伊藤　正興 （イトウ　マサオキ）

研究者情報

学位

• 医学博士（2014年05月 広島大学）

ホームページURL

https://jglobal.jst.go.jp/detail?JGLOBAL_ID=202301008355698156

科研費研究者番号

• 80526236

J-Global ID

• 202301008355698156

研究活動情報

論文

• Secondary Mutations of the EGFR Gene That Confer Resistance to Mobocertinib in EGFR Exon 20 Insertion.

  Akira Hamada; Kenichi Suda; Masaya Nishino; Keiko Obata; Hana Oiki; Tomoyo Fukami; Shota Fukuda; Toshio Fujino; Shuta Ohara; Takamasa Koga; Masato Chiba; Masaki Shimoji; Masaoki Ito; Toshiki Takemoto; Junichi Soh; Yasuhiro Tsutani; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 19 1 71 - 79 2024年01月 

  INTRODUCTION: Approximately 10% of mutations in the EGFR gene in NSCLC are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR tyrosine kinase inhibitors (TKIs). Several novel EGFR TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the U.S. Food and Drug Administration. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR TKIs of earlier generations. METHODS: We chronically exposed murine pro-B-cell line cells transduced with the five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH, and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib exhibited good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.
• FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung.

  Koichi Tomoshige; William D Stuart; Iris M Fink-Baldauf; Masaoki Ito; Tomoshi Tsuchiya; Takeshi Nagayasu; Tomoki Yamatsuji; Morihito Okada; Takuya Fukazawa; Minzhe Guo; Yutaka Maeda

  Cancer research 83 9 1443 - 1458 2023年05月 

  UNLABELLED: The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation. SIGNIFICANCE: FOXA2 expression combined with mutant KRAS drives invasive mucinous adenocarcinoma of the lung by synergistically promoting a mucous transcriptional program, suggesting strategies for targeting this lung cancer type that lacks effective therapies.
• Current clinical trials with non-coding RNA-based therapeutics in malignant diseases: A systematic review.

  Masaoki Ito; Yoshihiro Miyata; Morihito Okada

  Translational oncology 31 101634 - 101634 2023年05月 

  This systematic review aimed to shed light on the trend of current clinical trials of non-coding RNA (ncRNA)-based therapeutics for malignant diseases. We conducted a database search for published literature and ongoing clinical trials using PubMed, clinicaltrials.gov, and University Medical Information Network (UMIN) clinical trial registry. To ensure that our review was based on up-to-date clinical trials, we limited our search to literature published within the last five years (January 2017-September 2022). Furthermore, due to the "clinical" nature of our review, we focused only on studies involving human participants. Among ncRNAs, microRNAs have been extensively explored in observational studies of malignant diseases as potential diagnostic markers and prognostic predictors, as well as for their therapeutic monitoring and profiling capabilities. As therapeutic agents, microRNA or siRNA were estimated in interventional human clinical trials and showed promising outcomes; however, the number of trials was small. Evidence and ongoing clinical trials in which ncRNAs other than microRNA or siRNA have been evaluated for their potential as therapeutic agents are limited. Here, we summarized microRNA as a potential therapeutic agent in malignant diseases, but most of the current evidence suggests that it is useful as a potential biomarker. siRNA is also a promising ncRNA technique in cancer, however more data from clinical trials are warranted for clinical use.
• Macrophage CD5L is a target for cancer immunotherapy.

  Lidia Sanchez-Moral; Tony Paul; Clara Martori; Joan Font-Díaz; Lucía Sanjurjo; Gemma Aran; Érica Téllez; Julià Blanco; Jorge Carrillo; Masaoki Ito; Martina Tuttolomondo; Henrik J Ditzel; Caterina Fumagalli; Gustavo Tapia; Julia Sidorova; Helena Masnou; Marco-Antonio Fernández-Sanmartín; Juan-José Lozano; Cristina Vilaplana; Alhelí Rodriguez-Cortés; Carolina Armengol; Annabel F Valledor; Leonor Kremer; Maria-Rosa Sarrias

  EBioMedicine 91 104555 - 104555 2023年05月 

  BACKGROUND: Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. METHODS: Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. FINDINGS: Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. INTERPRETATION: CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. FUNDING: For a full list of funding bodies, please see the Acknowledgements.
• Acquired BRAF gene fusions in Osimertinib resistant EGFR-mutant non-small cell lung cancer.

  Rafael Rosell; María González-Cao; Jordi Codony-Servat; Miguel Angel Molina-Vila; Clara Mayo de Las Casas; Masaoki Ito

  Translational cancer research 12 3 456 - 460 2023年03月
• Distribution and prognostic impact of EGFR and KRAS mutations according to histological subtype and tumor invasion status in pTis-3N0M0 lung adenocarcinoma.

  Masaoki Ito; Yoshihiro Miyata; Kei Kushitani; Daisuke Ueda; Yukio Takeshima; Morihito Okada

  BMC cancer 23 1 248 - 248 2023年03月 

  BACKGROUND: The prognostic impact of EGFR mutation as major targetable somatic gene variant on lung adenocarcinoma is controversial. KRAS is another major somatic variant in lung adenocarcinoma, and a therapeutic agent for KRAS G12C became available in clinical settings. These mutations represent clinicopathological features of lung adenocarcinoma and can guide the treatment choice after recurrence. We evaluated the prognostic impact of EGFR and KRAS mutations by considering other clinicopathological recurrence risks in resected pTis-3N0M0 lung adenocarcinoma. METHODS: Clinicopathological features related to recurrence and genetic status were estimated in consecutive 877 resected cases. Recurrence-free survival (RFS), cumulative recurrence rate (CRR), and overall survival (OS) were compared. Uni- and multivariate analyses for RFS were performed after excluding cases with little or no recurrence risks. RESULTS: EGFR mutation was more likely to be harbored in female, never-smoker, or patients accompanied by > 5% lepidic component. KRAS mutation was more likely to be harbored in patients with current/ex-smoking history, International Association for the Study of Lung Cancer (IASLC) grade 3, or accompanied lymphatic or vascular invasion. In IASLC grade 2 and 3 patients, EGFR or KRAS mutation cases had significantly worse 5-year RFS than wild type patients (76.9% vs. 85.0%, hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.62-6.41, P < 0.001). EGFR or KRAS mutation cases had significantly higher 5-year CRR than wild type patients (17.7% vs. 9.8%, HR = 1.69, 95% CI = 1.44-6.59, P = 0.0038). KRAS mutation cases had higher 5-year CRR than EGFR mutation cases (16.7% vs. 21.4%, HR = 1.62, 95% CI = 0.96-7.19, P = 0.061). There was no significant difference in OS between cohorts. Multivariate analysis revealed that a positive EGFR/KRAS mutation status was risk factor for worse RFS (HR = 2.007, 95% CI = 1.265-3.183, P = 0.003). CONCLUSION: Positive EGFR and KRAS mutation statuses were risk factors for recurrence in resected IASLC grade 2 and 3 patients. KRAS mutations were more likely to be confirmed in cases with an increased risk of recurrence. EGFR and KRAS mutation statuses should be evaluated simultaneously when assessing the risk of recurrence.
• The role of biomarkers in stage III non-small cell lung cancer.

  Rafael Rosell; María González-Cao; Masaoki Ito; Mariacarmela Santarpia; Andrés Aguilar; Jordi Codony-Servat

  Expert review of respiratory medicine 17 6 469 - 480 2023年 

  INTRODUCTION: Stage III non-small cell lung cancer (NSCLC) is a composite of the regional spread of lung cancer with different levels of potential lymph node involvement and tumor size that often deem the stage at time of diagnosis to be unresectable and suitable for chemoradiation plus consolidation immunotherapy with durvalumab for 12 months. Chemoradiation plus durvalumab consolidation yielded a landmark 49.2% 5-year overall survival in unresectable NSCLC. AREAS COVERED: Sub-optimal results lead us to focus on the mechanisms of resistance responsible for intractability in a significant proportion of cases that fail with chemoradiation and immunotherapy. In stage III NSCLC it is opportune to explore the accumulated evidence on ferroptosis resistance that can lead to cancer progression and metastasis. Strong data shows that three anti-ferroptosis pathways are principally involved in resistance to chemotherapy, radiation, and immunotherapy. EXPERT OPINION: Because a large part of stage III NSCLCs is resistant to chemoradiation and durvalumab consolidation, a ferroptosis-based therapeutic approach, combined with standard-of-care therapy, can lead to improved clinical outcomes in patients diagnosed with stage III and possibly stage IV NSCLCs.
• Impact of the amount of preoperative erector spinae muscle in stage I non-small-cell lung cancer.

  Daisuke Ueda; Yasuhiro Tsutani; Atsushi Kamigaichi; Nobutaka Kawamoto; Norifumi Tsubokawa; Masaoki Ito; Takahiro Mimae; Yoshihiro Miyata; Morihito Okada

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 63 1 2022年12月 

  OBJECTIVES: Erector spinae muscle (ESM) is an antigravity muscle group that can be evaluated as an index of muscle loss on chest computed tomography. The amount of ESM has been reported to be related to the prognosis of several respiratory diseases. However, few studies clarify the impact on postoperative non-small-cell lung cancer (NSCLC). We investigated the relationship between ESM and postoperative prognosis in patients with early-stage NSCLC. METHODS: We reviewed the medical records of 534 patients with stage I NSCLC who underwent lobectomy or segmentectomy. The ESM was identified by preoperative computed tomography, and the amount was normalized according to height and sex. Overall survival, lung cancer-related deaths and non-lung cancer-related deaths (NLCRD) were analysed using log-rank and Gray's tests. Multivariable analyses were conducted to identify factors that influenced overall survival (OS) and NLCRD. RESULTS: The amount of ESM normalized according to height and sex was significantly associated with age and body mass index. When the amount was low, OS (5-year OS, 79.6 vs 89.5%; P< 0.001) and NLCRD (5-year cumulative mortality rate, 14.7 vs 6.8%; P< 0.001) were significantly worse, although no difference was found in lung cancer-related deaths. CONCLUSIONS: The amount of preoperative ESM was strongly related to non-lung cancer-related death and was a significant prognostic factor for stage I NSCLC. Patients with a low amount of the muscle should be treated based on proper risk assessment.
• The impact of epidermal growth factor receptor mutation status on adjuvant chemotherapy for patients with high-risk stage I lung adenocarcinoma.

  Yasuhiro Tsutani; Masaoki Ito; Yoshihisa Shimada; Hiroyuki Ito; Norihiko Ikeda; Haruhiko Nakayama; Morihito Okada

  The Journal of thoracic and cardiovascular surgery 164 5 1306 - 1315 2022年11月 

  OBJECTIVE: The aim of this study was to evaluate the role and effect of adjuvant chemotherapy based on epidermal growth factor receptor mutation status in patients with stage I lung adenocarcinoma. METHODS: Between 2010 and 2016, of 1901 patients with pathologic stage I (8th edition) non-small cell lung cancer, we identified 475 with high-risk (pT1c/T2a or positive for lymphovascular invasion) stage I lung adenocarcinoma who underwent lobectomy. We estimated propensity scores to adjust for confounding variables, including age, sex, Brinkman index, pulmonary functions, comorbidities, surgical approach, invasive component tumor size, visceral pleural, lymphatic, and vascular invasion, adenocarcinoma subtype, epidermal growth factor receptor mutation status, postoperative complications, and institution associated with the administration of adjuvant chemotherapy. The primary end point was recurrence-free survival. RESULTS: Of 292 patients without/unknown epidermal growth factor receptor mutation, 105 (36.0%) received adjuvant chemotherapy and 187 (64.0%) did not. In 69 pairs of patients who were propensity score matched, the 5-year recurrence-free survival was significantly better in those who underwent adjuvant chemotherapy (88.4%) than in those who did not (63.6%; P = .001). Of 183 patients with epidermal growth factor receptor mutation, 78 (42.6%) received adjuvant chemotherapy and 105 (57.4%) did not. In 49 pairs of propensity score-matched patients, there was no significant difference in the 5-year recurrence-free survival between those who underwent adjuvant chemotherapy (74.3%) and those who did not (80.5%; P = .573). CONCLUSIONS: The effect of adjuvant chemotherapy for high-risk stage I lung adenocarcinoma varied by epidermal growth factor receptor mutation status. Epidermal growth factor receptor mutation status may help to identify patients with high-risk stage I lung adenocarcinoma who may benefit from adjuvant chemotherapy.
• Kisspeptins and norepinephrine regulate different G-protein-coupled receptor signaling pathways.

  Rafael Rosell; María González-Cao; Masaoki Ito; Mireia Marco Jordan; José Luis Gómez-Vázquez; Jing-Hua Chen; Andrés Aguilar; Imane Chaib

  Translational lung cancer research 11 8 1517 - 1521 2022年08月
• Sensitivity and optimal clinicopathological features for mutation-targeted liquid biopsy in pN0M0 EGFR-mutant lung adenocarcinoma.

  Masaoki Ito; Yoshihiro Miyata; Shoko Hirano; Fumiko Irisuna; Kei Kushitani; Yuichiro Kai; Naoto Kishi; Yasuhiro Tsutani; Yukio Takeshima; Morihito Okada

  Journal of cancer research and clinical oncology 148 6 1419 - 1428 2022年06月 

  PURPOSE: Liquid biopsy for early-stage lung cancer diagnosis is challenging, and optimal candidates' clinicopathological features are unknown. We investigated utility and clinicopathological features of optimal candidates in somatic mutation-targeted liquid biopsy using droplet digital polymerase chain reaction (ddPCR) in pN0M0 EGFR mutation-positive lung adenocarcinoma patients. METHODS: We performed EGFR mutation-targeted ddPCR liquid biopsy in 100 patients with resected pN0M0 invasive lung adenocarcinoma, whose tumor diameter in high-resolution computed tomography (HRCT) was ≤ 5 cm. Peripheral blood-derived serum was collected preoperatively. Two representative EGFR somatic variants (exon 19 [E746-A750 del (2235_2249 del)]; exon 21 (L858R)) were utilized as liquid biopsy targets. Clinicopathological features including radiological appearance, subhistology, and invasive status were compared between ddPCR-positive and ddPCR-negative patients. RESULTS: Among the 100 patients, 98 showed part-solid or pure-solid appearance in HRCT and 2 showed non-solid appearance; 98 were pathological stage IA1-IB. Of the 66 patients with EGFR mutation detection in ddPCR, 12 were significantly positive and 10 (83.3%, 10/12) exhibited pure-solid appearance in HRCT. Clinical invasive tumor ratio was significantly higher in ddPCR-positive than in ddPCR-negative patients (median: 100% vs. 85.4%, P = 0.0212), whereas other clinicopathological features were not significantly different. CONCLUSION: Mutation-targeted liquid biopsy using ddPCR detected lung cancer in 12.0% (12/100) of pN0M0 EGFR-mutant lung adenocarcinoma patients. In 83.3% of the ddPCR-positive patients, tumors showed pure-solid appearance in HRCT. The detection ratio increased to 21.3% (10/47) among patients with pure-solid appearance tumors. Tumor appearance might be useful for better selection of liquid biopsy candidates.
• Digital multiplexed analysis of circular RNAs in FFPE and fresh non-small cell lung cancer specimens.

  Carlos Pedraz-Valdunciel; Stavros Giannoukakos; Nicolas Potie; Ana Giménez-Capitán; Chung-Ying Huang; Michael Hackenberg; Alberto Fernandez-Hilario; Jill Bracht; Martyna Filipska; Erika Aldeguer; Sonia Rodríguez; Trever G Bivona; Sarah Warren; Cristina Aguado; Masaoki Ito; Andrés Aguilar-Hernández; Miguel Angel Molina-Vila; Rafael Rosell

  Molecular oncology 16 12 2367 - 2383 2022年06月 

  Although many studies highlight the implication of circular RNAs (circRNAs) in carcinogenesis and tumor progression, their potential as cancer biomarkers has not yet been fully explored in the clinic due to the limitations of current quantification methods. Here, we report the use of the nCounter platform as a valid technology for the analysis of circRNA expression patterns in non-small cell lung cancer (NSCLC) specimens. Under this context, our custom-made circRNA panel was able to detect circRNA expression both in NSCLC cells and formalin-fixed paraffin-embedded (FFPE) tissues. CircFUT8 was overexpressed in NSCLC, contrasting with circEPB41L2, circBNC2, and circSOX13 downregulation even at the early stages of the disease. Machine learning (ML) approaches from different paradigms allowed discrimination of NSCLC from nontumor controls (NTCs) with an 8-circRNA signature. An additional 4-circRNA signature was able to classify early-stage NSCLC samples from NTC, reaching a maximum area under the ROC curve (AUC) of 0.981. Our results not only present two circRNA signatures with diagnosis potential but also introduce nCounter processing following ML as a feasible protocol for the study and development of circRNA signatures for NSCLC.
• Clinical Behavior of Combined Versus Pure High-Grade Neuroendocrine Carcinoma.

  Yoshinori Handa; Yasuhiro Tsutani; Masaoki Ito; Yoshihiro Miyata; Hidenori Mukaida; Mayumi Kaneko; Yukio Takeshima; Morihito Okada

  Clinical lung cancer 23 1 e9-e16.e1  2022年01月 

  BACKGROUND: The aim of this study was to investigate and compare the clinical behaviors of combined and pure high-grade neuroendocrine carcinoma (large-cell neuroendocrine carcinoma [LCNEC] and small-cell lung carcinoma [SCLC]). PATIENTS AND METHODS: Data of 132 patients who underwent complete resection for combined or pure high-grade neuroendocrine carcinoma (combined group, 67; pure group, 65) between January 2001 and December 2015 were retrospectively reviewed. The clinicopathological features were analyzed and compared, and the prognoses were assessed by performing the Kaplan-Meier method and Cox regression analysis. RESULTS: The combined and pure groups had nearly equivalent clinicopathological characteristics, specifically, older males with smoking history, almost the same percentage of pleural/lymphatic/vascular invasion, and nearly the same recurrence rates and relapse patterns. The combined group had prognosis equivalent to that of the pure group (5-year overall survival [OS] rates: 61.8% vs. 52.2%, respectively; P = .82 and 5-year recurrence-free survival [RFS] rates: 42.4% vs. 43.9%, respectively; P = .96), and this trend was identified in sub-analyses only for patients with LCNEC, SCLC, and the same pathological stage. Multivariable Cox regression analysis in patients with high-grade neuroendocrine carcinoma revealed that vascular invasion and pathological stage were independent prognostic factors for OS; more importantly, combined and pure histologies were proven to have nearly equivalent associations with prognosis (hazard ratio, 0.96; 95% confidence interval, 0.22to 1.66; P = .96). RESULTS: Combined high-grade neuroendocrine carcinoma had clinical behavior equivalent to those of pure high-grade neuroendocrine carcinoma, with similar clinicopathological characteristics.
• Comprehensive analysis of the clinicopathological features, targetable profile, and prognosis of mucinous adenocarcinoma of the lung.

  Daisuke Ueda; Masaoki Ito; Yasuhiro Tsutani; Ana Giménez-Capitán; Ruth Román-Lladó; Ana Pérez-Rosado; Cristina Aguado; Kei Kushitani; Yoshihiro Miyata; Koji Arihiro; Miguel Angel Molina-Vila; Rafael Rosell; Yukio Takeshima; Morihito Okada

  Journal of cancer research and clinical oncology 147 12 3709 - 3718 2021年12月 

  PURPOSE: The clinicopathological or genetic features related to the prognosis of mucinous adenocarcinoma are unknown because of its rarity. The clinicopathological or targetable features were investigated for better management of patients with mucinous adenocarcinoma of the lung. METHODS: We comprehensively evaluated the clinicopathological and genetic features of 60 completely resected mucinous lung adenocarcinomas. Targetable genetic variants were explored using nCounter and polymerase chain reaction, PD-L1 and TTF-1 expression were evaluated using immunohistochemistry. We analyzed the prognostic impact using the Kaplan-Meier method and log-rank test. RESULTS: Of the 60 enrolled patients, 13 (21.7%) had adenocarcinoma in situ/minimally invasive adenocarcinoma, and 47 (78.3%) had invasive mucinous adenocarcinoma (IMA). Fifteen patients (25%) showed a pneumonic appearance on computed tomography (CT). CD74-NRG1 fusion, EGFR mutations, and BRAF mutation were detected in three (5%), four (6.7%), and one (1.7%) patient(s), respectively. KRAS mutations were detected in 31 patients (51.7%). Two patients (3.5%) showed immunoreactivity for PD-L1. No in situ or minimally invasive cases recurred. IMA patients with pneumonic appearance had significantly worse recurrence-free survival (RFS) and overall survival (OS) (p < 0.001). Furthermore, IMA patients harboring KRAS mutations had worse RFS (p = 0.211). Multivariate analysis revealed that radiological pneumonic appearance was significantly associated with lower RFS (p < 0.003) and OS (p = 0.012). KRAS mutations served as an unfavorable status for RFS (p = 0.043). CONCLUSION: Mucinous adenocarcinoma had a low frequency of targetable genetic variants and PD-L1 immunoreactivity; however, KRAS mutations were frequent. Pneumonic appearance on CT imaging and KRAS mutations were clinicopathological features associated with a worse prognosis.
• Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities.

  Rafael Rosell; Andrés Felipe Cardona; Oscar Arrieta; Andrés Aguilar; Masaoki Ito; Carlos Pedraz; Jordi Codony-Servat; Mariacarmela Santarpia

  British journal of cancer 125 12 1602 - 1611 2021年12月 

  Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.
• Pathological high malignant grade is higher risk of recurrence in pN0M0 invasive lung adenocarcinoma, even with small invasive size.

  Masaoki Ito; Yoshihiro Miyata; Kei Kushitani; Atsushi Kagimoto; Daisuke Ueda; Yasuhiro Tsutani; Yukio Takeshima; Morihito Okada

  Thoracic cancer 12 23 3141 - 3149 2021年12月 

  INTRODUCTION: Tumor size is an absolute recurrence risk in lung cancer. Although morphological features also reflect recurrence risk, its significance among lower-risk cases characterized by small size is unknown. We aimed to evaluate the relationship between pathological invasive tumor size and morphological features, and their prognostic impact by considering them simultaneously in lung adenocarcinoma. PATIENTS AND METHODS: We retrospectively reviewed 563 pN0M0 patients with pathological invasive size of ≤40 mm. The patients were classified by pathological invasive size and pathological malignant grading using the proportion of subhistological components. The prognostic impact was evaluated using recurrence-free survival (RFS) and overall survival (OS). The impact on prognosis was evaluated using uni- and multivariate analyses. RESULTS: The proportion of histological grade changed according to invasive tumor size. Patients with high malignant grade (G3) showed worse RFS than those with low and intermediate malignant grade (G1+2) with invasive size ≤20 mm. The 5-year RFS (G1+2 vs. G3) in 5-10 mm was 96.0% vs. 83.3% (HR = 5.505, 95% CI = 7.156-1850, p < 0.001) and in 10-20 mm was 87.8% vs. 67.1% (HR = 2.829, 95% CI = 4.160-43.14, p < 0.001). G3 patients were significantly bigger in invasive size and included more pleural/lymphatic/vascular invasion and recurrence. Multivariate analysis indicated pathological G3 status was significantly associated with worse RFS (HR = 2.097, 95% CI = 1.320-3.333, p = 0.002). CONCLUSIONS: Invasive tumor size and pathological malignant grade overlap in invasive adenocarcinoma. G3 patients are more likely to have pleural/lymphatic/vascular invasion and significantly worse RFS compared to G1/G2 cases, even with a small invasive size of ≤20 mm.
• Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer.

  Ai Amioka; Takayuki Kadoya; Satoshi Sueoka; Yoshie Kobayashi; Shinsuke Sasada; Akiko Emi; Norio Masumoto; Masaoki Ito; Koh Nakayama; Morihito Okada

  Breast cancer (Tokyo, Japan) 28 5 1062 - 1071 2021年09月 

  BACKGROUND: Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. METHODS: In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K-AKT-mTOR signaling pathway was also examined. RESULTS: The relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. CONCLUSIONS: In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K-AKT-mTOR signaling pathway.
• Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry.

  Alexander Drilon; Michael Duruisseaux; Ji-Youn Han; Masaoki Ito; Christina Falcon; Soo-Ryum Yang; Yonina R Murciano-Goroff; Haiquan Chen; Morihito Okada; Miguel Angel Molina; Marie Wislez; Philippe Brun; Clarisse Dupont; Eva Branden; Giulio Rossi; Alexa Schrock; Siraj Ali; Valérie Gounant; Fanny Magne; Torsten Gerriet Blum; Alison M Schram; Isabelle Monnet; Jin-Yuan Shih; Joshua Sabari; Maurice Pérol; Viola W Zhu; Misako Nagasaka; Robert Doebele; D Ross Camidge; Maria Arcila; Sai-Hong Ignatius Ou; Denis Moro-Sibilot; Rafael Rosell; Lucia Anna Muscarella; Stephen V Liu; Jacques Cadranel

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology 39 25 2791 - 2802 2021年09月 

  PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.
• Correction to: Effect of Wnt5a on drug resistance in estrogen receptor‑positive breast cancer.

  Ai Amioka; Takayuki Kadoya; Satoshi Sueoka; Yoshie Kobayashi; Shinsuke Sasada; Akiko Emi; Norio Masumoto; Masaoki Ito; Koh Nakayama; Morihito Okada

  Breast cancer (Tokyo, Japan) 28 5 1072 - 1072 2021年09月
• Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma.

  Masaoki Ito; Jordi Codony-Servat; Ana Giménez-Capitán; Mireia Serra-Mitjans; Francisco Pérez-Ochoa; David Llige; Imane Chaib; Ramón Rami-Porta; Carme Obiols; Sergi Call; Manuela Iglesias; José Belda-Sanchis; Xavier Tarroch-Sarasa; Niki Karachaliou; Miguel Angel Molina-Vila; Morihito Okada; Rafael Rosell

  JTO clinical and research reports 1 4 100084 - 100084 2020年11月 

  INTRODUCTION: EGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. METHODS: We examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. RESULTS: A total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05-3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. CONCLUSIONS: Elevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.
• Prognostic impact of targetable genetic variants in resected adenocarcinoma of the lung: a narrative review and model proposal for precise evaluation

  Masaoki Ito; Yoshihiro Miyata; Morihito Okada

  Precision Cancer Medicine 3 19 - 19 2020年09月
• Neoadjuvant atezolizumab plus chemotherapy in resectable non-small-cell lung cancer.

  Rafael Rosell; Masaoki Ito

  The Lancet. Oncology 21 6 736 - 738 2020年06月
• Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

  Tomoharu Yoshiya; Takahiro Mimae; Masaoki Ito; Shinsuke Sasada; Yasuhiro Tsutani; Kenichi Satoh; Takeshi Masuda; Yoshihiro Miyata; Noboru Hattori; Morihito Okada

  Investigational new drugs 38 2 485 - 492 2020年04月 

  Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.
• Intense Expression of EGFR L858R Characterizes the Micropapillary Component and L858R Is Associated with the Risk of Recurrence in pN0M0 Lung Adenocarcinoma with the Micropapillary Component.

  Naoto Kishi; Masaoki Ito; Yoshihiro Miyata; Akinori Kanai; Yoshinori Handa; Yasuhiro Tsutani; Kei Kushitani; Yukio Takeshima; Morihito Okada

  Annals of surgical oncology 27 3 945 - 955 2020年03月 

  BACKGROUND: Lung adenocarcinoma with the micropapillary (MP) component poses a higher risk of recurrence even when the MP component is not predominant. This study explored genetic features associated with highly malignant behavior of lung adenocarcinoma with the MP component. METHODS: The MP and papillary (PaP) components were captured separately in three patients. Comprehensive mRNA expressions of somatic variants were compared between the MP and PaP components of each patient using next-generation sequencing (NGS). The protein expression of the NGS-detected variant was validated by immunohistochemistry. The prognostic impact of the detected variant was evaluated in 288 adenocarcinoma patients with resection of pN0M0. RESULTS: In two cases, NGS suggested higher RNA expression of EGFR L858R in the MP component than in the PaP component (allele frequency, 0.485 vs. 0.155 and 1.000 vs. 0.526, respectively; P < 0.001 for both). Immunohistochemistry validated intense expression of L858R in the MP component of 27 MP-positive (MP+) patients. Among 288 pN0M0 patients, L858R was more frequently harbored in the MP+ patients than in the MP-negative (MP-) patients. The MP+ patients harboring L858R showed significantly worse recurrence-free survival (RFS) than the MP+ patients without L858R (median RFS 38.7 and 55.0 months, respectively; hazard ratio [HR] 3.004; 95% confidence interval [CI] 1.306-9.132; P = 0.012). Multivariate analysis of the MP+ patients showed that positive L858R status was associated with poorer RFS (HR 2.976; 95% CI 1.190-7.442; P = 0.020). CONCLUSIONS: EGFR L858R was more frequently harbored in the MP+ adenocarcinoma patients than in the MP- adenocarcinoma patients. Intense expression of L858R in the MP component was suggested, and the MP+ patients harboring L858R were at comparatively higher risk of recurrence in the group with pN0M0 lung adenocarcinoma.
• Positive EGFR mutation status is a risk of recurrence in pN0-1 lung adenocarcinoma when combined with pathological stage and histological subtype: A retrospective multi-center analysis.

  Masaoki Ito; Yoshihiro Miyata; Yasuhiro Tsutani; Hiroyuki Ito; Haruhiko Nakayama; Kentaro Imai; Norihiko Ikeda; Morihito Okada

  Lung cancer (Amsterdam, Netherlands) 141 107 - 113 2020年03月 

  OBJECTIVES: Recurrence risk of resected lung adenocarcinoma is represented by pathological stage (pStage), histological subtype, and potentially by EGFR mutation. However, the relationship among these factors and their combined impact on prognosis are unclear. MATERIALS AND METHODS: Using a multicenter database, we retrospectively investigated the prognostic impact of EGFR mutation status in relation to pStage and histological subtype in resected pN0-1M0 lung adenocarcinoma. RESULTS: Among 1155 pN0-1M0 adenocarcinoma cases, pStage 0 and IA1-IB were confirmed predominantly in EGFR-positive cases. AIS, MIA, and lepidic predominant adenocarcinoma were also more frequently found in EGFR-positive cases and showed no/little recurrence regardless of EGFR mutation status. The 5-year recurrence-free survival (RFS) of papillary, acinar, solid, and micropapillary predominant adenocarcinoma was stratified by pStage (IA1-IB, IIA-IIIA) or histological malignant subtype (intermediate or high malignant subtype), and more finely subdivided by EGFR mutation status. Positive EGFR mutation cases showed worse RFS in both classifications. Low malignant subtype and pStage IA1-IB intermediate malignant subtype showed low frequency of recurrence. Whereas, in pStage IA1-IB high malignant subtype and pStage IIA-IIIA cases, EGFR-positive cases showed poorer 5-year RFS than EGFR-negative (49.6% and 75.6%, respectively, hazard ratio [HR] = 1.84, 95% CI = 1.38-7.42, p <  0.01) and multivariate analysis indicated positive EGFR mutation status was significantly related to poorer PRF (HR = 2.005, 95% CI = 1.029-3.906, p =  0.041). CONCLUSION: EGFR mutation harbored primarily in early-stage or low-malignant histological subtypes with no/little recurrence. In pN0-1M0 adenocarcinoma with higher risk of recurrence, positive EGFR mutation cases showed worse RFS. EGFR mutation status enables better stratification of recurrence risk when considering pStage and histological malignant subtype.
• Osimertinib and dihydroartemisinin: a novel drug combination targeting head and neck squamous cell carcinoma.

  Imane Chaib; Xueting Cai; David Llige; Mariacarmela Santarpia; Eloisa Jantus-Lewintre; Martyna Filipska; Carlos Pedraz; Jean Cui; Jie Yang; Jing Miao; Rongwei Sun; Jillian Wilhelmina Paulina Bracht; Masaoki Ito; Jordi Codony-Servat; Niki Karachaliou; Andrés Aguilar; Rafael Rosell; Peng Cao

  Annals of translational medicine 7 22 651 - 651 2019年11月 

  BACKGROUND: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis with limited progression-free survival and overall survival, even when treated with different combinations of chemotherapy, targeted therapies and immunotherapy. We explored in vitro and in vivo the effect of the epidermal growth factor receptor (EGFR) inhibitor, osimertinib, alone and in combination with dihydroartemisinin (DHA) in HNSCC. METHODS: The combination of osimertinib with DHA was tested in the FaDu and CAL27 HNSCC cell lines. Tumor cell proliferation assays were conducted in cultured cells and mouse xenografts. Western blotting analysis of related signal pathways was performed to investigate the molecular mechanisms of the inhibitory effect of DHA and the combination. Other compounds, which inhibit signal transducer and activator of transcription 3 (STAT3), Src-family kinases (SFKs), sphingosine kinase 1 (SPHK1), or the receptor tyrosine kinase (RTK) AXL were also combined with osimertinib in vitro. RESULTS: Osimertinib exerted synergistic cytotoxicity toward FaDu and CAL27 HNSCC cells when combined with DHA. DHA reversed the osimertinib-induced STAT3 and Src phosphorylation. The double combination inhibited AXL expression. The anticancer potential of osimertinib plus DHA combination was validated in vivo on FaDu and CAL27 xenografts in mice without notable side effects. CONCLUSIONS: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings strongly indicate that a clinical trial is warranted to confirm the benefit of the combination.
• Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma.

  Masaoki Ito; Carles Codony-Servat; Jordi Codony-Servat; David Lligé; Imane Chaib; Xiaoyan Sun; Jing Miao; Rongwei Sun; Xueting Cai; Alberto Verlicchi; Morihito Okada; Miguel Angel Molina-Vila; Niki Karachaliou; Peng Cao; Rafael Rosell

  Cell communication and signaling : CCS 17 1 137 - 137 2019年10月 

  INTRODUCTION: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. METHODS: The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. RESULTS: The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. CONCLUSIONS: Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.
• Characterising acquired resistance to erlotinib in non-small cell lung cancer patients.

  Niki Karachaliou; Jordi Codony-Servat; Jillian Wilhelmina Paulina Bracht; Masaoki Ito; Martyna Filipska; Carlos Pedraz; Imane Chaib; Jordi Bertran-Alamillo; Andres Felipe Cardona; Miguel Angel Molina; Rafael Rosell

  Expert review of respiratory medicine 13 10 1019 - 1028 2019年10月 

  Introduction: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges. Areas covered: In this review we will focus on the mechanisms of resistance to the first-generation EGFR TKI, erlotinib, and will mainly summarize the findings throughout the last 10 years in the field of EGFR-mutant lung cancer. Expert opinion: Widespread research has been performed and several mechanisms of resistance to EGFR TKIs, especially first- and second-generation, have been identified. Still, no adequate combinatory therapies have received regulatory approval for the treatment of EGFR-mutant patients at the time of resistance. The third-generation EGFR TKI, osimertinib has been approved for patients whose tumor has become resistant through the secondary T790M resistant EGFR mutation. The identification of the mechanisms of resistance and the application of the adequate therapy to each patient is still an unmet need.
• Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer.

  Masaoki Ito; Carles Codony-Servat; Niki Karachaliou; Rafael Rosell

  Translational lung cancer research 8 5 667 - 673 2019年10月 

  BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. METHODS: The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. RESULTS: The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated. CONCLUSIONS: The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.
• Breast cancer cell motility is promoted by 14-3-3γ

  Emiko Hiraoka; Takahiro Mimae; Masaoki Ito; Takayuki Kadoya; Yoshihiro Miyata; Akihiko Ito; Morihito Okada

  Breast Cancer 26 5 581 - 593 2019年09月 [査読有り]
   

  © 2019, The Japanese Breast Cancer Society. Purpose: Pseudopodia are actin-rich ventral protrusions associated with cell motility and cancer cell invasion. We previously applied our established method of using excimer laser cell etching to isolate pseudopodial proteins from MDA-MB-231 breast cancer cells. We later identified 14-3-3γ as an oncogenic molecule among 46 candidate proteins that are specific to pseudopodia. The present study aimed to determine the function of 14-3-3γ in the motility of breast cancer cells. Methods: MDA-MB-231 cells were cultured on 3-µm porous membranes and double stained to localize 14-3-3γ and phalloidin in pseudopodia using confocal imaging. We assessed pseudopodia numbers and length, as well as migration and wound healing in MDA-MB-231 cells with knockdown and forced expression of 14-3-3γ to determine 14-3-3γ involvement in cell motility. We also immunohistochemically analyzed 14-3-3γ in human breast cancer tissues with high-grade lymphatic invasion. Results: We specifically located 14-3-3γ in pseudopodia of MDA-MB-231 cells. Knockdown and forced expression of 14-3-3γ, respectively, decreased and increased pseudopodial formation and elongation. Migration and wound healing assays also showed that 14-3-3γ knockdown and forced expression, respectively, decreased and increased the number of underside cells and acellular areas in MDA-MB-231 breast cancer cells. More 14-3-3γ was expressed in sites of lymphatic invasion, than in the center and periphery of human breast cancer tissues. Conclusion: The role of 14-3-3γ in breast cancer invasiveness might be to promote cell motility. Inhibition of 14-3-3γ could, therefore, become a novel target of therapy to prevent invasion and metastasis in patients with breast cancers expressing 14-3-3γ.
• Correction to: Breast cancer cell motility is promoted by 14-3-3γ.

  Emiko Hiraoka; Takahiro Mimae; Masaoki Ito; Takayuki Kadoya; Yoshihiro Miyata; Akihiko Ito; Morihito Okada

  Breast cancer (Tokyo, Japan) 26 5 594 - 594 2019年09月 

  The correct name of the corresponding author should be ''Takahiro Mimae'', and not ''Emiko Hiraoka'' as given in the original publication of the article.
• Synchronicity of genetic variants between primary sites and metastatic lymph nodes, and prognostic impact in nodal metastatic lung adenocarcinoma.

  Masaoki Ito; Yoshihiro Miyata; Shoko Hirano; Shingo Kimura; Fumiko Irisuna; Kyoko Ikeda; Kei Kushitani; Naoto Kishi; Yasuhiro Tsutani; Yukio Takeshima; Morihito Okada

  Journal of cancer research and clinical oncology 145 9 2325 - 2333 2019年09月 

  PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated. METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence. RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy. CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.
• Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines.

  Jordi Codony-Servat; Santiago Viteri; Carles Codony-Servat; Masaoki Ito; Jillian Willhelmina Paulina Bracht; Jordi Berenguer; Imane Chaib; Miguel Angel Molina-Vila; Niki Karachaliou; Rafael Rosell

  Translational lung cancer research 8 4 340 - 351 2019年08月 

  BACKGROUND: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. METHODS: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. RESULTS: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. CONCLUSIONS: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.
• Cancer Stem Cell Biomarkers in EGFR-Mutation-Positive Non-Small-Cell Lung Cancer.

  Jordi Codony-Servat; Carles Codony-Servat; Andrés Felipe Cardona; Ana Giménez-Capitán; Ana Drozdowskyj; Jordi Berenguer; Jillian Wilhelmina Paulina Bracht; Masaoki Ito; Niki Karachaliou; Rafael Rosell

  Clinical lung cancer 20 3 167 - 177 2019年05月 

  INTRODUCTION: Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in non-small-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem cells (CSCs). Src through Yes-associated protein 1 (YAP1) activates NOTCH. Signal transduction and activator of transcription 3 (STAT3) activation occurs upon EGFR blockade and regulates the generation of CSCs. PATIENTS AND METHODS: Using the Aldefluor assay kit, we investigated the enrichment of aldehyde dehydrogenase (ALDH)-positive cells in EGFR-mutation-positive cells treated with gefitinib, afatinib, and osimertinib. Western blot analysis was performed to evaluate changes in CSC marker expression upon EGFR blockade. We performed gene expression analysis in a cohort of EGFR-mutation-positive non-small-cell lung cancer patients. We evaluated the association of gene expression with treatment outcomes. RESULTS: The cell subpopulation surviving EGFR inhibition had high ALDH activity and elevated CSC marker expression. Concurrent inhibition of EGFR, STAT3, and Src diminished the CSC subpopulation in an EGFR-mutation-positive cellular model. In a cohort of 64 EGFR-mutation-positive patients, 2 ALDH1 isoforms and the NOTCH target hairy and enhancer of split 1 (HES1), when highly expressed, were predictive of worse outcome to EGFR blockade. The gene expression of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) that maintains the self-renewal of stem cells was also related to treatment outcome. CONCLUSION: Single EGFR inhibitors increase the population of CSCs. Combinatory therapy targeting STAT3 and Src may be of potential benefit. ALDH1, HES1, and Bmi-1 are essential biomarkers in the initial assessment of EGFR-mutation-positive patients.
• Prolonged post-recurrence survival following pleurectomy/decortication for malignant pleural mesothelioma.

  Yuichiro Kai; Yasuhiro Tsutani; Norifumi Tsubokawa; Masaoki Ito; Takeshi Mimura; Yoshihiro Miyata; Morihito Okada

  Oncology letters 17 3 3607 - 3614 2019年03月 

  The present study analyzed surgical results in patients with malignant pleural mesothelioma (MPM) who underwent extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). Data for 44 patients who achieved macroscopic complete resection following neoadjuvant chemotherapy followed by EPP (n=29) or P/D (n=15) were reviewed. Patient demographics and oncological outcomes were compared between the EPP and P/D groups. The median overall (OS) and progression-free survival (PFS) times were 22 and 14 months, respectively. OS was significantly different between the EPP and P/D groups (median OS, 17 vs. 34 months; 5-year OS, 11 vs. 44%; P=0.019); no difference was noted in PFS (median PFS, 13 vs. 21 months; 5-year PFS, 11 vs. 17%; P=0.373). Univariate analysis demonstrated that epithelial histology (P=0.0003) and P/D (P=0.018) were significant favorable prognostic factors for OS. Using multivariate analysis, epithelial histology (P=0.001) remained the only significant factor. Post-recurrence survival (PRS) among all patients was significantly longer in the P/D group (median PRS, 3 vs. 20 months; 1.5-year PRS, 5 vs. 54%; P=0.003), even among patients with epithelial-type MPM (median PRS, 6 s vs. 20 months; 1.5-year PRS, 8 vs. 61%; P=0.012). Chemotherapy following recurrence (P=0.033) was significantly associated with superior PRS in multivariate analysis. Postoperative pulmonary function was significantly improved in the P/D group. In summary, P/D may be an alternative procedure to EPP for resectable MPM providing similar PFS and improved PRS.
• Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC).

  Niki Karachaliou; Andres Felipe Cardona; Jillian Wilhelmina Paulina Bracht; Erika Aldeguer; Ana Drozdowskyj; Manuel Fernandez-Bruno; Imane Chaib; Jordi Berenguer; Mariacarmela Santarpia; Masaoki Ito; Jordi Codony-Servat; Rafael Rosell

  EBioMedicine 39 207 - 214 2019年01月 

  BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. METHODS: We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. RESULTS: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. INTERPRETATION: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).
• Metachronous Lung Cancer After Pleurectomy/Decortication.

  Yuichiro Kai; Yasuhiro Tsutani; Masaoki Ito; Takeshi Mimura; Yoshihiro Miyata; Morihito Okada

  The Annals of thoracic surgery 107 1 e1-e3  2019年01月 

  Pleurectomy/decortication is a surgical procedure for malignant pleural mesothelioma (MPM) and has been proposed as an alternative to extrapleural pneumonectomy. We report a second primary lung cancer developing after pleurectomy/decortication for MPM. A 59-year-old man was diagnosed with MPM on the right side and underwent pleurectomy/decortication. Follow-up computed tomography detected a nodule in the right upper lobe that was diagnosed as adenocarcinoma by wedge resection. Lung cancer and MPM are associated with asbestos exposure. However, predicting lung cancer after treatment for MPM is difficult. Careful follow-up of the spared lung is necessary for detecting second primary lung cancer or MPM recurrence.
• Increased risk of recurrence in resected EGFR-positive pN0M0 invasive lung adenocarcinoma.

  Masaoki Ito; Yoshihiro Miyata; Kei Kushitani; Tomoharu Yoshiya; Yuichiro Kai; Yasuhiro Tsutani; Takeshi Mimura; Kazuo Konishi; Yukio Takeshima; Morihito Okada

  Thoracic cancer 9 12 1594 - 1602 2018年12月 

  BACKGROUND: This study was conducted to evaluate the prognostic and recurrent impact of EGFR mutation status in resected pN0M0 lung adenocarcinoma with consideration of the histological subtype. METHODS: Following retrospective analysis of whole 474 consecutive pathological N0M0 lung adenocarcinoma patients, the prognostic significance of EGFR mutation status was evaluated in limited 394 subjects. Overall survival and recurrence-free interval (RFI) were estimated using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazard models. RESULTS: The five-year RFI was 85.7% and 93.3% for EGFR positive (n = 176) and negative (n = 218) cases, respectively (hazard ratio [HR] 1.992, 95% confidence interval [CI] 1.005-3.982; P = 0.048). Following the exclusion of specific subtypes free from recurrence or EGFR mutation (adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive mucinous adenocarcinoma), the five-year RFI was obviously poorer in EGFR positive compared to negative cases (80.7% and 92.1%, respectively; HR 2.163, 95% CI 1.055-4.341; P = 0.035). Multivariate analysis excluding the specific subtypes confirmed that male sex, age, current or Ex-smoking status, pleural invasion, and EGFR-positive status were independently associated with shorter RFI. No significant differences in five-year overall survival were found between the EGFR mutation positive and negative groups (88.7% and 93.7%, respectively; HR 1.630, 95% CI 0.787-3.432; P = 0.2). CONCLUSION: EGFR mutations are associated with recurrence in pN0M0 lung adenocarcinoma. EGFR mutation status and histological subtype should be considered when evaluating the risk of recurrence in resected lung adenocarcinoma patients.
• Inhibition of MEK, a canonical KRAS pathway effector in KRAS mutant NSCLC.

  Rafael Rosell; Niki Karachaliou; Carles Codony-Servat; Masaoki Ito

  Translational lung cancer research 7 Suppl 3 S183-S186  2018年09月
• Management pathways for solitary pulmonary nodules.

  Masaoki Ito; Yoshihiro Miyata; Morihito Okada

  Journal of thoracic disease 10 Suppl 7 S860-S866  2018年04月 

  Pulmonary nodules are often detected during the clinical course of several diseases or through routine screening. Various guidelines have proposed management algorithms for suspicious solitary nodules in lung cancer. Generally, solitary pulmonary nodules are managed according to nodule appearance and risk of lung cancer using low-dose, thin section computed tomography (CT). Liquid biopsy is promising for diagnosis, therapeutic-monitoring and follow-up in lung cancer; however, diagnosis and management pathways based on genetic examination alone have not been established. Management of solitary pulmonary nodules should be carried out by a multidisciplinary team and tissue biopsy is necessary for the diagnosis of lung cancer. Genetic analysis via liquid biopsy is warranted in addition to more established techniques in pulmonary nodule management.
• Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis.

  Niki Karachaliou; Imane Chaib; Andres Felipe Cardona; Jordi Berenguer; Jillian Wilhelmina Paulina Bracht; Jie Yang; Xueting Cai; Zhigang Wang; Chunping Hu; Ana Drozdowskyj; Carles Codony Servat; Jordi Codony Servat; Masaoki Ito; Ilaria Attili; Erika Aldeguer; Ana Gimenez Capitan; July Rodriguez; Leonardo Rojas; Santiago Viteri; Miguel Angel Molina-Vila; Sai-Hong Ignatius Ou; Morihito Okada; Tony S Mok; Trever G Bivona; Mayumi Ono; Jean Cui; Santiago Ramón Y Cajal; Alex Frias; Peng Cao; Rafael Rosell

  EBioMedicine 29 112 - 127 2018年03月 

  Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.
• Postoperative complications and prognosis after lobar resection versus sublobar resection in elderly patients with clinical Stage I non-small-cell lung cancer.

  Yasuhiro Tsutani; Norifumi Tsubokawa; Masaoki Ito; Keizo Misumi; Hideaki Hanaki; Yoshihiro Miyata; Morihito Okada

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 53 2 366 - 371 2018年02月 

  OBJECTIVES: The study aimed to investigate the outcomes of sublobar resection in elderly patients with non-small-cell lung cancer. METHODS: A total of 205 patients aged ≥75 years were identified from 794 consecutive patients who underwent complete surgical resection for clinical Stage I non-small-cell lung cancer. The outcomes of lobectomy and sublobar resection were compared. Propensity scores were estimated for multivariable analyses and matching. RESULTS: Sublobar resection (n = 99) was more frequently performed than lobectomy (n = 106) in older patients (P = 0.027) and those with lower maximum standardized uptake on positron emission tomography (P < 0.001), lower T stage (P < 0.001), lower %vital capacity (P = 0.007) and lower %diffusing capacity of the lungs for carbon monoxide (P = 0.025). Severe (≥Grade IIIa) postoperative complications occurred more frequently with lobectomy (11 of 106 procedures, 10.4%) than with sublobar resection (5 of 99, 5.1%; P = 0.16). In propensity score-adjusted multivariable analysis, lobectomy was an independent predictive factor for severe postoperative complications (odds ratio 3.49, 95% confidence interval 1.01-12.05; P = 0.048). Overall survival (OS) was not significantly different following lobectomy (5-year OS 67.2%) or sublobar resection (5-year OS 73.9%; P = 0.93). In multivariable analysis, the surgical procedure was not an independent predictive factor for OS (lobectomy: hazard ratio 1.03, 95% confidence interval 0.49-2.16; P = 0.94). CONCLUSIONS: Sublobar resection may be the optimal procedure in elderly patients with clinical Stage I non-small-cell lung cancer and is associated with less severe postoperative complications than lobectomy and similar OS.
• STAT3 as a potential immunotherapy biomarker in oncogene-addicted non-small cell lung cancer.

  Ilaria Attili; Niki Karachaliou; Laura Bonanno; Jordi Berenguer; Jillian Bracht; Jordi Codony-Servat; Carles Codony-Servat; Masaoki Ito; Rafael Rosell

  Therapeutic advances in medical oncology 10 1758835918763744 - 1758835918763744 2018年 

  Immune checkpoint blockade has modified the treatment landscape for many types of tumors, including lung cancer. Still our knowledge on the biology of the interaction between tumor cells and the microenvironment is limited, preventing the optimal use of these new compounds and the maximum benefit that the patients can derive from them. We have actively worked on the role of STAT3, a transcriptional factor that causes innate resistance to targeted therapies in oncogene-addicted tumors. In this short review we take the opportunity to express our opinion and review existing knowledge on the immune role of STAT3 and the possible implications that this may have for the discovery of new biomarkers to predict response to immunotherapy, as well as new partners to combine with and increase the efficacy of immune checkpoint inhibitors.
• Therapeutic strategies and genetic profile comparisons in small cell carcinoma and large cell neuroendocrine carcinoma of the lung using next-generation sequencing.

  Masaoki Ito; Yoshihiro Miyata; Shoko Hirano; Shingo Kimura; Fumiko Irisuna; Kyoko Ikeda; Kei Kushitani; Yasuhiro Tsutani; Daisuke Ueda; Norifumi Tsubokawa; Yukio Takeshima; Morihito Okada

  Oncotarget 8 65 108936 - 108945 2017年12月 

  Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. The case harboring EGFR mutation showed response to EGFR-tyrosine kinase inhibitor. However, there are no clinicopathological features associated with therapeutically targetable cases. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types. In conclusion, although patients with SCLC and LCNEC may benefit from target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.
• The combination of checkpoint immunotherapy and targeted therapy in cancer.

  Niki Karachaliou; Maria Gonzalez-Cao; Aaron Sosa; Jordi Berenguer; Jillian Wilhelmina Paulina Bracht; Masaoki Ito; Rafael Rosell

  Annals of translational medicine 5 19 388 - 388 2017年10月 

  The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).
• Outcomes after lobar versus sublobar resection for clinical stage I non-small cell lung cancer in patients with interstitial lung disease.

  Yasuhiro Tsutani; Takeshi Mimura; Yuichiro Kai; Masaoki Ito; Keizo Misumi; Yoshihiro Miyata; Morihito Okada

  The Journal of thoracic and cardiovascular surgery 154 3 1089 - 1096 2017年09月 

  OBJECTIVE: Since the prognosis after standard lobectomy for non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD) is poor, we investigated the possibility of sublobar resection for the improvement of the surgical results in such patients. METHODS: Of 796 consecutive patients with clinical stage I NSCLC who underwent pulmonary resection, 107 were diagnosed with ILD using high-resolution computed tomography (HRCT). Overall survivals (OS) were compared between patients with non-ILD and those with ILD or between patients with ILD who underwent lobectomy and those who underwent sublobar resection. ILD patterns consisted of usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. The log-rank statistics and Cox proportional hazard models were used to test for survival differences. RESULTS: OS was significantly lower in patients with "ILD inconsistent with UIP" pattern (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.19-5.97; P = .014), or "ILD with possible UIP or UIP" patterns (HR, 2.38; 95% CI, 1.76-3.21; P < .001) compared with patients with non-ILD. No significant difference in OS was observed between patients with ILD who underwent either lobectomy or sublobar resection (HR, 1.82; 95% CI, 0.81-4.06; P = .19). Multivariable Cox analysis demonstrated diffusing capacity of the lung for carbon monoxide (HR, 0.95; 95% CI, 0.91-0.99; P = .009) and not surgical procedure (HR, 2.76; 95% CI, 0.83-9.16; P = .099), as an independent prognostic factor for OS. CONCLUSIONS: Sublobar resection may be a potential alternative choice for clinical stage I NSCLC with ILD on HRCT.
• Second predominant subtype predicts outcomes of intermediate-malignant invasive lung adenocarcinoma†.

  Masaoki Ito; Yoshihiro Miyata; Tomoharu Yoshiya; Yasuhiro Tsutani; Takeshi Mimura; Shuji Murakami; Hiroyuki Ito; Haruhiko Nakayama; Morihito Okada

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 51 2 218 - 222 2017年02月 

  OBJECTIVES: Acinar predominant and papillary predominant invasive adenocarcinomas are likely to be classified as intermediate-malignant types. Although these two types of adenocarcinoma are distinguished morphologically, the differences between their malignant behaviours and prognoses are not clear. The aim of this study is to provide a prognostically relevant stratification of these similar subtypes based on pathological features. METHODS: We retrospectively reviewed 347 consecutive clinically N0M0 lung adenocarcinomas of ≤3 cm in diameter that were resected between April 2006 and December 2010 at two institutes. Acinar and papillary predominant adenocarcinomas were classified into acinar/papillary-lepidic type and acinar/papillary-non-lepidic type according to whether the second predominant component was a lepidic or invasive component. RESULTS: Fifty-four acinar and 59 papillary predominant adenocarcinoma cases were classified as acinar/papillary-lepidic type (n = 65) or acinar/papillary-non-lepidic type (n = 48) cases. Acinar/papillary-non-lepidic type cases were accompanied by more vascular invasion (13.8% vs 31.3%, P = 0.0451) and pleural invasion (9.2% vs 25.0%, P = 0.0450) than were acinar/papillary-lepidic type cases. Five-year overall survival (OS) and recurrence-free survival (RFS) also differed significantly between these types (5-year OS: acinar/papillary-lepidic type, 96.3% vs acinar/papillary-non-lepidic type, 61.8%, hazard ratio = 6.315, P = 0.00650; 5-year RFS: acinar/papillary-lepidic type, 91.4% vs acinar/papillary-non-lepidic type, 68.8%, hazard ratio = 2.967, P = 0.0210). Multivariate analysis revealed that a second predominant component was an independent prognostic factor for RFS (acinar/papillary-non-lepidic type: hazard ratio = 3.784, 95% confidence interval 1.091–13.128, P = 0.036). CONCLUSIONS: The pathological second predominant component allows intermediate-malignant adenocarcinomas to be subclassified with prognostic significance. It can be utilized when assessing postoperative risks for recurrence and when considering therapeutic strategies.
• pN0 small(<20mm)invasive adenocarcinomaにおけるsubtypeの重要性

  吉屋 智晴; 宮田 義浩; 甲斐 佑一郎; 伊藤 正興; 津谷 康大; 三村 剛史; 伊藤 宏之; 中山 治彦

  日本呼吸器外科学会雑誌 30 3 O9 - 2 (一社)日本呼吸器外科学会 2016年04月
• 病理腫瘍径20mm以下肺腺癌の予後予測におけるLepidic componentの重要性

  吉屋 智晴; 宮田 義浩; 甲斐 佑一郎; 伊藤 正興; 津谷 康大; 三村 剛史; 村上 修司; 伊藤 宏之; 中山 治彦; 岡田 守人

  肺癌 55 5 650 - 650 (NPO)日本肺癌学会 2015年10月
• Pathological Second-Predominant Component Predicts Recurrence in Lung Adenocarcinoma

  Masaoki Ito; Yoshihiro Miyata; Yasuhiro Tsutani; Takeshi Mimura; Shuji Murakami; Hiroyuki Ito; Haruhiko Nakayama; Morihito Okada

  JOURNAL OF THORACIC ONCOLOGY 10 9 S263 - S263 2015年09月
• Prediction for prognosis of resected pT1a-1bN0M0 adenocarcinoma based on tumor size and histological status: relationship of TNM and IASLC/ATS/ERS classifications.

  Masaoki Ito; Yoshihiro Miyata; Kei Kushitani; Tomoharu Yoshiya; Takahiro Mimae; Yuta Ibuki; Keizo Misumi; Yukio Takeshima; Morihito Okada

  Lung cancer (Amsterdam, Netherlands) 85 2 270 - 5 2014年08月 

  OBJECTIVES: This study aimed to estimate the relationship between 7th TNM classification and IASLC/ATS/ERS classification with regard to tumor size and pathological status and to determine the utility of these classifications for predicting prognosis in resected node-negative adenocarcinoma with tumor size ≤2.0 cm and >2.0-3.0 cm. MATERIALS AND METHODS: We reviewed 321 pN0M0 lung adenocarcinoma cases resected at Hiroshima University Hospital from January 1991 to December 2010. Histological differences between T1a and T1b based on the IASLC/ATS/ERS classification were estimated and followed by evaluation of overall survival (OS) and recurrence-free interval (RFI) based on differences in tumor size and histological features. RESULTS: We found 188 cases of pT1a-1bN0M0 (135 T1a, 53 T1b). Pathological T1a tumors included significantly more adenocarcinoma in situ (AIS) cases and minimally invasive adenocarcinoma (MIA) cases than T1b tumors (60.7% vs 18.8%, respectively; p<0.0001), while more invasive adenocarcinoma cases were included in pT1b. By considering the two classifications simultaneously, the 5-year OS rates of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 97.5%, 87.5%, 95.8%, and 86.8%, respectively. The 5-year RFIs of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 100%, 100%, 91.3%, and 72.5%, respectively. T1a AIS/MIA and T1b AIS/MIA could be separated as good prognostic cases with a 100% RFI. Multivariate analysis indicated that only T1b invasive adenocarcinoma was an independent factor for predicting recurrence (p=0.001). CONCLUSION: Compared to a single classification, combining TNM and IASLC/ATS/ERS classifications could provide more detail information concerning disease recurrence. AIS and MIA should be handled equally, regardless of tumor size, because their non-/less invasive status is more useful for predicting prognosis than their tumor size classification. In contrast, the T descriptors based on TNM classification are important for predicting prognosis in invasive adenocarcinoma.
• α-Parvin, a pseudopodial constituent, promotes cell motility and is associated with lymph node metastasis of lobular breast carcinoma.

  Masaoki Ito; Man Hagiyama; Takahiro Mimae; Takao Inoue; Takashi Kato; Azusa Yoneshige; Jun Nakanishi; Tadashi Kondo; Morihito Okada; Akihiko Ito

  Breast cancer research and treatment 144 1 59 - 69 2014年02月 

  Invasive lobular carcinoma (ILC) is more frequently lymph node positive than is invasive ductal carcinoma (IDC), and ILC cell infiltration shows distinctive histological characteristics, suggesting the action of ILC-specific invasion molecules. To identify such a molecule, we used a proteomic approach in the pseudopodia of MDA-MB-231 breast cancer cells. A pseudopodial constituent was identified using excimer laser ablation, two-dimensional difference gel electrophoresis, mass spectroscopy, and immunocytofluorescence. MDA-MB-231 cells were modified to express various levels of this constituent by transient transfection and were examined for pseudopodia formation and migratory abilities using wound healing and two-chamber assays. Immunohistochemical positivity of human breast cancer cells (56 ILCs and 21 IDCs) was compared with clinicopathological variables. An actin-binding adaptor protein, α-parvin, was found to localize to pseudopodia and to form focal adhesions in cells not induced to extend pseudopodia. Pseudopodial length and density and migratory abilities correlated with α-parvin expression. Twenty-one (37.5 %) ILCs stained positive for α-parvin, whereas the results were negative for all 21 IDCs (P < 0.001). α-Parvin positivity in ILC was significantly associated with lymphatic invasion (P = 0.038) and lymph node metastasis (P = 0.003) in univariate analyses and to lymph node metastasis (P = 0.020) in multivariate analyses. α-Parvin, a pseudopodial constituent, was found to promote migration of breast cancer cells and to be expressed exclusively by ILC, suggesting that α-parvin is an ILC-specific invasion molecule that may have clinical utility as a biomarker for aggressive subsets of ILC.
• Classifications of n2 non-small-cell lung cancer based on the number and rate of metastatic mediastinal lymph nodes.

  Masaoki Ito; Yoshinori Yamashita; Yasuhiro Tsutani; Keizo Misumi; Hiroaki Harada; Yoshihiro Miyata; Morihito Okada

  Clinical lung cancer 14 6 651 - 7 2013年11月 

  BACKGROUND: Subdivisions of N2 non-small-cell lung cancer (NSCLC) cases based on metastatic status of mediastinal and non-mediastinal lymph nodes have been proposed. This study aimed to evaluate N2 disease classification by mediastinal lymph nodes alone. PATIENTS AND METHODS: We reviewed 187 patients with NSCLC pN1-N2 who were surgically treated to evaluate the proposed classifications: number, rate, nodal zone of metastatic lymph nodes. We evaluated N2 disease classification based on mediastinal lymph nodes alone in 136 pN2 cases. RESULTS: The number (1-2, 3-5, and 6 ≤) or rate (15%≥, 15%< to 40%>, and 40%≤) classification based on all metastatic lymph nodes was validated by the log-rank test and Cox proportional hazards model. After reclassification by number or rate of metastatic mediastinal lymph nodes alone, a significant difference was maintained among all groups except between the 3-5 and 6 ≤ groups. The 5-year survival rates of the 1-2, 3-5, and 6 ≤ groups were 63.4%, 32.4%, and 18.2%, respectively (1-2 vs. 3-5, P = .015; 3-5 vs. 6 ≤, P = .134). With rate classification, the 5-year survival rates of the 15%≥, 15%-40% (15%< to 40%>), and 40%≤ groups were 56.0%, 27.3%, and 5.04%, respectively (15%≥ vs. 15%-40%, P = .011; 15-40% vs. 40%≤, P = .011). The Spearman's rank correlation coefficient showed a highly significant correlation of metastatic status between mediastinal lymph nodes and all lymph nodes (both P < .001). CONCLUSION: Classification by number and rate of mediastinal lymph nodes alone enabled subdivision of N2 NSCLC cases. Metastatic status of mediastinal lymph nodes reflects that of all lymph nodes and is prognostic indicators.
• Lung metastasis of adenoid cystic carcinoma, which mimicked primary lung cancer.

  Masaoki Ito; Riki Okita; Yasuhiro Tsutani; Takeshi Mimura; Yukari Kawasaki; Yoshihiro Miyata; Morihito Okada

  Thoracic cancer 4 3 327 - 329 2013年08月 

  We report a case of adenoid cystic carcinoma of the submandibular gland where pulmonary metastasis occurred twice 16 years after resection, and each metastasis mimicked primary lung adenocarcinoma in imaging findings. The first pulmonary relapse was clinically diagnosed as primary lung adenocarcinoma and intraoperative pathological examination showed that the tumor was an adenocarcinoma; lobectomy with mediastinal lymph node dissection was performed. However, postoperative immunohistochemical analysis showed that the tumor was a metastatic adenoid cystic carcinoma. During the secondary pulmonary relapse, although the tumor was correctly diagnosed as a metastatic adenoid cystic carcinoma by intraoperative examination, it again mimicked primary lung adenocarcinoma.
• Novel application for pseudopodia proteomics using excimer laser ablation and two-dimensional difference gel electrophoresis.

  Akihiko Ito; Takahiro Mimae; Ying-Shan-Zhu Yamamoto; Man Hagiyama; Jun Nakanishi; Masaoki Ito; Yoichiroh Hosokawa; Morihito Okada; Yoshinori Murakami; Tadashi Kondo

  Laboratory investigation; a journal of technical methods and pathology 92 9 1374 - 85 2012年09月 

  We developed a novel application to conduct pseudopodia proteomics. Pseudopodia are ventral actin-rich protrusions and play functional roles in cell migrations. Identification of pseudopodia proteins leads to a further understanding of malignant phenotypes of tumor cells and novel therapeutic strategies. In our application, tumor cells were placed on a fibronectin-coated porous membrane to form pseudopodia. According to the motile potentials of the cells, the cells formed pseudopodial microprocesses in the pores. An excimer laser, which was used for ophthalmic refractive surgeries, horizontally ablated cells at the membrane surface to remove the cell body. The microscopic observations and the protein expression studies suggested that the laser treatment caused no apparent damages to pseudopodia. Proteins in whole cells and pseudopodia fractions were individually solubilized, labeled with a highly sensitive fluorescent dye, and separated using two-dimensional difference gel electrophoresis. Among 2508 protein spots observed, 211 had different intensity between whole cells and pseudopodia fractions (more than fourfold differences and P-value of <0.05). The protein enrichment depended on the pore size. Mass spectrometric protein identification revealed 46 pseudopodia-localizing proteins. The localization of novel pseudopodia-localizing proteins such as RAB1A, HSP90B, TDRD7, and vimentin was confirmed using immunohistochemical examinations. The previous studies demonstrated that these four proteins may function in the cell migration process. This method will provide insights into the molecular details of pseudopodia and a further understanding of malignant phenotypes of tumor cells and novel therapeutic strategies.
• Prognostic impact of the primary tumor location based on the hilar structures in non-small cell lung cancer with mediastinal lymph node metastasis.

  Masaoki Ito; Yoshinori Yamashita; Yoshihiro Miyata; Masahiro Ohara; Yasuhiro Tsutani; Takuhiro Ikeda; Keizo Misumi; Hiroaki Harada; Ken-ichi Omori

  Lung cancer (Amsterdam, Netherlands) 76 1 93 - 7 2012年04月 

  The status of mediastinal lymph node metastasis is one of the main factors determining the treatment strategy for non-small cell lung cancer (NSCLC), but the primary tumor location is not considered crucial in the tumor-node-metastasis (TMN) classification at present. The aim of this study was to estimate the prognostic value of the primary tumor location on the basis of the hilar structures in NSCLC with mediastinal lymph node metastasis. We retrospectively reviewed the cases of 337 consecutive patients who underwent surgical resection for NSCLC between 1995 and 2004, divided the pN2 NSCLC cases (n=40) into central- and peripheral-type tumors according to the distance of the primary tumor from the first branch of the extrapulmonary bronchus, and compared the surgical outcomes between these tumor groups. Eighteen and twenty-two cases were classified as central- and peripheral-type tumors, respectively. The 5-year survival rate was significantly better for patients with central-type tumors than peripheral-type tumors (51.5% vs. 21.2%, P=0.034). The location-specific prognostic tendency was noted irrespective of the presence (n=13) or absence of skip metastasis. In a multivariate Cox analysis of the N2 NSCLC cases, the primary tumor location was a significant (P=0.026) prognostic factor for overall survival. In conclusion, evaluation of the primary tumor location based on the hilar structures is useful to predict the prognosis in N2 NSCLC.
• Unilateral absence of the left pulmonary artery accompanied by right lung cancer.

  Masaoki Ito; Yoshinori Yamashita; Hiroaki Harada; Ken-Ichi Omori

  The Annals of thoracic surgery 90 1 e6-8  2010年07月 

  Unilateral absence of a pulmonary artery is a rare congenital anomaly that is often accompanied by other cardiovascular anomalies. Surgical treatment for this rare disease is usually performed only on the abnormal side. We report on a case of unilateral absence of a pulmonary artery that was complicated by contralateral primary lung cancer. We performed a right middle lobectomy despite the absence of the left pulmonary artery and detected changes in respiratory function during the operation. The present case provides information on the surgical tolerability and predictable morbidity following lung resection of the normal side in unilateral absence of a pulmonary artery.

MISC

• 肺がん周術期がん免疫治療の現状とバイオマーカー

  須田健一; 小原秀太; 濱田顕; 千葉眞人; 伊藤正興; 下治正樹; 武本智樹; 宗淳一; 光冨徹哉; 津谷康大 日本気管食道科学会総会ならびに学術講演会プログラム・予稿集 74th 2023年
• Inmune gene expression by nCounter in mucinous adenocarcinoma lung cancer

  Ruth Roman Llado; Cristina Aguado Esteban; Ana Gimenez-Capitan; Ueda Daisuke; Masaoki Ito; Yasuhiro Tsutani; Yoshihiro Miyata; Cristina Teixid; Noemi Reguart; Morihito Okada; Sonia Rodriguez; Ariadna Balada; Erika Aldeguer; Santiago Viteri Ramirez; Maria Gonzalez Cao; Andres Aguilar; Rafael Rosell; Miguel Angel Molina Vila CANCER RESEARCH 80 (16) 2020年08月
• Increased Risk of Postoperative Recurrence in EGFR-Positive Stage IA to IB Invasive Lung Adenocarcinoma

  Masaoki Ito; Yoshihiro Miyata; Kei Kushitani; Tomoharu Yoshiya; Yasuhiro Tsutani; Kazuo Konishi; Yukio Takeshima; Morihito Okada JOURNAL OF THORACIC ONCOLOGY 12 (1) S649 -S649 2017年01月
• Comparison of Prognosis between Lobectomy and Sublobar Resection for Clinical Stage I Non-Small Cell Lung Cancer with Interstitial Lung Disease

  Yasuhiro Tsutani; Takeshi Mimura; Yuichiro Kai; Masaoki Ito; Yoshinori Handa; Norifumi Tsubokawa; Keizo Misumi; Hideaki Hanaki; Yoshihiro Miyata; Morihito Okada JOURNAL OF THORACIC ONCOLOGY 12 (1) S302 -S302 2017年01月
• Pathologic response to predict survival in patients who underwent surgery after neoadjuvant chemotherapy with bevacizumab for clinical stage II/IIIA non-squamous non-small cell lung cancer.

  Yasuhiro Tsutani; Yuichiro Kai; Masaoki Ito; Takeshi Mimura; Yoshihiro Miyata; Kenji Suzuki; Kazuya Takamochi; Fumihiro Tanaka; Haruhiko Nakayama; Yoshinori Yamashita; Makoto Oda; Masahiro Tsuboi; Morihito Okada JOURNAL OF CLINICAL ONCOLOGY 34 (15) 2016年05月

共同研究・競争的資金等の研究課題

• 網羅的プロテオミクスとジェノミクスによる肺癌リンパ節転移機構の解明と新分類の提唱

  日本学術振興会：科学研究費助成事業

  研究期間 : 2015年04月 -2017年03月 

  代表者 : 伊藤 正興; 岡田 守人; 宮田 義浩; 津谷 康大; 三隅 啓三; 岸 直人; 上田 大介; 平野 尚子; 木村 真吾; 入砂 文子; 池田 今日子

   

  現行の肺癌stagingは腫瘍の大きさや転移の有無・場所で規定され、それを参考に治療方針が決まる。肺腺癌治療は分子標的薬剤が広く使われ、使用の可否は特定の遺伝子形態の有無によるが、現行のstagingは遺伝子形態の有無は考慮しない。 本研究では分子標的薬剤使用の指標となる遺伝子形態の発現が、肺癌切除後の再発因子と判明し、さらに次世代シークエンサーによる遺伝子の網羅的解析で原発巣と転移巣に同様に存在すると判明した。 この結果に基づき、遺伝子形態の有無で過去の肺腺癌症例を層別化すると遺伝子形態の有無が再発後の予後に関係しており、特定の遺伝子形態の有無による腺癌の新たな分類方法の提唱に至った。

その他のリンク

researchmap

https://researchmap.jp/masaokiito