto, Norihisa Yada, Masatoshi Kudo, Takamichi Murakami, Journal of magnetic resonance imaging : JMRI, Journal of magnetic resonance imaging : JMRI, 51(4), 1053 - 1064, Apr. 2020 , Refereed
  Summary:BACKGROUND: Differentiation between inflammation and fibrosis is an important clinical distinction in patients with chronic liver disease, which has been difficult so far with MR elastography. PURPOSE: To investigate whether dual-frequency MR elastography can estimate necroinflammation of the liver and improve diagnostic performance for the staging of liver fibrosis. STUDY TYPE: Retrospective. SUBJECTS: In all, 30 patients (14 males, 16 females) with chronic liver disease. FIELD STRENGTH/SEQUENCE: 1.5T/dual-frequency MR elastography at 60-Hz and 80-Hz vibration frequencies. [Correction added on November 12, 2019, after first online publication: The field strength in the preceding sentence was corrected.] ASSESSMENT: Necroinflammation activity and fibrosis were assessed using the METAVIR scoring system. Stiffness values at 60-Hz (G60-Hz ) and 80-Hz (G80-Hz ) were obtained with an MR elastogram. The difference value between G80-Hz and G60-Hz (ΔG) was calculated. Four values (G60-Hz , G80-Hz , G60-Hz - ΔG, and G80-Hz  + ΔG) were generated to estimate necroinflammation and fibrosis. STATISTICAL TESTS: The ΔG were correlated with necroinflammation activity grade and fibrosis stage using Spearman's rank correlation. Diagnostic performance of the four values for necroinflammation activity grade and fibrous stage was assessed by using area under the receiver operating characteristic curve (AUC). RESULTS: The mean value of G80-Hz (6.23 ± 3.67 kPa) was significantly higher than that of G60-Hz (5.27 ± 3.14 kPa) (P < 0.0001). The ΔG demonstrated a strong correlation with necroinflammation grade (ρ = 0.625, P < 0.001) and no correlation with fibrosis stage (ρ = 0.306, P = 0.113). The AUC of the G80-Hz and G80-Hz  + ΔG showed higher accuracy for necroinflammation, and optimal cutoff values yielded better discrimination of ≥A1, ≥A2, and = A3. The AUC demonstrated that all the generated values had high diagnostic performance (≥0.87 for all) for fibrosis. DATA CONCLUSION: Dual-frequency MR elastography shows potential in estimating necroinflammation of the liver and may improve diagnostic performance for staging liver fibrosis. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1053-1064.
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• A New Era in Systemic Therapy for Hepatocellular Carcinoma: Atezolizumab plus Bevacizumab Combination Therapy., Masatoshi Kudo, Liver cancer, Liver cancer, 9(2), 119 - 137, Apr. 2020 , Refereed
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• Ultrasound fusion imaging technologies for guidance in ablation therapy for liver cancer., Yasunori Minami, Masatoshi Kudo, Journal of medical ultrasonics (2001), Journal of medical ultrasonics (2001), 47(2), 257 - 263, Apr. 2020 , Refereed
  Summary:With advances in imaging technology, images from ultrasound (US) and computed tomography (CT) or magnetic resonance imaging (MRI) can be displayed simultaneously and in real time, according to the angle of the transducer. CT/MR-US fusion imaging improves the visualization of inconspicuous hepatocellular carcinoma (HCC) and helps us to understand the three-dimensional relationship between the liver vasculature and HCC. US fusion imaging guidance facilitates improvement in the treatment response for HCC with poor conspicuity, and the rates of technical success of ablation and local tumor progression for inconspicuous HCC range from 94.4 to 100% and 0 to 8.3%, respectively. Moreover, the development of image fusion has made it possible to compare and overlay pre- and post-ablation US images. This US-US fusion imaging allows side-by-side comparison of the ablative margin, while US-US overlay fusion can visualize the ablative margin because the tumor image is projected onto the ablative hyperechoic zone. Thus, US-US overlay fusion guidance is highly effective for safety margin achievement in local ablation therapy for HCC, providing a lower risk of local tumor progression. This manuscript reviews the current status of ultrasound fusion imaging for percutaneous ablation therapy of HCC.
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• Clinical utility of treatment method conversion during single-session endoscopic ultrasound-guided biliary drainage., Kosuke Minaga, Mamoru Takenaka, Kentaro Yamao, Ken Kamata, Shunsuke Omoto, Atsushi Nakai, Tomohiro Yamazaki, Ayana Okamoto, Rei Ishikawa, Tomoe Yoshikawa, Yasutaka Chiba, Tomohiro Watanabe, Masatoshi Kudo, World journal of gastroenterology, World journal of gastroenterology, 26(9), 947 - 959, Mar. 07 2020 , Refereed
  Summary:BACKGROUND: Although several techniques for endoscopic ultrasound-guided biliary drainage (EUS-BD) are available at present, an optimal treatment algorithm of EUS-BD has not yet been established. AIM: To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD. METHODS: This was a single-center retrospective analysis using a prospectively accumulated database. Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included. The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session. Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success, clinical success, and adverse events (AEs). RESULTS: A total of 208 patients underwent EUS-BD during the study period. For 18.8% (39/208) of the patients, the treatment methods were converted to another EUS-BD technique from the initial plan. Biliary obstruction was caused by pancreatobiliary malignancies, other malignant lesions, biliary stones, and other benign lesions in 22, 11, 4, and 2 patients, respectively. The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures: Target puncture (n = 13), guidewire manipulation (n = 18), and puncture tract dilation (n = 8). Technical success was achieved in 97.4% (38/39) of the cases and clinical success was achieved in 89.5% of patients (34/38). AEs occurred in 10.3% of patients, including bile leakage (n = 2), bleeding (n = 1), and cholecystitis (n = 1). The puncture target and drainage technique were altered in subsequent EUS-BD procedures in 25 and 14 patients, respectively. The final technical success rate with 95%CI for all 208 cases was 97.1% (95%CI: 93.8%-98.9%), while that of the initially planned EUS-BD was 78.8% (95%CI: 72.6%-84.2%). CONCLUSION: Among multi-step procedures in EUS-BD, guidewire manipulation appeared to be the most technically challenging. When initially planned EUS-BD is technically difficult, treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.
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• Successful biliary cannulation using a novel rotatable sphincterotome in a patient with situs inversus totalis., Akihiro Yoshida, Kosuke Minaga, Osami Takeda, Hajime Hanno, Shigenori Takayanagi, Toshio Dozaiku, Masatoshi Kudo, Endoscopy, Endoscopy, Mar. 04 2020 , Refereed
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• Efficacy of a modified double-guidewire technique using an uneven double lumen cannula (uneven method) in patients with surgically altered gastrointestinal anatomy (with video)., Mamoru Takenaka, Kosuke Minaga, Ken Kamata, Kentaro Yamao, Tomoe Yoshikawa, Rei Ishikawa, Ayana Okamoto, Tomohiro Yamazaki, Atsushi Nakai, Shunsuke Omoto, Yoriaki Komeda, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Yasutaka Chiba, Chang-Il Kwon, Seok Jeong, Tae Hoon Lee, Masatoshi Kudo, Surgical endoscopy, Surgical endoscopy, 34(3), 1432 - 1441, Mar. 2020 , Refereed
  Summary:BACKGROUND: Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) has been reported to be effective for patients with surgically altered gastrointestinal anatomy. However, selective biliary cannulation remains difficult in BE-ERCP. We examined the usefulness of a modified double-guidewire technique using an uneven double lumen cannula (the uneven method) for BE-ERCP in patients with surgically altered gastrointestinal anatomy. METHODS: To clarify the usefulness of the uneven method for selective biliary cannulation in BE-ERCP in comparison to the pancreatic guidewire (PGW) method, 40 patients with surgically altered gastrointestinal anatomy who underwent BE-ERCP with successful placement of a guidewire in the pancreatic duct were evaluated. The uneven method was used in 18 cases (uneven group) and the PGW method was used in the remaining 22 cases (PGW group). RESULTS: The technical success rate of biliary cannulation was higher in the uneven group than in the PGW group (83.3 vs. 59.0%; P = 0.165). In addition, the time to biliary cannulation were significantly shorter in the uneven group than in the PGW group (6 vs. 18 min; P = 0.004; respectively). In the PGW group, post-ERCP pancreatitis (PEP) occurred in 3 of 22 cases (13.6%). No adverse events, including PEP, occurred in the uneven group. CONCLUSIONS: The uneven method may be a useful option of selective biliary cannulation in BE-ERCP for the patients with surgically altered gastrointestinal anatomy.
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• Severe Immune-Related Hepatitis Treated With Plasma Exchange., Hiroaki Kanemura, Hidetoshi Hayashi, Satoru Hagiwara, Tomoyuki Otani, Koji Haratani, Kimio Yonesaka, Akihiko Ito, Masatoshi Kudo, Kazuhiko Nakagawa, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 15(3), e39-e42, Mar. 2020 , Refereed
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• Recurrent abdominal pain caused by nephroptosis., Saki Yoshida, Mariko Matsumura, Kiyoshi Maekawa, Kosuke Minaga, Ken Kamata, Masahiro Nozawa, Tomohiro Watanabe, Masatoshi Kudo, Clinical journal of gastroenterology, Clinical journal of gastroenterology, Feb. 28 2020 , Refereed
  Summary:Nephroptosis is a benign disorder defined as a significant descent of the affected kidney as the patient moves from supine to erect. Patients with nephroptosis sometimes manifest symptoms including abdominal pain, back pain, nausea and hematuria, while the majority of those are asymptomatic. Downward migration of the affected kidney induced by a postural change from the supine to the upright position underlies the pathophysiology of nephroptosis. The diagnosis of nephroptosis is difficult since routine imaging examinations are conducted in the supine position alone. Here, we report a case presenting recurrent abdominal pain due to unknown causes. This patient was successfully diagnosed as nephroptosis by ultrasonography and drip infusion pyelography, both of which were performed in both supine and upright positions. This case report strongly suggests that we need to take into consideration a possibility of nephroptosis when we encounter with patients complaining abdominal and/or back pain due to unknown causes.
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• Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial., Masatoshi Kudo, Takuji Okusaka, Kenta Motomura, Izumi Ohno, Manabu Morimoto, Satoru Seo, Yoshiyuki Wada, Shinpei Sato, Tatsuya Yamashita, Masayuki Furukawa, Takeshi Aramaki, Seijin Nadano, Kazuyoshi Ohkawa, Hirofumi Fujii, Toshihiro Kudo, Junji Furuse, Hiroki Takai, Gosuke Homma, Reigetsu Yoshikawa, Andrew X Zhu, Journal of gastroenterology, Journal of gastroenterology, Feb. 27 2020 , Refereed
  Summary:BACKGROUND: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.
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• Utility and Safety of a Novel Fully Covered Metal Stent in Unresectable Distal Malignant Biliary Obstruction., Kentaro Yamao, Mamoru Takenaka, Takeshi Ogura, Hiroaki Hashimoto, Hisakazu Matsumoto, Masashi Yamamoto, Tsukasa Ikeura, Akira Kurita, Zhao Liang Li, Hideyuki Shiomi, Yasutaka Chiba, Masatoshi Kudo, Tsuyoshi Sanuki, Digestive diseases and sciences, Digestive diseases and sciences, Feb. 08 2020 , Refereed
  Summary:BACKGROUND: Self-expandable metal stents (SEMSs) are widely used in patients with distal malignant biliary obstruction. A SEMS that can avoid occlusion as much as possible is desirable. AIMS: The aim of this multicenter single-arm prospective study was to assess the clinical effectiveness and safety of a novel fully covered braided SEMS. METHODS: We enrolled consecutive patients with distal malignant biliary obstruction between February 2016 and November 2017 at ten tertiary-care medical centers. RESULTS: We included 79 patients with a median age of 76 years; 47 (59.5%) patients were men. The technical and clinical success rate was 98.7% and 93.6%, respectively. Recurrent biliary obstruction occurred in 14 patients (17.9%); stent ingrowth, overgrowth, migration, and other occurred in five (6.4%), four (5.1%), four (5.1%), and one (1.3%) patients, respectively. All reinterventions in patients with recurrent biliary obstruction were successful via the transpapillary approach. Adverse events occurred in 15 patients (19.2%); cholangitis, pancreatitis, and others occurred in ten (12.8%), three (3.8%), and two (2.6%) patients, respectively. The stent patency probability at 6 months was 48.5%. Median time to stent patency was 171 days, median time to recurrent biliary obstruction was 536 days, and median survival time was 195 days. CONCLUSIONS: We confirmed the utility and safety of a novel fully covered braided SEMS with low axial force and high radial force in patients with malignance biliary obstruction. This novel SEMS is recommended in patients with distal malignant biliary obstruction.
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• Effect of surgical margin width after R0 resection for intrahepatic cholangiocarcinoma: A nationwide survey of the Liver Cancer Study Group of Japan., Yukihiro Watanabe, Yutaka Matsuyama, Namiki Izumi, Shoji Kubo, Norihiro Kokudo, Michiie Sakamoto, Shuichiro Shiina, Tadatoshi Takayama, Osamu Nakashima, Masatoshi Kudo, Surgery, Surgery, Feb. 07 2020 , Refereed
  Summary:BACKGROUND: Data are inconsistent regarding the effects of a wide surgical margin for intrahepatic cholangiocarcinoma on recurrence-free survival and overall survival. This study was performed to investigate the effect of surgical margin width in patients undergoing R0 resection for intrahepatic cholangiocarcinoma, using a nationwide database in Japan. METHODS: In total, 635 patients with intrahepatic cholangiocarcinoma who were treated by an R0 resection from 2000 to 2007 were identified from the database of a Japanese nationwide survey. Patients were divided into quartiles of the surgical margin width as follows: marginal (<1 mm), narrow (1-4 mm), intermediate (5-9 mm), and wide groups (≥10 mm). Multivariable Cox regression models for recurrence-free survival and overall survival were constructed with adjustment for preoperative and postoperative clinicopathologic factors. RESULTS: Compared with the marginal group, the risk-adjusted hazard ratios (95% confidence intervals) in the narrow, intermediate, and wide groups for recurrence-free survival were 0.92 (0.62-1.37), 0.91 (0.61-1.37), and 0.81 (0.56-1.17), and those for overall survival were 0.79 (0.51-1.24), 0.93 (0.59-1.47), and 0.70 (0.46-1.08), respectively. In 398 patients without lymph node metastasis, the hazard ratios for overall survival were 0.62 (0.34-1.11), 0.63 (0.34-1.17), and 0.51 (0.29-0.90), and those of mass-forming type intrahepatic cholangiocarcinoma were 0.48 (0.21-1.08), 0.43 (0.19-0.96), and 0.40 (0.19-0.82), respectively. CONCLUSION: Surgical margin width appears to have a limited effect on the prognosis of intrahepatic cholangiocarcinoma except in patients without lymph node metastasis, where a wide surgical margin is associated with favorable outcomes. This survival benefit of a wide surgical margin is especially apparent for the mass-forming type intrahepatic cholangiocarcinoma.
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• Endoscopic sclerotherapy under balloon-assisted enteroscopy for hemorrhagic jejunal varices after choledocho-jejunostomy., Kota Takashima, Shigenaga Matsui, Yoriaki Komeda, Tomoyuki Nagai, Sakurai Toshiharu, Hiroshi Kashida, Masatoshi Kudo, Endoscopy, Endoscopy, 52(2), E41-E42, Feb. 2020 , Refereed
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• Requirement of Additional Surgery after Non-Curative Endoscopic Submucosal Dissection for Early Colorectal Cancer., Yoriaki Komeda, Tomohiro Watanabe, Masatoshi Kudo, Journal of investigative surgery : the official journal of the Academy of Surgical Research, Journal of investigative surgery : the official journal of the Academy of Surgical Research, 1 - 2, Jan. 30 2020 , Refereed
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• Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis., Kosuke Minaga, Tomohiro Watanabe, Yasuyuki Arai, Masahiro Shiokawa, Akane Hara, Tomoe Yoshikawa, Ken Kamata, Kouhei Yamashita, Masatoshi Kudo, Journal of gastroenterology, Journal of gastroenterology, Jan. 20 2020 , Refereed
  Summary:BACKGROUND: Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified. METHODS: Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients. RESULTS: IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP. CONCLUSIONS: These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
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• Navigator-triggered and breath-hold 3D MRCP using compressed sensing: image quality and method selection factor assessment., Daisuke Morimoto, Tomoko Hyodo, Ken Kamata, Tomoya Kadoba, Makoto Itoh, Hiroyuki Fukushima, Yasutaka Chiba, Mamoru Takenaka, Tomohiro Mochizuki, Yu Ueda, Keizou Miyagoshi, Masatoshi Kudo, Kazunari Ishii, Abdominal radiology (New York), Abdominal radiology (New York), Jan. 10 2020 , Refereed
  Summary:PURPOSE: To examine whether MRCP using a combination of compressed sensing and sensitivity encoding with navigator-triggered and breath-hold techniques (NT C-SENSE and BH C-SENSE, respectively) have comparable image quality to that of navigator-triggered MRCP using only sensitivity encoding (NT SENSE) at 1.5-T. METHODS: Fifty-one participants were enrolled in this prospective study between July and October 2018 and underwent the three 3D MRCP sequences each. The acquisition time and relative duct-to-periductal contrast ratios (RC values) of each bile duct segment were obtained. Visualization of the bile and main pancreatic ducts, background suppression, artifacts, and overall image quality were scored on 5-point scales. Mean and median differences in RC values and qualitative scores of NT C-SENSE and BH C-SENSE relative to NT SENSE were calculated with 95% confidence intervals (CIs). RESULTS: Acquisition time of NT SENSE, NT C-SENSE, and BH C-SENSE were 348, 143 (mean for both), and 18 s (for all participants), respectively. The RC value of each bile duct segment was inferior, but the lower limits of the 95% CIs of the mean differences were ≥ - 0.10, for both NT C-SENSE and BH C-SENSE. The visualization score of the intrahepatic duct in BH C-SENSE was inferior to that in NT SENSE (lower 95% CI limit, - 1.5). In both NT C-SENSE and BH C-SENSE, the 95% CIs of the median differences in the other qualitative scores were from - 1.0 to 0.0. CONCLUSION: NT C-SENSE and BH C-SENSE have comparable image quality to NT SENSE at 1.5-T.
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• Navigator-triggered and breath-hold 3D MRCP using compressed sensing: image quality and method selection factor assessment., Daisuke Morimoto, Tomoko Hyodo, Ken Kamata, Tomoya Kadoba, Makoto Itoh, Hiroyuki Fukushima, Yasutaka Chiba, Mamoru Takenaka, Tomohiro Mochizuki, Yu Ueda, Keizou Miyagoshi, Masatoshi Kudo, Kazunari Ishii, Abdominal radiology (New York), Abdominal radiology (New York), [Epub ahead of print], Jan. 10 2020 , Refereed
  Summary:PURPOSE: To examine whether MRCP using a combination of compressed sensing and sensitivity encoding with navigator-triggered and breath-hold techniques (NT C-SENSE and BH C-SENSE, respectively) have comparable image quality to that of navigator-triggered MRCP using only sensitivity encoding (NT SENSE) at 1.5-T. METHODS: Fifty-one participants were enrolled in this prospective study between July and October 2018 and underwent the three 3D MRCP sequences each. The acquisition time and relative duct-to-periductal contrast ratios (RC values) of each bile duct segment were obtained. Visualization of the bile and main pancreatic ducts, background suppression, artifacts, and overall image quality were scored on 5-point scales. Mean and median differences in RC values and qualitative scores of NT C-SENSE and BH C-SENSE relative to NT SENSE were calculated with 95% confidence intervals (CIs). RESULTS: Acquisition time of NT SENSE, NT C-SENSE, and BH C-SENSE were 348, 143 (mean for both), and 18 s (for all participants), respectively. The RC value of each bile duct segment was inferior, but the lower limits of the 95% CIs of the mean differences were ≥ - 0.10, for both NT C-SENSE and BH C-SENSE. The visualization score of the intrahepatic duct in BH C-SENSE was inferior to that in NT SENSE (lower 95% CI limit, - 1.5). In both NT C-SENSE and BH C-SENSE, the 95% CIs of the median differences in the other qualitative scores were from - 1.0 to 0.0. CONCLUSION: NT C-SENSE and BH C-SENSE have comparable image quality to NT SENSE at 1.5-T.
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• Possible involvement of autophagy in esophageal ulcers in anorexia nervosa., Sho Masaki, Tomohiro Watanabe, Kosuke Minaga, Ken Kamata, Yoriaki Komeda, Masatomo Kimura, Masatoshi Kudo, Clinical journal of gastroenterology, Clinical journal of gastroenterology, Jan. 03 2020 , Refereed
  Summary:Although patients with anorexia nervosa (AN) present with various gastrointestinal disorders, little has been understood regarding the incidence and pathophysiology of gastrointestinal ulcers related to AN. A 20-year-old woman with a past history of AN was hospitalized for further examination of dysphagia and chest pain. Her nutritional status was very poor as evidenced by very low body mass index. Esophagogastroduodenoscopy detected longitudinal and geographical ulcers in the entire circumference of the cervical and upper esophagus. Enhanced expression of autophagy-related proteins, LC3B and p62, was seen in the esophageal epithelium surrounding the active ulcers. Expression of these autophagy markers disappeared from the esophageal epithelium soon after the nutritional rehabilitation. Given the fact that starvation and malnutrition are potent inducers for autophagy, these findings suggest that autophagy might be involved in the development of gastrointestinal ulcers in patients with AN.
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• Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan., Masatoshi Kudo, Namiki Izumi, Shoji Kubo, Norihiro Kokudo, Michiie Sakamoto, Shuichiro Shiina, Ryosuke Tateishi, Osamu Nakashima, Takamichi Murakami, Yutaka Matsuyama, Arata Takahashi, Hiroaki Miyata, Tadatoshi Takayama, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 50(1), 15 - 46, Jan. 2020 , Refereed
  Summary:In the 20th Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 21 075 new patients and 40 769 previously followed patients were compiled from 544 institutions over a 2-year period from 1 January 2008 to 31 December 2009. Compared with the previous 19th survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, included more female patients, included more patients with non-B non-C HCC, had smaller tumor diameters and more frequently received radiofrequency ablation as local ablation therapy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and by background characteristics for patients newly registered between 1998 and 2009 whose final outcome was survival or death. Cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, and Child-Pugh grade) and by treatment types (hepatectomy, local ablation therapy, and transcatheter arterial chemoembolization). Cumulative survival rates and median overall survival in patients treated by resection, transcatheter arterial chemoembolization, and local ablation therapy were calculated. The same values were also calculated by the registration date by dividing patients newly registered between 1978 and 2009 into four time period groups . The results of the analysis show that the prognosis of HCC is improving dramatically. It is expected that the data obtained from this nationwide follow-up survey will contribute to advancing clinical research, including the design of clinical trials, as well as the treatment strategy of primary liver cancer in the clinical practice setting.
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• Effects of Subsequent Systemic Anticancer Medication Following First-Line Lenvatinib: A Post Hoc Responder Analysis from the Phase 3 REFLECT Study in Unresectable Hepatocellular Carcinoma., Angel Alsina, Masatoshi Kudo, Arndt Vogel, Ann-Lii Cheng, Won Young Tak, Baek-Yeol Ryoo, Thomas R Jeffry Evans, Carlos López López, Bruno Daniele, Soamnauth Misir, Min Ren, Namiki Izumi, Shukui Qin, Richard S Finn, Liver cancer, Liver cancer, 9(1), 93 - 104, Jan. 2020 , Refereed
  Summary:Introduction: Understanding the relationship between subsequent-line therapies and overall survival (OS) is important for maximizing OS for patients with hepatocellular carcinoma. Objective: In this post hoc analysis, we investigated OS in lenvatinib- and sorafenib-treated patients from the REFLECT study, who then received subsequent anticancer medication during the survival follow-up period. Methods: The follow-up period commenced at the first off-treatment visit after stopping the study medication and continued until study termination, withdrawal of consent, or death. OS and objective response rate were calculated for patients who did or did not receive poststudy anticancer medication for both treatment arms, as well as for the overall cohort. We investigated the subset of patients who responded to first-line treatment and subsequently received anticancer medication. Results: The OS for patients initially randomized to first-line lenvatinib (versus first-line sorafenib) and who then received any subsequent anticancer medication was 20.8 vs. 17.0 months (hazard ratio [HR] 0.87; 95% CI 0.67-1.14). The OS for patients who initially received first-line lenvatinib (versus first-line sorafenib) and who did not receive any subsequent anticancer medication was 11.5 vs. 9.1 months (HR 0.90; 95% CI 0.75-1.09). Responders to first-line lenvatinib who received subsequent medication had a median OS of 25.7 months (95% CI 18.5-34.6); responders to first line-sorafenib who received subsequent medication had a median OS of 22.3 months (95% CI 14.6-not evaluable). Conclusions: In this post hoc analysis of all patients in the REFLECT study who received subsequent anticancer medication, OS was increased compared with patients who did not receive any subsequent anticancer medication. In a subset analysis of responders who had received subsequent anticancer medication, use of first-line lenvatinib led to a slightly longer median OS; more research is needed on the benefits of using first-line lenvatinib compared with sorafenib.
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• Post-Progression Treatment Eligibility of Unresectable Hepatocellular Carcinoma Patients Treated with Lenvatinib., Atsushi Hiraoka, Takashi Kumada, Shinya Fukunishi, Masanori Atsukawa, Masashi Hirooka, Kunihiko Tsuji, Toru Ishikawa, Koichi Takaguchi, Kazuya Kariyama, Ei Itobayashi, Kazuto Tajiri, Noritomo Shimada, Hiroshi Shibata, Hironori Ochi, Toshifumi Tada, Hidenori Toyoda, Keisuke Yokohama, Kazuhiro Nouso, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Korenobu Hayama, Taeang Arai, Michitaka Imai, Kouji Joko, Yohei Koizumi, Yoichi Hiasa, Kojiro Michitaka, Masatoshi Kudo, Liver cancer, Liver cancer, 9(1), 73 - 83, Jan. 2020 , Refereed
  Summary:Background/Aim: Post-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN). Materials/Methods: From March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated. Results: The median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577-4.129; p < 0.001). Conclusion: Introduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤-2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.
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• Nutritional Index as Prognostic Indicator in Patients Receiving Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma., Atsushi Hiraoka, Takashi Kumada, Toshifumi Tada, Shinya Fukunishi, Masanori Atsukawa, Masashi Hirooka, Kunihiko Tsuji, Toru Ishikawa, Koichi Takaguchi, Kazuya Kariyama, Ei Itobayashi, Kazuto Tajiri, Noritomo Shimada, Hiroshi Shibata, Hironori Ochi, Kazuhito Kawata, Hidenori Toyoda, Hideko Ohama, Akemi Tsutsui, Norio Itokawa, Korenobu Hayama, Taeang Arai, Michitaka Imai, Shinichiro Nakamura, Kojiro Michitaka, Yoichi Hiasa, Masatoshi Kudo, Oncology, Oncology, 98(5), 295 - 302, 2020 , Refereed
  Summary:BACKGROUND/AIM: Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the prognostic/predictive value of nutritional status using Onodera's prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib. METHODS: Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36). RESULTS: The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were "not reached" (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = -0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve [AUC] = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571. CONCLUSIONS: OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.
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• The Efficacy of Sonazoid-enhanced Ultrasonography in Decision-making for Liver Abscess Treatment., Masahiro Morita, Chikara Ogawa, Akina Omura, Teruyo Noda, Atsushi Kubo, Toshihiro Matsunaka, Hiroyuki Tamaki, Mitsushige Shibatoge, Hiroshi Seno, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 59(4), 471 - 477, 2020 , Refereed
  Summary:Objective The usefulness of contrast-enhanced ultrasonography (CEUS) for making decisions in the treatment of liver abscess is unknown. Methods We evaluated the internal blood flow in the arterial-predominant phase by CEUS using Sonazoid^® in 21 patients. The stain area rate was evaluated in maximum parting plane of abscess in CEUS. Patients were divided into two groups: the vascular phase enhancement (VE) group, in which ≥50% of the abscess cavity was enhanced (12 patients), and the vascular phase non-enhancement (VNE) group, in which <50% of the abscess cavity was enhanced (9 patients). The rate of patients who were cured by conservative treatment alone was examined in both groups. The defect rate of all liver abscesses in the post-vascular phase was also evaluated. Results In the VE group, improvement by conservative treatment alone was obtained in 11 out of 12 patients (91.7%), while in the VNE group, improvement by conservative treatment alone was obtained in only 1 out of 9 patients (11.1%), a significant difference (p<0.001). In the VE group, one patient did not improve with conservative treatment alone because the abscess ruptured near the liver surface. In the VE group, the abscess size was smaller than in the VNE group. By examining the defect rate in the post-vascular phase, it was found that 16 out of 21 patients (76.2%) showed 71% or more defects. Conclusion The enhancement rate in the arterial-predominant phase of CEUS was considered useful for determining the treatment approach for liver abscess.
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• Radiofrequency ablation for hepatocellular carcinoma: Clinical value of ultrasound-ultrasound overlay fusion for optimal ablation and local controllability., Yasunori Minami, Tomohiro Minami, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 50(1), 67 - 74, Jan. 2020 , Refereed
  Summary:AIM: To retrospectively investigate the potential benefit of ultrasound-ultrasound (US-US) overlay fusion guidance for local controllability of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). METHODS: Patients (n = 101) with 121 HCCs (mean ± SD, 1.8 ± 0.7 cm) who underwent RFA guided by US-US overlay fusion were included in the retrospective study. By overlaying pre/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. The ablative margin could thereby be evaluated three-dimensionally during the RFA procedure. As a control group, all 325 patients with 453 HCCs who underwent conventional RFA during the same study period were selected. RESULTS: The total number of RF needle insertions per tumor for ablation was significantly more in the US overlay fusion group (mean 1.9 vs. 1.2; P < 0.01). The technical success rates of ablation after a single session were 100% (101/101) and 96.6% (314/325) for the US overlay fusion group and the control group, respectively. For early assessment of RFA response, 5-mm safety margins were achieved in 89.3% (108/121) and 47.0% (213/453) of nodules in the US overlay fusion group and the control group, respectively (P < 0.01). During the follow-up period (median 19 months), the 2-year local tumor progression rates were 0.8% (1/121) and 6.0% (27/453) in the US overlay fusion group and the control group, respectively (P = 0.022, log-rank test). CONCLUSIONS: US-US overlay fusion guidance can be highly effective for safety margin achievement in RFA for HCC, providing a lower risk of local tumor progression.
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• Revisionary antireflux metal stent placement for stent occlusion after endoscopic ultrasound-guided hepaticojejunostomy., Kosuke Minaga, Mamoru Takenaka, Ayana Okamoto, Shunsuke Omoto, Ken Kamata, Kentaro Yamao, Masatoshi Kudo, Endoscopy, Endoscopy, Nov. 15 2019 , Refereed
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• Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells., Ken Kamata, Tomohiro Watanabe, Kosuke Minaga, Akane Hara, Tomoe Yoshikawa, Ayana Okamoto, Kentaro Yamao, Mamoru Takenaka, Ah-Mee Park, Masatoshi Kudo, International immunology, International immunology, 31(12), 795 - 809, Nov. 08 2019 , Refereed
  Summary:Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
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• Scientific Rationale for Combination Immunotherapy of Hepatocellular Carcinoma with Anti-PD-1/PD-L1 and Anti-CTLA-4 Antibodies., Masatoshi Kudo, Liver cancer, Liver cancer, 8(6), 413 - 426, Nov. 2019 , Refereed
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• Switching from entecavir to tenofovir alafenamide versus maintaining entecavir for chronic hepatitis B., Satoru Hagiwara, Naoshi Nishida, Hiroshi Ida, Kazuomi Ueshima, Yasunori Minami, Masahiro Takita, Yoriaki Komeda, Masatoshi Kudo, Journal of medical virology, Journal of medical virology, 91(10), 1804 - 1810, Oct. 2019 , Refereed
  Summary:Tenofovir alafenamide (TAF) is a newly developed prodrug of tenofovir (TFV). We divided 48 chronic hepatitis B patients who had taken entecavir (ETV) for ≥2 years into two groups: the ETV continuation (n = 24) and the TAF switching (n = 24) groups, and compared the antiviral effects and safety until 48 weeks after the start of the study. There were no significant differences in the alterations in the serum levels of HBs antigen (HBsAg) level between the ETV continuation and the TAF switching groups at 24 or 48 weeks. We also examined the effect of baseline HBsAg level on the decrease of HBsAg during the treatment; in the TAF switching group, the decrease of HBsAg level at 48 weeks was more significant in patients with low baseline HBsAg (<800 IU/mL) than those with high baseline HBsAg ( >800 IU/mL) (change of HBsAg; - 0.029 vs - 0.132 for high and low baseline HBsAg, respectively, P = .007). Also, the effect on renal function was found to be comparable between the TAF switch group and the ETV continuation group. In this study, switching from ETV to TAF may represent higher efficacy for a decrease of HBsAg than a continuation of ETV among the patients with low baseline HBsAg level.
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• Prediction of Prognosis of Intermediate-Stage HCC Patients: Validation of the Tumor Marker Score in a Nationwide Database in Japan., Atsushi Hiraoka, Kojiro Michitaka, Takashi Kumada, Namiki Izumi, Masumi Kadoya, Norihiro Kokudo, Shoji Kubo, Yutaka Matsuyama, Osamu Nakashima, Michiie Sakamoto, Tadatoshi Takayama, Takashi Kokudo, Kosuke Kashiwabara, Susumu Eguchi, Tatsuya Yamashita, Masatoshi Kudo, Liver cancer, Liver cancer, 8(5), 403 - 411, Oct. 2019 , Refereed
  Summary:Background/Aim: Adequate assessment of transcatheter arterial chemoembolization (TACE)-refractory status has become more important for switching treatment in intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) patients treated with TACE. The usefulness of a previously proposed tumor marker score for predicting prognosis of BCLC-B HCC patients treated with TACE was investigated. Methods: Using a nationwide database, we examined the records of 1,306 naïve BCLC-B HCC with Child-Pugh A who were treated from 2001 to 2007, after excluding those with missing data (hepatic function or tumor markers) or cases with a single large tumor. Alpha-fetoprotein (AFP) ≥100 ng/mL, fucosylated AFP (AFP-L3) ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL were markers used to define positive cases. The number of positive tumor markers was used as a prognostic score, and its predictive value was evaluated in a retrospective manner. Results: Median survival time became shorter along with increased score (0, 1, ≥2 = 4.8, 3.8, 3.2 years, respectively; p < 0.01). Tumor marker score (≥2; hazard ratio [HR] 1.675, 95% confidence interval [CI] 1.372-2.044, p < 0.001), serum levels of albumin (≥3.5 g/dL; HR 0.726, 95% CI 0.528-0.997, p = 0.048), and up-to-7 criteria (HR 1.673, 95% CI 1.400-2.000, p < 0.001) were significant prognostic factors for death in the Cox hazard multivariate analysis. Conclusion: Tumor marker score had a useful predictive prognostic value in BCLC-B HCC treated with TACE. Especially in patients with a tumor marker score of 2 or greater, a poor therapeutic response should be expected, and appropriate judgement of TACE-refractory status is necessary.
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• Contrast-enhanced harmonic endoscopic ultrasonography for evaluating the response to chemotherapy in pancreatic cancer., Hidekazu Tanaka, Ken Kamata, Mamoru Takenaka, Tomoe Yoshikawa, Rei Ishikawa, Ayana Okamoto, Tomohiro Yamazaki, Atsushi Nakai, Shunsuke Omoto, Kosuke Minaga, Kentaro Yamao, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Yasutaka Chiba, Masayuki Kitano, Masatoshi Kudo, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 51(8), 1130 - 1134, Aug. 2019 , Refereed
  Summary:BACKGROUND AND AIMS: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the diagnosis of pancreatic cancer (PC). Here, we examined the usefulness of CH-EUS for evaluating therapeutic responses in PC. METHODS: The study included 23 patients with PC who received chemotherapy. Patients underwent contrast-enhanced computed tomography (CE-CT) and CH-EUS before chemotherapy and at the time of evaluation of the therapeutic response. Patients with a ≧50% reduction in serum carbohydrate antigen 19-9 levels after chemotherapy were defined as "super responders". The incidence of an avascular area in the tumor on CH-EUS after chemotherapy was compared between "super responders" and non-super responders. RESULTS: Nine patients were included in the "super responders" group.Tumor reduction rates did not differ significantly between CE-CT and CH-EUS in the "super responders". The appearance of an avascular area was detected in 7 of 9 super responders (77.8%) and in 4 of 14 non-super responders (28.6%), and the difference was significant (P = 0.036). The mean survival time of patients with an avascular area after chemotherapy was longer than that of without an avascular area. CONCLUSIONS: Detection of avascular areas by CH-EUS after chemotherapy may predict long-term survival of patients with PC.
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• Paradoxical ulcerative colitis during treatment with secukinumab for psoriasis., Shusuke Uchida, Naoki Oiso, Yoriaki Komeda, Masatoshi Kudo, Akira Kawada, European journal of dermatology : EJD, European journal of dermatology : EJD, 29(4), 444 - 445, Aug. 01 2019 , Refereed
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• Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study., Masatoshi Kudo, Kazuomi Ueshima, Stephan Chan, Tomohiro Minami, Hirokazu Chishina, Tomoko Aoki, Masahiro Takita, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Masahiro Morita, Chikara Ogawa, Yoshiyuki Wada, Masafumi Ikeda, Hiroshi Ishii, Namiki Izumi, Naoshi Nishida, Cancers, Cancers, 11(8), Jul. 31 2019 , Refereed
  Summary:Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in the lenvatinib group (p = 0.254) and -2.66 to -2.09 in the cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.
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• Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study., Kentaro Yamao, Mamoru Takenaka, Tomoe Yoshikawa, Rei Ishikawa, Ayana Okamoto, Tomohiro Yamazaki, Atsushi Nakai, Shunsuke Omoto, Ken Kamata, Kosuke Minaga, Satoru Hagiwara, Toshiharu Sakurai, Naoshi Nishida, Yasutaka Chiba, Tomohiro Watanabe, Masatoshi Kudo, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 58(14), 1993 - 2002, Jul. 15 2019 , Refereed
  Summary:Objective Although modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. Methods Advanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. Results Among 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. Conclusion The scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles.
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• Usefulness of Ustekinumab for Treating a Case of Myelodysplastic Syndrome-associated Inflammatory Bowel Disease., Masashi Kono, Toshiharu Sakurai, Kazuki Okamoto, Tomoyuki Nagai, Yoriaki Komeda, Hiroshi Kashida, Kosuke Minaga, Ken Kamata, Mamoru Takenaka, Satoru Hagiwara, Tomohiro Watanabe, Naoshi Nishida, Eisuke Enoki, Hiroaki Inoue, Itaru Matsumura, Masatoshi Kudo, Internal medicine (Tokyo, Japan), Internal medicine (Tokyo, Japan), 58(14), 2029 - 2033, Jul. 15 2019 , Refereed
  Summary:Autoimmune diseases including inflammatory bowel disease (IBD) occur in association with myelodysplastic syndrome (MDS). MDS-associated IBD frequently demonstrates a complicated course. We herein report the first case with MDS-associated IBD that was successfully treated with ustekinumab (UST), an anti-interleukin (IL) 12/23p40 monoclonal antibody. A 63-year-old man with a 7-year history of MDS was referred for examination of diarrhea, abdominal pain and fever. A blood examination revealed a marked elevation of C-reactive protein. Colonoscopy showed multiple ulcers in the terminal ileum. He was resistant to anti-tumor necrosis factor (TNF)-α antibody and azacitidine. Subsequently, UST treatment reduced colonic IL-17 and IL-6 expression and the patient currently maintains a state of remission.
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• Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study., Kazuomi Ueshima, Naoshi Nishida, Satoru Hagiwara, Tomoko Aoki, Tomohiro Minami, Hirokazu Chishina, Masahiro Takita, Yasunori Minami, Hiroshi Ida, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Masahiro Morita, Chikara Ogawa, Atsushi Hiraoka, Philip Johnson, Masatoshi Kudo, Cancers, Cancers, 11(7), Jul. 07 2019 , Refereed
  Summary:BACKGROUND: This study investigated the impact of baseline liver function according to the Child-Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. METHODS: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child-Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child-Pugh score 5 and ALBI grade 1 (group 1), (2) Child-Pugh score 5 and ALBI grade 2 (group 2), (3) Child-Pugh score 6 (group 3), and (4) Child-Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child-Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.
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• Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency., Naosuke Yokomichi, Naoshi Nishida, Yuzo Umeda, Fumitaka Taniguchi, Kazuya Yasui, Toshiaki Toshima, Yoshiko Mori, Akihiro Nyuya, Takehiro Tanaka, Takeshi Yamada, Takahito Yagi, Toshiyoshi Fujiwara, Yoshiyuki Yamaguchi, Ajay Goel, Masatoshi Kudo, Takeshi Nagasaka, Liver cancer, Liver cancer, 8(4), 239 - 254, Jul. 2019 , Refereed
  Summary:Objective: Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. Patients and Methods: In vitro, KRT19 promoter methylation was analyzed and 5-aza-2'-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). Results: KRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2'-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively). Conclusions: K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.
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• Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions-Multicenter analysis., Atsushi Hiraoka, Takashi Kumada, Masanori Atsukawa, Masashi Hirooka, Kunihiko Tsuji, Toru Ishikawa, Koichi Takaguchi, Kazuya Kariyama, Ei Itobayashi, Kazuto Tajiri, Noritomo Shimada, Hiroshi Shibata, Hironori Ochi, Toshifumi Tada, Hidenori Toyoda, Kazuhiro Nouso, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Korenobu Hayama, Michitaka Imai, Kouji Joko, Yohei Koizumi, Yoichi Hiasa, Kojiro Michitaka, Masatoshi Kudo, Cancer medicine, Cancer medicine, 8(8), 3719 - 3728, Jul. 2019 , Refereed
  Summary:BACKGROUND/AIM: We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u-HCC) by investigating real-world clinical features of patients. MATERIALS/METHODS: One hundred fifty two u-HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child-Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin-bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively. RESULTS: Overall-response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine-kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649-13.02, P = 0.004) in Cox-hazard multivariate analysis. In patients with Child-Pugh A, c-index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2 , P < 0.001), while patients with a hand-foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007). CONCLUSION: Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.
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• Intracystic papillary neoplasm preoperatively diagnosed by high-quality cytology derived from endoscopic nasogallbladder drainage., Akane Hara, Ken Kamata, Mamoru Takenaka, Takaaki Chikugo, Masatoshi Kudo, Gastrointestinal endoscopy, Gastrointestinal endoscopy, 89(6), 1257 - 1259, Jun. 2019 , Refereed
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• Validation of Modified ALBI Grade for More Detailed Assessment of Hepatic Function in Hepatocellular Carcinoma Patients: A Multicenter Analysis., Atsushi Hiraoka, Takashi Kumada, Kunihiko Tsuji, Koichi Takaguchi, Ei Itobayashi, Kazuya Kariyama, Hironori Ochi, Kazuto Tajiri, Masashi Hirooka, Noritomo Shimada, Toru Ishikawa, Yoshihiko Tachi, Toshifumi Tada, Hidenori Toyoda, Kazuhiro Nouso, Kouji Joko, Yoichi Hiasa, Kojiro Michitaka, Masatoshi Kudo, Liver cancer, Liver cancer, 8(2), 121 - 129, Mar. 2019 , Refereed
  Summary:Background/Aim: The frequency of hepatocellular carcinoma (HCC) in patients with good hepatic reserve function has been increasing in Japan along with the progression of antiviral therapies and aging of the society. We evaluated the usefulness of modified albumin-bilirubin (ALBI) grade as a tool for assessment of hepatic reserve function. Materials/Methods: We enrolled 6,649 naïve HCC patients treated from 2000 to 2017 and divided them into training (Ehime Prefecture group: E group, n = 2,357) and validation (validation group: V group, n = 4,292) cohorts. Child-Pugh classification and ALBI and modified ALBI (mALBI) grading were compared using with Japan Integrated Staging (JIS), ALBI-TNM (ALBI-T), and mALBI-T scores, which were calculated based on TNM stage and each assessment tool, retrospectively. Results: In the E group, Akaike's Information Criterion (AIC) and c-index values for mALBI-T (13,725.2/0.744) were better as compared to those of ALBI-T (13,772.6/0.733) and JIS score (13,874.7/0.720), with similar results observed in the V group (mALBI-T: 27,727.4/0.760; ALBI-T: 27,817.8/0.750; JIS: 27,807.5/0.748). Although there were some significant differences between the groups with regard to clinical background factors (age, etiology, tumor size, tumor number, treatment modalities), for all patients the AIC and c-index values of mALBI-T (45,327.1/0.755) were also better than those of ALBI-T (45,467.7/0.744) and JIS scores (45,555.8/0.739), indicating its superior stratification ability and prognostic predictive value in patients with HCC. Conclusion: The detailed stratification ability of mALBI grade for hepatic reserve function is suitable for the recent trend of HCC patients, while mALBI-T may provide a more accurate predictive value than existing total staging scoring systems.
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• Liver Resection for Multiple Hepatocellular Carcinomas: A Japanese Nationwide Survey., Yasuyuki Fukami, Yuji Kaneoka, Atsuyuki Maeda, Takashi Kumada, Junko Tanaka, Tomoyuki Akita, Shoji Kubo, Namiki Izumi, Masumi Kadoya, Michiie Sakamoto, Osamu Nakashima, Yutaka Matsuyama, Takashi Kokudo, Kiyoshi Hasegawa, Tatsuya Yamashita, Kosuke Kashiwabara, Tadatoshi Takayama, Norihiro Kokudo, Masatoshi Kudo, Annals of surgery, Annals of surgery, Jan. 16 2019 , Refereed
  Summary:OBJECTIVE: The aim of the study was to evaluate the survival benefits of liver resection (LR) compared with transarterial chemoembolization (TACE) for patients with multiple hepatocellular carcinomas (HCCs). BACKGROUND: Despite significant improvements in diagnostic imaging and the widespread application of screening programs, some patients with HCC continue to present with multiple tumors. The surgical indications for multiple HCCs remain controversial. METHODS: Among 77,268 patients with HCC reported in a Japanese nationwide survey, 27,164 patients had multiple HCCs. The exclusion criteria were Child-Pugh B/C, treatment other than LR and TACE, >3 tumors, and insufficient available data. Ultimately, 3246 patients (LR: n = 1944, TACE: n = 1302) were included. The survival benefit of LR for patients multiple HCCs was evaluated by using propensity score matching analysis. RESULTS: The study group of 2178 patients (LR: n = 1089, TACE: n = 1089) seemed to be well matched. The overall survival rate in the LR group was 60.0% at 5 years, which was higher than that in the TACE group (41.6%, P < 0.001). Among patients with a tumor size of 30 mm or more, LR showed a survival benefit over TACE at 5 years (53.0% vs 32.7%, P < 0.001). The multivariate analysis indicated that age, serum albumin level, serum alpha-fetoprotein (AFP) level, macrovascular invasion, tumor size, and TACE were independent predictors of poor prognosis in multiple HCCs. CONCLUSIONS: LR could offer better long-term survival than TACE for patients with multiple HCCs (up to 3 tumors). If patients have good liver function (Child-Pugh A), LR is recommended, even for those with multiple HCCs with tumor sizes of 30 mm or more.
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• New diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient on ultrasound B mode., Yohei Koizumi, Masashi Hirooka, Nobuharu Tamaki, Norihisa Yada, Osamu Nakashima, Namiki Izumi, Masatoshi Kudo, Yoichi Hiasa, PloS one, PloS one, 14(8), e0221548, 2019 , Refereed
  Summary:PURPOSE: We have developed a diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient (ATT) in ultrasound B mode imaging. A controlled attenuation parameter (CAP) by vibration-controlled transient elastography (VCTE) has also been used to evaluate hepatic steatosis. As that method uses ultrasound A mode, visualizing the liver in real time is difficult. We designed this clinical study to evaluate the diagnostic advantage of our technique using ATT compared to CAP. MATERIALS AND METHODS: The study group included 94 patients with chronic liver disease who had undergone both ATT and CAP assessment at the time of liver biopsy. The M-probe and XL-probe were used for CAP measurement. Data for ATT and CAP were compared as a function of the steatosis grade. RESULTS: The area under the receiver operating characteristic curve (AUC-ROCs) for ATT and PAC as a function of the steatosis grade were as follows: grade 1, 0.74 and 0.81; grade 2, 0.80 and 0.85; and grade 3, 0.96 and 0.98, respectively. CONCLUSION: The accuracy of steatosis grade diagnosis using ATT was the same as that using CAP, with no significant differences and with the added advantage of B mode ultrasound being more convenient and rapid, compared to A mode ultrasound, particularly for patients with subcutaneous fat thickness ≥2 cm.
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• Current status of radiation exposure to crystalline lens in ERCP (endoscopic retrograde cholangiopancreatography), Mamoru Takenaka, Makoto Hosono, Atsushi Nakai, Shunsuke Omoto, Kosuke Minaga, Ken Kamata, Kentaro Yamao, Shiro Hayashi, Tsutomu Nishida, Masatoshi Kudo, Journal of Japanese Society of Gastroenterology, Journal of Japanese Society of Gastroenterology, 116(12), 1053 - 1055, 2019 , Refereed
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• Novel quantitative assessment system of liver steatosis using a newly developed attenuation measurement method., Nobuharu Tamaki, Yohei Koizumi, Masashi Hirooka, Norihisa Yada, Hitomi Takada, Osamu Nakashima, Masatoshi Kudo, Yoichi Hiasa, Namiki Izumi, Hepatology research : the official journal of the Japan Society of Hepatology, Hepatology research : the official journal of the Japan Society of Hepatology, 48(10), 821 - 828, Sep. 2018 , Refereed
  Summary:AIM: The present study has developed and evaluated the effectiveness of a new echo attenuation measurement function combined with an ultrasonic diagnostic system for the accurate diagnosis of liver steatosis. METHODS: A multicenter prospective study involving patients with chronic hepatitis was carried out. All patients underwent liver biopsy, and attenuation coefficient (ATT) was measured on the same day. The fat area (%) of biopsy specimens was quantitatively evaluated. Correlations between ATT, steatosis grade, and fat area were evaluated. RESULTS: A total of 351 patients were enrolled in this study. The median values of fat area for steatosis grades S0, S1, S2, and S3 were 0.6%, 3.2%, 6.4%, and 15.5%, respectively. A significant correlation was found between fat area and steatosis grade (P < 0.001). Similarly, the median values of ATT for steatosis grades S0, S1, S2, and S3 were 0.55, 0.63, 0.69, and 0.85 dB/cm/MHz, respectively, and ATT increased with an increase in the steatosis grade (P < 0.001). Attenuation coefficient was significantly correlated with fat area (r = 0.50, P < 0.001). The area under the receiver operating characteristic curve corresponding to S ≥ 1, S ≥ 2, and S ≥ 3 were 0.79, 0.87, and 0.96, respectively. Similarly, the sensitivity and specificity of S ≥ 1, S ≥ 2, and S ≥ 3 were 72%, 82%, and 87% and 72%, 82%, and 89%, respectively. CONCLUSIONS: The newly developed ATT measurement for evaluation of liver steatosis was closely correlated with steatosis grade and automated quantification of fat area, and it provides clinically relevant information.
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• A novel biliary cannulation method for difficult cannulation cases using a unique, uneven, double-lumen cannula (Uneven method)., Takenaka M, Arisaka Y, Sakai A, Kobayashi T, Shiomi H, Masuda A, Kudo M, Endoscopy, Endoscopy, 50(8), E229 - E230, Jun. 2018 , Refereed
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• Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study., Masatoshi Kudo, Yoon-Koo Kang, Joong-Won Park, Shukui Qin, Yoshitaka Inaba, Eric Assenat, Yoshiko Umeyama, Maria José Lechuga, Olga Valota, Yosuke Fujii, Jean-Francois Martini, J Andrew Williams, Shuntaro Obi, Liver cancer, Liver cancer, 7(2), 148 - 164, May 2018 , Refereed
  Summary:Background: An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. Methods: The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. Results: Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. Conclusions: Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.
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• Impact of avascular areas, as measured by contrast-enhanced harmonic EUS, on the accuracy of FNA for pancreatic adenocarcinoma, Ken Kamata, Mamoru Takenaka, Shunsuke Omoto, Takeshi Miyata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Toshiharu Sakurai, Naoshi Nishida, Takaaki Chikugo, Yasutaka Chiba, Ippei Matsumoto, Yoshifumi Takeyama, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 87(1), 158 - 163, Jan. 2018 , Refereed
  Summary:Background and Aims: EUS-guided FNA (EUS-FNA) is used for the diagnosis of pancreatic adenocarcinoma, but sometimes the method results in a false negative. Occasionally, an avascular area may be observed within the pancreatic adenocarcinoma tumor during contrast-enhanced harmonic EUS (CH-EUS). The aim of this study was to evaluate whether the diagnostic sensitivity of EUS-FNA for pancreatic adenocarcinoma was affected by the presence of avascularity on CH-EUS. Methods: Two hundred ninety-two patients with pancreatic adenocarcinoma who presented at Kindai University Hospital for EUS-FNA and CH-EUS between June 2009 and August 2013 were retrospectively evaluated. This was a single-center retrospective analysis of prospectively collected data held in a registry. The overall sensitivity of EUS-FNA for the diagnosis of pancreatic adenocarcinoma was calculated. The sensitivities of cytology, histology, and the combination of cytology and histology were also evaluated. These variables were individually evaluated according to the presence or absence of an avascular area on CH-EUS to assess whether the diagnostic sensitivity of EUS-FNA for pancreatic adenocarcinoma was related to the presence of an avascular area within the tumors. Results: The overall sensitivity of EUS-FNA was 90.8% (265/292). The sensitivities of EUS-FNA for lesions with and without an avascular area were 72.9% (35/48) and 94.3% (230/244), respectively, with the difference being statistically significant (P <.001). Conclusions: EUS-FNA has lower sensitivity for pancreatic adenocarcinoma with avascular areas on CH-EUS.
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• Electronic hydraulic lithotripsy by antegrade digital cholangioscopy through endoscopic ultrasound-guided hepaticojejunostomy, Yasuo Otsuka, Ken Kamata, Mamoru Takenaka, Kosuke Minaga, Hidekazu Tanaka, Masatoshi Kudo, ENDOSCOPY, ENDOSCOPY, 49(12), E316 - E318, Dec. 2017 , Refereed
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• Portal vein stenting for portal vein stenosis caused by bile duct cancer, Ken Kamata, Mamoru Takenaka, Masakatsu Tsurusaki, Masatoshi Kudo, DIGESTIVE AND LIVER DISEASE, DIGESTIVE AND LIVER DISEASE, 49(11), 1282 - 1282, Nov. 2017 , Refereed
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• Endoscopic ultrasound-guided choledochoduodenostomy with novel use of contrastenhanced harmonic imaging, Kosuke Minaga, Mamoru Takenaka, Ken Kamata, Takeshi Miyata, Kentaro Yamao, Hajime Imai, Masatoshi Kudo, ENDOSCOPY, ENDOSCOPY, 49(11), E281 - E282, Nov. 2017 , Refereed
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• Rescue EUS-guided intrahepatic biliary drainage for malignant hilar biliary stricture after failed transpapillary re-intervention, Kosuke Minaga, Mamoru Takenaka, Masayuki Kitano, Yasutaka Chiba, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Shunsuke Omoto, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES, SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES, 31(11), 4764 - 4772, Nov. 2017 , Refereed
  Summary:Treatment of unresectable malignant hilar biliary stricture (UMHBS) is challenging, especially after failure of repeated transpapillary endoscopic stenting. Endoscopic ultrasonography-guided intrahepatic biliary drainage (EUS-IBD) is a recent technique for intrahepatic biliary decompression, but indications for its use for complex hilar strictures have not been well studied. The aim of this study was to assess the feasibility and safety of EUS-IBD for UMHBS after failed transpapillary re-intervention. Retrospective analysis of all consecutive patients with UMHBS of Bismuth II grade or higher who, between December 2008 and May 2016, underwent EUS-IBD after failed repeated transpapillary interventions. The technical success, clinical success, and complication rates were evaluated. Factors associated with clinical ineffectiveness of EUS-IBD were explored. A total of 30 patients (19 women, median age 66 years [range 52-87]) underwent EUS-IBD for UMHBS during the study period. Hilar biliary stricture morphology was classified as Bismuth II, III, or IV in 5, 13, and 12 patients, respectively. The median number of preceding endoscopic interventions was 4 (range 2-14). EUS-IBD was required because the following procedures failed: duodenal scope insertion (n = 4), accessing the papilla after duodenal stent insertion (n = 5), or achieving desired intrahepatic biliary drainage (n = 21). Technical success with EUS-IBD was achieved in 29 of 30 patients (96.7%) and clinical success was attained in 22 of these 29 (75.9%). Mild peritonitis occurred in three of 30 (10%) and was managed conservatively. Stent dysfunction occurred in 23.3% (7/30). There was no procedure-related mortality. On multivariable analysis, Bismuth IV stricture predicted clinical ineffectiveness (odds ratio = 12.7, 95% CI 1.18-135.4, P = 0.035). EUS-IBD may be a feasible and effective rescue alternative with few major complications after failed transpapillary endoscopic re-intervention in patients with UMHBS, particularly for Bismuth II or III strictures.
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• Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma, Toshiharu Sakurai, Norihisa Yada, Satoru Hagiwara, Tadaaki Arizumi, Kosuke Minaga, Ken Kamata, Mamoru Takenaka, Yasunori Minami, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, CANCER SCIENCE, CANCER SCIENCE, 108(10), 1996 - 2003, Oct. 2017 , Refereed
  Summary:Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation-induced tumorigenesis in the colon. Although the invitro function of gankyrin is well known, its role invivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrin(f/f)) and gankyrin deletion both in liver parenchymal and non-parenchymal cells (Mx1-Cre;gankyrin(f/f)). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), mainly expressed in liver non-parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non-parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)-6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression-free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.
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• Nucleotide-binding oligomerization domain 1 and gastrointestinal disorders, Tomohiro Watanabe, Naoki Asano, Masatoshi Kudo, Warren Strober, PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES, PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES, 93(8), 578 - 599, Oct. 2017 , Refereed
  Summary:Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular sensor that detects small peptides derived from the cell wall component of intestinal microflora. NOD1 is expressed in both non-hematopoietic cells such as epithelial cells and hematopoietic cells such as antigen-presenting cells. Detection of its ligand by NOD1 leads to innate immune responses through activation of nuclear factor kappa B and type I interferon as well as induction of autophagy. Innate immune responses through NOD1 activation play an indispensable role both in host defense against microbial infection and in the development of gastrointestinal disorders. Of particular importance, NOD1-mediated innate immune responses are associated with mucosal host defenses against Helicobacter pylori (H. pylori) infection of the stomach and with the development of pancreatitis. In this review, we discuss the molecular mechanisms by which NOD1 activation leads to the development of H. pylori-related gastric diseases and pancreatitis.
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• Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of submucosal tumors of the upper gastrointestinal tract, Ken Kamata, Mamoru Takenaka, Masayuki Kitano, Shunsuke Omoto, Takeshi Miyata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Takaaki Chikugo, Yasutaka Chiba, Haruhiko Imamoto, Takushi Yasuda, Andrea Lisotti, Pietro Fusaroli, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 32(10), 1686 - 1692, Oct. 2017 , Refereed
  Summary:Background and Aim: The study aims to evaluate contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for the differential diagnosis of submucosal tumors (SMT) of the upper gastrointestinal tract. Methods: Between June 2008 and May 2015, 157 consecutive patients with submucosal lesions of the upper gastrointestinal tract were evaluated by CH-EUS. This was a single-center retrospective analysis of prospectively collected data in a registry. The data from 73 patients who later underwent surgical resection were analyzed in this study. Surgical specimens served as the final diagnoses. The two CH-EUS variables of blood flow (hyper-enhancement vs hypo-enhancement) and homogeneity of enhancement pattern were evaluated. Results: The final diagnoses were 58 gastrointestinal stromal tumors (GISTs) and 15 benign SMTs (two lipomas, five leiomyomas, five schwannomas, two glomus tumors, and one ectopic pancreas). On CH-EUS, 49 of 58 (84.5%) GISTs presented with hyper-enhancement, whereas 4 of 15 (26.7%) benign SMTs showed hyper-enhancement; 21 of 58 (36.2%) GISTs showed inhomogeneous contrast enhancement, while only 2 of 15 (13.3%) benign SMTs demonstrated inhomogeneous contrast enhancement. If hyper-enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 84.5%, 73.3%, and 82.2%, respectively. If inhomogeneous enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 36.2%, 86.7%, and 46.6%, respectively. In lesions of less than 2cm, hyper-enhancement was a more sensitive indicator of GISTs than inhomogeneous enhancement. Conclusions: Hyper-enhancement and inhomogeneous enhancement were found to be a characteristic of GISTs. CH-EUS was useful for discrimination of benign SMTs from GISTs.
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• Validation of serological models for staging and prognostication of HCC in patients from a Japanese nationwide survey, Hienori Toyoda, Toshifumi Tada, Philip J. Johnson, Namiki Izumi, Masumi Kadoya, Shuichi Kaneko, Norihiro Kokudo, Yonson Ku, Shoji Kubo, Takashi Kumada, Yutaka Matsuyama, Osamu Nakashima, Michiie Sakamoto, Tadatoshi Takayama, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 52(10), 1112 - 1121, Oct. 2017 , Refereed
  Summary:Background Two serology-based scoring models for prognostication of patients with hepatocellular carcinoma (HCC), the BALAD and BALAD-2 models, were applied to a Japanese cohort of a nationwide follow-up survey of HCC. The ability of these models to predict the progression of HCC and the deterioration of liver function and to assess prognosis was evaluated. Methods BALAD and BALAD-2 scores were calculated in 24,029 patients from a cohort of Japanese nationwide survey based on the serum levels of five markers (bilirubin, albumin, lens culinaris agglutinin-reactive alpha-fetoprotein, alpha-fetoprotein, and des-gamma-carboxy prothrombin) measured at the time of HCC diagnosis. The associations of these scores with the progression of HCC and liver function and with survival rates were analyzed. Results There were good correlations between BALAD and BALAD-2 scores and the progression of HCC and Child-Pugh class. Both scores accurately categorized patients into risk groups with different survival rates. BALAD-2 showed superior discrimination of patient survival compared with the original BALAD. Conclusions Serology-based scoring models for prognostication, especially the BALAD-2 model, were useful for staging and prognostication of survival in a cohort of Japanese patients with HCC from a nationwide survey.
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• Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis, Satoru Hagiwara, Naoshi Nishida, Ah-Mee Park, Yoriaki Komeda, Toshiharu Sakurai, Tomohiro Watanabe, Masatoshi Kudo, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 7(1), 10440, Sep. 2017 , Refereed
  Summary:Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV-related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of beta-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis.
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• Management of developmental enamel defects in the primary dentition, Kanae Wada, Hanae Kanazawa, Mifune Kudo, Junko Kindaichi, Michiyo Miyashin, JOURNAL OF ORAL SCIENCE, JOURNAL OF ORAL SCIENCE, 59(3), 457 - 460, Sep. 2017 , Refereed
  Summary:This study attempted to identify appropriate materials for restoration of enamel defects in the primary dentition, which were classified by severity and region with the modified developmental defects of enamel index. To identify the most appropriate materials, we used restorative materials to protect teeth and evaluated clinical outcomes of restoration. Three materials were used for restoration or repair after dislodgement of restorations. Our findings in this case suggest that, because of its durability and esthetic advantages, adhesive resin is beneficial for patients with enamel defects, particularly for restorations of less than two-thirds of the extent of the defect.
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• High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells, Hiroki Shimada, Naotaka Kogure, Erika Noro, Masataka Kudo, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Makoto Kobayashi, Dai Suzuki, Rehana Parvin, Takako Saito-Ito, Akira Uruno, Akiko Saito-Hakoda, William E. Rainey, Sadayoshi Ito, Atsushi Yokoyama, Akira Sugawara, FEBS OPEN BIO, FEBS OPEN BIO, 7(9), 1410 - 1421, Sep. 2017 , Refereed
  Summary:Aldosterone synthase is the key rate-limiting enzyme in adrenal aldosterone production, and induction of its gene (CYP11B2) results in the progression of hypertension. As hypertension is a frequent complication among patients with diabetes, we set out to elucidate the link between diabetes mellitus and hypertension. We examined the effects of high glucose on CYP11B2 expression and aldosterone production using human adrenal H295R cells and a stable H295R cell line expressing a CYP11B2 5-flanking region/luciferase cDNA chimeric construct. d-glucose (d-glu), but not its enantiomer l-glucose, dose dependently induced CYP11B2 transcription and mRNA expression. A high concentration (450 mgdL(-1)) of d-glu time dependently induced CYP11B2 transcription and mRNA expression. Moreover, high glucose stimulated secretion of aldosterone into the media. Transient transfection studies using deletion mutants/nerve growth factor-induced clone B (NGFIB) response element 1 (NBRE-1) point mutant of CYP11B2 5-flanking region revealed that the NBRE-1 element, known to be activated by transcription factors NGFIB and NURR1, was responsible for the high glucose-mediated effect. High glucose also induced the mRNA expression of these transcription factors, especially that of NURR1, but NURR1 knockdown using its siRNA did not affect high glucose-induced CYP11B2 mRNA expression. Taken together, it is speculated that high glucose may induce CYP11B2 transcription via the NBRE-1 element in its 5-flanking region, resulting in the increase in aldosterone production although high glucose-induced NURR1 is not directly involved in the effect. Additionally, glucose metabolism and calcium channels were found to be involved in the high glucose effect. Our observations suggest one possible explanation for the high incidence of hypertension in patients with diabetes.
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• Rapid Screening of Primary Aldosteronism by a Novel Chemiluminescent Immunoassay, Ryo Morimoto, Yoshikiyo Ono, Yuta Tezuka, Masataka Kudo, Sachiko Yamamoto, Toshiaki Arai, Celso E. Gomez-Sanchez, Hironobu Sasano, Sadayoshi Ito, Fumitoshi Satoh, HYPERTENSION, HYPERTENSION, 70(2), 334 - +, Aug. 2017 , Refereed
  Summary:Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results when measured by radioimmunoassay and development of more rapid assays has been long expected. We have developed chemiluminescent enzyme immunoassays enabling the simultaneous measurement of both aldosterone and renin concentrations in 10 minutes by a fully automated assay using antibody-immobilized magnetic particles with quick aggregation and dispersion. We performed clinical validation of diagnostic ability of this newly developed assay-based screening of 125 patients with primary aldosteronism from 97 patients with essential hypertension. Results of this novel assay significantly correlated with the results of radioimmunoassay (aldosterone, active renin concentration, and renin activity) and liquid chromatography-tandem mass spectrometry (aldosterone). The analytic sensitivity of this particularly novel active renin assay was 0.1 pg/mL, which was better than that of radioimmunoassay (2.0 pg/mL). The ratio of aldosterone-to-renin concentrations of 6.0 (ng/dL per pg/mL) provided 92.0% sensitivity and 76.3% specificity as a cutoff for differentiating primary aldosteronism from essential hypertension. This novel measurement is expected to be a clinically reliable alternative for conventional radioimmunoassay and to provide better throughput and cost effectiveness in diagnosis of hyperaldosteronism from larger numbers of hypertensive patients in clinical settings.
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• Cyclocarya paliurus extract activates insulin signaling via Sirtuin1 in C2C12 myotubes and decreases blood glucose level in mice with impaired insulin secretion, Hisae Yoshitomi, Rika Tsuru, Linyi Li, Jingxin Zhou, Maya Kudo, Tonghua Liu, Ming Gao, PLOS ONE, PLOS ONE, 12(8), e0183988, Aug. 2017 , Refereed
  Summary:Diabetes is caused by the lack of release or action of insulin. Some foods and supplements can compensate for this deficiency; thus, they can aid in the prevention or treatment of diabetes. The aim of this study was to investigate the effects of Cyclocarya paliurus extract (CPE) on insulin signaling and its capacity to correct hyperglycemia in the absence of insulin. To investigate the hypoglycemic effects of CPE, C2C12 cells were exposed to CPE (50 and 100 mu g/mL). CPE promoted 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose (2NBDG) uptake into the cells via translocation of glucose transporter 4 (Glut4) to the plasma membrane. In addition, CPE enhanced tyrosine phosphorylation of insulin receptor substrate and activated phosphatidylinositol 3-kinase and protein kinase B (Akt) via sirtuin1 in C2C12 cells. Moreover, we found that oral administration of CPE (1 g/kg) to streptozotocin-induced hyperglycemic mice produced a progressive decrease in plasma glucose levels at 1 h after single dosing. At that point, CPE significantly increased the expression of skeletal muscle membrane Glut4 and enhanced the phosphorylation of Akt. These results suggest that CPE exerts antidiabetic effects similar to those of insulin, and may be an oral therapeutic alternative for the management of diabetes.
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• Liver Resection for Hepatocellular Carcinoma Associated With Hepatic Vein Invasion: A Japanese Nationwide Survey, Takashi Kokudo, Kiyoshi Hasegawa, Yutaka Matsuyama, Tadatoshi Takayama, Namiki Izumi, Masumi Kadoya, Masatoshi Kudo, Shoji Kubo, Michiie Sakamoto, Osamu Nakashima, Takashi Kumada, Norihiro Kokudo, HEPATOLOGY, HEPATOLOGY, 66(2), 510 - 517, Aug. 2017 , Refereed
  Summary:Because of the rarity of hepatic vein tumor thrombus (HVTT) compared with portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma, little is known about this disease entity. The aim of this study was to evaluate the prognosis of each treatment modality for HVTT through an analysis of data collected in a Japanese nationwide survey. We analyzed data for 1,021 Child-Pugh A hepatocellular carcinoma patients with HVTT without inferior vena cava invasion registered between 2000 and 2007. Of these patients, 540 who underwent liver resection (LR) and 481 who received other treatments were compared. Propensity scores were calculated, and we successfully matched 223 patients (49.0% of the LR group). The median survival time in the LR group was 2.89 years longer than that in the non-LR group (4.47 versus 1.58 years, P < 0.001) and 1.61 years longer than that in the non-LR group (3.42 versus 1.81 years, P = 0.023) in a propensity score-matched cohort. After curative resection, median survival times were similar between patients with HVTT in the peripheral hepatic vein and those with HVTT in the major hepatic vein (4.85 versus 4.67 years, P = 0.974). In the LR group, the postoperative 90-day mortality rate was 3.4% (16 patients). In patients without PVTT, the median survival time was significantly better than that in patients with PVTT (5.67 versus 1.88 years, P < 0.001). Conclusion: LR is associated with a good prognosis in hepatocellular carcinoma patients with HVTT, especially in patients without PVTT.
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• Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer, Hisato Kawakami, Junko Tanizaki, Kaoru Tanaka, Koji Haratani, Hidetoshi Hayashi, Masayuki Takeda, Ken Kamata, Mamoru Takenaka, Masatomo Kimura, Takaaki Chikugo, Takao Sato, Masatoshi Kudo, Akihiko Ito, Kazuhiko Nakagawa, INVESTIGATIONAL NEW DRUGS, INVESTIGATIONAL NEW DRUGS, 35(4), 529 - 536, Aug. 2017 , Refereed
  Summary:Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with in-travenous nivolumab monotherapy (3.0 mg/kg) every 2 weeks until disease progression or irAEs occurred. Clinical data regarding the duration of nivolumab treatment, symptoms, laboratory abnormalities, pathological findings of liver parenchyma biopsy specimens, and management of nivolumab-related cholangitis were analyzed. Results Our analysis revealed that nivolumab-related cholangitis was characterized by (1) localized extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) a dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to the hepatic enzymes aspartate and alanine aminotransferase; (4) normal or reduced levels of the serum immunological markers antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and immunoglobulin G4; (5) the pathological finding of biliary tract cluster of differentiation 8-positive T cell infiltration from liver biopsy; and (6) amoderate to poor response to steroid therapy. Conclusions Nivolumab-related cholangitis is associated with distinct imaging and clinicopathological features that distinguish it from acute cholangitis of common etiologies and other immune-related cholangitis. Further studies are warranted to establish the optimal management of patients with this irAE.
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• Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study, Ian Chau, Markus Peck-Radosavljevic, Christophe Borg, Peter Malfertheiner, Jean Francois Seitz, Joon Oh Park, Baek-Yeol Ryoo, Chia-Jui Yen, Masatoshi Kudo, Ronnie Poon, Davide Pastorelli, Jean-Frederic Blanc, Hyun Cheol Chung, Ari D. Baron, Takuji Okusaka, L. Bowman, Zhanglin Lin Cui, Allicia C. Girvan, Paolo B. Abada, Ling Yang, Andrew X. Zhu, EUROPEAN JOURNAL OF CANCER, EUROPEAN JOURNAL OF CANCER, 81, 17 - 25, Aug. 2017 , Refereed
  Summary:Purpose: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. Methods: Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a >= 3-point decrease from baseline and PS deterioration was defined as a change of >= 2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) >= 400 ng/mL were assessed. Results: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP >= 400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. Conclusions: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP >= 400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patientfocused outcome benefits. Clinical trial registration: NCT01140347. (C) 2017 Elsevier Ltd. All rights reserved.
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• Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update, Masao Omata, Ann-Lii Cheng, Norihiro Kokudo, Masatoshi Kudo, Jeong Min Lee, Jidong Jia, Ryosuke Tateishi, Kwang-Hyub Han, Yoghesh K. Chawla, Shuichiro Shiina, Wasim Jafri, Diana Alcantara Payawal, Takamasa Ohki, Sadahisa Ogasawara, Pei-Jer Chen, Cosmas Rinaldi A. Lesmana, Laurentius A. Lesmana, Rino A. Gani, Shuntaro Obi, A. Kadir Dokmeci, Shiv Kumar Sarin, HEPATOLOGY INTERNATIONAL, HEPATOLOGY INTERNATIONAL, 11(4), 317 - 370, Jul. 2017 , Refereed
  Summary:There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.
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• Stent migration during EUS-guided hepaticogastrostomy in a patient with massive ascites: Troubleshooting using additional EUS-guided antegrade stenting, Ken Kamata, Mamoru Takenaka, Kosuke Minaga, Shunsuke Omoto, Takeshi Miyata, Kentaro Yamao, Hajime Imai, Masatoshi Kudo, ARAB JOURNAL OF GASTROENTEROLOGY, ARAB JOURNAL OF GASTROENTEROLOGY, 18(2), 120 - 121, Jun. 2017 , Refereed
  Summary:EUS-guided hepaticogastrostomy (EUS-HGS) is useful for treating obstructive jaundice. However, stent migration may sometimes occur both during and after the procedure. This report describes a patient with pancreatic cancer and massive ascites who underwent EUS-HGS combined with EUS-guided antegrade stenting (EUS-AS), with additional EUS-AS playing a role in troubleshooting for stent migration during EUS-HGS. (C) 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
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• Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC, Riccardo Lencioni, Robert Montal, Ferran Torre, Joong-Won Park, Thomas Decaens, Jean-Luc Raoul, Masatoshi Kudo, Charissa Chang, Jose Rios, Valerie Boige, Eric Assenat, Yoon-Koo Kang, Ho-Yeong Lim, Ian Walters, Josep M. Llovet, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 66(6), 1166 - 1172, Jun. 2017 , Refereed
  Summary:Background & Aims: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this endpoint as a potential surrogate of OS. Methods: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n = 334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. Results: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4 months, p < 0.001). In addition, objective response had an independent prognostic value (HR = 0.48; 95% confidence interval [CI], 0.26-0.91, p = 0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R = -0.92; 95% CI, -1 to -0.73, p < 0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4 months). Conclusions: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. Lay summary: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. Clinical trial number: NCT00825955. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Magnetic resonance elastography in the assessment of hepatic fibrosis: a study comparing transient elastography and histological data in the same patients, Masafumi Toguchi, Masakatsu Tsurusaki, Norihisa Yada, Keitaro Sofue, Tomoko Hyodo, Minori Onoda, Isao Numoto, Mitsuru Matsuki, Izumi Imaoka, Masatoshi Kudo, Takamichi Murakami, ABDOMINAL RADIOLOGY, ABDOMINAL RADIOLOGY, 42(6), 1659 - 1666, Jun. 2017 , Refereed
  Summary:Purpose: To evaluate the quantitative measurement of liver stiffness (LS), compare the diagnostic performance of magnetic resonance elastography (MRE) and ultrasound-based transient elastography (TE), and evaluate two different MRE-based LS measurement methods. Methods: Between October 2013 and January 2015, 116 consecutive patients with chronic liver disease underwent MRE to measure LS (kilopascals; kPa). Of the 116 patients, 51 patients underwent both TE and liver biopsy, and the interval between the liver biopsy and both the MRE and TE was less than 90 days. MRE-derived LS values were measured on the anterior segment of the right lobe (single small round regions of interest per slice; srROIs) and whole right lobe of the liver (free hand region of interest; fhROI), and these values were correlated with pathological fibrosis grades and diagnostic performance. Results: Pathological fibrosis stage was significantly correlated with srROIs (r = 0.87, p < 0.001), fhROI (r = 0.80, p < 0.001), and TE (r = 0.73, p < 0.001). For detection of significant fibrosis (>= F2), advanced fibrosis (>= F3), and cirrhosis, the area under the curve (AUC) associated with the srROIs was largest, and there was a significant difference between srROIs and TE (0.93 vs. 0.82, p = 0.006), srROIs and fhROI (0.93 vs. 0.89, p = 0.04) for detection of >= F2. For advanced fibrosis and cirrhosis detection, AUCs were not significant (0.92-0.96). Conclusions: MRE and TE detected liver fibrosis with comparable accuracy. In particular, the srROIs method was effective for detecting of significant fibrosis.
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• Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial, Anthony B. El-Khoueiry, Bruno Sangro, Thomas Yau, Todd S. Crocenzi, Masatoshi Kudo, Chiun Hsu, Tae-You Kim, Su-Pin Choo, Jorg Trojan, Theodore H. Welling, Tim Meyer, Yoon-Koo Kang, Winnie Yeo, Akhil Chopra, Jeffrey Anderson, Christine dela Cruz, Lixin Lang, Jaclyn Neely, Hao Tang, Homa B. Dastani, Ignacio Melero, LANCET, LANCET, 389(10088), 2492 - 2502, Jun. 2017 , Refereed
  Summary:Background For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (>= 18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load < 100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+ 3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Findings Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Interpretation Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.
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• Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib, Eri Banno, Yosuke Togashi, Marco A. De Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio, INTERNATIONAL JOURNAL OF ONCOLOGY, INTERNATIONAL JOURNAL OF ONCOLOGY, 50(6), 2049 - 2058, Jun. 2017 , Refereed
  Summary:Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0.16 and 0.19, respectively). In vitro, an Akt2-amplified PC cell line and Akt2-overexpressed cell lines exhibited resistance to anti-EGFR therapies, including erlotinib, but combined treatment with BYL719 (a PI3K inhibitor) cancelled this resistance. Our findings suggest that Akt2 might be associated with the resistance to anti-EGFR therapies, especially the use of erlotinib against PC, and that this resistance can be overcome by combined treatment with a PI3K inhibitor. Akt2 expression could become a predictive biomarker for erlotinib resistance in PC.
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• A Case of Type II Enteropathy-Associated T-Cell Lymphoma in a Patient With Ulcerative Colitis, Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Masashi Kono, Tomoyuki Nagai, Yutaka Asakuma, Satoru Hagiwara, Shigenaga Matsui, Tomohiro Watanabe, Takaaki Chikugo, Masatoshi Kudo, AMERICAN JOURNAL OF GASTROENTEROLOGY, AMERICAN JOURNAL OF GASTROENTEROLOGY, 112(6), 833 - 833, Jun. 2017 , Refereed
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• Follow-Up Examination of the Recurrence After Endoscopic Treatment of Colorectal Tumors, Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Tomoyuki Nagai, Shigenaga Matsui, Tomohiro Watanabe, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 85(5), AB392 - AB392, May 2017 , Refereed
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• Investigation on the Efficacy of Alteration of Treatment Methods for Difficult Cases in Eus-Bd, Kosuke Minaga, Mamoru Takenaka, Masayuki Kitano, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Shunsuke Omoto, Tomoe Yoshikawa, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 85(5), AB493 - AB493, May 2017 , Refereed
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• Improved Diagnosis of Liver Metastases Using Kupffer-Phase Image of Contrast-Enhanced Harmonic Endoscopic Ultrasonography in Patients With Pancreatic Cancer, Kosuke Minaga, Mamoru Takenaka, Masayuki Kitano, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Shunsuke Omoto, Tomoe Yoshikawa, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 85(5), AB53 - AB53, May 2017 , Refereed
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• Outcomes of Biliary Drainage in Pancreatic Cancer Patients With an Indwelling Gastroduodenal Stent: A Multicenter Retrospective Study in West Japan, Kentaro Yamao, Masayuki Kitano, Takahisa Kayahara, Etsuji Ishida, Hiroshi Yamamoto, Tomoe Yoshikawa, Kosuke Minaga, Yukitaka Yamashita, Masanori Asada, Yoshihiro Okabe, Yukio Osaki, Juri Ikemoto, Keiji Hanada, Mamoru Takenaka, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 85(5), AB327 - AB328, May 2017 , Refereed
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• Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib, Jessica A. Howell, David J. Pinato, Ramya Ramaswami, Tadaaki Arizumi, Carlotta Ferrari, Antonello Gibbin, Michela E. Burlone, Giulia Guaschino, Pierluigi Toniutto, James Black, Laura Sellers, Masatoshi Kudo, Mario Pirisi, Rohini Sharma, ONCOTARGET, ONCOTARGET, 8(22), 36161 - 36170, May 2017 , Refereed
  Summary:Background and Aims: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. Results: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p < 0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p < 0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p < 0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RDCLIP score (CLIP score multiplied by RDW) >= 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score >= 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival. Methods: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. Conclusion: The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.
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• On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study, J. Howell, D. J. Pinato, R. Ramaswami, D. Bettinger, T. Arizumi, C. Ferrari, C. Yen, A. Gibbin, M. E. Burlone, G. Guaschino, L. Sellers, J. Black, M. Pirisi, M. Kudo, R. Thimme, J. -W. Park, R. Sharma, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 45(8), 1146 - 1155, Apr. 2017 , Refereed
  Summary:Background Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. Aim To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. Methods In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. Results A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. Conclusion Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.
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• Reply to the Letter to the editor 'Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus Sorafenib for advanced hepatocellular carcinoma: randomized phase II trial' by Fornaro et al., M. Ikeda, S. Shimizu, T. Sato, M. Morimoto, Y. Kojima, Y. Inaba, A. Hagihara, M. Kudo, S. Nakamori, S. Kaneko, R. Sugimoto, T. Tahara, T. Ohmura, K. Yasui, K. Sato, H. Ishii, J. Furuse, T. Okusaka, ANNALS OF ONCOLOGY, ANNALS OF ONCOLOGY, 28(4), 903 - 904, Apr. 2017 , Refereed
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• Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial, Masatoshi Kudo, Etsuro Hatano, Shinichi Ohkawa, Hirofumi Fujii, Akihide Masumoto, Junji Furuse, Yoshiyuki Wada, Hiroshi Ishii, Shuntaro Obi, Shuichi Kaneko, Seiji Kawazoe, Osamu Yokosuka, Masafumi Ikeda, Katsuaki Ukai, Sojiro Morita, Akihito Tsuji, Toshihiro Kudo, Mitsuo Shimada, Yukio Osaki, Ryosuke Tateishi, Gen Sugiyama, Paolo Benjamin Abada, Ling Yang, Takuji Okusaka, Andrew Xiuxuan Zhu, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 52(4), 494 - 503, Apr. 2017 , Refereed
  Summary:Bckground REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline alpha-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed. Methods An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93). Results The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263]. Conclusion In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients.
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• Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma, Kenji Ikeda, Masatoshi Kudo, Seiji Kawazoe, Yukio Osaki, Masafumi Ikeda, Takuji Okusaka, Toshiyuki Tamai, Takuya Suzuki, Takashi Hisai, Seiichi Hayato, Kiwamu Okita, Hiromitsu Kumada, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 52(4), 512 - 519, Apr. 2017 , Refereed
  Summary:Background Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). Methods Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (< 30 days) dose withdrawal or reduction than in those without. Conclusion Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight.
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• Multimaterial Decomposition Algorithm for the Quantification of Liver Fat Content by Using Fast-Kilovolt-Peak Switching Dual-Energy CT: Clinical Evaluation, Tomoko Hyodo, Norihisa Yada, Masatoshi Hori, Osamu Maenishi, Peter Lamb, Kosuke Sasaki, Minori Onoda, Masatoshi Kudo, Teruhito Mochizuki, Takamichi Murakami, RADIOLOGY, RADIOLOGY, 283(1), 108 - 118, Apr. 2017 , Refereed
  Summary:Purpose: To assess the clinical accuracy and reproducibility of liver fat quantification with the multimaterial decomposition (MMD) algorithm, comparing the performance of MMD with that of magnetic resonance (MR) spectroscopy by using liver biopsy as the reference standard. Materials and Methods: This prospective study was approved by the institutional ethics committee, and patients provided written informed consent. Thirty-three patients suspected of having hepatic steatosis underwent non-contrast material-enhanced and triple-phase dynamic contrast-enhanced dual-energy computed tomography (CT) (80 and 140 kVp) and single-voxel proton MR spectroscopy within 30 days before liver biopsy. Percentage fat volume fraction (FVF) images were generated by using the MMD algorithm on dual-energy CT data to measure hepatic fat content. FVFs determined by using dual-energy CT and percentage fat fractions (FFs) determined by using MR spectroscopy were compared with histologic steatosis grade (0-3, as defined by the nonalcoholic fatty liver disease activity score system) by using Jonck-heere-Terpstra trend tests and were compared with each other by using Bland-Altman analysis. Real non-contrast-enhanced FVFs were compared with triple-phase contrast-enhanced FVFs to determine the reproducibility of MMD by using Bland-Altman analyses. Results: Both dual-energy CT FVF and MR spectroscopy FF increased with increasing histologic steatosis grade (trend test, P <.001 for each). The Bland-Altman plot of dual-energy CT FVF and MR spectroscopy FF revealed a proportional bias, as indicated by the significant positive slope of the line regressing the difference on the average (P < .001). The 95% limits of agreement for the differences between real non-contrast- enhanced and contrast-enhanced FVFs were not greater than about 2%. Conclusion: The MMD algorithm quantifying hepatic fat in dual-energy CT images is accurate and reproducible across imaging phases. (C) RSNA, 2017
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• The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3, Toshiharu Sakurai, Hiroaki Higashitsuji, Hiroshi Kashida, Tomohiro Watanabe, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Masayuki Kitano, Naoshi Nishida, Takaya Abe, Hiroshi Kiyonari, Katsuhiko Itoh, Jun Fujita, Masatoshi Kudo, ONCOTARGET, ONCOTARGET, 8(15), 24762 - 24776, Apr. 2017 , Refereed
  Summary:Although long-standing colonic inflammation due to refractory inflammatory bowel disease (IBD) promotes the development of colitis-associated cancer (CAC), the molecular mechanisms accounting for the development of CAC remains largely unknown. In this study, we investigated the role of gankyrin in the development of CAC since gankyrin is overexpressed in sporadic colorectal cancers. We analyzed gene expression of colon tissues obtained from 344 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. Over-expressing studies utilizing tagged ganlyrin-cDNA identified physical interaction between ganlyrin and Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1). Importantly, the interaction between ganlyrin and SHP1 leads to inhibition of STAT3 activation and to enhancement of TNF-alpha and IL-17 in inflammatory cells. To further address the role of gankyrin in the development of CAC, we created mice with intestinal epithelial cell-specific gankyrin ablation (Vil-Cre; Gankyrin(f/f)) and deletion of gankyrin in myeloid and epithelial cells (Mx1Cre; Gankyrin(f/f)). Gankyrin deficiency in myeloid cells, but not in epithelial cells, reduced the activity of mitogen activated protein kinase and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.
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• Cost-effectiveness of EOB-MRI for Hepatocellular Carcinoma in Japan, Akihiro Nishie, Satoshi Goshima, Hiroki Haradome, Etsuro Hatano, Yasuharu Imai, Masatoshi Kudo, Masanori Matsuda, Utaroh Motosugi, Satoshi Saitoh, Kengo Yoshimitsu, Bruce Crawford, Eliza Kruger, Graeme Ball, Hiroshi Honda, CLINICAL THERAPEUTICS, CLINICAL THERAPEUTICS, 39(4), 738 - 750, Apr. 2017 , Refereed
  Summary:Purpose: The objective of the study was to evaluate the cost-effectiveness of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan compared with extracellular contrast media-enhanced MRI (ECCM-MRI) and contrast media-enhanced computed tomography (CE-CT) scanning. Methods: A 6-stage Markov model was developed to estimate lifetime direct costs and clinical outcomes associated with EOB-MRI. Diagnostic sensitivity and specificity, along with clinical data on HCC survival, recurrence, treatment patterns, costs, and health state utility values, were derived from predominantly Japanese publications. Parameters unavailable from publications were estimated in a Delphi panel of Japanese clinical experts who also confirmed the structure and overall approach of the model. Sensitivity analyses, including one-way, probabilistic, and scenario analyses, were conducted to account for uncertainty in the results. Findings: Over a lifetime horizon, EOB-MRI was associated with lower direct costs ((sic)2,174,869) and generated a greater number of quality-adjusted life years (QALYs) (9.502) than either ECCM-MRI ((sic)2,365,421, 9.303 QALYs) or CE-CT ((sic)2,482,608, 9.215 QALYs). EOB-MRI was superior to the other diagnostic strategies considered, and this finding was robust over sensitivity and scenario analyses. A majority of the direct costs associated with HCC in Japan were found to be costs of treatment. The model results revealed the superior cost-effectiveness of the EOB-MRI diagnostic strategy compared with ECCM-MRI and CE-CT. Implications: EOB-MRI could be the first-choice imaging modality for medical care of HCC among patients with hepatitis or liver cirrhosis in Japan. Widespread implementation of EOB-MRI could reduce health care expenditures, particularly downstream treatment costs, associated with HCC. (C) 2017 Elsevier HS Journals, Inc. All rights reserved.
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• Immunopathogenesis of pancreatitis, T. Watanabe, M. Kudo, W. Strober, MUCOSAL IMMUNOLOGY, MUCOSAL IMMUNOLOGY, 10(2), 283 - 298, Mar. 2017 , Refereed
  Summary:The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic-or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstreaminduction of Tcells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
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• Semiquantitative prediction of early response of conventional transcatheter arterial chemoembolization for hepatocellular carcinoma using postprocedural plain cone-beam computed tomography, Yasunori Minami, Masahiro Takita, Masakatsu Tsurusaki, Yukinobu Yagyu, Kazuomi Ueshima, Takamichi Murakami, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 47(3), E113 - E119, Mar. 2017 , Refereed
  Summary:AimTo investigate whether plain cone-beam computed tomography (CT) immediately after conventional transcatheter arterial chemoembolization (c-TACE) can help to predict tumor response semiquantitatively in patients with hepatocellular carcinoma (HCC). MethodsAnalysis was carried out retrospectively on 262 targeted HCCs in 169 patients treated with c-TACE. Dynamic CT was performed at baseline and 1-4months after c-TACE. Receiver-operating characteristic curve analysis was undertaken to evaluate whether voxel values of cone-beam CT could predict a complete response and to identify the cut-off value. Final tumor response assessment and early prediction using the retention pattern of iodized oil, the cut-off value of the density, and the combination of the cut-off density value and retention pattern of iodized oil in HCCs on postprocedural cone-beam CT were compared. ResultsComplete response was obtained in 72.9% of lesions. According to the pattern of iodized oil uptake, the sensitivity, specificity, and accuracy for predicting complete response were 85.9%, 70.4%, and 81.7%, respectively by excellent uptake on cone-beam CT. The area under the curve was 0.86 with the optimal cut-off at a voxel value of 200.13. According to not only the density but also the homogeneity of iodized oil retention, the sensitivity, specificity, and accuracy values for predicting complete response were 86.4%, 95.8%, and 88.9%, respectively. The predictive accuracy was significantly better than that of the pattern of iodized oil retention only (P=0.019). ConclusionThe combination of density and visual estimate of homogeneity is superior to either alone in predicting tumor response of c-TACE in HCC patients.
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• Endoscopic ultrasonography-guided choledochoduodenostomy using a newly designed laser-cut metal stent: Feasibility study in a porcine model, Kosuke Minaga, Masayuki Kitano, Chimyon Gon, Kentaro Yamao, Hajime Imai, Takeshi Miyata, Ken Kamata, Shunsuke Omoto, Mamoru Takenaka, Masatoshi Kudo, DIGESTIVE ENDOSCOPY, DIGESTIVE ENDOSCOPY, 29(2), 211 - 217, Mar. 2017 , Refereed
  Summary:Background and AimEndoscopic ultrasonography (EUS)-guided choledochoduodenostomy (EUS-CDS) is increasingly used in the treatment of malignant distal biliary obstruction. Standardized use of this technique requires improvements in instruments, including more convenient and safer devices. The present study was designed to evaluate the resistance force to migration (RFM) of a newly designed laser-cut metal stent and the feasibility of EUS-CDS using this stent. MethodsThis experimental study used a porcine model of biliary dilatation involving five male pigs. The new stent is a fully covered laser-cut stent with anti-migration anchoring hooks. The RFM of the new stents was compared with those of three commercially available covered metal stents using a phantom model. In the animal study, after ligation of Vater's ampulla with endoscopic clips, the dilated common bile duct was punctured under EUS guidance, followed by EUS-CDS using the new stent. One week after the procedure, the stents were removed endoscopically and the fistulas were assessed after the pigs were killed. Technical feasibility and clinical outcomes were evaluated. ResultsAmong the four stents, the new stent had the highest RFM. Metal stent placement was successful in all five pigs, with no procedure-related complications occurring during and 1 week after endoscopic intervention. All stents remained in place without migration and were removed easily using a snare. At necropsy, fistulas were created between the bile duct and duodenum in all pigs. ConclusionEUS-CDS using a newly designed metal stent was feasible and effective in this porcine model of biliary dilatation.
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• The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development, D. J. Pinato, C. Yen, D. Bettinger, R. Ramaswami, T. Arizumi, C. Ward, M. Pirisi, M. E. Burlone, R. Thimme, M. Kudo, R. Sharma, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 45(5), 714 - 722, Mar. 2017 , Refereed
  Summary:Background Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. Aim To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment. Methods From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses. Results Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001). Conclusions The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.
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• Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma Analysis of REACH Trial Results by Child-Pugh Score, Andrew X. Zhu, Ari David Baron, Peter Malfertheiner, Masatoshi Kudo, Seiji Kawazoe, Denis Pezet, Florian Weissinger, Giovanni Brandi, Carlo A. Barone, Takuji Okusaka, Yoshiyuki Wada, Joon Oh Park, Baek-Yeol Ryoo, Jae Yong Cho, Hyun Cheol Chung, Chung-Pin Li, Chia-Jui Yen, Kuan-Der Lee, Shao-Chun Chang, Ling Yang, Paolo B. Abada, Ian Chau, JAMA ONCOLOGY, JAMA ONCOLOGY, 3(2), 235 - 243, Feb. 2017 , Refereed
  Summary:IMPORTANCE REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline a-fetoprotein (aFP). OBJECTIVE To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS Ramucirumab (8mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES Overall survival (OS), defined as time from randomization to death from any cause. RESULTS In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P =.06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline aFP levels of 400 ng/mL (to convert ng/mL to mu g/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 9HR, 0.61; 95% CI, 0.43-0.87; P =.01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P =.04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline aFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline aFP levels of 400 ng/mL or more.
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• The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma, David J. Pinato, Rohini Sharma, Elias Allara, Clarence Yen, Tadaaki Arizumi, Keiichi Kubota, Dominik Bettinger, Jeong Won Jang, Carlo Smirne, Young Woon Kim, Masatoshi Kudo, Jessica Howell, Ramya Ramaswami, Michela E. Burlone, Vito Guerra, Robert Thimme, Mitsuru Ishizuka, Justin Stebbing, Mario Pirisi, Brian I. Carr, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 66(2), 338 - 346, Feb. 2017 , Refereed
  Summary:Background & Aims: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross validation, especially in intermediate stage HCC, where OS is highly heterogeneous. Methods: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n = 1461) accrued from Europe, the United States and Asia. Results: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p <0.001), transarterial chemoembolization (p <0.001) and sorafenib (p <0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p <0.001). Conclusions: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. Lay summary: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer, Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Tomohiro Watanabe, Masayuki Kitano, Naoshi Nishida, Jun Fujita, Masatoshi Kudo, INFLAMMATORY BOWEL DISEASES, INFLAMMATORY BOWEL DISEASES, 23(1), 66 - 74, Jan. 2017 , Refereed
  Summary:Background: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and heat shock protein A4 are involved in the refractory clinical course and development of CAC. RNAbinding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. Methods: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3(-/-)) mice. Results: Expression of RBM3 was correlated with the expression of stress response proteins Cirp, heat shock protein A4, and HSP27 in the colonic mucosa of patients with IBD. Significant correlation was observed between the expression of RBM3 and that of Bcl-xL or stem cell markers. RBM3 expression increased and significantly correlated with R-spondin expression in the colonic mucosa of patients with refractory IBD, a condition associated with increased cancer risk, and RBM3 was overexpressed in human CACs. In the murine CAC model, Rbm3 deficiency decreased R-spondin and Bcl-xL expression and increased apoptotic cell number in the colonic mucosa, leading to reduced tumor multiplicity. Transplantation of wild-type and Rbm3(-/-) bone marrow did not alter tumor burden, indicating the importance of RBM3 in epithelial cells. Conclusions: Our findings indicated that RBM3 was required for efficient inflammatory carcinogenesis in the murine CAC model and suggested that RBM3 could be a predictive biomarker of CAC risk and a new therapeutic target for cancer prevention in patients with IBD.
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• Evaluation of shear wave dispersion caused by fibrous structure and tissue viscosity using hepatic fibrosis progression and histological models, Shiori Fujii, Makoto Yamakawa, Kengo Kondo, Takeshi Namita, Masatoshi kudo, Tsuyoshi Shiina, 2017 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 2017 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 2017 , Refereed
  Summary:Shear wave elasticity imaging has been utilized for chronic hepatitis diagnosis. The relationship between hepatic fibrosis and elasticity or viscosity has been described recently. Therefore, it is expected that viscosity analysis will improve the accuracy of staging fibrosis, in addition to elasticity measuring. However, fibrous structures affect dispersion slope analysis, so it is necessary to investigate the effect of fibrous structure on dispersion slope analysis. In order to simulate shear wave propagation in liver tissue, we use two types of models representing fibrosis progression. One is created using a potential function, and the other is created from hepatic histological sections. Simulating shear wave propagation in these models without viscosity in order to examine the effect of fibrous structure alone, dispersion analysis was applied to the particle velocity data. We evaluated the dispersion slope and shear wave phase velocity at 200 Hz (c (200 Hz)). In both models, the dispersion slope increased significantly with fibrosis progression. The resulting dispersion slope is about 30% of the dispersion slope in in vivo measurements, indicating that the effect of fibrous structure is large enough for viscosity analysis.
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• Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study, Clarence Yen, Rohini Sharma, Lorenza Rimassa, Tadaaki Arizumi, Dominik Bettinger, Huay Yee Choo, Tiziana Pressiani, Michela E. Burlone, Mario Pirisi, Laura Giordano, Anisa Abdulrahman, Masatoshi Kudo, Robert Thimme, Joong Won Park, David James Pinato, LIVER CANCER, LIVER CANCER, 6(4), 313 - 324, 2017 , Refereed
  Summary:Background: Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogeneity in efficacy exists due to varying clinicopathologic features of the disease. Aim: We evaluated whether prior treatment with curative or locoregional therapies influences sorafenib-specific survival. Methods: From a prospective data set of 785 consecutive patients from international specialist centres, 264 patients (34%) were treatment naive (TN) and 521 (66%) were pre-treated (PT), most frequently with transarterial chemoembolization (n = 413; 79%). The primary endpoint was overall survival (OS) from sorafenib initiation with prognostic factors tested on uni- and multivariate analyses. Results: Median OS for the entire cohort was 9 months; the median sorafenib duration was 2.8 months, with discontinuation being secondary to progression (n = 454; 58%) or toxicity (n = 149; 19%). PT patients had significantly longer OS than TN patients (10.5 vs. 6.6 months; p < 0.001). Compared to TN patients, PT patients had a better Child-Pugh (CP) class (CP A: 57 vs. 47%; p < 0.001) and a lower BCLC stage (BCLC A-B, 40 vs. 30%; p = 0.007). PT status preserved an independent prognostic role (p = 0.002) following adjustment for BCLC stage, a-fetoprotein, CP class, aetiology, and post-sorafenib treatment status. PT patients were more likely to receive further anticancer treatment after sorafenib (31 vs. 9%; p < 0.001). Conclusion: Patients receiving sorafenib after having failed curative or locoregional therapies survive longer and are more likely to receive further treatment after sorafenib. This suggests an incremental benefit to OS from sequential exposure to multiple lines of therapy, justifying treatment stage migration in eligible patients. (C) 2017 S. Karger AG, Basel
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• Chronic Pancreatitis Finding by Endoscopic Ultrasonography in the Pancreatic Parenchyma of Intraductal Papillary Mucinous Neoplasms Is Associated with Invasive Intraductal Papillary Mucinous Carcinoma., Takenaka M, Masuda A, Shiomi H, Yagi Y, Zen Y, Sakai A, Kobayashi T, Arisaka Y, Okabe Y, Kutsumi H, Toyama H, Fukumoto T, Ku Y, Kudo M, Azuma T, Oncology, Oncology, 93 Suppl 1, 61 - 68, 2017 , Refereed
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• Validation of Newly Proposed Time to Transarterial Chemoembolization Progression in Intermediate-Stage Hepatocellular Carcinoma Cases., Hirofumi Izumoto, Atsushi Hiraoka, Yoshihiro Ishimaru, Tadashi Murakami, Shogo Kitahata, Hidetaro Ueki, Toshihiko Aibiki, Tomonari Okudaira, Yuji Miyamoto, Hiroka Yamago, Ryuichiro Iwasaki, Hideomi Tomida, Kenichiro Mori, Masato Kishida, Eiji Tsubouchi, Hideki Miyata, Tomoyuki Ninomiya, Hideki Kawasaki, Masashi Hirooka, Bunzo Matsuura, Masanori Abe, Yoichi Hiasa, Kojiro Michitaka, Masatoshi Kudo, Oncology, Oncology, 93 Suppl 1, 120 - 126, 2017 , Refereed
  Summary:BACKGROUND/AIM: Determination of failure of transarterial chemoembolization (TACE) for treatment of Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) has become important because of the development of tyrosine kinase inhibitor (TKI) treatment. We evaluated the usefulness and efficacy of the newly proposed time to TACE progression (TTTP). PATIENTS AND METHODS: From 2006 to 2016, 192 BCLC-B HCC patients [median age 72 years, male/female ratio = 149/43, Child-Pugh score 5/6/7 = 106/56/30, albumin-bilirubin (ALBI) grade 1/2 = 64/128, Kinki criteria B1/B2 = 64/128] were enrolled. TTTP was defined based on a previous report and first imaging performed 3 months after initial TACE had been used to obtain baseline images. The patients were divided into three groups according to TTTP (<5, 5-10, and ≥10 months; group I, II, and III, respectively). We evaluated the relationship between TTTP and overall survival (OS) as well as the prognostic factors for death. RESULTS: The median number of TACE procedures was 4 (interquartile range 3-7). There was a moderate correlation between TTTP and OS (r = 0.527, 95% CI 0.416-0.622, p < 0.001). The median survival for group I (n = 78), II (n = 49), and III (n = 65) was 24.6, 34.7, and 49.5 months, respectively (group I vs. group II, p = 0.023; group I vs. group III, p < 0.001; group II vs. group III, p = 0.037; Holm's method). ALBI grade 2 (HR 1.548, 95% CI 1.004-2.388, p = 0.048), alpha-fetoprotein (>100 ng/mL) (HR 1.540, 95% CI 1.035-2.291, p = 0.033), and TTTP (<5 months) (HR 2.157, 95% CI 1.447-3.215, p < 0.001) were significant prognostic factors for death in multivariate Cox hazard analysis. CONCLUSION: In patients with reduced TTTP, especially <5 months, it might be difficult to improve prognosis with a repeated TACE procedures. In such cases, reconsideration of the therapeutic strategy might be needed when possible.
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• ALBI Score as a Novel Tool in Staging and Treatment Planning for Hepatocellular Carcinoma: Advantage of ALBI Grade for Universal Assessment of Hepatic Function, Atsushi Hiraoka, Kojiro Michitaka, Takashi Kumada, Masashi Kudo, LIVER CANCER, LIVER CANCER, 6(4), 377 - 379, 2017 , Refereed
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• Validation and Potential of Albumin-Bilirubin Grade and Prognostication in a Nationwide Survey of 46,681 Hepatocellular Carcinoma Patients in Japan: The Need for a More Detailed Evaluation of Hepatic Function, Atsushi Hiraoka, Kojiro Michitaka, Takashi Kumada, Namiki Izumi, Masumi Kadoya, Norihiro Kokudo, Shoji Kubo, Yutaka Matsuyama, Osamu Nakashima, Michiie Sakamoto, Tadatoshi Takayama, Takashi Kokudo, Kosuke Kashiwabara, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 6(4), 325 - 336, 2017 , Refereed
  Summary:Background/Aim: Recently, albumin-bilirubin (ALBI) scoring/grading, consisting of only albumin and total bilirubin, has been proposed. We examined the efficacy of this grading system for determining hepatic function in patients with hepatocellular carcinoma (HCC). Methods/Materials: The prognoses of 46,681 HCC patients based on results obtained from a nationwide survey conducted in Japan from 2001 to 2007 were evaluated using (1) Japan Integrated Staging (JIS), consisting of Child-Pugh classification and TNM staging (TNM), (2) modified JIS (m-JIS), consisting of liver damage grading and TNM, and (3) ALBI-TNM (ALBI-T), consisting of ALBI grading and TNM, and the results were compared. A subanalysis was also performed to define a cutoff value for ALBI scores for a more detailed stratification of hepatic function. Results: ALBI-T, JIS, and m-JIS each showed good capacity for the stratification of prognoses. Although the Akaike information criterion for ALBI-T was nearly equal to that for JIS and m-JIS, the Kaplan-Meier curves and median survival times obtained with ALBI-T were always superior to the corresponding scores. When the indocyanine green retention test (<30%) was used as an additional cutoff value for ALBI score (-2.270, area under the curve 0.828) to divide ALBI grade into 4 levels (modified ALBI [mALBI] grade), mALBI grade was able to stratify the prognosis of patients at any TNM stage in order of grade. Modified ALBI-T (mALBI-T), using mALBI grading and TNM, produced a more detailed stratification for prognosis. Conclusion: The predictive value for prognosis of ALBI-T was found to be equal to that of JIS and m-JIS. In addition, mALBI grading and mALBI-T, as proposed in the present study, might provide a more detailed assessment of the hepatic function and prognosis of HCC patients. (C) 2017 S. Karger AG, Basel
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• Lenvatinib in Advanced Hepatocellular Carcinoma, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 6(4), 253 - 263, 2017 , Refereed
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• New Era of the Management of Liver Diseases and Liver Cancer: State-of-the-Art Progress in 2017, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 493 - 497, 2017 , Refereed
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• Non-Hypervascular Hypointense Hepatic Nodules during the Hepatobiliary Phase of Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid-Enhanced MRI as a Risk Factor of Intrahepatic Distant Recurrence after Radiofrequency Ablation of Hepatocellular Carcinoma, Takayuki Iwamoto, Yasuharu Imai, Takumi Igura, Sachiyo Kogita, Yoshiyuki Sawai, Kazuto Fukuda, Yoshitaka Yamaguchi, Yasushi Matsumoto, Masanori Nakahara, Osakuni Morimoto, Hiroshi Ohashi, Norihiko Fujita, Masatoshi Kudo, Tetsuo Takehara, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 574 - 582, 2017 , Refereed
  Summary:Background: Non-hypervascular hypointense hepatic nodules during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI have been reported to be associated with intrahepatic distant recurrence (IDR) after hepatectomy or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). IDR is categorized into hypervascular transformation of non-hypervascular hypointense hepatic nodules and new intrahepatic recurrence. The aim of this study was to evaluate the relationship between non-hypervascular hypointense hepatic nodules on Gd-EOB-DTPA-enhanced MRI and IDR after RFA, focusing on new intrahepatic recurrence. Methods: Ninety-one consecutive patients with 115 HCCs undergoing pretreatment Gd-EOB-DTPA-enhanced MRI and RFA for treatment of HCC were enrolled. Results: Of the 91 patients who underwent RFA for HCC, 24 had non-hypervascular hypointense hepatic nodules on pretreatment Gd-EOB-DTPA-enhanced MRI. Recurrences were observed in 15 and 19 patients with and without non-hypervascular hypointense hepatic nodules, respectively. Of the 15 recurrences in patients with non-hypervascular hypointense hepatic nodules, 10 patients had new intrahepatic recurrences. The cumulative incidence of new intrahepatic recurrence was significantly higher in patients with non-hypervascular hypointense hepatic nodules than in those without non-hypervascular hypointense hepatic nodules (p < 0.0001). Multivariate analysis revealed that the presence of non-hypervascular hypointense hepatic nodules and Child-Pugh score were independent risk factors for new intrahepatic recurrence. Conclusions: Non-hypervascular hypointense hepatic nodules during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI were a useful predictive factor for IDR, particularly for new intrahepatic recurrence, after RFA. (C) 2017 S. Karger AG, Basel
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• Hand-Foot Syndrome and Post-Progression Treatment Are the Good Predictors of Better Survival in Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Study., Chikara Ogawa, Masahiro Morita, Akina Omura, Teruyo Noda, Atsushi Kubo, Toshihiro Matsunaka, Hiroyuki Tamaki, Mitsushige Shibatoge, Akemi Tsutsui, Tomonori Senoh, Takuya Nagano, Kouichi Takaguchi, Joji Tani, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Akio Moriya, Masaharu Ando, Akihiro Deguchi, Yasutaka Kokudo, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, Oncology, Oncology, 93 Suppl 1(in press), 113 - 119, 2017 , Refereed
  Summary:OBJECTIVE: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. METHODS: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. RESULTS: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). CONCLUSION: In sorafenib therapy, patients with HFS and those who received post-progression treatment exhibited good OS.
  DOI
• Role of Immune Checkpoint Blockade in the Treatment for Human Hepatocellular Carcinoma, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 618 - 622, 2017 , Refereed
  Summary:With the development of molecular targeting therapy, several treatment options for advanced hepatocellular carcinoma (HCC) have become available in cases where curative and other palliative treatments, such as radiofrequency ablation, surgical resection, and transarterial chemoembolization, are not applicable. However, with the detection of a variety of mutations in cancer-related genes in a single tumor, molecular heterogeneity is commonly observed in HCC. Therefore, mutations in the major cellular signaling pathways underlie the development of resistance to molecular targeting agents. On the contrary, immune checkpoint inhibitors have proven effective in patients who are refractory to conventional treatments and molecular targeting therapy. Several clinical trials are currently investigating the efficacy of immune checkpoint inhibitors both individually and in combination with other types of anticancer agents. In this review, we focus on the potential of immune checkpoint blockade in the treatment of human HCC. (C) 2017 S. Karger AG, Basel
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• Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 611 - 617, 2017 , Refereed
  Summary:Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC. (C) 2017 S. Karger AG, Basel
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• Hepatic Function during Repeated TACE Procedures and Prognosis after Introducing Sorafenib in Patients with Unresectable Hepatocellular Carcinoma: Multicenter Analysis, Atsushi Hiraoka, Takashi Kumada, Masatoshi Kudo, Masashi Hirooka, Yohei Koizumi, Yoichi Hiasa, Kazuto Tajiri, Hidenori Toyoda, Toshifumi Tada, Hironori Ochi, Koji Joko, Noritomo Shimada, Akihiro Deguchi, Toru Ishikawa, Michitaka Imai, Kunihiko Tsuji, Kojiro Michitaka, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 602 - 610, 2017 , Refereed
  Summary:Background/Aim: We evaluated the relationship of hepatic function with repeated transarterial catheter chemoembolization (TACE) and prognosis after sorafenib treatment in various patient cohorts. Methods: Study 1 comprised of 212 Barcelona clinic liver cancer stage-B (BCLC-B) HCC patients classified as Child-Pugh A (CP-A) and who had received repeated TACE treatments (r-TACE) (naive: recurrence = 66: 146). Study 2 comprised of 435 patients with unresectable HCC classified as CP-A in who sorafenib was introduced (naive: recurrence = 37: 398; CP score 5: 6 = 282: 153; macrovessel invasion [MVI]+: extrahepatic metastasis [EHM]+ both negative = 124: 226: 143). Changes in hepatic function along with CP and albumin-bilirubin (ALBI) score/grade during r-TACE in Study 1, and prognosis after introducing sorafenib in Study 2 were evaluated. Results: Hepatic function worsened to CP-B in 9-14% with each TACE procedure, while 18-21% had a change of classification from ALBI-1 to ALBI-2. When the prognosis of patients with the best CP score of 5 was analyzed, those with ALBI-1 (n = 154) had a better outcome than those with ALBI-2 (n = 128) (MST 17.5 vs. 9.9 months; p = 0.01), while ALBI-1 (n = 43) patients also showed a better outcome than ALBI-2 (n = 34) patients with a CP score of 5 without MVI/EHM (MST: 17.5 vs. 10.0 months; p = 0.029). The Akaike's Information criterion for ALBI-grade (MST: grade 1 vs. 2 = 16.9 vs. 10.4 months; p = 0.001) was also better than that for CP (MST: score 5 vs. 6 = 14.4 vs. 10.5 months; p = 0.003) (3195.6 vs. 3197.5) in all 435 patients. Conclusion: The rate of patients with downgraded hepatic function during r-TACE, especially with regard to ALBI-grade, was not low. ALBI-grade was shown to be a better hepatic function assessment tool than CP in patients receiving sorafenib treatment. Strict judgment of TACE-refractory status in patients with unresectable HCC is needed to improve prognosis before downgrading the hepatic function. (C) 2017 S. Karger AG, Basel
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• Hemodynamic Changes on Cone-Beam Computed Tomography during Balloon-Occluded Transcatheter Arterial Chemoembolization Using Miriplatin for Hepatocellular Carcinoma: A Preliminary Study, Toru Ishikawa, Michitaka Imai, Takashi Owaki, Hiroki Sato, Yujiro Nozawa, Tomoe Sano, Akito Iwanaga, Keiichi Seki, Terasu Honma, Toshiaki Yoshida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 598 - 601, 2017 , Refereed
  Summary:Background/Aim: Balloon-occluded transcatheter arterial chemoembolization (B-TACE) using miriplatin (MPT) is anticipated as a new strategy for hepatocellular carcinoma (HCC). This study was aimed at evaluating the hemodynamic changes with/without balloon occlusion of the hepatic artery, correlation of cone-beam CT (CBCT) pixels, and CT value after B-TACE for HCC. Methods: A total of 52 patients with HCC, who underwent B-TACE using MPT in addition to the balloon-occluded CBCT hepatic arteriography, were studied. Results: After balloon occlusion, CBCT pixel values increased in 37 lesions, whereas it decreased in 15 lesions. Intratumoral CT values after B-TACE were lower with decreased CBCT pixel values than with increased CBCT pixel values. Conclusion: Hemodynamic changes on CBCT during balloon occlusion can be used to predict the efficacy of B-TACE using MPT. (C) 2017 S. Karger AG, Basel
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• Time to Transcatheter Arterial Chemoembolization Refractoriness in Patients with Hepatocellular Carcinoma in Kinki Criteria Stages B1 and B2, Tadaaki Arizumi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 589 - 597, 2017 , Refereed
  Summary:Background: Transarterial chemoembolization (TACE) is recommended for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage B. However, because of the heterogeneity of HCC in BCLC stage B; various subclassification systems have been proposed to predict the prognosis of patients. Previously, we proposed the Kinki criteria for precise classification of HCC cases in BCLC stage B. In this study, we compared the time to TACE refractoriness in HCC patients with Kinki criteria substages B1 and B2-HCC. Summary: Between January 2006 and December 2013, 592 HCC patients (substage B1, n = 118; substage B2, n = 170) underwent TACE. Time to progression under TACE treatment was defined as the time to untreatable progression (TTUP). TTUP and changes in liver function were analyzed in patients with substages B1 and B2-HCC. The median TTUP was 25.7 months (95% CI 19.3-37.3) and 16.4 months (95% CI 13.1-20.2) in patients with substage B1-HCC and substage B2-HCC, respectively (p = 0.0050). In patients with substage B2-HCC, median Child-Pugh scores after the first TACE session was significantly different from those after third and fifth TACE sessions (first-third, p = 0.0020; first-fifth, p = 0.0008). Key Message: TACE refractoriness occurred earlier in patients with substage B2-HCC than those with substage B1-HCC; deterioration of liver function with repeated TACE was more obvious in HCC cases with stage-B1 tumor. Shorter TTUP and impaired liver function due to repeated TACE could be responsible for the shorter survival in patients with substage B2-HCC. (C) 2017 S. Karger AG, Basel
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• Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2, Tadaaki Arizumi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Ken Kamata, Kosuke Minaga, Yoriaki Komeda, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 583 - 588, 2017 , Refereed
  Summary:Background: Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). Methods: Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size <= 6 cm and total number of tumors <= 6; B2b group, size <= 6 cm and number >6; B2c group, size >6 cm and number <= 6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. Results: There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). Conclusion: No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b + B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function. (C) 2017 S. Karger AG, Basel
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• Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection, Hiroshi Ida, Satoru Hagiwara, Masashi Kono, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Norihisa Yada, Yasunori Minami, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 565 - 573, 2017 , Refereed
  Summary:Background: Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection. Summary: Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/ 17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases. (C) 2017 S. Karger AG, Basel
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• Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals, Masashi Kono, Naoshi Nishida, Satoru Hagiwara, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Kosuke Minaga, Ken Kamata, Yoriaki Komeda, Toshiharu Sakurai, Mamoru Takenaka, Masahiro Takita, Norihisa Yada, Hiroshi Ida, Yasunori Minami, Kazuomi Ueshima, Tomohiro Watanabe, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 556 - 564, 2017 , Refereed
  Summary:Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on a-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP > 5 ng/mL and ALT level >= 20 IU/L after SVR were clarified using multivariate analyses. Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level = 30 IU/L after SVR (p = 0.0430). Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC. (C) 2017 S. Karger AG, Basel
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• Hepatocarcinogenesis Is Associated with Serum Albumin Levels after Sustained Virological Responses with Interferon-Based Therapy in Patients with Hepatitis C, Yasuko Umehara, Satoru Hagiwara, Naoshi Nishida, Toshiharu Sakurai, Hiroshi Ida, Yasunori Minami, Masahiro Takita, Tomohiro Minami, Hirokazu Chishina, Kazuomi Ueshima, Yoriaki Komeda, Tadaaki Arizumi, Tomohiro Watanabe, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 548 - 555, 2017 , Refereed
  Summary:Objective: It is a generally accepted fact that eradication of hepatitis virus C inhibits the subsequent development of hepatocellular carcinoma (HCC). On the contrary, a significant population of patients developed HCC despite sustained virological responses (SVRs) to interferon (IFN) therapy. Methods: A total of 415 patients with chronic hepatitis C, who were treated at our hospital between 2004 and 2014, were enrolled for this study. We examined the risk factors for HCC development after IFN therapy. Results: After analyzing various clinical parameters, it was concluded that a serum albumin (ALB) level <4.0 g/dL and the presence or absence of SVR achievement were risk factors for the development of HCC. When analyzing pre-and posttreatment factors, only a serum ALB level <4.0 g/dL was considered a significant risk factor. The presence or absence of liver fibrosis progression was not identified as a risk factor. Conclusions: In patients with a serum ALB level <4.0 g/dL before IFN therapy, hepatic carcinogenesis after SVR achievement need to be considered. Furthermore, the serum ALB level may be more useful than the degree of fibrosis for the prediction of HCC after SVR in chronic hepatitis C. (C) 2017 S. Karger AG, Basel
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• Comparison of Sofosbuvir Plus Ribavirin Treatment with Pegylated Interferon Plus Ribavirin Treatment for Chronic Hepatitis C Genotype 2, Kayo Seo, Soo Ki Kim, Soo Ryang Kim, Aya Ohtani, Mana Kobayashi, Airi Kato, Eri Morimoto, Yuka Saijo, Ke Ih Kim, Susumu Imoto, Chi Wan Kim, Yoshihiko Yano, Masatoshi Kudo, Yoshitake Hayashi, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 541 - 547, 2017 , Refereed
  Summary:Background: Sofosbuvir plus ribavirin (RBV) therapy showed higher sustained virological response at 12 weeks after treatment (SVR12) than pegylated interferon (peg-IFN) plus RBV; however, liver function, fibrosis, and hepatocellular carcinoma markers have not been assessed so far. Summary: Patients (n = 21) receiving Sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV were enrolled in this study. Changes in alanine aminotransferase (ALT) and alpha-fetoprotein (AFP) levels, platelet (PLT) counts, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) in both groups were assessed in patients achieving SVR12. Also, fibrosis regression was assessed using pathophysiological biomarkers, such as hyaluronic acid, bone morphogenetic protein 7 (BMP-7), and connective tissue growth factor (CTGF) in the Sofosbuvir plus RBV group. In both groups, while the reduction in ALT levels was significant that of AFP was not. Compared with the baseline, although serum PLT count at the end of treatment (EOT) was significantly higher in the Sofosbuvir plus RBV group, it was significantly lower in the peg-IFN plus RBV group. Although a significant decline in fibrosis markers such as FIB-4 and APRI was observed between the baseline and at EOT in the Sofosbuvir plus RBV group, no significant change of these markers was observed in the pegIFN plus RBV group. Moreover, BMP-7 and CTGF were significantly lower at EOT than the baseline in the Sofosbuvir plus RBV group. Key Message: The treatment with Sofosbuvir plus RBV results in not only a higher SVR, but also improves the liver function and the degree of fibrosis. (C) 2017 S. Karger AG, Basel
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• Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients, Natsuko Kobayashi, Takashi Kumada, Hidenori Toyoda, Toshifumi Tada, Takanori Ito, Masayoshi Kage, Takeshi Okanoue, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 521 - 530, 2017 , Refereed
  Summary:Background: Several laboratory markers used in lieu of liver biopsy are reportedly useful in the diagnosis of nonalcoholic steatohepatitis (NASH). In the present study, we investigated the diagnostic impact of various non-invasive markers for predicting NASH. Methods: A total of 229 nonalcoholic fatty liver disease (NAFLD) patients who underwent liver biopsy were enrolled for the study. The diagnostic ability of various markers to diagnose NASH from NAFLD was investigated. Results: A total of 140 patients were histologically diagnosed with NASH. Of these, 104 had degree 0-2 fibrosis (F0-2), and 36 had degree 3-4 fibrosis (F3-4). Multiple logistic regression analysis identified hyaluronic acid (HA) (OR 1.014; 95% CI 1.002-1.026; p = 0.024), FIB-4 index (OR 2.097; 95% CI 1.177-3.735; p = 0.012), and cytokeratin-18 fragments (CK-18F) (OR 1.002; 95% CI 1.001-1.002; p < 0.001) as factors independently associated with the diagnosis of NASH. The areas under the receiver operating characteristic curves (AUROCs) of HA, FIB-4 index, and CK-18F for the diagnosis of NASH were 0.77, 0.76, and 0.72, respectively. In addition, FIB-4 index (OR 1.907; 95% CI 1.063-3.419; p = 0.03) and CK-18F (OR 1.002; 95% CI 1.001-1.002; p < 0.001) could differentiate between NASH and NAFL, even when NASH patients with advanced fibrosis (F3-4) were excluded. AUROCs of FIB-4 index and CK-18F for the diagnosis of NASH with mild fibrosis (F0-2) from NAFLD were 0.70 and 0.70, respectively. Conclusions: FIB-4 index and CK-18F have good diagnostic abilities not only for NASH overall, but also for NASH with mild fibrosis. (C) 2017 S. Karger AG, Basel
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• Diagnosis of Fibrosis and Activity by a Combined Use of Strain and Shear Wave Imaging in Patients with Liver Disease, Norihisa Yada, Nobuhura Tamaki, Yohei Koizumi, Masashi Hirooka, Osamu Nakashima, Yoichi Hiasa, Namiki Izumi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 515 - 520, 2017 , Refereed
  Summary:Objective: Performing shear wave imaging is simple, but can be difficult when inflammation, jaundice, and congestion are present. Therefore, the correct diagnosis of liver fibrosis using shear wave imaging alone might be difficult in mild-to-moderate fibrosis cases. Strain imaging can diagnose liver fibrosis without the influence of inflammation. Therefore, the combined use of strain and shear wave imaging (combinational elastography) for cases without jaundice and congestion might be useful for evaluating fibrosis and inflammation. Methods: We enrolled consecutive patients with liver disease, without jaundice or liver congestion. Strain and shear wave imaging, blood tests, and liver biopsy were performed on the same day. The liver fibrosis index (LF index) was calculated by strain imaging; real-time tissue elastography, and the shear wave velocity (V-s) was calculated by shear wave imaging. Fibrosis index (F index) and activity index (A index) were calculated as a multiple regression equation for determining hepatic fibrosis and inflammation using histopathological diagnosis as the gold standard. The diagnostic ability of F index for fibrosis and A index for inflammation were compared using LF index and V-s. Results: The total number of enrolled cases was 388. The area under the receiver operating characteristic (AUROC) was 0.87, 0.80, 0.83, and 0.80, at diagnosis of fibrosis stage with an F index of F1 or higher, F2 or higher, F3 or higher, and F4, respectively. The AUROC was 0.94, 0.74, and 0.76 at diagnosis of activity grade with an A index of A1 or higher, A2 or higher, and A3, respectively. The diagnostic ability of F index for liver fibrosis and A index for inflammation was higher than for other conventional diagnostic values. Conclusions: The combined use of strain and shear wave imaging (combinational elastography) might increase the positive diagnosis of liver fibrosis and inflammation. (C) 2017 S. Karger AG, Basel
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• Clinicopathological Study of Autoimmune Hepatitis Cases That Were Difficult to Differentiate from Drug-Induced Liver Injury, Akemi Tsutsui, Kenichi Harada, Koichi Tsuneyama, Tomonori Senoh, Takuya Nagano, Koichi Takaguchi, Midori Ando, Satoko Nakamura, Koichi Mizobuchi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 506 - 514, 2017 , Refereed
  Summary:Aim: Acute-onset autoimmune hepatitis (AIH) histopathologically presents with features of acute hepatitis and lacks a specific diagnostic method. Also, AIH is often difficult to differentiate from drug-induced liver injury (DILI). We aimed to investigate the final clinical diagnosis of these cases, and compare the clinical, biochemical, and histological characteristics of AIH vs. DILI. Methods: We examined the Digestive Disease Week Japan 2004 (DDW-J) scale scores, AIH scores, clinical data, and pathological findings in 20 patients in whom it was difficult to differentiate autoimmune liver disease from DILI. Results: In cases with a DDW-J scale score of >= 5, there was a good correlation between the final diagnosis and DDW-J scale assessments, but in cases with a DDW-J scale score of <= 4 they did not correlate well. The scores for pathological findings, such as cobblestone hepatocellular change (p = 0.015), interface hepatitis (p = 0.012), and prominent plasma cells in portal areas (p = 0.011), were higher in the AIH group than in the DILI group. Conclusion: This study showed that DDW-J scale was useful for differentiating AIH from DILI in cases with a DDW-J scale score of >= 5. The histologic features of AIH were characterized by cobblestone hepatocellular change, interface hepatitis, and plasma cell infiltration of the portal region. (C) 2017 S. Karger AG, Basel
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• Abdominal Ultrasound Findings of Tumor-Forming Hepatic Malignant Lymphoma, Shogo Kitahata, Atsushi Hiraoka, Masatoshi Kudo, Taisei Murakami, Marie Ochi, Hirofumi Izumoto, Hidetaro Ueki, Miho Kaneto, Toshihiko Aibiki, Tomonari Okudaira, Hiroka Yamago, Yuji Miyamoto, Ryuichiro Iwasaki, Hideomi Tomida, Kenichiro Mori, Masato Kishida, Hideki Miyata, Eiji Tsubouchi, Masashi Hirooka, Yohei Koizumi, Tomoyuki Ninomiya, Yoichi Hiasa, Kojiro Michitaka, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 35(6), 498 - 505, 2017 , Refereed
  Summary:Aim/Background: Evaluations of abdominal ultrasonography (US) findings of primary and secondary tumor-forming hepatic malignant lymphoma (HML) have not been adequately reported. In this study, we elucidated US and contrast-enhanced US (CEUS) findings in patients with HML. Materials/Methods: From January 2006 to March 2017, 25 patients with HML were enrolled (primary 7, secondary 18), each of whom was diagnosed pathologically. They were divided into 2 groups based on tumor diameter (cutoff, 30 mm). US imaging findings were retrospectively analyzed. Results: All tumors in patients with a small HML (<30 mm in diameter, small group, n = 14) were revealed as homogeneous hypo-echoic type (100%), with penetrating sign observed in only 1 patient. Tumors in 11 patients in the small group, examined with CEUS, showed homogeneous enhancement in the early vascular phase (91%) and a washout pattern in the portal phase (100%), and they were revealed as defective in the post-vascular phase (100%). In the large group (>= 30 mm; n = 11), tumors were revealed as a heterogeneous hypo-echoic lesion in 10 (91%) and penetrating sign was observed in 8 (73%). Dilatation of the distal intrahepatic bile duct by the tumor was observed in 4 patients in the large group. In 7 large group patients examined with CEUS, imaging findings in the early vascular phase varied, with 5 (71%) showing a washout pattern in the portal phase and 5 (71%) revealed as defective in the post-vascular phase. Conclusion: We found that US imaging features of HML differ depending on the tumor diameter. (C) 2017 S. Karger AG, Basel
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• A Case of Waldenstrom Macroglobulinemia with Temporary Appearance of 7S IgM Half Molecule, Mayumi Imoto, Koji Yoshida, Yasuhiro Maeda, Ken-Ichi Nakae, Masatoshi Kudo, Ikunosuke Sakurabayashi, Toshiyuki Yamada, Toshinori Kamisako, CLINICAL LABORATORY, CLINICAL LABORATORY, 63(5-6), 983 - 989, 2017 , Refereed
  Summary:Background: We encountered a rare case of Waldenstrom macroglobulinemia with temporary appearance of 7S IgM half molecule and with monoclonal proteins binding to agarose gel. Methods: The patient's serum and urine were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The N-terminal amino acid sequences of the IgM with abnormal mass (68 kDa) were determined and compared with those of known immunoglobulin. Results: The 68 kDa IgM consisted of a defective Et chain (36 kDa) and an intact kappa chain. N-terminal amino acid sequence analysis demonstrated that the defective It chain had the variable region of IgM. The agarose gel-binding ability of the IgM-w M-protein was lost after reduction or alkaline treatment of serum. Conclusions: The 7S half molecule IgM in the present case may miss a large part of the constant region of the mu chain.
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• The Overall Survival of Patients with Hepatocellular Carcinoma Correlates with the Newly Defined Time to Progression after Transarterial Chemoembolization, Tadaaki Arizumi, Kazuomi Ueshima, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Yoriaki Komeda, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 6(3), 227 - 235, 2017 , Refereed
  Summary:Aim/Background: The ultimate aim of any treatment for hepatocellular carcinoma (HCC) is to improve overall survival (OS); however, the clinical significance of time to progression (TTP) after transarterial chemoembolization (TACE) is unclear. This retrospective study examined the association between OS and the newly defined time to TACE progression (TTTP) to assess whether TTTP can be an alternative to OS in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B. Methods: Between January 2006 and December 2013, 592 patients with HCC (BCLC B1, n = 118; BCLC B2, n = 170) underwent TACE. TTTP was then redefined as time to progression from the first image taken after TACE. The relationship between TTTP and OS was then examined based on survival time. Results: Survival analysis revealed significant differences in the OS of patients with BCLC B1 and those with BCLC B2 (median OS: 42.3 months, 95% confidence interval [CI] 34.4-50.7; and 29.3 months, 95% CI 26.1-37.6, respectively, p = 0.0348). The median TTTP values were 9.5 months (95% CI 7.0-10.9) and 5.3 months (95% CI 4.6-6.7), respectively (p = 0.0078). There was a moderate positive correlation between OS and TTTP for both B1 (R-2 = 0.6563, p = 0.0045) and B2 (R-2 = 0.6433, p = 0.0052) substages. There was also a positive correlation between OS and TTTP for the combined B1 and B2 substages (R-2 = 0.6590, p = 0.0024). Conclusions: There was a moderate correlation between the TTTP and OS of patients with HCC after TACE therapy, where the patients with short TTTP represented short OS, indicating that TTTP is an alternative parameter for survival analysis of HCC patients with BCLC stage B tumors who undergo TACE. (C) 2017 S. Karger AG, Basel
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• Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update, M. Kudo, LIVER CANCER, LIVER CANCER, 6(1), 1 - 12, 2017 , Refereed
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• Stent migration into the abdominal cavity after EUS-guided hepaticogastrostomy, Kosuke Minaga, Masayuki Kitano, Yukitaka Yamashita, Yasuki Nakatani, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 85(1), 263 - 264, Jan. 2017 , Refereed
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• IgG4-Related Disease and Innate Immunity, Tomohiro Watanabe, Kouhei Yamashita, Masatoshi Kudo, IGG4-RELATED DISEASE, IGG4-RELATED DISEASE, 401, 115 - 128, 2017 , Refereed
  Summary:An increased number of clinicopathological studies on autoimmune pancreatitis, cholangitis, and sialoadenitis have led to the recognition of immunoglobulin G4-related disease (IgG4-RD) as a novel disorder, characterized by elevated levels of serum IgG4 and infiltration of IgG4-expressing plasma cells in the affected organs. Although the immunological background associated with the development of IgG4-RD remains poorly understood, recent studies have suggested involvement of the innate immune response in its pathogenesis. Peripheral blood innate immune cells, such as plasmacytoid dendritic cells and monocytes isolated from patients with IgG4-RD, promote IgG4 production by B cells. Activation of the innate immune response by microbe-and/or damage-associated molecular patterns stimulates production of type I interferon and B cell-activating factor by innate immune cells and results in IgG4 production by B cells. Elucidation of the innate immune response associated with IgG4-RD may help identify a new therapeutic target for this immune disorder.
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• Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer, Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Tomohiro Watanabe, Masayuki Kitano, Naoshi Nishida, Jun Fujita, Masatoshi Kudo, INFLAMMATORY BOWEL DISEASES, INFLAMMATORY BOWEL DISEASES, 23(1), 57 - 65, Jan. 2017 , Refereed
  Summary:Background: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and HSPA4 are involved in the refractory clinical course and development of CAC. RNA-binding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. Methods: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3(-/-)) mice. Results: Expression of RBM3 was correlated with the expression of stress response proteins Cirp, HSPA4, and HSP27 in the colonic mucosa of patients with IBD. Significant correlation was observed between the expression of RBM3 and that of Bcl-xL or stem cell markers. RBM3 expression increased and significantly correlated with R-spondin expression in the colonic mucosa of patients with refractory IBD, a condition associated with increased cancer risk, and RBM3 was overexpressed in human CACs. In the murine CAC model, Rbm3 deficiency decreased R-spondin and Bcl-xL expression and increased apoptotic cell number in the colonic mucosa, leading to reduced tumor multiplicity. Transplantation of wild-type and Rbm3(-/-) bone marrow did not alter tumor burden, indicating the importance of RBM3 in epithelial cells. Conclusions: Our findings indicated that RBM3 was required for efficient inflammatory carcinogenesis in the murine CAC model and suggested that RBM3 could be a predictive biomarker of CAC risk and a new therapeutic target for cancer prevention in patients with IBD.
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• Immune Checkpoint Inhibition in Hepatocellular Carcinoma: Basics and Ongoing Clinical Trials, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 50 - 62, 2017 , Refereed
  Summary:Clinical trials of antibodies targeting the immune checkpoint inhibitors programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or cytotoxic T-Iymphocyte-associated protein 4 (CTLA-4) for the treatment of advanced hepatocellular carcinoma (HCC) are ongoing. Expansion cohorts of a phase I/II trial of the anti-PD-1 antibody nivolumab in advanced HCC showed favorable results. Two phase III studies are currently ongoing: a comparison of nivolumab and sorafenib in the first-line setting for advanced HCC, and a comparison of the anti-PD-1 antibody pembrolizumab and a placebo in the second-line setting for patients with advanced HCC who progressed on sorafenib therapy. The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies is being evaluated in other phase I/II trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. Immune checkpoint inhibitors may therefore open new doors to the treatment of HCC. (C) 2017 S. Karger AG, Basel
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• Albumin-Bilirubin (ALBI) Grade as Part of the Evidence-Based Clinical Practice Guideline for HCC of the Japan Society of Hepatology: A Comparison with the Liver Damage and Child-Pugh Classifications, Atsushi Hiraoka, Takashi Kumada, Masatoshi Kudo, Masashi Hirooka, Kunihiko Tsuji, Ei Itobayashi, Kazuya Kariyama, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Toshifumi Tada, Hidenori Toyoda, Kazuhiro Nouso, Kouji Joko, Hideki Kawasaki, Yoichi Hiasa, Kojiro Michitaka, LIVER CANCER, LIVER CANCER, 6(3), 204 - 215, 2017 , Refereed
  Summary:Aim/Background: The purpose of this study was to evaluate the validity of 3 classifications for assessing liver function, the liver damage and Child-Pugh classifications and the newly proposed albumin-bilirubin (ALBI) grade, in order to examine the feasibility of evaluating hepatic function using ALBI grade with the hepatocellular carcinoma (HCC) treatment algorithm used in Japan. Methods: We analyzed the medical records of 3,495 Japanese HCC patients admitted from 2000 to 2015, which were comprised of 1,580 patients hospitalized in the Ehime Prefecture area and used as a training cohort (Ehime group), and 1,915 others who were used for validation (validation group). ALBI score used for grading (<= -2.60 = grade 1, greater than -2.60 to <= -1.39 = grade 2, greater than -1.39 = grade 3) as well as clinical features and prognosis (Japan Integrated Staging [JIS], modified JIS, ALBI-TNM [ALBI-T] score) were retrospectively investigated. Results: For prediction of liver damage A, the values for sensitivity and specificity, positive predictive and negative predictive values, and positive and negative likelihood ratios of ALBI-1 and Child-Pugh A were similar among the 2 groups. Akaike information criterion results showed that prognosis based on ALBI grade/ALBI-T score was better than that based on liver damage/modified JIS score and Child-Pugh/JIS score (22,291.8/21,989.4, 22,379.6/22,076.0, 22,392.1/22,075.1, respectively). The cutoff values for ALBI score for indocyanine green retention rate at 15 min (ICG-R15) < 10, < 20, and < 30% were -2.623 (area under the curve [AUC]: 0.798), -2.470 (AUC: 0.791), and -2.222 (AUC: 0.843), respectively. The distribution of ICG-R15 (< 10%, 10 to < 20%, 20 to < 30%, and >= 30%) for ALBI grade 1 was similar to that for liver damage A. There were only small differences with regard to therapeutic selection with the Japanese HCC treatment algorithm between liver damage and ALBI grade. Conclusion: ALBI grade is a useful and easy classification system for assessment of hepatic function for therapeutic decision making. (C) 2017 S. Karger AG, Basel
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• Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent, Ken Kamata, Mamoru Takenaka, Masayuki Kitano, Shunsuke Omoto, Takeshi Miyata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Toshiharu Sakurai, Tomohiro Watanabe, Naoshi Nishida, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 23(4), 661 - 667, Jan. 2017 , Refereed
  Summary:AIM To assess the long-term outcomes of this procedure after removal of self-expandable metal stent (SEMS). The efficacy and safety of endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with SEMS were also assessed. METHODS Between January 2010 and April 2015, 12 patients with acute calculous cholecystitis, who were deemed unsuitable for cholecystectomy, underwent EUS-GBD with a SEMS. EUS-GBD was performed under the guidance of EUS and fluoroscopy, by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a SEMS. The SEMS was removed and/or replaced with a 7-Fr plastic pigtail stent after cholecystitis improved. The technical and clinical success rates, adverse event rate, and recurrence rate were all measured. RESULTS The rates of technical success, clinical success, and adverse events were 100%, 100%, and 0%, respectively. After cholecystitis improved, the SEMS was removed without replacement in eight patients, whereas it was replaced with a 7-Fr pigtail stent in four patients. Recurrence was seen in one patient (8.3%) who did not receive a replacement pigtail stent. The median follow-up period after EUS-GBD was 304 d (78-1492). CONCLUSION EUS-GBD with a SEMS is a possible alternative treatment for acute cholecystitis. Long-term outcomes after removal of the SEMS were excellent. Removal of the SEMS at 4-wk after SEMS placement and improvement of symptoms might avoid migration of the stent and recurrence of cholecystitis due to food impaction.
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• Albumin-Bilirubin Grade and Hepatocellular Carcinoma Treatment Algorithm, Masatoshi kudo, LIVER CANCER, LIVER CANCER, 6(3), 185 - 188, 2017 , Refereed
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• A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib, M. Kudo, LIVER CANCER, LIVER CANCER, 6(3), 177 - 184, 2017 , Refereed
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• CD68-Positive Cells in Hepatic Angiomyolipoma, Hitoshi Tochio, Eriko Tamaki, Yukihiro Imai, Nobuhiro Iwasaki, Kazushi Minowa, Hobyung Chung, Yoshiki Suginoshita, Tetsurou Inokuma, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 35 - 39, 2017 , Refereed
  Summary:Four resected specimens of hepatic angiomyolipoma in which uptake of Sonazoid was observed in the postvascular phase of Sonazoid-enhanced ultrasonography were analyzed. Macrophage localization in the tumor was revealed pathologically by immunohistochemical staining for CD68. CD68-positive cells were observed in the tumor in all cases. The density of CD68-positive cells was 100/mm(2), and the ratio of CD68-positive cell density in the tumor to that in the surrounding parenchyma was 32-171%. These results suggested that the uptake of the contrast agent Sonazoid was related to the density of CD68-positive cells. (C) 2016 S. Karger AG, Basel
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• immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 40 - 49, 2017 , Refereed
  Summary:Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC. (C) 2016 S. Karger AG, Basel
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• Influence of Liver Inflammation on Liver Stiffness Measurement in Patients with Autoimmune Hepatitis Evaluation by Combinational Elastography, Norihisa Yada, Toshiharu Sakurai, Tomohiro Minami, Tadaaki Arizumi, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 10 - 15, 2017 , Refereed
  Summary:Objective: In order to evaluate the influence of liver inflammation on liver stiffness measurement (LSM) by the simultaneous use of shear wave and strain imaging (combinational elastography), shear wave and strain imaging were compared before and after initial therapy for autoimmune hepatitis (AIH). Methods: Nine AIH patients initially treated with steroid were enrolled. Transient elastography and real-time tissue elastography were performed just before and 1 month after the start of initial steroid treatment. Blood samples, LSM, and the liver fibrosis index (LFI) were compared. Results: Aspartate aminotransferase (p = 0.002) and alanine aminotransferase (ALT) (p = 0.015) were significantly decreased after initial treatment. The LSM was 15.5 +/- 9.6 kPa at baseline, decreasing to 7.2 +/- 2.3 kPa after initial treatment p = 0.034). The LFI was 1.67 +/- 0.67 at baseline and 1.61 +/- 0.66 after initial treatment; no significant change in LFI was recognized (p = 0.842). Between Delta ALT and Delta LSM, a significant regression equation could be calculated as follows: Delta ALT = -0.55 + 0.654 x Delta LSM. Conclusions: Combinational elastography was useful in evaluating not only the degree of liver fibrosis, but also the degree of liver inflammation in AIH. (C) 2017 S. Karger AG, Basel
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• A New Horizon Liver Disease, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 1 - 2, 2017 , Refereed
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• Outcome of Combination Therapy with Sofosbuvir and Ledipasvir for Chronic Type C Liver Disease, Satoru Hagiwara, Naoshi Nishida, Tomohiro Watanabe, Toshiharu Sakurai, Hiroshi Ida, Yasunori Minami, Masahiro Takita, Tomohiro Minami, Mina Iwanishi, Hirokazu Chishina, Kazuomi Ueshima, Yoriaki Komeda, Tadaaki Arizumi, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 3 - 9, 2017 , Refereed
  Summary:Introduction: Recently, the treatment of chronic hepatitis C has markedly advanced. A phase III clinical study of combination therapy with sofosbuvir (SOF) and ledipasvir (LDV) was conducted in Japan, and the additive therapeutic effects were reported. In this study, we report the results of treatment in our hospital. Methods: Of 147 patients with chronic type C liver disease who had consulted our hospital since September 2015 and received SOF/LDV therapy, in 91 subjects a sustained virological response of 12 weeks (SVR12) could be evaluated. Results: In all 91 patients, end treatment response was achieved. Subsequently, recrudescence was noted in 1 before the completion of treatment (week 12); an SVR12 was achieved in 90 patients (99%). The following adverse reactions were observed in 3 patients (3.3%): bradycardia, paroxysmal atrial fibrillation, and heart failure with QT prolongation, which were associated with heart disease. Conclusion: A favorable SVR was achieved by SOF/LDV therapy even in elderly patients, those with liver cirrhosis, or those having undergone radical treatment of liver cancer. Furthermore, a high tolerance was demonstrated, but adverse reactions associated with the heart may appear in patients with heart disease as an underlying disease; strict management during treatment is necessary. (C) 2016 S. KargerAG, Basel
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• Malignant Transformation of Hepatocellular Adenoma, Wing Yee Kwok, Satoru Hagiwara, Naoshi Nishida, Tomohiro Watanabe, Toshiharu Sakurai, Hiroshi Lda, Yasunori Minami, Masahiro Takita, Tomohiro Minami, Mina Lwanishi, Hirokazu Chishina, Masashi Kono, Kazuomi Ueshima, Yoriaki Komeda, Tadaaki Arizumi, Eisuke Enoki, Takuya Nakai, Tsutomu Kumabe, Osamu Nakashima, Fukuo Kondo, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 16 - 28, 2017 , Refereed
  Summary:The patient was a 20-year-old male in whom a hepatic hyper vascular mass accompanied by intratumoral hemorrhage was detected on examination for epigastric pain. Based on the enlargement of the mass and diagnostic imaging, hepatocellular adenoma (HCA) was suspected and hepatectomy was performed. The lesion was diagnosed as malignant transformation of P-catenin-activated HCA. There are only few reports of cases with malignant transformation of HCA in Japan; it is necessary to accumulate cases to investigate it. (C) 2016 S. Karger AG, Basel
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• Contrast-Enhanced Tissue Harmonic Imaging versus Phase Inversion Harmonic Sonographic Imaging for the Delineation of Hepatocellular Carcinomas, Masashi Kono, Yasunori Minami, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Yoriaki Komeda, Toshiharu Sakurai, Masahiro Takita, Norihisa Yada, Hiroshi Ida, Satoru Hagiwara, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 92, 29 - 34, 2017 , Refereed
  Summary:Objective: To compare contrast tissue harmonic imaging (THI) with low mechanical index (MI) and conventional contrast harmonic imaging (CHI) with respect to lesion visibility of hepatocellular carcinoma (HCC). Methods: One hundred and twenty-five patients (84 men and 41 women, age range 39-94 years, mean age 74 years) with 100 naive HCCs and 30 lesions after radiofrequency ablation (RFA) for HCC were evaluated. One hundred and four patients had liver cirrhosis of Child-Pugh class A, and the remaining 21 had Child-Pugh class B cirrhosis. The lesion conspicuity and intratumoral echogenicity during the postvascular phase were compared using conventional CHI and contrast THI with low MI. Results:The MI values ranged from 0.20 to 0.30 on conventional CHI and from 0.30 to 0.35 on contrast THI. Regarding HCC lesion conspicuity, contrast THI with low MI was clearer in 79 lesions (60.8%), equal in 34 lesions (26.2%), and less clear in 17 lesions (13.1%) when compared with conventional CHI. The lesion conspicuity with contrast THI was significantly better than that with conventional CHI (p < 0.01). All of the postablative lesions were well delineated in patients who received RFA. Conclusion: Low-MI contrast THI was superior to conventional CHI with respect to lesion visibility of HCCs and might offer good imaging for the guiding of RFA. (C) 2016 S. Karger AG, Basel
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• Diagnosis of Hepatocellular Carcinoma with Non-Invasive Imaging: a Plea for Worldwide Adoption of Standard and Precise Terminology for Describing Enhancement Criteria, Fabio Piscaglia, Masatoshi Kudo, Kwang-Hyub Han, Claude Sirlin, ULTRASCHALL IN DER MEDIZIN, ULTRASCHALL IN DER MEDIZIN, 38(1), 9 - 11, Jan. 2017 , Refereed
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• Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer, Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Tomohiro Watanabe, Masayuki Kitano, Naoshi Nishida, Jun Fujita, Masatoshi Kudo, INFLAMMATORY BOWEL DISEASES, INFLAMMATORY BOWEL DISEASES, 23(1), 57 - 65, Jan. 2017 , Refereed
  Summary:Background: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and HSPA4 are involved in the refractory clinical course and development of CAC. RNA-binding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. Methods: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3(-/-)) mice. Results: Expression of RBM3 was correlated with the expression of stress response proteins Cirp, HSPA4, and HSP27 in the colonic mucosa of patients with IBD. Significant correlation was observed between the expression of RBM3 and that of Bcl-xL or stem cell markers. RBM3 expression increased and significantly correlated with R-spondin expression in the colonic mucosa of patients with refractory IBD, a condition associated with increased cancer risk, and RBM3 was overexpressed in human CACs. In the murine CAC model, Rbm3 deficiency decreased R-spondin and Bcl-xL expression and increased apoptotic cell number in the colonic mucosa, leading to reduced tumor multiplicity. Transplantation of wild-type and Rbm3(-/-) bone marrow did not alter tumor burden, indicating the importance of RBM3 in epithelial cells. Conclusions: Our findings indicated that RBM3 was required for efficient inflammatory carcinogenesis in the murine CAC model and suggested that RBM3 could be a predictive biomarker of CAC risk and a new therapeutic target for cancer prevention in patients with IBD.
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• Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial, Jordi Bruix, Shukui Qin, Philippe Merle, Alessandro Granito, Yi-Hsiang Huang, Gyrogy Bodoky, Marc Pracht, Osamu Yokosuka, Olivier Rosmorduc, Valeriy Breder, Rene Gerolami, Gianluca Masi, Paul J. Ross, Tianqiang Song, Jean-Pierre Bronowicki, Isabelle Ollivier-Hourmand, Masatoshi Kudo, Ann-Lii Cheng, Josep M. Llovet, Richard S. Finn, Marie-Aude LeBerre, Annette Baumhauer, Gerold Meinhardt, Guohong Han, LANCET, LANCET, 389(10064), 56 - 66, Jan. 2017 , Refereed
  Summary:Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (>= 400 mg/day for >= 20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2: 1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and a-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50-0.79; one-sided p<0.0001); median survival was 10.6 months (95% CI 9.1-12.1) for regorafenib versus 7.8 months (6.3-8.8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer.
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• Removal of diminutive colorectal polyps: A prospective randomized clinical trial between cold snare polypectomy and hot forceps biopsy, Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, George Tribonias, Kazuki Okamoto, Masashi Kono, Mitsunari Yamada, Teppei Adachi, Hiromasa Mine, Tomoyuki Nagai, Yutaka Asakuma, Satoru Hagiwara, Shigenaga Matsui, Tomohiro Watanabe, Masayuki Kitano, Takaaki Chikugo, Yasutaka Chiba, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 23(2), 328 - 335, Jan. 2017 , Refereed
  Summary:AIM To compare the efficacy and safety of cold snare polypectomy (CSP) and hot forceps biopsy (HFB) for diminutive colorectal polyps. METHODS This prospective, randomized single-center clinical trial included consecutive patients >= 20 years of age with diminutive colorectal polyps 3-5 mm from December 2014 to October 2015. The primary outcome measures were en-bloc resection (endoscopic evaluation) and complete resection rates (pathological evaluation). The secondary outcome measures were the immediate bleeding or immediate perforation rate after polypectomy, delayed bleeding or delayed perforation rate after polypectomy, use of clipping for bleeding or perforation, and polyp retrieval rate. Prophylactic clipping after polyp removal wasn't routinely performed. RESULTS Two hundred eight patients were randomized into the CSP (102), HFB (106) and 283 polyps were evaluated (CSP: 148, HFB: 135). The en-bloc resection rate was significantly higher with CSP than with HFB [99.3% (147/148) vs 80.0% (108/135), P < 0.0001]. The complete resection rate was significantly higher with CSP than with HFB [80.4% (119/148) vs 47.4% (64/135), P < 0.0001]. The immediate bleeding rate was similar between the groups [8.6% (13/148) vs 8.1% (11/135), P = 1.000], and endoscopic hemostasis with hemoclips was successful in all cases. No cases of perforation or delayed bleeding occurred. The rate of severe tissue injury to the pathological specimen was higher HFB than CSP [52.6% (71/135) vs 1.3% (2/148), P < 0.0001]. Polyp retrieval failure was encountered CSP (7), HFB (2). CONCLUSION CSP is more effective than HFB for resecting diminutive polyps. Further long-term follow-up study is required.
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• MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in human Hepatocellular Carcinoma, Naoshi Nishida, Tadaaki Arizumi, Satoru Hagiwara, Hiroshi Ida, Toshiharu Sakurai, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 6(2), 113 - 125, 2017 , Refereed
  Summary:Background: Several studies suggest the role of circulating microRNAs (miRNAs) as biomarkers of hepatocellular carcinoma (HCC). However, the serum miRNA profile associated with the response to sorafenib remains to be elucidated. The aim of this study was to clarify the specific miRNAs in serum that could predict the early response of HCC to sorafenib treatment. Summary: Analyzing the sera from 16 HCC patients, we selected five miRNAs that showed differences in serum levels between patients with and without tumor responses among 179 known secretory miRNAs by using locked nucleic acid probe -based quantitative PCR. Through further analysis using a validation cohort that included 53 HCC patients who underwent sorafenib treatment and 8 healthy control subjects, we found that miR-181a-5p and miR-3395p showed significant differences in serum levels among patients with partial response (PR), stable disease (SD), and progressive disease (PD), where PR patients showed the highest and PD the lowest levels. We also analyzed the factors associated with disease control (DC; PR or SD) 3 months after the initiation of sorafenib treatment; patients with DC showed a significantly higher level of serum miR-181a-5p than non -DC patients or healthy control subjects (p = 0.0349 and 0.0180 for DC vs. non -DC and control vs. non -DC by Tukey-Kramer test, respectively). We further conducted multivariate analysis among HCC patients with Barcelona Clinic Liver Cancer stage C using extrahepatic metastasis, serum decarboxyprothrombin, and miR-181a-5p levels as covariables; serum miR-181a-5p was the only independent factor for achieving DC (p = 0.0092, odds ratio 0.139, and 95% confidence interval 0.011-0.658). In addition, miR-181a-5p level was also the only independent factor affecting overall survival (p = 0.0194, hazard ratio 0.267, and 95% confidence interval 0.070-0.818). Key Messages: A high serum level of miR-181a-5p before treatment is associated with DC after the initiation of sorafenib. (C) 2016 S. Karger AG, Basel
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• Molecular Targeted Agents for Hepatocellular Carcinoma: Current Status and Future Perspectives, M. Kudo, LIVER CANCER, LIVER CANCER, 6(2), 101 - 112, 2017 , Refereed
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• Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment, Masatoshi Kudo, Franco Trevisani, Ghassan K. Abou-Alfa, Lorenza Rimassa, LIVER CANCER, LIVER CANCER, 6(1), 16 - 26, 2017 , Refereed
  Summary:Western and Eastern perspectives on therapeutic guidelines for hepatocellular carcinoma (HCC) have many commonalities but may also differ in certain aspects, as described in this article. In view of the limited therapeutic options for advanced HCC, evidence-based therapies are few, and thus there is a dependence on consensus-based guidelines. This article focuses on the Italian Association for the Study of the Liver guidelines and the Japanese approaches to therapy, while drawing attention to certain controversies from other academic bodies where applicable and appropriate. Copyright (C) 2016 S. Karger AG, Basel
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• Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study, Jorge A. Marrero, Masatoshi Kudo, Alan P. Venook, Sheng-Long Ye, Jean-Pierre Bronowicki, Xiao-Ping Chen, Lucy Dagher, Junji Furuse, Jean-Francois H. Geschwind, Laura Ladron de Guevara, Christos Papandreou, Tadatoshi Takayama, Arun J. Sanyal, Seung Kew Yoon, Keiko Nakajima, Robert Lehr, Stephanie Heldner, Riccardo Lencioni, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 65(6), 1140 - 1147, Dec. 2016 , Refereed
  Summary:Background & Aims: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. Methods: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. Results: In the overall safety population (n = 3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800 mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n = 3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). Conclusions: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. Lay summary: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON, Masatoshi Kudo, Masafumi Ikeda, Tadatoshi Takayama, Kazushi Numata, Namiki Izumi, Junji Furuse, Takuji Okusaka, Masumi Kadoya, Satoshi Yamashita, Yuichiro Ito, Norihiro Kokudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 51(12), 1150 - 1160, Dec. 2016 , Refereed
  Summary:GIDEON was a prospective, global, non-interventional study evaluating the safety of sorafenib in patients with unresectable hepatocellular carcinoma in real-world practice. The aim of this subgroup analysis was to assess the safety and efficacy of sorafenib as used by Japanese patients. In Japan, 508 patients were valid for safety analysis. Efficacy and safety were evaluated by the Child-Pugh score. The number of patients with Child-Pugh A and B was 432 (85.0 %) and 58 (11.4 %), respectively. The median overall survival time and time to progression in patients with Child-Pugh A and Child-Pugh B were 17.4 and 4.9 months, 3.7 and 2.3 months, respectively. The most common drug-related adverse events (AEs) included hand-foot skin reaction (47.8 %), diarrhea (35.8 %) and hypertension (24.2 %). The incidences of all or drug-related AEs were similar between patients with Child-Pugh A and B. However, all or drug-related serious AEs, AEs resulting in permanent discontinuation of sorafenib and deaths were observed more frequently in patients with Child-Pugh B compared with Child-Pugh A. Duration of treatment tended to be shorter as the Child-Pugh score worsened. Sorafenib was well tolerated by Japanese HCC patients in clinical settings. Patients with Child-Pugh B had shorter duration of treatment and higher incidence of SAEs. It is important to carefully evaluate patients' conditions and assess the benefit and risk before making a decision to treat patients with sorafenib.
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• Removal of diminutive colorectal polyps: A prospective randomized comparative study between cold snare polypectomy (CSP) and hot forceps biopsy (HFB), Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Teppei Adachi, Hiromasa Mine, Tomoyuki Nagai, Yoshihisa Okazaki, Yutaka Asakuma, Shigenaga Matsui, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 31, 268 - 268, Nov. 2016 , Refereed
• A validation study of the Japan NBI Expert Team (JNET) of NBI magnifying endoscopy classification for the treatment of colorectal tumors, Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Tomoyuki Nagai, Hiromasa Mine, Teppei Adachi, Shigenaga Matsui, Tomohiro Watanabe, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 31, 307 - 308, Nov. 2016 , Refereed
• The oncoprotein gankyrin promotes the development of colitis-associated cancer by mediating STAT3 and ERK activation, Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Shigenaga Matsui, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 31, 136 - 136, Nov. 2016 , Refereed
• The usefulness of computed tomography immediately after ERCP for early detection of post ERCP pancreatitis, Takeshi Miyata, Mamoru Takenaka, Masayuki Kitano, Tomohiko Matsuda, Syunsuke Omoto, Ken Kamata, Kosuke Minaga, Kentaro Yamao, Hajime Imai, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 31, 248 - 248, Nov. 2016 , Refereed
• Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis, Joon Oh Park, Baek-Yeol Ryoo, Chia-Jui Yen, Masatoshi Kudo, Ling Yang, Paolo B. Abada, Rebecca Cheng, Mauro Orlando, Andrew X. Zhu, Takuji Okusaka, ONCOTARGET, ONCOTARGET, 7(46), 75482 - 75491, Nov. 2016 , Refereed
  Summary:Purpose: REACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma. Results: Median overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634-1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690-1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein >= 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519-1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371-0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade >= 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression. Materials and methods: A post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed. Conclusions: In East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha-fetoprotein >= 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians.
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• Factors predicting through-the-scope gastroduodenal stenting outcomes in patients with gastric outlet obstruction: a large multicenter retrospective study in West Japan, Kentaro Yamao, Masayuki Kitano, Takahisa Kayahara, Etsuji Ishida, Hiroshi Yamamoto, Kosuke Minaga, Yukitaka Yamashita, Jun Nakajima, Masanori Asada, Yoshihiro Okabe, Yukio Osaki, Yasutaka Chiba, Hajime Imai, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 84(5), 757 - +, Nov. 2016 , Refereed
  Summary:Background and Aims: Endoscopic gastroduodenal stenting for malignant gastric outlet obstruction recently has become more effective, but the factors that predict gastroduodenal stenting outcomes are poorly defined. This multicenter retrospective cohort study evaluated the clinical outcomes of gastroduodenal stenting in malignant gastroduodenal obstruction and identified factors predicting clinical ineffectiveness, stent dysfunction, and adverse events. Methods: All consecutive patients with malignant gastroduodenal obstruction who underwent through-the-scope gastroduodenal stenting from 2009 to 2014 at 4 tertiary-care medical centers were identified. Clinically ineffective stenting was defined as symptom recurrence and a gastric outlet obstruction scoring system (GOOSS) score < 2. Results: Of the 278 patients (mean age +/- standard deviation [SD] 71.7 +/- 11.4 years), 121 (43.5%) and 87 (31.3%) had pancreatic and gastric cancer, respectively. Technical success was achieved in 277 patients (99.6%). GOOSS scores rose from 0.5 +/- 0.6 to 2.6 +/- 0.8. Stenting was ineffective in 32 patients (12.6%). Stent dysfunction that caused symptom recurrence during follow-up developed in 46 patients (16.6%). Adverse events occurred in 49 patients (17.7%). Three or more stenosis sites (odds ratio [OR] = 6.11; P < .01) and Karnofsky performance scores <= 50 (OR Z 6.63; P < .01) predicted clinical ineffectiveness. Karnofsky performance scores <= 50 predicted stent dysfunction (hazard ratio [HR] = 3.63; P < .01). Bile duct stenosis (HR = 9.55; P =. 02) and liver metastasis (HR = 9.42; P <.01) predicted stent overgrowth. Covered stent predicted stent migration (HR = 12.63; P < .01). Deployment of 2 stents predicted perforation (HR Z 854.88; P < .01). Conclusions: Through-the-scope gastroduodenal stenting tended to be ineffective in patients with poor performance status and long stenosis sites. Stent dysfunction occurred more frequently in patients with poorer performance status. Deployment of 2 stents was a risk factor for perforation. Identification of these risk variables may help yield better gastroduodenal stenting outcomes.
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• Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion, Takashi Kokudo, Kiyoshi Hasegawa, Yutaka Matsuyama, Tadatoshi Takayama, Namiki Izumi, Masumi Kadoya, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Shuichi Kaneko, Norihiro Kokudo, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 65(5), 938 - 943, Nov. 2016 , Refereed
  Summary:Background & Aims: The presence of portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC) is regarded as indicating an advanced stage, and liver resection (LR) is not recommended. The aim of this study was to evaluate the survival benefit of LR for HCC patients with PVTT through the analysis of the data from a Japanese nationwide survey. Methods: We analyzed data for 6474 HCC patients with PVTT registered between 2000 and 2007. Of these patients, 2093 patients who underwent LR and 4381 patients who received other treatments were compared. The propensity scores were calculated and we successfully matched 1058 patients (66.1% of the LR group). Results: In the Child-Pugh A patients, the median survival time (MST) in the LR group was 1.77 years longer than that in the non-LR group (2.87 years vs. 1.10 years; p <0.001) and 0.88 years longer than that in the non-LR group (2.45 years vs. 1.57 years; p <0.001) in a propensity score-matched cohort. A subgroup analysis revealed that LR provides a survival benefit regardless of age, etiology of HCC, tumor marker elevation, and tumor number. The survival benefit was not statistically significant only in patients with PVTT invading the main trunk or contralateral branch. In the LR group, the postoperative 90-day mortality rate was 3.7% (68 patients). Conclusions: As long as the PVTT is limited to the first-order branch, LR is associated with a longer survival outcome than non-surgical treatment. Lay summary: The presence of portal vein tumor thrombosis in patients with hepatocellular carcinoma is regarded as indicating an advanced stage, and liver resection is not recommended. We performed a multicenter, nationwide study to assess the survival benefit of liver resection in hepatocellular carcinoma patients with portal vein tumor thrombosis using propensity score based matching. As long as the portal vein tumor thrombosis is limited to the first-order branch, liver resection is associated with a longer survival outcome than non-surgical treatment. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Bile duct adenoma in patient with chronic hepatitis C: As a benign neoplasm by pathological and imaging studies, Soo Ki Kim, Soo Ryang Kim, Susumu Imoto, Chi Wan Kim, Toshiyuki Matsuoka, Osamu Nakashima, Motoko Sasaki, Tsutomu Kumabe, Masatoshi Kudo, Toshio Fukusato, Fukuo Kondo, PATHOLOGY INTERNATIONAL, PATHOLOGY INTERNATIONAL, 66(11), 640 - 642, Nov. 2016 , Refereed
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• Needle-Tract Seeding on the Proximal Gastric Wall After EUS-Guided Fine-Needle Aspiration of a Pancreatic Mass, Kosuke Minaga, Masayuki Kitano, Eisuke Enoki, Hiroshi Kashida, Masatoshi Kudo, AMERICAN JOURNAL OF GASTROENTEROLOGY, AMERICAN JOURNAL OF GASTROENTEROLOGY, 111(11), 1515 - 1515, Nov. 2016 , Refereed
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• Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial, M. Ikeda, S. Shimizu, T. Sato, M. Morimoto, Y. Kojima, Y. Inaba, A. Hagihara, M. Kudo, S. Nakamori, S. Kaneko, R. Sugimoto, T. Tahara, T. Ohmura, K. Yasui, K. Sato, H. Ishii, J. Furuse, T. Okusaka, ANNALS OF ONCOLOGY, ANNALS OF ONCOLOGY, 27(11), 2090 - 2096, Nov. 2016 , Refereed
  Summary:Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC. We conducted a multicenter open-labeled randomized phase II trial in chemo-na < ve patients with advanced HCC with Child-Pugh scores of 5-7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m(2), day 1, every 4-6 weeks) or Sor (400 mg bid). The primary end point was overall survival. A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38-0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated. SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC. UMIN-CTR (), identification number: UMIN000005703.
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• Prognostic sub-classification of intermediate-stage hepatocellular carcinoma: a multicenter cohort study with propensity score analysis, Ramya Ramaswami, David J. Pinato, Keiichi Kubota, Mitsuru Ishizuka, Tadaaki Arizumi, Masatoshi Kudo, Jeong Won Jang, Young Woon Kim, Mario Pirisi, Elias Allara, Rohini Sharma, MEDICAL ONCOLOGY, MEDICAL ONCOLOGY, 33(10), 114 - 121, Oct. 2016 , Refereed
  Summary:There is significant heterogeneity in the clinicopathological characteristics of intermediate hepatocellular carcinoma (IHCC). This also translates to treatment as transarterial chemoembolization (TACE) is used as firstline therapy for patients with IHCC; however, in Asia liver resection (LR) is preferred. Prognostic tools are required to help guide clinicians in deciding treatment options. This study evaluates the prognostic impact of the Intermediate Stage Score (ISS) on overall survival (OS) in a large, multicenter cohort study of patients with IHCC treated with TACE or surgery LR. Consecutive patients from centers in Japan, Korea, Italy and the United Kingdom who underwent TACE or LR between 2001 and 2015 were enrolled. Propensity score (PS) adjustment was used to remove residual confounding and applied to LR (n = 162) and TACE (n = 449) to determine the prognostic significance of ISS. Among 611 patients, 75 % were men and 25 % women, with a mean age of 70 years. ISS is a valid prognostic tool in the BCLC-B population with a median OS ISS 1-51, 2-38.3, 3-24.3, 4-15.6, 5-16 months (p < 0.0001). ISS was analyzed within each treatment modality, and this was a valid prognostic score among those treated with TACE and LR (p < 0.001 vs. p = 0.008). In the PS-adjusted model, ISS retained its prognostic utility in TACE and LR groups (p < 0.001 vs. p = 0.007). ISS optimizes prognostic prediction in IHCC, reducing clinical heterogeneity, and is a useful tool for patients treated for TACE or LR.
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• Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis, T. Watanabe, Y. Sadakane, N. Yagama, T. Sakurai, H. Ezoe, M. Kudo, T. Chiba, W. Strober, MUCOSAL IMMUNOLOGY, MUCOSAL IMMUNOLOGY, 9(5), 1234 - 1249, Sep. 2016 , Refereed
  Summary:Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist ( cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-beta 1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-gamma and TNF-alpha production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways.
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• Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease, Naoshi Nishida, Norihisa Yada, Satoru Hagiwara, Toshiharu Sakurai, Masayuki Kitano, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 31(9), 1646 - 1653, Sep. 2016 , Refereed
  Summary:Background and AimNon-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC). Previously, we reported that DNA oxidation induced epigenetic alteration of tumor suppressor genes (TSGs) and contributed to HCC emergence. Here, we examine the associations between clinicopathological characteristics of NAFLD and advanced oxidative DNA damage that is associated with TSG methylation in the NAFLD liver. MethodsLiver biopsies from 65 NAFLD patients were analyzed for clinicopathological features and oxidative DNA damage using immunohistochemistry of 8-hydroxydeoxyguanosine (8-OHdG). Abnormal DNA methylation in the promoters of 6 TSGs, HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, and APC, was examined using MethyLight. Associations between clinicopathological characteristics, methylation of TSGs, and accumulation of 8-OHdG were analyzed. ResultsWe found that aspartate aminotransferase/alanine aminotransferase ratio, the fibrosis-4 index, and serum -fetoprotein (AFP) level were associated with degree of 8-OHdG, and AFP was an independent factor among them (P=0.0271). Regarding pathological findings, hepatocellular ballooning and stage of fibrosis were also associated with oxidative DNA damage (P=0.0021 and 0.0054); ballooning was an independent risk for detecting high degree of 8-OHdG in hepatocytes (odds ratio 7.38, 95% confidence interval 1.41-49.13, P=0.0171). Accumulation of methylated TSGs was significantly associated with deposition of 8-OHdG (P=0.0362). ConclusionsPatients with high serum AFP and high degree of ballooning showed accumulation of oxidative DNA damage that could be a seed of DNA methylation responsible for hepatocarcinogenesis. These characteristics could be risk of HCC; such patients require urgent intervention such as lifestyle modification.
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• Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma, Ann-Lii Cheng, Sumitra Thongprasert, Ho Yeong Lim, Wattana Sukeepaisarnjaroen, Tsai-Shen Yang, Cheng-Chung Wu, Yee Chao, Stephen L. Chan, Masatoshi Kudo, Masafumi Ikeda, Yoon-Koo Kang, Hongming Pan, Kazushi Numata, Guohong Han, Binaifer Balsara, Yong Zhang, Ana-Marie Rodriguez, Yi Zhang, Yongyu Wang, Ronnie T. P. Poon, HEPATOLOGY, HEPATOLOGY, 64(3), 774 - 784, Sep. 2016 , Refereed
  Summary:Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). Conclusion: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784)
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• Evaluation of anti-migration properties of biliary covered self-expandable metal stents, Kosuke Minaga, Masayuki Kitano, Hajime Imai, Yogesh Harwani, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Shunsuke Omoto, Kumpei Kadosaka, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 22(30), 6917 - 6924, Aug. 2016 , Refereed
  Summary:AIM: To assess anti-migration potential of six biliary covered self-expandable metal stents (C-SEMSs) by using a newly designed phantom model. METHODS: In the phantom model, the stent was placed in differently sized holes in a silicone wall and retracted with a retraction robot. Resistance force to migration (RFM) was measured by a force gauge on the stent end. Radial force (RF) was measured with a RF measurement machine. Measured flare structure variables were the outer diameter, height, and taper angle of the flare (ODF, HF, and TAF, respectively). Correlations between RFM and RF or flare variables were analyzed using a linear correlated model. RESULTS: Out of the six stents, five stents were braided, the other was laser-cut. The RF and RFM of each stent were expressed as the average of five replicate measurements. For all six stents, RFM and RF decreased as the hole diameter increased. For all six stents, RFM and RF correlated strongly when the stent had not fully expanded. This correlation was not observed in the five braided stents excluding the laser cut stent. For all six stents, there was a strong correlation between RFM and TAF when the stent fully expanded. For the five braided stents, RFM after full stent expansion correlated strongly with all three stent flare structure variables (ODF, HF, and TAF). The laser-cut C-SEMS had higher RFMs than the braided C-SEMSs regardless of expansion state. CONCLUSION: RF was an important anti-migration property when the C-SEMS did not fully expand. Once fully expanded, stent flare structure variables plays an important role in anti-migration.
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• Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study, Masatoshi Kudo, Riccardo Lencioni, Jorge A. Marrero, Alan P. Venook, Jean-Pierre Bronowicki, Xiao-Ping Chen, Lucy Dagher, Junji Furuse, Jean-Francois H. Geschwind, Laura Ladron de Guevara, Christos Papandreou, Arun J. Sanyal, Tadatoshi Takayama, Seung Kew Yoon, Keiko Nakajima, Robert Lehr, Stephanie Heldner, Sheng-Long Ye, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 36(8), 1196 - 1205, Aug. 2016 , Refereed
  Summary:Background & AimsTreatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib. MethodsGIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included. Results3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months). ConclusionsData from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients.
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• Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma, Ghassan K. Abou-Alfa, Oscar Puig, Bruno Daniele, Masatoshi Kudo, Philippe Merle, Joong-Won Park, Paul Ross, Jean-Marie Peron, Oliver Ebert, Stephen Chan, Tung Ping Poon, Massimo Colombo, Takuji Okusaka, Baek-Yeol Ryoo, Beatriz Minguez, Takayoshi Tanaka, Toshihiko Ohtomo, Stacey Ukrainskyj, Frederic Boisserie, Olga Rutman, Ya-Chi Chen, Chao Xu, Eliezer Shochat, Lori Jukofsky, Bernhard Reis, Gong Chen, Laura Di Laurenzio, Ray Lee, Chia-Jui Yen, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 65(2), 289 - 295, Aug. 2016 , Refereed
  Summary:Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FccRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Methods: Patients with advanced HCC who had failed prior systemic therapy, >= 18 years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2: 1 to biweekly codrituzumab 1600 mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. Results: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extrahepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p = 0.87), and 8.7 vs. 10 (hazard ratios 0.96, p = 0.82). Projected Ctrough at cycle 3 day 1 based exposure, high CD16/FccRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. Conclusions: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. Lay summary: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Role of ABCG2 in Liver Injury Associated With Erythropoietic Protoporphyria REPLY, Satoru Hagiwara, Naoshi Nishida, Masatoshi Kudo, HEPATOLOGY, HEPATOLOGY, 64(1), 306 - 306, Jul. 2016 , Refereed
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• Predictors of pain response in patients undergoing endoscopic ultrasound-guided neurolysis for abdominal pain caused by pancreatic cancer, Kosuke Minaga, Masayuki Kitano, Hiroki Sakamoto, Takeshi Miyata, Hajime Imai, Kentaro Yamao, Ken Kamata, Shunsuke Omoto, Kumpei Kadosaka, Toshiharu Sakurai, Naoshi Nishida, Yasutaka Chiba, Masatoshi Kudo, THERAPEUTIC ADVANCES IN GASTROENTEROLOGY, THERAPEUTIC ADVANCES IN GASTROENTEROLOGY, 9(4), 483 - 494, Jul. 2016 , Refereed
  Summary:Background: Interventional endoscopic ultrasound (EUS)-guided procedures such as EUS-guided celiac ganglia neurolysis (EUS-CGN) and EUS-guided broad plexus neurolysis (EUS-BPN) were developed to treat abdominal cancer-associated pain; however, these procedures are not always effective. The aim of this study was to explore predictors of pain response in EUS-guided neurolysis for pancreatic cancer-associated pain. Methods: This was a retrospective analysis of prospectively collected data of 112 consecutive patients who underwent EUS-BPN in our institution. EUS-CGN was added in cases of visible celiac ganglia. The neurolytic-spread area was divided into six sections and evaluated by post-procedural computed tomography scanning. Pain intensity was assessed using a visual analog scale (VAS), and a decrease in VAS scores by 3 points after neurolysis was considered a good pain response. Univariable and multivariable logistic regression analyses were performed to explore predictors of pain response at 1 and 4 weeks, and complications. Results: A good pain response was obtained in 77.7% and 67.9% of patients at 1 and 4 weeks, respectively. In the multivariable analysis of these patients, the combination method (EUS-BPN plus CGN) was a significant positive predictive factor at 1 week (odds ratio = 3.69, p = 0.017) and 4 weeks (odds ratio = 6.37, p = 0.043). The numbers of neurolytic/contrast spread areas (mean SD) were 4.98 +/- 1.08 and 4.15 +/- 1.12 in patients treated with the combination method and single method, respectively (p < 0.001). There was no significant predictor of complications. Conclusions: EUS-BPN in combination with EUS-CGN was a predictor of a good pain response in EUS-guided neurolysis for pancreatic cancer-related pain. The larger number of neurolytic/contrast spread areas may lead to better outcomes in patients receiving combination treatment.
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• Combined sequential use of HAP and ART scores to predict survival outcome and treatment failure following chemoembolization in hepatocellular carcinoma: a multi-center comparative study, David J. Pinato, Tadaaki Arizumi, Jeong Won Jang, Elias Allara, Puvan I. Suppiah, Carlo Smirne, Paul Tait, Madhava Pai, Glenda Grossi, Young Woon Kim, Mario Pirisi, Masatoshi Kudo, Rohini Sharma, ONCOTARGET, ONCOTARGET, 7(28), 44705 - 44718, Jul. 2016 , Refereed
  Summary:Background: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction. Results: In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors. Patients and Methods: Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE. Conclusion: ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies.
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• EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP, Hajime Imai, Masayuki Kitano, Shunsuke Omoto, Kumpei Kadosaka, Ken Kamata, Takeshi Miyata, Kentaro Yamao, Hiroki Sakamoto, Yogesh Harwani, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 84(1), 147 - 151, Jul. 2016 , Refereed
  Summary:Background and Aims: EUS-guided bile duct drainage (EUS-BD) is a well-recognized rescue biliary drainage method after unsuccessful ERCP. EUS-guided gallbladder drainage (EUS-GBD) was recently used to treat acute cholecystitis. The aim of this study was to assess the efficacy and safety of EUS-GBD for malignant biliary stricture-induced obstructive jaundice after unsuccessful ERCP as well as unsuccessful or impractical EUS-BD. Methods: Between January 2006 and October 2014, 12 patients with obstructive jaundice due to unresectable malignant distal biliary stricture underwent EUS-GBD after ERCP failed. EUS-GBD was performed under the guidance of EUS and fluoroscopy by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a stent. The technical and functional success rates, adverse events rate, overall patient survival time, and stent dysfunction rate during patient survival were measured. Results: The rates of technical success, functional success, adverse events, and stent dysfunction were 100%, 91.7%, 16.7%, and 8.3%, respectively. The median survival time after EUS-GBD was 105 days (range 15 - 236 days). Conclusions: EUS-GBD is a possible alternative route for decompression of the biliary system when ERCP is unsuccessful.
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• Histologic diagnosis of pancreatic masses using 25-gauge endoscopic ultrasound needles with and without a core trap: a multicenter randomized trial, Ken Kamata, Masayuki Kitano, Satoru Yasukawa, Masatoshi Kudo, Yasutaka Chiba, Takeshi Ogura, Kazuhide Higuchi, Nobuyasu Fukutake, Reiko Ashida, Tomoaki Yamasaki, Hiroko Nebiki, Satoru Hirose, Noriyuki Hoki, Masanori Asada, Shujiro Yazumi, Makoto Takaoka, Kazuichi Okazaki, Fumihiro Matsuda, Yoshihiro Okabe, Akio Yanagisawa, ENDOSCOPY, ENDOSCOPY, 48(7), 632 - 638, Jul. 2016 , Refereed
  Summary:Background and study aims: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with 25-gauge needles yields small volume samples that are mainly processed for cytology. Using 25-gauge needles with a core trap may overcome this limitation. This trial compared 25-gauge needles with and without a core trap in terms of their ability to obtain histologic samples from solid pancreatic masses. Patients and methods: Consecutive patients with solid pancreatic masses who presented to eight Japanese referral centers for EUS-FNA in April-September 2013 were randomized to undergo sampling with a 25-gauge needle with a core trap (ProCore) or a standard 25-gauge needle. Tissue samples were fixed in formalin and processed for histologic evaluation. For the purpose of this study only samples obtained with the first needle pass were used for comparison of: (i) accuracy for the diagnosis of malignancy, (ii) rate of samples with preserved tissue architecture adequate for histologic evaluation, and (iii) sample cellularity. Results: A total of 214 patients were enrolled. Compared to the first pass with a standard needle (n=108), the first pass with the ProCore needle (n=106) provided samples that were more often adequate for histologic evaluation (81.1% vs. 69.4 %; P=0.048) and had superior cellularity (rich/moderate/poor, 36%/27%/37% vs. 19%/26%/ 55%; P=0.003). There were no significant differences between the two needles in sensitivity (75.6% vs. 69.0 %, P=0.337) and accuracy (79.2% vs. 75.9 %, P=0.561) for the diagnosis of malignancy. Conclusions: In patients with solid pancreatic masses, a 25-gauge EUS-FNA needle with a core trap provides histologic samples of better quality than a standard 25-gauge needle. There was no difference in accuracy for the diagnosis of malignancy between the needles. Clinical trial number: UMIN000010021.
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• Modified single transluminal gateway transcystic multiple drainage technique for a huge infected walled-off pancreatic necrosis: A case report, Kosuke Minaga, Masayuki Kitano, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Tomohiko Matsuda, Shunsuke Omoto, Kumpei Kadosaka, Tomoe Yoshikawa, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 22(21), 5132 - 5136, Jun. 2016 , Refereed
  Summary:We report a successful endoscopic ultrasonography-guided drainage of a huge infected multilocular walled-off necrosis (WON) that was treated by a modified single transluminal gateway transcystic multiple drainage (SGTMD) technique. After placing a wide-caliber fully covered metal stent, follow-up computed tomography revealed an undrained subcavity of WON. A large fistula that was created by the wide-caliber metal stent enabled the insertion of a forward-viewing upper endoscope directly into the main cavity, and the narrow connection route within the main cavity to the subcavity was identified with a direct view, leading to the successful drainage of the subcavity. This modified SGTMD technique appears to be useful for seeking connection routes between subcavities of WON in some cases.
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• Removal of Diminutive Colorectal Polyps: A Prospective Randomized Comparative Study between Cold Snare Polypectomy (CSP) and Hot Biopsy Forceps (HBF), Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Yoshihisa Okazaki, Tomoyuki Nagai, Hiromasa Mine, Teppei Adachi, Rie Tanaka, Mitsunari Yamada, Masashi Kono, Toshiki Okamoto, Shigenaga Matsui, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 83(5), AB392 - AB392, May 2016 , Refereed
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• EUS-Guided Intrahepatic Biliary Drainage for Treatment of Obstructive Jaundice in Patients With Malignant Hilar Biliary Stricture After Ineffective or Unsuccessful Transpapillary Approach, Kosuke Minaga, Masayuki Kitano, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Tomohiko Matsuda, Shunsuke Omoto, Kumpei Kadosaka, Tomoe Yoshikawa, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 83(5), AB521 - AB521, May 2016 , Refereed
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• Reply to: "Impaired Expression of Multidrug Resistance-Associated Protein 2 and Liver Damage in Erythropoietic Protoporphyria" REPLY, Satoru Hagiwara, Naoshi Nishida, Masatoshi Kudo, HEPATOLOGY, HEPATOLOGY, 63(5), 1744 - 1745, May 2016 , Refereed
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• TACE Treatment in Patients with Sorafenib-treated Unresectable Hepatocellular Carcinoma in Clinical Practice: Final Analysis of GIDEON, Jean-Francois Geschwind, Masatoshi Kudo, Jorge A. Marrero, Alan P. Venook, Xiao-Ping Chen, Jean-Pierre Bronowicki, Lucy Dagher, Junji Furuse, Laura Ladron de Guevara, Christos Papandreou, Arun J. Sanyal, Tadatoshi Takayama, Sheng-Long Ye, Seung Kew Yoon, Keiko Nakajima, Robert Lehr, Stephanie Heldner, Riccardo Lencioni, RADIOLOGY, RADIOLOGY, 279(2), 630 - 640, May 2016 , Refereed
  Summary:Purpose: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions. Materials and Methods: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points. Results: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia- Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients. Conclusion: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach. (C) RSNA, 2016
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• Acute spinal cord infarction after EUS-guided celiac plexus neurolysis, Kosuke Minaga, Masayuki Kitano, Hajime Imai, Takeshi Miyata, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 83(5), 1039 - 1040, May 2016 , Refereed
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• The Oncoprotein Gankyrin Links Inflammation and Tumorigenesis in Inflammatory Bowel Disease, Toshiharu Sakurai, Hiroshi Kashida, Rie Tanaka, Toshiki Okamoto, Mitsunari Yamada, Teppei Adachi, Hiromasa Mine, Tomoyuki Nagai, Yutaka Asakuma, Yoriaki Komeda, Yoshihisa Okazaki, Shigenaga Matsui, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 150(4), S83 - S83, Apr. 2016 , Refereed
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• Prospective Randomized Controlled Study of Helicobacter pylori Eradication in Japan, Teppei Adachi, Shigenaga Matsui, Rie Tanaka, Mitsunari Yamada, Hiromasa Mine, Tomoyuki Nagai, Yoshihisa Okazaki, Yutaka Asakuma, Yoriaki Komeda, Toshiharu Sakurai, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 150(4), S881 - S881, Apr. 2016 , Refereed
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• Gastric Perineurioma, Shigenaga Matsui, Hiroshi Kashida, Masatoshi Kudo, AMERICAN JOURNAL OF GASTROENTEROLOGY, AMERICAN JOURNAL OF GASTROENTEROLOGY, 111(4), 453 - 453, Apr. 2016 , Refereed
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• Report of the 19th follow-up survey of primary liver cancer in Japan, Masatoshi Kudo, Namiki Izumi, Takafumi Ichida, Yonson Ku, Norihiro Kokudo, Michiie Sakamoto, Tadatoshi Takayama, Osamu Nakashima, Osamu Matsui, Yutaka Matsuyama, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 46(5), 372 - 390, Apr. 2016 , Refereed
  Summary:The 19th Nationwide Follow-up Survey of Primary Liver Cancer in Japan comprised 20 850 primary liver cancer patients newly registered at 482 medical institutions over a period of 2 years (from 1 January 2006 to 31 December 2007). Of these, 94.7% had hepatocellular carcinoma (HCC) and 4.4% had intrahepatic cholangiocarcinoma (ICC). In addition, follow-up data were obtained regarding 34 752 patients who were registered in the previous survey. Epidemiological and clinicopathological factors, diagnosis, and treatment were examined in newly registered patients. Compared with the 18th follow-up survey, the present follow-up survey suggested an increase in the number of elderly and female patients, a reduction in the number of hepatitis B surface antigen-and anti-hepatitis C virus antibody-positive patients, and a reduction in tumor size at the time of clinical diagnosis. In terms of local ablation therapy, the number of patients receiving radiofrequency ablation therapy increased. The cumulative survival rates for newly registered patients between 1996 and 2007 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified according to background factors and treatments. The cumulative survival rates of newly registered patients between 1978 and 2007 were calculated after dividing individuals into groups according to registration date (1978-1987, 1988-1997, and 1998-2007). The data obtained from this follow-up survey will contribute to the medical management of primary liver cancer and facilitate future research.
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• Urgent endoscopic ultrasound-guided choledochoduodenostomy for acute obstructive suppurative cholangitis-induced sepsis, Kosuke Minaga, Masayuki Kitano, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Shunsuke Omoto, Kumpei Kadosaka, Tomoe Yoshikawa, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 22(16), 4264 - 4269, Apr. 2016 , Refereed
  Summary:Acute obstructive suppurative cholangitis (AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis.
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• Contrast-enhanced harmonic endoscopic ultrasonography for assessment of lymph node metastases in pancreatobiliary carcinoma, Takeshi Miyata, Masayuki Kitano, Shunsuke Omoto, Kumpei Kadosaka, Ken Kamata, Hajime Imai, Hiroki Sakamoto, Naoshi Nisida, Yogesh Harwani, Takamichi Murakami, Yoshifumi Takeyama, Yasutaka Chiba, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 22(12), 3381 - 3391, Mar. 2016 , Refereed
  Summary:AIM: To assess the usefulness of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for lymph node metastasis in pancreatobiliary carcinoma. METHODS: All patients suspected of pancreatobiliary carcinoma with visible lymph nodes after standard EUS between June, 2009 and January, 2012 were enrolled. In the primary analysis, patients with successful EUS-fine needle aspiration (FNA) were included. The lymph nodes were assessed by several standard EUS variables (short and long axis lengths, shape, edge characteristic and echogenicity), color Doppler EUS variable [central intranodal blood vessel (CIV) presence] and CH-EUS variable (heterogeneous/homogeneous enhancement patterns). The diagnostic accuracy relative to EUS-FNA was calculated. In the second analysis, N-stage diagnostic accuracy of CH-EUS was compared with EUS-FNA in patients who underwent surgical resection. RESULTS: One hundred and nine patients (143 lymph nodes) fulfilled the criteria. The short axis cutoff >= 13 mm predicted malignancy with a sensitivity and specificity of 72% and 85%, respectively. These values were 72% and 63% for the long axis cut-off >= 20 mm, 62% and 75% for the round shape variable, 81% and 30% for the sharp edge variable, 66% and 61% for the hypoechogenicity variable, 70% and 72% for the CIV-absent variable, and 83% and 91% for the heterogeneous CH-EUS-enhancement variable, respectively. CH-EUS was more accurate than standard and color Doppler EUS, except the short axis cut-off. Notably, three patients excluded because of EUS-FNA failure were correctly N-staged by CH-EUS. CONCLUSION: CH-EUS complements standard and color Doppler EUS and EUS-FNA for assessment of lymph node metastases.
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• Kupffer phase image of Sonazoid-enhanced US is useful in predicting a hypervascularization of non-hypervascular hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced MRI: a multicenter retrospective study, Tatsuo Inoue, Tomoko Hyodo, Keiko Korenaga, Takamichi Murakami, Yasuharu Imai, Atsushi Higaki, Takeshi Suda, Toru Takano, Kennichi Miyoshi, Masahiko Koda, Hironori Tanaka, Hiroko Iijima, Hironori Ochi, Masashi Hirooka, Kazushi Numata, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 51(2), 144 - 152, Feb. 2016 , Refereed
  Summary:Background It remains unknown whether Kupffer-phase images in Sonazoid-enhanced ultrasonography (US) can be used to predict hypervascularization of borderline lesions. Therefore, we aimed to clarify whether Kupffer-phase images in Sonazoid-enhanced ultrasonography can predict subsequent hypervascularization in hypovascular borderline lesions detected on hepatobiliary-phase gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (GdEOB-DTPA)-enhanced magnetic resonance imaging. Methods From January 2008 to March 2012, 616 low-intensity hypovascular nodules were detected in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MRI at nine institutions. Among these, 167 nodules, which were confirmed as hypovascular by Gd-EOB-DTPA-enhanced MRI and Sonazoid-enhanced US, were evaluated in this study. Potential hypervascularization factors were selected based on their clinical significance and the results of previous reports. The Kaplan-Meier model and log-rank test were used for univariate analysis and the Cox regression model was used for multivariate analysis. Results The cumulative incidence of hypervascularization of borderline lesions was 18, 37, and 43 % at 1, 2, and 3 years, respectively. Univariate analyses showed that tumor size (p = 0.0012) and hypoperfusion on Kupffer-phase images in Sonazoid-enhanced US (p = 0.004) were associated with hypervascularization of the tumor. Multivariate analysis showed that tumor size [HR: 1.086, 95 % confidence interval = 1.027-1.148, p = 0.004] and hypo perfusion on Kupffer-phase images [HR: 3.684, 95 % confidence interval = 1.798-7.546, p = 0.0004] were significantly different. Conclusions Kupffer-phase images in Sonazoid-enhanced US and tumor diameter can predict hypervascularization of hypointense borderline lesions detected on hepatobiliary-phase Gd-EOB-DTPA-enhanced MRI.
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• Risk of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Who Achieved Sustained Virological Response, M. Kudo, LIVER CANCER, LIVER CANCER, 5(3), 155 - 161, 2016 , Refereed
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• Breakthrough Imaging in Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 5(1), 47 - 54, 2016 , Refereed
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• Proposal of a new staging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from a nationwide survey of the Liver Cancer Study Group of Japan, Yoshihiro Sakamoto, Norihiro Kokudo, Yutaka Matsuyama, Michiie Sakamoto, Namiki Izumi, Masumi Kadoya, Shuichi Kaneko, Yonson Ku, Masatoshi Kudo, Tadatoshi Takayama, Osamu Nakashima, CANCER, CANCER, 122(1), 61 - 70, Jan. 2016 , Refereed
  Summary:BACKGROUNDIn the current American Joint Committee on Cancer/International Union Against Cancer staging system (seventh edition) for intrahepatic cholangiocarcinoma (ICC), tumor size was excluded, and periductal invasion was added as a new tumor classification-defining factor. The objective of the current report was to propose a new staging system for ICC that would be better for stratifying the survival of patients based on data from the nationwide Liver Cancer Study Group of Japan database.METHODSOf 756 patients who underwent surgical resection for ICC between 2000 and 2005, multivariate analyses of the clinicopathologic factors of 419 patients who had complete data sets were performed to elucidate relevant factors for inclusion in a new tumor classification and staging system.RESULTSOverall survival data were best stratified using a cutoff value of 2cm using a minimal P value approach to discriminate patient survival. The 5-year survival rate of 15 patients who had ICC measuring 2cm in greatest dimension without lymph node metastasis or vascular invasion was 100%, and this cohort was defined as T1. Multivariate analysis of prognostic factors for 267 patients with lymph node-negative and metastasis-negative (N0M0) disease indicated that the number of tumors, the presence arterial invasion, and the presence major biliary invasion were independent and significant prognostic factors. The proposed new system, which included tumor number, tumor size, arterial invasion, and major biliary invasion for tumor classification, provided good stratification of overall patient survival according to disease stage. Macroscopic periductal invasion was associated with major biliary invasion and an inferior prognosis.CONCLUSIONSThe proposed new staging system, which includes a tumor cutoff size of 2cm and major biliary invasion, may be useful for assigning patients to surgery. Cancer 2016;122:61-70. (c) 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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• Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts, Ken Kamata, Masayuki Kitano, Shunsuke Omoto, Kumpei Kadosaka, Takeshi Miyata, Kentaro Yamao, Hajime Imai, Hiroki Sakamoto, Yogesh Harwani, Takaaki Chikugo, Yasutaka Chiba, Ippei Matsumoto, Yoshifumi Takeyama, Masatoshi Kudo, ENDOSCOPY, ENDOSCOPY, 48(1), 35 - 41, Jan. 2016 , Refereed
  Summary:Background and study aim: Comparison of fundamental B-mode endoscopic ultrasonography (FB-EUS) and contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in the differential diagnosis of pancreatic cysts according to presence of mural nodules. Patients and methods: Between April 2007 and April 2012, FB-EUS and CH-EUS data were prospectively collected from 581 consecutive patients with pancreatic cysts, and were retrospectively analyzed from 70 with subsequent cyst resection. Presence and height of mural nodules as detected on FB-EUS and CH-EUS were evaluated, and thence accuracies of both methods for diagnosing mucinous versus nonmucinous and malignant versus benign cysts. Results: On pathological examination 48 cysts were mucinous and 22 were nonmucinous; 30 cysts were malignant (high grade dysplasia or invasive carcinoma) and 40 were benign. If presence of a mural nodule was considered to indicate a mucinous cyst, FB-EUS and CH-EUS accuracies did not differ significantly (respectively: sensitivity 85% vs. 79%; specificity 46% vs. 96%; accuracy 73% vs. 84%, P=0.057). If presence of mural nodule was considered to indicate malignancy, CH-EUS was significantly more accurate than FB-EUS (respectively: sensitivity 97% vs. 97%; specificity 75% vs. 40%; accuracy 84% vs. 64%, P=0.0001). For diagnosing malignancy by evaluating mural nodule height, the area under the receiver operating characteristic (AUROC) was 0.84 and 0.93 for FB-EUS and CH-EUS, respectively (P=0.028). Presence of a mural nodule of height >= 4mm on CH-EUS was a sign of malignancy (false-positive fraction 0.2; true-positive fraction 0.93; odds ratio 56.0). Conclusions: CH-EUS is more accurate than FB-EUS for diagnosing malignant pancreatic cysts.
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• Hepaticogastrostomy guided by real-time contrast-enhanced harmonic endoscopic ultrasonography: a novel technique, Kosuke Minaga, Masayuki Kitano, Tomoe Yoshikawa, Shunsuke Omoto, Ken Kamata, Kentaro Yamao, Masatoshi Kudo, ENDOSCOPY, ENDOSCOPY, 48, E228 - E229, 2016 , Refereed
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• Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis, Satoshi Kitai, Masatoshi Kudo, Naoshi Nishida, Namiki Izumi, Michiie Sakamoto, Yutaka Matsuyama, Takafumi Ichida, Osamu Nakashima, Osamu Matsui, Yonson Ku, Norihiro Kokudo, Masatoshi Makuuchi, LIVER CANCER, LIVER CANCER, 5(3), 175 - 189, 2016 , Refereed
  Summary:Background & Aims: Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. Methods: Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. Results: Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) = 0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR = 0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. Conclusions: For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible. Copyright (C) 2016 S. Karger AG, Basel
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• Safety, Tolerability, and Efficacy of Sofosbuvir Plus Ribavirin in Elderly Patients Infected with Hepatitis C Virus Genotype 2, Naoshi Nishida, Masashi Kono, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Norihisa Yada, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Tashiharu Sakurai, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 632 - 639, 2016 , Refereed
  Summary:Background: An interferon-free regimen including sofosbuvir and ribavirin (RBV) for patients with hepatitis C virus (HCV) genotype 2 (G2) infection leads to a drastic improvement of sustained virological response (SVR). However, the safety, tolerability, and efficacy in patients aged 75 or older have not been completely understood. Summary: Fifty-six patients with HCV G2 infection who were treated with sofosbuvir and weight-based dose of RBV were enrolled. Thirty-seven patients aged and 19 patients aged were classified as the aged and non-aged groups, respectively. The aged group was characterized by significantly more number of women, history of hepatocellular carcinoma, low serum albumin (ALB) level, low hemoglobin (Hb) concentration, low estimated glomerular filtration rate (eGFR), and high fibrosis-4 index (p = 0.0029). Forty-one patients were evaluated for SVR at 12 weeks after the end of therapy (SVR12); of them, all but one completed the treatment scheduled for 12 weeks. The aged group showed lower SVR12 rate than the non aged group (81.3%for aged and 96.0%for non-aged groups). Although the Hb concentration and eGFR are significantly lower in the aged group throughout the clinical course, all patients in the aged group completed the 12-week treatment with a gradual increase of serum ALB level. Key Messages: The combination of sofosbuvir plus RBV is tolerable and beneficial in patients aged >75. However, intensive management of anemia by dose reduction of RBV is necessary, which could lead to a low SVR12 rate compared to that observed in patients younger than 75 years. (C) 2016 S. Karger AG, Basel
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• Cases with Refractory Ascites and a Delayed Response to Tolvaptan, Satoru Hagiwara, Naoshi Nishida, Hirokazu Chishina, Hiroshi Ida, Toshiharu Sakurai, Yoriaki Komeda, Masayuki Kitano, Masatoshi Kudo, INTERNAL MEDICINE, INTERNAL MEDICINE, 55(22), 3273 - 3277, 2016 , Refereed
  Summary:The patient was a 67-year-old female with liver cirrhosis due to hepatitis C. She was administered furosemide at 20 mg/day and spironolactone at 25 mg/day, but the ascites did not improve. Despite the additional administration of tolvaptan at 3.75 mg/day, the response to ascites was still poor. While the dose of tolvaptan was thereafter increased to 7.5 mg/day on the 7th hospital day, the ascites still persisted. However, she continued to receive tolvaptan (7.5 mg/day) because the worsening of her subjective symptoms was mild and she wished to do so. The ascites was later found to have almost completely disappeared on computed tomography (CT) at 6 months.
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• Through-the-mesh technique after endoscopic ultrasonography-guided hepaticogastrostomy: a novel re-intervention method, Kosuke Minaga, Mamoru Takenaka, Takeshi Miyata, Yasuhiro Ueda, Masayuki Kitano, Masatoshi Kudo, ENDOSCOPY, ENDOSCOPY, 48(S 01), E369 - E370, 2016 , Refereed
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• Regorafenib as Second-Line Systemic Therapy May Change the Treatment Strategy and Management Paradigm for Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 5(4), 235 - 244, 2016 , Refereed
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• Feasibility of Extracted-Overlay Fusion Imaging for Intraoperative Treatment Evaluation of Radiofrequency Ablation for Hepatocellular Carcinoma, Yuki Makino, Yasuharu Imai, Takumi Igura, Sachiyo Kogita, Yoshiyuki Sawai, Kazuto Fukuda, Takayuki Iwamoto, Junya Okabe, Manabu Takamura, Norihiko Fujita, Masatoshi Hori, Tetsuo Takehara, Masatoshi Kudo, Takamichi Murakami, LIVER CANCER, LIVER CANCER, 5(4), 269 - 279, 2016 , Refereed
  Summary:Background and Aims: Extracted-overlay fusion imaging is a novel computed tomography/magnetic resonance-ultrasonography (CT/MR-US) imaging technique in which a target tumor with a virtual ablative margin is extracted from CT/MR volume data and synchronously overlaid on US images. We investigated the applicability of the technique to intraoperative evaluation of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Methods: This retrospective study analyzed 85 HCCs treated with RFA using extracted-overlay fusion imaging for guidance and evaluation. To perform RFA, an electrode was inserted targeting the tumor and a virtual 5-mm ablative margin overlaid on the US image. Following ablation, contrast-enhanced US (CEUS) was performed to assess the ablative margin, and the minimal ablative margins were categorized into three groups: (I) margin <0 mm (protrusion), (II) margin 0 to <5 mm, and (III) margin >= 5 mm. Margin assessment was based on the positional relationship between the overlaid tumor plus margin and the perfusion defect of the ablation zone. Tumors in group I underwent repeat ablation until they were in groups II or III. The final classifications were compared with those obtained by retrospectively created fusion images of pre- and post-RFA CT or MR imaging (CT-CT/MR-MR fusion imaging). Results: Treatment evaluation was impossible using CEUS in six HCCs because the tumors were located far below the body surface. Of the remaining 79 HCCs, the categorizations of minimal ablative margins between CEUS extracted-overlay fusion imaging and CT-CT/MR-MR fusion imaging were in agreement for 72 tumors (91.1%) (Cohen's quadratic-weighted kappa coefficient 0.66, good agreement, p<0.01). Conclusions: Extracted-overlay fusion imaging combined with CEUS is feasible for the evaluation of RFA and enables intraoperative treatment evaluation without the need to perform contrast-enhanced CT. Copyright (C) 2016 S. Karger AG, Basel
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• Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan, Masatoshi Kudo, Namiki Izumi, Michiie Sakamoto, Yutaka Matsuyama, Takafumi Ichida, Osamu Nakashima, Osamu Matsui, Yonson Ku, Norihiro Kokudo, Masatoshi Makuuchi, LIVER CANCER, LIVER CANCER, 5(3), 190 - 197, 2016 , Refereed
  Summary:Background: Beginning in 1967, the Liver Cancer Study Group of Japan (LCSGJ) started a nationwide prospective registry of all patients with hepatocellular carcinoma (HCC) diagnosed at more than 700 institutions. To determine the effectiveness of surveillance and treatment methods longitudinally, we analyzed improvements over time in overall survival (OS) of 173,378 patients with HCC prospectively entered into the LCSGJ registry between 1978 and 2005. Methods: All patients from more than 700 institutions throughout Japan with HCC were entered into the LCSGJ registry. Patients were grouped by years of diagnosis, with OS and 5-year OS rates being calculated. We also assessed OS and 5-year OS rates in patients who underwent resection, local ablation, transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy (HAIC) and in those with baseline serum alpha-fetoprotein (AFP) levels >= 400 ng/ml. Results: The 5- and 10-year OS rates in the cohort of 173,378 patients were 37.9% and 16.5%, respectively. However, over time, the mean maximum tumor size decreased significantly, whereas 5-year OS rates and median survival time increased significantly. Similar findings were observed separately in patients who underwent resection, local ablation, TACE, and HAIC, as well as in patients with AFP levels >= 400 ng/ml. Conclusion: The establishment of a nationwide HCC surveillance program in Japan has contributed to longer median OS and increased OS rates in patients diagnosed with this disease. These findings suggest that the establishment of a surveillance program in other countries with patients at risk for HCC may provide significant survival benefits. Copyright (C) 2016 S. Karger AG, Basel
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• Impact of Tight Junction Protein ZO-1 and TWIST Expression on Postoperative Survival of Patients with Hepatocellular Carcinoma, Tomoyuki Nagai, Tokuzo Arao, Kazuto Nishio, Kazuko Matsumoto, Satoru Hagiwara, Toshiharu Sakurai, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Naoshi Nishida, Kazuko Sakai, Nagahiro Saijo, Kanae Kudo, Hiroyasu Kaneda, Daisuke Tamura, Keiichi Aomatsu, Hideharu Kimura, Yoshihiko Fujita, Seiji Haji, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 702 - 707, 2016 , Refereed
  Summary:Background: Epithelial-mesenchymal transition (EMT) is considered to play a critical role in cancer progression and metastasis. However, the impact of EMT on the prognosis of hepatocellular carcinoma (HCC) is still elusive. In this study, we examined the relationship between the expression of EMT markers and recurrence-free survival (RFS) and overall survival (OS) in HCC patients after hepatic resection. Summary:The mRNA expression of 15 genes related to EMT was assessed by quantitative real-time polymerase chain reaction in cancerous tissues from 72 patients who underwent hepatic resection of HCC between January 2005 and December 2010 at our hospital. The upregulation of TWIST and the downregulation of tight junction protein ZO-1 (TJP1) were significantly associated with shorter RFS as well as OS. Increased levels of TWIST and decreased levels of TJP1 should be predictive markers for poor prognosis in patients with HCC after hepatectomy; those could serve as potential biomarkers for the treatment of HCC. Key Messages: A low level of TJP1 and high level of TWIST expression were prognostic factors predicting HCC after hepatic resection. (C) 2016 S. Karger AG, Basel
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• Comparison of Two-Dimensional Shear Wave Elastography and Real-Time Tissue Elastography for Assessing Liver Fibrosis in Chronic Hepatitis B, Tao Wu, Ping Wang, Ting Zhang, Jian Zheng, Shuoyang Li, Jie Zeng, Masatoshi Kudo, Rongqin Zheng, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 640 - 649, 2016 , Refereed
  Summary:Background: Noninvasive assessment of liver fibrosis has important clinical significance. Different techniques including two-dimensional shear-wave elastography (2D SWE) and real-time tissue elastography (RTE) are reported to be useful for the noninvasive diagnosis of hepatic fibrosis. All these techniques are affected by many factors. How to choose a reasonable method needs further studies. Purpose: This study was conducted to comparatively assess the diagnostic performance of 2D SWE and RTE in patients with Chronic Hepatitis B (CHB) and influence of inflammation on the stiffness values obtained by both techniques, so as to objectively assess the reasonable choice between these 2 elastography techniques for noninvasive assessment of hepatic fibrosis in clinical practice. Materials and Methods: Four hundred and thirty-seven patients with CHB meeting the inclusion criteria were enrolled in the study. All patients underwent liver stiffness measurements by using 2D SWE and RTE on the same day. Histologic fibrosis was staged and inflammation activity was graded based on the METAVIR scoring system on liver biopsy specimens. Results: The liver stiffness values by using 2D SWE and RTE both increased in parallel with the degree of liver fibrosis and the grade of inflammation. However, the diagnostic efficacy of significant fibrosis and cirrhosis using 2D SWE was significantly higher than that of RTE. The 2D SWE measurement values were statistically different in different alanine aminotransferase (ALT) levels and METAVIR activity grades; however, no statistically significant differences were observed by using RTE. The diagnostic efficacy of 2D SWE significantly varied with elevated ALT levels compared with RTE. Conclusion: 2D SWE was more accurate than RTE in the assessment of significant fibrosis and cirrhosis in patients with CHB. Compared with RTE, the measurement values and diagnostic performance obtained by 2D SWE were prone to be more easily affected by the inflammation fluctuations. (C) 2016 S. Karger AG, Basel
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• Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Toshiharu Sakurai, Masayuki Kitano, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 671 - 678, 2016 , Refereed
  Summary:Background: The standard treatment option that is available for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE). However, the condition of the patients with BCLC stage B disease is heterogeneous showing different tumor statuses and Child Pugh scores; treatment strategies other than TACE are frequently employed for the patients in this stage. Based on the subclassification system proposed by Bolondi et al. [Semin Liver Dis 2012;32:348-359], we developed the Kinki criteria focusing on a substaging for BCLC stage B disease, which is simpler and should be more suitable in actual clinical setting in Japan. In this study, we evaluated the performance of Kinki criteria. Summary: This study included 1,633 HCC patients who received first line treatment at the Kindai University Hospital. Patients were classified into subgroups based on the Kinki criteria and the survival time was estimated for each group. There were 156 (33.3%) patients in subclass B1, 278 (59.3%) in B2, and 35 (7.4%) in B3. The median overall survival times and 95% CI for BCLC B subclasses B1, B2, and B3 were 4.3 years (3.7-4.9), 2.9 years (2.2-3.4), and 1.1 years (0.5-1.8), respectively (p < 0.001). Key Messages: Classification of HCC patients in BCLC stage B based on the Kinki criteria showed statistically significant differences in survival, indicating the performance of Kinki criteria, which takes Child Pugh score and tumor status into account for determining treatment options for HCC in BCLC stage B. (C) 2016 S. Karger AG, Basel
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• Comparison of Contrast-Enhanced Ultrasound and Gadoliniurn-Ethoxybenzyl-Diethylenetriarnine Pentaacetic Acid-Enhanced MIDI for the Diagnosis of Macroscopic Type of Hepatocellular Carcinoma, Takayuki Iwamoto, Yasuharu Imai, Sachiyo Kogita, Takumi Igura, Yoshiyuki Sawai, Kazuto Fukuda, Yoshitaka Yamaguchi, Yasushi Matsumoto, Masanori Nakahara, Osakuni Morimoto, Yasushi Seki, Hiroshi Ohashi, Norihiko Fujita, Masatoshi Kudo, Tetsuo Takehara, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 679 - 686, 2016 , Refereed
  Summary:Objective: We compared the efficacy of contrast-enhanced ultrasound sonography (CEUS) with sonazoid and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (GdEOB-DTPA)-enhanced MRI for the assessment of macroscopic classification of nodular hepatocellular carcinoma (HCC). Methods: Seventy-seven consecutive patients with 79 surgically resected HCCs who underwent both preoperative CEUS and Gd-EOB-DTPA-enhanced MRI were enrolled in this retrospective study. Based on the macroscopic diagnosis of resected specimens, nodules were categorized into the simple nodular (SN) and non-SN type HCC. Two hepatologists independently assessed image datasets of the post-vascular phase of CEUS and hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to compare their diagnostic performance. Results: Gd-EOB-DTPA-enhanced MRI enabled the evaluation of macroscopic classification in a significantly larger number of nodules than CEUS (78/79 (98.7%) vs. 70/79 (88.6%), p < 0.05). Of 70 nodules that could be evaluated by both modalities, 41 and 29 nodules were pathologically categorized as SN and non-SN, respectively. The areas under the receiver operating characteristic curve (AUC) for non-SN did not differ between CEUS and Gd-EOB-DTPA-enhanced MRI (reader 1: 0.748 for CEUS, 0.808 for MRI; reader 2: 0.759 for CEUS, 0.787 for MRI). The AUC of combined CEUS and Gd-EOB-DTPA-enhanced MRI for SN HCC was 0.855 (reader 1) and 0.824 (reader 2), indicating higher AUC values for the combined modalities. Conclusions: The diagnostic performance for macroscopic classification of nodular HCC of CEUS was comparable with that of Gd-EOB-DTPA-enhanced MRI, although some HCCs could not be evaluated by CEUS owing to lower detectability. The combination of the 2 modalities had a more accurate diagnostic performance. (C) 2016 S. Karger AG, Basel
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• Radiofrequency Ablation Guided by Contrast-Enhanced Sonography versus B-Mode Sonography for Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization, Toshihiko Kawasaki, Kan-yun Hata, Daisuke Kinoshita, Masaki Takayama, Hideyuki Okuda, Shigeto Mizuno, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 692 - 695, 2016 , Refereed
  Summary:Purpose: Contrast-enhanced sonography increases negative enhancement in the Kupffer phase after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We compared contrast-enhanced sonography with B-mode sonography for guidance of radiofrequency ablation (RFA) of HCC after TACE. Methods: After TACE was performed, 18 nodules in 12 patients were treated by B mode sonography guided RFA, while 22 nodules in 18 patients were treated by contrast-enhanced sonography-guided RFA. Results: The success rate of initial RFA was 83.3% (15/18 nodules) in the B-mode sonography group. On the other hand, the success rate was 100% (22/22 nodules) in the contrast-enhanced sonography group and the difference was significant (p = 0.046). Conclusion: These findings suggest that RFA guided by Kupffer phase contrast-enhanced sonography after TACE is a promising therapeutic option for curing HCC. (C) 2016 S. Karger AG, Basel
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• Efficacy and Safety of Sofosbuvir Plus Ribavirin Treatment for Patients with Chronic Hepatitis C Genotype 2, Kayo Sugimoto, Soo Ki Kim, Soo Ryang Kim, Mana Kobayashi, Airi Kato, Eri Morimoto, Susumu Imoto, Chi Wan Kim, Yasuhito Tanaka, Masatoshi Kudo, Yoshihiko Yano, Yoshitake Hayashi, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 627 - 631, 2016 , Refereed
  Summary:Objectives: The efficacy of sofosbuvir plus ribavirin (RBV) treatment for hepatitis C virus (HCV) genotype 2 focusing on virological response was compared with that of pegylated interferon (peg-IFN) plus RBV treatment. Safety of the former focusing on the decline in hemoglobin levels was compared with that of the latter and assessed in terms of age and inosine triphosphatase (ITPA). Methods: Patients (n = 17) receiving sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV diagnosed with chronic HCV genotype 2 were enrolled in this study, and the efficacy and safety of both treatments were assessed. Results: Rapid virological response was attained with sofosbuvir plus RBV treatment compared with peg-IFN plus RBV treatment. All patients under sofosbuvir plus RBV treatment achieved end-of-treatment response compared with 70% who sustained viral response under the peg-IFN plus RBV treatment, with the former demonstrating greater virological response. The decline in hemoglobin levels under the former treatment was greater than that under the latter and in patients over 65 years of age with ITPA gene major. Conclusion: Efficacy and safety of sofosbuvir plus RBV treatment were clearly demonstrated compared with those of peg-IFN plus RBV treatment. The decline in hemoglobin levels was not related to the discontinuation of the former treatment, irrespective of age or the effect of the ITPA gene. (C) 2016 S. Karger AG, Basel
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• Prospective Risk Analysis of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C by Ultrasound Strain Elastography, Norihisa Yada, Toshiharu Sakurai, Tomohiro Minami, Tadaaki Arizumi, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 650 - 653, 2016 , Refereed
  Summary:Objective: We have reported about real-time tissue elastography (RTE), which displays relative strain by measuring the relative distortion of the tissue, and found this information to be useful for diagnosing liver fibrosis. However, its use in predicting hepatocellular carcinoma has not been reported as yet. Here, we investigated RTE to predict liver carcinogenesis in patients with chronic hepatitis C virus (HCV) infection. Methods: We enrolled 160 patients with chronic HCV, who were followed up for 39.9 +/- 22.9 weeks (median). They underwent RTE and then ultrasounds every 3-6 months. Results: Respective cumulative liver cancer incidences for years 1, 2, 3, 4, and 5 were, for the entire cohort: 2.0, 5.6, 8.8, 13.1, and 23.9%; for those whose liver fibrosis index (LFI) was <= 2.0: 0.0, 0.0, 0.0, 0.0, and 0.0%; for those whose LFI was 2-2.8:0.0, 7.4, 7.4, 13.2 and 19.9%; and for those whose LFI was >2.8: 12.9, 12.9, 21.7, 31.4, and 31.4% (p = 0.011; log-rank test). Conclusions: Measurements of LFI by strain imaging can effectively predict liver cancer risk in patients with chronic HCV infection. (C) 2016 S. Karger AG, Basel
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• Coffee intake and Liver Enzyme Association in Korean immigrants and Japanese: A Comprehensive Cross-Sectional Study, Soo Ki Kim, Myung-Hee Shin, Kayo Sugimoto, Soo Ryang Kim, Susumu Imoto, Ke Ih Kim, Miyuki Taniguchi, Hyun-Kyung Oh, Yoshihiko Yano, Yoshitake Hayashi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 665 - 670, 2016 , Refereed
  Summary:Objectives: Significant inverse association between coffee intake and the levels of liver enzymes has been reported. We demonstrated higher prevalence of metabolic syndrome in Korean immigrants (KIs) than in indigenous Japanese (Us). The aim of this study was to investigate whether the association between coffee intake and liver enzyme levels was different between the 2 ethnic groups. Methods: This study is a cross-sectional study including a total of 966 subjects comprising KIs and Us. The association between the quintiles of coffee intake and dichotomous values of liver enzymes was evaluated by logistic regression analysis in KIs, Us, a high-risk group (current smokers or alcohol drinkers >= 45 g/day), and a low-risk group (non-smokers and alcohol drinkers <45 g/day). Results: In KIs, a significant inverse association between coffee intake and serum aspartate aminotransferase (AST) levels was observed. In the Us, a significant inverse association between coffee intake and serum alanine aminotransferase levels was observed. In the high-risk-group, a significant inverse association between coffee intake and serum AST and gamma-glutamyltransferase levels was observed. Conclusion: No difference was observed between KIs and Us regarding the association between coffee and liver enzymes. Coffee might inhibit hepatic damage by alcohol drinking and smoking. (C) 2016 S. Karger AG, Basel
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• Recent Trends in the Management of Hepatocellular Carcinoma with Special Emphasis on Treatment with Regorafenib and Immune Checkpoint Inhibitors, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 714 - 730, 2016 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide. Sonazoid-enhanced ultrasound and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI are the most important imaging modalities in diagnosing HCC. There are 2 non-contradictory HCC treatment algorithms in Japan. Hepatic arterial infusion chemotherapy plays an important role in the treatment of advanced HCC with main or branch portal vein invasion. Regorafenib, as a second-line systemic treatment, prolongs survival in patients with intermediate and advanced HCC who progressed on sorafenib. In recent clinical trials, immune check point inhibitors show promising results for the treatment of HCC. This review describes recent trends in the management of HCC. (C) 2016 S. Karger AG, Basel
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• Prediction of Embolization Area after Conventional Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma Using SYNAPSE VINCENT, Chikara Ogawa, Yasunori Minami, Masahiro Morita, Teruyo Noda, Soichi Arasawa, Masako Izuta, Atsushi Kubo, Toshihiro Matsunaka, Hiroyuki Tamaki, Mitsushige Shibatoge, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 696 - 701, 2016 , Refereed
  Summary:Purpose: Transcatheter arterial chemoembolization (TACE) is one of the most effective therapeutic options for hepatocellular carcinoma (HCC) and it is important to protect residual liver function after treatment as well as the effect. To reduce the liver function deterioration, we evaluated the automatic software to predict the embolization area of TACE in 3 dimensions. Materials and Methods: Automatic prediction software of embolization area was used in chemoembolization of 7 HCCs. Embolization area of chemoembolization was evaluated within 1 week CT findings after TACE and compared simulated area using automatic prediction software. Results: The maximal diameter of these tumors is in the range 12-42 mm (24.6 +/- 9.5 mm). The average time for detecting tumor-feeding branches was 242 s. The total time to detect tumor-feeding branches and simulate the embolization area was 384 s. All cases could detect all tumor-feeding branches of HCC, and the expected embolization area of simulation with automatic prediction software was almost the same as the actual areas, as shown by CT after TACE. Conclusion: This new technology has possibilities to reduce the amount of contrast medium used, protect kidney function, decrease radiation exposure, and improve the therapeutic effect of TACE. (C) 2016 S. Karger AG, Basel
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• US-US Fusion Imaging in Radiofrequency Ablation for Liver Metastases, Yasunori Minami, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Tadaaki Arizumi, Masahiro Takita, Norihisa Yada, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 687 - 691, 2016 , Refereed
  Summary:Objective: Radiofrequency ablation (RFA) induces gas bubbles in ablation zones, and the ablative margin cannot be evaluated accurately on ultrasound (US) during and immediately after RFA. This study assessed the usefulness of US-US fusion imaging to visualize the ablative margin of RFA for liver metastasis. Methods: RFA guided by US-US fusion imaging was performed on 12 targeted tumors in 10 patients. Secondary hepatic malignancies included patients with colorectal cancer (n = 4), breast cancer (n = 2), lung cancer (n = 1), gastrointestinal stromal tumor (n = 1), pancreatic neuroendocrine tumor (n = 1), and adrenocortical carcinoma (n = 1). The maximal diameter of the tumors ranged from 0.8 to 4.0 cm (mean SD 1.6 +/- 0.9 cm). Results: The mean number of electrode insertions was 1.6 per session (range 1-3). Technically, effective ablation was achieved in a single session in all patients, and safety ablative margins were confirmed on contrast-enhanced CT for early assessment of tumor response. There were no serious adverse events or procedure-related complications. During the follow-up period (median 220 days, range 31-417 days), none of the patients showed local tumor progression. Conclusion: US-US fusion imaging could show the tumor images before ablation and the ablative area on US in real time. The image overlay of US-US fusion imaging made it possible to evaluate the ablative margin three dimensionally according to the US probe action. Therefore, US-US fusion imaging can contribute to RFA therapy with a safety margin, that is, the so-called precise RFA. (C) 2016 S. Karger AG, Basel
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• Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 708 - 713, 2016 , Refereed
  Summary:Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development. In addition, genetic mutations in histone modulators and chromatin regulators would be critical for the acceleration of epigenetic alteration. It is also possible that major genetic mutations of HCC, such as TP53 and CNTTB1 mutations, are associated with the disturbance of epigenetic integrity. For example, specific TP53 mutations frequently induced by aflatoxin B1 exposure might affect histone modifiers and nucleosome remodelers. Generally, epigenetic alteration is reversible, because of which dysregulation of transcription takes place, without affecting protein structure. Therefore, differentiation therapy is one of the potential approaches for HCC with advanced epigenetic alterations. On the other hand, a tumor carrying an accumulation of genetic mutations would result in many abnormal proteins that could be recognized as non-self and could be targets for immune reactions; thus, immune-checkpoint blockers should be effective for HCCs with genetic hypermutation. Although the emergence of genetic and epigenetic alterations could be linked to each other and there could be some crossover or convergence between these cancer pathways, characterization of the mutation spectrum of genetic and epigenetic alterations could influence future HCC treatment. (C) 2016 S. Karger AG, Basel
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• Clinical Factors Predicting the Effect of Tolvaptan for Refractory Ascites in Patients with Decompensated Liver Cirrhosis, Hirokazu Chishina, Satoru Hagiwara, Naoshi Nishida, Kazuomi Ueshima, Toshiharu Sakurai, Hiroshi Ida, Yasunori Minami, Masahiro Takita, Masashi Kono, Tomohiro Minami, Mina Iwanishi, Yasuko Umehara, Tomohiro Watanabe, Yoriaki Komeda, Tadaaki Arizumi, Masotoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 659 - 664, 2016 , Refereed
  Summary:Objective: Refractory ascites reduces the quality of life of liver cirrhosis patients. Albumin preparation and diuretics, such as furosemide, have been used to treat refractory ascites, but the effect was poor in many patients. In this study, we analyzed patients treated with tolvaptan (TLV) at our hospital and investigated predictors of the effect. Methods: The subjects were 70 patients for whom TLV was introduced to treat refractory ascites who could be analyzed between November 2013 and March 2015 at our hospital. Patient background before initiation of oral TLV treatment, the dose of diuretics, and each item of biochemical tests of blood and urine were investigated, and factors correlated with the treatment effect were analyzed. An increase of >= 1,000 ml in the daily urine volume from the day before oral treatment or a decrease of kg in the body weight within 7 days as an early effect was observed in 33 patients and not observed in 37 patients. TLV treatment was continued for 60 days or longer in 12 of the 37 patients in whom no early effect was observed, and the presence or absence of a delayed effect and predictors of the effect were investigated. A decrease in as cites on abdominal CT with improvement of subjective symptoms at 60 days was defined as a delayed effect. Results: When early predictors of the effect were investigated by univariate analysis, serum blood urea nitrogen (BUN) and serum creatinine (Cr) were significantly higher in the non responder group (BUN: p = 0.03, Cr: p = 0.04), but no factor independently associated with the treatment effect was extracted on multivariate analysis. The delayed effect was noted in 4 (33.3%) of the 12 patients, but no predictor of the effect before treatment was identified. However, reactions, such as an increase in serum Na and reduction of urinary osmotic pressure, were observed early after TLV administration in some patients in whom the delayed effect was observed. Conclusions: The diuretic effect of TLV may decrease in renal hypofunction patients. Since the delayed effect was noted in a specific ratio of patients, continuation of TLV administration is an option even though the early treatment effect is poor unless ascites aggravates or adverse effects develop. (C) 2016 S. Karger AG, Basel
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• Monoethanolamine Oleate Sclerotherapy for Polycystic Liver Disease, Masahiro Takita, Mina Iwanishi, Tomohiro Minami, Masashi Kono, Hirokazo Chishina, Tadaaki Arizumi, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Nishida Naoshi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 654 - 658, 2016 , Refereed
  Summary:Objective: The objective of treatment for polycystic liver disease is to reduce the liver volume and reduce or resolve compression symptoms such as abdominal fullness and abdominal pain due to hepatomegaly. Liver cysts are treated internally by puncture and aspiration of the cyst contents or hepatic artery embolization and surgically by cyst fenestration or hepatectomy, but no clear consensus has been reached concerning their selection. We introduced monoethanolamine oleate (EO) sclerotherapy therapy for liver cysts in 1999 and reported its effectiveness. In this study, cases were added, and the results including those of long-term follow-up were evaluated. Subjects: Twenty-two patients (5 males and 17 females, mean age 65.2) who underwent EO infusion therapy for liver cysts between January 1999 and June 2011 were evaluated. Methods: Liver cysts were punctured under ultrasound guidance, and a 7Fr pigtail catheter was inserted. After aspirating the cyst contents, EO was infused, and a clamp was applied for 24 h. Then, the catheter was declamped, cyst contents were aspirated again, and the catheter was removed. After the treatment, the cyst size was measured, and the patients were followed up. Results: Eight simple cysts in 8 patients (simple cyst group) and 21 cysts in 14 patients with multiple cysts (polycystic liver disease group) were treated and followed up over a median of 78 months (0-203 months). The mean volume reduction rate was 99% in the simple cyst group and 91% in the polycystic liver disease group (p = 0.04). One procedural accident resulting in liver abscess formation was observed in 1 patient 1 week after discharge, and it required drain placement and antibiotic administration. While mild abdominal pain was observed in a few patients, it was resolved spontaneously under observation. Conclusion: EO infusion therapy achieves fairly high treatment response in the volume reduction (99%) and sustained shrinkage over long-term follow-up. Therefore, this is a breakthrough technique in the treatment of polycystic liver disease as well as simple cyst and should be a standard of care in the treatment of this disease. (C) 2016 S. Karger AG, Basel
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• Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C, Satoru Hagiwara, Naoshi Nishida, Tomohiro Watanabe, Toshiharu Sakurai, Hiroshi Ida, Yasunori Minami, Masahiro Takita, Tomohiro Minami, Mina Iwanishi, Hirokazu Chishina, Kazuomi Ueshima, Yoriaki Komeda, Tadaaki Arizumi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 620 - 626, 2016 , Refereed
  Summary:Objective: Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. Methods: Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. Results: SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). Conclusions: ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important. (C) 2016 S. Karger AG, Basel
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• Chronic Liver Diseases and Liver Cancer: State-of-the Art Progress in 2016, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 34(6), 617 - 619, 2016 , Refereed
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• Heterogeneity and Subclassification of Barcelona Clinic Liver Cancer Stage B, M. Kudo, LIVER CANCER, LIVER CANCER, 5(2), 91 - 96, 2016 , Refereed
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• Response Evaluation Criteria in Cancer of the Liver (RECICL) (2015 Revised version), Masatoshi Kudo, Kazuomi Ueshima, Shoji Kubo, Michiie Sakamoto, Masatoshi Tanaka, Iwao Ikai, Junji Furuse, Takamichi Murakami, Masumi Kadoya, Norihiro Kokudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 46(1), 3 - 9, Jan. 2016 , Refereed
  Summary:The Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). Therefore, establishment of response evaluation criteria solely devoted to HCC is needed urgently in clinical practice as well as in clinical trials of HCC treatment, such as molecular-targeted therapies, which cause necrosis of the tumor. The Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2015 by the Liver Cancer Study Group of Japan based on the 2009 version of RECICL, which was commonly used in Japan. Major revised points of the RECICL 2015 is to define the target lesions of two lesions per organ or three lesions per liver, up to a maximum of five lesions. The second revised point is that setting the timing at which the overall treatment response has been changed. The third point is that the definition of treatment effect 1 has been changed to more than 50% tumor enlargement, excluding the area of necrosis after treatment. Overall evaluation of treatment response has been amended to make it possible to evaluate the overall response including extrahepatic lesions by systemic therapy, which is similar to RECIST ormodified RECIST. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit HCC treatment response evaluation in the setting of daily clinical practice and clinical trials, not only in Japan, but also internationally.
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• Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression, Akiko Saito-Hakoda, Akira Uruno, Atsushi Yokoyama, Kyoko Shimizu, Rehana Parvin, Masataka Kudo, Takako Saito-Ito, Ikuko Sato, Naotaka Kogure, Dai Suzuki, Hiroki Shimada, Takeo Yoshikawa, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Shigeo Kure, Sadayoshi Ito, Akira Sugawara, PLOS ONE, PLOS ONE, 10(12), Dec. 2015 , Refereed
  Summary:Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXR alpha. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing's disease.
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• A case of endoscopic mucosal resection for gastric perineurioma, Masashi Kono, Shigenaga Matsui, Kazuki Okamoto, Mitsunari Yamada, Rie Tanaka, Teppeiadachi Hiromasa Mine, Tomoyuki Nagai, Yoshihisa Okazaki, Yoriakikomeda, Yutaka Asakuma, Toshiharu Sakurai, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 30, 103 - 103, Dec. 2015 , Refereed
• Endoscopic resection for rectal nets (neuroendocrine tumors): EMR-C (EMR using a cap), EMR-L (EMR with a ligation device), or conventional EMR (EMR), Mitsunari Yamada, Hiroshi Kashida, Yoriaki Komeda, Kazuki Okamoto, Masashi Kono, Rie Tanaka, Teppei Adachi, Hiromasa Mine, Tomoyuki Nagai, Yoshihisa Okazaki, Yutaka Asakuma, Toshiharu Sakurai, Shigenaga Matsui, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 30, 18 - 18, Dec. 2015 , Refereed
• Usefulness of serum procalcitonin for diagnosis of acute pancreatitis, Shunsuke Omoto, Masayuki Kitano, Hiroki Sakamoto, Hajime Imai, Kentaro Yamao, Ken Kamata, Takeshi Miyata, Kosuke Minaga, Kumpei Kadosaka, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 30, 141 - 141, Dec. 2015 , Refereed
• Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma, Y. -K. Kang, T. Yau, J. -W. Park, H. Y. Lim, T. -Y. Lee, S. Obi, S. L. Chan, S. K. Qin, R. D. Kim, M. Casey, C. Chen, H. Bhattacharyya, J. A. Williams, O. Valota, D. Chakrabarti, M. Kudo, ANNALS OF ONCOLOGY, ANNALS OF ONCOLOGY, 26(12), 2457 - 2463, Dec. 2015 , Refereed
  Summary:Axitinib plus best supportive care failed to meet the primary end point of overall survival in second-line treatment of advanced hepatocellular carcinoma in a randomized phase II study. However, the axitinib arm showed substantially improved progression-free survival, time to tumour progression, and clinical benefit rate compared with the placebo arm, with acceptable safety profile. Background: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). Results: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. Conclusions: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. Trial Registration: ClinicalTrials.gov, NCT01210495.
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• Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents, Hideaki Takahashi, Masafumi Ikeda, Takashi Kumada, Yukio Osaki, Shunsuke Kondo, Shigeru Kusumoto, Kazuyoshi Ohkawa, Seijin Nadano, Junji Furuse, Masatoshi Kudo, Kiyoaki Ito, Masahiro Yokoyama, Takuji Okusaka, Masanori Shimoyama, Masashi Mizokami, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 45(12), 1220 - 1227, Dec. 2015 , Refereed
  Summary:Aim: The purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients' medical records. Methods: Records of a total of 27 patients (hematological malignancy, 14 patients; solid tumor, 13 patients) from 11 institutions who were diagnosed between June 2005 and October 2010 as having HBV reactivation following chemotherapy were reviewed. Results: Of the 27 patients with reactivation, 16 patients were hepatitis B surface antigen (HBsAg) positive and 11 were HBsAg negative prior to the commencement of chemotherapy. Of the 11 patients who were HBsAg negative prior to the chemotherapy, 10 had hematological malignancies and one had a solid tumor. Of the 14 patients with hematological malignancies with HBV reactivation enrolled in the study, the reactivation occurred more than 12 months after the completion of chemotherapy in five patients (36%); on the other hand, none of the patients (0%) with solid tumors developed HBV reactivation more than 12 months after the completion of chemotherapy. Of the 24 patients who had acute liver dysfunction at the diagnosis of HBV reactivation, nine (38%) had severe hepatitis and seven (29%) died of liver failure. Conclusion: Most of the patients with HBV reactivation who were HBsAg negative prior to the chemotherapy had underlying hematological malignancies. Furthermore, patients with hematological malignancies often developed late-onset HBV reactivation. The prognosis of patients who develop acute liver dysfunction as a complication of HBV reactivation is extremely dismal.
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• Impaired expression of ATP-binding cassette transporter G2 and liver damage in erythropoietic protoporphyria, Satoru Hagiwara, Naoshi Nishida, Ah-Mee Park, Toshiharu Sakurai, Akira Kawada, Masatoshi Kudo, HEPATOLOGY, HEPATOLOGY, 62(5), 1638 - 1639, Nov. 2015 , Refereed
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• Classification of tumors based on the integrated profile of genetic and epigenetic alterations and the biological behavior of human hepatocellular carcinoma, Naoshi Nishida, Toshimi Kaido, Masatoshi Kudo, HEPATOLOGY, HEPATOLOGY, 62, 1151A - 1152A, Oct. 2015 , Refereed
• Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial, Jordi Bruix, Tadatoshi Takayama, Vincenzo Mazzaferro, Gar-Yang Chau, Jiamei Yang, Masatoshi Kudo, Jianqiang Cai, Ronnie T. Poon, Kwang-Hyub Han, Won Young Tak, Han Chu Lee, Tianqiang Song, Sasan Roayaie, Luigi Bolondi, Kwan Sik Lee, Masatoshi Makuuchi, Fabricio Souza, Marie-Aude Le Berre, Gerold Meinhardt, Josep M. Llovet, LANCET ONCOLOGY, LANCET ONCOLOGY, 16(13), 1344 - 1354, Oct. 2015 , Refereed
  Summary:Background There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. Methods We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1: 1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. Findings We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (> 99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12.5 months (IQR 2.6-35.8) and 577 mg per day (SD 212.8) for sorafenib, compared with 22.2 months (8.1-38.8) and 778.0 mg per day (79.8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8.5 months (IQR 2.9-19.5) in the sorafenib group and 8.4 months (2.9-19.8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33.3 months in the sorafenib group vs 33.7 months in the placebo group; hazard ratio [HR] 0.940; 95% CI 0.780-1.134; one-sided p=0.26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [< 1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [< 1%]), and fatigue (three [< 1%]). There were four (< 1%) drug-related deaths in the sorafenib group and two (< 1%) in the placebo group. Interpretation Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.
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• Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study, Joong-Won Park, Minshan Chen, Massimo Colombo, Lewis R. Roberts, Myron Schwartz, Pei-Jer Chen, Masatoshi Kudo, Philip Johnson, Samuel Wagner, Lucinda S. Orsini, Morris Sherman, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 35(9), 2155 - 2166, Sep. 2015 , Refereed
  Summary:Background & AimsHepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death. MethodsData were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. ResultsForty-two sites in 14 countries contributed final data for 18031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23months for Japan, North America, South Korea, Europe and China respectively (P<0.0001). ConclusionsInitial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.
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• The role of hepatic resection in the treatment of hepatocellular cancer, Sasan Roayaie, Ghalib Jibara, Parissa Tabrizian, Joong-Won Park, Jijin Yang, Lunan Yan, Myron Schwartz, Guohong Han, Francesco Izzo, Mishan Chen, Jean-Frederic Blanc, Philip Johnson, Masatoshi Kudo, Lewis R. Roberts, Morris Sherman, HEPATOLOGY, HEPATOLOGY, 62(2), 440 - 451, Aug. 2015 , Refereed
  Summary:Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Child's A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow-up was 27 months. Log-rank and Cox's regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and other treatments, but was inferior to ablation and transplantation. Conclusions: The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities. (Hepatology 2015;62:440-451
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• Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial, Andrew X. Zhu, Joon Oh Park, Baek-Yeol Ryoo, Chia-Jui Yen, Ronnie Poon, Davide Pastorelli, Jean-Frederic Blanc, Hyun Cheol Chung, Ari D. Baron, Tulio Eduardo Flesch Pfiffer, Takuji Okusaka, Katerina Kubackova, Jorg Trojan, Javier Sastre, Ian Chau, Shao-Chun Chang, Paolo B. Abada, Ling Yang, Jonathan D. Schwartz, Masatoshi Kudo, LANCET ONCOLOGY, LANCET ONCOLOGY, 16(7), 859 - 870, Jul. 2015 , Refereed
  Summary:Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9.2 months (95% CI 8.0-10.6) versus 7.6 months (6.0-9.3) for the placebo group (HR 0.87 [95% CI 0.72-1.05]; p=0.14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (>= 1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.
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• Validation of the Hepatoma Arterial Embolization Prognostic Score in European and Asian Populations and Proposed Modification, David J. Pinato, Tadaaki Arizumi, Elias Allara, Jeong Won Jang, Carlo Smirne, Young Woon Kim, Masatoshi Kudo, Mario Pirisi, Rohini Sharma, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 13(6), 1204 - +, Jun. 2015 , Refereed
  Summary:BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is used to treat hepatocellular carcinoma (HCC), but it is a challenge to predict patient survival. The hepatic arterial embolization prognostic (HAP) score has been shown to predict which patients will have shorter survival times and should not undergo TACE. We aimed to validate this scoring system in a prospective study of patients in Europe and Asia. METHODS: We evaluated the prognostic accuracy of the HAP score in estimating overall survival (OS) of 126 patients with HCC who received TACE in the United Kingdom or Italy (training set) from 2001 through 2013. We also analyzed data from 723 patients treated in Korea and Japan (validation set), including 79 with newly diagnosed HCC, who underwent TACE in Korea or Japan from 2004 through 2013. Response to TACE was determined based on computed tomography analysis. OS was calculated from the time of the first TACE until death or the last follow-up evaluation. RESULTS: OS was associated with hypoalbuminemia, a-fetoprotein level greater than 400 ng/mL, and tumor size greater than 7 cm at diagnosis (P<.01), but not a bilirubin level greater than 17 umol/L (P>.05), in both data sets. The lack of association between OS and bilirubin level was confirmed using receiver operating characteristic analysis. We developed a modified version of the HAP score, based on the level of albumin and a-fetoprotein and tumor size, which predicted OS with increased accuracy in the training and validation cohorts. CONCLUSIONS: In a multicenter validation study, we developed a modified version of the HAP that predicts survival of patients with HCC treated with TACE in Europe and Asia. This system might be used to identify patients with HCC most likely to benefit from TACE in clinical practice.
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• Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial, Kiwamu Okita, Namiki Izumi, Kenji Ikeda, Yukio Osaki, Kazushi Numata, Masafumi Ikeda, Norihiro Kokudo, Kazuho Imanaka, Shuhei Nishiguchi, Shunsuke Kondo, Yoichi Nishigaki, Susumu Shiomi, Kazuomi Ueshima, Norio Isoda, Yoshiyasu Karino, Masatoshi Kudo, Katsuaki Tanaka, Shuichi Kaneko, Hisataka Moriwaki, Masatoshi Makuuchi, Takuji Okusaka, Norio Hayashi, Yasuo Ohashi, Hiromitsu Kumada, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 50(6), 667 - 674, Jun. 2015 , Refereed
  Summary:This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial. This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression. Survey data were collected from all patients (n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day (n = 132), peretinoin 300 mg/day (n = 131), and placebo (n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group (n = 105) was significantly longer than that of the placebo group (n = 108) (hazard ratio 0.575, 95 % CI 0.341-0.967; P = 0.0347). Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable.
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• Therapeutic Strategies for Four Subtypes of Laterally Spreading Tumors of the Colorectum, Yoriaki Komeda, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Yoshihisa Okazaki, Toshiki Okamoto, Mitsunari Yamada, Rie Tanaka, Teppei Adachi, Hiromasa Mine, Masaki Takayama, Tomoyuki Nagai, Masanori Kawasaki, Shigenaga Matsui, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 81(5), AB219 - AB219, May 2015 , Refereed
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• FOREWORD TO THE WFUMB GUIDELINES AND RECOMMENDATIONS ON THE CLINICAL USE OF ULTRASOUND ELASTOGRAPHY, Masatoshi Kudo, ULTRASOUND IN MEDICINE AND BIOLOGY, ULTRASOUND IN MEDICINE AND BIOLOGY, 41(5), 1125 - 1125, May 2015 , Refereed
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• Evaluation of the Response to Chemotherapy in Advanced Gastric Cancer by Contrast-Enhanced Harmonic EUS, Shigenaga Matsui, Masatoshi Kudo, Masayuki Kitano, Yutaka Asakuma, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 62(139), 595 - 598, May 2015 , Refereed
  Summary:Background/Aims: In advanced gastric cancers, a significant correlation exists between the response to chemotherapy in primary gastric cancers and patient prognosis. Therefore, accurate evaluation of the response to chemotherapy in primary gastric cancers is important. We examined the response to chemotherapy in primary gastric cancers by contrast enhanced harmonic endoscopic ultrasonography (CEH-EUS). Methodology: Thirty-five patients with advanced gastric cancer underwent CEH-EUS. Among these patients, 19 patients with stage IV advanced gastric cancer who received chemotherapy and CEH-EUS more than twice were enrolled, and evaluated the response to chemotherapy in primary gastric cancers by CEH-EUS and endoscopy. Results: In PRs evaluated by endoscopic findings, echo intensity ratio (EIR) was decreased, and in PDs EIR was increased significantly by CEH-EUS. Five cases had difficulty in evaluating the response of primary gastric cancers to chemotherapy by endoscopy, while evaluation was possible in those 5 cases by CEH-EUS. Conclusions: CEH-EUS is a new method to evaluate responses to chemotherapy in primary gastric cancers not only by a change in size but also in tumor vascularity. Correct evaluation of primary gastric cancers by CEH-EUS help predicting prognosis of patients.
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• WFUMB GUIDELINES AND RECOMMENDATIONS FOR CLINICAL USE OF ULTRASOUND ELASTOGRAPHY: PART 2: BREAST, Richard G. Barr, Kazutaka Nakashima, Dominique Amy, David Cosgrove, Andre Farrokh, Fritz Schafer, Jeffrey C. Bamber, Laurent Castera, Byung Ihn Choi, Yi-Hong Chou, Christoph F. Dietrich, Hong Ding, Giovanna Ferraioli, Carlo Filice, Mireen Friedrich-Rust, Timothy J. Hall, Kathryn R. Nightingale, Mark L. Palmeri, Tsuyoshi Shiina, Shinichi Suzuki, Ioan Sporea, Stephanie Wilson, Masatoshi Kudo, ULTRASOUND IN MEDICINE AND BIOLOGY, ULTRASOUND IN MEDICINE AND BIOLOGY, 41(5), 1148 - 1160, May 2015 , Refereed
  Summary:The breast section of these Guidelines and Recommendations for Elastography produced under the auspices of the World Federation of Ultrasound in Medicine and Biology (WFUMB) assesses the clinically used applications of all forms of elastography used in breast imaging. The literature on various breast elastography techniques is reviewed, and recommendations are made on evidence-based results. Practical advice is given on how to perform and interpret breast elastography for optimal results, with emphasis placed on avoiding pitfalls. Artifacts are reviewed, and the clinical utility of some artifacts is discussed. Both strain and shear wave techniques have been shown to be highly accurate in characterizing breast lesions as benign or malignant. The relationship between the various techniques is discussed, and recommended interpretation based on a BI-RADS-like malignancy probability scale is provided. This document is intended to be used as a reference and to guide clinical users in a practical way. (C) 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.
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• WFUMB GUIDELINES AND RECOMMENDATIONS FOR CLINICAL USE OF ULTRASOUND ELASTOGRAPHY: PART 3: LIVER, Giovanna Ferraioli, Carlo Filice, Laurent Castera, Byung Ihn Choi, Ioan Sporea, Stephanie R. Wilson, David Cosgrove, Christoph F. Dietrich, Dominique Amy, Jeffrey C. Bamber, Richard Barr, Yi-Hong Chou, Hong Ding, Andre Farrokh, Mireen Friedrich-Rust, Timothy J. Hall, Kazutaka Nakashima, Kathryn R. Nightingale, Mark L. Palmeri, Fritz Schafer, Tsuyoshi Shiina, Shinichi Suzuki, Masatoshi Kudo, ULTRASOUND IN MEDICINE AND BIOLOGY, ULTRASOUND IN MEDICINE AND BIOLOGY, 41(5), 1161 - 1179, May 2015 , Refereed
  Summary:The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases. (C) 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.
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• WFUMB GUIDELINES AND RECOMMENDATIONS FOR CLINICAL USE OF ULTRASOUND ELASTOGRAPHY: PART 1: BASIC PRINCIPLES AND TERMINOLOGY, Tsuyoshi Shiina, Kathryn R. Nightingale, Mark L. Palmeri, Timothy J. Hall, Jeffrey C. Bamber, Richard G. Barr, Laurent Castera, Byung Ihn Choi, Yi-Hong Chou, David Cosgrove, Christoph F. Dietrich, Hong Ding, Dominique Amy, Andre Farrokh, Giovanna Ferraioli, Carlo Filice, Mireen Friedrich-Rust, Kazutaka Nakashima, Fritz Schafer, Ioan Sporea, Shinichi Suzuki, Stephanie Wilson, Masatoshi Kudo, ULTRASOUND IN MEDICINE AND BIOLOGY, ULTRASOUND IN MEDICINE AND BIOLOGY, 41(5), 1126 - 1147, May 2015 , Refereed
  Summary:Conventional diagnostic ultrasound images of the anatomy (as opposed to blood flow) reveal differences in the acoustic properties of soft tissues (mainly echogenicity but also, to some extent, attenuation), whereas ultrasound-based elasticity images are able to reveal the differences in the elastic properties of soft tissues (e.g., elasticity and viscosity). The benefit of elasticity imaging lies in the fact that many soft tissues can share similar ultrasonic echogenicities but may have different mechanical properties that can be used to clearly visualize normal anatomy and delineate pathologic lesions. Typically, all elasticity measurement and imaging methods introduce a mechanical excitation and monitor the resulting tissue response. Some of the most widely available commercial elasticity imaging methods are 'quasi-static' and use external tissue compression to generate images of the resulting tissue strain (or deformation). In addition, many manufacturers now provide shear wave imaging and measurement methods, which deliver stiffness images based upon the shear wave propagation speed. The goal of this review is to describe the fundamental physics and the associated terminology underlying these technologies. We have included a questions and answers section, an extensive appendix, and a glossary of terms in this manuscript. We have also endeavored to ensure that the terminology and descriptions, although not identical, are broadly compatible across the WFUMB and EFSUMB sets of guidelines on elastography (Bamber et al. 2013; Cosgrove et al. 2013). (C) 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.
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• Stress Response Links Inflammation and Tumorigenesis in Inflammatory Bowel Disease, Toshiharu Sakurai, Yoshihisa Okazaki, Yoriaki Komeda, Teppei Adachi, Satoru Hagiwara, Shigenaga Matsui, Naoshi Nishida, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 148(4), S141 - S141, Apr. 2015 , Refereed
• Cold-inducible RNA-binding protein promotes the development of liver cancer, Toshiharu Sakurai, Norihisa Yada, Tomohiro Watanabe, Tadaaki Arizumi, Satoru Hagiwara, Kazuomi Ueshima, Naoshi Nishida, Jun Fujita, Masatoshi Kudo, CANCER SCIENCE, CANCER SCIENCE, 106(4), 352 - 358, Apr. 2015 , Refereed
  Summary:Most hepatocellular carcinomas (HCCs) develop in the context of chronic liver inflammation. Oxidative stress is thought to play a major role in the pathogenesis of HCC development. In this study, we examined whether cold-inducible RNA-binding protein (Cirp) controls reactive oxygen species (ROS) accumulation and development of HCC by using murine models of hepatocarcinogenesis and human liver samples. Cirp expression, ROS accumulation, and CD133 expression were increased in the liver of tumor-harboring mice. Cirp deficiency reduced production of interleukin-1 and interleukin-6 in Kupffer cells, ROS accumulation, and CD133 expression, leading to attenuated hepatocarcinogenesis. Thioacetamide treatment enhanced hepatic expression of CD133 and phosphorylated signal transducer and activator of transcription 3 (STAT3), which was prevented by treatment with the antioxidant butylated hydroxyanisole. Intriguingly, the risk of human HCC recurrence is positively correlated with Cirp expression in liver. Cirp appears to play a critical carcinogenic function and its expression might be a useful biomarker for HCC risk prediction.
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• Contrast-enhanced harmonic endoscopic ultrasonography for pancreatobiliary diseases, Masayuki Kitano, Ken Kamata, Hajime Imai, Takeshi Miyata, Satoru Yasukawa, Akio Yanagisawa, Masatoshi Kudo, DIGESTIVE ENDOSCOPY, DIGESTIVE ENDOSCOPY, 27, 60 - 67, Apr. 2015 , Refereed
  Summary:The combination of second-generation ultrasound contrast agents and an endoscopic ultrasonography (EUS) system with a broad-band transducer has allowed contrast-enhanced harmonic imaging in the field of EUS. In contrast-enhanced harmonic EUS (CH-EUS), diffuse homogeneous enhancement is obtained in normal parenchyma of the pancreas. The bile duct and pancreatic duct are depicted as non-enhanced ductal structures with strong contrast in comparison to the surrounding parenchyma. CH-EUS identifies pancreatic adenocarcinomas as solid lesions exhibiting hypo-enhancement with a sensitivity and specificity of 88-96% and 88-94%, respectively. In particular, 80-100% of false-negative cases in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are correctly classified by CH-EUS, suggesting CH-EUS complements EUS-FNA. Moreover, CH-EUS improves depiction of some subtle lesions in conventional EUS, thus facilitating EUS-FNA. For quantitative perfusion analysis, a time-intensity curve (TIC) for the region of interest can be generated during CH-EUS. The maximum intensity gain and the echo intensity reduction rate from the peak at 1min obtained by TIC can be used for differentiation of pancreatic adenocarcinoma from other tumors. CH-EUS is also useful for differentiation of invasive intraductal papillary mucinous neoplasms (IPMN) from non-invasive IPMN, identification of malignant lesions in the gallbladder, and T- and N-staging of pancreatobiliary tumors.
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• Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing, Toshiharu Sakurai, Hiroshi Kashida, Satoru Hagiwara, Naoshi Nishida, Tomohiro Watanabe, Jun Fujita, Masatoshi Kudo, DIGESTIVE DISEASES AND SCIENCES, DIGESTIVE DISEASES AND SCIENCES, 60(4), 850 - 857, Apr. 2015 , Refereed
  Summary:Aims and Methods Heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, regulates the immune response in the gut. Here, we assessed the involvement of HSPA4 in gastric ulcer healing by using fibroblasts from wild-type and HSPA4-deficient mice, a murine gastric ulcer model, and samples from 65 patients with gastric cancer. Results HSPA4 expression was inversely correlated with gastric ulcer healing following endoscopic resection of gastric cancer. In the human gastric mucosa, the expression of HSPA4 was inversely correlated with the expression of stromal cell-derived factor 1 (SDF-1), its cognate receptor CXC chemokine receptor 4(CXCR4), the stromal cell marker vimentin, and the epithelial-mesenchymal transition regulator Twist. HSPA4 was overexpressed in stromal cells as well as in human gastric cancer cells. HSPA4 deficiency increased the expression of SDF-1 and CXCR4, as well as the number of fibroblast-specific protein 1-positive cells, leading to accelerated ulcer healing in the murine gastric ulcer model. Deletion of HSPA4 promoted cell migration in mouse fibroblasts through increased expression of SDF-1 and Twist. Conclusion HSPA4 regulates the expression of SDF-1 and Twist in fibroblasts, thereby controlling gastric ulcer healing.
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• Value of dynamic contrast enhanced MRI in predicting outcomes of HCC receiving radiotherapy, Masatoshi Kudo, HEPATOLOGY INTERNATIONAL, HEPATOLOGY INTERNATIONAL, 9(2), 155 - 156, Apr. 2015 , Refereed
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• A Comparison of the Surgical Outcomes Among Patients With HBV-positive, HCV-positive, and Non-B Non-C Hepatocellular Carcinoma A Nationwide Study of 11,950 Patients, Tohru Utsunomiya, Mitsuo Shimada, Masatoshi Kudo, Takafumi Ichida, Osamu Matsui, Namiki Izumi, Yutaka Matsuyama, Michiie Sakamoto, Osamu Nakashima, Yonson Ku, Tadatoshi Takayama, Norihiro Kokudo, ANNALS OF SURGERY, ANNALS OF SURGERY, 261(3), 513 - 520, Mar. 2015 , Refereed
  Summary:Objective: To compare the prognostic factors and outcomes after hepatic resection among patients with hepatitis B virus (HBV)-positive, hepatitis C virus (HCV)-positive, and negative for hepatitis B surface antigen and hepatitis Cantibody, so-called "NBNC"-hepatocellular carcinoma (HCC) using the data from a nationwide survey. Background: The incidence of NBNC-HCC is rapidly increasing in Japan. Methods: A total of 11,950 patients with HBV-HCC (n = 2194), HCV-HCC (n = 7018), or NBNC-HCC (n = 2738) who underwent a curative hepatic resection were enrolled in this study. The clinicopathological features were compared among the groups. The significant prognostic variables determined by univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. Results: Liver function in the HCV-HCC group was significantly worse than that in the HBV-HCC and NBNC-HCC groups. The NBNC-HCC group had significantly more advanced HCC than the HCV-HCC group. The 5-year overall survival rates after hepatectomy in the HBV-HCC, HCV-HCC, and NBNC-HCC groups were 65%, 59%, and 68%, respectively. The 5-year recurrence-free survival (RFS) rates in these 3 groups were 41%, 31%, and 47%, respectively. Stratifying the RFS rates according to the TNM stage showed that the NBNC-HCC group had a significantly better prognosis than the HBV-HCC group in stages II, III, and IVA, and a significantly better prognosis than the HCV-HCC group in stages I and II. Multivariate analysis revealed a significantly better RFS rate in the NBNC-HCC group. Conclusions: The findings of this nationwide survey indicated that patients with NBNC-HCC had a significantly lower risk of HCC recurrence than those with HBV-HCC and HCV-HCC.
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• Comparison Between T1 Relaxation Time of Gd-EOB-DTPA-Enhanced MRI and Liver Stiffness Measurement of Ultrasound Elastography in the Evaluation of Cirrhotic Liver, Masahiro Okada, Takamichi Murakami, Norihisa Yada, Kazushi Numata, Minori Onoda, Tomoko Hyodo, Tatsuo Inoue, Kazunari Ishii, Masatoshi Kudo, JOURNAL OF MAGNETIC RESONANCE IMAGING, JOURNAL OF MAGNETIC RESONANCE IMAGING, 41(2), 329 - 338, Feb. 2015 , Refereed
  Summary:PurposeTo compare four imaging approaches in cirrhotic estimation; pre-enhancement T1 relaxation time (T1RT), reduction rate (RR) of T1RT, signal-based liver-to-muscle ratio (L/M ratio) on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), and liver stiffness measurement (LSM) of US elastography. Materials and MethodsConsecutive 58 patients with chronic liver diseases who underwent both Gd-EOB-DTPA-enhanced MRI and FibroScan were analyzed. Four imaging approaches were evaluated by fibrosis score from liver biopsy and receiver operating characteristic (ROC) analysis. ResultsRR was found to be inversely correlated with LSM (r=-0.65). RR decreased with degree of fibrosis (F0-F1, 58.56.2%, versus F2-F3-F4, 48.8 +/- 11.7%, P=0.010, F0-F1-F2, 58.2 +/- 6.2% versus F3-F4, 45.5 +/- 12.3%, P=0.010 and F0-F1, 58.5 +/- 6.2%, versus F2-F3, 52.1 +/- 12.0%, P=0.0038). LSM increased with degree of fibrosis (F0-F1, 5.4 +/- 2.2 kPa versus F2-F3-F3, 19.3 +/- 15.5 kPa, P=0.0011 and F0-F1-F2, 6.8 +/- 3.6 kPa versus F3-F4, 23.8 +/- 17.1 kPa, P=0.0029 and F0-F1, 5.4 +/- 2.2 kPa, versus F2-F3, 11.4 +/- 7.2 kPa, P=0.0098). Area under ROC curves were 0.83 (F3-F4), 0.72 (F2-F3-F4), 0.68 (F2-F3) for RR and 0.83 (F3-F4), 0.88 (F2-F3-F4), 0.81 (F2-F3) for LSM in discriminating between patients with fibrosis. ConclusionThe capability by LSM was better than those by RR of T1RT, pre-enhancement T1RT, and L/M ratio to differentiate F2, but LSM and RR of T1RT showed the same value to differentiate F3. J. Magn. Reson. Imaging 2015;41:329-338.(c) 2013 Wiley Periodicals, Inc.
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• Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study, Kiwamu Okita, Namiki Izumi, Osamu Matsui, Katsuaki Tanaka, Shuichi Kaneko, Hisataka Moriwaki, Kenji Ikeda, Yukio Osaki, Kazushi Numata, Kohei Nakachi, Norihiro Kokudo, Kazuho Imanaka, Shuhei Nishiguchi, Takuji Okusaka, Yoichi Nishigaki, Susumu Shiomi, Masatoshi Kudo, Kenichi Ido, Yoshiyasu Karino, Norio Hayashi, Yasuo Ohashi, Masatoshi Makuuchi, Hiromitsu Kumada, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 50(2), 191 - 202, Feb. 2015 , Refereed
  Summary:Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.
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• Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines), Norihiro Kokudo, Kiyoshi Hasegawa, Masaaki Akahane, Hiroshi Igaki, Namiki Izumi, Takafumi Ichida, Shinji Uemoto, Shuichi Kaneko, Seiji Kawasaki, Yonson Ku, Masatoshi Kudo, Shoji Kubo, Tadatoshi Takayama, Ryosuke Tateishi, Takashi Fukuda, Osamu Matsui, Yutaka Matsuyama, Takamichi Murakami, Shigeki Arii, Masatoshi Okazaki, Masatoshi Makuuchi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 45(2), 123 - 127, Feb. 2015 , Refereed
  Summary:The 3rd version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine, which was published in October 2013 in Japanese. Here, we briefly describe new or changed recommendations with a special reference to the two algorithms for surveillance, diagnosis, and treatment.
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• Percutaneous endoscopic gastrostomy with Funada-style gastropexy greatly reduces the risk of peristomal infection, Naoki Okumura, Naoko Tsuji, Nobuto Ozaki, Nozomu Matsumoto, Takehisa Takaba, Masanori Kawasaki, Takafumi Tomita, Yasuko Umehara, Satoko Taniike, Masashi Kono, Masatoshi Kudo, GASTROENTEROLOGY REPORT, GASTROENTEROLOGY REPORT, 3(1), 69 - 74, Feb. 2015 , Refereed
  Summary:Background and aims: Peristomal wound infections are common complications of percutaneous endoscopic gastrostomy (PEG). The Funada-style gastropexy device has two parallel needles with a wire loop and suture thread, and was developed about 20 years ago in Japan. This kit has allowed us to perform dual gastropexy very easily; PEG with gastropexy has become a very popular technique in Japan. The present study aimed to compare the advantages and disadvantages of PEG with the gastropexy technique with the standard 'pull' method. Methods: We retrospectively reviewed 182 consecutive, non-randomized patients undergoing PEG in our hospital, and a comparative analysis was made between the gastropexy (87 patients) and non-gastropexy (95 patients) groups. Results: The rates of patients having erythema (11.6% vs. 47.9%; P<0.001), exudates (2.3% vs. 14.9%; P<0.01) and infection (0% vs. 6.4%; P=0.01) in the peristomal area were lower in the gastropexy than in the non-gastropexy group. The rate of minor bleeding from the peristomal area was higher in the gastropexy than in the non-gastropexy group (12.8% vs. 2.1%; P<0.01), but no patient required a blood transfusion. Mean procedure time was longer in the gastropexy group than in the non-gastropexy group (31 vs. 24 min; P<0.001). The 30-day mortality rates were 4.7% and 5.3% respectively, and these deaths were not related to the gastrostomy procedure. Conclusion: PEG with gastropexy markedly reduces peristomal inflammation. Although minor bleeding and a longer procedure time were disadvantages, there were no severe complications. The findings suggested that PEG with Funada-style gastropexy was a safe and feasible method for reducing early complications of PEG.
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• Immune Checkpoint Blockade in Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 4(4), 201 - 207, 2015 , Refereed
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• Molecular Targeted Therapy for Hepatocellular Carcinoma: Where Are We Now?, M. Kudo, LIVER CANCER, LIVER CANCER, 4(3), I - VII, 2015 , Refereed
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• Locoregional Therapy for Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 4(3), 163 - 164, 2015 , Refereed
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• Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe, M. Kudo, LIVER CANCER, LIVER CANCER, 4(2), 85 - 95, 2015 , Refereed
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• Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer, Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Kiyotaka Okuno, Masatoshi Kudo, Kazuto Nishio, CANCER LETTERS, CANCER LETTERS, 356(2), 819 - 827, Jan. 2015 , Refereed
  Summary:We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Contrary to our expectations, however, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA (beta subunit of inhibin)overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia. The activin signal might be a novel target for the treatment of PC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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• Surveillance, Diagnosis, Treatment, and Outcome of Liver Cancer in Japan, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 4(1), 39 - 50, 2015 , Refereed
  Summary:Background: Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third leading cause of cancer-related death worldwide. HCC is most common in Asia, but its prevalence is rapidly increasing in Western countries; consequently, HCC is a global medical issue that urgently needs to be addressed. Japan is the only developed country that has experienced both hepatitis B-related and hepatitis C-related HCC and has a long history of innovation when it comes to new diagnostic and therapeutic modalities, such as computed tomography angiography, anatomical resection, ablation, and transarterial chemoembolization. Among these innovations, a nationwide surveillance program was well established by the 1980s, and such a long-term national program does not exist anywhere else in the world. Summary: More than 60% of the initially detected HCCs in Japan are Barcelona Clinic Liver Cancer stage 0 or A, which can undergo curative therapies such as resection, ablation, or transplantation. The recent 5-year survival rate of HCC patients in Japan was 43% and the median survival time was 50 months. In addition, both incidence and mortality rates are drastically declining as a result of the successful surveillance program, careful diagnostic flow, and extensive repeated treatments. Key Message: Japan's successful model in the surveillance, diagnosis, and treatment of HCC should be adopted as widely as possible to improve the survival of HCC patients worldwide. Copyright (C) 2015 S. Karger AG, Basel
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• Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria), Masatoshi Kudo, Tadaaki Arizumi, Kazuomi Ueshima, Toshiharu Sakurai, Masayuki Kitano, Naoshi Nishida, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 751 - 758, 2015 , Refereed
  Summary:Intermediate stage hepatocellular carcinoma (HCC) is a very heterogeneous tumor in terms of tumor size (>3 cm similar to over 10 cm), tumor number (4 similar to over 20) and liver function (Child-Pugh score 5-9). However, transarterial chemoembolization is the only recommended treatment option according to the Barcelona Clinic Liver Cancer (BCLC) staging. Bolondi's subclassification of BCLC B stage is feasible; however, there are several weak points. Therefore, by modifying Bolondi's subclassification, we have proposed a more simplified subclassification, Kinki criteria. The Kinki criteria consist of 2 factors: liver function (Child-Pugh score 5-7 or 8, 9) and tumor status (Beyond Milan and within up-to-7 criteria; IN and OUT). The Kinki criteria classifies BCLC B stage from B1 (Child-Pugh score 5-7 and within up-to-7), B2 (Child-Pugh score 5-7 and beyond up-to-7) and B3 (Child-Pugh score 8, 9 and any tumor status). These criteria are simple and easy to apply to clinical practice. Therefore, these criteria will stratify the heterogeneous population of BCLC B group patient well and give the treatment indication according to each substage. These criteria should be further validated both retrospectively and prospectively. (C) 2015 S. Karger AG, Basel
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• Phase II Study of Personalized Peptide Vaccination with Both a Hepatitis C Virus-Derived Peptide and Peptides from Tumor-Associated Antigens for the Treatment of HCV-Positive Advanced Hepatocellular Carcinoma Patients, Shigeru Yutani, Kazuomi Ueshima, Kazumichi Abe, Atsushi Ishiguro, Junichi Eguchi, Satoko Matsueda, Nobukazu Komatsu, Shigeki Shichijo, Akira Yamada, Kyogo Itoh, Tetsuro Sasada, Masatoshi Kudo, Masanori Noguchi, JOURNAL OF IMMUNOLOGY RESEARCH, JOURNAL OF IMMUNOLOGY RESEARCH, 2015, 473909, 2015 , Refereed
  Summary:Objective. To evaluate safety and immune responses of personalized peptide vaccination (PPV) for hepatitis C virus-(HCV-) positive advanced hepatocellular carcinoma (HCC). Patients and Methods. Patients diagnosed with HCV-positive advanced HCC were eligible for this study. A maximum of four HLA-matched peptides were selected based on the preexisting IgG responses specific to 32 different peptides, which consisted of a single HCV-derived peptide at core protein positions 35-44 (C-35) and 31 peptides derived from 15 different tumor-associated antigens (TAAs), followed by subcutaneous administration once per week for 8 weeks. Peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses were measured before and after vaccination. Results. Forty-two patients were enrolled. Grade 3 injection site skin reaction was observed in 2 patients, but no other PPV-related severe adverse events were noted. Peptide-specific CTL responses before vaccination were observed in only 3 of 42 patients, but they became detectable in 23 of 36 patients tested after vaccination. Peptide-specific IgG responses were also boosted in 19 of 36 patients. Peptide-specific IgG1 responses to both C-35 and TAA-derived peptides could be potentially prognostic for overall survival. Conclusion. Further clinical study of PPV would be warranted for HCV-positive advanced HCC, based on the safety and strong immune induction.
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• Evidence and Consensus on the Management of Hepatocellular Carcinoma: Update 2015, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 1 - 3, 2015 , Refereed
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• Imaging Modalities for Assessment of Treatment Response to Nonsurgical Hepatocellular Carcinoma Therapy: Contrast-Enhanced US, CT, and MRI, Yasunori Minami, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 4(2), 106 - 114, 2015 , Refereed
  Summary:Tumor response and time to progression have been considered pivotal for surrogate assessment of treatment efficacy for patients with hepatocellular carcinoma (HCC). Recent advancements in imaging modalities such as contrast-enhanced ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are playing an important role in assessing the therapeutic effects of HCC treatments. According to some HCC clinical guidelines, post-therapeutic evaluation of HCC patients is based exclusively on contrast-enhanced dynamic imaging criteria. The recommended techniques are contrast-enhanced CT or contrastenhanced MRI. Contrast-enhanced US is employed more in the positive diagnosis of HCC than in post-therapeutic monitoring. Although contrast enhancement is an important finding on imaging, enhancement does not necessarily depict the same phenomenon across modalities. We need to become well acquainted with the characteristics of each modality, including not only contrast-enhanced CT and MRI but also contrast-enhanced US. Many nonsurgical treatment options are now available for unresectable HCC, and accurate assessment of tumor response is essential to achieve favorable outcomes. For the assessment of successful radiofrequency ablation (RFA), the achievement of a sufficient ablation margin as well the absence of tumor vascular enhancement is essential. To evaluate the response to transcatheter arterial chemoembolization (TACE), enhanced tumor shrinkage is relied on as a measure of antitumor activity. Here, we give an overview of the current status of imaging assessment of HCC response to nonsurgical treatments including RFA and TACE. Copyright (C) 2015 S. Karger AG, Basel
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• Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Tomohiro Minami, Masashi Kono, Hirokazu Chishina, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 4(4), 253 - 262, 2015 , Refereed
  Summary:Background and Aims: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. Methods: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. Results: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group ( p=0.002). Conclusions: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure. Copyright (C) 2015 S. Karger AG, Basel
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• Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil, Kazuomi Ueshima, Masatoshi Kudo, Masatoshi Tanaka, Takashi Kumada, Hobyung Chung, Satoru Hagiwara, Tatsuo Inoue, Norihisa Yada, Satoshi Kitai, LIVER CANCER, LIVER CANCER, 4(4), 263 - 273, 2015 , Refereed
  Summary:We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. Copyright (C) 2015 S. Karger AG, Basel
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• Synchronous pancreatic and gastric metastasis from an ovarian adenocarcinoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration, Kentaro Yamao, Masayuki Kitano, Masatoshi Kudo, Osamu Maenishi, ENDOSCOPY, ENDOSCOPY, 47, E596 - E597, 2015 , Refereed
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• Recent Advances in the Management of Chronic Hepatitis B Including Suppression of Hepatocellular Carcinoma by Entecavir and Interferon, Soo Ki Kim, Soo Ryang Kim, Susumu Imoto, Madoka Tohyama, Yumi Otono, Tomoko Tamura, Ke Ih Kim, Mana Kobayashi, Aya Ohtani, Kayo Sugimoto, Aya Mizuguchi, Yukiko Hiramatsu, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 60 - 69, 2015 , Refereed
  Summary:At present, for adults with chronic hepatitis B virus (HBV) infection, two new analogues, entecavir (ETV) and tenofovir, are recommended as the first-line therapy by the EASL (European Association for the Study of the Liver), AASLD (American Association for the Study of Liver Diseases), and APASL (Asian Pacific Association for the Study of the Liver) guidelines. The use of pegylated interferon-alpha (PEG IFN-alpha) is recommended as the first-line therapy instead of standard IFN-alpha according to the above 3 guidelines. In this paper, the aim was to assess: (1) the long-term efficacy and safety as well as the resistance to ETV and tenofovir disoproxil fumarate (TDF); (2) the efficacy of PEG IFN-alpha; (3) the role of combination therapy with IFN plus two analogues, such as lamivudine and ETV; (4) the efficacy and safety of two analogues with cirrhosis, and (5) suppression of hepatocellular carcinoma (HCC) by EN and IFN treatment. The results are as follows: (1) both EN and TDF showed long-term efficacy and safety; (2) PEG IFN-alpha resulted in a greater decline in HBV DNA levels and a higher rate of HBeAg seroconversion;(3) combination therapy with IFN plus two analogues did not elevate the rate of sustained responses; (4) both ETV and TDF showed efficacy and safety with cirrhosis (EN especially displayed efficacy and safety with decompensated cirrhosis), and (5) suppression of HCC was observed by EN and IFN. (C) 2015 S. Karger AG, Basel
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• A Newly Developed Shear Wave Elastography Modality: With a Unique Reliability Index, Norihisa Yada, Toshiharu Sakurai, Tomohiro Minami, Tadaaki Arizumi, Masahiro Takita, Satoru Hagiwara, Kazuomi Ueshima, Hiroshi Ida, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 53 - 59, 2015 , Refereed
  Summary:Objective: The aim of this study was to prospectively assess the usefulness of the reliability index, namely the percentage of the net amount of effective shear wave velocity (VsN). Methods: One hundred and sixty-eight patients with chronic liver disease, who underwent ultrasound elastography, were consecutively enrolled. Shear wave measurement (SWM), FibroScan, virtual touch quantification, and shear wave elastography were performed for all patients, and the variations in the measurement results were compared with VsN. The absolute average value of the difference between SWM_Vs and Vs measured using other elastography devices is termed vertical bar Delta Vs vertical bar. VsN was classified into three groups: 50, <50, and 0 (failure measurement). In these groups, there was a significant difference in abdominal circumference, body mass index, the distance between the ultrasound probe surface and the liver, and vertical bar Delta Vs vertical bar. When the distance between the ultrasound probe surface and the liver was >2cm, VsN tended to be significantly lower (p < 0.001). Results: When VsN was <50, bVsI became high, and there was variation in the results between each device. Conclusions:The results of this study show that VsN is a useful value to decide whether Vs is appropriate or not. (C) 2015 S. Karger AG, Basel
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• Validation of a Modified Substaging System (Kinki Criteria) for Patients with Intermediate-Stage Hepatocellular Carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Hiroshi Ida, Yasunori Minami, Toshiharu Sakurai, Masayuki Kitano, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 47 - 52, 2015 , Refereed
  Summary:Introduction: Barcelona Clinic Liver Cancer (BCLC) stage B, an intermediate stage, includes various conditions of hepatocellular carcinoma (HCC). This heterogeneity of the patients with intermediate-stage HCC makes it difficult to predict their survival rates. In the present study, we examined the validity of the modified Bolondi classification (Kinki criteria) as a subclassification of patients with BCLC stage B HCC. Methods: Of 906 patients who underwent conventional transarterial chemoembolization at Kinki University Hospital, 753, who met the inclusion criteria, were examined. Of these 753 patients, 425 (56.4%) with BCLC stage B were subclassified using the Kinki criteria to examine the survival rate. Results: According to the Kinki criteria, 158 (37.2%) were subclassified into subclass B1,236 (55.53) into B2, and 31(7.3%) into B3. The comparison of the survival rates showed that the median overall survival was 3.9 years (95% CI, 3.2-4.6) in the BCLC subclass B1 group, 2.5 years (95% Cl, 2.2-3.1) in the B2 group, and 1.1 years (95% Cl, 0.6-1.5) in the B3 group (p < 0.001). Conclusion: When the BCLC stage B patients were subclassified according to the Kinki criteria, survival curves were stratified with significant differences, suggesting that the Kinki criteria were suitable for the subclassification of the intermediate-stage HCC patients. (C) 2015 S. Karger AG, Basel
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• Comparison of Daclatasvir and Asunaprevir for Chronic HCV 1b Infection with Telaprevir and Simeprevir plus Peginterferon and Ribavirin, with a Focus on the Prevention of Occurrence and Recurrence of Hepatocellular Carcinoma, Kayo Sugimoto, Soo Ryang Kim, Soo Ki Kim, Susumu Imoto, Madoka Tohyama, Ke Ih Kim, Aya Ohtani, Takashi Hatae, Yoshihiko Yano, Masatoshi Kudo, Yoshitake Hayashi, ONCOLOGY, ONCOLOGY, 89, 42 - 46, 2015 , Refereed
  Summary:Objectives:The efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and a-fetoprotein (AFP) as suppressive markers of HCC were also measured. Methods: Patients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups. Results: No difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEGIFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups. Conclusion: The preventive effect of the IFN-free,all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV. (C) 2015 S. Karger AG, Basel
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• Hyperenhanced Rim Surrounding Liver Metastatic Tumors in the Postvascular Phase of Sonazoid-Enhanced Ultrasonography: A Histological Indication of the Presence of Kupffer Cells, Hitoshi Tochio, Masafumi Sugahara, Yukihiro Imai, Hiroshi Tei, Yoshiyuki Suginoshita, Nobuhiro Imawsaki, Ichiro Sasaki, Michio Hamada, Kazushi Minowa, Tetsuo Inokuma, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 33 - 41, 2015 , Refereed
  Summary:Aim: A hyperenhanced rim (termed 'HER') in the postvascular phase is detected in some cases of liver metastasis by Sonazoid-enhanced ultrasonography (US). Here, the association of the HER with histological features was investigated to clarify the cause of this characteristic imaging pattern. Subjects and Methods: A total of 13 hepatic nodules obtained from 11 patients with metastatic liver cancer who underwent Sonazoid-enhanced US followed by surgical resection were analyzed. The distribution density of CD68-positive cells in the tumor rim and the nontumor area was calculated and compared between the HER-positive and HER-negative groups. The relation between the pathological features of the tumor rim and the rate of necrosis within the tumor was also investigated. Results: In the HER-positive group (n = 8), the distribution density of CD68-positive cells was 2.9 +/- 0.9, which was significantly higher than that (1.0 +/- 0.3) in the HER-negative group (p < 0.05). Inflammatory cell infiltrates, including CD8-positive lymphocytes, were detected in all the HER-positive cases in the area surrounding the tumor, while fibrosis was observed in all the HER-negative cases. The necrotic area within the tumor was significantly larger in the HER-negative group. Conclusion: The HER-positive sign in liver metastases could reflect an increase in Kupifer cells in the tumor rim. The presence of the HER was associated with inflammatory cell infiltrates including CD8-positive lymphocytes surrounding the metastatic liver tumor. (C) 2015 S. Karger AG, Basel
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• Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience, Yasunori Minami, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Masakatsu Tsurusaki, Yukinobu Yagyu, Kazuomi Ueshima, Naoshi Nishida, Takamichi Murakami, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 27 - 32, 2015 , Refereed
  Summary:Objective: To investigate whether balloon-occluded transcatheter arterial chemoembolization (b-TACE) can produce a more dense accumulation of iodized oil in various stages of hepatocellular carcinoma (HCC), from single to uncountable, to overcome inferior local control. Materials and Methods: We studied 27 patients with HCC, including single to uncountable multiple lesions, who underwent b-TACE between August 2013 and April 2015. Dynamic CT was performed at baseline and 1-3 months after b-TACE. The treatment effect (TE) after b-TACE was evaluated using the Response Evaluation Criteria in Cancer of the Liver (RECICL) proposed by the Liver Cancer Study Group of Japan. Results: In the countable HCC group, contrast-enhanced CT demonstrated RECICL TE4 in 43.8% (14/32), TE3 in 12.5% (4/32), TE2 in 37.5% (12/32), and TEl in 6.3% (2/32) of patients. For the TACE-naive cohort, the objective response rate was 52.9%. The objective response rate was 60% for the previously lACE-treated cohort. In the uncountable multiple HCC group, the objective response rate was 0% (0/10), with progressive disease in 90% (9/10) of patients. Conclusion: Our observations suggested that b-TACE did not reduce the efficacy of retreatment for HCC with an insufficient outcome from conventional TACE, but it could not improve the efficacy of treatment for uncountable multiple HCCs. (C) 2015 S. Karger AG, Basel
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• Percutaneous Radiofrequency Ablation for Intermediate-Stage Hepatocellular Carcinoma, Kazuya Kariyama, Akiko Wakuta, Mamoru Nishimura, Masayuki Kishida, Ayano Oonishi, Atsushi Ohyama, Kazuhiro Nouso, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 19 - 26, 2015 , Refereed
  Summary:Objectives: Radiofrequency ablation plays a key role in the treatment of early-stage hepatocellular carcinoma. However, it is not recommended for intermediate-stage hepatocellular carcinoma. The objective of this study was to clarify the efficacy and safety of radiofrequency ablation for treating intermediate-stage hepatocellular carcinoma. Methods: We examined the outcome of 65 consecutive patients who were treated with radiofrequency ablation with or without transarterial chemoembolization for intermediate-stage hepatocellular carcinoma. Results: With a median follow-up of 37 months, overall survival rates of 65 cases at 1,3,5, and 7 years were 90, 70,51, and 36%, respectively. Multivariate analysis of clinical parameters revealed that the multicentric occurrence (MC)/intrahepatic metastasis (IM) was the only significant prognostic factor for overall survival (hazard ratio, 4.9; 95% confidence intervals, 2.1-11.4). Tumor size and tumor number were not significant factors for survival. The overall survival rates of patients with MC (n = 33) at 1, 3, 5, and 7 years were 97, 90, 80, and 59%, respectively; those for patients with IM (n = 32) were 86, 55, 14, and 8%, respectively (p < 0.0001). Two cases (4.9%) had complications of hemothorax and diaphragmatic burn; however, no major complications were observed. Conclusion: Radiofrequency ablation is safe and effective for the treatment of intermediate-stage hepatocellular carcinoma, especially for patients with MC. (C) 2015 S. Karger AG, Basel
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• Initial Experience Performing Percutaneous Ultrasound Examination with Real-Time Virtual Sonography with Color Display, Chikara Ogawa, Yasunori Minami, Turuyo Noda, Soichi Arasawa, Masako Izuta, Atsushi Kubo, Toshihiro Matsunaka, Hiroyuki Tamaki, Mitsunari Shibatoge, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 11 - 18, 2015 , Refereed
  Summary:Purpose: We report the efficacy of percutaneous ultrasound (US) examination using a novel real-time virtual sonography (RVS) method that collates multiple Digital Imaging and Communications in Medicine (DICOM) data sources and displays reference images in color. Materials and Methods: A total of 7 patients with 9 hepatocellular carcinomas were evaluated. Using the SYNAPSE VINCENT volume analyzer, DICOM data of the portal vein, hepatic vein, tumor, and hepatic segment were isolated from contrast-enhanced computed tomography DICOM data. Each portion of DICOM data was uploaded into an US scanner (HI VISION Ascendus, Hitachi Aloka Medical Ltd., Tokyo, Japan) and unified on a US platform to create a single reference image. Each uploaded portion of DICOM data was assigned a different color. Further, conventional RVS was performed using this information. Results: The maximal tumoral diameter ranged from 6.4 to 15 mm (mean +/- SD, 11.0 +/- 2.8). DICOM data could be isolated, enabling the display of color RVS in all patients. Color RVS facilitated superior visibility compared with conventional grayscale RVS and facilitated the comprehension of spatial positioning. Conclusion: RVS with color display demonstrates utility in increasing operator comprehension of spatial and positional relationships during percutaneous US examination. (C) 2015 S. Karger AG, Basel
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• Evaluation of ART Scores for Repeated Transarterial Chemoembolization in Japanese Patients with Hepatocellular Carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Hiroshi Ida, Yasunori Minami, Toshiharu Sakural, Naoshi Nishida, Masayuki Kitano, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 89, 4 - 10, 2015 , Refereed
  Summary:Objective: Transarterial chemoembolization (TACE) is recommended as a first-line therapy for hepatocellular carcinoma (HCC) patients ineligible for curative therapy and without portal invasion. The Assessment for Retreatment with TACE (ART) scoring system was recently proposed for identifying patients who would not show sufficient survival benefit from repeated TACE. We reevaluated the performance of ART in HCC patients treated in Japan, where selective TACE is commonly used. Methods: Between 2000 and 2013, 988 patients with HCC underwent TACE at Kinki University Hospital, and 627 received >= 2 sessions of TACE. Seventy-six patients who underwent >= 2 TACE sessions within 90 days were investigated for their performance of the ART score in the context of overall survival (OS). Results: Only 12% (76/627) of patients underwent >= 2 TACE sessions within 90 days. Of those, 52 patients showed a low ART score (0-1.5), and 24 had a high ARTscore (>= 2.5); the median OS was 20.2 and 37.6 months, respectively (p = 0.8207). Conclusion:The ART scoring system did not demonstrate a sufficiently predictive impact on OS among the patients who underwent 2 TACE sessions within 90 days. Application of the ART score should be carefully considered because differences in TACE procedures and post-TACE treatment can affect the results while evaluating OS. (C) 2015 S. Karger AG, Basel
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• Challenges of Clinical Research on Hepatocellular Carcinoma, Masatoshi Kudo, Masayuki Kitano, Toshiharu Sakurai, Naoshi Nishida, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 780 - 790, 2015 , Refereed
  Summary:Challenges of clinical practice and research on hepatocellular carcinoma (HCC) were reviewed. There are several differences in clinical practice between Japan and the Western countries such as tumor markers, understanding of pathological early HCC, imaging diagnosis, treatment strategy, staging system and subclassification of HCC. Further studies are warranted for the clinical practices of Japan to be adopted in the rest of the world. (C) 2015 5. Karger AG, Basel
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• Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma, Naoshi Nishida, Masayuki Kitano, Toshiharu Sakurai, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 771 - 779, 2015 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC. (C) 2015 S. Karger AG, Basel
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• General Rules for the Clinical and Pathological Study of Primary Liver Cancer, Nationwide Follow-Up Survey and Clinical Practice Guidelines: The Outstanding Achievements of the Liver Cancer Study Group of Japan, Masatoshi Kudo, Masayuki Kitano, Toshiharu Sakurai, Naoshi Nishida, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 765 - 770, 2015 , Refereed
  Summary:This review outlines the significance of establishing general rules, a nationwide follow-up survey, and clinical practice guidelines for liver cancer in Japan. The general rules are an essential part of hepatocellular carcinoma (HCC) treatment, enabling a 'common language' to be used in daily clinical practice and for the nationwide follow-up survey. The Japanese General Rules for the Clinical and Pathological Study of Primary Liver Cancer, which provide detailed descriptions of HCC, are excellent and are unique to Japan. Items in the General Rules for the Clinical and Pathological Study of Primary Liver Cancer are used substantially in another important project, the Nationwide Follow-Up Survey of Primary Liver Cancer, which has been rigorously undertaken with great effort by the Liver Cancer Study Group of Japan biannually since 1969. Both evidence-based and consensus-based treatment algorithms for HCC are used to complement each other in clinical practice in Japan. (C) 2015 S. Karger AG, Basel
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• Cone-Beam CT Angiography for Hepatocellular Carcinoma: Current Status, Yasunori Minami, Takamichi Murakami, Masayuki Kitano, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 759 - 764, 2015 , Refereed
  Summary:Cone-beam CT (CBCT) is generated during a rotational sweep of the C-arm around the patient, and can be a valuable imaging technique, providing in situ cross-sectional imaging. It is easy to evaluate the morphologic characteristics of hepatic arteries from multiple views with the use of various reconstruction techniques, such as maximum intensity projection (MIP) and volume rendering. CBCTangiography is capable of providing more information than the standard 2-dimensional angiography in visualizing hepatocellular carcinomas (HCCs) and targeting tumors though precise microcatheter placement in close proximity to HCCs. It can also be useful in evaluating treatment success at the time of the procedure. It is anticipated that CBCT could reduce radiation exposure, the overall procedure time and contrast material use because it allows immediate feedback for an efficient angiographic procedure. Therefore, CBCT angiography is an exciting technology with the potential to significantly impact the practice of interventional radiology. The purpose of this article is to provide a review of the principles, clinical applications and technique of CBCT angiography for HCC treatment. (C) 2015 S. Karger AG, Basel
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• Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus, Naoshi Nishida, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshirna, Toshiharu Sakurai, Masayuki Kitano, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 745 - 750, 2015 , Refereed
  Summary:Objectives: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. Methods: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC-HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non-cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non-cancerous liver tissue that is affected by specific HCC risk factors. Results: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of beta-value between HCC and non-cancerous liver and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. Conclusions: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals. (C) 2015 S. Karger AG, Basel
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• Real-Life Clinical Practice with Sorafenib in Advance Hepatocellular Carcinoma: A Single-Center Experience Second Analysis, Tadaaki Arizumi, Kazuomi Ueshima, Mina Iwanishi, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Hiroshi Ida, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masayuki Kitano, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 728 - 734, 2015 , Refereed
  Summary:Objectives: Sorafenib has become a standard therapy for advanced hepatocellular carcinoma following the demonstration of significant increase in progression-free survival as well as overall survival (OS) in the 2-phase III trials. We examined efficacy and adverse events (AEs) in patients treated with sorafenib over a 6-year period since approval in Japan. Methods: Two hundred and forty-one patients treated with sorafenib at the Kinki University Hospital were retrospectively analyzed clinically for the factors related to survival periods, tumor response evaluated by the Response Evaluation Criteria In Cancer of the Liver (RECICL) and AEs. Results: OS was 14.3 months. According to the RECICL, the objective response and disease control rates were 18.6% (43 of 241) and 61.1% (137 of 241), respectively. AEs were seen in 77.3% (187 of 241), with Grade 3 or higher in 23.6% (57 of 241). The most frequent AE was hand-foot skin reaction in 109 patients (45.0%), and 28 patients (11.8%) showed Grade 3 or higher. Significant factors contributing to the OS were treatment duration (p = 0.0204), up-to-7 criteria (p = 0.0400), increase of Child-Pugh score (p = 0.0008) and tumor response determined by the RECICL (p = 0.0007). Conclusion: Based on the analysis, using many cases at a single center, we concluded that continuation of treatment with sorafenib for >= 90 days without decrease of liver function was critical if tumor response was determined as stable disease or higher. (C) 2015 S. Karger AG, Basel
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• Characteristics of Hypovascular versus Hypervascular Well-Differentiated Hepatocellular Carcinoma Smaller Than 2 cm - Focus on Tumor Size, Markers and Imaging Detectability, Kayo Sugimoto, Soo Ryang Kim, Susumu Imoto, Madoka Tohyama, Soo Ki Kim, Toshiyuki Matsuoka, Yoshihiko Yano, Masatoshi Kudo, Yoshitake Hayashi, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 721 - 727, 2015 , Refereed
  Summary:Objectives: The characteristics of hypovascular and hypervascular well-differentiated hepatocellular carcinomas (HCCs) were compared in terms of tumor size, tumor markers and detectability by imaging modalities. Methods: Well-differentiated HCC nodules that are smaller than 2 cm (n = 27) were evaluated in 27 patients using histopathology and divided into 2 groups: hypovascular (n = 10) and hypervascular (n = 17). The diagnostic sensitivity of imaging modalities was then evaluated for efficiency in disclosing tumor size and tumor markers in the 2 types. Results: No difference was observed in tumor size and tumor markers between the 2 types; however, the sensitivity of contrast-enhanced CT, contrast-enhanced ultrasonography and arterioportal angiography was significantly different between the 2 types, whereas that by Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging (Gd-EOB-DTPA MRI) demonstrated no difference. Conclusion: Hypovascular HCC could be diagnosed by Gd-EOB-DTPA MRI in the hepatobiliary phase. (C) 2015 S. Karger AG, Basel
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• Usefullness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population, Yutaka Hasegawa, Soo Ryang Kim, Takashi Hatae, Mitsuhiro Ohta, Aya Fujinami, Kayo Sugimoto, Ke Ih Kim, Susumu Imoto, Madoka Tohyama, Soo Ki Kim, Yoshihiro Ikura, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 715 - 720, 2015 , Refereed
  Summary:Objective:The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. Methods: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Results: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/I, CK-18M65 had an AUC value of 0.7369,60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 +/- 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 +/- 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 +/- 229.65, n = 9) and moderate steatosis (>= 33%,655.13 +/- 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. Conclusion: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population. (C) 2015 S. Karger AG, Basel
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• Early Viral Response Predicts the Efficacy of Antiviral Triple Therapy with Simeprevir, Peg-Interferon and Ribavirin in Patients Infected with Hepatitis C Virus Genotype 1, Naoshi Nishida, Mina Iwanishi, Tomohiro Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Masayuki Kitano, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 708 - 714, 2015 , Refereed
  Summary:Objectives: Triple therapy using peg-interferon, ribavirin and simeprevir (PEG-IFN/RBV/SMV) has reportedly resulted in high-sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC), especially in naive cases and relapsers to prior PEG-IFN/RBV therapy. Here, we retrospectively analyzed the antiviral response associated with a triple regimen, in the context of early reduction of viral load during treatment. Methods: Forty-six CHC patients with HCV genotype 1b were treated with PEG-IFN/RBV/SMV triple therapy: 20 were naive cases, 12 were relapsers and 14 were non-responders to prior PEG-IFN/RBV therapy. We evaluated rapid virological response (RVR), complete early virological response (EVR), viral clearance at the end of the treatment (EOT) and at 12 weeks after the EOT (SVR12). In addition, we quantified the serum HCV-RNA on the 1st day and the 7th day after initiating treatment. Results: Multivariate analysis revealed that response to prior treatment was identified as an independent factor for achieving SVR12 after triple therapy (p = 0.0005). The achievement of serum HCV-RNA <2 log(10) IU/ml on day 7, RVR, EVR and EOT were associated with SVR12 (p = 0.0050, p = 0.0002, p = 0.0009 and p = 0.0002, respectively). Conclusions: Rapid decline of HCV is a predictive factor for the achievement of SVR12, even in antiviral triple therapy with PEG-IFN/RBV/SMV. An extended treatment period should be applied for patients who show detectable serum HCV-RNA at week 4. (C) 2015 S. Karger AG, Basel
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• Chronic Liver Diseases and Liver Cancer: An Update in 2015, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 33(6), 705 - 707, 2015 , Refereed
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• Linifanib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma: Results of a Randomized Phase III Trial, Calin Cainap, Shukui Qin, Wen-Tsung Huang, Ik Joo Chung, Hongming Pan, Ying Cheng, Masatoshi Kudo, Yoon-Koo Kang, Pei-Jer Chen, Han-Chong Toh, Vera Gorbunova, Ferry A. L. M. Eskens, Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, Saied El-Nowiem, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 33(2), 172 - U77, Jan. 2015 , Refereed
  Summary:Purpose This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. Patients and Methods Patients were randomly assigned in a 1: 1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. Results We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P = .001). Conclusion Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and non-inferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib. (C) 2014 by American Society of Clinical Oncology
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• Malignant Transformation of Hepatocellular Adenoma: How Frequently Does It Happen?, M. Kudo, LIVER CANCER, LIVER CANCER, 4(1), 1 - 5, 2015 , Refereed
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• Involvement of Heat Shock Protein A4/Apg-2 in Refractory Inflammatory Bowel Disease, Teppei Adachi, Toshiharu Sakurai, Hiroshi Kashida, Hiromasa Mine, Satoru Hagiwara, Shigenaga Matsui, Koji Yoshida, Naoshi Nishida, Tomohiro Watanabe, Katsuhiko Itoh, Jun Fujita, Masatoshi Kudo, INFLAMMATORY BOWEL DISEASES, INFLAMMATORY BOWEL DISEASES, 21(1), 31 - 39, Jan. 2015 , Refereed
  Summary:Background: Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated. Methods: We assessed HSPA4 expression and function by generating HSPA4-deficient mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). Results: In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of HSPA4 and antiapoptotic protein Bcl-2, a T-cell-derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4-deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox(2+) cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4(+/-) bone marrow into wild-type mice reduced the immune response. Conclusions: Upregulation of Bcl-2 and IL-17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.
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• Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study, D. J. Pinato, G. Karamanakos, T. Arizumi, D. Adjogatse, Y. W. Kim, J. Stebbing, M. Kudo, J. W. Jang, R. Sharma, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 40(11-12), 1270 - 1281, Dec. 2014 , Refereed
  Summary:BackgroundTransarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation-based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC. AimTo explore the prognostic ability of IBI as a predictor of survival after TACE. MethodsBaseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n=76) and Japan (n=577). ResultsPre-treatment IBI predicted for OS in the derivation set (P=0.001). Other univariate predictors of OS included radiological response to TACE (P<0.001), pre-TACE CLIP score (P<0.01), tumour diameter >5cm (P=0.05) and AFP 400 (P<0.001). Normalisation of IBI post-TACE was associated with radiological response by mRECIST criteria and improved OS (P<0.001). Normalisation of IBI remained a significant multivariate predictor of OS in both the derivation and validation sets (P<0.001). ConclusionsNormalisation of IBI after TACE is shown to be an independent predictor of survival and may be integrated into the retreatment criteria for repeat TACE in intermediate stage HCC. IBI and its dynamic changes after treatment are validated as a biomarker allowing the stratification of patients with a significant survival advantage following initial TACE.
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• Comparison of systems for assessment of post-therapeutic response to sorafenib for hepatocellular carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Haruhiko Takeda, Yukio Osaki, Masahiro Takita, Tatsuo Inoue, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 49(12), 1578 - 1587, Dec. 2014 , Refereed
  Summary:To test the hypothesis that use of the response evaluation criteria in cancer of the liver (RECICL), an improved evaluation system designed to address the limitations of the response evaluation criteria in solid tumors 1.1 (RECIST1.1) and modified RECIST (mRECIST), provides for more accurate evaluation of response of patients with hepatocellular carcinoma (HCC) to treatment with sorafenib, a molecularly targeted agent, as assessed by overall survival (OS). The therapeutic response of 156 patients with advanced HCC who had been treated with sorafenib therapy for more than 1 month was evaluated using the RECIST1.1, mRECIST, and RECICL. After categorization as showing progressive disease (PD), stable disease (SD), or objective response, the association between OS and categorization was examined using the Kaplan-Meier method to develop survival curves. The 141 cases categorized as PD or SD by the RECIST1.1, but objective response by the mRECIST and RECICL, were further analyzed for determination of the association between OS and categorization. Only categorization using the RECICL was found to be significantly correlated with OS (p = 0.0033). Among the patients categorized as SD or PD by the RECIST1.1, reclassification by the RECICL but not the mRECIST was found to be significantly associated with OS and allowed for precise prediction of prognosis (p = 0.0066). Only the use of the RECICL allowed for identification of a subgroup of HCC patients treated with sorafenib with improved prognosis. The RECICL should, therefore, be considered a superior system for assessment of therapeutic response.
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• Small-intestinal mucosal injury induced by non-steroidal anti-inflammatory drugs or antiplatelet agents in our hospital, Tomoyuki Nagai, Rie Tanaka, Mitsunari Yamada, Teppei Adachi, Masaki Takayama, Hiromasa Mine, Yoshihisa Okazaki, Yoriaki Komeda, Yutaka Asakuma, Toshiharu Sakurai, Shigenaga Mastui, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 168 - 168, Nov. 2014 , Refereed
• The usefulness of single-balloon endoscopy for the small bowel lesions, Teppei Adachi, Rie Tanaka, Mitsunari Yamada, Masaki Takayama, Hiromasa Mine, Tomoyuki Nagai, Masanori Kawasaki, Yutaka Asakuma, Yoshihisa Okazaki, Yoriaki Komeda, Toshiharu Sakurai, Shigenaga Matsui, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 3 - 4, Nov. 2014 , Refereed
• Endoscopic resection for rectal nets (neuroendocrine tumors): EMR-C (EMR using a cap), EMR-L (EMR with a ligation device), or conventional EMR, Mitsunari Yamada, Hiroshi Kashida, Rie Tanaka, Teppei Adachi, Hiromasa Mine, Masaki Takayama, Yoshihiro Okazaki, Yoshiaki Nagata, Tomoyuki Nagai, Masanori Kawasaki, Noriaki Komeda, Yutaka Asakuma, Yoshiharu Sakurai, Shigenaga Matsui, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 265 - 266, Nov. 2014 , Refereed
• Comparison of Japanese primary and secondary regimen of Helicobacter pylori eradication, Teppei Adachi, Rie Tanaka, Mitsunari Yamada, Masaki Takayama, Hiromasa Mine, Tomoyuki Nagai, Masanori Kawasaki, Yutaka Asakuma, Yoshihisa Okazaki, Yoriaki Komeda, Toshiharu Sakurai, Shigenaga Matsui, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 22 - 22, Nov. 2014 , Refereed
• Two cases of gastric amyloidosis, Shigenaga Matsui, Hiroshi Kashida, Kazuki Okamoto, Yutaka Asakuma, Toshiharu Sakurai, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 114 - 114, Nov. 2014 , Refereed
• The clinical characteristics and treatment of eosinophilic esophagitis, Shigenaga Matsui, Hiroshi Kashida, Masanori Kawasaki, Yutaka Asakuma, Toshiharu Sakurai, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 29, 114 - 115, Nov. 2014 , Refereed
• Brivanib as Adjuvant Therapy to Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma: A Randomized Phase III Trial, Masatoshi Kudo, Guohong Han, Richard S. Finn, Ronnie T. P. Poon, Jean-Frederic Blanc, Lunan Yan, Jijin Yang, Ligong Lu, Won-Young Tak, Xiaoping Yu, Joon-Hyeok Lee, Shi-Ming Lin, Changping Wu, Tawesak Tanwandee, Guoliang Shao, Ian B. Walters, Christine Dela Cruz, Valerie Poulart, Jian-Hua Wang, HEPATOLOGY, HEPATOLOGY, 60(5), 1697 - 1707, Nov. 2014 , Refereed
  Summary:Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1: 1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P50.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS.
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• NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6, T. Watanabe, N. Asano, G. Meng, K. Yamashita, Y. Arai, T. Sakurai, M. Kudo, I. J. Fuss, A. Kitani, T. Shimosegawa, T. Chiba, W. Strober, MUCOSAL IMMUNOLOGY, MUCOSAL IMMUNOLOGY, 7(6), 1312 - 1325, Nov. 2014 , Refereed
  Summary:It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-kappa B activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
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• Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer, Toshiharu Sakurai, Hiroshi Kashida, Tomohiro Watanabe, Satoru Hagiwara, Tsunekazu Mizushima, Hideki Iijima, Naoshi Nishida, Hiroaki Higashitsuji, Jun Fujita, Masatoshi Kudo, CANCER RESEARCH, CANCER RESEARCH, 74(21), 6119 - 6128, Nov. 2014 , Refereed
  Summary:Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNF alpha, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp(-/-) mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNF alpha, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNF alpha, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1(+) cells, leading to attenuated tumorigenic potential. Transplantation of Cirp(-/-) bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNF alpha and IL23 in inflammatory cells. (C) 2014 AACR.
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• Current treatment status of polycystic liver disease in Japan, Koichi Ogawa, Kiyoshi Fukunaga, Tomoyo Takeuchi, Naoki Kawagishi, Yoshifumi Ubara, Masatoshi Kudo, Nobuhiro Ohkohchi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 44(11), 1110 - 1118, Oct. 2014 , Refereed
  Summary:AimPolycystic liver disease (PLD) is a genetic disorder characterized by the progressive development of multiple liver cysts. No standardized criteria for the selection of treatment exist because PLD is a rare condition and most patients are asymptomatic. We here aimed to clarify the status of treatment and to present a therapeutic strategy for PLD in Japan. MethodsFrom 1 June 2011 to 20 December 2011, we administered a questionnaire to 202 PLD patients from 86 medical institutions nationwide. ResultsThe patients included 45 men and 155 women, and the median age was 63 years. Two hundred and eighty-one treatments were performed for these patients, as follows: cyst aspiration sclerotherapy (AS) in 152 cases, cyst fenestration (FN) in 53, liver resection (LR) in 44, liver transplantation (LT) in 13 and other treatments in 19. For cases of type I PLD (mild form) according to Gigot's classification, the therapeutic effects of AS, FN and LR were similar. For type II (moderate form), LT demonstrated the best therapeutic effects, followed by LR and FN. For type III (severe form), the effects of LT were the best. The incidences of complications were 23.0% in AS, 28.4% in FN, 31.8% in LR and 61.5% in LT. ConclusionConsidering the therapeutic effects and complications, AS, LR and LT showed good results for type I, type II and type III PLD, respectively. However, LT for PLD was performed in a small number of patients. In Japan, the transplantation therapy is expected to be common in the future.
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• Endoscopic ultrasonography-guided gallbladder drainage procedures: Is the glass half-full or half-empty?, Masayuki Kitano, Ken Kamata, Masatoshi Kudo, DIGESTIVE ENDOSCOPY, DIGESTIVE ENDOSCOPY, 26(5), 636 - 637, Sep. 2014 , Refereed
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• Nationwide survey in Japan regarding splenectomy/partial splenic embolization for interferon treatment targeting hepatitis C virus-related chronic liver disease in patients with low platelet count, Naoto Ikeda, Hiroyasu Imanishi, Nobuhiro Aizawa, Hironori Tanaka, Yoshinori Iwata, Hirayuki Enomoto, Masaki Saito, Hiroko Iijima, Yuji Iimuro, Jiro Fujimoto, Satoshi Yamamoto, Shozo Hirota, Masatoshi Kudo, Shigeki Arii, Shuhei Nishiguchi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 44(8), 829 - 836, Aug. 2014 , Refereed
  Summary:Aim: In chronic liver disease associated with hepatitis C virus (HCV), a low platelet count is a major obstacle in carrying out interferon (IFN) treatment. We used a questionnaire to clarify the extent to which splenectomy/partial splenic embolization (PSE) is performed before IFN treatment, as well as the efficacy and complications thereof. Methods: Two questionnaires were distributed to 413 medical institutes in Japan specializing in the treatment of liver diseases, and responses were obtained from 204 institutes. Furthermore, a more detailed questionnaire was completed by 10 institutes that experienced cases of death. Results: In patients with HCV genotype 1b and a high viral load (HCV1b/High), the sustained viral response (SVR) rate was 28% for the splenectomy group and 22% for the PSE group, with no significant difference between these groups. In patients that were not HCV1b/High, the SVR rate was higher in those that underwent splenectomy (71%) compared to the PSE group (56%; P = 0.025). There were cases of death in seven of 799 splenectomy cases (0.89%) and four of 474 PSE cases (0.84%). Infectious diseases were involved in nine of 11 cases of death, with a peculiar patient background of Child-Pugh B (6/10) and an age of 60 years or greater (7/11). Conclusion: The application of splenectomy/PSE before IFN treatment should be avoided in patients with poor residual hepatic function and/or elderly patients. In HCV1b/High patients, splenectomy/PSE should be performed only after selecting those in which IFN treatment should be highly effective.
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• Effect of Everolimus on Survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib The EVOLVE-1 Randomized Clinical Trial, Andrew X. Zhu, Masatoshi Kudo, Eric Assenat, Stephane Cattan, Yoon-Koo Kang, Ho Yeong Lim, Ronnie T. P. Poon, Jean-Frederic Blanc, Arndt Vogel, Chao-Long Chen, Etienne Dorval, Markus Peck-Radosavljevic, Armando Santoro, Bruno Daniele, Junji Furuse, Annette Jappe, Kevin Perraud, Oezlem Anak, Dalila B. Sellami, Li-Tzong Chen, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 312(1), 57 - 67, Jul. 2014 , Refereed
  Summary:IMPORTANCE Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2: 1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P=.68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P=.01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib.
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• Assessment for Retreatment (ART) Score for Repeated Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma, Masatoshi Kudo, Tadaaki Arizumi, Kazuomi Ueshima, HEPATOLOGY, HEPATOLOGY, 59(6), 2424 - 2425, Jun. 2014 , Refereed
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• Serum amyloid A and C-reactive protein positive nodule in alcoholic liver cirrhosis, hard to make definite diagnosis, Soo Ryang Kim, Fukuo Kondo, Yumi Otono, Susumu Imoto, Kenji Ando, Makoto Hirakawa, Katsumi Fukuda, Madoka Sasaki, Soo Ki Kim, Takamitsu Komaki, Shinobu Tsuchida, Sawako Kobayashi, Toshiyuki Matsuoka, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 44(5), 584 - 590, May 2014 , Refereed
  Summary:We describe a case of serum amyloid A (SAA) and C-reactive protein (CRP) positive nodule detected by immunohistochemical analysis in a 37-year-old woman with alcohol-related cirrhosis. Imaging studies at first admission pointed to hepatocellular carcinoma (HCC), a dysplastic nodule, an inflammatory pseudotumor or focal nodular hyperplasia (FNH). Ultrasonography-guided biopsy in Segment 2 showed minimal atypical changes, except for a slight increase in cell density and micronodular cirrhosis in the non-nodular portion. gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging carried out after a year and a half revealed hypervascularity in the arterial phase and isointensity in the hepatobiliary phase. Three years thereafter, however, the imaging displayed a change from isointensity to a defect in the hepatobiliary phase, and the nodule demonstrated minimal histological atypia. Immunohistochemical staining of the nodule was positive for SAA, CRP, liver fatty acid-binding protein and glutamine synthetase, but negative for beta-catenin, heat shock protein 70 and Glypican 3. Organic anion transporter (OATP)8 staining was weaker in the nodule than in the non-nodular portion of the alcohol-related micronodular cirrhosis. The nodule was diagnosed as an SAA and CRP positive nodule, and HCC was ruled out. Despite the change from isointensity to a defect in the hepatobiliary phase, no evidence of HCC was found in the biopsy specimen. The change may be explained more by the weak OATP8 staining compared with that of alcohol-related liver cirrhosis than by malignant transformation into HCC.
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• GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis, R. Lencioni, M. Kudo, S. -L. Ye, J. -P. Bronowicki, X. -P. Chen, L. Dagher, J. Furuse, J. F. Geschwind, L. Ladron de Guevara, C. Papandreou, T. Takayama, S. K. Yoon, K. Nakajima, R. Lehr, S. Heldner, A. J. Sanyal, INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, 68(5), 609 - 617, May 2014 , Refereed
  Summary:BackgroundGIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. MethodsPatients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when similar to 1500 treated patients were followed up for 4months. ResultsOf the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. ConclusionsConsistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in >3000 patients are ongoing.
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• Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer, Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Akihiko Ito, Masatoshi Kudo, Kazuto Nishio, MOLECULAR CANCER, MOLECULAR CANCER, 13, 126 - 136, May 2014 , Refereed
  Summary:Background: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. Methods and results: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21(CIP1/WAF1) in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. Conclusion: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.
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• Therapeutic response assessment of RFA for HCC: Contrast-enhanced US, CT and MRI, Yasunori Minami, Naoshi Nishida, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 20(15), 4160 - 4166, Apr. 2014 , Refereed
  Summary:Radiofrequency ablation (RFA) is commonly applied for the treatment of hepatocellular carcinoma (HCC) because of the facile procedure, and the safety and effectiveness for the treatment of this type of tumor. On the other hand, it is believed that HCC cells should spread predominantly through the blood flow of the portal vein, which could lead to the formation of intrahepatic micrometastases. Therefore, monitoring tumor response after the treatment is quite important and accurate assessment of treatment response is critical to obtain the most favorable outcome after the RFA. Indeed, several reports suggested that even small HCCs of <= 3 cm in diameter might carry intrahepatic micrometastases and/or microvascular invasion. From this point of view, for preventing local recurrences, RFA should be performed ablating a main tumor as well as its surrounding non-tumorous liver tissue where micrometastases and microvascular invasion might exist. Recent advancement of imaging modalities such as contrast-enhanced ultrasonic, computed tomography, and magnetic resonance imaging are playing an important role on assessing the therapeutic effects of RFA. The local recurrence rate tends to be low in HCC patients who were proven to have adequate ablation margin after RFA; namely, not only disappearance of vascular enhancement of main tumor, but also an adequate ablation margin. Therefore, contrast enhancement gives important findings for the diagnosis of recurrent HCCs on each imaging. However, hyperemia of non-tumorous liver surrounding the ablated lesion, which could be attributed to an inflammation after RFA, may well obscure the findings of local recurrence of HCCs after RFA. Therefore, we need to carefully address to these imaging findings given the fact that diagnostic difficulties of local recurrence of HCC. Here, we give an overview of the current status of the imaging assessment of HCC response to RFA. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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• Can low-dose CT with iterative reconstruction reduce both the radiation dose and the amount of iodine contrast medium in a dynamic CT study of the liver?, Hiroto Takahashi, Masahiro Okada, Tomoko Hyodo, Syojiro Hidaka, Yuki Kagawa, Mitsuru Matsuki, Masakatsu Tsurusaki, Takamichi Murakami, EUROPEAN JOURNAL OF RADIOLOGY, EUROPEAN JOURNAL OF RADIOLOGY, 83(4), 684 - 691, Apr. 2014 , Refereed
  Summary:Purpose: To investigate whether low-dose dynamic CT of the liver with iterative reconstruction can reduce both the radiation dose and the amount of contrast medium. Materials and methods: This study was approved by our institutional review board. 113 patients were randomly assigned to one of two groups. Group A/group B (fifty-eight/fifty-five patients) underwent liver dynamic CT at 120/100 kV, with 0/40% adaptive statistical iterative reconstruction (ASIR), with a contrast dose of 600/480 mg I/kg, respectively. Radiation exposure was estimated based on the manufacturer's phantom data. The enhancement value of the hepatic parenchyma, vessels and the tumor-to-liver contrast of hepatocellular carcinomas (HCCs) were compared between two groups. Two readers independently assessed the CT images of the hepatic parenchyma and HCCs. Results: The mean CT dose indices: 6.38/4.04 mGy, the dose-length products: 194.54/124.57 mGy cm, for group A/group B. The mean enhancement value of the hepatic parenchyma and the tumor-to-liver contrast of HCCs with diameters greater than 1 cm in the post-contrast all phases did not differ significantly between two groups (P > 0.05). The enhancement values of vessels in group B were significantly higher than that in group A in the delayed phases (P < 0.05). Two reader's confidence levels for the hepatic parenchyma in the delayed phases and HCCs did not differ significantly between the groups (P > 0.05). Conclusions: Low-dose dynamic CT with ASIR can reduce both the radiation dose and the amount of contrast medium without image quality degradation, compared to conventional dynamic CT without ASIR. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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• Prognostic Impact of Spontaneous Tumor Rupture in Patients With Hepatocellular Carcinoma An Analysis of 1160 Cases From a Nationwide Survey, Taku Aoki, Norihiro Kokudo, Yutaka Matsuyama, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Masatoshi Makuuchi, ANNALS OF SURGERY, ANNALS OF SURGERY, 259(3), 532 - 542, Mar. 2014 , Refereed
  Summary:Objective: The aim of the present study was to investigate the background characteriscs of ruptured hepatocellular carcinoma (HCC) and to clarify the true impact of tumor rupture on patient prognosis in a large patient cohort. Background: Spontaneous tumor rupture of HCC has been associated with a very poor patient prognosis and the current TNM staging systems classify ruptured HCC as T4 based on insufficient evidence. Methods: In total, 1106 patients with ruptured HCC were extracted from the database of a nationwide survey conducted in Japan from 2000 to 2005. The clinicopathological parameters associated with HCC rupture were investigated using univariate and multivariate logistic regression models. The survival curves for ruptured and nonruptured HCC were generated and compared to evaluate the impact of the event (rupture) itself on patient prognosis and the TNM staging systems. Results: The multivariate analyses showed that tumor rupture was associated with both a poor liver functional reserve and an advanced tumor status. Analyses of the survival curves stratified according to the baseline TNM staging showed that tumor rupture had an additional impact on the baseline survival curves without rupture, and the impact corresponded to the addition of 0.5 to 2 stages to the baseline tumor staging. Conclusions: The present study suggested that tumor rupture itself had a negative impact on patient survival. However, its impact was not strong enough to cancel the effects of the other tumor-related parameters. Therefore, it may be appropriate to give additional stages to the baseline tumor staging in cases of ruptured HCC.
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• Prognostic Impact of Spontaneous Tumor Rupture in Patients With Hepatocellular Carcinoma An Analysis of 1160 Cases From a Nationwide Survey, Taku Aoki, Norihiro Kokudo, Yutaka Matsuyama, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Masatoshi Makuuchi, ANNALS OF SURGERY, ANNALS OF SURGERY, 259(3), 532 - 542, Mar. 2014 , Refereed
  Summary:Objective: The aim of the present study was to investigate the background characteriscs of ruptured hepatocellular carcinoma (HCC) and to clarify the true impact of tumor rupture on patient prognosis in a large patient cohort. Background: Spontaneous tumor rupture of HCC has been associated with a very poor patient prognosis and the current TNM staging systems classify ruptured HCC as T4 based on insufficient evidence. Methods: In total, 1106 patients with ruptured HCC were extracted from the database of a nationwide survey conducted in Japan from 2000 to 2005. The clinicopathological parameters associated with HCC rupture were investigated using univariate and multivariate logistic regression models. The survival curves for ruptured and nonruptured HCC were generated and compared to evaluate the impact of the event (rupture) itself on patient prognosis and the TNM staging systems. Results: The multivariate analyses showed that tumor rupture was associated with both a poor liver functional reserve and an advanced tumor status. Analyses of the survival curves stratified according to the baseline TNM staging showed that tumor rupture had an additional impact on the baseline survival curves without rupture, and the impact corresponded to the addition of 0.5 to 2 stages to the baseline tumor staging. Conclusions: The present study suggested that tumor rupture itself had a negative impact on patient survival. However, its impact was not strong enough to cancel the effects of the other tumor-related parameters. Therefore, it may be appropriate to give additional stages to the baseline tumor staging in cases of ruptured HCC.
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• Re-evaluating transarterial chemoembolization for the treatment of Hepatocellular Carcinoma: Consensus recommendations and review by an International Expert Panel, Ann Lii Cheng, Deepak Amarapurkar, Yee Chao, Pei-Jer Chen, Jean-Francois Geschwind, Khean L. Goh, Kwang-Hyub Han, Masatoshi Kudo, Han Chu Lee, Rheun-Chuan Lee, Laurentius A. Lesmana, Ho Yeong Lim, Seung Woon Paik, Ronnie T. Poon, Chee-Kiat Tan, Tawesak Tanwandee, Gaojun Teng, Joong-Won Park, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 34(2), 174 - 183, Feb. 2014 , Refereed
  Summary:Patients with unresectable hepatocellular carcinoma (HCC) usually receive transarterial chemoembolization (TACE) or systemic therapies with intermediate and advanced-stage disease. However, intermediate-stage HCC patients often have unsatisfactory clinical outcomes with repeated TACE and there is considerable uncertainty surrounding the criteria for repeating or stopping TACE treatment. In July 2012, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was re-convened in Shanghai in an attempt to provide a consensus on the practice of TACE, particularly in regard to evaluating TACE failure'. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies for intermediate HCC. This review summarizes the evidence discussed at the meeting and provides expert recommendations regarding the use of TACE for unresectable intermediate-stage HCC. A key consensus of the Expert Panel was that the current definitions of TACE failure are not useful in differentiating between situations where TACE is no longer effective in controlling disease locally vs. systemically. By redefining these concepts, it may be possible to provide a clearer indication of when TACE should be repeated and more importantly, when TACE should be discontinued.
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• Nationwide Study of 4741 Patients With Non-B Non-C Hepatocellular Carcinoma With Special Reference to the Therapeutic Impact, Tohru Utsunomiya, Mitsuo Shimada, Masatoshi Kudo, Takafumi Ichida, Osamu Matsui, Namiki Izumi, Yutaka Matsuyama, Michiie Sakamoto, Osamu Nakashima, Yonson Ku, Norihiro Kokudo, Masatoshi Makuuchi, ANNALS OF SURGERY, ANNALS OF SURGERY, 259(2), 336 - 345, Feb. 2014 , Refereed
  Summary:Objective: To examine the prognostic factors and outcomes after several types of treatments in patients with hepatocellular carcinoma (HCC) negative for hepatitis B surface antigen and hepatitis C antibody, so-called non-B non-C HCC using the data of a nationwide survey. Background: The proportion of non-B non-C HCC is rapidly increasing in Japan. Methods: A total of 4741 patients with non-B non-C HCC, who underwent hepatic resection (HR, n = 2872), radiofrequency ablation (RFA, n = 432), and transcatheter arterial chemoembolization (TACE, n = 1437) as the initial treatment, were enrolled in this study. The exclusion criteria included extrahepatic metastases and/or Child-Pugh C. Significant prognostic variables determined by a univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. Results: The degree of liver damage in the HR group was significantly lower than that in the RFA and TACE groups. The HR and TACE groups had significantly more advanced HCC than the RFA group. The 5-year survival rates after HR, RFA, and TACE were 66%, 49%, and 32%, respectively. Stratifying the survival rates, according to the TNM stage and the Japan Integrated Staging (JIS) score, showed the HR group to have a significantly better prognosis than the RFA group in the stage II and in the JIS scores 1 and 2. The multivariate analysis showed 12 independent prognostic factors. HR offers significant prognostic advantages over TACE and RFA. Conclusions: The findings of this large prospective cohort study indicated that HR may be recommended, especially in patients with TNM stage II and JIS scores 1 and 2 of non-B non-C HCC.
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• Value of EUS in early detection of pancreatic ductal adenocarcinomas in patients with intraductal papillary mucinous neoplasms, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Hiroki Sakamoto, Kumpei Kadosaka, Takeshi Miyata, Hajime Imai, Kiyoshi Maekawa, Takaaki Chikugo, Masashi Kumano, Tomoko Hyodo, Takamichi Murakami, Yasutaka Chiba, Yoshifumi Takeyama, ENDOSCOPY, ENDOSCOPY, 46(1), 22 - 29, Jan. 2014 , Refereed
  Summary:Background and study aims: Pancreatic ductal adenocarcinomas (PDAC) sometimes arise in patients with intraductal papillary mucinous neoplasms (IPMNs). This study examined the incidence of PDACs concomitant to or derived from branch duct IPMNs. The usefulness of endoscopic ultrasonography (EUS) relative to other imaging methods for detecting these tumors was also assessed. Patients and methods: This retrospective study used data from clinical records and imaging studies that were collected prospectively. During 2001-2009, 167 consecutive patients with IPMNs underwent EUS, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). The 102 patients whose branch duct IPMNs lacked mural nodules/symptoms and thus did not qualify for resection were followed up by semiannual EUS and annual ultrasonography, CT, and MRI. The sensitivity and specificity with which the four modalities detected IPMN-derived and -concomitant PDACs at the first examination and throughout the study period were evaluated. The rate of PDAC development during follow-up was analyzed by the Kaplan-Meier method. Results: A total of 17 IPMN-derived and 11 IPMN-concomitant PDACs were diagnosed at the first examination. Lesions that did not qualify for resection or chemotherapy were followed up for a median of 42 months. Seven IPMN-concomitant PDACs and no IPMN-derived PDACs were detected during follow-up. The 3- and 5-year rates of IPMN-concomitant PDAC development were 4.0% and 8.8%, respectively. At the first examination, EUS was superior to other imaging modalities in terms of IPMN-derived and -concomitant PDAC detection. Throughout the study period, including follow-up, EUS was significantly better at detecting IPMN-concomitant PDACs than the other modalities. Conclusions: IPMN-concomitant PDACs are quite often found at diagnosis and during follow-up.EUS examination of the whole pancreas plays an important role in the management of IPMNs as it allows the early detection of these small invasive carcinomas.
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• The Gross Classification of Hepatocellular Carcinoma: Usefulness of Contrast-enhanced US, Kinuyo Hatanaka, Yasunori Minami, Masatoshi Kudo, Tatsuo Inoue, Hobyung Chung, Seiji Haji, JOURNAL OF CLINICAL ULTRASOUND, JOURNAL OF CLINICAL ULTRASOUND, 42(1), 1 - 8, Jan. 2014 , Refereed
  Summary:BackgroundThis study investigated the usefulness of postvascular images of contrast-enhanced ultrasonography (CE-US) in the gross classification of hepatocellular carcinoma (HCC) in comparison with contrast-enhanced CT (CE-CT) findings. MethodsThis is a prospective study with consecutive HCC patients who had both CE-US and CE-CT prior to surgical resection. Fifty-one patients (32 men, 19 women; mean age, 68.9 years) with 61 HCCs were enrolled. The maximal diameters of all tumors ranged from 1.0 to 5.0 cm (meanSD, 2.5 cm1.1). Weighted kappa statistics were used to assess the agreement of the sonographic or CT findings versus the results of macroscopic configurations. ResultsThirty-nine tumors were macroscopically diagnosed as simple nodule type; 19 tumors were macroscopically diagnosed as simple nodular type with extranodular growth, and 3 were macroscopically diagnosed as confluent multinodular type from the resected specimen. The diagnostic accuracy was 86.9% (53/61) for CE-US and 65.6% (40/61) for CE-CT. The differences in accuracy between CE-US and CE-CT were statistically significant (McNemar; p=0.007). Agreement analysis between gross classification using CE-US and final macroscopic results gave a kappa value of 0.74 (95% CI: 0.65-0.82), which was considered a good agreement. On the other hand, kappa coefficient value was 0.38 (95% CI: 0.28-0.48) between gross classification using CE-CT and final macroscopic results. ConclusionsCE-US is a more reliable tool than CE-CT to evaluate the gross type of HCC than CE-CT. Accurate gross classification using imaging is considered to be essential for the determination of the correct treatment strategy and the estimates of the patients' prognosis. (c) 2013 Wiley Periodicals, Inc. J Clin Ultrasound42:1-8, 2014
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• Quantitative Levels of Hepatitis B Virus DNA and Surface Antigen and the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Receiving Long-Term Nucleos(t)ide Analogue Therapy, Miwa Kawanaka, Ken Nishino, Jun Nakamura, Takahito Oka, Noriyo Urata, Daisuke Goto, Mitsuhiko Suehiro, Hirofumi Kawamoto, Masatoshi Kudo, Gotaro Yamada, LIVER CANCER, LIVER CANCER, 3(1), 41 - 52, 2014 , Refereed
  Summary:Background: Serum levels of hepatitis B virus (HBV) DNA are an important predictor of the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. However, little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk for HCC. Methods: We investigated 167 patients who were treated with nucleos(t)ide analogues (NA) for at least 2 years (median: 5.8 years, range: 2-13.1 years). Relationships between reduced levels of HBsAg and various factors were evaluated. In addition, we evaluated the usefulness of quantitative serum levels of HBV DNA and HBsAg as predictors of HCC development in patients receiving long-term NA therapy. Results: HCC developed in 9 of the 167 NA-treated patients. In the 9 patients with HCC, HBV DNA was undetectable (<2.1 log copies/ mL), but HBsAg levels were >= 2000 degrees C.O.I. in 7 patients. No maternal transmission, long NA treatment period, HBV DNA levels <3.0 log copies/mL, and reduced hepatitis B e antigen levels during the first 24 weeks of treatment were a significant factor of HBsAg levels <2000 C.O.I.. Conclusions: Hepatocarcinogenesis was observed in patients with high HBsAg levels, despite the negative conversion of HBV DNA as a result of long-term NA therapy. Therefore, to suppress hepatocarcinogenesis, it is important to control not only HBV DNA levels but also HBsAg levels. Copyright (C) 2014 S. Karger AG, Basel
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• Tracking Navigation Imaging of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma Using Three-Dimensional Cone-Beam CT Angiography, Yasunori Minami, Yukinobu Yagyu, Takamichi Murakami, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 3(1), 53 - 61, 2014 , Refereed
  Summary:Purpose: New tracking navigation imaging software was used to evaluate the usefulness of three dimensional (3D) CT angiography for transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Materials and Methods: Fifty-two patients with 73 HCCs were enrolled in this study retrospectively. Rotational angiography was performed from the hepatic artery for evaluation of the tumor feeding vessels. Arteries feeding the tumor were traced automatically by adjusting the region of interest around the targeted tumor on axial and coronal images using tracking navigation imaging with 3D cone-beam CT angiography. Results: Using final selective angiographic findings as the gold standard, the detection of feeding vessels was 90.4% (66/73) for tracking navigation imaging and 50.7% (37/73) for celiac trunk angiography. This difference was statistically significant (Wilcoxon rank sum test, p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of feeding arteries were 97.1% (66/68), 80.0% (4/5), 98.5% (66/67), and 66.7% (4/6), respectively. The kappa coefficient had a value of 0.638 (95% CI: 0.471-0.805), which is considered to indicate a good degree of agreement. With the as-sistance of tracking navigation imaging, the disease control rate of TACE for HCC was 67.3% (35/52) according to the modified Response Evaluation Criteria in Solid Tumors. During follow- up periods of 1-11 months, 10 patients (19.2%) remained cancer-free after TACE. Conclusion: Tracking navigation imaging with 3D cone-beam CT angiography should be useful for TACE in HCC patients with complicated feeding arteries. Copyright (C) 2014 S. Karger AG, Basel
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• Prediction of incidence risk of hepatocellular carcinoma by ultrasound elastography, Kudo M, Liver Cancer, Liver Cancer, 3, 1 - 5, 2014
• Impact of Histologically Confirmed Lymph Node Metastases on Patient Survival After Surgical Resection for Hepatocellular Carcinoma Report of a Japanese Nationwide Survey, Kiyoshi Hasegawa, Masatoshi Makuuchi, Norihiro Kokudo, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Yutaka Matsuyama, ANNALS OF SURGERY, ANNALS OF SURGERY, 259(1), 166 - 170, Jan. 2014 , Refereed
  Summary:Objective: To clarify the clinical significance of resection of lymph node metastases in patients' hepatocellular carcinoma (HCC). Background: Although the presence of lymph node metastasis form HCC has been considered as a systemic disease, prognosis after resection of them remains unknown. Methods: From the database of a Japanese nationwide survey, 14,872 patients of HCC treated by surgical resection between 2000 and 2005 were enrolled. We modified the current Japanese staging system for HCC, by further dividing stage IVA into stage IVAnon-n1 and stage n1, according to the absence or presence of pathologically proven lymph node metastasis. Thus, the patients classified into 6 disease stages, that is, I (n = 1494), II (n = 8056), III (n = 4243), IVAnon-n1 (n = 701), n1 (n = 112), and IVB (n = 266), and their long-term outcomes were compared. Results: The median follow-up period was 20.6 months. The 3-year overall survival rates of the patients with stage IVAnon-n1, stage n1, and stage IVB were 51.6%, 38.9% and 27.2%, respectively. A multivariate analysis showed that stage IVAnon-n1 would have a similar impact on the survival as stage n1 (hazard ratio: 0.88, 95% confidence interval: 0.59-1.33, P = 0.555), and that stage n1 still represented one class less advanced than stage IVB (hazard ratio: 0.52, 95% confidence interval: 0.34-0.80, P = 0.003). Conclusions: The prognosis of patients with histologically node-positive HCC was similar to that of patients with locally advanced HCC (stage IVA), which supports the validity of the current Japanese staging system and also partially validates the system proposed by the UICC/AJCC.
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• Pathological feature, oxidative DNA damage and epigenetic alteration of tumor suppressor genes in non-alcoholic fatty liver disease, Naoshi Nishida, Norihisa Yada, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Masatoshi Kudo, HEPATOLOGY, HEPATOLOGY, 60, 758A - 758A, 2014 , Refereed
• Recent Advances in Bioinformatics Reveal the Molecular Heterogeneity of Hepatocellular Carcinoma, M. Kudo, LIVER CANCER, LIVER CANCER, 3(2), 68 - 70, 2014 , Refereed
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• Prediction of Hepatocellular Carcinoma Incidence Risk by Ultrasound Elastography, M. Kudo, LIVER CANCER, LIVER CANCER, 3(1), 1 - 5, 2014 , Refereed
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• Impact of Histologically Confirmed Lymph Node Metastases on Patient Survival After Surgical Resection for Hepatocellular Carcinoma Report of a Japanese Nationwide Survey, Kiyoshi Hasegawa, Masatoshi Makuuchi, Norihiro Kokudo, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Yutaka Matsuyama, ANNALS OF SURGERY, ANNALS OF SURGERY, 259(1), 166 - 170, Jan. 2014 , Refereed
  Summary:Objective: To clarify the clinical significance of resection of lymph node metastases in patients' hepatocellular carcinoma (HCC). Background: Although the presence of lymph node metastasis form HCC has been considered as a systemic disease, prognosis after resection of them remains unknown. Methods: From the database of a Japanese nationwide survey, 14,872 patients of HCC treated by surgical resection between 2000 and 2005 were enrolled. We modified the current Japanese staging system for HCC, by further dividing stage IVA into stage IVAnon-n1 and stage n1, according to the absence or presence of pathologically proven lymph node metastasis. Thus, the patients classified into 6 disease stages, that is, I (n = 1494), II (n = 8056), III (n = 4243), IVAnon-n1 (n = 701), n1 (n = 112), and IVB (n = 266), and their long-term outcomes were compared. Results: The median follow-up period was 20.6 months. The 3-year overall survival rates of the patients with stage IVAnon-n1, stage n1, and stage IVB were 51.6%, 38.9% and 27.2%, respectively. A multivariate analysis showed that stage IVAnon-n1 would have a similar impact on the survival as stage n1 (hazard ratio: 0.88, 95% confidence interval: 0.59-1.33, P = 0.555), and that stage n1 still represented one class less advanced than stage IVB (hazard ratio: 0.52, 95% confidence interval: 0.34-0.80, P = 0.003). Conclusions: The prognosis of patients with histologically node-positive HCC was similar to that of patients with locally advanced HCC (stage IVA), which supports the validity of the current Japanese staging system and also partially validates the system proposed by the UICC/AJCC.
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• Breakthroughs in the Management of Hepatocellular Carcinoma: Celebrating 50 Years of the Liver Cancer Study Group of Japan, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 1 - 6, 2014 , Refereed
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• Surveillance and Diagnostic Algorithm for Hepatocellular Carcinoma Proposed by the Liver Cancer Study Group of Japan: 2014 Update, Masatoshi Kudo, Osamu Matsui, Namiki Izumi, Hiroko Iijima, Masumi Kadoya, Yasuharu Imai, ONCOLOGY, ONCOLOGY, 87, 7 - 21, 2014 , Refereed
  Summary:Surveillance and diagnostic algorithms for hepatocellular carcinoma (HCC) have already been described in guidelines published by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver and the European Organisation for Research and Treatment of Cancer (EASL-EORTC), and the Japan Society of Hepatology (JSH), but the content of these algorithms differs slightly. The JSH algorithm mainly differs from the other two algorithms in that it is highly sophisticated and considers the functional imaging techniques of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI (EOB-MRI) and Sonazoid contrast-enhanced ultrasound (CEUS) to be very important diagnostic modalities. In contrast, the AASLD and EASL-EORTC algorithms are less advanced and suggest that a diagnosis be made based solely on hemodynamic findings using dynamic CT/MRI and biopsy findings. A consensus meeting regarding the JSH surveillance and diagnostic algorithm was held at the 50th Liver Cancer Study Group of Japan Congress, and a 2014 update of the algorithm was completed. The new algorithm reaffirms the very important role of EOB-MRI and Sonazoid CEUS in the surveillance and diagnosis of liver cancer and is more sophisticated than those currently used in the United States and Europe. This is now an optimized algorithm that can be used to diagnose early-stage to classical HCC easily and highly accurately. (C) 2014 S. Karger AG, Basel
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• Transarterial Chemoembolization Failure/Refractoriness: JSH-LCSGJ Criteria 2014 Update, Masatoshi Kudo, Osamu Matsui, Namiki Izumi, Masumi Kadoya, Takuji Okusaka, Shiro Miyayama, Koichiro Yamakado, Kaoru Tsuchiya, Kazuomi Ueshima, Atsushi Hiraoka, Masafumi Ikeda, Sadahisa Ogasawara, Tatsuya Yamashita, Tetsuya Minami, ONCOLOGY, ONCOLOGY, 87, 22 - 31, 2014 , Refereed
  Summary:In the 2010 version of the Japan Society of Hepatology (JSH) consensus-based treatment algorithm for the management of hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) failure/refractoriness was defined assuming the use of superselective lipiodol TACE, which has been widely used worldwide and particularly in Japan, and areas with lipiodol deposition were considered to be necrotic. However, this concept is not well accepted internationally. Furthermore, following the approval of microspheres, an embolic material that does not use lipiodol, in February 2014 in Japan, the phrase 'lipiodol deposition' needed to be changed to 'necrotic lesion or viable lesion'. Accordingly, the respective section in the JSH guidelines was revised to define TACE failure as an insufficient response after >= 2 consecutive TACE procedures that is evident on response evaluation computed tomography or magnetic resonance imaging after 1-3 months, even after chemotherapeutic agents have been changed and/or the feeding artery has been reanalyzed. In addition, the appearance of a higher number of lesions in the liver than that recorded at the previous TACE procedure (other than the nodule being treated) was added to the definition of TACE failure/refractoriness. Following the discussion of other issues concerning the continuous elevation of tumor markers, vascular invasion, and extrahepatic spread, descriptions similar to those in the previous version were approved. The revision of these TACE failure definitions was approved by over 85% of HCC experts. (C) 2014 S. Karger AG, Basel
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• Validation of the Criteria of Transcatheter Arterial Chemoembolization Failure or Refractoriness in Patients with Advanced Hepatocellular Carcinoma Proposed by the LCSGJ, Tadaaki Arizumi, Kazuomi Ueshima, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 32 - 36, 2014 , Refereed
  Summary:Background: Transcatheter arterial chemoembolization (TACE) failure or refractoriness is an indication for sorafenib therapy in patients with advanced hepatocellular carcinoma. The study evaluated the validity of the definition of TACE failure or refractoriness as proposed by the Liver Cancer Study Group of Japan (LCSGJ) through a retrospective analysis of sorafenib treatment. Methods: Out of 265 patients with advanced hepatocellular carcinoma who were treated with sorafenib at our hospital, 45 experienced TACE failure or refractoriness and were included in this study and retrospectively analyzed. Results: Multivariate analysis only identified the number of ineffective TACE procedures performed before starting sorafenib treatment as significant factors. Overall survival (OS) after starting sorafenib was statistically longer in patients treated with <= 2 consecutive ineffective TACE procedures before sorafenib administration than in patients treated with >= 3 consecutive ineffective TACE procedures (p < 0.005). This result matched the LCSGJ criteria. Conclusion: In patients treated with sorafenib, OS was extended with <= 2 consecutive ineffective TACE procedures compared to that with >= 3 consecutive ineffective TACE procedures. Thus, if tumors are uncontrolled, TACE should not be repeated. The result of this study supports the definition of TACE failure or refractoriness proposed by the LCSGJ. (C) 2014 S. Karger AG, Basel
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• Pathological Diagnosis of Benign Hepatocellular Nodular Lesions Based on the New World Health Organization Classification, Fukuo Kondo, Toshio Fukusato, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 37 - 49, 2014 , Refereed
  Summary:There are various types of benign hepatocellular nodular lesions, and their diagnostic criteria were formulated in detail. However, in 2010, the new World Health Organization (WHO) classification introduced immunohistochemical diagnostic criteria for hepatocellular adenoma (HCA) reflecting molecular pathological properties, and HCA was classified into 4 subtypes. These criteria were useful for its differential diagnosis from focal nodular hyperplasia (FNH). They were also useful for the diagnosis of HCA, its subtyping, and differentiation from FNH in Japan. However, the new WHO classification is based on principles that differ from those of conventional definitions of disease concepts and methods for the differential diagnosis. Therefore, it has caused disagreements in the diagnosis in some cases. Based on this background, we present a new perspective on the diagnosis of benign hepatocellular nodular lesions. (C) 2014 S. Karger AG, Basel
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• Combination Guidance of Contrast-Enhanced US and Fusion Imaging in Radiofrequency Ablation for Hepatocellular Carcinoma with Poor Conspicuity on Contrast-Enhanced US/Fusion Imaging, Tomohiro Minami, Yasunori Minami, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 55 - 62, 2014 , Refereed
  Summary:Purpose: The purpose of this study was to evaluate the usefulness of the combination guidance of contrast-enhanced US (CEUS) and fusion imaging in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) with poor conspicuity on B-mode US and CEUS/fusion imaging. Materials and Methods: We conducted a retrospective cohort study, which included 356 patients with 556 HCCs that were inconspicuous on B-mode US. A total of 192 patients with 344 HCCs, 123 patients with 155 HCCs, and 37 patients with 57 HCCs underwent RFA under CEUS guidance, fusion imaging guidance, and the combination of CEUS and fusion imaging guidance. Results: The average number of treatment sessions was 1.1 (range: 1-2) in the CEUS guidance group, 1.1 (range: 1-2) in the fusion imaging guidance group, and 1.1 (range: 1-3) in the combination of CEUS and fusion imaging guidance group. Treatment analysis did not reveal significantly more RFA treatment sessions in the combination guidance group than in the other groups (p = 0.97, Student's t test). During the follow-up period (1.1-85.3 months, mean +/- SD, 43.2 +/- 59.5), the 3-year local tumor progression rates were 4.9, 7.2, and 5.9% in the CEUS guidance group, the fusion imaging guidance group, and the combination guidance group, respectively (p = 0.84, log-rank test). Conclusion: In spite of selection bias, session frequency and local tumor progression were not different under the combination guidance with CEUS and fusion imaging in RFA. The combination of fusion imaging and CEUS guidance in RFA therapy is an effective treatment for HCC with poor conspicuity on B-mode US and CEUS/fusion imaging. (C) 2014 S. Karger AG, Basel
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• Noninvasive Diagnosis of Liver Fibrosis: Utility of Data Mining of Both Ultrasound Elastography and Serological Findings to Construct a Decision Tree, Norihisa Yada, Masatoshi Kudo, Norifumi Kawada, Shuichi Sato, Yukio Osaki, Akihisa Ishikawa, Hisaaki Miyoshi, Michiie Sakamoto, Masayoshi Kage, Osamu Nakashima, Akiko Tonomura, ONCOLOGY, ONCOLOGY, 87, 63 - 72, 2014 , Refereed
  Summary:Objective: Although liver biopsy is the gold standard for viral liver disease management, it is invasive and the sampling error rate is problematic. Real-time tissue elastography (RTE), a recently developed method of ultrasound elastography, can be used to assess liver fibrosis noninvasively but the overlap between fibrosis stages limits its ability to assess liver fibrosis adequately when used alone. Methods: A multicenter collaborative study involving 542 patients with chronic viral hepatitis and cirrhosis who were scheduled to undergo liver biopsy compared the image features obtained from RTE image analysis, the liver fibrosis index (LFI), and pathological diagnosis. RTE and a blood test were performed on the same day as the liver biopsy. Data mining was also performed to construct a decision tree, and its diagnostic performance for assessing liver fibrosis was evaluated. Results: The LFI was higher in patients with chronic hepatitis C (CHC) than in those with chronic hepatitis B (CHB). When a decision tree was constructed by data mining of RTE and serological findings, the diagnostic accuracy was very high for all fibrosis stages, with respective rates at F1, F2, F3, and F4 of 94.4, 54.1, 38.7, and 81.3% for patients with CHC and of 97.1, 50.0, 43.8, and 80.6% for patients with CHB. Conclusions: The variation in LFI values between the different etiologies appears to reflect the difference in the development style of liver fibrosis. The decision tree for assessing liver fibrosis constructed by data mining of both RTE and serological findings had a high diagnostic performance in assessing liver fibrosis and shows promising clinical utility. (C) 2014 S. Karger AG, Basel
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• Recent Progress in Radiofrequency Ablation Therapy for Hepatocellular Carcinoma, Kenji Ikeda, Yukio Osaki, Hiroyuki Nakanishi, Akihiro Nasu, Yusuke Kawamura, Koji Jyoko, Takatomo Sano, Hajime Sunagozaka, Koji Uchino, Yasunori Minami, Yu Saito, Kazumasa Nagai, Ryosuke Inokuchi, Shigehiro Kokubu, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 73 - 77, 2014 , Refereed
  Summary:In order to attain better ablation and more effective management of hepatocellular carcinoma (HCC), new approaches and devices in radiofrequency ablation (RFA) therapy were presented and discussed in a workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan. A novel bipolar RFA apparatus was introduced in Japan in January 2013. Hundreds of subjects with HCC were treated with multipolar RFA with varied devices and plans. Among these, no-touch ablation was one of the most useful procedures in the treatment of HCC with the apparatus. In RFA therapy, a few assisting devices and techniques were applied for convenience and improvement of the thermal ablation procedure. Contrast-enhanced ultrasonography and three-dimensional fusion imaging technique using volume data of CT or MRI could improve exact targeting and shorten the treatment time for RFA procedures under ultrasonographic guidance. A more complicated method using a workstation was also reported as being helpful in planning the ablated shape and volume in multineedle RFA. The effective use of sedatives and antianalgesics as well as a novel microwave apparatus with a cooled-tip electrode was also discussed. (C) 2014 S. Karger AG, Basel
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• Treatment Strategies of Intermediate-Stage Hepatocellular Carcinomas in Japan (Barcelona Clinic Liver Cancer Stage B), Koichiro Yamakado, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 78 - 81, 2014 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and it shows increasing incidence worldwide. The Barcelona Clinic Liver Cancer (BCLC) staging system has become widely accepted in clinical practice, but in Japan, two clinical practice guidelines have been used for HCC: the Evidence-Based Clinical Practice Guidelines and the Consensus-Based Clinical Practice Guidelines. Although, in Japan, chemoembolization is the first-line treatment of intermediate-stage (stage B) HCC patients in the BCLC staging system, along with chemoembolization, locoregional treatments, such as resection and radiofrequency ablation, and hepatic arterial infusion chemotherapy are incorporated into the treatment algorithm based on the tumor number and size as well as on the liver profile. (C) 2014 S. Karger AG, Basel
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• Treatment of Hepatocellular Carcinoma with Child-Pugh C Cirrhosis, Kazuhiro Nouso, Norihiro Kokudo, Masatoshi Tanaka, Ryoko Kuromatsu, Hiroki Nishikawa, Hidenori Toyoda, Naoki Oishi, Kenji Kuwaki, Masashi Kusanaga, Takuki Sakaguchi, Zenichi Morise, Satoshi Kitai, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 99 - 103, 2014 , Refereed
  Summary:Background: In most guidelines, no other interventional therapy but liver transplantation is recommended for the treatment of hepatocellular carcinoma (HCC) with Child-Pugh C cirrhosis (CP-C). However, in Japan, patients were sometimes treated with expectation of benefit. Summary: A workshop was conducted to explore the state of treatments for CP-C HCC in Japan. After the workshop, a questionnaire on therapies was given to the panelists. Clinical data of 769 patients with CP-C HCC from 8 hospitals as well as analyses of data collected by the Liver Cancer Study Group of Japan (LCSGJ) consisting of 1,344 CP-C HCC cases were presented. Patients who underwent liver transplantation were excluded. In total, 424 out of the 769 patients (55.1%) from the 8 hospitals and 537 out of 828 CP-C HCC cases (64.8%) from the LCSGJ data received interventional therapies, such as local ablation and transcatheter arterial chemoembolization. All panelists agreed that there was a subgroup of CP-C patients who benefitted from the locoregional therapies. The major goals for the therapies were to prevent HCC rupture and avoid obstruction of major vessels by tumor growth, which can lead to a sudden deterioration of the patients' condition. Patient liver function and tumor stage are both important factors for the decision to undergo treatment; however, the inclusion criteria for the treatments varied among the centers. Key Message: There exists a subgroup of CP-C patients who benefit from interventions for HCC. (C) 2014 S. Karger AG, Basel
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• Characteristics of Long-Term Survivors following Sorafenib Treatment for Advanced Hepatocellular Carcinoma: Report of a Workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan, Katsuaki Tanaka, Mitsuo Shimada, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 104 - 109, 2014 , Refereed
  Summary:Background: Little data are available on the long-term survival of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC). Summary: During a consensus workshop at the 50th annual meeting of the Liver Cancer Study Group of Japan held in Kyoto (June 5-6, 2014), experts met to discuss the characteristics of long-term (>3 years) survivors of advanced HCC following sorafenib treatment. A total of 70 long-term survivors following sorafenib treatment at eight institutions were included, and the long-term survival rate (>3 years) at each institution ranged from 2.6 to 6.9% (mean, 4.5). The long-term survival-related factors presented can be categorized as follows: (1) conversion options, including hepatic resection following successful sorafenib treatment, (2) additional salvage options when progressive disease is confirmed, (3) long-term sorafenib treatment, (4) effective post-sorafenib options to prolong postprogression survival, and (5) good pretreatment liver function. Sorafenib monotherapy exceeding 3 years is rare, and most of the patients receiving sorafenib required other treatment modalities in the form of multidisciplinary therapy. Conclusion: The overview obtained from the workshop reflects the pattern of management in practice for long-term survivors following sorafenib treatment for HCC in Japan and may also provide valuable information for other countries. (C) 2014 S. Karger AG, Basel
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• Efficacy and Safety of Telaprevir-Based Antiviral Treatment for Elderly Patients with Hepatitis C Virus, Masahiro Takita, Satoru Hagiwara, Masatoshi Kudo, Masashi Kono, Hirokazu Chishina, Tadaaki Arizumi, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, ONCOLOGY, ONCOLOGY, 87, 110 - 117, 2014 , Refereed
  Summary:Background: Telaprevir-based antiviral therapy has been the primary treatment for chronic hepatitis C genotype 1 at a high viral load since November 2011. On the other hand, a number of patients have been reported to require withdrawal from or reduced doses of drugs due to side effects, such as eruptions, anemia, and renal dysfunction. In addition, as hepatitis C patients are growing older, it is imperative to investigate the tolerability of triple combination therapy for elderly patients. Subjects and Methods: The study subjects comprised 35 patients who received telaprevir combination therapy after November 2011. They were divided into group A (age: <65 years; n = 21) and group B (age: >= 65 years; n = 14) in order to compare the treatment completion rate, sustained virological response at week 24 (SVR24), and adverse events between the groups. Results: The treatment completion rate was 82.8% (29/35) in all subjects, 90.4% (19/21) in group A, and 78.5% (11/14) in group B. The rate was lower in group B but without a significant difference between the groups (p = 0.804). The SVR24 rate was 88.5% (31/35) in all subjects, 90.4% (19/21) in group A, and 85.7% (12/14) in group B, without a significant difference between the groups (p = 0.161). Conclusion: Although the incidence of anemia was higher in group B, there was no significant difference in the treatment completion or SVR24 rate between the groups. Telaprevir combination therapy is suggested to be tolerable for elderly hepatitis C patients. (C) 2014 S. Karger AG, Basel
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• Ultrasound Elastography Correlates Treatment Response by Antiviral Therapy in Patients with Chronic Hepatitis C, Norihisa Yada, Toshiharu Sakurai, Tomohiro Minami, Tadaaki Arizumi, Masahiro Takita, Tatsuo Inoue, Satoru Hagiwara, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 87, 118 - 123, 2014 , Refereed
  Summary:Objective: To investigate the relationship between tissue elasticity before and after antiviral therapy and shear wave as well as strain elastography. Methods: FibroScan and real-time tissue elastography were performed before and after antiviral therapy for chronic hepatitis C, and treatment efficacy and elastographic findings were comparatively analyzed. Elasticity was evaluated by measuring liver stiffness (LS) in kilopascals using FibroScan, and the liver fibrosis index (LFI) was assessed by real-time tissue elastography. Results: LS and LFI correlated well before and after therapy (r = 0.567, p = 0.003 and r = 0.576, p = 0.002, respectively). In the group without a sustained virological response (SVR), LS increased in 4 of 5 patients. Patients with an increase in both LS and LFI were all in the non-SVR group (3/3, 100%). In addition, LS increased in all patients except 1 in the non-SVR group (4/5, 80%). In the SVR group, both LS and LFI decreased in all patients except 1 (18/19, 94.7%). In the patient with an increase in LS despite achieving SVR, LS decreased quickly after alcohol cessation. Conclusions: With a few exceptions, SVR improved LS. All patients with an increase in LFI were in the non-SVR group, even though LFI decreased in 2 patients. Our findings suggest that an LFI increase indicates lack of treatment efficacy with antiviral therapy. LFI may be useful for the assessment of treatment efficacy in patients with worsening of LS despite achieving SVR with antiviral therapy. (C) 2014 S. Karger AG, Basel
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• JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan, Masatoshi Kudo, Osamu Matsui, Namiki Izumi, Hiroko Iijima, Masumi Kadoya, Yasuharu Imai, Takuji Okusaka, Shiro Miyayama, Kaoru Tsuchiya, Kazuomi Ueshima, Atsushi Hiraoka, Masafumi Ikeda, Sadahisa Ogasawara, Tatsuya Yamashita, Tetsuya Minami, Koichiro Yamakado, LIVER CANCER, LIVER CANCER, 3(3-4), 458 - 468, 2014 , Refereed
  Summary:The Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma proposed by the Japan Society of Hepatology was updated in June 2014 at a consensus meeting of the Liver Cancer Study Group of Japan. Three important items have been updated: the surveillance and diagnostic algorithm, the treatment algorithm, and the definition of transarterial chemoembolization (TACE) failure/refractoriness. The most important update to the diagnostic algorithm is the inclusion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging as a first line surveillance/diagnostic tool. Another significant update concerns removal of the term "lipiodol" from the definition of TACE failure/refractoriness. Copyright (C) 2014 S. Karger AG, Basel
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• Accuracy of Real-Time Tissue Elastography for the Evaluation of Hepatic Fibrosis in Patients with Chronic Hepatitis B: A Prospective Multicenter Study, Tao Wu, Jie Ren, Shu-zhen Cong, Fan-kun Meng, Hong Yang, Yan Luo, Hong-jun Lin, Yan Sun, Xiu-yan Wang, Shu-Fang Pei, Ying Zheng, Yun He, Yang Chen, Yu Hu, Na Yang, Ping Li, Masatoshi Kudo, Rong-qin Zheng, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 791 - 799, 2014 , Refereed
  Summary:Background: The prognosis and management of hepatic fibrosis are closely related to the stage of the disease. The limitations of liver biopsy, which is the gold standard for treatment, include its invasiveness and sampling error. Ultrasound elasticity might be the most promising imaging technology for the noninvasive and accurate assessment of hepatic fibrosis. Real-time tissue elastography (RTE) measures the relative stiffness of the tissue in the region of interest caused by the heartbeat. Many studies have verified that RTE is useful for the diagnosis of hepatic fibrosis in patients with chronic hepatitis C (CHC). Purpose: To determine the formula of the liver fibrosis index for chronic hepatitis B (BLFI) and to validate the diagnostic accuracy of the BLFI for hepatic fibrosis compared with the liver fibrosis index (LFI). Materials and Methods: RTE was performed in 747 prospectively enrolled patients with chronic hepatitis B (CHB) or cirrhosis from 8 centers in China; 375 patients were analyzed as the training set, and 372 patients were evaluated as the validation set. The fibrosis stage was diagnosed from pathological specimens obtained by ultrasound-guided liver biopsy. Nine image features were measured from strain images, and the new formula for the BLFI was obtained by combining the nine imaging features of the RTE images using multiple regression analysis of the training set. The BLFI and LFI were compared with the pathological fibrosis stage at diagnosis, and the diagnostic performances of the indexes were compared. Results: The Spearman correlation coefficient between the BLFI and hepatic fibrosis stages was significantly positive (r = 0.711, p < 0.001), and significant differences were present between all disease stages. The areas under the receiver-operating characteristic (AUROC) curves of the BLFI and LFI for predicting significant fibrosis (S0-S1 vs. S2-S4) were 0.858 and 0.858, respectively. For cirrhosis (S0-S3 vs. S4), the AUROC curves of the BLFI and LFI were 0.868 and 0.862, respectively. Conclusion: The results of this large, multicenter study confirmed that RTE is valuable for the diagnosis of hepatic fibrosis in patients with CHB. However, the diagnostic efficiencies of the new BLFI and the original LFI, which were based on CHC, for the assessment of CHB hepatic fibrosis were similar; thus, the LFI has the potential to be used to directly evaluate the extent of hepatic fibrosis in patients with CHB. (C) 2014 S. Karger AG, Basel
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• Clinical Features of Vascular Disorders Associated with Chronic Hepatitis Virus Infection, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 786 - 790, 2014 , Refereed
  Summary:Hepatitis virus infections can be accompanied by extrahepatic manifestations that may be caused by the host's immune reaction to the viral infection. Vascular involvement is one of these manifestations and is occasionally associated with life-threatening conditions due to systemic organ failure. The unique profile of hepatitis-related vascular involvement is associated with infection by different types of hepatitis viruses. For example, polyarteritis nodosa is more frequently reported in patients with chronic hepatitis B than those with chronic hepatitis C. Similarly, membranous nephropathy is a notable manifestation among hepatitis B virus-positive patients. In contrast, patients infected with hepatitis C virus are at risk for cryoglobulinemia and membranoproliferative glomerulonephritis. Antiviral therapy is necessary to control these kinds of vasculitis related to hepatitis virus infections; however, imnnunosuppressive agents may be required to treat severe cases. New antiviral drugs for viral hepatitis could improve the prognosis of vascular and renal involvement. (C) 2014 S. Karger AG, Basel
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• Identification of Epigenetically Inactivated Genes in Human Hepatocellular Carcinoma by Integrative Analyses of Methylation Profiling and Pharmacological Unmasking, Naoshi Nishida, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 740 - 746, 2014 , Refereed
  Summary:Objectives: DNA methylation-dependent transcriptional inactivation of tumor suppressor genes (TSGs) is critical for the pathogenesis of hepatocellular carcinoma (HCC). This study identifies potential TSGs in HCCs using methylation profiling and pharmacological unmasking of methylated TSGs. Methods: Methylation profiling was performed on 22 pairs of HCCs and their corresponding noncancerous liver tissues using the Infinium HumanMethylation27 BeadChip. We also determined the gene reexpression after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) in 5 HCC cell lines. Results: We selected CpGs that exhibited a significant increase in methylation in HCC tissues compared with that of the noncancerous control group. Two hundred and thirteen CpGs on different gene promoters with a mean difference in the beta value >= 0.15 and a value of p < 0.05 were selected. Of the 213 genes, 45 genes were upregulated in 3 or more HCC cell lines with multiplier value of differences after 5-Aza-dC and TSA treatment. Conclusions: We identified several potential TSGs that participate in transcription inactivation through epigenetic interactions in HCC. The results of this study are important for the understanding of functionally important epigenetic alterations in HCC. (C) 2014 S. Karger AG, Basel
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• Decreased Blood Flow after Sorafenib Administration Is an Imaging Biomarker to Predict Overall Survival in Patients with Advanced Hepatocellular Carcinoma, Tadaaki Arizumi, Kazuomi Ueshima, Hirokazu Chishina, Masashi Kono, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 733 - 739, 2014 , Refereed
  Summary:Background: Sorafenib is a multikinase inhibitor targeting Raf and protein tyrosine kinases, which are involved in cell growth and tumor angiogenesis. Sorafenib administration induces temporary inhibition of tumor growth and a decrease in arterial blood flow in a considerable number of hepatocellular carcinoma (HCC) patients. We retrospectively evaluated the association between decreased blood flow and the overall survival (OS) of HCC patients after the initiation of sorafenib therapy. Patients and Methods: Therapeutic responses of 158 advanced HCC patients with hypervascular tumors who had received sorafenib for more than 1 month were analyzed. To assess their therapeutic response, patients underwent radiological evaluation before and every 4-6 weeks after the initiation of sorafenib treatment. After the classification of patients into three groups based on the change in arterial enhancement during treatment (no change, decrease and disappearance), the OS of each group was compared using the Kaplan-Meier method. Results:Statistically significant differences in OS were observed among the three groups (p < 0.001). A decrease or disappearance of arterial enhancement was significantly associated with improved OS compared to patients with no change in arterial enhancement; the median OS was 19.9 months (95% confidence interval, CI, 16.4-24.5 months) and 6.0 months (95% CI, 4.0-8.8 months), respectively (p < 0.001). However, there was no difference in OS between the decrease and disappearance groups (p = 0.88). Conclusion: We conclude that decreased arterial enhancement during sorafenib treatment was associated with the longest OS and could therefore reflect an effective response. (C) 2014 S. Karger AG, Basel
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• Validation of Three Staging Systems for Hepatocellular Carcinoma (JIS Score, Biomarker-Combined JIS Score and BCLC System) in 4,649 Cases from a Japanese Nationwide Survey, Satoshi Kitai, Masatoshi Kudo, Namiki Izumi, Shuichi Kaneko, Yonson Ku, Norihiro Kokudo, Michiie Sakamoto, Tadatoshi Takayama, Osamu Nakashima, Masumi Kadoya, Yutaka Matsuyama, Takashi Matsunaga, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 717 - 724, 2014 , Refereed
  Summary:Objective: Clinical staging is very important for optimal therapeutic strategy and prognostic prediction in patients with hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used and best-validated method for HCC. Similarly, the conventional Japan Integrated Staging (c-JIS) score and the biomarker-combined JIS (bm-JIS) score have also been reported to effectively stratify HCC patients. The aim of this study was to evaluate the performance of these three staging systems for prognostic prediction. Methods: A total of 4,649 HCC patients were included in this study. A multivariate analysis identified the independent risk factors associated with overall survival. The stratification ability and the suitability as a prognostic model of the three staging systems were compared. Results: Multivariate analysis revealed that male sex, higher Child-Pugh score, tumor size >2.0 cm, multiple tumors, vascular invasion, higher alpha-fetoprotein (AFP) level, higher des-gamma-carboxyprothrombin level, higher Lens culinaris agglutinin-reactive AFP level, and a performance status of 3-4 were independent risk factors in HCC. The independent homogenizing ability and stratification value of the bm-JIS score were higher than those of the c-JIS score and the BCLC system (X-2 = 972.7581, 758.1041 and 679.6832, respectively). Moreover, the bm-JIS score had the lowest Akaike Information Criteria value, followed by the c-JIS score and the BCLC system (9,844.278, 10,054.93 and 10,131.35, respectively). Conclusions: Our results suggest that the bm-JIS score offers good stratification ability and is a better prognostic predictor than the c-JIS score and the BCLC system. (C) 2014 S. Karger AG, Basel
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• Duration of Stable Disease Is Associated with Overall Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib, Tadaaki Arizumi, Kazuomi Ueshirna, Hirokazu Chishina, Masashi Kono, Mashiro Takita, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Naoshi Nishida, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 705 - 710, 2014 , Refereed
  Summary:Background: Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. Methods: From May 2009 to January 2013, 269 patients with advanced-stage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (<3 months) and long SD (>= 3 months). The relationship between the duration of SD and OS was analyzed among patients with complete (CR) and partial response (PR), and long and short SD using the Kaplan-Meier method. Results:The median OS was 5.7 months in the short SD, 20.8 months in the long SD and 17.9 months in the CR + PR group. Although the duration of OS was significantly longer in the long SD group than the short SD group, no difference in OS was detected between the patients with CR + PR and patients with long SD. The impact of long SD on OS could be as strong as that of CR + PR. Conclusion: Achievement of long SD is one of the important goals for improving survival in patients with HCC treated with sorafenib. (C) 2014 S. Karger AG, Basel
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• Ultrasound Fusion Imaging of Hepatocellular Carcinoma: A Review of Current Evidence, Yasunori Minami, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 690 - 695, 2014 , Refereed
  Summary:With advances in technology, imaging techniques that entail fusion of sonography and CT or MRI have been introduced in clinical practice. Ultrasound fusion imaging provides CT or MRI cross-sectional multiplanar images that correspond to the sonographic images, and fusion imaging of B-mode sonography and CT or MRI can be displayed simultaneously and in real time according to the angle of the transducer. Ultrasound fusion imaging helps us understand the three-dimensional relationship between the liver vasculature and tumors, and can detect small liver tumors with poor conspicuity. This fusion imaging is attracting the attention of operators who perform radiofrequency ablation (RFA) for the treatment of hepatic malignancies because this real-time, multimodality comparison can increase monitoring and targeting confidence during the procedure. When RFA with fusion imaging was performed on small hepatocellular carcinomas (HCCs) with poor conspicuity, it was reported that the rates of technical success and local tumor progression were 94.4-100% and 0-8.3%. However, there have been no studies comparing fusion imaging guidance and contrast-enhanced sonography, CT or MRI guidance in ablation. Fusion imaging-guided RFA has proved to be effective for HCCs that are poorly defined on not only conventional B-mode sonography but also contrast-enhanced sonography. In addition, fusion imaging could be useful to assess the treatment response of RFA because of three-dimensional information. Here, we give an overview of the current status of ultrasound fusion imaging for clinical application in the liver. (C) 2014 S. Karger AG, Basel
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• Radiofrequency Ablation for Hepatocellular Carcinoma Measuring 2 cm or Smaller: Results and Risk Factors for Local Recurrence, Masashi Kono, Tatsuo Inoue, Masatoshi Kudo, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Kazuorni Ueshima, Naoshi Nishida, Takamichi Murakami, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 670 - 677, 2014 , Refereed
  Summary:Objective:The purpose of this study was to evaluate the risk factors for local recurrence with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) measuring <= 2 cm. Methods: This study involved 234 patients with 274 HCCs measuring cm who had undergone RFA as the initial treatment. The mean tumor diameter was 1.478 cm. The median follow-up period was 829 days. We evaluated the post-RFA cumulative local recurrence rate and analyzed the risk factors contributing to clinical outcomes. Results: Cumulative local recurrence rates were 9, 19 and 19% at 1,2 and 3 years, respectively. Among the 145 cases with a complete safety margin (SM) after RFA, only 4 developed local tumor recurrence and the cumulative rates of local tumor recurrence at 1, 2 and 3 years were 2, 3 and 3%, respectively. Among the 129 cases with incomplete SM, local tumor recurrence developed in 34 and the cumulative rates of local tumor progression at 1, 2 and 3 years were 14, 36 and 36%, respectively. In multivariate analysis, significant risk factors were tumor location (liver surface), irregular gross type and SM <5 mm. Conclusion: Even with HCC measuring cm, location and gross type of tumor should be carefully evaluated before RFA is performed. (C) 2014 S. Karger AG, Basel
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• Genome-Wide Profiling of DNA Methylation and Tumor Progression in Human Hepatocellular Carcinoma, Naoshi Nishida, Takafumi Nishimura, Takuya Nakai, Hirokazu Chishina, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 658 - 663, 2014 , Refereed
  Summary:Objective: To clarify the progression pattern of abnormal DNA methylation during the development of hepatocellular carcinoma (HCC) using a comprehensive methylation assay. Methods: We used an Infinium HumanMethylation450 BeadChip array that can analyze >485,000 CpG sites distributed throughout the genome for a comprehensive methylation study of 117 liver tissues consisting of 59 HCC and 58 noncancerous livers. Altered DNA nnethylation patterns during tumor progression were also analyzed. Results: We identified 38,330 CpG sites with significant differences in methylation levels between HCCs and noncancerous livers (DM-CpGs) using strict criteria. Of the DM-CpGs, 92% were hypomethylated and only 3,051 CpGs (8%) were hypermethylated in HCC. The DM-CpGs were more prevalent within intergenic regions with isolated CpGs. In contrast, DM-CpGs that were hypermethylated in HCC were predominantly located within promoter regions and CpG islands (p < 0.0001). The association between methylation profiles of DM-CpGs and tumor size was statistically significant, especially in hepatitis C virus (HCV)-positive cases (p = 0.0001). Conclusions: We clarified the unique characteristics of DM-CpGs in human HCCs. The stepwise progression of alterations in DNA methylation was a common feature of HCV-related hepatocarcinogenesis. (C) 2014 S. Karger AG, Basel
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• Emerging Strategies for the Management of Hepatocellular Carcinoma Preface, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 32(6), 655 - 657, 2014 , Refereed
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• Alteration of Epigenetic Profile in Human Hepatocellular Carcinoma and Its Clinical Implications, Naoshi Nishida, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 3(3-4), 417 - 427, 2014 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is a common cancer worldwide and develops against a background of chronic liver damage. A variety of HCC-related genes are known to be altered by genetic and epigenetic mechanisms. Therefore, information regarding alteration of the genetic and epigenetic profiles in HCC is essential for understanding the biology of this type of tumor. Methylation at CpG sites in gene promoters is known to affect the transcription of the corresponding genes. Abnormal regional hypermethylation is observed in the 5' region of several tumor suppressor genes (TSGs) in HCC, and this hypermethylation may promote carcinogenesis through the transcriptional inactivation of downstream TSGs. The DNA damage induced by oxidation is a trigger of abnormal DNA methylation and inactivation of TSGs through recruitment of the polycomb repressive complex to the promoter sequence. Thus, oxidative stress may be responsible for the emergence of HCC from chronic hepatitis and liver cirrhosis through the epigenetic alteration of TSGs. There have been several attempts to apply epigenetic information to the diagnosis and treatment of HCC. The predictive value of selected methylation events on survival in HCC patients has been reported, and the methylation profile of background liver could be associated with recurrence-free survival of HCC patients who have undergone hepatectomy. Another study detected methylated DNA from HCC cells in serum, and the circulating tumor DNA was regarded as a potential tumor marker. In addition, several trials of HCC therapy have targeted the epigenetic machinery and were based upon comprehensive analyses of DNA methylation of this type of tumor. Here, we present an overview of research regarding DNA methylation status in human HCC and describe the clinical application of epigenetic information to HCC. Copyright (C) 2014 S. Karger AG, Basel
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• Biomarkers and Personalized Sorafenib Therapy, M. Kudo, LIVER CANCER, LIVER CANCER, 3(3-4), 399 - 404, 2014 , Refereed
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• The clinical characteristics of small bowel diseases in the eider patients with obscure GI bleeding, Chishina Hirokazu, Takayama Masaki, Adachi Teppei, Mine Hiromasa, Nagai Tomoyuki, Nagata Yoshiaki, Kawasaki Masanori, Asakuma Yutaka, Sakurai Toshiharu, Matsui Shigenaga, Kashida Hiroshi, Kudo Masatoshi, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 28, 533 - 533, Oct. 2013 , Refereed
• Role of oxidative stress and epigenetic alteration on chronic hepatitis C-related human hepatocarcinogenesis, Naoshi Nishida, Masatoshi Kudo, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Kazuomi Ueshima, Takeshi Nagasaka, Ajay Goel, HEPATOLOGY, HEPATOLOGY, 58, 1065A - 1066A, Oct. 2013 , Refereed
• Optimal scan timing of hepatic arterial-phase imaging of hypervascular hepatocellular carcinoma determined by multiphasic fast CT imaging technique, Yuki Kagawa, Masahiro Okada, Yukinobu Yagyu, Seishi Kumano, Masayuki Kanematsu, Masayuki Kudo, Takamichi Murakami, ACTA RADIOLOGICA, ACTA RADIOLOGICA, 54(8), 843 - 850, Oct. 2013 , Refereed
  Summary:Background: A new multiphasic fast imaging technique, known as volume helical shuttle technique, is a breakthrough for liver imaging that offers new clinical opportunities in dynamic blood flow studies. This technique enables virtually real-time hemodynamics assessment by shuttling the patient cradle back and forth during serial scanning. Purpose: To determine optimal scan timing of hepatic arterial-phase imaging for detecting hypervascular hepatocellular carcinoma (HCC) with maximum tumor-to-liver contrast by volume helical shuttle technique. Material and Methods: One hundred and one hypervascular HCCs in 50 patients were prospectively studied by 64-channel multidetector-row computed tomography (MDCT) with multiphasic fast imaging technique. Contrast medium containing 600 mg iodine per kg body weight was intravenously injected for 30 s. Six seconds after the contrast arrival in the abdominal aorta detected with bolus tracking, serial 12-phase imaging of the whole liver was performed during 24-s breath-holding with multiphasic fast imaging technique during arterial phase. By placing regions of interest in the abdominal aorta, portal vein, liver parenchyma, and hypervascular HCCs on the multiphase images, time-density curves of anatomical regions and HCCs were composed. Timing of maximum tumor-to-liver contrast after the contrast arrival in the abdominal aorta was determined. Results: For the detection of hypervascular HCC at arterial phase, mean time and value of maximum tumor-to-liver contrast after the contrast arrival were 21 s and 38.0 HU, respectively. Conclusion: Optimal delay time for the hepatic arterial-phase imaging maximizing the contrast enhancement of hypervascular HCCs was 21 s after arrival of contrast medium in the abdominal aorta.
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• Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study, Philip J. Johnson, Shukui Qin, Joong-Won Park, Ronnie T. P. Poon, Jean-Luc Raoul, Philip A. Philip, Chih-Hung Hsu, Tsung-Hui Hu, Jeong Heo, Jianming Xu, Ligong Lu, Yee Chao, Eveline Boucher, Kwang-Hyub Han, Seung-Woon Paik, Jorge Robles-Avina, Masatoshi Kudo, Lunan Yan, Abhasnee Sobhonslidsuk, Dmitry Komov, Thomas Decaens, Won-Young Tak, Long-Bin Jeng, David Liu, Rana Ezzeddine, Ian Walters, Ann-Lii Cheng, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 31(28), 3517 - +, Oct. 2013 , Refereed
  Summary:Purpose Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. Patients and Methods Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. Results The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR <= 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. Conclusion Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.
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• Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study, Josep M. Llovet, Thomas Decaens, Jean-Luc Raoul, Eveline Boucher, Masatoshi Kudo, Charissa Chang, Yoon-Koo Kang, Eric Assenat, Ho-Yeong Lim, Valerie Boige, Philippe Mathurin, Laetitia Fartoux, Deng-Yn Lin, Jordi Bruix, Ronnie T. Poon, Morris Sherman, Jean-Frederic Blanc, Richard S. Finn, Won-Young Tak, Yee Chao, Rana Ezzeddine, David Liu, Ian Walters, Joong-Won Park, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 31(28), 3509 - +, Oct. 2013 , Refereed
  Summary:Purpose Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. Patients and Methods In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Results Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). Conclusion In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.
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• JSUM ultrasound elastography practice guidelines: liver, Masatoshi Kudo, Tsuyoshi Shiina, Fuminori Moriyasu, Hiroko Iijima, Ryosuke Tateishi, Norihisa Yada, Kenji Fujimoto, Hiroyasu Morikawa, Masashi Hirooka, Yasukiyo Sumino, Takashi Kumada, JOURNAL OF MEDICAL ULTRASONICS, JOURNAL OF MEDICAL ULTRASONICS, 40(4), 325 - 357, Oct. 2013 , Refereed
  Summary:In diffuse liver disease, it is extremely important to make an accurate diagnosis of liver fibrosis prior to determining indications for therapy or predicting treatment outcome and malignant potential. Although liver biopsy has long been the gold standard in the diagnosis of liver fibrosis, it is still an invasive method. In addition, the sampling error is an intrinsic problem of liver biopsy. Non-invasive serological methods for the diagnosis of liver fibrosis can be affected by factors unrelated to the liver. Recently, after the introduction of FibroScan, it became possible to measure liver fibrosis directly and non-invasively by elastography, which has attracted attention as a non-invasive imaging diagnostic tool for liver fibrosis. In addition, real-time tissue elastography is currently being used to conduct clinical trials at many institutions. Moreover, virtual touch quantification enables the observation of liver stiffness at any location by simply observing B-mode images. Furthermore, the recently developed ShearWave elastography visualizes liver stiffness on a color map. Elastography is thought to be useful for all types of diffuse liver diseases. Because of its association with portal hypertension and liver carcinogenesis, elastography is expected to function as a novel prognostic tool for liver disease. Although various elastographic devices have been developed by multiple companies, each device has its own measurement principle, method, and outcome, creating confusion in clinical settings. Therefore, it is extremely important to understand the characteristics of each device in advance. The objective of this guideline, which describes the characteristics of each device based on the latest knowledge, is for all users to be able to make the correct diagnosis of hepatic fibrosis by ultrasound elastography.
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• A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation, Yoshitaka Inaba, Fumihiko Kanai, Takeshi Aramaki, Takanobu Yamamoto, Toshihiro Tanaka, Koichiro Yamakado, Shuichi Kaneko, Masatoshi Kudo, Kazuho Imanaka, Shinichi Kora, Norifumi Nishida, Nobuyuki Kawai, Hiroshi Seki, Osamu Matsui, Hitoshi Arioka, Yasuaki Arai, EUROPEAN JOURNAL OF CANCER, EUROPEAN JOURNAL OF CANCER, 49(13), 2832 - 2840, Sep. 2013 , Refereed
  Summary:Background: TSU-68 is an antitumour drug that acts by inhibiting angiogenesis. We evaluated the efficacy and safety of TSU-68 in combination with transarterial chemoembolisation (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC). Patients and Methods: In this multicenter, open-label phase II study, we randomised patients with HCC who had been treated with a single session of TACE to receive either 200 mg TSU-68 twice daily or no medication. The primary end-point was progression-free survival (PFS). Results: A total of 103 patients were enrolled. Median PFS was 157.0 days (95% confidence interval [CI], 124.0-230.0 days) in the TSU-68 group and 122.0 days (95% CI, 73.0-170.0 days) in the control group. The hazard ratio was 0.699 (95% CI, 0.450-1.088). Fatigue, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, oedema and anorexia were more frequent in the TSU-68 group than in the control group. The most frequent grade 3/4 adverse events were AST elevation (46% of patients in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation (26% of patients in the TSU-68 group and 8% of controls). Two deaths, grade 5 hepatic failure and melena were noted in the TSU-68 group. Conclusion: This exploratory study shows a trend towards prolonged PFS with TSU-68 treatment after a single session of TACE, but this observation was not statistically significant. The two deaths were related to the study treatment. These results suggest that further examination of the study design is necessary to determine whether TSU-68 has any clinical benefits when combined with TACE. (C) 2013 Elsevier Ltd. All rights reserved.
  DOI
• A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation, Yoshitaka Inaba, Fumihiko Kanai, Takeshi Aramaki, Takanobu Yamamoto, Toshihiro Tanaka, Koichiro Yamakado, Shuichi Kaneko, Masatoshi Kudo, Kazuho Imanaka, Shinichi Kora, Norifumi Nishida, Nobuyuki Kawai, Hiroshi Seki, Osamu Matsui, Hitoshi Arioka, Yasuaki Arai, EUROPEAN JOURNAL OF CANCER, EUROPEAN JOURNAL OF CANCER, 49(13), 2832 - 2840, Sep. 2013 , Refereed
  Summary:Background: TSU-68 is an antitumour drug that acts by inhibiting angiogenesis. We evaluated the efficacy and safety of TSU-68 in combination with transarterial chemoembolisation (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC). Patients and Methods: In this multicenter, open-label phase II study, we randomised patients with HCC who had been treated with a single session of TACE to receive either 200 mg TSU-68 twice daily or no medication. The primary end-point was progression-free survival (PFS). Results: A total of 103 patients were enrolled. Median PFS was 157.0 days (95% confidence interval [CI], 124.0-230.0 days) in the TSU-68 group and 122.0 days (95% CI, 73.0-170.0 days) in the control group. The hazard ratio was 0.699 (95% CI, 0.450-1.088). Fatigue, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, oedema and anorexia were more frequent in the TSU-68 group than in the control group. The most frequent grade 3/4 adverse events were AST elevation (46% of patients in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation (26% of patients in the TSU-68 group and 8% of controls). Two deaths, grade 5 hepatic failure and melena were noted in the TSU-68 group. Conclusion: This exploratory study shows a trend towards prolonged PFS with TSU-68 treatment after a single session of TACE, but this observation was not statistically significant. The two deaths were related to the study treatment. These results suggest that further examination of the study design is necessary to determine whether TSU-68 has any clinical benefits when combined with TACE. (C) 2013 Elsevier Ltd. All rights reserved.
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• Diagnostic value of endoscopic ultrasound-guided directional eFLOW in solid pancreatic lesions, Kunal Das, Masatoshi Kudo, Masayuki Kitano, Hiroki Sakamoto, Takamitsu Komaki, Tadayuki Takagi, Kenji Yamao, JOURNAL OF MEDICAL ULTRASONICS, JOURNAL OF MEDICAL ULTRASONICS, 40(3), 211 - 218, Jul. 2013 , Refereed
  Summary:Ultrasound using microbubble-based contrast agents is useful for vascular imaging. Directional eFLOW (D-eFLOW) is a novel technology for vascular assessment that provides high spatial and temporal resolution. The purpose of this study was to investigate the utility of endoscopic ultrasound (EUS)-guided D-eFlow before and after administration of an ultrasound contrast agent (USCA) for assessing the vascularity of solid pancreatic lesions. D-eFlow was compared to power Doppler EUS (PD-EUS) or color Doppler EUS (CD-EUS) before and after USCA injection. We also evaluated the Visual Vascular Assessment (ViVA) scale for the estimation of vascularity and investigated its reliability using the interclass correlation coefficient (ICC). From January 2007 to March 2007, 35 patients (mean age, 64.5 years old; age range, 28-81 years) underwent EUS followed by D-eFLOW EUS, PD-EUS, and CD-EUS before and after administration of USCA. The pancreatic parenchymal ViVA score, pancreatic vascular pattern, and ICC were evaluated for all lesions. Concerning the sensitivity for detection of the hypovascular pattern in pancreatic adenocarcinoma, D-eFLOW (before and after USCA) had similar sensitivity to PD-EUS (before and after USCA) and CD-EUS (before and after USCA). D-eFLOW after contrast showed the highest accuracy (82.3 %) and negative predictive value (53.8 %) among all the modalities investigated. There was a good correlation among the ViVA scores for D-eFLOW before contrast, those for D-eFLOW EUS, and those for PD-EUS and CD-EUS. The reliability of the ViVA scale was excellent with an ICC of 0.81. In conclusion, D-eFLOW EUS is a sensitive, reliable, and highly accurate method of assessment of pancreatic vascularity. D-eFLOW EUS with contrast was more sensitive than PD-EUS and CD-EUS for assessment of pancreatic vascularity.
  DOI
• Senile systemic amyloidosis localized to the stomach, Shigenaga Matsui, Hiroshi Kashida, Masatoshi Kudo, DIGESTIVE ENDOSCOPY, DIGESTIVE ENDOSCOPY, 25(4), 468 - 469, Jul. 2013 , Refereed
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• Noninvasive Assessment of Liver Fibrosis by Measurement of Lf Index in Patients With Chronic Viral Hepatitis, Norihisa Yada, Satoru Hagiwara, Tadaaki Arizumi, Masahiro Takita, Satoshi Kitai, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 144(5), S1041 - S1041, May 2013 , Refereed
• Heat Shock Protein 27 Expression Is Inversely Correlated With Intraepithelial Neoplasia and Positively Correlated With Poor Differentiation of Gastric Cancer, Yoshiaki Nagata, Toshiharu Sakurai, Masaki Takayama, Tomoyuki Nagai, Masanori Kawasaki, Yutaka Asakuma, Satoru Hagiwara, Naoshi Nishida, Shigenaga Matsui, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 144(5), S883 - S883, May 2013 , Refereed
• Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2012 A WFUMB-EFSUMB Initiative in Cooperation With Representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS, M. Claudon, C. F. Dietrich, B. I. Choi, D. O. Cosgrove, M. Kudo, C. P. Nolsoe, F. Piscaglia, S. R. Wilson, R. G. Barr, M. C. Chammas, N. G. Chaubal, M. -H. Chen, D. A. Clevert, J. M. Correas, H. Ding, F. Forsberg, J. B. Fowlkes, R. N. Gibson, B. B. Goldberg, N. Lassau, E. L. S. Leen, R. F. Mattrey, F. Moriyasu, L. Solbiati, H. -P. Weskott, H. -X. Xu, ULTRASCHALL IN DER MEDIZIN, ULTRASCHALL IN DER MEDIZIN, 34(1), 11 - 29, Feb. 2013 , Refereed
  Summary:Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.
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• GUIDELINES AND GOOD CLINICAL PRACTICE RECOMMENDATIONS FOR CONTRAST ENHANCED ULTRASOUND (CEUS) IN THE LIVER - UPDATE 2012 A WFUMB-EFSUMB INITIATIVE IN COOPERATION WITH REPRESENTATIVES OF AFSUMB, AIUM, ASUM, FLAUS AND ICUS, Michel Claudon, Christoph F. Dietrich, Byung Ihn Choi, David O. Cosgrove, Masatoshi Kudo, Christian P. Nolsoe, Fabio Piscaglia, Stephanie R. Wilson, Richard G. Barr, Maria C. Chammas, Nitin G. Chaubal, Min-Hua Chen, Dirk Andre Clevert, Jean Michel Correas, Hong Ding, Flemming Forsberg, J. Brian Fowlkes, Robert N. Gibson, Barry B. Goldberg, Nathalie Lassau, Edward L. S. Leen, Robert F. Mattrey, Fuminori Moriyasu, Luigi Solbiati, Hans-Peter Weskott, Hui-Xiong Xu, ULTRASOUND IN MEDICINE AND BIOLOGY, ULTRASOUND IN MEDICINE AND BIOLOGY, 39(2), 187 - 210, Feb. 2013 , Refereed
  Summary:Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide. (E-mail: Christoph.dietrich@ckbm.de) (C) 2013 World Federation for Ultrasound in Medicine & Biology.
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• Hypovascular Nodules in Patients with Chronic Liver Disease: Risk Factors for Development of Hypervascular Hepatocellular Carcinoma, Tomoko Hyodo, Takamichi Murakami, Yasuharu Imai, Masahiro Okada, Masatoshi Hori, Yuki Kagawa, Sachiyo Kogita, Seishi Kumano, Masatoshi Kudo, Teruhito Mochizuki, RADIOLOGY, RADIOLOGY, 266(2), 480 - 490, Feb. 2013 , Refereed
  Summary:Purpose: To identify patient characteristics and magnetic resonance (MR) imaging findings associated with subsequent hypervascularization in hypovascular nodules that show hypointensity on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with chronic liver diseases. Materials and Methods: Institutional review board approval was obtained, and informed consent was waived. At multiple follow-up gadoxetic acid-enhanced MR imaging examinations of 68 patients, 160 hypovascular nodules were retrospectively reviewed. A Cox regression model for hypervascularization was developed to explore the association of baseline characteristics, including patient factors (Child-Pugh classification, etiology of liver disease, history of local therapy for hepatocellular carcinoma [HCC], and coexistence of hypervascular HCC) and MR imaging findings (fat content, signal intensity on T2-weighted images, and nodule size). In addition, the growth rate was calculated as the reciprocal of tumor volume doubling time to investigate its relationship with subsequent hypervascularization by using receiver operating characteristic and Kaplan-Meier analyses. Results: The prevalence of subsequent hypervascularization was 31% (50 of 160 nodules). Independent Cox multivariable predictors of increased risk of hypervascularization were hyperintensity on T2-weighted images (hazard ratio [HR] = 8.7; 95% confidence interval [CI]: 3.6, 20.8), previous local therapy for hypervascular HCC (HR = 5.0; 95% CI: 1.8, 13.6), Child-Pugh B cirrhosis (HR = 3.6; 95% CI: 1.4, 9.5) and coexistence of hypervascular HCC (HR = 2.0; 95% CI: 1.0, 3.8). The mean growth rate was significantly higher in nodules that showed subsequent hypervascularization than in those without hypervascularization. Kaplan-Meier analysis based on the receiver operating characteristic cutoff level (1.8 x 10(-3)/day [tumor volume doubling time, 542 days]) showed that nodules with a higher growth rate had a significantly higher incidence of hypervascularization (P = 5.2 x 10(-8), log-rank test). Conclusion: Hyperintensity on T2-weighted images is an independent and strong risk factor at baseline for subsequent hypervascularization in hypovascular nodules in patients with chronic liver disease. Tumor volume doubling time of less than 542 days was associated with a high rate of subsequent hypervascularization. (C)RSNA, 2013
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• Unique association between global DNA hypomethylation and hromosomal alterations in human hepatocellular carcinoma, Nishida N, Kudo M, Nishimura T, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Yokomichi N, Nagasaka T, Goel A, Plos One, Plos One, 8, e72312, 2013 , Refereed
• Brivanib in patients with advanced hepatocellular carcinoma who failed or were intolerant to sorafenib: or for whom sorafenib faied results from the randomized phase 3 BRISK-PS study, Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc, JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW, J Clin Oncol, J Clin Oncol, 31, 3509 - 3516, 2013
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• Contrast-Independent Liver-Fat Quantification from Spectral CT Exams, Paulo R. S. Mendonca, Peter Lamb, Andras Kriston, Kosuke Sasaki, Masayuki Kudo, Dushyant V. Sahani, MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION (MICCAI 2013), PT I, MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION (MICCAI 2013), PT I, 8149, 324 - 331, 2013 , Refereed
  Summary:The diagnosis and treatment of fatty liver disease requires accurate quantification of the amount of fat in the liver. Image-based methods for quantification of liver fat are of increasing interest due to the high sampling error and invasiveness associated with liver biopsy, which despite these difficulties remains the gold standard. Current computed tomography (CT) methods for liver-fat quantification are only semi-quantitative and infer the concentration of liver fat heuristically. Furthermore, these techniques are only applicable to images acquired without the use of contrast agent, even though contrast-enhanced CT imaging is more prevalent in clinical practice. In this paper, we introduce a method that allows for direct quantification of liver fat for both contrast-free and contrast-enhanced CT images. Phantom and patient data are used for validation, and we conclude that our algorithm allows for highly accurate and repeatable quantification of liver fat for spectral CT.
• Alpha-fetoprotein-L3: Useful or Useless for Hepatocellular Carcinoma?, M. Kudo, LIVER CANCER, LIVER CANCER, 2(3-4), 151 - 152, 2013 , Refereed
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• Real-time high-resolution vascular ultrasound using frequency domain interferometry with the ROI-division process, Hirofumi Taki, Takuya Sakamoto, Kousuke Taki, Makoto Yamakawa, Tsuyoshi Shiina, Motoi Kudo, Toni Sato, 2013 35TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC), 2013 35TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC), 2013, 1398 - 1401, 2013 , Refereed
  Summary:We have proposed a high-range-resolution ultrasound imaging method for human carotid artery using an adaptive beamforming technique based on frequency domain interferometry (FDI). The method assumes that the received signal consists of multiple echoes of targets and noise, where the waveform of each echo is similar to that of the reference signal. In this study, we examine the dependence of the echo waveform on the target depth, and investigate the proper measurement-range for the FDI imaging method using a reference signal. Furthermore, we propose a ROI-division process, where each sub-ROI has a proper measurement-range for the application of the FDI imaging method. Simulation and experimental results show the efficiency of the ROI-division process in improving the image quality of human carotid artery acquired using the FDI imaging method. We believe that the modified FDI imaging method with the ROI-division process has the potential to facilitate significant progress in the detection of vessel stenosis and in the assessment of cardiovascular disease risk.
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• Chronic Liver Diseases and Hepatocellular Carcinoma: An Update for 2013 Preface, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 31(5-6), 405 - 407, 2013 , Refereed
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• Outcome of Double-Filtration Plasmapheresis plus Interferon Treatment in Nonresponders to Pegylated Interferon plus Ribavirin Combination Therapy, Kayo Sugimoto, Soo Ryang Kim, Ahmed El-Shamy, Susumu Imoto, Haruma Fujioka, Ke Ih Kim, Yasuhito Tanaka, Yoshihiko Yano, Soo Ki Kim, Yutaka Hasegawa, Aya Fujinami, Mitsuhiro Ohta, Takashi Hatae, Hak Hotta, Yoshitake Hayashi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 31(5-6), 434 - 439, 2013 , Refereed
  Summary:Objectives: We assessed the outcome of double-filtration plasmapheresis (DFPP) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients infected with hepatitis C virus (HCV)-1b whose HCV had not disappeared during PEG-IFN/RBV combination therapy, or who had relapsed after the end of the therapy. Additionally, we investigated factors predictive of sustained virological response (SVR), including host and viral genetic factors, to DFPP plus IFN/RBV therapy. Methods: A total of 40 patients infected with HCV-1b whose HCV virus had not been eradicated by previous PEG-IFN/RBV therapy were enrolled for treatment by DFPP plus IFN/RBV. Rapid virological response (RVR) and SVR were assessed, and pretreatment factors associated with SVR the interleukin (IL)28B gene, the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR) were analyzed. Results: Of the 40 patients, 9 (23%) achieved RVR and 10 (25%) achieved SVR. The significant factors associated with SVR were IL28B major and RVR, as assessed by multivariate analysis (p = 0.0182, p = 0.0005). Conclusion: Patients whose HCV is not eradicated by previous PEG-IFN/RBV would be good candidates for combined DFPP and IFN/RBV retreatment provided they demonstrate IL28B major and have achieved RVR. (C) 2013 S. Karger AG, Basel
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• Radiofrequency Ablation for Hepatic Malignancies: Is Needle Tract Cauterization Necessary for Preventing Iatrogenic Bleeding?, Yasunori Minanni, Sosuke Hayaishi, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 31(5-6), 480 - 484, 2013 , Refereed
  Summary:Objective: To evaluate whether iatrogenic hemorrhage can be prevented by intrahepatic tract ablation following radiofrequency ablation (RFA) therapy for hepatic malignancies. Methods: A retrospective cohort study analyzing a prospective database in a single institution was conducted. The incidence of postprocedural complications was compared in two groups: one with cauterization of the needle tracts after RFA and the other without. Results: The complication rates of intraperitoneal hemorrhage were 1.05% (4/380) and 0.92% (6/652) in the nonablation group and the ablation group, respectively (p = 0.90). All of these 10 patients with iatrogenic bleeding were classified as Child-Pugh grade A. Among the 15 hemodialysis patients in this study, hemorrhage was seen in 2 (13.3%), compared with 8 (0.79%) of the nonhemodialysis patients (p = 0.0002). There were no statistically significant differences in the incidence of other complications including pleural effusion, serous ascites, pneumothorax, hemothorax, hepatic infarction, bile duct injury and pericardial effusion between the two groups. Gastrointestinal perforation, peritonitis or tumor seeding were not observed. Conclusion: Our study found a high incidence of bleeding after RFA among hemodialysis patients. Irrespective of tract ablation being after RFA, iatrogenic hemorrhage appeared to be equivalent in this population. (C) 2013 S. Karger AG, Basel
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• Usefulness of the Extracted-Overlay Function in CT/MR-Ultrasonography Fusion Imaging for Radiofrequency Ablation of Hepatocellular Carcinoma, Yuki Makino, Yasuharu Imai, Takumi Igura, Sachiyo Kogita, Yoshiyuki Sawai, Kazuto Fukuda, Masatoshi Hori, Masatoshi Kudo, Takamichi Murakami, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 31(5-6), 485 - 489, 2013 , Refereed
  Summary:Objectives: We developed a novel technique of the extracted-overlay function in CT/MR-ultrasonography (US) fusion imaging for radiofrequency ablation (RFA), in which only a tumor extracted from CT/MR images with a virtual ablative margin of arbitrary thickness is overlaid on US. The usefulness of this function is investigated in this preliminary report. Methods: The volume data of the extracted tumor with a virtual ablative margin were created on an image-processing workstation, and transported into a US unit equipped with a CT/MR-US fusion imaging system. After the positional registration of US and transported images, the extracted tumor with an ablative margin could be overlaid on US. In RFA, using this function, an electrode was inserted targeting the overlaid tumor with an ablative safety margin of 5 mm on US, and the treatment effect was evaluated by dynamic CT. Treatment results of 23 consecutive hepatocellular carcinomas (HCCs) that underwent RFA using this function were retrospectively analyzed. Results: Complete tumor ablation was achieved in 22 (95.7%) and 1 (4.3%) HCCs in 1 and 2 treatment sessions, respectively. Conclusions: Due to the visualization of an extracted tumor with an ablative safety margin on a US image, even during and after ablation, this function is useful for treatment planning and guidance of RFA. (C) 2013 S. Karger AG, Basel
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• Molecular Link between Liver Fibrosis and Hepatocellular Carcinoma, Toshiharu Sakurai, Masatoshi Kudo, LIVER CANCER, LIVER CANCER, 2(3-4), 365 - 366, 2013 , Refereed
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• Comparison of different proton pump inhibitors (PPI) in helicobacter pylori eradication, Teppei Adachi, Shigenaga Matsui, Masaki Takayama, Masanori Kawasaki, Yutaka Yutaka, Toshiharu Sakurai, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 425 - 426, Dec. 2012 , Refereed
• A prospective randomized controlled study of a rebamipid monotherapy in the treatment of endoscopic submucosal dissection (ESD)-induced ulcers, Masaki Takayama, Shigenaga Matsui, Masanori Kawasaki, Yutaka Asakuma, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 419 - 419, Dec. 2012 , Refereed
• Albumin levels can be a predictive factor for the short-term complications after percutaneous endoscopic gastrostomy in retrospective study, Tomoyuki Nagai, Teppei Adachi, Masaki Takayama, Hiromasa Mine, Yoshiaki Nagata, Masanori Kawasaki, Yutaka Asakuma, Toshiharu Sakurai, Shigenaga Matsui, Mikio Shiomi, Hiroshi Kashida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 409 - 409, Dec. 2012 , Refereed
• Endoscopic submucosal dissection for the colorectum: Usefulness and feasibility, Hiroshi Kashida, Toshiharu Sakurai, Yutaka Asakuma, Masanori Kawasaki, Yoshiaki Nagata, Tomoyuki Nagai, Masaki Takayama, Hiromasa Mine, Teppei Adachi, Shigenaga Matsui, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 202 - 202, Dec. 2012 , Refereed
• The clinical characteristics and endoscopic treatment of duodenal varices, Shigenaga Matsui, Hiroshi Kashida, Masanori Kawasaki, Yutaka Asakuma, Toshiharu Sakurai, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 392 - 392, Dec. 2012 , Refereed
• The retrospective study of novel anticancer agent, miriplatin in TACE and TAI for unresectable hepatocellular carcinoma in Japan, Tomoyuki Nagai, Ueshima Kazuomi, Sosuke Hayaishi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Yasunori Minami, Naoshi Nishida, Masatoshi Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 27, 225 - 225, Dec. 2012 , Refereed
• Targeted Therapy for Liver Cancer: Updated Review in 2012, Masatoshi Kudo, CURRENT CANCER DRUG TARGETS, CURRENT CANCER DRUG TARGETS, 12(9), 1062 - 1072, Nov. 2012 , Refereed
  Summary:May 2007, sorafenib (Nexavar (R)) was approved for "unresectable hepatocellular carcinoma (HCC)", and was the first molecular targeted agent for use in HCC. To date, sorafenib is the only molecular-targeted agent, whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has now been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Phase III clinical trials of several targeted agents comparing them with placebo as second-line treatment agents for patients who failed or was intolerable to sorafenib are also ongoing. In addition, combination of sorafenib with standard treatment such as resection, ablation, transarterial chemoembolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the clinical utility of sorafenib in the treatment algorithm of HCC. Furthermore, it also reviews the current status of clinical trials of new agents or combination therapy with sorafenib and standard treatment. Finally, further prospect of the paradigm shift of the HCC treatment is also discussed.
• Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 18(42), 6005 - 6017, Nov. 2012 , Refereed
  Summary:Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth, invasion, and metastasis, and enabled the development of molecular-targeted agents. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. In addition, the combination of sorafenib with standard treatment, such as resection, ablation, transarterial embolization, and hepatic arterial infusion chemotherapy are ongoing. This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways. Finally, the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed. (C) 2012 Baishideng. All rights reserved.
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• A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma, Takuji Okusaka, Hiroshi Kasugai, Hiroshi Ishii, Masatoshi Kudo, Michio Sata, Katsuaki Tanaka, Yasukazu Shioyama, Kazuaki Chayama, Hiromitsu Kumada, Masaharu Yoshikawa, Toshihito Seki, Hidetugu Saito, Naoaki Hayashi, Keiko Shiratori, Kiwamu Okita, Isao Sakaida, Masao Honda, Yukio Kusumoto, Takuya Tsutsumi, Kenji Sakata, INVESTIGATIONAL NEW DRUGS, INVESTIGATIONAL NEW DRUGS, 30(5), 2015 - 2025, Oct. 2012 , Refereed
  Summary:Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4-12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of a parts per thousand yenaEuro parts per thousand grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.
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• Transcatheter endoscopy for pancreaticobiliary duct diseases, Hiroki Sakamoto, Masayuki Kitano, Ken Kamata, Takeshi Miyata, Kunpei Kadosaka, Hajime Imai, Yoshifumi Takeyama, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 76(4), 892 - 899, Oct. 2012 , Refereed
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• Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT, Tatsuo Inoue, Masatoshi Kudo, Mina Komuta, Sosuke Hayaishi, Taisuke Ueda, Masahiro Takita, Satoshi Kitai, Kinuyo Hatanaka, Norihisa Yada, Satoru Hagiwara, Hobyung Chung, Toshiharu Sakurai, Kazuomi Ueshima, Michiie Sakamoto, Osamu Maenishi, Tomoko Hyodo, Masahiro Okada, Seishi Kumano, Takamichi Murakami, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 47(9), 1036 - 1047, Sep. 2012 , Refereed
  Summary:We aimed to evaluate gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the detection of hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) compared with dynamic multi-detector row computed tomography (MDCT), and to discriminate between HCCs and DNs. Eighty-six nodules diagnosed as HCC or DNs were retrospectively investigated. Gd-EOB-DTPA-enhanced MRI and dynamic MDCT were compared with respect to their diagnostic ability for hypervascular HCCs and detection sensitivity for hypovascular tumors. The ability of hepatobiliary images of Gd-EOB-DTPA-enhanced MRI to discriminate between these nodules was assessed. We also calculated the EOB enhancement ratio of the tumors. For hypervascular HCCs, the diagnostic ability of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of MDCT for tumors less than 2 cm (p = 0.048). There was no difference in the detection of hypervascular HCCs between hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (43/45: 96%) and dynamic MDCT (40/45: 89%), whereas the detection sensitivity of hypovascular tumors by Gd-EOB-DTPA-enhanced MRI was significantly higher than that by dynamic MDCT (39/41: 95% vs. 25/41: 61%, p = 0.001). EOB enhancement ratios were decreased in parallel with the degree of differentiation in DNs and HCCs, although there was no difference between DNs and hypovascular well-differentiated HCCs. The diagnostic ability of Gd-EOB-DTPA-enhanced MRI for hypervascular HCCs less than 2 cm was significantly higher than that of MDCT. For hypovascular tumors, the detection sensitivity of hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of dynamic Gd-EOB-DTPA-enhanced MRI and dynamic MDCT. It was difficult to distinguish between DNs and hypovascular well-differentiated HCCs based on the EOB enhancement ratio.
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• Estimation of liver function using T2* mapping on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging, Takashi Katsube, Masahiro Okada, Seishi Kumano, Izumi Imaoka, Yuki Kagawa, Masatoshi Hori, Kazunari Ishii, Noboru Tanigawa, Yasuharu Imai, Masatoshi Kudo, Takamichi Murakami, EUROPEAN JOURNAL OF RADIOLOGY, EUROPEAN JOURNAL OF RADIOLOGY, 81(7), 1460 - 1464, Jul. 2012 , Refereed
  Summary:Purpose: To investigate the usefulness of T2* mapping of liver on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI for estimating liver function. Materials and methods: 33 patients were classified into 3 groups as follows: normal liver function (NLF) (n = 7); mild liver damage (MLD) (n = 16) with Child-Pugh A; severe liver damage (SLD) (n = 10) with Child-Pugh B. T2*-weighted gradient-echo (T2* W-GRE) and T1-weighted gradient-echo (T1W-GRE) images were obtained before and after Gd-EOB-DTPA administration (3, 8, 13, and 18 min; 5, 10,15, and 20 min; respectively). T2* mapping of liver was calculated from T2* W-GRE, then T2* values of liver and T2* reduction rates of T2* value between pre-and post-contrast enhancement were measured. The increase rates of liver-to-muscle signal intensity (LMS) ratio on T1W-GRE between pre-and post-contrast enhancement were calculated. Results: T2* values on pre-and post-contrast showed no significant differences among three groups. Significant differences in T2* reduction rates were found among groups, and those of LCB were lower than those of other groups (NLF: MLD: SLD, 3.8: 6.0: 0.6% at 3 min, 8.2: 10.3: 1.0% at 8 min, 10.7: 11.5: 1.2% at 13 min, and 16.1: 13.2: 3.5% at 18 min, respectively) (P < 0.05). Significant differences in increase rates of LMS ratio on T1W-GRE were identified (NLF: MLD: SLD, 1.53: 1.46: 1.35 at 5 min, 1.68: 1.64: 1.37 at 10 min, 1.79: 1.76: 1.44 at 15 min, and 1.89: 1.78: 1.49 at 20 min, respectively). Conclusion: T2* reduction rate and increase rate of LMS ratio on T1W-GRE may allow us estimation of liver function according to Child-Pugh score. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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• Welcome to the First Issue of Liver Cancer, M. Kudo, LIVER CANCER, LIVER CANCER, 1(1), 1 - 1, Jun. 2012 , Refereed
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• p38MAPK suppresses chronic pancreatitis by regulating HSP27 and BAD expression, Ah-Mee Park, Masatoshi Kudo, Satoru Hagiwara, Masaki Tabuchi, Tomohiro Watanabe, Hiroshi Munakata, Toshiharu Sakurai, FREE RADICAL BIOLOGY AND MEDICINE, FREE RADICAL BIOLOGY AND MEDICINE, 52(11-12), 2284 - 2291, Jun. 2012 , Refereed
  Summary:Mitogen-activated protein kinases (MAPKs) are ubiquitous proteins that function in both normal and stress-related pathophysiological states of the cell. This study aimed to analyze the importance of p38MAPK in pancreatic injury using WBN/Kob rats with spontaneous chronic pancreatitis. Male WBN/Kob rats were injected with the p38MAPK inhibitor SB203580, starting at the age of 4 weeks, and sacrificed 6 weeks later. Compared with vehicle-treated rats, p38 inhibitor-treated rats exhibited a significant increase in pancreatic cell death and inflammation as assessed by histologic examination and myeloperoxidase activity, respectively. p38 inhibition decreased the expression of heat shock protein 27 (HSP27), an antioxidant protein, and enhanced accumulation of reactive oxygen species (ROS). In addition, the proapoptotic protein BAD was increased in the pancreas of rats treated with p38 inhibitor. In a pancreatic cell line (PANC-1), HSP27 knockdown augmented reactive oxygen species accumulation and cell death induced by tumor necrosis factor-alpha plus actinomycin D. In conclusion, p38MAPK suppresses chronic pancreatitis by upregulating HSP27 expression and downregulating BAD expression. (C) 2012 Elsevier Inc. All rights reserved.
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• Guideline on the use of new anticancer drugs for the treatment of Hepatocellular Carcinoma 2010 update, Shuichi Kaneko, Junji Furuse, Masatoshi Kudo, Kenji Ikeda, Masao Honda, Yasunari Nakamoto, Morikazu Onchi, Goshi Shiota, Osamu Yokosuka, Isao Sakaida, Tetsuo Takehara, Yoshiyuki Ueno, Kazumasa Hiroishi, Shuhei Nishiguchi, Hisataka Moriwaki, Kazuhide Yamamoto, Michio Sata, Shuntaro Obi, Shiro Miyayama, Yukinori Imai, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 42(6), 523 - 542, Jun. 2012 , Refereed
  Summary:The Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma was prepared by the Study Group on New Liver Cancer Therapies established by the Research Project on Emergency Measures to Overcome Hepatitis under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents clinical questions on issues pertaining to medical care, makes recommendations on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of scientific statements.
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• Can the biliary enhancement of Gd-EOB-DTPA predict the degree of liver function?, Masahiro Okada, Kazunari Ishii, Kazushi Numata, Tomoko Hyodo, Seishi Kumano, Masayuki Kitano, Masatoshi Kudo, Takamichi Murakami, HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, 11(3), 307 - 313, Jun. 2012 , Refereed
  Summary:BACKGROUND: Excretion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) in the bile may be related to liver function, because of elimination from the liver after preferential uptake by hepatocytes. The purpose of this study was to investigate the relation between liver and biliary enhancement in patients with or without liver dysfunction, and to compare the tumor-to-liver contrast in these patients. METHODS: Forty patients [group 1: normal liver and Child-Pugh class A in 20 patients, group 2: Child-Pugh class B in 18 patients and Child-Pugh C in 2] were evaluated. All patients underwent MR imaging of the liver using a 1.5-Tesla system. T1-weighted 3D images were obtained at 5, 10, 15 and 20 minutes after Gd-EOB-DTPA injection. The relation between group 3 (total bilirubin <1.8 mg/dL) and group 4 (total bilirubin >= 1.8 mg/dL) was investigated at 20 minutes. Liver and biliary signals were measured, and compared between groups 1 and 2 or groups 3 and 4. Tumor-to-liver ratio was also evaluated between groups 1 and 2. Scheffes post-hoc test after two-way repeated-measures ANOVA and Pearson's correlation test were used for statistical analysis. RESULTS: Liver enhancement showed significant difference at all time points between groups 1 and 2. Biliary enhancement did not show a significant difference between groups 1 and 2 at 5 minutes, but did at 10, 15 and 20 minutes. At 20 minutes, significant differences between groups 3 and 4 were seen for liver and biliary enhancement. At all time points, liver enhancement correlated with biliary enhancement in both groups. At 5 minutes and 20 minutes, statistical differences between groups 1 and 2 were seen for tumor-to-liver ratio. CONCLUSIONS: The degree of biliary enhancement has a close correlation to that of liver enhancement. It is especially important that insufficient liver enhancement causes lower tumor-to-liver contrast in the hepatobiliary phase of Gd-EOB-DTPA.
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• The Gross Classification of Hepatocellular Carcinoma: Usefulness of Contrast-Enhanced Sonography Using Perfluorocarbon Microbubbles (Sonazoid), Yasunori Minami, Kinuyo Hatanaka, Tadaaki Arizumi, Sosuke Hayaishi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 142(5), S1002 - S1002, May 2012 , Refereed
• Usefullness of Contrast-Enhanced Ultrasonography to Evaluate a Post Treatment Effect of Radiofrequentry Ablation About Hepatocellular Carcinoma; Comparion With Contrast-Enhanced CT, Tatsuo Inoue, Tadaaki Arizumi, Satoshi Kitai, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Toshiharu Sakurai, Kazuomi Ueshima, Naoshi Nishida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 142(5), S1002 - S1002, May 2012 , Refereed
• Novel Association Between Global DNA Hypomethylation and Chromosomal Instability Phenotype in Human Hepatocellular Carcinoma, Naoshi Nishida, Masatoshi Kudo, Tadaaki Arizumi, Sosuke Hayaishi, Masahiro Takita, Satoshi Kitai, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Toshiharu Sakurai, Takeshi Nagasaka, Ajay Goel, GASTROENTEROLOGY, GASTROENTEROLOGY, 142(5), S910 - S911, May 2012 , Refereed
• Activation of JNK in the Non-Cancerous Liver Tissue Predicts a High Risk of Recurrence After Hepatic Resection for Hepatocellular Carcinoma, Toshiharu Sakurai, Satoru Hagiwara, Tatsuo Inoue, Kazuomi Ueshima, Shigenaga Matsui, Naoshi Nishida, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 142(5), S452 - S452, May 2012 , Refereed
• Effect of Rebamipide for Endoscopic Submucosal Dissection (ESD)-induced Ulcer in Early Gastric Cancer: A Randomized Controlled Trial, Shigenaga Matsui, Masatoshi Kudo, Hiroshi Kashida, Yutaka Asakuma, Toshiharu Sakurai, Masanori Kawasaki, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 75(4), 237 - 237, Apr. 2012 , Refereed
• Quantitative myocardial perfusion analysis using multi-row detector CT in acute myocardial infarction, Yoshifumi Nakauchi, Yoshitaka Iwanaga, Shinichiro Ikuta, Masayuki Kudo, Kazuhiro Kobuke, Takamichi Murakami, Shunichi Miyazaki, HEART, HEART, 98(7), 566 - 572, Apr. 2012 , Refereed
  Summary:Objective To assess the feasibility of quantitative myocardial perfusion imaging (MPI) in acute myocardial infarction (AMI), using multi-row detector CT (MDCT) with a model-based deconvolution method. Design, setting, patients and interventions Fifteen normal subjects with normal coronary arteries and 26 patients with AMI after reperfusion therapy underwent MPI with MDCT. Perfusion parameters: tissue blood flow (TBF), tissue blood volume (TBV) and mean transit time (MTT) were obtained and compared with clinical parameters, angiography and single-photon emission CT (SPECT) data. Furthermore, the MPI data were compared with data from myocardial magnetic resonance (MR) in 10 subjects. Results The TBF and TBV of infarcted myocardium were significantly lower than those of non-infarcted areas (TBF, 51.96 +/- 19.42 vs 108.84 +/- 13.29 ml/100 g/min, p<0.01; TBV, 4.47 +/- 2.23 vs 9.79 +/- 2.58 ml/100 g, p<0.01). The MTT of infarcted areas did not differ from that of non-infarcted areas. The defect areas on TBV colour maps were significantly associated with peak creatine kinase level, QRS score and SPECT defect score. The ratio of TBF or TBV in the epicardial to endocardial side was significantly higher in infarct myocardium with good collateral circulation than in myocardium with poor/no collateral circulation (p<0.01 for both). The TBF measurements with CT- and MR-MPI were in good agreement by linear regression analysis (R=0.55, p<0.01). Conclusions This study demonstrated that MDCT perfusion imaging with deconvolution analysis could quantitatively detect myocardial perfusion abnormalities in patients with AMI and may provide the basis for the non-invasive and quantitative assessment of myocardial infarction.
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• Activation of c-Jun N-terminal kinase in non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection for hepatocellular carcinoma, Satoru Hagiwara, Masatoshi Kudo, Hobyung Chung, Kazuomi Ueshima, Tatsuo Inoue, Seiji Haji, Tomohiro Watanabe, Ah-Mee Park, Hiroshi Munakata, Toshiharu Sakurai, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 42(4), 394 - 400, Apr. 2012 , Refereed
  Summary:Aim: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. Methods: From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross- sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. Results: Multivariate analysis using a Logistic regression model showed that JNK activity in non- cancerous liver tissue was correlated with postoperative late recurrence. (P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33- 25.36). Conclusions: JNK activity in non- cancerous liver tissue is considered as a reliable predictive biomarker for postoperative recurrence in HCC.
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• Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis, Tomohiro Watanabe, Kouhei Yamashita, Saori Fujikawa, Toshiharu Sakurai, Masatoshi Kudo, Masahiro Shiokawa, Yuzo Kodama, Kazushige Uchida, Kazuichi Okazaki, Tsutomu Chiba, ARTHRITIS AND RHEUMATISM, ARTHRITIS AND RHEUMATISM, 64(3), 914 - 924, Mar. 2012 , Refereed
  Summary:Objective IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production. Methods. IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis. Results. Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands. Conclusion. The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease.
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• High Range Resolution Ultrasonographic Vascular Imaging Using Frequency Domain Interferometry With the Capon Method, Hirofumi Taki, Kousuke Taki, Takuya Sakamoto, Makoto Yamakawa, Tsuyoshi Shiina, Motoi Kudo, Toru Sato, IEEE TRANSACTIONS ON MEDICAL IMAGING, IEEE TRANSACTIONS ON MEDICAL IMAGING, 31(2), 417 - 429, Feb. 2012 , Refereed
  Summary:For high range resolution ultrasonographic vascular imaging, we apply frequency domain interferometry with the Capon method to a single frame of in-phase and quadrature (IQ) data acquired using a commercial ultrasonographic device with a 7.5 MHz linear array probe. In order to tailor the adaptive beamforming algorithm for ultrasonography we employ four techniques: frequency averaging, whitening, radio-frequency data oversampling, and the moving average. The proposed method had a range resolution of 0.05 mm in an ideal condition, and experimentally detected the boundary couple 0.17 mm apart, where the boundary couple was indistinguishable from a single boundary utilizing a B-mode image. Further, this algorithm could depict a swine femoral artery with a range beam width of 0.054 mm and an estimation error for the vessel wall thickness of 0.009 mm, whereas using a conventional method the range beam width and estimation error were 0.182 and 0.021 mm, respectively. The proposed method requires 7.7 s on a mobile PC with a single CPU for a 1 x 3 cm region of interest. These findings indicate the potential of the proposed method for the improvement of range resolution in ultrasonography without deterioration in temporal resolution, resulting in enhanced detection of vessel stenosis.
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• Japan's Successful Model of Nationwide Hepatocellular Carcinoma Surveillance Highlighting the Urgent Need for Global Surveillance, M. Kudo, LIVER CANCER, LIVER CANCER, 1(3-4), 141 - 143, 2012 , Refereed
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• Quantification of tumor vascularity with contrast-enhanced ultrasound for early response of transcatheter arterial chemoembolization for hepatocellular carcinoma: a report of three cases, Yasunori Minami, Naoya Okumura, Norio Yamamoto, Naoko Tsuji, Yuko Kono, Masatoshi Kudo, JOURNAL OF MEDICAL ULTRASONICS, JOURNAL OF MEDICAL ULTRASONICS, 39(1), 15 - 19, Jan. 2012 , Refereed
  Summary:Many contrast-enhanced ultrasound (CE-US) studies have been conducted by qualitative analysis of blood flow, such as classification of enhancement pattern. We evaluated early response of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) by quantitative analysis of intratumoral vascularity with CE-US in three patients. Three patients (one man, two women) with HCCs were treated in July 2009. CE-US with perfluorocarbon microbubbles (Sonazoid) and CT were performed serially before and 5 days after TACE. Post-processing enhancement intensity on US was analyzed to determine mean transit time (s), time to peak (s), enhancement peak intensity (dB), and "A" (scaling factor) by ultrasound quantification software after the data were fitted to a gamma variate curve. Mean transit time was prolonged by TACE in all three patients. Mean transit time rates on CE-US were 64.3, 33.8, and 65.6%, respectively, whereas the avascular rates on CT were 59.07, 31.71, and 62.25%, respectively. Mean transit time rates on CE-US approximated avascular rates on CT. Mean transit time rate may quantitatively indicate the early response of HCC to TACE.
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• Current Status of Hepatocellular Carcinoma Treatment in Japan Case Study and Discussion-Voting System, Masatoshi Kudo, Ryosuke Tateishi, Tatsuya Yamashita, Masafumi Ikeda, Junji Furuse, Kenji Ikeda, Norihiro Kokudo, Namiki Izumi, Osamu Matsui, CLINICAL DRUG INVESTIGATION, CLINICAL DRUG INVESTIGATION, 32, 37 - 51, 2012 , Refereed
  Summary:The Toward Integrated Treatment of Advanced Hepatocellular Carcinoma with Nexavar (TiTAN) Symposium was held in August 2010 in Tokyo, Japan, during which the position of sorafenib (Nexavar) in the treatment of HCC in Japan (for which it received approval in 2009) was discussed by a panel of eight expert hepatologists in a session chaired by Dr Kudo. The following article focuses on the discussion that went on during this session, including question and answer sessions regarding the experiences of the 350 conference attendees in treating patients with HCC, as well as some of the more challenging disease management issues. Since 2008, when the phase III Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial demonstrated an increase in the median overall survival (OS) for patients with unresectable HCC treated with sorafenib compared with placebo, international and Japanese guidelines recommend sorafenib as a first-line option for patients with advanced HCC Child-Pugh liver function class A who have extrahepatic metastasis. Sorafenib is also recommended for patients unresponsive to transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC). Importantly, if HCC is judged to be unresponsive to TACE, treatment should be switched to sorafenib in a timely manner. Almost half of the conference attendees said that they used both the Japan Society of Hepatology clinical practice guidelines and the clinical practice guidelines for HCC when determining treatment strategies for individual HCC patients. Sorafenib should currently not be used as adjuvant therapy or in combination with TACE or HAIC until evidence from ongoing clinical trials shows that it is beneficial in these settings.
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• Hepatic Nodules Associated with an Inferior Mesentric Arteriovenous Malformation, Ken Takahashi, Hiroshi Kashida, Masatoshi Kudo, INTERNAL MEDICINE, INTERNAL MEDICINE, 51(19), 2753 - 2755, 2012 , Refereed
  Summary:Splanchnic arteriovenous malformation (AVM) is a rare condition in which patients present with portal hypertension, which thus causes bleeding varices and ascites. However, to our knowledge, hepatic nodules associated with splanchnic AVM have not yet been described. We herein first report the case of a 78-year-old man with inferior mesenteric AVM presenting with portal hypertension and multiple hepatic nodules dominantly supplied by the portal vein. This unique case not only extends the spectrum of hepatic nodules resulting from abnormal hepatic circulation, but also provides clues for better understanding the etiology of hepatic nodules.
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• Viral Hepatitis and Hepatocellular Carcinoma: Update in 2012, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 30(6), 539 - 540, 2012 , Refereed
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• Hepatocellular Carcinoma with Obstructive Jaundice: Endoscopic and Percutaneous Biliary Drainage, Yasunori Minami, Masatoshi Kudo, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 30(6), 592 - 597, 2012 , Refereed
  Summary:Among patients with later stage hepatocellular carcinoma (HCC), only 1-12% manifest obstructive jaundice as the initial complaint. Endoscopic retrograde binary drainage (ERBD) and percutaneous transhepatic biliary drainage (PTBD) are the two main non-surgical treatment options for obstructive jaundice in patients with HCC. ERBD is usually the first-line treatment because of its low hemorrhage risk. Some have reported that the successful drainage rate ranges from 72 to 100%. Mean stent patency time and mean survival range from 1.0 to 15.9 and 2.8 to 12.3 months, respectively. PTBD is often an important second-line treatment when ERBD is impossible. With regard to materials, metallic stents offer the benefit of longer patency than plastic stents. The dominant effect of biliary drainage suggests that successful jaundice therapy could enhance anti-cancer treatment by increasing life expectancy, decreasing mortality, or both. We present an overview of the efficacy of endoscopic and percutaneous drainage for obstructive jaundice in patients with HCC who are not candidates for surgical resection and summarize the current indications and outcomes of reported clinical use. Copyright (C) 2012 S. Karger AG, Basel
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• IMPACT ON ABERRANT METHYLATION OF AN UNIQUE SUBSET OF TUMOR SUPPRESSOR GENES ON THE INITIAL STEPS OF HUMAN HEPATOCARCINOGENESIS, Naoshi Nishida, Masatoshi Kudo, Takeshi Nagasaka, Ajay Goel, HEPATOLOGY, HEPATOLOGY, 54, 462A - 462A, Oct. 2011 , Refereed
• P38alpha Inhibits Liver Fibrogenesis and Consequent Hepatocarcinogenesis by Curtailing Accumulation of Reactive Oxygen Species, Toshiharu Sakurai, Masatoshi Kudo, Kazuomi Ueshima, Shigenaga Matsui, Hiroshi Kashida, Michael Karin, GASTROENTEROLOGY, GASTROENTEROLOGY, 140(5), S927 - S927, May 2011 , Refereed
• The Usefulness of Helicobacter pylori Eradication Therapy for the Healing of Artificial Gastric Ulcer After Endoscopic Submucosal Dissection for Early Gastric Cancer, Masanori Kawasaki, Yutaka Asakuma, Shigenaga Matsui, Toshiharu Sakurai, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 140(5), S312 - S312, May 2011 , Refereed
• Prevention of Delayed Bleeding After Endoscopic Submucosal Dissection (ESD) for Gastric Tumors, Yutaka Asakuma, Shigenaga Matsui, Masanori Kawasaki, Toshiharu Sakurai, Hiroshi Kashida, Masatoshi Kudo, GASTROENTEROLOGY, GASTROENTEROLOGY, 140(5), S235 - S235, May 2011 , Refereed
• Antitumor Activity of BIBF 1120, a Triple Angiokinase Inhibitor, and Use of VEGFR2(+)pTyr(+) Peripheral Blood Leukocytes as a Pharmacodynamic Biomarker In Vivo, Kanae Kudo, Tokuzo Arao, Kaoru Tanaka, Tomoyuki Nagai, Kazuyuki Furuta, Kazuko Sakai, Hiroyasu Kaneda, Kazuko Matsumoto, Daisuke Tamura, Keiichi Aomatsu, Marco A. De Velasco, Yoshihiko Fujita, Nagahiro Saijo, Masatoshi Kudo, Kazuto Nishio, CLINICAL CANCER RESEARCH, CLINICAL CANCER RESEARCH, 17(6), 1373 - 1381, Mar. 2011 , Refereed
  Summary:Purpose: BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials. Experimental Design: We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120. Results: BIBF 1120 (0.01 mu mol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC50 values: 2-5 mu mol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker. Conclusions: We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo. Clin Cancer Res; 17(6); 1373-81. (C)2010 AACR.
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• Estimation of malignant potential of GI stromal tumors by contrast-enhanced harmonic EUS, Hiroki Sakamoto, Masayuki Kitano, Shigenaga Matsui, Ken Kamata, Takamitsu Komaki, Hajime Imai, Kensaku Dote, Masatoshi Kudo, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 73(2), 227 - 237, Feb. 2011 , Refereed
  Summary:Background: Contrast-enhanced harmonic EUS (CEH-EUS) is a new sonographic technique that uses US contrast agents and depicts intratumoral vessels in real time. Objective: To evaluate whether assessment of tumor vascularity by CEH-EUS can predict the preoperative malignancy risk of GI stromal tumors (GISTs). Design: Prospective study to observe GIST vascularity.. Setting: Kinki University School of Medicine. Patients: Between June 2007 and September 2009, 76 consecutive patients suspected of having subepithelial lesions underwent CEH-EUS. Intervention: CEH-EUS was performed by using a prototype echoendoscope in an extended pure harmonic detection mode. Main Outcome Measurements: Resected GIST specimens in 29 patients who underwent surgical resection were divided into high-grade (n = 16) and low-grade (n = 13) malignancy groups based on mitotic activity. The abilities of EUS-guided FNA and CEH-EUS to diagnose the malignant potential were compared. The sensitivities with which contrast-enhanced multidetector CT, power-Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs also were compared. Results: CEH-EUS identified irregular vessels and thereby predicted GIST malignancies with a sensitivity, specificity, and accuracy of 100%, 63%, and 83%, respectively. Diagnosis of high-grade malignancy GISTs by EUS-guided FNA had a sensitivity, specificity, and accuracy of 63%, 92%, and 81%, respectively. Contrast-enhanced multidetector CT, power-Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs with sensitivities of 31%, 63%, and 100%, respectively (P < .05). Limitations: A single center was involved in this study. Conclusions: CEH-EUS successfully visualized intratumoral vessels and may play an important role in predicting the malignancy risk of GISTs. (Gastrointest Endosc 2011;73:227-37.)
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• Double-Contrast Ultrasound: A Novel Surveillance Tool for Hepatocellular Carcinoma, Masatoshi Kudo, Kinuyo Hatanaka, Takashi Kumada, Hidenori Toyoda, Toshifumi Tada, AMERICAN JOURNAL OF GASTROENTEROLOGY, AMERICAN JOURNAL OF GASTROENTEROLOGY, 106(2), 368 - 370, Feb. 2011 , Refereed
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• Management of hepatitis B: Consensus of the Japan Society of Hepatology 2009, Osamu Yokosuka, Masayuki Kurosaki, Fumio Imazeki, Yasuji Arase, Yasuhito Tanaka, Kazuaki Chayama, Eiji Tanaka, Hiromitsu Kumada, Namiki Izumi, Masashi Mizokami, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 41(1), 1 - 21, Jan. 2011 , Refereed
  Summary:Recently, much progress has been made in the field of hepatitis B, such as natural history of the disease in relation to the amount of hepatitis B virus (HBV) DNA, genotypes of HBV influencing the natural course and treatment effects, mutations of HBV influencing the severity of the disease and development of hepatocellular carcinoma, and antiviral treatment such as nucleos(t)ide analogues and pegylated interferon. To make the consensus for the diagnosis, management and treatment of hepatitis B, a meeting was held during 45th annual meeting of Japan Society of Hepatology (JSH) in June 2009. In the meeting, recommendations and informative statements were discussed on the following subjects: (i) natural history of HBV infection; (ii) clinical implication of HBV genotypes; (iii) HBV mutations and their potential impact on pathogenesis of HBV infection; (iv) indications for antiviral treatment of chronic hepatitis B; (v) nucleos(t)ide analogues for chronic hepatitis B; and (vi) interferon therapy for chronic hepatitis B. The presenters reviewed the data on these subjects and proposed the consensus statements and recommendations. These statements were discussed among the organizers and presenters, and were approved by the participants of the meeting. In the current report, the relevant data were reviewed and the 12 consensus statements and nine recommendations on chronic hepatitis B were described.
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• Endoscopic Ultrasonography and Contrast-Enhanced Endoscopic Ultrasonography, Masayuki Kitano, Masatoshi Kudo, Hiroki Sakamoto, Takamitsu Komaki, PANCREATOLOGY, PANCREATOLOGY, 11, 28 - 33, 2011 , Refereed
  Summary:Endoscopic ultrasonography (EUS) is superior to all other imaging modalities in detecting small pancreatic cancers. However, its ability to characterize hypoechoic pancreatic masses is limited: most carcinomas, neuroendocrine tumors, and inflammatory pseudotumors are simply depicted as hypoechoic masses. Contrast enhancement helps EUS to characterize such hypoechoic masses. Intravenous ultrasound (US) agents increase the signal from the blood and, thus, act as amplifiers and improve visualization of blood flow in small vessels using Doppler US. Contrast-enhanced Doppler EUS can differentiate small pancreatic carcinomas that cannot be detected by other imaging modalities. The development of second-generation US contrast agents and an EUS system with a broad-band transducer enabled the visualization of microvessels and the parenchymal perfusion in the pancreas. This contrast-enhanced harmonic EUS has shown that most pancreatic cancers exhibit hypovascular heterogeneous enhancement with irregular network-like microvessels. Moreover, it can diagnose pancreatic cancers with a high sensitivity (89-92%). Copyright (C) 2011 S. Karger AG, Basel and IAP
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• Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event-Free Survival in Patients with Liver Cirrhosis, Sosuke Hayaishi, Hobyung Chung, Masatoshi Kudo, Emi Ishikawa, Masahiro Takita, Taisuke Ueda, Satoshi Kitai, Tatsuo Inoue, Norihisa Yada, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 29(3), 326 - 332, 2011 , Refereed
  Summary:Background: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. Methods: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for 6 6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. Results: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216-0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336-1.017, p = 0.0575). Conclusions: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis. Copyright (C) 2011 S. Karger AG, Basel
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• Management of Hepatocellular Carcinoma in Japan: Consensus-Based Clinical Practice Guidelines Proposed by the Japan Society of Hepatology (JSH) 2010 Updated Version, Masatoshi Kudo, Namiki Izumi, Norihiro Kokudo, Osamu Matsui, Michiie Sakamoto, Osamu Nakashima, Masamichi Kojiro, Masatoshi Makuuchi, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 29(3), 339 - 364, 2011 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but also worldwide. Clinical practice guidelines for HCC were first published in 2001 by the European Society of Study of the Liver (EASL) followed by the American Association for the Study of Liver Disease (AASLD) published in 2005 and updated in 2010. However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labour and Welfare, evidence-based clinical practice guidelines for HCC were compiled in Japan. In 2009, a revised version of evidence-based guidelines was published. Based on both 'evidence-based' guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007 and updated in 2010. In this article, the 2010 updated version of this manual, especially issues on prevention, surveillance, pathology, diagnosis, staging, and treatment algorithm are summarized. Copyright (C) 2011 S. Karger AG, Basel
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• Adjuvant Therapy after Curative Treatment for Hepatocellular Carcinoma, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 81, 50 - 55, 2011 , Refereed
  Summary:It is widely accepted that hepatocellular carcinoma (HCC) has an annual recurrence rate of approximately 15-20% even after potentially curative treatment, with the 5-year recurrence rate reaching 80-90%. This recurrence rate is also known to be similar after various curative treatments including resection, percutaneous ethanol injection therapy, and radiofrequency ablation. Generally, in treating patients with HCC associated with hepatitis C or liver cirrhosis, aggressive efforts to prevent secondary carcinogenesis are necessary rather than simply observing the clinical course after treatment. Presently, a combination of peg-interferon and ribavirin is known to be highly effective in patients with difficult-to-treat hepatitis C with a high viral load and genotype I virus. Therefore, indications of these treatments must be considered to prevent secondary carcinogenesis in patients with hepatitis C. Recently, long-term follow-up of low-dose, long-term maintenance therapy using pegylated interferon-alpha 2a for cirrhotic patients clearly showed a preventive effect on HCC occurrence and recurrence. Preventing secondary carcinogenesis by suppressing inflammation employing the same treatment as that against primary carcinogenesis is also important. The molecular targeted agent sorafenib markedly suppresses the serine/threonine kinases of Raf in the MAP kinase cascade and inhibits the tyrosine kinases of angiogenesis factor receptors such as vascular endothelial growth factor and platelet-derived growth factor receptors. It thus simultaneously prevents the proliferation of tumors and inhibits angiogenesis. A clinical trial to examine the recurrence-preventing effect of sorafenib by administration of it after curative treatment such as resection or ablation is in progress (STORM trial: http://clinicaltrials.gov.com, NCT00692770). Treatments to prevent recurrence (including intrahepatic metastasis and multicentric carcinogenesis) as well as early detection and early curative treatment are extremely important to improve the prognosis of patients with HCC. Thus, further research on this issue should be carried out, especially in relation to molecular targeted therapy. Copyright (C) 2011 S. Karger AG, Basel
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• Diagnostic Imaging of Hepatocellular Carcinoma: Recent Progress, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 81, 73 - 85, 2011 , Refereed
  Summary:The diagnostic imaging of hepatocellular carcinoma (HCC) has recently undergone marked progress. The advent of the ultrasound (US) contrast agent Sonazoid, approved in January 2007, and magnetic resonance imaging (MRI) with the liver-specific MRI contrast agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA-MRI), approved in January 2008, are of particular significance. Sonazoid contrast-enhanced US (Sonazoid-CEUS) is useful not only for the diagnosis of HCC, but also for guiding treatment and assessing treatment response. Sonazoid-CEUS has proven to be particularly effective for screening and staging, which used to be considered impossible with CEUS, through the introduction of the newly developed diagnostic technique of defect reperfusion imaging. It is still not possible if other vascular agents such as SonoVue and Definity are used. In particular, Gd-EOB-DTPA-MRI has been suggested to be much more reliable in the differentiation of early HCC from precancerous dysplastic nodules than any other modalities such as multidetector raw computed tomography, dynamic MRI, and superparamagnetic iron oxide-MRI. A decrease in contrast uptake in the hepatocyte phase observed on EOB-MRI is strongly suggestive of cancer, and the absence of early staining in the arterial phase suggests early HCC. The differential diagnostic capacity of Gd-EOB-DTPA-MRI is considered to far exceed that of what were previously the most useful imaging techniques, computed tomography (CT) during hepatic arteriography or CT during arterial portography, and to be comparable to that of the pathological diagnosis by pathologists specialized in liver. Copyright (C) 2011 S. Karger AG, Basel
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• Endoscopic ultrasound (EUS)-guided transluminal endoscopic removal of gallstones, K. Kamata, M. Kitano, M. Kudo, H. Imai, H. Sakamoto, T. Komaki, ENDOSCOPY, ENDOSCOPY, 42, E331 - E332, Dec. 2010 , Refereed
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• Relationship between urinary sodium excretion and pioglitazone-induced edema, Akinobu Nakamura, Takeshi Osonoi, Yasuo Terauchi, JOURNAL OF DIABETES INVESTIGATION, JOURNAL OF DIABETES INVESTIGATION, 1(5), 208 - 211, Oct. 2010 , Refereed
  Summary:To investigate the factors contributing to pioglitazone-induced edema, we analyzed sodium excretion and several clinical parameters before and after administration of pioglitazone. We analyzed these parameters before and after 8 weeks of administration of pioglitazone to female subjects with type 2 diabetes. When we evaluated whether a significant correlation was found between salt excretion and blood pressure, six patients showed such correlation and 20 patients did not. After 8 weeks of pioglitazone administration, five patients had developed edema, and, surprisingly, such correlation was not found in all five subjects. Salt excretion after administration of pioglitazone was significantly lower in subjects who developed edema and those who showed the correlation, and the hematocrit was significantly lower after administration in the subjects who showed the correlation, but not in the edema group. Pioglitazone-induced edema would be caused not only by fluid retention, but also by other factors, such as vascular permeability. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00046.x, 2010)
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• Liver Cancer Working Group Report, Masatoshi Kudo, Kwang Hyub Han, Norihiro Kokudo, Ann-Lii Cheng, Byung Ihn Choi, Junji Furuse, Namiki Izumi, Joong-Won Park, Ronnie T. Poon, Michiie Sakamoto, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 40, i19 - i27, Sep. 2010 , Refereed
  Summary:Hepatocellular carcinoma is a highly prevalent disease in many Asian countries, accounting for 75-80% of victims worldwide. The incidence of hepatocellular carcinoma varies enormously across Asia, but tends to follow the incidences of hepatitis B infection and liver cirrhosis. The incidence and etiology of hepatocellular carcinoma in Japan are different from the rest of Asia, but similar to that in Western countries because hepatitis C infection is the main etiological factor in Japan. Hepatitis B virus vaccination programs are showing great success in reducing hepatitis B virus-related hepatocellular carcinoma. Screening program improves detection of early hepatocellular carcinoma and has some positive impact on survival, but the majority of hepatocellular carcinoma patients in Asia still present with advanced hepatocellular carcinoma. Long-term outcomes following treatment of even early/intermediate or advanced disease are often unsatisfactory because of a lack of effective adjuvant and systemic therapies. Various clinical practice guidelines for hepatocellular carcinoma have been established and are in use. Clinical diagnosis of hepatocellular carcinoma by imaging diagnosis is replacing diagnosis of hepatocellular carcinoma by pathological confirmation. New imaging and treatment techniques are continuously being developed and guidelines should be updated every 3 or 4 years, incorporating new evidence. New molecularly targeted therapies hold great promise. Sorafenib is the first systemic therapy to demonstrate prolonged survival vs. the placebo in patients with advanced hepatocellular carcinoma. Various other new molecularly targeted agents are currently under investigation.
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• Hepatitis C Virus Core Protein Induces Homotolerance and Cross-Tolerance to Toll-Like Receptor Ligands by Activation of Toll-Like Receptor 2, Hobyung Chung, Tomohiro Watanabe, Masatoshi Kudo, Tsutomu Chiba, JOURNAL OF INFECTIOUS DISEASES, JOURNAL OF INFECTIOUS DISEASES, 202(6), 853 - 861, Sep. 2010 , Refereed
  Summary:Background. Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. Methods. Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. Results. TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-kappa B activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infected patients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infected patients results in impaired production of interleukin 17 by naive CD4(+) T cells in the presence of TLR ligands. Conclusions. Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.
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• Response Evaluation Criteria in Cancer of the Liver (RECICL) proposed by the Liver Cancer Study Group of Japan (2009 Revised Version), Masatoshi Kudo, Shouji Kubo, Kenichi Takayasu, Michiie Sakamoto, Masatoshi Tanaka, Iwao Ikai, Junji Furuse, Kenji Nakamura, Masatoshi Makuuchi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 40(7), 686 - 692, Jul. 2010 , Refereed
  Summary:The World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST) are inappropriate to assess the direct effects of treatment on the hepatocellular carcinoma (HCC) by locoreginal therapies such as radio-frequency ablation (RFA) and transcatheter arterial chemo-embolization (TACE). Therefore, establishment of response evaluation criteria solely devoted for HCC is needed urgently in the clinical practice as well as in the clinical trials of HCC treatment, such as molecular targeted therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2009 by Liver Cancer Study Group of Japan based on the 2004 version of RECICL, which was commonly used in Japan. Major revised points of the RECICL 2009 is to provide TE4a (Complete response with enough ablative margin) and TE4b (complete response without enough ablative margin) for local ablation therapy. Second revised point is that setting the timing at which the overall treatment effects are assessed. Third point is that emergence of new lesion in the liver is regarded as progressive disease, different from 2004 version. Finally, 3 tumor markers including alpha-fetoprotein (AFP) and AFP-L3 and des-gamma-carboxy protein (DCP) were also added for the overall treatment response. We hope this new treatment response criteria, RECICL, proposed by Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of the daily clinical practice and clinical trials as well not only in Japan, but also internationally.
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• Overall Survival After Transarterial Lipiodol Infusion Chemotherapy With or Without Embolization for Unresectable Hepatocellular Carcinoma: Propensity Score Analysis, Kenichi Takayasu, Shigeki Arii, Iwao Ikai, Masatoshi Kudo, Yutaka Matsuyama, Masamichi Kojiro, Masatoshi Makuuchi, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 194(3), 830 - 837, Mar. 2010 , Refereed
  Summary:OBJECTIVE. Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival. SUBJECTS AND METHODS. A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups. RESULTS. During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%. CONCLUSION. Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients.
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• Identification and characterization of IgG4-associated autoimmune hepatitis, Hobyung Chung, Tomohiro Watanabe, Masatoshi Kudo, Osamu Maenishi, Yoshio Wakatsuki, Tsutomu Chiba, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 30(2), 222 - 231, Feb. 2010 , Refereed
  Summary:Background Autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) share clinical and pathological features such as high serum levels of immunoglobulin (Ig) G and autoantibodies, and lymphoplasmacytic infiltration, suggesting the presence of common immunological abnormalities. However, little is known about the possible involvement of IgG4, a hallmark of AIP, in AIH. Aims In this study, we examined whether the IgG4 response contributes to the histopathological and clinical findings in AIH. Methods Liver sections from 26 patients with AIH, 10 patients with primary biliary cirrhosis (PBC), three patients with primary sclerosing cholangitis (PSC) and 20 chronic hepatitis patients with hepatitis C virus (HCV) infection were immunostained for IgG4. We investigated the relationship among the histopathology, the responses to steroid therapy and the IgG4 staining. Results Nine of the 26 liver specimens from patients with AIH showed positive staining for IgG4 whereas none of the 10 samples from patients with PBC, the three samples from patients with PSC or the 20 samples from patients with HCV hepatitis were positive. Patients with IgG4-positive AIH also showed increased serum levels of IgG. The numbers of T cells, B cells and plasma cells were significantly increased in the livers of patients with IgG4-positive AIH as compared with those patients with IgG4-negative AIH. Patients with IgG4-positive AIH also showed a marked response to prednisolone therapy. Conclusions AIH may be classified into either an IgG4-associated type or an IgG4 non-associated type with the former showing a marked response to prednisolone treatment.
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• Usefulness of the Post-Vascular Phase of Contrast-Enhanced Ultrasonography with Sonazoid in the Evaluation of Gross Types of Hepatocellular Carcinoma, Kinuyo Hatanaka, Hobyung Chung, Masatoshi Kudo, Seiji Haji, Yasunori Minami, Kiyoshi Maekawa, Sousuke Hayaishi, Tomoyuki Nagai, Masahiro Takita, Kanae Kudo, Taisuke Ueda, Chie Tatsumi, Satoshi Kitai, Emi Ishikawa, Norihisa Yada, Tatsuo Inoue, Satoru Hagiwara, Kazuomi Ueshima, ONCOLOGY, ONCOLOGY, 78, 53 - 59, 2010 , Refereed
  Summary:Objective: The purpose of this study was to assess the usefulness of post-vascular phase (PVP) images of contrast-enhanced ultrasonography (CE-US) in the evaluation of the gross types of hepatocellular carcinoma (HCC) that is closely related to the malignant potential of the tumor. Methods: A total of 29 patients with 40 HCCs of <5 cm in diameter, who underwent hepatic resection, were enrolled. The gross type of the tumor was evaluated using real-time scanning during the PVP of CE-US with Sonazoid prior to surgery. The tumors were classified into three types based on the macroscopic classification of the Liver Cancer Study Group of Japan: single nodular (SN) type, single nodular with extranodular growth (SNEG) type, and confluent multinodular (CMN) type. The ability of CE-US to correctly depict the gross type of HCC was evaluated. Results: 26 tumors were macroscopically diagnosed as the SN type, 11 tumors as the SNEG type, and 3 tumors as the CMN type. The sensitivity, specificity and accuracy of CE-US were 96, 80 and 90%, respectively. Conclusion: The PVP image of CE-US with Sonazoid is a useful tool in the evaluation of the gross type of HCC and is considered essential in deciding treatment strategy. Copyright (C) 2010 S. Karger AG, Basel
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• Changing Trends in Hepatitis C Infection over the Past 50 Years in Japan, Hobyung Chung, Taisuke Ueda, Masatoshi Kudo, INTERVIROLOGY, INTERVIROLOGY, 53(1), 39 - 43, 2010 , Refereed
  Summary:In Japan, hepatocellular carcinoma (HCC) is the fourth leading cause of death in males and the fifth in females. Hepatitis C virus (HCV) is a major cause of HCC in Japan, with 70% of cases being HCV related. HCV genotype 1b, the most prevalent subtype in Japan, started to spread in the 1930s among injecting drug users (IDUs) during and after World War II or through medical procedures such as blood transfusion and use of contaminated syringes. The prevalence of HCV infection is much lower in the current younger generation compared with that in the older generation, particularly those aged 1 55 years (0.1-0.2% vs. >= 2%). Therefore, the total number of patients with HCV infection is estimated to decrease, even though sporadic HCV transmission is mainly seen among young IDUs. Of note, HCV genotype 2 seems to be spreading among IDUs, but the response to antiviral therapy in these patients seems to be better than that in older patients, irrespective of the genotype. Although the number of patients who die because of HCC has steadily increased over the last 50 years, the incidence of HCC is now decreasing, mainly because of the decreased prevalence of HCV-related HCC. Copyright (C) 2010 S. Karger AG, Basel
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• Double-Filtration Plasmapheresis plus IFN for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy: Early Viral Dynamics, Soo Ryang Kim, Susumu Imoto, Masatoshi Kudo, Keiji Mita, Miyuki Taniguchi, Ke Ih Kim, Noriko Sasase, Ikuo Shoji, Motoko Nagano-Fujii, Ahmed El-Shamy, Hak Hotta, Tomoyuki Nagai, Yoshiaki Nagata, Yoshitake Hayashi, INTERVIROLOGY, INTERVIROLOGY, 53(1), 44 - 48, 2010 , Refereed
  Summary:Double-filtration plasmapheresis (DFPP) was approved in Japan in April 2008 for the retreatment of chronic hepatitis C patients with genotype 1b and high viral loads, whose hepatitis C virus was not eradicated by earlier IFN therapy or by pegylated IFN plus ribavirin (PEG-IFN/RBV) combination therapy. In this study, we assessed the early viral dynamics of 9 patients with non-sustained virological response to the combination therapy. The overall viral dynamics of DFPP plus IFN treatment with or without RBV for 4 weeks showed a reduction of 6 1 log in the viral load in 22% (2 of 9 patients), 55.6% (5/9), 77.8% (7/9) and 77.8% (7/9) at 24 h, 1, 2 and 4 weeks after the start of treatment. By contrast, DFPP plus consecutive intravenous IFN-beta for 4 weeks reduced the viral load by >= 1 log in 33% (2/6), 50% (3/6), 83.3% (5/6) and 83.3% (5/6) at 24 h, 1, 2 and 4 weeks. The viral load declined by >= 2 log in 50% (3/6) at 4 weeks after the start of treatment. DFPP plus consecutive intravenous IFN-beta for 4 weeks is a promising treatment for non-sustained virolgical response patients. Copyright (C) 2010 S. Karger AG, Basel
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• Outcome and Early Viral Dynamics with Viral Mutation in PEG-IFN/RBV Therapy for Chronic Hepatitis in Patients with High Viral Loads of Serum HCV RNA Genotype 1b, Noriko Sasase, Soo Ryang Kim, Masatoshi Kudo, Ke Ih Kim, Miyuki Taniguchi, Susumu Imoto, Keiji Mita, Yoshitake Hayashi, Ikuo Shoji, Ahmed El-Shamy, Hak Hotta, INTERVIROLOGY, INTERVIROLOGY, 53(1), 49 - 54, 2010 , Refereed
  Summary:We investigated whether sustained virological response (SVR) and non-SVR by chronic hepatitis C patients to pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy are distinguishable by viral factors such as the IFN/RBV resistance-determining region (IRRDR) and by on-treatment factors through new indices such as the rebound index (RI). The first RI (RI-1st; the viral load at week 1 divided by the viral load at 24 h) and the second RI (RI-2nd; the viral load at week 2 divided by the viral load at 24 h) were calculated. The subject patients were divided into 3 groups based on RI-1st and RI-2nd: an RI-A group (RI-1st <= 1.0), an RI-B group (RI-1st > 1.0 and RI-2nd <0.7) and an RI-C group (RI-1st > 1.0 and RI-2nd >= 0.7). The SVR rate was 71.4% (10/14) in the RI-A group, 46.2% (6/13) in the RI-B group and 20.0% (3/15) in the RI-C group (p = 0.005 between the RI-A group and the RI-C group). In IRRDR >= 6 and IRRDR <= 5 the SVR rate was 81.3% (13/16) and 23.1% (6/26) (p = 0.0002), respectively. By combining RI and IRRDR as a predicting factor, the SVR rate was 87.5% (7/8) in the RI-A group (>= 6 mutations in the IRRDR) and 7.7% (1/13) in the RI-C group (<= 5 IRRDR mutations) (p = 0.0003). Copyright (C) 2010 S. Karger AG, Basel
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• PEG-IFN alpha/RBV Combination Therapy for Chronic Hepatitis C Patients Increases Serum Ferritin Level while It Improves Sustained Viral Response Rate, Norihisa Yada, Masatoshi Kudo, Hobyung Chung, Sosuke Hayaishi, Masahiro Takita, Taisuke Ueda, Chie Tatsumi, Kinuyo Hatanaka, Satoshi Kitai, Emi Ishikawa, Tatsuo Inoue, Satoru Hagiwara, Kazuomi Ueshima, INTERVIROLOGY, INTERVIROLOGY, 53(1), 60 - 65, 2010 , Refereed
  Summary:Objectives: We investigated the significance of serum ferritin levels in pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C (CHC) and examined its correlation with serum alanine aminotransferase (ALT) levels during therapy and response to the therapy. Methods: A total of 175 patients with CHC received the combination therapy. Correlations between serum ferritin levels and serum ALT levels at 12 and 24 weeks of therapy were examined. Differences in serum ferritin levels during therapy between patients with sustained viral response (SVR) and non-SVR were also examined. Results: Only 24 (13.7%) and 20 (11.4%) patients showed elevated serum ALT levels (6 70 IU/l) at 12 and 24 weeks of therapy, respectively. There was no correlation between serum ferritin levels and ALT levels. Ninety-five (54.3%) of 175 patients achieved SVR. Serum ferritin levels increased dramatically in both SVR and non-SVR groups after starting the therapy and were significantly higher in the SVR group throughout the therapy. Conclusions: Serum ferritin level increases during PEG-IFN and RBV combination therapy; however, it did not correlate with either serum ALT level or the total dose of RBV. Higher serum ferritin levels during combination therapy appear to be associated with favorable therapeutic response. Copyright (C) 2010 S. Karger AG, Basel
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• Radiofrequency Ablation for Hepatocellular Carcinoma: Assistant Techniques for Difficult Cases, Tatsuo Inoue, Yasunori Minami, Hobyung Chung, Sousuke Hayaishi, Taisuke Ueda, Chie Tatsumi, Masahiro Takita, Satoshi Kitai, Kinuyo Hatanaka, Emi Ishikawa, Norihisa Yada, Satoru Hagiwara, Kazuomi Ueshima, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 78, 94 - 101, 2010 , Refereed
  Summary:Purpose: To confirm the safety and effectiveness of techniques to assist radiofrequency ablation (RFA) for difficult cases, we retrospectively evaluated successful treatment rates, early complications and local tumor progressions. Patients and Methods: Between June 1999 and April 2009, a total of 341 patients with 535 nodules were treated as difficult cases. Artificial pleural effusion assisted ablation was performed on 64 patients with 82 nodules. Artificial ascites-assisted ablation was performed on 11 patients with 13 nodules. Cooling by endoscopic nasobiliary drainage (ENBD) tube-assisted ablation was performed on 6 patients with 8 nodules. When the tumors were not well visualized with conventional B-mode ultrasonography (US), contrast-enhanced US-assisted ablation with Levovist (R) or Sonazoid (R) or virtual CT sonography-assisted ablation was performed. Contrast-enhanced US-assisted ablation was performed on 139 patients with 224 nodules and virtual CT sonography-assisted ablation was performed on 121 patients with 209 nodules. Results: In total, complete ablation was achieved in 514 of 535 (96%) nodules in difficult cases. For RFA with artificial pleural effusion, artificial ascites and ENBD, complete response was confirmed in all cases. For contrast-enhanced US-and CT sonography-assisted ablation, complete response was 95%. Early complications were recognized in 24 cases (4.5%). All cases recovered with no invasive treatment. Local tumor recurrence was investigated in 377 nodules of 245 patients, and 69 (18%) nodules were positive. Tumor recurrences in each assisted technique were 14.7% in artificial pleural effusion cases, 7% in artificial ascites, 12.5% in ENBD tube cases, 31% in virtual CT sonography, and 8.5% in contrast-enhanced US. Conclusion: Although local tumor progression needs to be carefully monitored, assisted techniques of RFA for difficult cases are well tolerated and expand the indications of RFA. Copyright (C) 2010 S. Karger AG, Basel
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• Positioning of a Molecular-Targeted Agent, Sorafenib, in the Treatment Algorithm for Hepatocellular Carcinoma and Implication of Many Complete Remission Cases in Japan, Masatoshi Kudo, Kazuomi Ueshima, ONCOLOGY, ONCOLOGY, 78, 154 - 166, 2010 , Refereed
  Summary:Sorafenib, a molecular-targeted agent that inhibits tumor cell proliferation and angiogenesis by inhibiting RAF serine-threonine kinase and VEGF, PDGF, Flt-3, c-Kit receptor tyrosine kinase, was approved in Europe and North America in 2007 and in Japan on May 20, 2009. In the 10 months since its approval, sorafenib has been prescribed for more than 3,700 patients with advanced hepatocellular carcinoma (HCC), and its efficacy has been confirmed in many cases. According to the consensus statements of the Japan Society of Hepatology in 2010, sorafenib is recommended for advanced HCC with extrahepatic spread or major vascular invasion such as invasion of the 1st branch of the portal vein or the main portal branch of the portal vein in patients with Child-Pugh A liver function. In addition to that, transcatheter arterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) refractory HCC patients with Child-Pugh A liver function are also candidates of sorafenib monotherapy as a second-line treatment option. To date, 15 cases with complete remission (CR) to sorafenib in metastatic advanced HCC patients have been reported in Japan, an event that is rarely reported in other countries. Of the 90 cases treated by ourselves, 2 achieved CR. Factors indicating systemic cancer spread, including multiple liver lesions, lymph node metastases, adrenal metastases, lung metastases and vascular invasion, were completely absent in both cases of CR by 2 and 1 year, respectively. Similarly, three tumor markers (AFP, PIVKA-II, and AFP-L3) completely returned to normal values. Although cases of CR are rare, it seems that there might be racial differences in terms of gene mutations. Clinical trials for other molecular-targeted agents, including sunitinib, brivanib, or linifanib, are ongoing and their outcomes are eagerly awaited. According to a subanalysis of the SHARP study, it is expected that sorafenib in combination with resection, ablation, TACE or HAIC will markedly prolong the overall survival in early-, intermediate- and advanced-stage HCCs. Copyright (C) 2010 S. Karger AG, Basel
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• Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: A randomized phase III trial, Takuji Okusaka, Hiroshi Kasugai, Yasukazu Shioyama, Katsuaki Tanaka, Masatoshi Kudo, Hiromitsu Saisho, Yukio Osaki, Michio Sata, Shigetoshi Fujiyama, Takashi Kumada, Keiko Sato, Seiichiro Yamamoto, Shiro Hinotsu, Tosiya Sato, JOURNAL OF HEPATOLOGY, JOURNAL OF HEPATOLOGY, 51(6), 1030 - 1036, Dec. 2009 , Refereed
  Summary:Background/Aims: Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. Methods: Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. Results: Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646 days in the TACE group and 679 days in the TAI group (p = 0.383). Conclusions: The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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• Small invasive ductal carcinoma of the pancreas distinct from branch duct intraductal papillary mucinous neoplasm, Hiroki Sakamoto, Masayuki Kitano, Takamitsu Komaki, Hajime Imai, Ken Kamata, Masatomo Kimura, Yoshifumi Takeyama, Masatoshi Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 15(43), 5489 - 5492, Nov. 2009 , Refereed
  Summary:Endoscopic ultrasonography (EUS) is a highly sensitive diagnostic method for the detection of small pancreatic carcinomas. Recently, there have been some reports describing the utility of contrast-enhanced harmonic EUS (CEH-EUS) which uses sonographic contrast agent for differentiation of a pancreatic mass. This report describes a case of small adenocarcinoma of the pancreas distinct from branch duct intraductal papillary mucinous neoplasm (IPMN) in which investigation by EUS took place every 6 mo and diagnosis was made accurately by additional CEH-EUS during the follow-up of the branch duct IPMN. A 68-year-old female was admitted to our hospital because of a branch duct IPMN in the pancreatic body. She had been followed-up by EUS every 6 mo. However, after 2 years EUS demonstrated a low echoic area distinct from the branch duct IPMN which was; vaguely discernible by EUS, and accurate sizing and differential diagnosis were considered difficult on the EUS imaging. CH-EUS with Sonazoid revealed a hypovascular tumor and we suspected small pancreatic carcinoma. The histopathological diagnosis was adenocarcinoma (10 mm) in the pancreatic tail, distinct from the branch duct IPMN of the pancreatic body. EUS and CEH-EUS may play an important role in the correct diagnosis of small pancreatic tumors, including synchronous and metachronous occurrence of IPMN and ductal adenocarcinoma of the pancreas. (C) 2009 The WJG Press and Baishideng. All rights reserved.
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• Antitumor activity of a novel angiogenesis inhibitor BIBF1120 for hepatocellular carcinoma and a new pharamacodynamic biomarker in blood samples., Kanae Kudo, Tokuzo Arao, Kaoru Tanaka, Hiroyasu Kaneda, Mari Maegawa, Kazuko Matsumoto, Daisuke Tamura, Keiichi Aomatsu, Yoshihiko Fujita, Masatoshi Kudo, Kazuto Nishio, CANCER RESEARCH, CANCER RESEARCH, 69, May 2009 , Refereed
• Value of Liver Parenchymal Phase Contrast-Enhanced Sonography to Diagnose Premalignant and Borderline Lesions and Overt Hepatocellular Carcinoma, Tatsuo Inoue, Masatoshi Kudo, Osamu Maenishi, Mina Komuta, Osamu Nakashima, Masamichi Kojiro, Kiyoshi Maekawa, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 192(3), 698 - 705, Mar. 2009 , Refereed
  Summary:OBJECTIVE. The objective of our study was to investigate whether liver parenchymal phase contrast-enhanced sonography can provide additional information for assessing histologic grades of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS. Contrast-enhanced sonography using Levovist of 50 hepatic nodules was performed. The vascular and liver parenchymal perfusion patterns were evaluated. The sensitivity, specificity, and accuracy of the histologic diagnosis of the tumors using vascular phase imaging only and systematically combined vascular phase imaging with liver parenchymal phase imaging were calculated. We also performed histologic examination and immunostaining for the detection of Kupffer cells and calculated the Kupffer cell count in the tumorous tissue relative to that in the nontumorous tissue (Kupffer cell ratio) and quantitatively evaluated the relationship between the Kupffer cell ratio and the perfusion patterns seen on liver parenchymal phase imaging. RESULTS. The specificity and accuracy of contrast-enhanced sonography in the diagnosis of dysplastic nodules and of moderately and poorly differentiated HCCs were improved by adding liver parenchymal phase imaging (dysplastic nodules, 74% and 78% vs 83% and 86%, respectively; moderately and poorly differentiated HCCs, 74% and 86% vs 85% and 92%). The diagnostic accuracy of contrast-enhanced sonography for dysplastic nodules showed a trend of improvement with the addition of liver parenchymal phase imaging (p = 0.07). Kupffer cell ratios for tumors that showed hypoperfusion during the liver parenchymal phase were significantly lower than those for tumors showing isoperfusion (p < 0.05). CONCLUSION. Adding liver parenchymal phase imaging to contrast-enhanced sonography protocols may yield additional information that can be used to assess histologic grades of tumor and that leads to an improvement in the differential diagnosis of nodular lesions associated with the cirrhotic liver. Further case studies are required in larger numbers of patients for a longer follow-up period.
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• Evaluation of Therapeutic Response to Gemcitabine in Pancreatic Cancer, Yoichiro Suetomi, Masayuki Kitano, Masatoshi Kudo, Hiroki Sakamoto, Kiyoshi Maekawa, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 55(86-87), 1785 - 1788, Sep. 2008 , Refereed
  Summary:Background/Aims: Due to the development of contrast-enhanced harmonic imaging, ultrasound can reveal more precise hemodynamic information than conventional angiography. In this study, the value of contrast-enhanced harmonic imaging was studied in the evaluation of response in treatment of pancreatic cancer. Methodology: Thirteen pancreatic cancer patients treated with gemcitabine were enrolled in this study. Contrast-enhanced harmonic ultrasonography was performed to evaluate the treatment response during every period of treatment. After intravenously injecting the contrast agent, pancreatic tumors were observed in a real-time and subsequently in an intermittent fashion. Findings obtained by contrast-enhanced harmonic imaging were compared with dynamic CT findings and serum tumor marker levels. Results: Tumor markers were reduced by at least 50% in 6 patients. We could not evaluate tumor size reduction rates on the B-mode US because the tumor margin was unclear. On the other hand, the hypovascular area was clearly depicted on the perfusion image of contrast-enhanced harmonic imaging in all patients throughout the observation period, and changes in tumor size could be easily evaluated. The tumor size reduction rates in these 6 cases were 13.1 +/- 5.5% by dynamic CT and 21.1 +/- 1.41% by contrast-enhanced harmonic imaging. Conclusions: Contrast-enhanced harmonic imaging is useful for evaluating treatment response for pancreatic cancer.
• Molecular mechanisms of portal vein tolerance, Tomohiro Watanabe, Masatoshi Kudo, Tsutomu Chiba, Yoshio Wakatsuki, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 38(5), 441 - 449, May 2008 , Refereed
  Summary:The liver has been considered as a tolerogenic organ in the sense that favors the induction of peripheral tolerance. The administration of antigens (Ags) via the portal vein causes tolerance, which is termed portal vein tolerance and can explain the occurrence of tolerogenic responses in the liver. Here we discuss the fundamental mechanisms accounting for portal vein tolerance. Antigen-presenting cells (APCs) in the liver, especially dendritic cells and sinusoidal endothelial cells, have limited the ability to produce pro-inflammatory cytokines upon stimulation with endotoxin, an effect that could be due to the continuous exposure to bacterial Ags derived from intestinal microflora. Ag presentation by liver APCs results in T cell tolerance through clonal deletion and selection of regulatory T cells. Thus, APCs with immunosuppressive functions are associated with the achievement of portal vein tolerance via the induction of clonal deletion and generation of regulatory T cells.
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• The clinical characteristics, endoscopic treatment, and prognosis for patients presenting with duodenal varices, Shigenaga Matsui, Masatoshi Kudo, Tsutomu Ichikawa, Mumon Okada, Yoshio Miyabe, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 55(84), 959 - 962, May 2008 , Refereed
  Summary:Background/Aims: This study investigated the clinical characteristics, endoscopic appearances, usefulness of endoscopic treatments, and survival of patients kith duodenal varices. Methodology: Twelve patients were evaluated in whom endoscopy confirmed duodenal varices (13 lesions), and patient data was retrospectively analyzed regarding underlying diseases, hepatic function, endoscopic appearance, previous treatment for other complicated varices, endoscopic treatment for hemorrhage from duodenal varices, and survival. Results: Underlying diseases consisted of liver cirrhosis in 8 patients, and pancreatic cancer-related pylemphraxis in 4 patients. Endoscopic appearances of hemorrhage from duodenal varices revealed negative red color (RC) signs in all 6 lesions, and 5 of 6 lesions were F3 lesions Three of 5 patients with hemorrhagic duodenal varices had received treatment for esophageal varices. Successful. hemostasis and complete eradication by endoscopic treatments was achieved in all 5 patients (6 lesions). The 1, 3, and year cumulative survival rates were 66.7%, 48.6%, and 36.5% in the patients With duodenal varices. Conclusions: The hemorrhagic factor of duodenal varices. is F factor, but not RC sign. Changes of blood flow in the collateral circulatory pathway after treatment for esophageal varices may increase the risk of hemorrhage from duodenal varices. Endoscopic treatment is useful for hemorrhagic duodenal varices.
• Combination therapy of ecabet sodium and proton pump inhibitor (PPI) compared with PPI alone for endoscopic submucosal dissection (ESD)-induced ulcer in gastric cancer: Prospective randomized study, Shigenaga Matsui, Masatoshi Kudo, Mumon Okada, Yutaka Asakuma, Tsutomu Ichikawa, Masanori Kawasaki, GASTROENTEROLOGY, GASTROENTEROLOGY, 134(4), A240 - A240, Apr. 2008 , Refereed
• Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a Japanese nationwide survey, Susumu Eguchi, Takashi Kanematsu, Shigeki Arii, Masatoshi Okazaki, Kiwarnu Okita, Masao Omata, Iwao Ikai, Masatoshi Kudo, Masamichi Kojiro, Masatoshi Makuuchi, Morito Monden, Yutaka Matsuyama, Yasuni Nakanuma, Kenichi Takayasu, SURGERY, SURGERY, 143(4), 469 - 475, Apr. 2008 , Refereed
  Summary:Background. Although a surgical resection is an important modality for the treatment of hepatocellular carcinoma (HCC), the impact of the operative method on both the patient survival and disease-free survival (DTS) still remains controversial. Methods. Using a nationwide Japanese database, 72,744 patients with HCC who underwent a curative liver resection between 1994 and 2001 were divided into two groups based on whether an anatomical subsegmentectomy (AS) or a non-anatomical minor hepatectomy (MH) was performed. A total of 5, 781 patients with single HCCs were selected for the study and divided into 3 subgroups based on the size of the HCCs (less than 2cm, 2 to 5 cm, and greater than 5 cm in diameter). An AS was performed for 2,267 patients while an MH was performed for 3,514 patients. Results. The overall DTS was significantly better after an AS (P = .0089). When the patients were stratified according to the size of the HCC, a better DES was seen in the patients with HCC from 2 to 5 cm after an AS (P < .0005). Further stratification according to liver damage did not show any significant differences between an AS and an MH. Conclusion. An AS is therefore recommended, especially when the size of HCC ranges from 2 to 5 cm.
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• Long-term outcome of percutaneous ethanol injection therapy for minimum-sized hepatocellular carcinoma, Miyuki Taniguchi, Soo Ryang Kim, Susumu Imoto, Hirotsugu Ikawa, Kenji Ando, Keiji Mita, Shuichi Fuki, Noriko Sasase, Toshiyuki Matsuoka, Masatoshi Kudo, Yoshitake Hayashi, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 14(13), 1997 - 2002, Apr. 2008 , Refereed
  Summary:AIM: To evaluate long-term follow-up of minimum-sized hepatocellular carcinoma (HCC) treated with percutaneous ethanol injection (PEI). METHODS: PEI was applied to 42 lesions in 31 patients (23 male and eight female) with HCC < 15 mm in diameter, over the past 15 years. RESULTS: Overall survival rate was 74.1% at 3 years, 49.9% at 5 years, 27.2% at 7 years and 14.5% at 10 years. These results are superior to, or at least the same as those for hepatic resection and radiofrequency ablation. Survival was affected only by liver function, but not by sex, age, etiology of Hepatitis B virus or Hepatitis C virus, a-fetoprotein levels, arterial and portal blood flow, histological characteristics, and tumor multiplicity or size. Patients in Child-Pugh class A and B had 5-, 7- and 10-years survival rates of 76.0%, 42.2% and 15.8%, and 17.1%, 8.6% and 0%, respectively (P = 0.025). CONCLUSION: Treatment with PEI is best indicated for patients with HCC < 15 mm in Child-Pugh class A. (c) 2008 WJG. All rights reserved.
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• Comparison of three current staging systems for hepatocellular carcinoma: Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification, and Tokyo score, Hobyung Chung, Masatoshi Kudo, Shunsuke Takahashi, Satoru Hagiwara, Yasuhiro Sakaguchi, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, Toyokazu Fukunaga, Takashi Matsunaga, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 23(3), 445 - 452, Mar. 2008 , Refereed
  Summary:Background and Aim: Although various staging systems for hepatocellular carcinoma (HCC) have been developed in recent years, there is no worldwide consensus which staging system is best. The aim of the present study was to compare the performance of the currently developed three staging systems: the Japan integrated staging (JIS) score, new Barcelona Clinic Liver Cancer (BCLC) staging classification, and the Tokyo score. Methods: A total of 290 consecutive patients with HCC before initial treatment at Kinki University between January 1999 and December 2001 were included. The patients were stratified according to the three staging systems, and the performance of the staging systems was compared using survival time as the only outcome measure. Results: There were significant differences between all stages in the JIS score, while no significant difference was found between stages C and D in the BCLC staging classification and between all the scores, except between scores 0 and 1 and 2 and 3 in the Tokyo score. For all patients (n = 290), the radical treatment group (n = 208) and the non-radical treatment group (n = 82), the likelihood ratio chi(2)-test showed the highest value, and the Akaike information criterion value was lowest in the JIS score. Conclusion: The JIS score provided the best prognostic stratification in a Japanese cohort of HCC patients who were mainly diagnosed at early stages and treated with radical therapies.
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• Foreign body granuloma mimicking disseminated tumour recurrence after radiofrequency ablation for hepatocellular carcinoma, Shunsuke Takahashi, Hobyung Chung, Satoshi Kitai, Tatsuo Inoue, Yasunori Minami, Kazuomi Ueshima, Masatoshi Kudo, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 28(3), 414 - 415, Mar. 2008 , Refereed
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• Effects of decorin on the expression of alpha-smooth muscle actin in a human myofibroblast cell line, Tatsuya Nakatani, Eiko Honda, Sumio Hayakawa, Mayumi Sato, Ken Satoh, Masatoshi Kudo, Hiroshi Munakata, MOLECULAR AND CELLULAR BIOCHEMISTRY, MOLECULAR AND CELLULAR BIOCHEMISTRY, 308(1-2), 201 - 207, Jan. 2008 , Refereed
  Summary:Myofibroblasts are metabolically and morphologically distinctive fibroblasts expressing alpha-smooth muscle actin (alpha-SMA), and their activation plays a key role in development of the fibrotic response. In an activated state, myofibroblasts cease to proliferate and start to synthesize large amounts of extracellular component proteins. The expression of alpha-SMA correlates with the activation of myofibroblasts. Decorin, a member of the small leucine-rich proteoglycan gene family, has been implicated in the negative control of cell proliferation primarily by upregulating the expression of p21, a potent inhibitor of cyclin-dependent kinase. In order to examine the effect of decorin on myofibroblast cell growth, we rendered a human lung myofibroblast cell line, MRC-5, quiescent by either cell-cell contact or serum starvation, and examined the relationship between decorin and alpha-SMA expression in these cells. The expression of decorin in cells made quiescent by serum starvation was lower than that in cells made quiescent by cell-cell contact. In contrast, the expression of alpha-SMA in cells made quiescent by cell-cell contact was lower than that in cells made quiescent by serum starvation. Furthermore, forced expression of decorin was accompanied by a suppression of alpha-SMA expression, whereas knocking down of decorin expression by RNA interference increased the expression of alpha-SMA.
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• Diagnostic accuracy of imaging for liver cirrhosis compared to histologically proven liver cirrhosis, Masatoshi Kudo, Rong Qin Zheng, Soo Ryang Kim, Yoshihiro Okabe, Yukio Osaki, Hiroko Iijima, Toshinao Itani, Hiroshi Kasugai, Masayuki Kanematsu, Katsuyoshi Ito, Norio Usuki, Kazuhide Shimamatsu, Masayoshi Kage, Masamichi Kojiro, INTERVIROLOGY, INTERVIROLOGY, 51, 17 - 26, 2008 , Refereed
  Summary:Objective: To evaluate the diagnostic accuracy of liver cirrhosis by imaging modalities, including CT, MRI and US, compared to results obtained from histopathological diagnoses of resected specimens. Materials and Methods: CT, MRI and US examinations of 142 patients with chronic liver disease who underwent surgery for complicated hepatocellular carcinoma (< 3 cm in diameter) in 10 institutions were blindly reviewed in a multicenter study by three radiologists experienced in CT, MRI and US. The images were evaluated for five imaging parameters ( irregular or nodular liver surface, blunt liver edge, liver parenchymal abnormalities, liver morphological changes and manifestations of portal hypertension) using a severity scale. The diagnostic imaging impression score was also calculated. Patients were histologically classified into chronic hepatitis ( CH; n = 54), liver cirrhosis ( LC; n = 71) and pre- cirrhosis ( P- LC; n = 17) by three pathologists, independently, who reviewed the resected liver specimens. The results of the three imaging methods were compared to those from histological diagnoses, and a multivariate analysis ( stepwise forward logistic regression analysis) was performed to identify independent predictive signs of cirrhosis. The diagnostic efficacies for LC and early cirrhosis were also compared among CT, MRI and US using a receiver- operating characteristic ( ROC) curve analysis. Results: The differences in the five imaging parameters evaluated by CT, MRI and US between LC and CH were statistically significant ( p < 0.001) except for the manifestations of portal hypertension on US. Irregular or nodular surface, blunt edge or morphological changes in the liver were selected as the best predictive signs for cirrhosis on US whereas liver parenchymal abnormalities, manifestations of portal hypertension and morphological changes in the liver were the best predictive signs on MRI and CT by multivariate analysis. The predictive diagnostic accuracy, sensitivity and specificity in discriminating LC from CH based on the best predictive signs were 71.9, 77.1 and 67.6% by CT; 67.9, 67.5 and 68.3% by MRI, and 66.0, 38.4 ( lower than CT and MRI, p = 0.001) and 88.8% ( higher than CT and MRI, p = 0.001) by US. According to the imaging impression scoring system, diagnostic accuracy, sensitivity and specificity were 67.0, 84.3 and 52.9% by CT; 70.3, 86.7 and 53.9% by MRI, and 64.0, 52.4 ( lower than CT and MRI, p = 0.0001) and 73.5% ( higher than CT and MRI, p < 0.003) by US. ROC analysis showed that MRI and CT were slightly superior to US in the diagnosis of LC but no statistically significant difference was found between them. For the pathological diagnosis of P- LC, cirrhosis was diagnosed in 59.5, 46.7 and 41.7% of the P- LC cases by US, CT and MRI, respectively, with no significant difference among these methods. Conclusion: US, CT and MRI had different independent predictive signs for the diagnosis of LC. MRI and CT were slightly superior to US in predicting cirrhosis, especially regarding sensitivity. Noninvasive imaging techniques play an important role in the diagnosis of cirrhosis, especially in the evaluation of P- LC. Copyright (c) 2008 S. Karger AG, Basel.
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• Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography, Chie Tatsumi, Masatoshi Kudo, Kazuomi Ueshima, Satoshi Kitai, Shunsuke Takahashi, Tatsuo Inoue, Yasunori Minami, Hobyung Chung, Kiyoshi Maekawa, Kenji Fujimoto, Tonomura Akiko, Mitake Takeshi, INTERVIROLOGY, INTERVIROLOGY, 51, 27 - 33, 2008 , Refereed
  Summary:Objective: The aim of this study was to investigate the accuracy of noninvasive tests, e. g. serum fibrotic markers, transient elastography and real-time tissue elastography, in the diagnosis of hepatic fibrosis, and to determine whether they can replace liver biopsy. Methods: 119 patients with chronic liver disease were included in this study. Serum fibrotic markers including hyaluronic acid, type IV collagen, type IV collagen 7S domain and type III procollagen-N-peptide were measured. Aspartate aminotransferase (AST) and platelet counts were also measured to calculate the AST to platelet ratio index ( APRI). Liver stiffness was measured using FibroScan and real-time tissue elastography. Results: The fibrotic stage, determined by histopathological diagnosis of a liver biopsy sample, did not correlate as well with serum fibrotic markers although it was useful to diagnose liver cirrhosis. However, the stage of hepatic fibrosis correlated well with liver stiffness measured by FibroScan. FibroScan was also a much better predictor of liver cirrhosis than APRI. Furthermore, the levels of liver strain measured by real-time tissue elastography correlated well with liver stiffness ( p < 0.05). Conclusion: Serum fibrotic markers and FibroScan are useful for distinguishing liver cirrhosis ( F 4) from chronic hepatitis (F(1)-F(3)). In addition, real- time tissue elastography is a novel and promising method to determine the stage of hepatic fibrosis. Copyright (c) 2008 S. Karger AG, Basel.
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• Usefulness of a new immunoradiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral load of serum HCV RNA genotype 1b, Noriko Sasase, Soo Ryang Kim, Ke Ih Kim, Miyuki Taniguchi, Susumu Imoto, Keiji Mita, Hak Hotta, Ikuo Shouji, Ahmed El-Shamy, Norifumi Kawada, Masatoshi Kudo, Yoshitake Hayashi, INTERVIROLOGY, INTERVIROLOGY, 51, 70 - 75, 2008 , Refereed
  Summary:We investigated the clinical usefulness of a new immunoradiometric ( IRM) assay of hepatitis C virus ( HCV) core antigen in predicting virological response during pegylated interferon plus ribavirin ( PEG-IFN/RBV) combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b. Thirty-nine patients received a regimen of PEG- IFN alpha - 2b ( 1.5 mu g/ kg/ week s. c.) in combination with RBV ( 600 - 1,000 mg/ day). Of the 39 patients, 18 ( 46.2%) achieved sustained virological response ( SVR), 11 ( 28.2%) attained partial response ( PR) and 10 ( 25.6%) showed no response (NR). Four weeks after the start of therapy, 1- and 2-log reductions in the amount of HCV core antigen were observed in 20 (2/10) and 0% (0/10) showing NR, 91 (10/11) and 63.6% 7/ 11) with PRs, and 88.9 (16/18) and 55.6% (10/18) of patients with SVR, respectively. The 1- and 2-log reductions 4 weeks after the start of therapy were not a defining condition for PR and SVR. The amount of HCV core antigen was significantly different between SVR and PR patients on days 1 and 7, and between patients with NR and SVR at all points of time. In conclusion, this new IRM assay is useful in predicting virological response during PEG-IFN/RBV therapy. Copyright (c) 2008 S. Karger AG, Basel.
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• Case of rapidly progressed sarcomatoid hepatocellular carcinoma in a young female without risk factor, Tatsuo Inoue, Masatoshi Kudo, Yasunori Minami, Hobyung Chung, Toyokazu Fukunaga, Toshihiko Kawasaki, LIVER INTERNATIONAL, LIVER INTERNATIONAL, 27(10), 1428 - 1430, Dec. 2007 , Refereed
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• Treatment of large and/or multiple hepatic malignancies: Open surgical approaches of radiofrequency ablation, Yasunori Minami, Toshihiko Kawasaki, Masatoshi Kudo, Seiji Haji, Osamu Shiraishi, Takashi Kawabe, Chikao Yasuda, Takuya Nakai, Yoshihumi Takeyama, Hitoshi Shiozaki, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 54(80), 2358 - 2360, Dec. 2007 , Refereed
  Summary:Background/Aims: Patients with hepatic malignancies are often poor candidates for resection because of the lack of hepatic reserve as a result of coexisting cirrhosis or the presence of multiple tumors. The purpose of this study was to determine the safety and efficacy of open intraoperative radiofrequency ablation of unresectable hepatic malignancies with size larger than 4cm in diameter and/or more than three in number. Methodology: Between May 2000 and September 2003, 30 patients (24 men, 6 women; age range, 5972 years; mean age, 63 years) with 51 hepatic malignancies. The maximal diameter of all tumors ranged from 1.0 to 10cm (mean +/- SD, 3.2 +/- 1.8). Results: All tumors achieved necrosis completely in a. single session. The mean follow-up from the initial ablation in this study was 18.9 +/- 10.1 months (range, 0-41). The 1-, 2 and 3-year overall survival rates were 86.1%, 71.6% and 71.6%, respectively. The 1-, 2 and 3-year disease-free survival rates were 70.9%, 37.6% and 25.1%, respectively. Conclusions: Open radiofrequency ablation is a safety and efficient approach for hepatic malignancies sized more than 4cm in diameter and/or located more than three in number.
• Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan, Iwao Ikai, Shigeki Arii, Masatoshi Okazaki, Kiwamu Okita, Masao Omata, Masamichi Kojiro, Kenichi Takayasu, Yasuni Nakanuma, Masatoshi Makuuchi, Yutaka Matsuyama, Morito Monden, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 37(9), 676 - 691, Sep. 2007 , Refereed
  Summary:In the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan, 18 213 individuals were newly registered as patients with primary liver cancer at 645 medical institutions over a period of 2 years (from 1 January 2002 to 31 December 2003). Of these patients, 94.2% had hepatocellular carcinoma (HCC) and 4.1% had intrahepatic cholangiocarcinoma (ICC). In addition, 24 705 follow-up patients were registered in the survey. Epidemiological and clinicopathological factors, diagnosis and treatment were investigated in the newly registered patients, and the cumulative survival rates of newly registered patients in the 12th to 17th follow-up surveys conducted between 1992 and 2003 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified by background factors and treatment. The data obtained in this follow-up survey should contribute to future research and medical practice for primary liver cancer.
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• Role of tumor markers in assessment of tumor progression and prediction of outcomes in patients with hepatocellular carcinoma, Hidenori Toyoda, Takashi Kumada, Yukio Osaki, Hiroko Oka, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 37, S166 - S171, Sep. 2007 , Refereed
  Summary:The efficacies of tumor markers, alfa-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of alfa-fetoprotein (AFP-L3), and des-gamma-carboxy prothrombin (DCP) were evaluated for assessment of progression of hepatocellular carcinoma (HCC) and patient prognosis. The prevalence of elevated levels of each tumor marker increased with progression of tumor stage for all three markers among patients with HCC. Survival was poorer among patients with elevated levels of tumor markers than among those without elevated levels. Evaluation of tumor progression with tumor markers was based only on the results of laboratory tests. The tests are objective, simple to perform, and easy to repeat, and therefore, may be useful to supplement conventional tumor staging for the evaluation of tumor progression and prediction of patient outcome.
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• International comparison of treatment outcomes based on staging systems, Masatoshi Kudo, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 37, S216 - S222, Sep. 2007 , Refereed
  Summary:Treatment outcomes were compared among several countries based on different staging systems. Data were collected from published data. Treatment outcomes based on Cancer of the Liver Italian Program (CLIP) scores 0-3 were best in Japan when compared among several countries. Furthermore, treatment outcomes in Japan based on Japan Integrated Staging (JIS) scores 0-3 were much better than in the USA. However, Barcelona Clinic Liver Cancer (BCLC) staging was not useful forinternational comparison, suggesting that BCLC staging is not helpful for prognostic staging but for treatment allocation staging. This is an extremely important point, which should be kept in mind.
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• Quantitative tissue blood flow measurement of the liver parenchyma: Comparison between xenon CT and perfusion CT, Kazuhiko Hashimoto, Takamichi Murakami, Keizo Dono, Masatoshi Hori, Tonsok Kim, Masayuki Kudo, Shigeru Marubashi, Atsushi Miyamoto, Yutaka Takeda, Hiroaki Nagano, Koji Umeshita, Hironobu Nakamura, Morito Monden, DIGESTIVE DISEASES AND SCIENCES, DIGESTIVE DISEASES AND SCIENCES, 52(4), 943 - 949, Apr. 2007 , Refereed
  Summary:The purpose of this study was to compare measurements of hepatic tissue blood flow (TBF) calculated by xenon and perfusion CT. Seven patients with normal liver and eight with chronic liver disease underwent both xenon and perfusion CT. During xenon CT examinations, serial abdominal CT scans were obtained every minute before and during 4 min of nonradioactive 25% (v/v) xenon gas inhalation and 5 min of administration of oxygen-rich air. Hepatic arterial and portal venous TBF were measured separately with a special imaging system using the Kety-Schmidt expression based on the Fick principle (AZ-7000W; Anzai Medical Co.). The hepatic arterial fraction (HAF) was calculated as follows: [hepatic arterial TBF/(hepatic arterial TBF + portal venous TBF)]. During perfusion CT examinations, total hepatic TBF and HAF were also calculated from the enhanced CT cine image data on a workstation using a commercially available software package based on a deconvolution algorithm (CT Perfusion 3 GE Healthcare, USA). Total hepatic TBF measured by xenon and perfusion CT was 82.9 +/- 15 and 82.8 +/- 18 ml/min/100 g, respectively. The measured values by the two techniques showed a significant correlation (R-2 = 0.657, P < 0.05). HAF measured by xenon and perfusion CT was 26.6 +/- 11 and 21.8 +/- 13%, respectively. The measured values by the two techniques also showed a significant correlation (R-2 = 0.869, P < 0.05). We conclude that there was a good correlation between hepatic TBF quantified by xenon CT and perfusion CT.
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• Radiofrequency ablation combined with reduction of hepatic blood flow: Effect of lipiodol on coagulation diameter and ablation time in normal pig liver, Hobyung Chung, Masatoshi Kudo, Yasunori Minami, Toshihiko Kawasaki, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 54(75), 701 - 704, Apr. 2007 , Refereed
  Summary:Background/Aims: We evaluated the effectiveness of radiofrequency (RF) ablation combined with transarterial embolization using Lipiodol and gelatin sponge. Methodology: A total of 18 normal pig liver lobes were randomly assigned to the following three different RF ablation groups, 1) combined with TAE using Lipiodol and gelatin sponge as "LpTAE group"; 2) combined with TAE using gelatin sponge only as "TAE group"; 3) ablation alone as "control group". Ablations were performed under open laparotomy using an RF generator and a 2-cm expandable needle. The diameter of coagulation and the ablation time were compared among the three groups. Results: The characteristic shape of coagulated area differed among the three groups. The long-axis diameter showed no significant difference among the three groups (27.5mm, 27.5mm, 26.7mm; respectively), while the short-axis diameter was significantly larger in the LpTAE group compared with the control groups (25.2min vs. 20.5mm; p < 0.05). The total ablation time was significantly shorter in the LpTAE and TAE groups compared with the control group (166, 204 seconds vs. 309 seconds; p=0.001, p=0.01). Conclusions: RF ablation combined. with LpTAE produced larger and more spherical areas of coagulation in a shorter ablation time. Such an advantage could potentially enhance the clinical effectiveness of RF ablation.
• Multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated hepatocellular carcinoma in a patient with alcohol-related liver cirrhosis, Soo Ryang Kim, Hirotsugu Ikawa, Kenji Ando, Keiji Mita, Shuichi Fuki, Michiie Sakamoto, Yoshihiro Kanbara, Toshiyuki Matsuoka, Masatoshi Kudo, Yoshitake Hayashi, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 13(8), 1271 - 1274, Feb. 2007 , Refereed
  Summary:We describe a rare case of the transformation of a dysplastic nodule into well-differentiated hepatocellular carcinoma (HCC) in a 56-year-old man with alcohol related liver cirrhosis. Ultrasound (US) disclosed a 10 mm hypoechoic nodule and contrast enhanced US revealed a hypovascular nodule, both in segment seven. US-guided biopsy revealed a high-grade dysplastic nodule characterized by enhanced cellularity with a high N/C ratio, increased cytoplasmic eosinophilia, and slight cell atypia. One year later, the US pattern of the nodule changed from hypoechoic to hyperechoic without any change in size or hypovascularity. US-guided biopsy revealed well-differentiated HCC of the same features as shown in the first biopsy, but with additional pseudoglandular formation and moderate cell atypia. Moreover, immunohistochemical staining of cyclase-associated protein 2, a new molecular marker of well-differentiated HCC, turned positive. This is the first case of multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated HCC within one year in alcohol-related liver cirrhosis. (C) 2007 The WJG Press. All rights reserved.
• Clinical characteristics of NonBNonC-HCC: Comparison with HBV and HCV related HCC, Kinuyo Hatanaka, Masatoshi Kudo, Toyokazu Fukunaga, Kazuomi Ueshima, Hobyung Chung, Yasunori Minami, Yasuhiro Sakaguchi, Satoshi Hagiwara, Akio Orino, Yukio Osaki, INTERVIROLOGY, INTERVIROLOGY, 50(1), 24 - 31, 2007 , Refereed
  Summary:Objective: To clarify the frequency and trends of both HBsAg and HCVAb negative hepatocellular carcinoma (NonBNonC-HCC) in all HCC, to clarify the etiology of NonBNonC-HCC, and to elucidate the clinical characteristics of NonBNonC-HCC compared with those of HBsAg-positive HCC (B-HCC) and HCVAb-positive HCC (C-HCC). Methods: A total of 2,542 patients with HCC examined at three institutions between 1991 and 2004 were categorized based on their serum viral antigen/antibody positivities, and compared between groups for the etiology, annual trend of the incidence, and clinical characteristics. Results: For the etiology, C-HCC was most prevalent, followed by B-HCC, NonBNonC-HCC, and both HBsAg and HCVAb-positive HCC (BC-HCC) in order. For survival, C-HCC had the most favorable prognosis, followed by NonBNonC-HCC, and B-HCC patients had the poorest prognosis in the three groups (C-HCC, B-HCC, and NonBNonC-HCC). In tumor-node metastasis (TNM) stages I+II, however, NonBNonC-HCC patients took the most favorable clinical course. The incidence of NonB-NonC-HCC in all HCC was 5 - 8% from 1991 to 1998, and has increased to 10 - 12% since 1999. Additionally, the incidence of HBcAb-positive HCC in NonBNonC-HCC declined each year. Among NonBNonC-HCC patients, the morbidity of diabetic complications was significantly higher in HBcAb-negative patients than in HBcAb-positive patients. Conclusion: Although the incidence of NonBNonC-HCC among all HCC has an increasing trend recently, the incidence of HBcAb-positive HCC in NonBNonC-HCC has a tendency of decreasing. This fact suggest its etiology might be changing from occult HBV related HCC to unknown etiology such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) related HCC. The prognosis of NonBNonC-HCC was fairly good if the HCC was found in its early stage.
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• Outcomes of nontransplant potentially curative therapy for early-stage hepatocellular carcinoma in child-pugh stage a cirrhosis is comparable with liver transplantation, Shunsuke Takahashi, Masatoshi Kudo, Hobyung Chung, Tatsuo Inoue, Miki Nagashima, Satoshi Kitai, Tatsumi Chie, Minami Yasunori, Ueshima Kazuomi, Fukunaga Toyokazu, Seiji Haji, DIGESTIVE DISEASES, DIGESTIVE DISEASES, 25(4), 303 - 309, 2007 , Refereed
  Summary:Background: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection ( 53 cases) or radiofrequency ablation ( RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow- up period was 36.7 months. Results: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). Conclusion: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.
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• Management of hepatocellular carcinoma in Japan: Consensus-based clinical practice manual proposed by the Japan Society of Hepatology, Masatoshi Kudo, Takeshi Okanoue, ONCOLOGY, ONCOLOGY, 72, 2 - 15, 2007 , Refereed
  Summary:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but worldwide. Clinical Practice Guidelines for HCC were published in 2001 by the European Society of Study of the Liver (EASL) and in 2005 by the American Association for the Study of Liver Disease (AASLD). However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labor and Welfare, Evidence-Based Clinical Practice Guidelines for HCC were compiled. Based on 'evidence-based' guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007. In this article, the content of this manual, especially issues on surveillance, diagnosis, staging, and treatment, is summarized.
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• Superiority of CT arterioportal angiography to contrast-enhanced CT and MRI in the diagnosis of hepatocellular carcinoma in nodules smaller than 2 cm, Soo Ryang Kim, Kenji Ando, Keiji Mita, Shuichi Fuki, Hirotsugu Ikawa, Yoshihiro Kanbara, Susumu Imoto, Toshiyuki Matsuoka, Yoshitake Hayashi, Masatoshi Kudo, ONCOLOGY, ONCOLOGY, 72, 58 - 66, 2007 , Refereed
  Summary:To evaluate the effectiveness of computed tomography (CT) arterioportal angiography in the diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm, we compared the findings of CT during arteriography (CTA) and CT during arterial portography (CTAP) with those of enhanced CT and enhanced magnetic resonance imaging (MRI). Sixty-eight nodules smaller than 2 cm in 53 patients with liver cirrhosis were classified into three groups of CTA and CTAP: (group 1) hyperattenuation on CTA, and hypoattenuation on CTAP (56 nodules, 41 patients); (group 2) hypoattenuation on CTA, and hypoattenuation on CTAP (10 nodules, 10 patients); (group 3) hypoattenuation on CTA, and hyperattenuation on CTAP (2 nodules, 2 patients). Histologically, 96% (54/56), 80% (8/10), and 100% (2/2) of the nodules in groups 1, 2 and 3, respectively, were diagnosed as HCC. In group 1, enhanced CT or enhanced MRI confirmed hypervascularity in only 77% (30/39) and venous washout in 21% (8/39). In groups 2 and 3, enhanced CT or enhanced MRI on 7 and 2 nodules, respectively, revealed no hypervascularity (0%). The results suggested that CT arterioportal angiography is superior to enhanced CT and MRI in nodules smaller than 2 cm for diagnosing HCC (p < 0.01 group 1, p < 0.01 group 2).
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• Initial treatment response is essential to improve survival in patients with hepatocellular carcinoma who underwent curative radiofrequency ablation therapy, Shunsuke Takahashi, Masatoshi Kudo, Hobyung Chung, Tatsuo Inoue, Emi Ishikawa, Satoshi Kitai, Chie Tatsumi, Taisuke Ueda, Yasunori Minami, Kazuomi Ueshima, Seiji Haji, ONCOLOGY, ONCOLOGY, 72, 98 - 103, 2007 , Refereed
  Summary:Objective: This study was undertaken to assess the outcome of potentially curative radiofrequency ablation (RFA) therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 171 Child-Pugh stage A cirrhotic patients who received RFA for naive HCC within the Milan criteria. The median follow-up period was 36.7 months. Results: Cumulative survival rates estimated by the Kaplan-Meier method for all patients were 98.8, 91.1 and 76.8% at 1, 3 and 5 years, respectively. Cumulative probabilities of local tumor recurrence at 1, 2 and 3 years were 9.0, 14.1 and 17.7%, respectively. Cumulative survival rates in patients without local tumor recurrence were 96.6, 94.6 and 84.4% at 1, 3 and 5 years, respectively, compared with patients with local tumor recurrence (96.6, 74.8 and 42.1% at 1, 3 and 5 years, respectively; p = 0.0002). Cox regression analysis showed that low serum albumin (p = 0.009, RR 3.04, CI 1.32-6.98), high range of PIVKA-II ( prothrombin induced by vitamin K absence or agonist II) (p = 0.025, RR 2.57, CI 1.13-5.89), with multiple (less than 3) nodules (p = 0.021, RR 2.61, CI 1.15-5.91), and with local tumor recurrence (p = 0.004, RR 3.62, CI 1.51-8.69) were significant risk factors for death. Conclusion: Initial complete response of curative RFA therapy in patients with Child-Pugh stage A cirrhosis and early-stage HCC is associated with improved survival. Therefore, clinicians should aim to achieve complete ablation of all detectable HCC nodules with adequate safety margins.
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• Regulatory failure of serum prohepcidin levels in patients with hepatitis C, Miki Nagashima, Masatoshi Kudo, Hobyung Chung, Emi Ishikawa, Satoru Hagiwara, Tatsuya Nakatani, Kensaku Dote, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 36(4), 288 - 293, Dec. 2006 , Refereed
  Summary:Background/Aims: Elevated serum ferritin and hepatic iron concentrations are frequently observed in chronic hepatitis C (CHC), which may be related to hepcidin. Because the role of hepcidin in CHC patients remains unknown, we aimed in this study to generate some information about hepcidin in CHC. Methods: To determine whether serum hepcidin correlates with markers of iron status in patients with viral hepatitis, we measured serum prohepcidin levels in patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and in healthy controls. Results: Serum prohepcidin and ferritin levels were negatively correlated (r = -0.182, P = 0.037) in HCV patients and positively correlated in HBV patients and in healthy controls. The total iron scores in liver specimens from HCV patients were also negatively correlated ( r = -0.403, P = 0.013). Serum prohepcidin levels in patients with liver cirrhosis (LC) were significantly lower than in patients with chronic hepatitis (CH). In both CH and LC patients, serum prohepcidin levels were significantly lower in HCV patients than in HBV patients. Conclusion: Failure of homeostatic regulation of serum prohepcidin concentrations may be induced by HCV infection, resulting in elevation of serum ferritin levels, which leads to the progression of liver injury by iron overload in CHC patients. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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• Assessment of the severity of liver disease and fibrotic change: The usefulness of hepatic CT perfusion imaging, Kazuhiko Hashimoto, Takamichi Murakami, Keizo Dono, Masatoshi Hori, Tonsok Kim, Masayuki Kudo, Shigeru Marubashi, Atsushi Miyamoto, Yutaka Takeda, Hiroaki Nagano, Koji Umeshita, Hironobu Nakamura, Morito Monden, ONCOLOGY REPORTS, ONCOLOGY REPORTS, 16(4), 677 - 683, Oct. 2006 , Refereed
  Summary:This study assessed the utility of CT perfusion for quantitative assessment of liver function and fibrosis. Tissue blood flow (TBF), tissue blood volume (TBV), mean transit time (MTT) and hepatic arterial fraction (HAF) were measured with CT perfusion using the deconvolution algorithm in 38 patients with chronic liver diseases and 10 patients without liver disease. Using Child-Pugh classification, 21 patients were classified as Child A, 10 as Child B, and 7 as Child C. In 20 patients, the degree of fibrosis was quantitated in surgically-resected specimens and compared with the perfusion parameters. The mean TBF, TBV, MTT and HAF of patients without liver disease were 103.9 +/- 18 ml/min/100 g, 12.5 +/- 2.0 ml/100 g, 11.1 +/- 1.6 sec and 18.4 +/- 5.6%, respectively (+/- SD). The mean TBF of patients with Child A, B and C were 95.1 +/- 24, 86.7 +/- 29 and 75.5 +/- 6.5 ml/min/100 g, respectively. TBF tended to decrease with the severity of chronic liver disease. The mean HAF of patients with Child A, B and C were 18.6 +/- 8.3, 29.8 +/- 11.2 and 40.2 +/- 11.1%, respectively. HAF of patients without liver disease was significantly different from those of Child B and C (p < 0.05, each). However, there were no significant differences in TBV and MTT between each groups. HAF correlated significantly with the degree of fibrosis (R-2-0.588, p < 0.05). Our results showed that parameters of CT perfusion correlated significantly with the severity of liver fibrosis and cirrhosis. Quantitative measurement of hepatic tissue blood flow by CT perfusion is useful for evaluation of the severity of disease and fibrotic change.
• Cecal necrosis due to ischemic colitis mimicking an abscess on sonography, T Watanabe, S Tomita, H Shirane, Y Okabe, A Orino, A Todo, T Chiba, M Kudo, JOURNAL OF ULTRASOUND IN MEDICINE, JOURNAL OF ULTRASOUND IN MEDICINE, 25(3), 393 - 396, Mar. 2006 , Refereed
  Summary:Ischemic colitis is a vascular disorder of the colon that causes rectal bleeding and abdominal pain in elderly patients.(1,2) It is classified into gangrenous and nongangrenous forms. Nongangrenous colonic ischemia usually requires only medical treatment and is associated with a good prognosis. In contrast, urgent surgical intervention is required for the treatment of gangrenous colonic ischemia, which is associated with high mortality.(3) Thus, in patients with ischemic colitis, it is especially important to determine whether colonic ischemia is the gangrenous or nongangrenous type. Endoscopic assessment of the colon is the most sensitive and reliable method of evaluating the ischemic colon mucosa(4); however, it is not always possible to perform a colonoscopic examination in patients with gangrenous ischemic colitis because of the severe general condition of these patients. Therefore, a noninvasive and rapid examination procedure is necessary for the diagnosis of gangrenous ischemic colitis. In this regard, a sonographic examination may be useful because it can be easily performed even in patients with shock status. In fact, several studies have reported that bowel wall thickening and decreased arterial flow in the affected colon are characteristic findings of patients with nongangrenous ischemic colitis(5-8); however, few articles have addressed the sonographic findings of gangrenous colonic ischemia. In this report, we describe the case of a patient with cecal necrosis due to ischemic colitis and discuss its unique sonographic findings.
• What is the best staging system for hepatocellular carcinoma?, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 41(3), 290 - 291, Mar. 2006 , Refereed
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• Comparison of standard-dose and low-dose gemcitabine regimens in pancreatic adenocarcinoma patients: a prospective randomized trial, H Sakamoto, M Kitano, Y Suetomi, Y Takeyama, H Ohyanagi, T Nakai, C Yasuda, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 41(1), 70 - 76, Jan. 2006 , Refereed
  Summary:Background. A prospective, randomized study was performed to determine whether gemcitabine infusion at a low dose (250mg/m(2)) is comparable or superior to the standard-dose infusion (1000mg/m(2)) in terms of the survival period, clinical benefit, and frequency of adverse effects in patients with advanced pancreatic adenocarcinoma. Methods. Twenty-five patients who were histologically proven to have locally advanced pancreatic cancer or pancreatic cancer with distant metastases were initially enrolled in the present study. They were treated with gemcitabine infusion at either a dose of 1000mg/m(2) over 30 min (the standard regimen) on days 1, 8, and 15 of every 4-week cycle or at a dose of 250mg/ m(2) over 30 min every week. Survival time, response rate, time to treatment failure, clinical benefit response, and adverse effects were compared between the two groups. Results. Twenty-one patients received gemcitabine for more than 1 month. The median survival period was 7.2 months for patients who received the low-dose infusion regimen, in contrast to 5.2 months for patients administered the standard-dose infusion regimen. The time to treatment failure was 5.6 months for patients in the low-dose infusion regimen, in contrast to 3.4 months for patients in the standard-dose infusion regimen. There were no significant differences in either survival time to time to treatment failure or clinical benefits between the two groups, but the incidence of adverse reactions in patients administered the low-dose therapy was significantly lower than that in patients receiving the standard-dose therapy (P < 0.05). In particular, patients in the standard infusion regimen group experienced more hematologic toxicity than those in the low-dose regimen. Conclusions. These findings suggest that the low-dose gemcitabine infusion regimen can be continuously administered to patients with locally advanced and systemically spreading pancreatic cancer because of its reduced toxicity, resulting in better quality of life and an improved safety profile as compared to the standard infusion treatment regimen.
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• Studies on the variation in clinical laboratory data and safety evaluation of pharmaceuticals, M Nomura, T Hata, S Naitoh, H Kuwao, K Moriyama, M Fukuoka, M Kudo, Y Tohda, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 125(12), 997 - 1004, Dec. 2005 , Refereed
  Summary:The safety of pharmaceuticals has become increasingly important not only in daily medical treatment but also in clinical trials. Although clinical laboratory data are more objective than clinical symptoms, the determination as to whether they indicate abnormal variations depends largely upon the clinical judgment of physicians. The process of determination has not been sufficiently objectified. The present study investigated the indices of criteria for variations in clinical laboratory data obtained in clinical trials. Then, detection rates of abnormal variations were compared between our determination method that employs the reference change value (RCV) expressing the width of biological variation for each test component and conventional determination methods. The study also demonstrated that by combining standard values and the RCV for determination, abnormal variations were found at a rate greater than 50%. The method we propose was applied to the safety evaluation of pharmaceuticals. In clinical trials on the antiviral drug ribavirin administered alone, components of laboratory tests were selected that should be noted in studies on its effects. Expect for decreases in red blood cell counts and hemoglobin values, which are closely associated with anemic symptoms and well known to hepatologists, the increasing trend in platelet counts and decreasing trend in albumin were found to be laboratory test components that should be paid attention to, even though they may not be obvious.
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• Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images, T Inoue, M Kudo, R Watai, Z Pei, T Kawasaki, Y Minami, H Chung, T Fukunaga, K Awai, O Maenishi, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 40(12), 1139 - 1147, Dec. 2005 , Refereed
  Summary:Background. We investigated the diagnostic utility of post-vascular phase contrast-enhanced ultrasonography (US) and superparamagnetic iron oxide (SPIO)enhanced magnetic resonance imaging (MRI) as compared to the histological diagnosis of differential grades of hepatocellular carcinomas (HCCs). Methods. Forty-nine patients with histologically characterized liver nodules (well-differentiated HCC, n = 20; moderately differentiated HCC, n = 19; poorly differentiated HCC, n = 1; dysplastic nodule, n = 9) received contrast-enhanced US and SPIO-MRI. Subsequently, we quantitatively evaluated the relationships between the images of the nodules and their histological diagnosis and differential grades. Results. The ratio of the echogenicity of the tumorous area to that of the nontumorous area with post-vascular phase contrast-enhanced US (post-vascular phase ratio) decreased as nodules became less differentiated (P < 0.05; Kruskal-Wallis test). The ratio of the intensity of the nontumorous area to that of the tumorous area on SPIO-enhanced MR images (SPIO intensity index) also decreased as nodules became less differentiated (P < 0.01). The post-vascular phase ratio correlated with the SPIO intensity index for HCCs and dysplastic nodules (r = 0.76). The conformity of the result from the post-vascular phase contrast-enhanced US and SPIO-MRI was 96%. Conclusions. Contrast-enhanced US is a valuable method for predicting the histological grade of HCCs in cirrhotic patients, and may be a good alternative to SPIO-enhanced MRI.
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• Hemodynamic and morphologic changes of peripheral hepatic vasculature in cirrhotic liver disease: A preliminary study using contrast-enhanced coded phase inversion harmonic ultrasonography, Rong-Qin Zheng, Bo Zhang, Masatoshi Kudo, Yasuhiro Sakaguchi, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 11(40), 6348 - 6353, Oct. 2005 , Refereed
  Summary:AIM: To provide the useful information for the diagnosis of liver cirrhosis by observing the morphology of peripheral hepatic vessels and the hemodynamics of microbubble arrival time in these vessels. METHODS: Twenty-one subjects including 5 normal volunteers and 16 patients (liver cirrhosis, n=10; chronic hepatitis, n=6) were studied by contrast-enhanced coded phase inversion harmonic sonography (GE LOGIQ 9 series) using a 6-8 MHz convex-arrayed wide-band transducer. The images of peripheral hepatic artery, portal and hepatic vein were observed in real-time for about 2 min after intravenous injection of Levovist. The time when microbubbles appeared in the peripheral vessels (microbubble arrival time) was also recorded. The morphologic changes of peripheral hepatic vasculature were classified as marked, slight, and no changes based on the regularity in caliber, course, ramification, and the delineation of vessels compared to normal subjects. RESULTS: The microbubble arrival time at peripheral artery, portal, and hepatic vein was shorter in cirrhotic patients than in chronic hepatitis patients and normal subjects. The marked, slight and no morphologic changes of peripheral hepatic vasculature found in 5 (5/6, 83.3%), 1 (1/6, 16.7%), and 0 (0/6, 0%) liver cirrhosis patients, respectively, and in 1 (1/10, 10%), 6 (6/10, 60%), and 3 (3/10, 30%) chronic hepatitis patients, respectively. There was a significant difference between the two groups (P < 0.001). CONCLUSION: Evaluation of the hemodynamics and morphology of peripheral hepatic vasculature by contrast-enhanced coded pulse inversion harmonic sonography can provide useful information for the diagnosis of liver cirrhosis. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.
• Imaging findings of biliary hamartomas, Rong-Qin Zheng, Bo Zhang, Masatoshi Kudo, Hirokazu Onda, Tatsuo Inoue, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 11(40), 6354 - 6359, Oct. 2005 , Refereed
  Summary:AIM: To evaluate the imaging findings of biliary hamartomas (von Meyenburg complexes, VMCs) and discuss the differential diagnosis with other related diseases. METHODS: Imaging findings of biliary hamartomas on ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), MR cholangiopancreatography (MRCP) and hepatobiliary scintigraphy were retrospectively analyzed in six patients. RESULTS: On ultrasound images, five of the six cases showed multiple small hyper-and hypo-echoic lesions with comet-tail echoes, especially when magnified by us with the usage of zoom function. In all the six cases, multiple tiny hypodense lesions less than 10 mm in diameter were revealed as scattered throughout the liver with no enhancement on CT. These tiny lesions were demonstrated to be hyper-and hypo-intensity on T2- and TI-weighed images, respectively, in three patients who underwent MRI examinations. MRCP was performed in two patients, and clearly showed multiple tiny irregular-and round-shaped hyper-intensity lesions. MRCP and hepatobiliary scintigraphy showed normal appearances of intra-and extra-hepatic bile ducts in two and one patients, respectively. CONCLUSION: Imaging modalities are useful in the diagnosis and differential diagnosis of VMCs. A correct diagnosis might be obtained when typical imaging findings are present even without a histological confirmation. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.
• Well-differentiated HCC manifesting hyperattenuation on CT during arterial portography, Kim, SR, KI Kim, Y Maekawa, S Imoto, T Ninomiya, K Mita, K Ando, K Fukuda, S Fuki, M Kudo, T Matsuoka, N Sasase, M Taniguchi, Y Hayashi, HEPATO-GASTROENTEROLOGY, HEPATO-GASTROENTEROLOGY, 52(65), 1559 - 1562, Sep. 2005 , Refereed
  Summary:A rare case of well-differentiated minute hepatocellular carcinoma (HCC) with hepatitis C virus-related cirrhosis, with unusual radiologic features, is presented, A 10-mm hypoechoic nodule disclosed by ultrasound in segment six showed hypoattenuation on computed tomography hepatic arteriography and hyperattenuation on computed tomography during arterial portography, indicating that the portal vein may have been the dominant vascularity of the nodule. Contrast-enhanced ultrasound revealed hypovascularity in the early arterial phase, isovascularity in the late vascular phase, and the same perfusion as that surrounding the liver parenchyma in the post-vascular phase, with the same pattern observed on the two imaging techniques. These findings were considered not compatible with those of well-differentiated HCC. Ultrasound-guided biopsy showed histological features of well-differentiated HCC with over two-fold the cellularity of the non-tumorous area with a high nuclear/cytoplasmic ratio, increased cytoplasmic eosinophilia, slight atypia and fatty change with an irregular thin trabecular pattern. Further studies may provide insights into the correlation between tumor neovascularity in multistep hepatocarcinogenesis and dual hemodynamics, including the artery and the portal vein.
• Ischemia of rat stomach mobilizes ECL cell histamine, M Kitano, M Bernsand, Y Kishimoto, P Norlen, R Hakanson, Y Haenuki, M Kudo, J Hasegawa, AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 288(5), G1084 - G1090, May 2005 , Refereed
  Summary:Microdialysis was used to study how ischemia-evoked gastric mucosal injury affects rat stomach histamine, which resides in enterochromaffin-like (ECL) cells and mast cells. A microdialysis probe was inserted into the gastric submucosa, and the celiac artery was clamped (30 min), followed by removal of the clamp. Microdialysate histamine was determined by enzyme-linked immunosorbent assay. In addition, we studied the long-term effects of ischemia on the oxyntic mucosal histidine decarboxylase activity in omeprazole-treated rats. Gastric mucosal lesions induced by the ischemia were enlarged on removal of the clamp. The microdialysate histamine concentration increased immediately on clamping (50-fold rise within 30 min) and declined promptly after the clamp was removed. In contrast, histidine decarboxylase activity of the ECL cells was lowered by the ischemia and returned to preischemic values 9 days later. Mast cell-deficient rats responded to ischemia-reperfusion much like wild-type rats with respect to histamine mobilization. Pretreatment with the irreversible inhibitor of histidine decarboxylase, alpha-fluoromethylhistidine, which is known to eliminate histamine from ECL cells, prevented the rise in microdialysate histamine. Pharmacological blockade of acid secretion (cimetidine or omeprazole) prevented the lesions induced by ischemia-reperfusion insult but not the mobilization of histamine. In conclusion, ischemia of the celiac artery mobilizes large amounts of histamine from ECL cells, which occurs independently of the gross mucosal lesions. The prompt reduction of the mucosal histidine decarboxylase activity in response to ischemia probably reflects ECL cell damage. The lesions develop not because of mobilization of histamine per se but because of ischemia plus reperfusion plus gastric acid.
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• Estimation of the malignant potential of gastrointestinal stromal tumors: the value of contrast-enhanced coded phase-inversion harmonics US, N Fukuta, M Kitano, K Maekawa, T Chikugo, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 40(3), 247 - 255, Mar. 2005 , Refereed
  Summary:Background. Recently. contrast agents for ultrasonography (US) such as Levovist have been introduced for routine clinical use. The contrast-enhanced US with Levovist permits evaluation of the intratumoral vascularity of hepatic and pancreatic tumors and is useful for their differential diagnosis. The purpose of the present study was to assess tumor vessels and the parenchymal flow of oastrointestinal stromal tumors (GISTs) by contrast-enhanced coded phase-inversion harmonic US and to evaluate whether vascularity is related to the malignant grade of the GISTs. Methods. Thirteen patients with GISTs were included in the present study. Tumors were observed in a real-time fashion of contrast-enhanced coded phase-inversion harmonic US after the injection of Levovist (400 mg/ml). The Vascular patterns were compared with tumor size, histological diagnosis. KIT mutations, and clinical findings such as metastasis. Results. The contrast-enhanced US images of the GISTs were classified into two types according to the blood flow area of the tumors as seen by real-time continuous imaging of the tumor vessels. The image pattern "Poor" represented vessels flowing only in the peripheral part of the tumor, and "Rich" represented abundant vessels flowing from the periphery to the central part of the tumor. According to the contrast-enhanced US images, five GISTs were classified as "Poor" and the others as "Rich." Based on the final diagnosis, all tumors with "Poor" images were determined to be benign GISTs. and the rest tumors except one with "Rich" images were determined to be malignant GISTs. Conclusions. Contrast-enhanced US image is more closely correlated with the final diagnosis than the histological findings.
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• Primary sclerosing cholangitis and hepatitis C virus infection, Kim, SR, S Imoto, M Taniguchi, KI Kim, N Sasase, T Matsuoka, Y Maekawa, T Ninomiya, K Ando, K Mita, S Fuki, T Koterazawa, K Fukuda, M Kudo, H Sakamoto, Y Hayashi, INTERVIROLOGY, INTERVIROLOGY, 48(4), 268 - 272, 2005 , Refereed
  Summary:Two cases of primary sclerosing cholangitis with hepatic C virus infection in a 62-year-old man and a 60-year-old woman are presented. The infection in the man was eradicated with interferon therapy in 1992. Seven years thereafter, endoscopic retrograde cholangiography revealed a diffuse 2.5-cm-long stenotic lesion in the common bile duct which was consequently resected. Histological examination of the resected specimen revealed proliferation of epithelial cells, plasma cell infiltration, and fibrosis in the submucosal layer of the common bile duct. The human leukocyte antigen DR loci were 2 and 9. In the woman, a 6-month course of interferon therapy in 1992 failed to eradicate the infection. Cholangiography in 1999 revealed multiple narrowings and dilatations of intra- and extrahepatic bile ducts. Ultrasound guided biopsy of the liver in 1992 had revealed onionskin lesions around the bile duct epithelium in the portal tract. The human leukocyte antigen DR locus was 2. From these findings, the 2 cases were diagnosed as primary sclerosing cholangitis. Further studies may provide insights into the relation between the pathogenesis of the disease and the infection. Copyright (C) 2005 S. Karger AG, Basel.
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• Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score, M Kudo, HY Chung, S Haji, Y Osaki, H Oka, T Seki, H Kasugai, Y Sasaki, T Matsunaga, HEPATOLOGY, HEPATOLOGY, 40(6), 1396 - 1405, Dec. 2004 , Refereed
  Summary:The Japan Integrated Staging score (JIS score), which combines the Child-Turcotte-Pugh classification and tumor-node-metastasis staging, has been proposed as a better prognostic staging system for hepatocellular carcinoma (HCC) than the Cancer of the Liver Italian Program (CLIP) scoring system. In this study, validation was performed among a larger patient population. A total of 4,525 consecutive patients with HCC who had been diagnosed at five institutions were included. Stratification ability, prognostic predictive power, and reproducibility were analyzed and compared with results from the CLIP scoring system. Only 45% (1,951 of 4,525) of all patients were categorized as early stage HCC according to JIS score (0 or 1), whereas 63% (2,878 of 4,525) of the patients were categorized as having a CLIP score of 0 or 1. Significant differences in survival curves were not observed among CLIP scores 3 to 6. In contrast, survival curves showed significant differences among all the JIS scores. The same JIS scoring subgroups showed a similar prognosis, and good internal reproducibility was observed in each of the institutions. Multivariate analysis of the prognosis in all 4,525 patients proved the JIS score to be the best prognostic factor. Furthermore, the Akaike information criteria proved that the JIS scoring system was statistically a better model for predicting outcome than the CLIP scoring system. In conclusion, the stratification ability and prognostic predictive power of the JIS score were much better than that of the CLIP score and were simple to obtain and remember.
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• Anisakis in a biopsy specimen from the edge of a gastric ulcer: report of a case, M Shiomi, T Kamisako, Yutani, I, R Yoshimoto, M Kudo, R Fujii, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 60(5), 854 - 856, Nov. 2004 , Refereed
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• Hepatocellular carcinoma that ruptured during radiofrequency ablation therapy, T Kawasaki, M Kudo, H Chung, Y Minami, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 39(10), 1015 - 1016, Oct. 2004 , Refereed
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• Hypervascular liver nodules in heavy drinkers of alcohol, Kim, SR, Y Maekawa, S Imoto, M Sugano, M Kudo, ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 28(8), 174S - 180S, Aug. 2004 , Refereed
  Summary:Background: Three cases of hypervascular nodules in the liver, without hepatitis B or C virus infection and with a history of alcohol abuse (120 ml/day for 15 to 30 years), are presented. Results: Ultrasound examination revealed hypoechoic nodules in segment 6 (2 cm in diameter, case 1), in the right and left lobes (1-2 cm multiple type, case 2), and in segment 4 (4 cm, case 3). Hepatic angiography and computed tomography during arteriography revealed hypervascular nodules in the three cases. First, hepatocellular carcinoma, focal nodular hyperplasia, hemangioma, hemangioendothelioma, inflammatory pseudotumor, and pseudolymphoma were diagnostically differentiated. Histologically, there was no evidence of hepatocellular carcinoma or of any of the pathologies considered in the differential diagnosis by imaging studies. In case 1, the lesion was composed of an irregular, thin, trabecular-pattemed hepatic acinus with slighter hypercellularity than in the nonnodular area. In cases 2 and 3, the lesions were composed mainly of fibrosis without hyperplasia, showing stellate scar-like fibrosis septa dividing the nodule. Marked pericellular fibrosis, neutrophilic infiltration, and Mallory bodies in the cytoplasm were also observed. In cases 1 and 2, small unpaired arteries explaining the hypervascularity of the nodules were observed. Conclusion: These hypervascular nodules were classified as regenerative, not neoplastic, nodules according to the classification of the International Working Party.
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• Percutaneous radiofrequency ablation guided by contrast-enhanced harmonic sonography with artificial pleural effusion for hepatocellular carcinoma in the hepatic dome, Y Minami, M Kudo, T Kawasaki, H Chung, C Ogawa, H Shiozaki, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 182(5), 1224 - 1226, May 2004 , Refereed
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• Characterization of hepatic tumors: Value of contrast-enhanced coded phase-inversion harmonic angio, YL Wen, M Kudo, RG Zheng, H Ding, P Zhou, Y Minami, HY Chung, M Kitano, T Kawasaki, K Maekawa, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 182(4), 1019 - 1026, Apr. 2004 , Refereed
  Summary:Objective. Our purpose was to evaluate the value of contrast-enhanced. coded phase-inversion harmonic imaging in showing the characteristic intranodular hemodynamics of hepatic tumors. Subjects and Methods. Using a microbubble contrast agent we performed coded harmonic angio in 163 patients with 192 hepatic tumor nodules: 153 hepatocellular carcinomas, 13 metastases, 14 hemangiomas, eight dysplastic nodules, and four focal nodular hyperplasias. After injecting Levovist, we performed real-time scanning, interval-delay fast low-angle shot imaging, and sweep scanning in the early arterial phase, late vascular phase, and postvascular phase, respectively. Results. On contrast-enhanced coded harmonic angio, the typical hemodynamic pattern of hepatocellular carcinomas was shown as abundant tumor vessels supplied from the periphery to the center of the tumor and dense parenchymal tumor staining with fast washout (sensitivity, 92.8%; specificity, 92.3%). The characteristic hemodynamic pattern of metastases was peripheral tumor vessels with a rim parenchymal stain in the vascular phase followed by a perfusion defect in the postvascular phase (sensitivity, 69.2%; specificity, 100%). Hemangiomas were hypovascular in the early arterial phase with gradual spotty or cotton-wool pooling continuing to the late vascular phase (sensitivity, 92.9%; specificity, 100%). Dysplastic nodules were shown as having no early arterial supply with isovascularity in the late vascular phase (sensitivity, 75%; specificity, 100%). Focal nodular hyperplasias were shown to have a spoked wheel pattern of blood vessels accompanied by dense staining in interval-delay scanning (sensitivity, 100%; specificity, 100%). Conclusion. Contrast-enhanced coded harmonic angio is a promising method to provide useful information for the differential diagnosis of hepatic tumors.
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• Comparison of argon plasma coagulation and paravariceal injection sclerotherapy with 1% polidocanol in mucosa-fibrosing therapy for esophageal varices, S Matsui, M Kudo, R Nakaoka, M Shiomi, T Kawasaki, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 39(4), 397 - 399, Apr. 2004 , Refereed
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• Hepatocellular carcinoma and NASH, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 39(4), 409 - 411, Apr. 2004 , Refereed
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• Local ablation therapy for hepatocellular carcinoma: current status and future perspectives, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 39(3), 205 - 214, Mar. 2004 , Refereed
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• Afferent and efferent vessels of premalignant and overt hepatocellular carcinoma: Observation by color Doppler Imaging, H Tochio, M Kudo, INTERVIROLOGY, INTERVIROLOGY, 47(3-5), 144 - 153, 2004 , Refereed
  Summary:Afferent and efferent vessels of premalignant and overt hepatocellular carcinoma (HCC) were analyzed using color Doppler imaging. With afferent blood flow, constant waveform signals reflecting portal inflow are a characteristic finding in dysplastic nodules and early well-differentiated HCC. Among advanced HCCs lacking portal blood flow, inflow of arterial pulsatile blood flow signals is characteristic for advanced HCC with increased arterial vascularity. Efferent blood flow enters the hepatic vein of the lowest pressure system in dysplastic nodules and early well-differentiated HCC with afferent portal blood flow. Analysis of waveforms of efferent blood flow signals in advanced HCC detects in the opposite direction adjacent to an accompanying afferent arterial pulsatile blood flow signal. In conclusion, during multistep human hepatocarcinogenesis hemodynamics show characteristic changes; the state of afferent portal blood with low arterial vascularity loses the portal blood flow, and arterial vascularity gradually increases. The efferent blood flow pathway also changes with the pathological multistep development process. Copyright (C) 2004 S. Karger AG, Basel.
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• Detection of intratumoral vascularity in small hepatocellular carcinoma by coded phase inversion harmonics, YL Wen, P Zhou, M Kudo, INTERVIROLOGY, INTERVIROLOGY, 47(3-5), 169 - 178, 2004 , Refereed
  Summary:Objective: To investigate the value of contrast-enhanced coded phase inversion harmonic imaging (PIHI) in the depiction of intratumoral vascularity in small hepatocellular carcinoma (HCC). Methods: Eighty-five patients with 106 HCCs less than or equal to3 cm in diameter were evaluated with coded harmonic angio (CHA), a coded PIHI, with use of an intravenous contrast medium, Levovist. Intratumoral vessels were detected in the early arterial phase, and tumor parenchymal stain was demonstrated in the late vascular phase. The detectability of intratumoral vascularity on contrast-enhanced CHA was compared with that on dynamic computed tomography (CT) and digital subtraction angiography (DSA). Results: With a combination of both vessel images and parenchymal flow images demonstrated by contrast-enhanced CHA, 98 of 106 small HCCs were evaluated as being hypervascular or isovascular. Using the results on dynamic CT as a gold standard, the sensitivity, specificity and accuracy were 95.1, 100 and 95.3%, respectively. The detection rate of intratumoral vascularity by contrast-enhanced CHA was 92.5% (98/106), compared with 97.2% (103/106) on dynamic CT (p=0.14) and 88.9% (40/45) on DSA (p=0.53). Conclusions: Contrast-enhanced coded PIHI is a sensitive tool for depicting intratumoral vascularity of small HCC. Copyright (C) 2004 S. Karger AG, Basel.
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• Hepatobiliary and pancreatic: Inflammatory pseudotumor of the liver, RQ Zheng, M Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 18(8), 994 - 994, Aug. 2003 , Refereed
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• Characterization of focal hepatic lesions with contrast-enhanced C-cube gray scale ultrasonography, WP Wang, H Ding, Q Qi, F Mao, ZZ Xu, M Kudo, WORLD JOURNAL OF GASTROENTEROLOGY, WORLD JOURNAL OF GASTROENTEROLOGY, 9(8), 1667 - 1674, Aug. 2003 , Refereed
  Summary:AIM: To characterize enhancement patterns of focal hepatic lesions using C-cube gray scale sonography with a microbubble contrast agent and to evaluate its usefulness in differential diagnosis of hepatic lesions. METHODS: Fifty-four patients with 58 focal hepatic lesions were examined with Levovist-enhanced C-cube gray scale sonography. The final diagnosis of hepatic lesions was 29 primary liver cancers, 4 metastases, 8 hemangiomas, 12 focal nodular hyperplasias, 2 inflammatory pseudotumors of the liver and 3 angiomyolipomas. The initiation time of enhancement in various lesions and enhancement duration after administration of contrast agent were compared. Vascular findings in lesions were classified as peripheral enhancement, homogenous enhancement, mosaic enhancement and no enhancement depending on microbubble signals in the lesion relative to the liver parenchyma. RESULTS: The initiation time of enhancement in hemangioma (48+/-12 s) was significantly later compared to other lesions (P<0.05). The enhancement duration of malignancies (69+/-33 s in primary liver cancer, 61+/-23 s in metastasis) was significantly shorter compared to benign lesions (P<0.05). Intranodular enhancement appearing at arterial phase and decreasing at portal venous phase was considered characteristic for malignancy. Intranodular enhancement did not appear earlier than the liver parenchyma, and peripheral enhancement pattern was regarded as positive findings for hemangioma. Intranodular enhancement appeared in the arterial phase, and homogenous enhancement pattern sustained in the whole portal venous phase were regarded as positive findings for focal nodular hyperplasia. No microbubble signals appeared in two inflammatory pseudotumors of the liver. CONCLUSION: C-cube gray scale sonography can demonstrate dynamic intranodular enhancement in various focal hepatic lesions. The information provided by this methodology may be useful in the differential diagnosis of hepatic lesions.
• Radiofrequency ablation of hepatocellular carcinoma: Therapeutic response using contrast-enhanced coded phase-inversion harmonic sonography, YL Wen, M Kudo, RQ Zheng, Y Minami, H Chung, Y Suetomi, H Onda, M Kitano, T Kawasaki, K Maekawa, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 181(1), 57 - 63, Jul. 2003 , Refereed
  Summary:OBJECTIVE. This study was performed to evaluate the usefulness of contrast-enhanced coded phase-inversion harmonic sonography in assessing the therapeutic response of percutaneous radiofrequency ablation in patients with hepatocellular carcinoma. SUBJECTS AND METHODS. Sixty-seven patients with a total of 107 examinations on 91 hepatocellular carcinoma nodules underwent coded harmonic angio, a technique of coded phase-inversion harmonic sonography, using the IV microbubble contrast agent Levovist before and after percutaneous radiofrequency ablation. The intratumoral blood vessels and tumor parenchymal stain were detected in the early arterial phase and the late vascular phase, respectively. The results of contrast-enhanced imaging with coded harmonic angio were compared with those of three-phase dynamic CT. RESULTS. Before treatment, all examined 107 hepatocellular carcinoma nodules were found to be hypervascular on contrast-enhanced imaging with coded harmonic angio. After radiofrequency ablation, contrast-enhanced coded harmonic angio detected persistent signal enhancement in 41 examined nodules (38.3%), whereas this technique showed no intratumoral enhancement in the remaining 66 (61.7%) examined nodules. Compared with dynamic CT, the sensitivity, specificity, and diagnostic accuracy of contrast-enhanced coded harmonic angio were 95.3%, 100%, and 98.1%, respectively. With contrast-enhanced coded harmonic angio, we found that it was difficult to identify the safety margin that can be detected on dynamic CT. CONCLUSION. Contrast-enhanced imaging with coded harmonic angio may provide an alternative approach that has high diagnostic agreement with dynamic CT in assessing the therapeutic effect of radiofrequency ablation in hypervascular hepatocellular carcinomas, in spite of having limitations in identifying the safety margin.
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• Hepatocellular carcinoma associated with secondary haemochromatosis in non-cirrhotic liver: a case report, HY Chung, M Kudo, T Kawasaki, M Kitano, Y Minami, Y Suetomi, H Onda, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 26(3), 254 - 258, Jul. 2003 , Refereed
  Summary:We describe one case of hepatocellular carcinoma (HCC) arising in secondary haemochromatosis in a non-cirrhotic liver. The patient was a 40-year-old male. He had severe pancytopenia due to myelodysplastic syndrome (MDS) and developed secondary haemochromatosis as a result of a large amount of erythrocyte transfusion. Multiple nodules of the liver appeared about 6 years after the diagnosis of MDS. Needle biopsy of the nodules histologically confirmed them to be moderately differentiated HCCs. The liver parenchyma was shown to be non-cirrhotic and a deposit of hemosiderin was also identified, consistent with a finding of haemochromatosis of the liver. Transarterial chemoembolization was performed to treat multiple HCCs. There are a number of reports describing HCC occurrence in non-cirrhotic patients with hereditary haemochromatosis. However, HCC in secondary haemochromatosis without cirrhosis is extremely rare. (C) 2003 Elsevier Science B.V. All rights reserved.
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• Stage IV hepatocellular carcinoma with portal venous tumor thrombus: complete response after combined therapy of repeated arterial chemoembolization and radiofrequency ablation, RQ Zheng, M Kudo, Y Minami, K Inui, HY Chung, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 38(4), 406 - 409, Apr. 2003 , Refereed
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• Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score), M Kudo, HB Chung, Y Osaki, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 38(3), 207 - 215, Mar. 2003 , Refereed
  Summary:A clinical staging system for cancer patients provides guidance for patient assessment and making therapeutic decisions. It is useful in deciding whether to treat a patient aggressively, and in avoiding the overtreatment of patients who would not tolerate the treatment or patients whose life expectancy rules out any chance of treatment. Clinical staging is also an essential tool for comparison between groups in therapeutic trials and for comparison between different studies. The current classifications most commonly used for hepatocellular carcinoma (HCC) are the Okuda stages, the Child-Pugh staging system, tumor node metastasis (TNM) staging, and the Cancer of the Liver Italian Program (CLIP) score. Among these, the CLIP score is currently the most commonly used integrated staging score, including both tumor stage and liver disease stage. Although the CLIP score has been well validated by many authors in terms of its prognostic value in HCC patients, this score has some problems and limitations when applied to currently diagnosed HCC patients, who are diagnosed in the early stage of disease. First, the CLIP score can discriminate score 0- to 3-patient populations, but it is not able to discriminate score 4- to 6-patient groups. Second, the definition of tumor morphology in the best prognostic group is too advanced, i.e., uninodular and a tumor extent of less than 50% of the liver. As a result, the prognosis of the CLIP system best prognostic group is not so good. In other words, this system cannot identify the best prognostic group who would benefit from curative and aggressive treatment. Third, nearly 80% of the patient population is classified as having a CLIP score of 0-2, as confirmed by many studies, which shows poor stratification ability. In contrast, a new staging system based on the Liver Cancer Study Group of Japan (LCSGJ), the Japan Integrated Staging (JIS) score is currently proposed in Japan. This staging system combines Child-Pugh grade (grade A, score 0; grade B, score 1; grade C, score 2) and TNM staging by the LCSGJ criteria (stage 1, score 0; stage 11, score 1; stage 111, score 2; stage IV, score 3). The stratification ability of the JIS scoring system is much better than that of the CLIP scoring system. The JIS scoring system also performed better than the CLIP scoring system in selecting the best prognostic patient group. The cumulative 10-year survival rates of the best prognostic groups in the CLIP staging system (CLIP score 0) and JIS staging system (JIS score 0) were 23% and 65%, respectively (P < 0.01). All scoring systems arise as a compromise between simplicity and discriminatory ability. We confirmed that the JIS score increases predictive efficacy, while remaining simple compared with the CLIP score. Because the JIS score is quite easily obtained and is objective, we strongly propose it for widespread use as a prognostic staging system for HCC in clinical practice.
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• Hepatocellular carcinoma mimicking cavernous hemangioma on angiography and contrast enhanced harmonic ultrasonography. A case report, T Kawasaki, M Kudo, K Inui, C Ogawa, H Chung, Y Minami, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 25(2), 202 - 212, Feb. 2003 , Refereed
  Summary:A 73-year-old man with chronic hepatitis due to hepatitis C virus was referred to our hospital for close examination of hepatic nodule. An abdominal ultrasonography revealed a mosaic pattern nodule with 3.7 cm in diameter. Arterial phase of dynamic CT revealed the small caudal part and marginal area of cranial part of the tumor were enhanced. The enhancement of marginal area of cranial part of the tumor continued up to portal phase and equilibrium phase and enhanced area was gradually filling in to the central area. On the other hand, the caudal part of the tumor was less enhanced compared with surrounding normal hepatic area in portal phase and equilibrium phase. An abdominal angiography revealed spotty tumor staining mimicking cotton-wool appearance, which is a typical finding for cavernous hemangioma. Contrast enhanced harmonic ultrasonography also showed hemangioma like finding (peripheral globular enhancing pattern). Because of these discrepancies on imagings, it was difficult to make final diagnosis of this tumor to be hepatocellular carcinoma since cavernous hemangioma cannot be completely ruled out. The pathological study of the specimen taken by US-guided percutaneous needle biopsy finally confirmed this nodule as hepatocellular carcinoma. In conclusion, we must keep in mind that some hepatocellular carcinomas could mimic hemangioma due to peliotic change or large acinar formation, therefore, needle liver biopsy may be essential for correct diagnosis if there is a discrepancy in several imaging findings. (C) 2002 Elsevier Science B.V. All rights reserved.
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• Scintigraphic study of regenerative nodules due to fulminant hepatic failure, T Watanabe, M Kondo, M Hirasa, H Shirane, Y Okabe, Y Ibuki, S Tomita, A Orino, A Todo, Y Wakatsuki, T Chiba, M Kudo, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 38(7), 695 - 699, 2003 , Refereed
  Summary:We report the case of a 25-year-old woman with fulminant hepatic failure (FHF). Liver scintigraphy using Tc-99m-galactosyl human serum albumin (GSA) and Tc-99m-phytate produced interesting findings; regenerative nodules appeared as nodules of increased accumulation of Tc-99m-GSA, whereas these nodules were expressed as defects of accumulation of Tc-99m-phytate. These scintigraphic findings suggested that the functions of hepatocytes in regenerative nodules were maintained, whereas those of Kupffer cells were impaired. Although Tc-99m-GSA scintigraphy indicated hepatic functional reserve enough to survive, she died despite intensive therapy including plasma exchange. Based on this case. it is recommended that not only Tc-99m-GSA scintigraphy but also 99mTc-phytate scintigraphy is required to evaluate the prognosis of patients with FHF.
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• Risk of HCV transmission after needlestick injury, and the efficacy of short-duration interferon administration to prevent HCV transmission to medical personnel, H Chung, M Kudo, T Kumada, S Katsushima, A Okano, T Nakamura, Y Osaki, K Kohigashi, Y Yamashita, H Komori, S Nishiuma, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 38(9), 877 - 879, 2003 , Refereed
  Summary:Background We carried out this study to assess the risk of hepatitis C virus (HCV) transmission after needlestick injuries in medical personnel, and to evaluate the efficacy of short-duration interferon administration to prevent HCV transmission. Methods. A total of 684 personnel who had been occupationally exposed to an anti-HCV-positive source and followed for more than 3 months were retrospectively examined. Results. Of the 684 subjects, 279 (41%) were treated with 1 to 3 days of interferon either just after or 1 to 12 days after the injury. One case of HCV infection was found in each of the treated (1/279; 0.4%) and nontreated (1/405; 0.2%) groups. There was no significant difference in the transmission of HCV between the two groups. Both infected patients were treated with interferon after developing acute hepatitis, and HCV was subsequently cleared. Conclusions. There is a lower risk of HCV transmission after needlestick accident than previously reported, and short-duration interferon administration at an early stage after the needlestick injury, to prevent HCV transmission, is unnecessary.
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• Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis, J Hayashi, K Kajino, T Umeda, S Takano, Y Arakawa, M Kudo, O Hino, INTERNATIONAL JOURNAL OF ONCOLOGY, INTERNATIONAL JOURNAL OF ONCOLOGY, 21(4), 847 - 850, Oct. 2002 , Refereed
  Summary:Human DNA-binding protein (dbpA) is a member of a Y-box binding protein family containing a cold shock domain. The increased expression of Y box binding proteins in somatic cells is associated with cell proliferation and transformation. Recently, we isolated a splicing variant of dbpA as a candidate for the cellular recombinogenic protein that leads to genomic instability and inflammation-mediated hepatocarcinogenesis. The expression of dbpA is enhanced in proliferating cells, but the manner in which it regulates transcription is largely unknown. In this study, we analyzed the transcriptional regulatory region of dbpA, and searched for the mutation in this region by a direct sequence method. In 3 of 55 human hepatocellular carcinoma (HCC) cases, we identified one nucleotide replacement (T-->G transversion) in nucleotide position -6 of the promoter region. Among 3 cases showing this transversion, one HCC case was due to a somatic mutation and the other two were due to single nucleotide polymorphism (SNP). By luciferase assay, we showed that the transcriptional activity of the promoter region with the transversion was significantly higher than that of the wildtype. Using the Southwestern blotting, we also confirmed the existence of a cellular proteins (about 25 and 50 kDa) that specifically bind to the sequence with this transversion. Our results suggested the biological significance of the transversion of dbpA's promoter region as one of the factors accelerating hepatocarcinogenesis.
• Eosionophilic pseudotumor of the liver due to Ascaris suum infection, Kim, SR, Y Maekawa, T Matsuoka, S Imoto, K Ando, K Mita, HB Kim, T Nakajima, KS Ku, T Koterazawa, K Fukuda, Y Yano, M Nakaji, M Kudo, KI Kim, M Hirai, Y Hayashi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 23(4), 306 - 314, Aug. 2002 , Refereed
  Summary:A case of eosinophilic pseudotumor of the liver due to Ascaris (A) suum is described in a 34-year-old-man with a high serum level of immunoglobulin E and hypereosinophilia ascribed to a history of atopic dermatitis since childhood. Multiple hepatic hypoechoic nodules detected by ultrasound were confirmed as low-density nodules on computed tomography (CT), and as low and high signal intensity lesions on T1- and T2-weighted magnetic resonance imaging (MRI), respectively. CT during arteriography (CTA) and arterial portography revealed multiple nodules with ring-shaped enhancement and perfusion defect, respectively. Biopsied liver tissue specimens did not contain tumor cells or atypical cells; instead, they showed marked infiltration of eosinophils with necrosis and Charcot-Leyden crystals in the portal tracts and hepatic sinusoides, suggesting parasitic infection, although neither larvae nor eggs were detected. The diagnosis of visceral larva migrans (VLM) due to A. suum was based on immunoserological tests. The patient was a habitual consumer of raw bovine liver, which may explain the A. suum infection. After drug therapy with albendazole, the hypoechoic nodules disappeared. Differential diagnoses and the possible transfection route of A. suum are discussed. (C) 2002 Elsevier Science B.V. All rights reserved.
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• Development of multicentric hepatocellular carcinoma after completion of interferon therapy, Kim, SR, T Matsuoka, Y Maekawa, Y Yano, S Imoto, M Kudo, S Shintani, K Ando, K Mita, K Fukuda, T Koterazawa, M Nakaji, H Ikawa, T Ninomiya, KI Kim, M Hirai, Y Hayashi, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 37(8), 663 - 668, Aug. 2002 , Refereed
  Summary:We report a case of multicentric hepatocellular carcinoma that developed in a 74-year-old man 3 and 6 years after interferon (IFN) treatment for chronic hepatitis C, despite sustained virologic, biochemical, and histological improvement. Initially, serum hepatitis C virus RNA was positive and the patients' serum level of alanine aminotransferase (ALT; 82IU/ml) was abnormal. Hepatitis B virus (HBV) in the serum was negative for surface antigen, surface antibody, core antibody, and DNA. The patient was started on 10 x 10(6) international units (IU) of IFNalpha, 3 days a week for a total of 24 weeks. After the IFN therapy, the patient demonstrated a normal serum ALT level, and was continuously negative for HCV-RNA, and histology improved from chronic active hepatitis to chronic persistent hepatitis. Follow-up studies with ultrasonography (US) every 3 months and computed tomography (CT) every 6 months revealed no space-occupying lesion (SOL) for 3 years after IFN treatment. US-guided biopsies of two 15-mm hypoechoic SOLs in segments eight (S8) and seven (S7) 34 and 74 months, respectively, after IFN treatment showed well-differentiated hepatocellular carcinoma (HCC). Clinical data, imaging studies, and histologic examinations showed that both tumors were multicentric HCC. Further studies may provide insights into the possible role of HCV in hepatocarcinogenesis in patients demonstrating HCV eradication by IFN treatment.
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• Multidetector CT: Diagnostic impact of slice thickness on detection of hypervascular hepatocellular carcinoma, S Kawata, T Murakami, T Kim, M Hori, MP Federle, S Kumano, E Sugihara, S Makino, H Nakamura, M Kudo, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 179(1), 61 - 66, Jul. 2002 , Refereed
  Summary:OBJECTIVE. The objective of our study was to evaluate the diagnostic impact of varying slice thickness on multidetector CT to optimize detection of hypervascular hepatocellular carcinoma. MATERIALS AND METHODS. Forty-three patients with 87 hypervascular hepatocellular carcinomas (diameter: range, 3-80 mm; mean, 22 mm) and 19 patients with either chronic hepatitis or liver cirrhosis and without hepatocellular carcinoma who had undergone early arterial and late arterial phase imaging of the entire liver on multidetector CT were retrospectively enrolled in this study. The detector row configuration was 2.5 x 4 mm, the pitch was 6, and the scanning time was 10.5 sec for each phase. All patients received contrast medium (2 mL/kg of body weight) at a rate of 5 mL/sec; the mean scanning delay for the early arterial phase was 19.0 sec, and the mean delay for the late arterial phase was 34.5 sec. Eighty 2.5-mm-thick reconstruction images, forty 5-mm-thick reconstruction images, and twenty-six 7.5-mm-thick reconstruction images were obtained for each phase. Each image set was interpreted separately by three observers to detect hypervascular hepatocellular carcinoma by viewing images on a workstation monitor. Sensitivity, positive predictive value, and area under the receiver operating characteristic curve (A(z)) were calculated. We used retrospectively excellent follow-up and imaging or pathologic proof as the gold standard. RESULTS. The mean sensitivity and positive predictive value for hypervascular hepatocellular carcinoma were 76% and 69% on 2.5-mm images, 73% and 69% on 5-mm, images, and 67% and 76% on 7.5-mm images, respectively. No significant difference in sensitivity among the images was detected, except by one observer who reported a significant difference in the sensitivity between 2.5- and 7.5-mm images (p < 0.05) and between 5- and 7.5-mm images (p < 0.05). The mean A(z) values were 0.79, 0.80, and 0.78 for 2.5-, 5-, and 7.5-mm images, respectively. No significant difference in A(z) values among the images obtained with different slice thicknesses was detected. CONCLUSION. For multidetector CT identification of hypervascular hepatocellular carcinoma, we found little or no advantage in reducing slice thickness to less than 5 mm.
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• Intrahepatic huge hematoma due to rupture of small hepatocellular adenoma: A case report, Y Minami, M Kudo, T Kawasaki, HB Chung, S Matsui, M Kitano, Y Suetomi, H Ondo, S Funai, K Kou, M Yasutomi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 23(2), 145 - 151, Jun. 2002 , Refereed
  Summary:Hepatocellular. adenoma sometimes causes intraperitoneal hemorrhage. It is, however, rare for small hepatocellular adenoma to cause intrahepatic huge hemorrhage without intraperitoneal bleeding. Here we describe such a rare case of hepatocellular adenoma with huge intrahepatic hemorrhage in a 25-year-old female, who had taken oral contraceptives for the last 2 weeks. She was admitted to our hospital with a sudden onset of right-upper-quadrant abdominal pain and temporally fell in shock state. Plain CT depicted low density area measuring more than 13 cm in diameter in the right lobe of the liver. Huge tumor was also suggested by abdominal ultrasound, contrast enhanced CT, magnetic resonance imaging (MRI) and angiography. The patient was diagnosed as intrahepatic rupture of hepatic tumor. Because of the risk of re-hemorrhage and malignancy, she underwent right hepatic lobectomy. Histopathologial examination of the resected specimen showed a typical small hepatocellular adenoma with the surrounding huge hematoma in the liver. The case presented here is very rare but seems to be suggestive to the natural course and management of hepatocellular adenoma. (C) 2002 Elsevier Science B.V. All rights reserved.
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• CEA producing primary hepatic carcinoid, Kim, SR, S Imoto, Y Maekawa, T Matsuoka, Y Hayashi, K Ando, K Mita, S Shintani, HB Kim, K Ku, T Koterazawa, K Fukuda, Y Yano, M Nakaji, H Ikawa, T Ninomiya, M Kudo, KH Kim, M Hirai, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 22(4), 313 - 321, Apr. 2002 , Refereed
  Summary:Imaging studies of a hepatic tumor in a 53-year-old woman with elevated serum levels of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and 5-hydroxyindole acetic acid (5HIAA) revealed a hypervascular tumor in the right lobe. Grossly, the brownish tumor was measured 13.5 x 12 cm with four daughter nodules. Microscopically, the majority of these columnar and round tumor cells had ribbon-or rosette-like patterns with the expression of neuroendocrine marker proteins, such as Grimelius, NSE, chromogranin A, and synaptophysin, and moderate expression of CEA but without the expression of cytokeratin nos 7,8,14,18,19 and OV-6; the minority had glandular patterns with a strong expression of CEA but without the expression of cytokeratin nos 7,8,14,18,19 and OV-6. Ultrastructurally, most tumor cells contained populations of electron-dense core granules ranging between 100 and 200 nm in diameter. After hepatectomy, serum CEA, NSE, and 5HIAA reverted to normal ranges and persisted for 19 months. These findings suggested that the diagnosis of primary hepatic carcinoid was tenable and that the tumor might derive from hepatic stem cells which acquired the additional nature of producing CEA without cytokeratins characteristic of hepatocytes or bile duct cells. Some molecular based approaches have attributed unique biological behavior and histogenesis to this carcinoid tumor. (C) 2002 Elsevier Science B.V. All rights reserved.
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• Multi-detector row helical CT angiography of hepatic vessels: Depiction with dual-arterial phase acquisition during single breath hold, S Takahashi, T Murakami, M Takamura, T Kim, M Hori, Y Narumi, H Nakamura, M Kudo, RADIOLOGY, RADIOLOGY, 222(1), 81 - 88, Jan. 2002 , Refereed
  Summary:PURPOSE: To determine by using multi-detector row computed tomography (CT), in a triphasic hepatic dynamic study, which included single breath-hold dual-arterial phase acquisition, the accuracy and frequency of visualization of the small hepatic arterial and portal venous anatomy with angiographic correlation. MATERIALS AND METHODS: In 62 patients, pre- and postcontrast triphasic helical CT were performed by using a multi-detector row CT scanner, with 2.5-mm detector row collimation, at a pitch of 6. The first and second arterial phases were performed during a single breath hold. One reader, blinded to the results of the angiography, reviewed the first arterial phase images on a cine display to assess hepatic arterial anatomy. Visualization of the portal vein and its branches was assessed by using second arterial and portal venous phase images. RESULTS: Major arterial trunks (celiac, hepatic, superior mesenteric, and left gastric) were depicted in all cases. Visualization of small arteries was as follows: right and left hepatic, 62 (100%) of 62; middle hepatic, 52 (87%) of 60; cystic, 47 (90%) of 52; right gastric, 50 (89%) of 56; and right and left inferior phrenic, 57 (92%) and 55 (89%) of 62 respectively Subsegmental or more peripheral branches of the portal vein were depicted in 83% of cases during the second arterial phase and in 96% during the portal phase. There was no difference in degree of visualization in these two phases. CONCLUSION: Multi-detector row CT angiography was able to depict the hepatic vascular anatomy.
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• Imaging blood flow characteristics of hepatocellular carcinoma, M Kudo, ONCOLOGY, ONCOLOGY, 62, 48 - 56, 2002 , Refereed
  Summary:Since a close relationship exists between intranodular hemodynamics and the grade of biological/pathological malignancy of a nodule occurring in the cirrhotic liver, an accurate evaluation of intranodular hemodynamics is highly essential. Intranodular hemodynamics in hepatocellular carcinoma (HCC) and borderline lesions can be evaluated correctly by invasive and noninvasive techniques. Invasive techniques such as ultrasound (US) angiography, computed tomographies during arteriography or arterial portography are sensitive in the detection of intranodular arterial and portal supplies, for accurate diagnosis of tumors and assessing grades of biologically malignant potential. However, these approaches require an angiographic procedure, which is not always available. Recently, perfusion imaging techniques under US, including contrast-enhanced harmonic imaging or real-time gray-scale harmonic imaging, have become available for routine clinical use. With these techniques, all the five roles of imaging in the management of HCC, i.e., detection, confirmation, staging, evaluation of malignancy grade, and postoperative follow-up, have become much simpler. Perfusion imaging techniques have reduced the requirement for dynamic CT or MRI and may replace some of their roles in the clinical setting. Since viable cancer cells are accurately imaged on US monitoring with sensitive perfusion imaging techniques, the contrast-enhanced harmonic imaging will be of great advantage in US-guided treatment of HCC. With the advent of rapid and remarkable advances in US harmonic imaging techniques, the diagnostic and therapeutic strategies for HCC are changing drastically. Copyright (C) 2002 S. Karger AG, Basel.
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• Intrahepatic spontaneous retrograde portal flow in patients with cirrhosis of the liver: Reversal by food intake, H Tochio, M Kudo, S Nishiuma, Y Okabe, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 177(5), 1109 - 1112, Nov. 2001 , Refereed
  Summary:OBJECTIVE. The purpose of our study was to assess whether intrahepatic spontaneous retrograde portal flow in patients with cirrhosis of the liver can be reversed to a normal portal venous flow by food intake. CONCLUSION. Of the 18 cirrhotic patients with intrahepatic spontaneous retrograde portal flow, 16 (89%) showed a marked change in portal flow direction after food intake. This evidence strongly suggests that intrahepatic spontaneous retrograde portal flow may be reversible. Furthermore, this finding implies that regular food intake may be important in the maintenance of effective hepatic blood flow in cirrhotic patients.
• Sonographic diagnosis of pancreatic islet cell tumor: Value of intermittent harmonic imaging, H Ding, M Kudo, H Onda, H Nomura, S Haji, JOURNAL OF CLINICAL ULTRASOUND, JOURNAL OF CLINICAL ULTRASOUND, 29(7), 411 - 416, Sep. 2001 , Refereed
  Summary:We describe a case of nonfunctioning islet cell tumor of the pancreas diagnosed preoperatively by intermittent harmonic power Doppler imaging and digital subtraction gray-scale harmonic imaging and the use of the contrast agent SH U 508A (Levovist). Hypervascularity and tumor perfusion were clearly demonstrated with both harmonic imaging techniques in the early arterial phase. Sonographic findings were confirmed by other modalities and by histopathologic examination. (C) 2001 John Wiley & Sons, Inc.
• Hepatobiliary and pancreatic: Intrahepatic portal vein anomaly - Hepatobiliary and pancreatic: Commentary, YL Wen, M Kudo, T Kawasaki, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 16(7), 821 - +, Jul. 2001 , Refereed
• A case of disseminated extrahepatic hepatocellular carcinoma after US-guided biopsy and percutaneous ethanol injection therapy, Kim, SR, T Matsuoka, Y Maekawa, Y Yano, Y Hayashi, M Kudo, K Kim, S Imoto, KB Song, K Ando, S Shintani, T Koterazawa, K Fukuda, K Mita, M Taniguchi, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 20(2), 244 - 254, Jun. 2001 , Refereed
  Summary:A case of disseminated extrahepatic hepatocellular carcinoma (HCC) occurring after ultrasound (US)-guided biopsy and percutaneous ethanol injection therapy is presented. A 72-year-old man with hepatitis-C-virus-related cirrhosis underwent percutanous ethanol injection therapy (PEIT) two times with complete remission: the first for moderately-differentiated HCC in segment six (S6), and the second for well-differentiated HCC in another part of S6. Imaging studies including carbon dioxide (CO2)-US angiography, incremental computed tomography, and dynamic magnet resonance imaging showed that both HCCs were hypovascular. Twenty-one months after the first PEIT and 7 months after the second, a 5.5 x 4.5 cm extrahepatic mass interfaced with S6 of the liver was detected by imaging studies. The patient underwent surgery for extrahepatic HCC. Grossly, the main tumor was 5.5 x 4.5 cm with capsule and septum; the disseminated tumors were detected on the surface of the liver, including the right diaphragm and the fair ligamentosa. Histologically, it was moderately- to poorly-differentiated HCC, which, although not attributed to direct track seeding, was suspected of being induced by the percutaneous US-guided biopsy procedure or by PEIT, irrespective of a hypovascular tumor. Further studies may provide insight into the risk factor engendered by these procedures. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
• Two cases of histopathologically advanced (stage IV) early gastric cancers, M Shiomi, T Kamisako, Yutani, I, M Kudo, H Shigeoka, A Tanaka, K Okuno, M Yasutomi, TUMORI, TUMORI, 87(3), 191 - 195, May 2001 , Refereed
  Summary:We report two cases of early gastric cancer with distant metastases (stage IV). At our institute 1428 cases of primary gastric cancer were resected between 1980 and 1997; 536 were diagnosed as early gastric cancer based on the resected specimens (304 cases of mucosal cancer, Tis - TNM classification - and 232 of submucosal cancer, T1), 528 of these 536 cases were classified as histological stage I, six as stage II, none as stage III and two as stage IV. The incidence of stage IV early gastric cancer was 0.14% of all gastric cancers and 0.37% of the early gastric cancers,The two patients with stage IV early gastric cancer were women. Both tumors were defined as early cancer because they were confined to the submucosa, One was a type 0 IIc + III early cancer, histologically classifiable as a small, moderately differentiated adenocarcinoma (tub2 according to the Japanese Classification of Gastric Carcinoma(1,2), G2; TNM classification: ICD-O C16), size 10 x 8 mm; the other was a surface spreading type 0 lie, classifiable as a signet-ring cell carcinoma (sig, G3), size 50 x 35 mm. Stage IV factors were N3 in the first and ovarian metastasis (Krukenberg tumor) in the second case.
• Vascularity of advanced gastric carcinoma: Evaluation by using power Doppler imaging, T Kawasaki, T Ueo, T Itani, M Shibatohge, J Mimura, H Komori, A Todo, M Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 16(2), 149 - 153, Feb. 2001 , Refereed
  Summary:Background: We investigated the vascularity of advanced gastric adenocarcinomas by using percutaneous power Doppler imaging. Methods: Seventeen patients with gastric cancer and 10 without a gastric tumor, but with a slightly thick gastric wall in the B-mode ultrasound, were investigated with the use of power Doppler imaging. The color signals of the gastric lesion were graded as follows: 1, no color signals or the same as the surroundings; 2, color signals were slightly increasing; and 3, color signals were obviously increasing. Results: The color signals of three patients were graded 1, those of eight patients were graded 2 and those of six patients were graded 3 in the gastric cancer group. The color signals of all 10 patients without a gastric tumor were grade 1. This difference was statistically significant (P = 0.0002). Conclusions: Power Doppler imaging showed vascularity of gastric cancer increasing in the majority of patients (14 of 17: 82%). Thus, power Doppler imaging might be a good screening examination method for gastric cancer. (C) 2001 Blackwell Science Asia Pty Ltd.
• Gastric submucosal microdialysis: A method to monitor ECL-cell histamine mobilization from rat stomach., M Kitano, P Norlen, Y Kishimoto, J Hasegawa, H Kawasaki, M Kudo, T Itoh, R Hakanson, HISTAMINE RESEARCH IN THE NEW MILLENNIUM, HISTAMINE RESEARCH IN THE NEW MILLENNIUM, 1224, 299 - 304, 2001 , Refereed
• TTV positivity and transfusion history in non-B, non-C hepatocellular carcinoma compared with HBV- and HCV-positive cases, Kim, SR, Y Hayashi, M Kudo, S Imoto, KB Song, K Ando, S Shintani, T Koterazawa, KI Kim, M Taniguchi, INTERVIROLOGY, INTERVIROLOGY, 43(1), 13 - 15, Jan. 2000 , Refereed
  Summary:The prevalence of TT virus (TTV) and its rate of transmission through transfusion were investigated to determine its possible hepatocarcinogenic role in non-B, non-C hepatocellular carcinoma (HCC) as compared with that in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-positive HCC. Its transfection route in TTV-positive cases was also studied. Serum was positive for TTV in 77.8% (7/9) of HBV-positive, 36.4% (12/33) of HCV-positive, and 63.6% (7/11) of non-B, non-C cases of HCC. The rate of transmission through transfusion was 52.4% (11/21) in HBV-positive, 40.1% (61/152) in HCV-positive, 33.3% (2/6) in HBV+HCV-positive, and 40% (8/20) in non-B, non-C HCCs, while it was 48.3% (14/29) in TTV-positive and 39.3% (11/28) in TTV-negative cases. The association between TTV and HCC was limited, and the main route of infection of TTV was not th rough transfusion. Copyright (C) 2000 S. Karger AG, Basel.
• Cronkhite-Canada syndrome associated with triple gastric cancers: a case report, T Watanabe, M Kudo, H Shirane, H Kashida, S Tomita, A Orino, A Todo, T Chiba, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 50(5), 688 - 691, Nov. 1999 , Refereed
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• Inflammatory pseudotumor of the liver in a patient with chronic hepatitis C: Difficulty in differentiating it from hepatocellular carcinoma, Kim, SR, Y Hayashi, M Kudo, T Matsuoka, S Imoto, K Sasaki, S Shintani, KB Song, SY Park, JH Kim, K Ando, T Koterazawa, KI Kim, T Ninomiya, PATHOLOGY INTERNATIONAL, PATHOLOGY INTERNATIONAL, 49(8), 726 - 730, Aug. 1999 , Refereed
  Summary:A case of an inflammatory pseudotumor of the liver in a 75-year-old female with chronic hepatitis C whose radiologic features simulated that of hepatocellular carcinoma (HCC) is presented. On imaging studies, hypervascularity by CO2 ultrasound (US) angiography, enhancement at an early phase and isodensity at a late phase by incremental dynamic computed tomography (CT), perfusion defect by CT during arteriography (CTAP), and clinical background of hepatitis C virus (HCV) infection strongly suggested HCC. A US-guided needle biopsy revealed a mainly diffuse and polyclonal proliferation of lymphocytes positive for leukocyte common antigen (pan-lymphocyte cells), L-26 (B cell lymphocytes), and UCHL-1 (T cell lymphocytes), negative for both x and lambda light chains and sparsely distributed neutrophils and histiocytes. No lymphoid follicles were observed. The liver tissue around this tumor showed chronic hepatitis with mild activity and mild fibrosis. These histopathologic findings suggested that the diagnosis of inflammatory pseudotumor of the liver was tenable. As it is difficult to differentiate between inflammatory pseudotumor of the liver and HCC by imaging studies alone, supplemental biopsy, where possible, should be obtained when diagnostic imaging of tumors suggesting HCC is carried out. We emphasize that histopathology is a true gold standard in the diagnosis of this disease.
• High prevalence of anti-hepatitis B virus serological markers in patients with hepatitis C virus related chronic liver disease in Japan, H Marusawa, Y Osaki, T Kimura, K Ito, Y Yamashita, T Eguchi, M Kudo, Y Yamamoto, H Kojima, H Seno, F Moriyasu, T Chiba, GUT, GUT, 45(2), 284 - 288, Aug. 1999 , Refereed
  Summary:Background/Aims-Evidence is accumulating that hepatitis B virus (HBV) is present in patients who are hepatitis B surface antigen negative but have antibody to hepatitis B core antigen (anti-HBc). Furthermore, recent studies have shown that patients with hepatocellular carcinoma who have antibody to hepatitis C virus (HCV) often possess HBV related serological markers. Data on the seroprevalence of HBV infection in patients with HCV related chronic liver disease were collected to evaluate the significance of the presence of antibodies to HBV. Methods-The prevalence of HBV related serological markers was analysed in a total of 2014 Japanese patients with HCV infection. The control group comprised 352 subjects without Liver disorder. Results-A large number of patients (49.9%) with HCV related chronic liver disease including hepatocellular carcinoma were positive for anti-HBc. In addition, the prevalence of anti-HBc closely correlated with the clinical stage of the liver disease. There was no relation between a past history of blood transfusion and the prevalence of anti-HBc. Notably, anti-HBc was the only serological marker for HBV infection in a significant number of patients with HCV related chronic liver disease (24.1%). Conclusions-Our data provide further evidence for the high prevalence of anti-HBc in patients with HCV related chronic liver disease, particularly those with hepatocellular carcinoma, suggesting that HBV infection, probably including latent infection, may play an important role in carcinogenesis in these patients.
• Massive rectal bleeding due to ileal tuberculosis, T Watanabe, M Kudo, M Kayaba, H Shirane, S Tomita, A Orino, A Todo, T Chiba, JOURNAL OF GASTROENTEROLOGY, JOURNAL OF GASTROENTEROLOGY, 34(4), 525 - 529, Aug. 1999 , Refereed
  Summary:A patient with massive rectal bleeding due to ileal tuberculosis is reported. Technetium-99m labelled red blood cell scintigraphy indicated hemorrhage from the ileum, and laparotomy was then carried out. A 70cm segment of ileum containing ulcers and erosions was resected, and epitheloid granuloma with Langhans-type giant cell was found in the resected specimen. Massive rectal bleeding is considered a rare presenting symptom of intestinal tuberculosis. Intestinal tuberculosis, including small intestinal tuberculosis, although uncommon, should be taken into consideration as a cause of rectal bleeding.
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• Detection of Helicobacter pylori gene by means of immunomagnetic separation-based polymerase chain reaction in feces, T Watanabe, S Tomita, M Kudo, M Kurokawa, A Orino, A Todo, T Chiba, SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 33(11), 1140 - 1143, Nov. 1998 , Refereed
  Summary:Background: Detection of Helicobacter pylori is usually performed by culture, polymerase chain reaction (PCR), histology, or urease test on gastric biopsy samples. Although methods based on feces are noninvasive, their sensitivity has been relatively low. In this study, to improve its sensitivity, immunomagnetic separation (LMS) was used as a pre-PCR step for direct detection of H. pylori in feces. Methods: Fresh fecal samples were taken from 72 patients attending for endoscopy. Of these, 57 patients had a positive H. pylori status according to the results of culture, histology, and PCR on gastric biopsy samples. Anti-H. pylori antibody-sensitized immunomagnetic beads were used to concentrate the bacteria. PCR was then performed to detect the H. pylori urease A-encoding gene. Results: Of the 57 H. pylori-positive patients, 35 (61.4%) had positive fecal samples by IMS-based PCR method. None of the 15 H. pylori-negative patients had positive fecal samples. The sensitivity of this method was 61.4%, and the specificity 100.0%. Conclusions: This study confirms that non-invasive diagnosis of H. pylori infection could be made from feces by using IMS-based PCR.
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• A case of well-differentiated minute hepatocellular carcinoma with extrahepatic metastasis, Kim, SR, Y Hayashi, T Matsuoka, SY Park, S Shintani, K Sasaki, J Asano, JH Kim, KIH Kim, S Imoto, H Itoh, M Kudo, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 13(9), 892 - 896, Sep. 1998 , Refereed
  Summary:A rare case of well-differentiated minute hepatocellular carcinoma (HCC) metastasizing to distant sites in a 77-year-old man with hepatitis C virus (HCV)-related cirrhosis is presented. Ultrasonography (US) disclosed a 9 mm hypoechoic lesion in segment seven (S-7) Of the liver, although computed tomography (CT), magnetic resonance imaging (MRI) and angiography did not reveal any space-occupying lesion. Ultrasound-guided biopsy showed the histological features of well-differentiated HCC. A plain film of the abdomen and CT revealed osteolytic changes in the sacrum and the lumbar vertebra. Ultrasound-guided biopsy of the sacrum revealed well-to-moderately differentiated HCC metastasizing from the liver. Percutaneous ethanol injection therapy (PEIT) effected complete response and completely eliminated the abnormal findings on US. Three months after PEIT, metastasis to the thoracic vertebra was revealed by CT, despite negative alpha-fetoprotein-mRNA in serum. This is the first report describing a well-differentiated HCC with metastatic potential. Further studies may provide insights into metastasis of well-differentiated HCC.
• Field cancerization of human hepatocellular carcinomas in the hypercarcinogenic state., T Yamamoto, K Kajino, M Kudo, Y Sasaki, Y Arakawa, O Hino, HEPATOLOGY, HEPATOLOGY, 26(4), 2009 - 2009, Oct. 1997 , Refereed
• ENDOSCOPIC RETROGRADE EXTRACTION OF COMMON BILE-DUCT STONES WITH DRIP INFUSION OF ISOSORBIDE DINITRATE, Y IBUKI, M KUDO, A TODO, GASTROINTESTINAL ENDOSCOPY, GASTROINTESTINAL ENDOSCOPY, 38(2), 178 - 180, Mar. 1992 , Refereed
• DISTINCTION BETWEEN HEMANGIOMA OF THE LIVER AND HEPATOCELLULAR-CARCINOMA - VALUE OF LABELED RBC-SPECT SCANNING, M KUDO, K IKEKUBO, K YAMAMOTO, Y IBUKI, M HINO, S TOMITA, H KOMORI, A ORINO, A TODO, AMERICAN JOURNAL OF ROENTGENOLOGY, AMERICAN JOURNAL OF ROENTGENOLOGY, 152(5), 977 - 983, May 1989 , Refereed

Books etc

• IgG4-related disease and innate immunity. In “IgG4-Related Disease”, Curr Top Microbiol Immunol, Okazaki K, ed, Watanabe T, Yamashita K, Kudo M, Joint author, Vol. 401, pp115-128, Springer,   2017
• WHO Classification of Tumours of the Digestive System (Blue Book), Hepatocellular carcinoma., Joint author, WHO Press World Health Organization, Geneva, Switzerland,   2010
• “Textbook of Practical Ultrasound.” Ahuja B ed, USCON Academic Press, New Delhi, India, 2008, Pancreatic Ultrasound with esmphasis on EUS, Sole author,   2008
• “Textbook of Practical Ultrasound.“ Ahuja B ed, USCON Academic Press, New Delhi, India, 2008, Ultrasonography of diffuse liver diseases, Sole author,   2008
• Postgraqduate Course & Current Reviews in HEPATOLOGY. Clinico-patho-radiological Correlation., Newer imaging modality of hepatocellular carcinoma: role of contrast-enhanced coded phase inversion harmonics, Joint author, CBS Publishers & Distributors, New Dehli, India,   2004
• Contrast harmonic imaging in the diagnosis and treatment of hepatic tumors, Joint author, Springer Verlag, Tokyo,   2003
• Contrast harmonic imaging in the diagnosis and treatment of hepatic tumors, Sole author, Springer Verlag, Tokyo,   2003
• Contrast harmonic imaging in the diagnosis and treatment of hepatic tumors, Sole author, Springer Verlag,   2003
• In Dynamic Study of Efferent Tumor Blood Fow, Itai Y, Miura Y, eds, Color Doppler observation of efferent blood flow in liver tumors, Joint author, BRACCO, Italy,   2000
• "Hepatology in the 21st Century: Diagnosis and Therapy." Tanikawa K, Kojiro M, Gollan J, eds, Advances in diagnostic imaging of hepatocellular carcinoma, Joint author, IASL, APASL, and JSH JOINT POST GRADUATE TEXTBOOK, IASL Publ, Fukuoka,   2000
• "Abdominal and Gastrointestinal Imaging Multimedia Virtual Textbook", Gourtsoyiannis NE, Yamada R, I, Liver Radiological Examination- Ultrasonography (including Biopsy), Joint author, Medic-Online, Euromultimedia S.A., Luxembourg,   1999
• "Diagnosis and Treatment of Hepatocellular Carcinoma", Livraghi T, Makuuchi M, Buscarini, eds, Scintigraphy, Joint author, Greenwich Medical Media Limited, London, UK,   1997
• Liver Cancer, Okuda K and Tabor E, eds, Ultrasound Diagnosis, Joint author, Churchill Livingstone, London,   1997

Conference Activities & Talks

• RECIST v1.1 and irRECIST outcomes in advanced HCC treated with pembrolizumab (pembro), Edeline J, Karwal M, Zhu AX, Finn RS, Cattan S, Ogasawara S, Verslype C, Zagonel V, Fartoux L, Vogel A, Rosmorduc O, Verset G, Chan SL, Knox J, Daniele B, Cheng AL, Goldmacher G, Jensen E, Siegel AB, Kudo M, 2020 Gastrointeritinal Cancers Symposium (ASCO-GI 2020),   2020 01
• A phase 1b study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) (Study 117), Kudo M, Ikeda M, Motomura K, Okusaka T, Kato N, Dutcus CE, Hisai T, Suzuki M, Ikezawa H, Iwata T, Kumada H, Kobayashi M, 2020 Gastrointeritinal Cancers Symposium (ASCO-GI 2020),   2020 01
• Phase 3 study of pembrolizumab (pembro) versus best supportive care (BSC) for second-line therapy in advanced hepatocellular carcinoma (aHCC): KEYNOTE-240 Asian subgroup, Kudo M, Lim HY, Cheng AL, Chao Y, Yau T, Ogasawara S, Kurosaki M, Morimoto N, Ohkawa K, Yamashita T, Lee DW, Chen E, Siegel A, Ryoo BY, 2020 Gastrointeritinal Cancers Symposium (ASCO-GI 2020),   2020 01
• Invited Lecture “Updates of targeted therapies for HCC, Masatoshi Kudo, Taiwan Association for the Study of the Liver (TASL 2019),   2019 12 14 , 招待有り
• Roche Symposium “Recent advances on cancer immunotherapy combination for advanced HCC”, Masatoshi Kudo, Taiwan Association for the Study of the Liver (TASL 2019),   2019 12 14 , 招待有り
• Keynote Lecture “Changing Paradigm of Treatment Strategy in Intermediate-stage HCC”, Masatoshi Kudo, 17th National Liver Cancer Conference,   2019 12 07 , 招待有り
• 司会; 招待講演「Recent advances in clinical research of HBV and HCC」, Masatoshi Kudo, 第23回日本肝臓学会大会,   2019 11 21 , 招待有り
• Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh a liver function: a multicenter propensity-score matched study, Kudo M, Ueshima K, Chan SL, Minami T, Chishina H, Aoki T, Takita M, Hagiwara S, Minami Y, Ida H, Takenaka M, Sakurai T, Watanabe T, Morita M, Ogawa C, Wada Y, Ikeda M, Ishii H, Izumi N, Nishida N, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11 11
• Checkmate 040: efficacy, hepatic safety, and biomarkers of Nivolumab + Ipilimumab combination therapy in patients with advanced hepatocellular carcinoma, Sangro B, Hsu C, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, He AR, El-Rayes B, Acosta-Rivera M, Lim HY, Neely J, Zhao H, Anderson J, Yau T, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11 11
• Development of AI-aided us diagnosis system of liver tumor using deep neural network., Nshida N, Yamakawa M, Shiina T, Kudo M, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11
• Clinical significance of tumor markers in surveillance for hepatocellular carcinoma in cirrhostic patients: a multicenter prospective cohort study in Japan., Ucnino K, Tateishi R, Fujiwara N, Moriyama M, Eguchi Y, Toyoda H, Ida Y, Karino Y, Kudo M, Chuma M, Takuma Y, Kaneko S, Kato N, Chayama K, Izumi N, Itoi T, Sakaida I, Komeda H, Umemura T, Ishikawa T, Nakamuta M, Takaki A, Terai S, Ido A, Enomoto N, Yoshida H, Baba T, Torimura T, Hiasa Y, Ogawa C, Takehara T, Kumada T, Koike K, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11
• Objective response by mrecist is a prognostic factor for overall survival in unresectable hepatocellular carcinoma treated with systemic therapy: a systematic review and metaanalysis of randomized controlled trials., Kudo M, Ueshima K, Nishida N, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11
• Lenvatinib for unresectable hepatocellular carcinoma in real-world practice: a multicenter analysis of prognostic factors., Hiraoka A, Kumada T, Atsukawa M, Hirooka M, Ishikawa T, Tsuji K, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Tada T, Toyoda H, Nouso K, Tsutsui A, Nagano T, Itokawa N, Hayama K, Imai M, Joko K, Koizumi Y, Hiasa Y, Michitaka K, Kudo M, American Association for the Study of Liver Diseases (AASLD 2019),   2019 11
• Safety and efficacy of Lenvatinib by starting dose based on bodyweight in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in REFLECT, Okusaka T, Ikeda K, Kudo M, Finn RS, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrwicz L, Yoon JH, Ren Z, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H, 31th Annual Conference, Canadian Association of Nurses in Oncology (CANO 2019),   2019 10 21
• Association between overall survival and adverse events with Lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT), Sung M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Kudo M, Tateishi R, Ikeda M, Breder V, Rau KM, Ma YT, Alsina A, Ryoo BY, Ren Z, Mody K, Dutcus C, Tamai T, Saito K, Piscaflia F, 31th Annual Conference, Canadian Association of Nurses in Oncology (CANO 2019),   2019 10 21
• Invited Lecture “Construction of big database of US digital image; Platform for creating artificial intelligence-aided US: Work in progress”, Masatoshi Kudo, The 1st Asia Pacific International Symposium on Advances in Medical Ultrasound,   2019 10 19 , 招待有り
• Clinicopathological and immunohistochemical study of the mechanism of sporadic fundic gland polyp proliferation and enlargement in long-term PPI-users, Matsumura M, Tsuji N, Yoshida S, Tomooka M, Umehara Y, Kudo M, United European Gastroenterology (UEGW 2019),   2019 10
• Ramucirumab in patients with advanced hepatocellular carcinoma and elevated alpha fetoprotein: an exposure-response analysis, Llovet JM, Kudo M, Kang YK, Yen CJ, Finn RS, Gale PR, Assenat E, Motomura K, Okusaka T, Berg T, Hsu CH, Ikeda M, Hsu Y, Liang K, Widau R, Schelman W, O’Braian L, Gao L, Zhu AX, European Society for Medical Oncology (ESMO 2019),   2019 09 29
• Health-related quality of life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240, Merle P, Kulkarni AS, Ryoo BY, Cheng AL, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Daniele B, Norquist J, Chen E, Siegel AB, Zhu AX, Finn RS, European Society for Medical Oncology (ESMO 2019),   2019 09 27
• Ramucirumab (RAM) effect on albumin-bilirubin (ALBI) grade during treatment of Japanese patients with hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following sorafenib from two randomized phase 3 studies (REACH, REACH-2), Kudo M, Okusaka T, Motomura K, Ikeda M, Morimoto M, Seo S, Wada Y, Sato S, Yamashita T, Furukawa M, Aramaki T, Hirota S, Homma G, Chunxiao W, Shinozaki K, Yoshikawa R, Zhu AX, European Society for Medical Oncology (ESMO 2019),   2019 09
• LEAP-002: Phase 3 Study of First-Line Lenvatinib (len) Plus Pembrolizumab (pembro) for patients with advanced hepatocellular carcinoma (HCC), Llovet JM, Kudo M, Cheng AL, Finn RS, Galle PR, Kaneko S, Meyer T, Qin S, Dutcus CE, Chen E, Dubrovsky L, Siegel AB, Zhu AX, European Society for Medical Oncology (ESMO 2019),   2019 09
• Alpha-fetoprotein (AFP) response in patients with unresectable hepatocellular carcinoma (HCC) in the phase 3 RESORCE trial, Bruix J, Reig M, Merle P, Kudo M, Meinhardt G, Zhang M, Ozgurdal K, European Society for Medical Oncology (ESMO 2019),   2019 09
• Safety profile of Nivolumab (NIVO) plus Ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study, El-Khoueiry AB, Hsu C, Kang YK, Kim TY, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, He AR, El-Rayes B, Acosta-Rivera M, Neely J, Shen Y, Baccan C, Yau T, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• CheckMate 040: Health-related quality of life (HRQoL) in patients (Pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B status treated with nivolumab (NIVO), Sangro B, Matilla A, Santoro A, Cubillo A, El-Khoueiry AB, El-Rayes B, Numata K, Itoh Y, Taylor F, Thompson G, Blum S, Wisniewski T, Baccan C, Kudo M, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• A Phase 3, randomized, double-blind, placebo-controlled study of transarterial chemoembolization combined with durvalumab or durvalumab plus bevacizumab therapy in patients with locoregional hepatocellular carcinoma (HCC): EMERALD-1, Sangro B, Kudo M, Qin S, Ren Z, Chan S, Erinjeri J, Arai Y, Mann H, Morgan S, Cohen G, Vlahovic G, Lencioni R, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• A post hoc analysis of neutrophil-lymphocyte ratios (NLR) in the REFLECT study: First-line lenvatinib (LEN) or sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC), Evans TRJ, Kudo M, Cheng AL, Gomez-Martin C, Daniele B, Izumi N, Yamashita T, Tateishi R, Lim HJ, Chan SL, Rau KM, Alsina A, Misir S, Dutcus C, Sung MW, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• Pembrolizumab vs placebo as adjuvant therapy in patients with hepatocellular carcinoma (HCC) and complete radiological response following surgical resection or local ablation: Phase 3 KEYNOTE-937 trial, Zhu AX, Cheng AL, Vogel A, Yau T, Zhou J, Chen E, Malhotra U, Siegel AB, Kudo M, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• First-line combination therapy with lenvatinib plus pembrolizumab for patients with advanced hepatocellular carcinoma: Phase 3 Leap-002 study, Llovet JM, Kudo M, Cheng AL, Finn RS, Galle PR, Kaneko S, Meyer T, Qin S, Dutcus CE, Chen E, Dubrovsky L, Zhu AX, 13th Annual Conference International Liver Cancer Association (ILCA),   2019 09
• Chair ; Cheng AL; minar 6 “A combined approach for advanced HCC checkpoint inhibitor plus VEGF blockade”, Masatoshi Kudo, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31 , 招待有り
• A phase 3 study of transarterial chemoembolization combined with durvalumab or durvalumab plus bevacizumab in patients with locoregional HCC: EMERALD-1, Kudo M, Sangro B, Qin S, Ren Z, Chan S, Erinjeri J, Arai Y, Mann H, Morgan S, Cohen G, Vlahovic G, Lencioni R, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Efficacy and safety of ramucirumab (RAM) in Asian and non-Asian patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): Subgroup analysis from two randomized studies, Okusaka T, Kang YK, Kudo M, Lim HY, Hsu CH, Vogel A, Brandi G, Cheng R, Carton I, Abada P, Hsu Y, Zhu A, Yen CJ, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Subsequent anticancer medication following first-line lenvatinib: Post Hoc responder analysis from the Phase 3 REFLECT study in unresectable hepatocellular carcinoma, Alsina A, Kudo M, Vogel A, Cheng AL, Tak WY, Ryoo BY, Evans TRJ, Lopez C, Daniele B, Misir S, Ren M, Izumi N, Qin S, Finn RS, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT), Sung M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Kudo M, Tateishi R, Ikeda M, Breder V, Rau KM, Ma YT, Alsina A, Ryoo BY, Ren Z, Mody K, Dutcus C, Tamai T, Saito K, Piscaglia F, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Nivolumab in patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh (CP) B status: Japanese subanalysis from the CheckMate 040 study, Kudo M, Matilla A, Santoro A, Melero I, Gracian AC, Acosta-Rivera M, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Takahashi H, Shen Y, Neely J, Anderson J, Sangro B, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Safety and efficacy of lenvatinib by starting dose based on bodyweight in patients with unresectable hepatocellular carcinoma (uHCC) in REFLECT, Okusaka T, Ikeda K, Kudo M, Finn RS, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrwicz L, Yoon JH, Ren Z, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Role of the liver tumor board in early- and intermediate-stage HCC. Sponsored Symposium 4, Kudo M, Han KH, Chan SL, Chow P, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31 , 招待有り
• Challenging Precise Ablation: CEUS Guidance & Fusion Imaging Guidance. Symposium 7 “Ablation therapy for hepatocellular carcinoma in Asia”, Minami Y, Kudo M, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Changing paradigm of treatment strategy for intermediate stage HCC: APPLE expert consensus, Ikeda M, Han KH, Miyayama S, Lin HM, Choo SP, Huang YH, Chan S, Kudo M, Wang CK, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a Phase 3 study of lenvatinib (REFLECT), Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Piscaglia F, Ueshima K, Aikata H, Vogel A, Lopez C, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Dutcus C, Tamai T, Saito K, Lencioni R, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 31
• Luncheon Seminar “Real-world experience with lenvatinib in patients with uHCC from Japan”, Masatoshi Kudo, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 30 , 招待有り
• Current and future treatment strategy for TACE failure or refractoriness. Morning Workshop 3, Masatoshi Kudo, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 30 , 招待有り
• Association between tumor response by mRECIST and overall survival in patients with poorly differentiated hepatocellular carcinoma (HCC) in REFLECT study, Kudo M, Ueshima K, Aikata H, Tamai T, Saito K, Ikeda K, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 29
• Using workstation for diagnosis and treatment of hepatocellular carcinoma, Ogawa C, Kudo M, The 10th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2019),   2019 08 29
• Internation Symposium “Lenvatinib as an initial treatment in patiens with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: A Multicentre propensity-score matched study., Masatoshi Kudo, The 55th Annual Meeting of Liver Cancer Study Group of Japan,   2019 07 05 , 招待有り
• Ramucirumab in advanced hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib: outcomes by prior transarterial chemoembolisation from two randomised, double-blind, placebo-controlled phase 3 studies (REACH-2 and REACH), Meyer T, Finn R, Kudo M, Kang YK, Yen CJ, Galle P, Llovet J, Assenat E, Brandi G, Motomura K, Okusaka T, Hubner R, Karwal M, Baron A, Ikeda M, Liang K, Wang C, Widau R, Schelman W, Zhu A, ESMO 21th World Congress on Gastrointestinal Cancer 2019 (ESMO-WCGC 2019),   2019 07 03
• Invited Lecture “Recent trends of treatment for intermediate stage HCC: Japanese experience”, Masatoshi Kudo, The Liver Week 2019,   2019 06 21 , 招待有り
• Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC)., Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder VV, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox JJ, Daniele B, Ebbinghaus S, Chen E, Siegel AB, Zhu AX, Cheng AL, for the KEYNOT, Investigators, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 06 02
• A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation on primary hepatocellular carcinoma (SURF trial), Izumi N, Hasegawa K, Nishioka Y, Takayama T, Yamanaka N, Kudo M, Shimada M, Inomata M, Kaneko S, Baba H, Koike K, Omata M, Makuuchi M, Matsuyama Y, Kokudo N, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 06 02
• Ramucirumab (RAM) for sorafenib intolerant patients with hepatocellular carcinoma (HCC) and elevated baseline alpha fetoprotein (AFP): outcomes from two randomized phase 3 studies (REACH, REACH2), Llovet JM, Yen CJ, Finn RS, Kang YK, Kudo M, Galle PR, Assenat E, Pracht M, Lim Y, Rau KM, Borg C, Hiriart JB, Daniele B, Berg T, Chung HC, Godinot N, Wang C, Hsu Y, Schelman WR, Zhu AX, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 06
• Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040, Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox J, He AR, El-Rayes B, Acosta-Rivera M, Neely J, Shen Y, Baccan C, Dela Cruz C, Hsu C, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 06
• First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: results from a phase 1b trial (VEGF Liver 100), Kudo M, Motomura K, Wada Y, Inaba Y, Sakamoto Y, Kurosaki M, Umeyama Y, Kamei Y, Yoshimitsu J, Fujii Y, Aizawa M, Robbins PB, Furuse J, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 06
• Efficacy, safety, and cancer-related symptoms in patients with hepatocellular carcinoma with alpha-fetoprotein ≥400 ng/ml: A pooled analysis from REACH and REACH-2 studies, Borbath I, Kudo M, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Peck-Radosavljevic M, Girvan A, Gable J, Bowman L, Abada P, Hsu Y, Zhu AX, Lee SY, Osterreichische Gesellschaft fur Gastroenterologie und Hepatologie (OGGH 2019),   2019 06
• State-of-the-Art Lecture “IO in liver cancer therapy now and future.”, Masatoshi Kudo, 2019 Joint International Conference of Taiwan Liver Cancer Association and Taiwan Academy of Tumor Ablation: Precision medicine in HCC: research and treatment,   2019 05 26 , 招待有り
• Keynote Lecture “When is the best time for TKI (LEN) be used in BCLC B & C HCC patients.", Masatoshi Kudo, Expert Round Table Meeting for Unresectable Hepatocellular Carcinoma,   2019 05 26 , 招待有り
• Invited Lecture “Evolving roles of targeted therapy in HCC”, Masatoshi Kudo, the 3rd Symposium of the Singapore Liver Cancer Consortium (SLCC),   2019 05 03 , 招待有り
• Lenvatinib (lenva) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study, Llovet J, Kudo M, Cheng AL, Finn R, Galle P, Kaneko S, Meyer T, Qin S, Dutcus C, Chen E, Dubrovsky L, Zhu A, American Society of Clinical Oncology Annual Meeting (ASCO 2019),   2019 05
• Practice patterns and outcomes of transarterial chemoembolization in patients with hepatocellular carcinoma who were ineligible and eligible for transarterial chemoembolization at inclusion: Global OPTIMIS exploratory analysis, Peck-Radosavljevic M, Lee HC, Kudo M, Nakajima K, Bayh I, Cheng AL, Raoul JL, The International Iiver Congress (EASL 2019),   2019 04
• A phase 1b trial of Lenvatinib (LEN) plus Pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results., Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, Kaneko S, Zhu AX, Kubota T, Kraljevic S, Ikezawa H, Dubrovsky L, Siegel AB, Kumada H, Okusaka T, American Association for Cancer Research Annual Meeting (AACR 2019),   2019 04 01
• Can lenvatinib meet clinical needs of patients with unresectable hepatocellular carcinoma? Multicenter analysis., Hiraoka A, Kumada T, Takaguchi K, Kariyama K, Tsuji K, Itobayashi E, Ochi H, Tajiri K, Hirooka M, Shimada N, Ishikawa T, Tsutsui A, Shibata H, Tada T, Toyoda H, Nouso K, Itokawa N, Joko K, Atsukawa M, Imai M, Michitaka K, Hiasa Y, Kudo M, The International Iiver Congress (EASL 2019),   2019 04
• Efficacy and hepatic safety of Nivolumab treatment in patients with Child-Pugh B disease and advanced hepatocellular carcinoma in CheckMate 040, Sangro B, Matilla A, Santoro A, Melero I, Gracian AC, Acosta MR, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Shen Y, Neely J, dela Cruz C, Baccan C, Kudo M, The International Iiver Congress (EASL 2019),   2019 04
• Efficacy, safety, and patient-reported outcomes in patients with hepatocellular carcinoma with alpha-fetoprotein ≥400 ng/ml: A pooled analysis from REACH and REACH-2 studies, Borbath I, Kudo M, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Peck-Radosavljevic M, Girvan A, Gable J, Bowman L, Abada P, Hsu Y, Zhu AX, Belgian Week of Gastroenterology,   2019 02 22
• Practice patterns, response rates, and deterioration of liver function after transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (uHCC): Final analysis of OPTIMIS in China, Shan H, Lee HC, Raoul JL, Peck-Radosavljevic M, Kudo M, Nakajima K, Bayh I, Yang Y, Wang W, Cheng AL, The 28th Annual Conference of Asian Pacific Association for the Study of the Liver (APASL 2019),   2019 02
• Invited Lecture “Ongoing trials in systemic therapies for HCC”, Masatoshi Kudo, Asian Pacific Association for the Study of the Liver (APASL 2019),   2019 02 , 招待有り
• Invited Lecture “Role of the hepatologist”, Masatoshi Kudo, Asian Pacific Association for the Study of the Liver (APASL 2019),   2019 02 , 招待有り
• Ramucirumab for patients with hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib treatment: exploratory analysis of REACH-2 trial results by albumin-bilirubin grade and Child-Pugh score, Brandi G, Kudo M, Kang Y, Yen C, Finn R, Galle P, Llovet J, Assenat E, Merle P, Jean-Baptiste H, Chan SL, Palmer D, Wang C, Widau R, Hsu Y, Abada PB, Zhu A, EASL HCC Summit 2019,   2019 02
• Ramucirumab (RAM) as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline α-fetoprotein (AFP): an analysis of AFP kinetics in the phase 3 REACH-2 study., Finn RS, Kudo M, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Lim HY, Pracht M, Rau KM, Merle P, Motomura K, Ohno I, Daniele B, Shin D, Gerken G, Abada P, Hsu Y, Zhu AX, American Society of Clinical Oncology, Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Sorafenib versus hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma: A Japanese multi-center large cohort study, Ogasawara S, Ueshima K, Ikeda M, Yasui Y, Terashima T, Yamashita T, Obi S, Sato S, Aikata H, Ohmura T, Kuroda H, Ohki T, Nagashima K, Kurosaki M, Chayama K, Kaneko S, Izumi N, Kato N, Kudo M, Omata M, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• CheckMate-040: Nivolumab (NIVO) in patients (Pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status, Kudo M, Matilla A, Santoro A, Melero I, Gracian A, Acosta MR, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Shen Y, Neely J, dela Cruz C, Baccan C, Sangro B, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase 3 study of lenvatinib (REFLECT), Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Piscaglia F, Ueshima K, Aikata H, Vogel A, Lopez C, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Dutcus C, Tamai T, Saito K, Lencioni R, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Subsequent anticancer medication following first-line lenvatinib: a posthoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma, Alsina A, Kudo M, Vogel A, Cheng AL, Tak WY, Ryoo BY, Evans TJ, Lopez CL, Daniele B, Misir S, Ren M, Izumi N, Qin S, Finn RS, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Safety and efficacy of lenvatinib by starting dose based on bodyweight in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in REFLECT, Okusaka T, Ikeda K, Kudo M, Finn RS, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrxicz L, Yoon JH, Ren Z, Stepan D, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT), Sung M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Kudo M, Tateishi R, Ikeda M, Breder V, Rau KM, Ma YT, Alsina A, Ryoo BY, Ren Z, Mody K, Dutcus C, Tamai T, Saito K, Piscaglia F, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 18
• Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety in Japanese patients across two global randomized phase III studi, Kudo M, Okusaka T, Motomura K, Ohno I, Morimoto M, Seo S, Wada Y, Sato S, Yamashita T, Furukawa M, Aramaki T, Nadano S, Ohkawa K, Fujii H, Kudo T, Furuse J, Takai H, Homma G, Yoshikawa R, Zhu AX, American Society of Clinical Oncology, 2017 Gastrointestinal Cancers Symposium (ASCO-GI 2019),   2019 01 17
• Invited Lecture “HCC and cholangiocarcinoma”, Masatoshi Kudo, Hot Topics at AASLD 2018,   2018 12 16 , 招待有り
• Invited Lecture “Newer diagnostic algorithm for a solid tumor <3 cm in a cirrhotic”, Masatoshi Kudo, Hot Topics at AASLD 2018,   2018 12 16 , 招待有り
• Practice patterns, radiologic tumor response, and deterioration of liver function after transarterial chemoembolization (TACE): Final analysis of OPTIMIS in Korea and other regions, Heo J, Cheng AL, Raoul JL, Peck-Radosavljevic M, Kudo M, Nakajima K, Bayh I, Lin SM, Lee HC, European Society for Medical Oncology Congress (ESMO-Asia 2018),   2018 11 25
• Efficacy and safety of ramucirumab (RAM) in Asian and non-Asian patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): Subgroup analysis from two randomized studies, Kang YK, Kudo M, Lim HY, Hsu CH, Vogel A, Brandi G, Cheng R, Carton I, Abada P, Hsu Y, Zhu A, Yen CJ, European Society for Medical Oncology Congress (ESMO-Asia 2018),   2018 11 25
• M7824 (MSB0011359C), a bifunctional fusion protein targeting transforming growth factor β (TGF-β) and PD-L1, in Asian patients with pretreated biliary tract cancer (BTC): Efficacy by BTC subtype, Yoo C, Oh DY, Choi HJ, Kudo M, Ueno M, Kondo S, Chen LT, Osada M, Helwig C, Dussault I, Ikeda M, European Society for Medical Oncology Congress (ESMO-Asia 2018),   2018 11 24
• Phase 3, randomized KEYNOTE-240 study of pembrolizumab (Pembro) versus best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC), Chan SL, Finn RS, Zhu AX, Knox J, Cheng AL, Siegel AB, Bautista O, Kudo M, European Society for Medical Oncology (ESMO)-ASIA 2017,   2018 11 18
• Clinical efficacy and safety of EUS-guided gallbladder drainage replacement of percutaneous drainage: A multicenter retrospective study in Japan, Minaga K, Yamashita Y, Ogura T, Takenaka M, Shimokawa Y, Hisa T, Itonaga M, Kato H, Nishikiori H, Okuda A, Matsumoto H, Uenoyama Y, Watanabe T, Chiba Y, Higuchi K, Kudo M, Kitano M, Asian Pacific Digestive Week (APDW 2018),   2018 11 17
• Nivolumab in patients with Child-Pugh B advanced hepatocellular carcinoma (aHCC) in the CheckMate-040 study, Kudo M, Matilla A, Santoro A, Melero I, Gracian AC, Acosta MR, Choo SP, El-Khoueiry AB, Kuromatsu R, El-Rayes B, Numata K, Itoh Y, Di Costanzo F, Crysler O, Reig M, Shen Y, Neely J, dela Cruz C, Baccan C, Sangro B, American Association for the study of liver diseases (AASLD 2018),   2018 11 12
• New diagnostic method for hepatic steatosis using attenuation measurement by ultrasound B mode: comparison with controlled attenuation parameter, Koizumi Y, Hirooka M, Yada N, Tamaki N, Izumi N, Kudo M, Hiasa Y, American Association for the study of liver diseases (AASLD 2018),   2018 11 12
• Stem cell feature and immune-suppressive microenvironment in human hepatocellular carcinoma, Nishida N, Kudo M, American Association for the study of liver diseases (AASLD 2018),   2018 11 12
• Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): Global OPTIMIS final analysis, Peck-Radosavljevic, Kudo M, Raoul JL, Lee HC, Decaens T, Heo J, Lin SM, Shan H, Yang Y, Bayh I, Nakajima K, Cheng AL, American Association for the study of liver diseases (AASLD 2018),   2018 11 12
• Ramucirumab as second-line treatment in patients with hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following sorafenib: pooled results from two global phase 3 studies (REACH-2 and REACH), Llovet JM, Kudo M, Finn R, Galle PR, Blanc JF, Okusaka T, Chau I, Abada PB, Hsu Y, Zhu AX, American Association for the study of liver diseases (AASLD 2018),   2018 11 12
• Validation of modified ALBI grade for more detailed assessment of hepatic function in hepatocellular carcinoma patients: multicenter analysis, Hiraoka A, Kumada T, Tsuji K, Takaguchi K, Itobayashi E, Kariyama K, Ochi H, Tajiri K, Hirooka M, Shimada N, Ishikawa T, Tachi Y, Tada T, Toyoda H, Nouso K, Joko K, Hiasa Y, Michitaka K, Kudo M, American Association for the study of liver diseases (AASLD 2018),   2018 11 10
• Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib (REACH-2): efficacy, safety, and patient-reported outcome results, Zhu A, Finn R, Galle P, Llovet J, Nipp R, Cella D, Girvan A, Gable J, Bowman L, Abada P, Hsu Y, Kudo M, Gastrointestinal Oncology Conference 2018 (ISGIO),   2018 11 01
• Special Remarks, International Session (Symposium) 2 “Hepatitis towards the control of HCC-the remaining issues and future directions in Japan and the world”, Masatoshi Kudo, Japan Digestive Disease Week 2018 (JDDW 2018)（the 60th Annual Meeting of the Japanese Society of Gastroenterology, the 96th Congress of the Japan Gastroenterological Endoscopy Society, the 22nd General Meeting of the Japan Society of Hepatology）,   2018 11 01 , 招待有り
• Independent imaging review analysis of REFLECT trial of lenvatinib in HCC, Aikata H, Kudo M, Ikeda K, Japan Digestive Disease Week (JDDW 2018)(The 60th Annual Meeting of the Japanese Society of Gastroenterolgy, the 22nd General Meeting of the Japan Society of Hepatology, the 96th Congress of the Japan Gastroenterological Endoscopy Society),   2018 11 01
• Practice patterns in the treatment of unresectablehepatocellular carcinoma with sorafenibin Latin America according to Child–Pugh score: Subgroup analysis of the GIDEON study, Ladron de, Guevara L, Dagher L, Miguel Viana, Arruda V, Nakajima K, Kudo M, Mexican Society of Oncology 36th National Congress 2018 (SMEO 2018),   2018 11
• Global phase 3 study of tislelizumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (HCC): A trial-in-progress, Qin S, Finn R, Kudo M, Meyer T, Vogel A, Ducreux M, Macarulla T, Tomasello G, Boisserie F, Hou J, Li C, Song J, Zhu A, European Society for Medical Oncology (ESMO 2018),   2018 10 21
• Practice patterns and deterioration of liver function after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): Final analysis of OPTIMIS in Europe and Canada, Raoul JL, Decaens T, Burak K, Koskinas J, Villadsen GE, Heurgue-Berlot A, Bayh I, Cheng AL, Kudo M, Lee HC, Nakajima K, Peck-Radosavljevic M, European Society for Medical Oncology (ESMO 2018),   2018 10 21
• A phase I, open-label, multi-center, dose-escalation study of codrituzumab, an anti-glypican-3 monoclonal antibody, in combination with atezolizumab in patients with locally advanced or metastatic hepatocellular carcinoma, Cheng AL, Yen CJ, Okusaka T, Ikeda M, Hsu CH, Wu SY, Morizane C, Hashimoto Y, Ueshima K, Ohtomo T, Tanaka T, Kudo M, European Society for Medical Oncology (ESMO 2018),   2018 10 21
• Invited Lecture “HCC Meet the Expert”, Masatoshi Kudo, European Society for Medical Oncology (ESMO 2018),   2018 10 21 , 招待有り
• Final analysis of serum biomarkers in patients (pts) from the phase 3 study of lenvatinib (LEN) vs sorafenib (SOR) in unresectable hepatocellular carcinoma (uHCC) [REFLECT], Finn RS, Kudo M, Cheng AL, Wyrwicz L, Ngan R, Blanc JF, Baron A, Vogel A, Ikeda M, Piscaglia F, Han KH, Qin S, Minoshima Y, Kanekiyo M, Ren M, Dairiki R, Tamai T, Dutcus C, Funahashi Y, Evans TRJ, European Society for Medical Oncology (ESMO 2018),   2018 10