近年、次世代シークエンサー(NGS)の臨床応用が進み、がんに生じた遺伝子変化を網羅的に解析することが可能となった。包括的がんゲノムプロファイリング(CGP)検査を実施することで、がん化に関わる原因遺伝子が明らかになると同時に、治療の選択肢が増え、恩恵を受ける症例が出てきている。近畿大学病院ゲノム医療センターでは、2019年に日本においてCGP検査が保険適応を受けて以降、がん関連遺伝子検査がスムーズに進むよう業務を行っている。エキスパートパネルの運営を通して、患者や主治医への適切な遺伝子解析結果を届けることを目標とし、また二次的所見への対応などを行ってきた。本稿では、CGP検査の現状について概説し、特に課題の多い出口戦略について、治療への到達率を高めるために必要なことは何か考察をしたい。(著者抄録)

BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.

BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.

: Recent progress in understanding the molecular basis of cancer-including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes-has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF and HER2 has already been successfully translated into clinical practice for individuals with solid tumor. Next-generation sequencing (NGS) technologies have led to the ability to test for multiple cancer-related genes at once with a small amount of cells and tissues. In Japan, several hospitals have started NGS-based mutational profiling screening in patients with solid tumor in order to guide patients to relevant clinical trials. The Ministry of Health, Labor, and Welfare of Japan has also approved several cancer gene panels for use in clinical practice. However, there is an urgent need to develop a medical curriculum of clinical variant interpretation and reporting. We review recent progress in the implementation of NGS in Japan.

We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM). Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume > 1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT. Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %. This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. Methods VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Results Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Background Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. Methods This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1: 1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102. Findings From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n= 329) or placebo (n= 332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30.7 weeks (95% CI 26.7-36.1) versus 27.1 weeks (23.1-31.9) for placebo (hazard ratio 0.98, 95% CI 0.83-1.17, p= 0.86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]). Interpretation In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma.

We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein-damaging variants/mutations (18-78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co-activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co-factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1-3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein-damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono-allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co-factors, and in regions prone to mono-allelic deletion during oncogenesis. What's new? Malignant mesotheliomas (MM) are highly aggressive neoplasms largely arising from asbestos exposure. Here, the authors investigated possible genetic causes for the low histone acetylation levels observed in MM cell lines resistant to histone deacetylase inhibitors. Using whole-exome sequencing, they are the first to present MM cases without history of familial MM with germline variants/mutations and somatic inactivation in multiple genes including mSWI/SNF. The genes containing rare germline variants/mutations were not limited to common tumor suppressor genes, and the molecular functions of these genes were related to transcriptional regulation. Such germline variants/mutations could be used as markers for MM predisposition.

Objective: Carbon monoxide (CO) levels in expired gas are higher in patients with bronchial asthma than in healthy individuals. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that catalyzes the degradation of heme to yield biliverdin, CO and free iron. Thus, HO-1 is implicated in the pathogenesis of bronchial asthma. However, whether HO-1 expression and activity in lung tissue are related to allergic airway inflammation remains unclear. We investigated whether expression of HO-1 is related to allergic airway inflammation in lungs and whether HO-1 could influence airway hyperresponsiveness and eosinophilia in mice sensitized to ovalbumin (OVA). Methods: C57BL/6 mice immunized with OVA were challenged thrice with an aerosol of OVA every second day for 8 days. HO-1-positive cells were identified by immunostaining in lung tissue, and zinc protoporphyrin (Zn-PP), a competitive inhibitor of HO-1, was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 23 (day before inhalation of OVA) and immediately before inhalation on the subsequent 4 days (total five doses). Mice were analyzed for effects of HO-1 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue. Ethical approval was obtained from the concerned institutional review board. Results: Number of HO-1-positive cells increased in the subepithelium of the bronchi after OVA challenge, and HO-1 localized to alveolar macrophages. Zn-PP clearly inhibited AHR, pulmonary eosinophilia and IL-5 and IL-13 expression in the lung tissue. Conclusion: Expression of HO-1 is induced in lung tissue during attacks of allergic bronchial asthma, and its activity likely amplifies and prolongs allergic airway inflammation.

Malignant mesothelioma is caused by exposure to asbestos, which is known to have carcinogenic effects. However, the development of mesothelioma takes a long period and results from a low or intermediate dose of exposure. These findings have motivated us to investigate the immunological effects of asbestos exposure and analyze immune functions of patients with mesothelioma and pleural plaque, a sign of exposure to asbestos. Here, we review our knowledge concerning natural killer (NK) cells and cytotoxic T lymphocytes (CTL). NK cells showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, while induction of granzyme(+) cells in CD8(+) lymphocytes was suppressed by asbestos exposure. It is interesting that a decrease in NKp46, a representative activating receptor, is common between NK cells in PBMC culture with asbestos and those of mesothelioma patients. Moreover, it was observed that CD8(+) lymphocytes may be stimulated by some kind of "nonself" cells in plaque-positive individuals and in mesothelioma patients, whereas CTL in mesothelioma is impaired by poststimulation maintenance of cytotoxicity. These findings suggest that analysis of immunological parameters might contribute to the evaluation of health conditions of asbestos-exposed individuals and to a greater understanding of the pathology of malignant mesothelioma.

Purpose. To investigate the diagnostic and prognostic value of circulating tumor cells (CTCs), a potential surrogate of micrometastasis, in malignant pleural mesothelioma (MPM). Methods. We prospectively evaluated CTCs in 7.5 mL of peripheral blood sampled from patients with a suspicion of MPM. A semiautomated system was used to capture CTCs with an antibody against the epithelial cell adhesion molecule. Results. Of 136 eligible patients, 32 were finally diagnosed with nonmalignant diseases (NM), and 104 had MPM. CTCs were detected in 32.7 % (34 of 104) of MPM patients but in only 9.4 % (3 of 32) of NM patients (P = 0.011). The CTC count was significantly higher in MPM patients than in NM patients (P = 0.007), and a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between MPM and NM, with an area under ROC curve of 0.623 (95 % confidence interval, 0.523-0.723; P = 0.036). Among MPM patients, CTCs were more frequently detected in patients with epithelioid subtype (39.7 %, 31 of 78) than in those with nonepithelioid subtypes (11.5 %, 3 of 26; P = 0.016). Positive CTCs (CTC count >= 1) were a significant factor to predict a poor prognosis among epithelioid patients (median overall survival, 22.3 months for positive CTCs vs. 12.6 months for negative CTCs; P = 0.004) and not in nonepithelioid patients (P = 0.649). A multivariate analysis showed that positive CTCs were a significant and independent factor to predict a poor prognosis (hazard ratio, 2.904; 95 % confidence interval, 1.530-5.511; P = 0.001) for epithelioid MPM patients. Conclusions. CTC was a promising marker in diagnosis and prediction of prognosis in MPM, especially in epithelioid MPM.

Aim: In order to determine if metastatic malignant mesothelioma cells are more aggressive than primary malignant mesothelioma cells, an analysis of the expression of the adhesion molecules E-cadherin and beta-catenin, concomitant with an assessment of the proliferative activity at primary and metastatic sites, was conducted in post-mortem samples. Materials and Methods: E-cadherin or beta-catenin expression was graded according to the percentage of positively-stained tumor cells. The proliferative activity was quantified by the Ki-67 labeling index. Results: Histologically, the majority of metastatic tumors matched the primary tumor. In the epithelioid component of primary tumors, E-cadherin and beta-catenin expression ranged from 1+ to 4+. Conclusion: Malignant mesothelioma cells acquire a higher proliferative potential after metastasis, without any significant changes in their histology, although metastasis produces no definite trend on the expression of E-cadherin or beta-catenin.

It is known that asbestos exposure can cause malignant mesothelioma (MM) and that CD8(+) T cells play a critical role in antitumor immunity. We examined the properties of peripheral blood CD8(+) lymphocytes from asbestos-exposed patients with pleural plaque (PL) and MM. The percentage of CD3(+)CD8(+) cells in PBMCs did not differ among the three groups, although the total numbers of PBMCs of the PL and MM groups were lower than those of the healthy volunteers (HV). The percentage of IFN-γ (+) and CD107a(+) cells in PMA/ionomycin-stimulated CD8(+) lymphocytes did not differ among the three groups. Percentages of perforin(+) cells and CD45RA(-) cells in fresh CD8(+) lymphocytes of PL and MM groups were higher than those of HV. Percentages of granzyme B(+) and perforin(+) cells in PMA/ionomycin-stimulated CD8(+) lymphocytes were higher in PL group compared with HV. The MM group showed a decrease of perforin level in CD8(+) lymphocytes after stimulation compared with patients with PL. These results indicate that MM patients have characteristics of impairment in stimulation-induced cytotoxicity of peripheral blood CD8(+) lymphocytes and that PL and MM patients have a common character of functional alteration in those lymphocytes, namely, an increase in memory cells, possibly related to exposure to asbestos.

Aim: Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Chemotherapy-naive patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days. The primary end-point was progression-free survival (PFS). Results: A total of 90 patients were enrolled. Overall response rate, median PFS and median survival time in the docetaxel-plus-carboplatin group and the paclitaxel-plus-carboplatin group were 23% vs. 33%, 4.8 months vs. 5.1 months, and 17.6 months vs. 15.6 months, respectively. The docetaxel-plus-carboplatin group had a higher incidence of grade 3 or 4 neutropenia (88% vs. 60%). Conclusion: Both regimens were similarly effective in Japanese patients with advanced NSCLC.

目的.Endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)の実態を調査するために、日本呼吸器内視鏡学会が全国調査を行った。対象と方法.調査対象は2011年1月〜2012年6月までの1年半にコンベックス型超音波気管支鏡を使用して行ったEBUS-TBNA症例で、日本呼吸器内視鏡学会認定および認定関連施設520施設に質問用紙を郵送した。結果.回収率は87.5%で、調査期間内にEBUS-TBNAを施行したと回答した施設は47.6%であった。主たる施行医が気管支鏡専門医である施設は73.1%で、EBUS-TBNAの経験が20例未満の施設が64.2%であった。さらに28.0%の施設で主たる施行医がハンズオンに参加していなかった。ほぼ全例入院でEBUS-TBNAを施行している施設が73.5%、ほぼ全例静脈麻酔を併用している施設が61.9%であった。穿刺するリンパ節数が通常1個である施設が76.4%、1個のリンパ節に対する穿刺回数は2〜3回の施設が89.0%と多かった。結語.EBUS-TBNA症例経験数の少ない施設や施行医が多く、ハンズオンなどの教育、啓発活動が引き続き必要と思われる。(著者抄録)

Background: With the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE).Methods: A questionnaire about EBUS-TBNA performed between January 2011 and June 2012 was mailed to 520 JSRE-accredited facilities.Results: Responses were obtained from 455 facilities (87.5%). During the study period, EBUS-TBNA was performed in 7,345 cases in 210 facilities (46.2%) using a convex probe ultrasound bronchoscope, for 6,836 mediastinal and hilar lesions and 275 lung parenchymal lesions. Ninety complications occurred in 32 facilities. The complication rate was 1.23% (95% confidence interval, 0.97%-1.48%), with hemorrhage being the most frequent complication (50 cases, 0.68%). Infectious complications developed in 14 cases (0.19%) (Mediastinitis, 7 pneumonia, 4 pericarditis, 1 cyst infection, 1 and sepsis, 1). Pneumothorax developed in 2 cases (0.03%), one of which required tube drainage. Regarding the outcome of the cases with complications, prolonged hospitalization was observed in 14 cases, life-threatening conditions in 4, and death in 1 (severe cerebral infarction) (mortality rate, 0.01%). Breakage of the ultrasound bronchoscope occurred in 98 cases (1.33%) in 67 facilities (31.9%), and that of the puncture needle in 15 cases (0.20%) in 8 facilities (3.8%).Conclusions: Although the complication rate associated with EBUS-TBNA was found to be low, severe complications, including infectious complications, were observed, and the incidence of device breakage was high. Since the use of EBUS-TBNA is rapidly expanding in Japan, an educational program for its safe performance should be immediately established. © 2013 Asano et al. licensee BioMed Central Ltd.

A prospective multi-institutional study has been initiated in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by pleurectomy/decortication aimed at macroscopic complete resection in patients with resectable malignant pleural mesothelioma. The study was initiated on September 2012, for which 24 patients will be recruited over a period of 2 years. The primary endpoint is the macroscopic complete resection rate, regardless of the surgical technique employed (i.e. pleurectomy/decortication or extrapleural pneumonectomy). The secondary endpoints are the pleurectomy/decortication rate, macroscopic complete resection rate by pleurectomy/decortication, pulmonary function at 3 months after surgery, adverse events, treatment-related mortality, response rate to chemotherapy and 3-year overall survival rate.

BACKGROUND: To select optimal candidates for extrapleural pneumonectomy (EPP), we retrospectively evaluated the usefulness of metabolic response by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemotherapy to predict prognosis for patients with resectable malignant pleural mesothelioma (MPM) who underwent EPP in a multicenter study. PATIENTS AND METHODS: We carried out high-resolution CT (HRCT) and FDG-PET/CT before and after neoadjuvant platinum-based chemotherapy on 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP ± postoperative hemithoracic radiotherapy. A decrease of ≥30% in the tumor maximum standardized uptake value (SUVmax) was defined as a metabolic responder. The radiologic response using the modified RECIST or metabolic response and surgical results were analyzed. RESULTS: The median overall survival (OS) from diagnosis was 20.5 months. Metabolic responders significantly correlated to OS with median OS for metabolic responders not reached versus 18.7 months for non-responders. No correlation was observed between OS and radiologic response with median OS for radiologic responders and non-responders. Based on the multivariate Cox analyses, decreased SUVmax and epithelioid subtype were significantly independent factors for OS. CONCLUSIONS: The metabolic response after neoadjuvant chemotherapy is an independent prognostic factor for patients with resectable MPM. Patients with metabolic responder or epithelioid subtype may be good candidates for EPP.

The purpose of this study was to investigate the diagnostic and prognostic value of circulating endothelial cell (CEC), a potential surrogate of tumor angiogenesis, in malignant pleural mesothelioma (MPM). We prospectively evaluated CEC count in 4.0 mL of peripheral blood sampled from patients with a suspicion of MPM. An automated system was used to capture CECs with an anti-CD146 antibody. Of 109 eligible patients, 30 were finally diagnosed with non-malignant diseases, and 79 were with MPM. CEC count was significantly higher in MPM patients than in NM patients (mean CEC count, 120.3 and 39.9, respectively; P = 0.001), and a receiver operating characteristic (ROC) curve analysis showed that CEC provided a significant diagnostic performance in discrimination between MPM and nonmalignant diseases with an area under curve (AUC-ROC) of 0.700 (95 % confidence interval [95 % CI], 0.595-0.806; P = 0.001). Among MPM patients, CEC count was positively correlated with intratumoral microvessel density (MVD), a measurement of tumor angiogenesis (Spearman correlation coefficiency [r] = 0.444; P = 0.001). Higher CEC count (> 50) was significantly associated with a poor prognosis (median overall survival, 11.4 months [95 % CI, 7.6-15.2] for higher CEC count patients versus 20.1 months [95 % CI, 16.0-24.2] for lower CEC count patients; P = 0.028). A multivariate analysis showed that higher CEC count was a significant and independent factor to predict a poor prognosis (hazard ratio [HR], 2.24, [95 % CI, 1.24-4.43]; P = 0.009). CEC, as a surrogate of tumor angiogenesis, was a promising marker in diagnosis and prediction of prognosis in MPM.

Background: Adenovirus vectors have been utilized for cancer gene therapies. The present study examined the oncolytic effects of adenovirus type 5 (Ad5) and fiber-substituted conditionally replicating adenovirus (CRAD) Ad5/F35 vectors on the human malignant mesothelioma cells MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452 cells. Materials and Method: For the adenovirus, the first mRNA/protein to be made (similar to 1 h after infection) is E1A. Ad5F35 and Ad5 CRAD vectors containing the El gene controlled by the human midkine promoter (Ad5F351MKp-E1 and Ad5/MKp-E1, respectively) were constructed. Western blotting and cell viability assays were carried out in cells transfected with Ad5/MKp-E1 and Ad5F35/MKp-E1. Results: Coxsackie and adenovirus receptor (CAR), a cell surface target of Ad5, and CD46, a cell surface target of Ad35, were expressed in all the malignant mesothelioma cell lines examined here, as much as in HEK293 cells, with no significant differences in the expression levels among cells. Both Ad5/MKp-E1 and Ad5F35/MKp-E1 induced oncolysis of malignant mesothelioma cells in a viral particle-dependent manner, with similar efficacy. Conclusion: The results of the present study suggest that both Ad5/MKp-E1 and Ad5F35/MKp-E1 are useful for the gene therapy of human malignant mesothelioma.

Malignant mesothelioma is an aggressive tumor of serosal surfaces that is closely associated with asbestos exposure which induces oxidative stress. Heme oxygenase (HO)-1, a rate-limiting enzyme of heme degradation, plays a protective role against oxidative stress. The HO-1 gene promoter carries (GT)n repeats whose number is inversely related to transcriptional activity of the HO-1 gene. To investigate the relationship between the length polymorphism of (GT)n repeats and mesothelioma susceptibility, we analyzed the HO-1 promoter in 44 asbestos-exposed subjects without mesothelioma and 78 asbestos-exposed subjects with mesothelioma using PCR-based genotyping. The number of repeats ranged from 16 to 38, with two peaks at 23 and 30 repeats. Polymorphisms of (GT)n repeats were grouped into two classes of alleles, short (S) (< 24) and long (L) (a parts per thousand yen24), and three genotypes: L/L, L/S, and S/S. The proportions of allele frequencies in class L as well as genotypic frequencies of L allele carriers (L/L and L/S) were significantly higher in the asbestos-exposed subjects with mesothelioma than in those without mesothelioma. The findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population.

In the present study, we analyzed genomic alterations of BRCA1-associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non-epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence-level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence-level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid-type MMs; BAP1 mutations were found in 13 of 16 epithelioid-type MMs, but in only one of seven non-epithelioid-type MMs (13/16 vs 1/7; P similar to=similar to 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40-transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti-BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation-positive MM tumors, whereas nuclear staining was observed among BAP1 mutation-negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non-epithelioid MM, and would be useful for diagnosis of epithelioid-type MM. (Cancer Sci 2012; 103: 868874)

Malignant pleural mesothelioma (MPM) remains suffering poor prognosis in spite of recent diagnostic and therapeutic progress. Although there is currently no established evidence, early diagnosis and early intervention may play a key role to improve prognosis of MPM, similarly to other malignancies. As pleural effusion is usually the first clinical sign of MPM, pleural effusion cytology is often the first diagnostic examination to be carried out. Since the sensitivity of pleural effusion cytology is approximately 60%, however, false-negative diagnosis is given to almost half of true MPM patients at this clinical step. One practical way to reduce the number of misdiagnosed MPM is to encourage performing thoracoscopic pleural biopsy unless definitive diagnosis other than MPM is established. There still remain a considerable number of patients with radiological/thoracoscopic T0 MPM who are misdiagnosed with nonspecific pleuritis after a complete investigation including thoracoscopic biopsies. Such patients will turn out to be malignant during follow-up period, although they have the best opportunity for long-term survival if only early therapeutic intervention is given. Currently, we are performing diagnostic total parietal pleurectomy in highly selected patients, who are characterized with strong clinical suspicion, positive pleural effusion cytology but uncertain pathological diagnosis, excellent cardiopulmonary reserve, and with written informed consent for highly invasive diagnostic surgery for pathologically unproven disease.

Malignant mesothelioma is an asbestos-related malignancy that arises primarily from mesothelial cells on the serosal surfaces of the pleural, peritoneal, and pericardial cavities. Malignant pleural mesothelioma (MPM) is most common, and its incidence is dramatically increasing worldwide as a result of widespread use of asbestos. Morphological discrimination between MPM and reactive mesothelial hyperplasia is difficult, and the most reliable pathological criterion for malignancy is mesothelial proliferation invading deeply into subpleural adipose tissues. To establish radical cure of MPM, it is crucial to find early-stage MPM of epithelial type, in which mesothelial proliferation is localized on the serosal surface of parietal pleura or limited within the submesothelial fibrous tissues of parietal pleura. The initial clinical presentation for patients with MPM is frequently dyspnea and/or chest pain due to large pleural effusion, and cytological analysis of pleural effusions is valuable to find patients with early-stage MPM of epithelial type. Recently, cytological features of MPM in pleural effusion, molecular markers for MPM, and genetic alternations of MPM have been reported. In this review, we discuss major issues on pathological and molecular biological approaches for diagnosis of early-stage MPM of epithelial type.

背景.悪性胸膜中皮腫は治療に抵抗する予後不良の腫瘍である.非切除例の生存期間は10〜12か月であり,化学療法で完全奏効(CR)が得られることは稀である.症例. 74歳女性,主訴は右胸部痛,アスベスト曝露歴がある.胸部圧迫感を自覚し近医を受診,右胸水貯留の指摘を受け来院した.胸水細胞診では癌胎児性抗原(CEA)染色陰性,カルレチニン染色陽性の悪性細胞が認められ,悪性胸膜中皮腫が強く疑われた.局所麻酔下胸腔鏡検査では,壁側胸膜に多数の顆粒ないし小豆大の腫瘍が散在していたが,臓側胸膜には明らかな腫瘍性病変は認めなかった.壁側胸膜の腫瘍を生検し,上皮型悪性胸膜中皮腫の診断を得た. International Mesothelioma Interest Group (IMIG)分類T1N0M0の臨床病期診断の下に,シスプラチン+イリノテカン+ドキソルビシンによる併用化学療法を4コース実施した. 2コース終了時より胸水は減少し, 4コース終了後の胸部コンピューター断層写真(CT)ではCRが認められた.化学療法開始から56か月後に,胸水の再貯留を認め進行(PD)となった.現在, performance status (PS)1,担癌生存中である.結論.本例は上皮型,早期臨床病期,PS良好,女性,血小板数増加なし,正常白血球数などの多くの好条件を有し,化学療法によりCRが得られている.悪性胸膜中皮腫は治療に抵抗する腫瘍であるが,好条件の予後因子が揃えば,化学療法が期待できることを示唆する症例であり,また,その早期診断に局所麻酔下胸腔鏡検査が有用であることを示す重要な症例である.

Background/Aims: The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells. Methods: MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells, and p53 or A(3) adenosine receptor was knocked-down by transfecting each siRNA into cells. Results: Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation. The adenosine effect was prevented by the adenosine transporter inhibitor dipyridamole, the adenosine kinase inhibitor ABT-702, or the A(3) adenosine receptor inhibitor MRS1191. Adenosine upregulated expression of the p53 mRNA and protein, that is abolished by ABT-702, but not by knocking-down A(3) adenosine receptor. Adenosine-induced apoptosis in NCI-H28 cells was significantly inhibited by knocking-down p53 and in part by knocking-down A(3) adenosine receptor. Conclusion: The results of the present study show that AMP converted from intracellularly transported adenosine upregulates p53 expression to induce caspase-independent apoptosis in malignant pleural mesothelioma cells and that A(3) adenosine receptor also participates partially in the apoptosis by the different mechanism. Copyright (c) 2012 S. Karger AG, Basel

Background/Aims: A(3) adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A(3) adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line. Methods: MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A(3) adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells. Results: Extracellular adenosine induces Lu-65 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A(3) adenosine receptor inhibitor MRS1191 or by knocking-down A(3) adenosine receptor or p53. Like adenosine, the A(3) adenosine receptor agonist 2-Cl-IB-MECA also induced Lu-65 cell apoptosis. Adenosine upregulated expression of p53 and Noxa mRNAs and activated caspase-3 and -9, but not caspase-8. Those adenosine effects were still inhibited by knocking-down A(3) adenosine receptor or p53. Conclusion: The results of the present study show that adenosine upregulates p53 expression via A(3) adenosine receptor, to promote p53-dependent Noxa gene transcription, causing activation of caspase-9 and the effector caspase-3 to induce Lu-65 cell apoptosis. Copyright (c) 2012 S. Karger AG, Basel

Background/Aims: Sphingosine regulates cellular differentiation, cell growth, and apoptosis. The present study aimed at understanding sphingosine-regulated mesothelioma cell proliferation. Methods: Human malignant mesothelioma cells such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells were cultured. The siRNA to silence the protein kinase C (PKC)-delta-targeted gene was constructed and transfected into cells. MTT assay, cell cycle analysis using a flow cytometry, and cell-free PKC-delta assay were carried out. Results: For all the cell types sphingosine inhibited cell growth in a concentration (1-100 mu M)-dependent manner. The sphingosine effect was not prevented by rottlerin, an inhibitor of protein kinase C-delta (PKC-delta); conversely, rottlerin further enhanced the sphingosine effect or rottlerin suppressed mesothelioma cell growth without sphingosine. In the cell-free PKC assay, sphingosine attenuated PKC-delta activity. Knocking-down PKC-delta induced cell cycle arrest at the G(0)/G(1) phase and inhibited cell growth. Conclusion: The results of the present study show that sphingosine suppressed mesothelioma cell proliferation by inhibiting PKC-delta, to induce cell cycle arrest at the G(0)/G(1) phase. Copyright (C) 2012 S. Karger AG, Basel

Array-based comparative genomic hybridization analysis was performed on 21 malignant mesothelioma (MM) samples (16 primary cell cultures and 5 cell lines) and two reactive mesothelial hyperplasia (RM) primary cell cultures. The RM samples did not have any genomic losses or gains. In MM samples, deletions in 1 p, 3p21, 4q, 9p21, 16p13 and 22q were detected frequently. We focused on 3p21 because this deletion was specific to the epithelioid type. Especially, a deletion in 3p21.1 region carrying seven genes including SEMA3G was found in 52% of MM samples (11 of 14 epithelioid samples). The allele loss of 3p21.1 might be a good marker for the epithelioid MM. A homozygous deletion in this region was detected in two MM primary cell cultures. A heterozygous deletion detected in nine samples contained the 3p21.I region and 3p21.31 one carrying the candidate tumor suppressor genes such as semaphorin 3F (SEMA3F), SEMA3B and Ras association (RalGDS/AF-6) domain family member I (RASSFIA). SEMA3B, 3F and 3G are class 3 semaphorins and inhibit growth by competing with vascular endothelial growth factor (VEGF) through binding to neuropil in. All MM samples downregulated the expression of more than one gene for SEMA38, 3F and 3G when compared with Met5a, a normal pleura-derived cell line. Moreover, in 12 of 14 epithelioid MM samples the expression level of SEMA3A was lower than that in Met5a and the two RM samples. An augmented expression of VEGFA was detected in half of the MM samples. The expression ratio of VEGFA/SEMA3A was significantly higher in the epithelioid MMs than in Met5a, RMs and the non-epithelioid MMs. Our data suggest that the downregulated expression of SEMA3A and several SEMA3s results in a loss of inhibitory activities in tumor angiogenesis and tumor growth of VEGFA; therefore, it may play an important role on the pathogenesis of the epithelioid type of MM.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy, so early diagnosis of MPM is very important. This study investigated the pleural effusion mesothelin levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion. Methods: The pleural effusion mesothelin concentrations were measured in 45 MPM patients and 53 non-MPM individuals (24 individuals with non-malignant pleural effusions and 29 individuals with lung cancer involving malignant pleural effusion). Results: This study demonstrated that patients with MPM had significantly higher pleural effusion mesothelin levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The difference in overall survival between the groups with pleural effusion mesothelin levels lower and higher than the assumed cut-off of 10 nM was significant. Conclusions: The data suggest that the pleural effusion mesothelin concentration could be useful as an aid for the diagnosis of MPM.

The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

Malignant mesothelioma (MM) is a highly aggressive, incurable neoplasm associated with asbestos exposure. Early detection of MM is not easy and radiological surveillance is imperfect. The use of blood-based biomarkers might solve this difficulty and allow detection of MM at an early stage when combined treatment involving surgery, chemotherapy and radiotherapy might be effective. In the research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)", we conducted an exploratory study on the detection of markers for diagnosing early-stage MM.
In this study, we have shown that serum soluble mesothelin-related peptide (SMRP) is a highly specific and moderately sensitive biomarker for diagnosing MM. SMRP levels in pleural effusion were elevated not only in advanced-stage malignant pleural mesothelioma (MPM), but also in early-stage disease. SMRP in pleural effusion can be an MPM-specific biomarker with greater sensitivity than in serum, especially for the early stage of the disease. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were considered to be useful surrogate markers of disease progression in MPM, although the lack of sensitivity for early-stage disease remains to be improved. Cytological analysis with gene expression profiling has been more effective in detecting early-stage MPM with pleural effusion.
In conclusion, blood or effusion-based biomarkers, possibly in combination with other new modalities, such as a thoracoscopy combined with the advanced imaging systems consisting of autofluorescence imaging (AFI) and narrow band imaging (NBI), will show some promise for curing MPM if the disease is detected at an early stage.

The feasibility and efficacy of trimodality therapy for malignant pleural mesothelioma (MPM) are still controversial mainly due to the lack of clinical evidence. Although three major clinical trials on this therapy have been recently reported from North America and Europe, it remains unclear whether results in Caucasian populations may be directly applicable to Asian populations. In this context, as a project of the "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Fund for Promoting Science and Technology of MEXT, Japan", a prospective multi-institutional study has been planned to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable MPM. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. The study was initiated in May 2008 and patient enrollment was finished in November 2010.

Objective. To evaluate the safety profile of combination therapy of pemetrexed plus cisplatin for malignant pleural mesothelioma (MPM) in an outpatient clinic. Methods. Patients received an intravenous infusion of 500 mg/m2 pemetrexed followed by an intravenous infusion of 60-75 mg/m2 cisplatin, on day 1 of every 21 days, concomitantly with vitamins. Results. We analyzed total of 105 patients who received combination therapy of pemetrexed plus cisplatin, after a histological diagnosis of MPM, but who had received no prior systemic chemotherapy, 77 (64 men, 13 women) of whom continued to receive this combination therapy as outpatients. The median age was 62.2 (range, 44 to 77). Epithelioid histology was present in 65 patients and 12 patients had non-epithelioid histology. There were 285 cycles administered in the outpatient setting, with a median cycle of 3 (range, 1 to 11). Hematological toxicities of grade ≥3 included leukopenia in 10 patients (13.0%), neutropenia in 15 patients (19.5%), and anemia in 8 patients (10.4%). Neither febrile neutropenia nor neutropenic infection was observed. Common non-hematological toxicities were gastrointestinal toxicities, such as nausea, constipation, anorexia, and vomiting, although toxicities of grade ≥3 were not observed. Other grade 3 adverse events were neurotoxicity and allergic reaction in 1 and 2 patients, respectively. The most common abnormal laboratory findings were increased creatinine levels in 21 patients (27.3%), followed by increased aminotransferase levels in 12 patients (15.6%). There were no treatment-related deaths. Conclusion. The safety of this combination therapy was confirmed in outpatients with MPM. © 2011 The Japan Lung Cancer Society.

Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia, and also to inhibit proliferation of several solid tumors including hepatoma, esophageal, and gastric cancer in vitro. Here we found that As2O3 inhibited cell viability of a mesothelioma cell line, NCI-H2052. As2O3 induced apoptosis of NCI-H2052 cells, which was accompanied by activation of c-Jun NH2-terminal kinase (JNK) 1/2, extracellular signal-regulated kinase (ERK) 1/2, and caspase-3. zVAD-fmk, a broad-spectrum caspase inhibitor, inhibited As2O3-induced apoptosis and activation of caspase-3, but not that of JNK1/2 and ERK1/2. Small interfering RNAs (siRNAs) targeting JNK1/2 suppressed As2O3-induced caspase-3 activation and apoptosis, indicating that JNK1/2 regulate As2O3-induced apoptosis though caspase cascade. Furthermore, JNK1 siRNA abrogated As2O3-induced JNK2 phosphorylation and JNK2 siRNA abrogated As2O3-induced JNK1 phosphorylation, suggesting that JNK1 and JNK2 interact with each other. Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated As2O3-induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed As2O3-induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that As2O3 induces apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in As2O3-induced apoptosis when JNK1/2 are inactivated. J. Cell. Physiol. 226: 762-768, 2011. (C) 2010 Wiley-Liss, Inc.

背景.胸水貯留例に対し局所麻酔下胸腔鏡検査が有用である.症例.75歳女性.1995年1月,近医にて右乳癌に対し乳房切除術を施行.術後タモキシフェン,フルオロウラシルを2年間投与され,経過観察されていた.2009年10月,健診時の胸部X線にて,右胸水を認め当科に紹介となった.胸水検査では原因となる所見は得られなかった.^<18>F-fluorodeoxyglucose positron-emission tomography (^<18>FDG-PET)にて右下葉と頸椎,胸椎などに多発するFDGの集積充進を認め,血清CA15-3 30.9U/mlと高値であり,乳癌の肺転移,骨転移が疑われた.気管支内視鏡にて乳癌肺転移と診断局所麻酔下胸腔鏡では,壁側胸膜に多発結節を認め,生検にて乳癌の胸膜転移と診断した.結論.呼吸器内視鏡検査は病理組織学的検索により,乳癌の胸膜転移や肺転移の診断や肺癌との鑑別に有用であると考えられた.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so early diagnosis of MPM is very important. Vascular endothelial growth factor (VEGF), a potent mitogen for the vascular endothelium, is also known to be an autocrine growth factor for MPM. Here, we investigated the pleural effusion VEGF levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion. Methods: The pleural effusion VEGF concentrations were measured in 46 MPM patients and 45 individuals with non-MPM individuals (25 individuals with non-malignant pleural effusions, and 20 individuals with lung cancer involving malignant pleural effusion). Results: We demonstrated that patients with MPM had significantly higher pleural effusion VEGF levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage MPM patients. The difference in overall survival between the groups with pleural effusion VEGF levels lower and higher than the assumed cut-off of 2000 pg/ml was significant. Conclusions: Our data suggest that the pleural effusion VEGF concentration could be useful as an aid for the diagnosis of MPM and as a prognostic factor. (C) 2010 Elsevier Ltd. All rights reserved.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor. Copyright©ERS 2010.

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so diagnosing MPM early is very important. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MPM. Here, we investigated the serum levels of VEGF in patients with MPM in comparison with a population that had been exposed to asbestos without developing MPM. Methods: Serum concentrations of VEGF were measured in 51 patients with MPM and 42 individuals with benign asbestos-related diseases (asbestosis or pleural plaques) or who were healthy despite asbestos exposure. Results: We demonstrated that patients with MPM had significantly higher serum levels of VEGF than a population who had been exposed to asbestos but had not developed MPM, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage patients with MPM. The difference in overall survival between the groups with VEGF serum levels lower and higher than the assumed cutoff of 460 pg/ml was significant. Conclusions: Our data suggest that the VEGF serum concentration could be a useful marker for screening MPM among asbestos-exposed individuals and as a prognostic factor.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor with a papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and good prognosis with prolonged survival. WDPM occurs primarily in the peritoneum of women, but also rarely in the pleura. We here report a case of 48-year-old woman who developed WDPM in the pleura with no history of asbestos exposure. Tumors were multifocal and widespread with a velvety appearance on the surface of parietal and visceral pleurae resected by extrapleural pneumonectomy (EPP). Tumors showed papillary structures with fibrovascular cores and lined by epithelioid cells. lmmunohistochemically, these epithelioid tumor cells were positive for epithelial membrane antigen (EMA), a marker of malignant mesothelioma, with more than 50% positive for p53. Tumor cells microinvaded into subpleural parenchyma of the lung and minimally spread to adipose tissues of the mediastinal lesion. In addition, tumor cells invaded into the chest wall with a trabecular or glandular architecture. Based on these findings, this case is pathologically considered as WDPM of the pleura with malignant potential. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Objective. To examine safety and efficacy of combination therapy with LY231514 (pemetrexed) plus cisplatin in malignant pleural mesothelioma. Methods. Patients aged between 20 and 75 years who were not candidates for surgery, who were given histological diagnoses of malignant pleural mesothelioma, had received no prior systemic chemotherapy, with a performance status (PS) of 0 or 1, and who had normal major organ function were enrolled. On day 1 of a 21-day cycle, patients received intravenous infusion of 500 mg/m2 pemetrexed, followed by intravenous infusion of 75 mg/m2 cisplatin, concomitantly with vitamin preparations. Results. Ten men and two women with a mean age of 63 years (range 50 to 73) were analyzed. The histological subtype was epithelioid in 8 patients, sarcomatoid in 2 patients, and biphasic in 2 patients. Ten patients had stage III/IV disease. Seven patients had a history of asbestos exposure. Hematological toxicities of grade 3 or more included decreased white blood cell count in 1 patient (8.3%) and decreased neutrophil count in 1 patient (8.3%), decreased lymphocyte count in 2 patients (16.7%) and decreased red blood cell count in 2 patients (16.7%), decreased hemoglobin in 4 patients (33.3%), and decreased platelet count in 2 patients (16.7%). Pneumonia was observed in 1 patient (8.3%). Common non-hematological toxicities included gastrointestinal toxicities, such as nausea, vomiting, and anorexia. The response rate was 25.0%. Conclusion. Safety of this combination therapy was confirmed in patients with malignant pleural mesothelioma. © 2009 The Japan Lung Cancer Society.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-β1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-β1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-β mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-β1, TGF-β1 receptors and PDGFR-β, and 2) TGF-β1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM. Copyright©ERS Journals Ltd 2009.

Purpose: To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer and nonmalignant diseases as well as in prediction of distant metastasis. Patients and Methods: We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion molecule. Results: Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary lung cancer with (n = 31) or without (n = 94) distant metastasis. CTCs were detected in 30.6% of lung cancer patients and in 12.0% of nonmalignant patients. CTC count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant diseases with an area under ROC curve of 0.598 (95% confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95% confidence interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the CTC test were 71.0% and 83.0%, respectively. Conclusions: CTC is a useful surrogate marker of distant metastasis in primary lung cancer. (Clin Cancer Res 2009;15(22):6980-6)

目的.早期中皮腫病変(EM)と反応性中皮過形成(RM)との鑑別は治療方針を決定する上で極めて重要であるが、これらの病変を形態的に鑑別することは難しい。我々は悪性胸膜中皮腫(MPM)ではp16INK4A遺伝子やNF2遺伝子が高頻度に欠失することに着目し、これらの遺伝子異常がEMとRMの鑑別に有用であるのかどうかを検討した。方法.形態的特徴に免疫組織化学染色を加えて評価し、MPM(16例)、RM(3例)、EM(2例)を選別した。これらの症例についてp16INK4A遺伝子とNF2遺伝子の欠失領域のプライマーを作製し、ゲノムDNAを鋳型にしたリアルタイムPCRにより遺伝子欠失の有無を検討した。結果.全てのRM症例でp16INK4A遺伝子とNF2遺伝子はともに保存されていたのに対して、MPMの全ての症例でp16INK4A遺伝子が欠失するとともにNF2遺伝子も高頻度に欠失していた。また、EMの2症例でp16INK4A遺伝子の欠失がみられ、その内の1例はNF2遺伝子も欠失していた。結論.p16INK4AとNF2の遺伝子診断は、EMとRMの鑑別に極めて有用であると考えられる。(著者抄録)

Background: Although serum osteopontin (OPN) concentration is elevated in patients with malignant pleural mesothelioma (MPM), the role of OPN in the pathogenesis and development of MPM remains unknown. Materials and Methods: To determine the roles of OPN in MPM, immunohistochemical staining was performed to investigate the concentration of OPN in the pleural tumor of patients with mesothelioma; cell adhesion, proliferation and migration assays of H28 cells, an MPM cell line, were also carried out in vitro. Results: H28 cells cultured on OPN-coated plates revealed enhanced adhesion, proliferation, migration, cell survival and phosphorylated focal adhesion kinase activities. As expected, these enhancements were markedly suppressed with the addition of anti-alpha v beta 3 antibody or arginine-glycine-aspartic acid serine (RGDS) peptide to the medium. Conclusion: OPN is speculated to play an important role in the enhancement of adhesion, proliferation and migration activities of H28 cells, presumably by interacting with the alpha v beta 3 integrin.

A prospective multi-institutional study has been commenced in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable malignant pleural mesothelioma. The study was initiated on May 2008 and 40 patients will be recruited over 3 years. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. Secondary endpoints include treatment completion rate, adverse events, response rate by chemotherapy and 2-year overall and relapse-free survival.

Asbestos is well-known for its tumorigenic activity, but its effect on anti-tumor immunity remains unclear. Therefore, we prepared a sub-line of YT-A1 human NK cells exposed to chrysotile B (CB) asbestos (YT-CB5) as an in vitro model to analyze the effect of asbestos exposure on NK cells, and examined cytotoxicity and expressions of its related molecules. The cytotoxicity of YT-CB5 against K562 cells decreased compared with the original line of YT-A1 (YT-Org). YT-CB5 exhibited significant decreases in expressions of cell surface NKG2D, 2B4 and intracellular granzyme A. YT-CB5 also exhibited a decrease in the 2B4-dependent cytotoxicity. In addition, the degranulations stimulated via cell surface NKG2D and 2B4 also decreased in YT-CB5. Therefore, peripheral blood NK cells in patients with malignant mesothelioma (MM) were examined and compared with healthy volunteers. NK cells in patients with MM also showed decreases in cytotoxicity against K562. Although the expressions of NKG2D and 2B4 did not decrease in NK cells of MM patients, the expression of cell surface NKp46 decreased. To confirm the effect of asbestos exposure on peripheral blood NK cells, PBMCs were cultured under exposure to CB. NK cells in PBMCs exposed to CB in vitro showed a significant decrease in the expression of NKp46, whereas NK cells in PBMCs exposed to glass wool did not show such a decrease. These results indicate that exposure to asbestos has the potential to impair the cytotoxicity of NK cells and alter the expression of NK cell-activating receptors including NKG2D, 2B4 and NKp46 and intracellular perforin/granzymes. Copyright © by BIOLIFE, s.a.s.

We report a case of cytomegalovirus (CMV) pneumonitis that presented as a cavitary lung lesion in a patient with systemic lupus erythematosus receiving immunosuppressive treatment. The lesion was confirmed by positive polymerase chain reaction (PCR) for CMV in bronchoalveolar lavage fluid (BALF) and CMV antigenemia. PCR for CMV in BALF was demonstrated to be useful for the diagnosis of CMV pneumonitis on the basis of high sensitivity and specificity. After initiating ganciclovir, the lesion gradually regressed. A cavitary lung lesion associated with CMV is extremely rare. This presentation suggests that the differential diagnosis of cavitary lung lesion in immunocompromised individuals should include CMV.

早期肺がんにおける光線力学的治療法（Photodynamic therapy: PDT）は機能温存性に優れた, 侵襲の少ない治療法としてすでに確立されている. 我々は難治性固形がんの1つである悪性胸膜中皮腫に対する新たな治療戦略として第2世代光感受性物質であるLaserphyrin^®と安価で様々な形態にあわせて使用可能である発光ダイオード（LED）によるPDTを開発することを目的として基礎的検討を行った. 照射可能なデバイスとしてLEDを羅列した光源を試作し, 接触型照射方法を考案して, 従来の半導体レーザーとLaserphyrin^®によるPDTの抗腫瘍効果と比較検討した.
まず悪性胸膜中皮腫細胞に対するin vitroにおけるPDT感受性試験では, 細胞株間で感受性の差は認められず, レーザー, LEDともにLaserphyrin^®濃度依存性に強い殺細胞効果を示した.このことは薬物療法の奏効率が低い悪性胸膜中皮腫に対する集学的治療法の1つとして, PDTの臨床的有用性を示唆している. 次にヌードマウスを用いてMSTO-211Hの移植腫瘍を作成し, PDTを施行することにより, in vivoにおけるレーザー, LEDの抗腫瘍効果について検討した. 照射条件は半導体レーザーでは出力100mW/cm², 照射線量100 J/cm²とした. 一方, 接触型LED照射では20 mW/cm², 照射線量100 J /cm²となるようPDTを施行した. その結果, 低出力・長時間の接触型LED照射群では半導体レーザー照射群と同程度の抗腫瘍効果を認めた.
以上の結果より, LEDによるPDTはin vitro, in vivoともに強い抗腫瘍効果を示し, 低コスト, 簡便性に優れるLEDの接触型照射方法を使用したPDTの悪性胸膜中皮腫に対する臨床的応用の可能性を示唆するものと考えられる.

It is common knowledge that asbestos exposure causes asbestos-related diseases such as asbestosis, lung cancer and malignant mesothelioma (MM) not only in people who have handled asbestos in the work environment, but also in residents living near factories that handle asbestos. These facts have been an enormous medical and social problem in Japan since the summer of 2005. We focused on the immunological effects of asbestos and silica on the human immune system. In this brief review, we present immunological changes in patients with MM and outline their experimental detection. For example, there is over-expression of bcl-2 in CD4+ peripheral T-cells, high plasma concentrations of interleukin (IL)-10 and transforming growth factor (TGF)-ß, and multiple over-representation of T cell receptor (TcR)-Vß in peripheral CD3+ T-cells found in MM patients. We also detail an experimental long-term exposure T-cell model. Analysis of the immunological effects of asbestos may help our understanding of the biological effects of asbestos.

It is common knowledge that exposure to asbestos causes asbestos-related diseases, such as asbestosis, lung cancer and malignant mesothelioma, not only in people who have had long-term contact with asbestos in their work environment but also in residents living near factories that handle asbestos. Since the summer of 2005, these revelations turned into a large medical problem and caused and social unrest. We have focused on the immunological effects of both asbestos and silica on the human immune system. In this brief review, we introduce immunological alterations found in patients with malignant mesothelioma and describe the experimental background in which these were found. Analyzing the immunological effects of asbestos may improve our understanding of the biological effects of asbestos.

背景と目的.中皮腫の病期診断において胸腔鏡は必須の検査である.しかしながら,早期中皮腫症例の一部は顆粒状腫瘍であり通常の胸腔鏡検査のみでは同定が困難な場合がある.胸腔鏡検査に蛍光観察(Autofluorescence imaging, AFI)及び狭帯域観察(Narrow band imaging, NBI)といった特殊光観察を用いることで,悪性中皮腫の早期診断への有用性について検討した.対象と方法.対象は2006年1月から5月の5ヶ月間で,画像や胸水所見から中皮腫を疑い診断目的で胸腔鏡を施行した12例.胸水貯留が著明であった7症例には局所麻酔下胸腔鏡を,少量胸水や胸膜の癒着が疑われた5症例には胸腔鏡下手術(VATS)を施行した.AFIはオリンパス社の専用スコープ(BF-F260),NBIは同社のLTF-240を使用した.結果.12例中7例で胸膜生検より悪性中皮腫との診断が得られた.中皮腫症例のAFI所見では病変部は自家蛍光が減弱しマゼンタとなった.NBIでは腫瘍部分は白く強調され胸膜表面の凹凸が明瞭化し,腫瘍内部には太い血管が散在する像が得られた.考察.胸腔鏡検査に特殊光観察を用いることにより胸膜面の腫瘍の局在の特定においての有用性が示唆され,中皮腫の早期発見や病期診断の手段として活用されることが期待される.

背景.^<18>FDG-PETは腫瘍組織において亢進した糖代謝を画像化する代謝画像診断法で,その有用性については多数の報告がなされているが,同様に偽陽性症例についても散見されてきている.症例1.73歳,男性.職業:築炉工.石綿肺による呼吸不全で通院中,^<18>FDG-PETにて縦隔リンパ節に強い集積を認め,縦隔鏡下にリンパ節生検を施行したところ,組織では線維芽細胞,組織球の著しい反応性増生を認めるのみであった.症例2.74歳,男性.職業:石綿パイプ加工業.上記と同様の経過で,組織でLanghans型巨細胞の出現する類上皮細胞肉芽腫が多数形成されていた.結果.今回我々は,^<18>FDG-PET強陽性所見を呈した縦隔リンパ節が,縦隔鏡で良性病巣であり偽陽性と判明した石綿肺を2症例経験した.結論.石綿肺の縦隔リンパ節は^<18>FDG-PETで偽陽性を呈する可能性も考慮し,今後同部位の生検に関しては,最初は非侵襲的な超音波内視鏡などで試行すべきであることが示唆された.

Silicosis patients (SILs) and patients who have been exposed to asbestos develop not only respiratory diseases but also certain immunological disorders. In particular, SIL sometimes complicates autoimmune diseases such as systemic scleroderma, rheumatoid arthritis (known as Caplan syndrome), and systemic lupus erythematoses. In addition, malignant complications such as lung cancer and malignant mesothelioma often occur in patients exposed to asbestos, and may be involved in the reduction of tumor immunity. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer of 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate nationwide anxiety.

Purpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer.Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo.Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC50 of 0.15 and 0.37 mu mol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 mu mol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar K-i values (similar to 0.05 mu mol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts.Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.

目的.アスベスト検診における呼吸器内視鏡検査の有用性について検討した.方法.2005年7月から2006年3月までの間,アスベスト検診目的で当施設を受診した132名を対象とした.検診受診歴に基づき,受診者を一次検診受診者群と二次検診受診者群とに分類した.前者は初回受診者76名で,後者は他施設での一次検診にて要精査と判定された受診者56名で構成された.アスベスト曝露歴聴取と胸部単純X線検査後,胸部CT検査を施行し,胸部悪性腫瘍を疑う症例を中心に呼吸器内視鏡検査を施行した.結果.両群間で年齢・性別分布に有意差を認めなかった.両群とも70%以上の症例が職業性曝露歴を有していた.全受診者中110名(83%)に画像上異常所見を認めた.アスベスト関連疾患は,延べ90例(68%)に発見され,その内訳は胸膜プラーク60例,肺線維症13例,肺癌5例,良性石綿胸膜炎4例,円形無気肺4例,びまん性胸膜肥厚2例,悪性胸膜中皮腫2例であった.肺癌および悪性胸腹中皮腫の発見率は,それぞれ3.8%,1.5%であった.呼吸器内視鏡検査は15例に施行され,その内訳は気管支鏡6例,VATS(video-assisted Thoracoscopic Surgery)を含む胸腔鏡8例(うち3例は縦隔鏡併用),縦隔鏡4例であった.2例の早期肺癌はVATS下肺生検にて,悪性胸腹中皮腫はVATS下胸膜生検にて診断された.呼吸谷内視鏡検査に関連した合併症を認めなかった.結論.呼吸器内視鏡検査は安全で確実性が高い診断手技であるため,アスベスト検診において胸部悪性腫瘍を疑う受診者に対して積極的に施行すべきである.

To explore the effects of asbestos and silica on the human immune system, an experimental model of low-dose and long-term exposure was established using a human HTLV-1-immortalized polyclonal T cell line, MT-2 (MT-2Org). MT-2 cells were continuously exposed to asbestos at a concentration (10 μg/ml) which does not induce complete cell death during short-term exposure. After acquiring resistance to CB-induced apoptosis (designated MT-2Rst), an immunological comparison was made between the MT-2Org and MT-2Rst lines in terms of T cell receptor-Vβ (TcR-Vβ) expression. MT-2Rst cells showed excess expression of various TcR-Vβ, although TcR-Vβ-overpresenting cells were characterized as undergoing apoptosis due to first contact with CB. Patients with asbestos-related diseases (ARD), such as asbestosis and malignant mesothelioma, were compared with silicosis (SIL) patients as a disease control and with healthy donors (HD). SIL and ARD not only differed in their causative materials, silica and asbestos as mineral silicates, but also in terms of complications; autoimmune disorders in SIL and tumors in ARD. ARD patients showed a restricted overpresentation of TcR-Vβ without clonal expansion, whereas SIL patients revealed significant overpresentation of TcR-Vβ 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of autoimmunity-inducing effects of asbestos and silica, respectively. Copyright © by Biolife, s.a.s.

非小細胞肺癌に対する分子標的治療薬である上皮成長因子受容体チロシンキナーゼ阻害薬のゲフィチニブを内服中に皮膚症状を生じた症例について検討した.その結果,ゲフィチニブ250mg/日,内服中に皮膚症状を生じた5症例ではゲフィチニブを隔日内服に減量したところ,皮膚症状は消失または軽快したことから用量依存性であることが確認された.挫創様皮疹・爪郭炎または浸潤性紅斑を生じた3症例の皮膚生検結果では,臨床症状が異なるにもかかわらず組織所見はいずれも表皮または毛包壁のbasal layerとsuprabasal layerに共通して障害が認められた.以上より,表皮ケラチノサイトにおけるepidermal growth factor reseptorを介する情報伝達のゲフィチニブによる阻害作用が皮膚症状の発症に関与している可能性が示唆された

Objective. When chemotherapy is conducted for the treatment of non-small cell lung cancer (NSCLC), we must pay attention to the degree of impairment of pulmonary function. So far, it is not clear whether the smoking affects pulmonary function in a different manner according to the histological types of lung cancer squamous cell carcinoma and adenocarcinoma of the lung. In order to clarify these issues, we investigated the relation of smoking index (SI), location of cancerous lesions, and pulmonary function in patients with NSCLC. Study design. A total of 307 cases (squamous cell carcinoma 117, adenocarcinoma 190), with bronchial lesions located at sites proximal to the orifice of segmental bronchi (central lesions), or beyond (peripheral lesions) using fiberoptic bronchoscopy, was divided into two groups according to SI. There were 159 cases with an SI of more than 800 (high SI), and 148 less than 400 (low SI). Results. Age and SI were higher in squamous cell carcinoma than in adenocarcinoma, and restrictive and obstructive disturbances and a decrease in DLco and widened alveolar-arterial oxygen difference (AaDO2) were more prominent in squamous cell carcinoma than in adenocarcinoma. Similar results were obtained from analyses in the patients with peripheral lesions. In particular, disturbance of diffusion capacity was more prominent in squamous cell carcinoma than in adenocarcinoma. Moreover, when the subjects were limited to the patients with peripheral lesions, pulmonary functions in the high SI group tended to be more markedly disturbed than in the low SI group. In squamous cell carcinoma, however, V̇25/Ht and DLco did not show a significant difference between high SI and low SI groups with deteriorations of these parameters being observed even in patients with low SI. Conclusion. It is concluded that the disturbance of respiratory function is more prominent in squamous cell carcinoma than in adenocarcinoma. Smoking affects the disturbance of respiratory functions in NSCLC with peripheral lesions. Squamous cell carcinoma shows greater impairment of the peripheral airways and diffusion capacity than adenocarcinoma, even in patients with an SI of less than 400.

Mycobacterium avium (M. avium) has been described traditionally as an opportunistic organism that causes disseminated disease in the human immunodeficiency virus (HIV)-positive population and that acts as a pulmonary pathogen in patients with underlying lung disease such as chronic obstructive pulmonary disease (COPD) or previously diagnosed tuberculosis.' Pulmonary involvement of M. avium may range from asymptomatic colonization of the airway to invasive parenchymal or cavitary disease. However, endobronchial lesions involved in M. avium infection are rare in either immunocompetent or immunosuppressed hosts.(2-6) We report here endobronchial mycobacterial infection in a HIV-negative patient.

Neurilemmomas are benign tumors which originate from Schwann cells. They rarely occur in the trachea or bronchus. We encountered two cases of endobronchial neurilemmoma and in this context, reviewed 48 cases previously reported in Japan. Neurilemmomas can occur in all regions of the bronchial tree and they often progress into both intraluminal and extraluminal spaces. Incomplete resection results in a local recurrence, despite being rare. As for appropriate therapies, surgery, bronchofiberoptic removal and yttrium aluminum garnet (YAG) laser resection can be chosen depending on the patient's status.

The human leukemia K562 cell line does not express wild-type p53 protein. Due to the loss of one p53 allele and an insertion mutation in exon 5 of the other allele resulting in a frameshift mutation, K562 cells express a truncated p53 protein of 148 amino acids. A human leukemia phorbol ester-resistant subline, K562/TPA, is cross-resistant to some anticancer agents. A remarkable difference in cell cycle progression at G1/S phase was observed in the synchronised K562/TPA cells as compared with K562 cells. Southern blot and DNA sequence analysis revealed no mutation in exon 5 of the p53 gene in K562/TPA cells. p21(Cip1) expression was also restored in K562/TPA cells confirming that the reversal of this p53 gene mutation restored wild-type p53 function in these cells. This is a unique report describing reversal of p53 gene mutation by drugs. This was associated with the expression of wild-type p53 mRNA and protein in K562/TPA cells. The K562/TPA cell line may provide a very useful tool for the investigation of the relationship between p53 status and chemosensitization.

Recently, several studies have suggested that a major mechanism of resistance to paclitaxel might involve mutations in the β-tubulin gene in tumor cells. To investigate the frequency of β-tubulin mutations in Japanese patients with small and non-small cell lung cancer, direct sequence analysis following reverse transcription-polymerase chain reaction (RT-PCR) of the β-tubulin gene was performed using total RNA from 20 lung cancer cell lines and 22 specimens from lung cancer patients. First-strand cDNA sequence analysis of the 42 samples showed silent mutations at codon 180 of the β-tubulin gene, which encodes the GTP-binding site of the protein, and codons 195 and 217. However, neither missense nor non-sense mutations affecting microtubule dynamics, within or near the GTP-binding site of the β-tubulin gene, were detected. These results indicate that β-tubulin gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients. Further investigations are needed to clarify the mechanism of drug resistance. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

HIV感染者に発症したPC肺炎11症例の発症時のBALF所見について検討を行った。PC肺炎発症時のCD4陽性Tリンパ球数は平均45/μl, 血清LDH-CRPの上昇を認めていた。PC肺炎のBALF所見では著しい総細胞数の増加はなく, 軽度〜中等度リンパ球分画の増加とCD4/8比の低値とを認めた。また喫煙・非喫煙者間でのBALF所見に差は認められなかった。BALF中のKL-6値はPC肺炎を合併していないHIV感染患者との比較ではPC肺炎発症例で有意に高値であり, BALF中のKL-6値は血清LDHと相関を認めた。

Interferon-γ (IFN-γ) and interleukin-10 (IL-10)-producing ability of peripheral blood plastic-dish adherent cells and non-adherent cells obtained from patients with active pulmonary tuberculosis (N=17) and healthy controls (N=14) upon stimulation with purified protein derivatives (PPD) were assessed. Adherent cells and non-adherent cells were obtained two times from each patient with active pulmonary tuberculosis without any underlying diseases, on admission before the initiation of administrering anti- tuberculous drugs and 2 months later from the negative conversion of Mycobacterium tuberculosis in sputum culture. ELISA was performed to measure IFN-γ and IL-10 levels in culture media of adherent cells and non-adherent cells stimulated with PPD. IFN-γ levels produced by non adherent cells on admission were significantly higher than that of healthy controls (p< 0.001). Elevated IFN-γ levels on admission was reduced after treatment for tuberculosis (p< 0.03), but still remained higher than that in healthy controls. IL-10 levels of non adherent cells of patients were lower than those of healthy controls, although the defference was not significant. IL- 10 levels produced by non adherent cells on admission correlated with the time needed for negative conversion of bacilli in sputum culture (p< 0.05). IL-10 level produced by adherent cells from nutritionally normal patients were significantly higher than that of healthy controls (p< 0.05), and elevated IL-10 level was significantly reduced after therapy (p< 0.05). In the normonourished patients, the time needed for negative conversion of the bacilli in sputum culture of patients kept higher level of L-10 of non- adherent cells (N=5) was significantly longer than that of patients reduced IL-10 level after therapy. These results suggest that IL-10 produced by monocytes may diminish the TH1 responses of patients with pulmonary tuberculosis.

It is assumed that soluble tumor necrosis factor receptor I and II (sTNF-R I, II) play important roles in the regulation of tumor necrosis factor alpha (TNF-α) activity.
We measured the levels of circulating sTNF-R in patients with active pulmonary tuberculosis (n=31) and the correlation between TNF-α and sTNF-R in serum level was investigeted. We also compared sTNF-R levels before and after the treatment in 7 cases.
Significant increase of circulating sTNF-R were found in patients with tuberculosis compared with the normal controls (n=28) (p<0.01). Moreover, significnt positive correlations were found between TNF-α and sTNF-RI and II (r=0.520, r=0.553) in serum comparing sTNF-R levels before and after the treatment for patients with tuberculosis, significant fall was found in sTNF-R I, but not in sTNF-R II.
As a result, it is suggested that sTNF-R regulates TNF-α activity in patients with tuberculosis, and that sTNF-R I levels could be used as one of the indices to evaluate the clinical activity of tuberculosis.

肺癌化学療法に伴う呼吸器感染症の発症要因を明らかにするため, 咽頭細菌叢構成菌と宿主感染防御能の経時的変動をprospectiveに解析した.対象は全身化学療法を施行した原発性肺癌患者20例で評価可能化学療法は32コースであった.呼吸器感染症発症コース (A群) は15コース, 非発症コース (B群) は17コースであった.A群では咽頭細菌叢構成菌は呼吸器病原菌を化学療法前後で持続的に, もしくは化学療法後, 新たに分離する変動パターンをとる傾向を認めた.両群間で化学療法前PS不良例, 白血球数nadirおよび咽頭細菌叢構成菌の変動パターンに有意な差異を認めた.多変量解析の結果から, 咽頭細菌叢構成菌の変動と化学療法前PSが呼吸器感染症発症に影響を及ぼす重要な要因であると考えられた.以上より, 肺癌化学療法に伴う呼吸器感染症の発症には咽頭細菌叢構成菌の変動と宿主感染防御能の低下の両者が密接に関連していることが示唆された.

Weight loss is common in patients with chronic obstructive pulmonary disease (COPD). Comprehensive nutritional assessment was conducted in two large groups of patients with COPD who were enrolled in the Respiratory failure Research Program sponsored by the Japanese Ministry of Health and Welfare and the Kinki COPD Research Group. The incidences of mild malnutrition (%IBW < 90%) were 74% and 62%, respectively. The incidences of hypoalbuminemia were low: 10.0% and 6.5%, respectively. The incidence of imbalance in plasma amino acids, which was defined as an abnormally low BCAA/AAA ratio, was as high as 93% in patients with COPD and chronic respiratory failure. The %IBW was significantly related to the FEV1 and to the DL(co)/V3. The moderately-malnourished subpopulation was characterized by a greater degree of hyperinflation and hypercapnea: the measured resting energy expenditure (REE) was significantly higher than the values in age- matched healthy controls. REE/REE(pred) was significantly and inversely related to BCAA/AAA and to P(1max). REE was inversely related to FEV1%. REE in the subgroup with severe hyperinflation was significantly higher than REE in those with milder hyperinflation. Among patients with an FEV1% of less than 50%, mortality tended to be higher in those with lower body weight, and this relationship was stronger in patients with an FEV1% of more than 50%. When patients were given a BCAA-enriched enteral formula in addition to their usual diet for 3 months, there was a significant increase in body weight, transferrin level, and P(1max).

症例は75歳男性。全身倦怠感を訴え当科受診。胸部レントゲン撮影にて右上肺野に塊状影を認め入院精査を行い, 肺大細胞癌と診断された。偶然気管支鏡検査で気管下部前壁に表面平滑な小隆起を認め, 同部位からの生検で軟骨腫の診断を得た。気管・気管支内軟骨腫は稀な疾患であり, 気管内軟骨腫の報告は本邦では本症例が初めてと考えられた。

We investigated the serum level of IL-8 and TNF-α using ELISA in 16 patients with active pulmonary tuberculosis before administration of antituberculous drugs and in age-, smoking habit-matched 20 healthy controls. The mean level of serum IL-8 in patients with active pulmonary tuberculosis was significantly higher than that in healthy controls (P< 0.001). The mean level of serum TNF-α in tuberculosis patients was also high, while TNF-α was not detectable in the sera of healthy controls. We also examined the relationship between clinical pictures mainly defined by radio graphic findings and the serum levels of IL-8 and TNF-α. The serum IL-8 level of 9 patients with tuberculous cavity is significantly higher than that of 7 patients without cavity. (P< 0.05) We classified the patients with cavities into two subgroups according to the radiographic classification of the Japanese Society of Tuberculosis. Four patients with advanced lesions on chest X-ray showed higher serum IL-8 level than 5 patients with moderate lesions (P< 0.05). On the other hand, there was no correlation between serum TNF-α level and radiographic findings. These results suggest that IL-8 appears to be involved in the formation of tuberculous cavitary lesion. © 1995, JAPANESE SOCIETY FOR TUBERCULOSIS. All rights reserved.

Production of Interleukin-1 β(IL-1β) and granulocyte macrophage-colony stimulating factor (GM-CSF) by peripheral blood monocytes (PBMs) from patients with Mycobacterium avium-intracellulare complex (MAC) infection was assesed and the relationship with their clinical course was analyzed. PBMs were obtained from MAC-infected patients in their active stage as well as in the inactive stage and the healthy controls. Spontaneous release of IL-1β by PBMs from patients in the active stage was higher than those by the cells in the inactive stage or the healthy controls. On the other hand, spontaneous GM-CSF release by PBMs from patients in the active stage was higher than the healthy controls. When PBMs were stimulated with MAC-derived purified protein derivatives (PPD-B), increased production of both IL-1β and GM-CSF were obtained for PBMs in their active stage. While these enhanced production upon stimulation with PPD-B related to the persistent infection with MAC, the increased IL-1β production correlated with the exhausted nutritional state. Both IL-1β and GM-CSF produced by PBMs seemed to be closely related with the clinical course of human MAC infection. © 1995, JAPANESE SOCIETY FOR TUBERCULOSIS. All rights reserved.

The production of tumor necrosis factor alpha (TNFα) and of interleukin- 6 (IL-6) by peripheral blood monocytes (PBMs) from patients infected with Mycobacterium avium intracellular complex (MAC) were assessed. Spontaneous release of both TNFα and IL-6 were greater during the active stage than during the inactive stage and in healthy controls. When the cells were stimulated with MAC-derived purified protein derivative B (PPD-B), TNFα production by PBMs in the active stage increased and IL-6 production by cells in both the active and inactive stages decreased. Moreover, the in vitro increase in TNFα production after stimulation in the active stage seemed to be related to the persistent MAC infection, which resulted in an exhaustion of nutrition. These results suggest that the ability of PBMs to produce TNFα and IL-6 in vitro is closely related to the clinical stage of MAC infection.

Mucociliary transport (MCT) was studied in 22 patients with atypical mycobacteriosis (Group 1 : 16 with M. avium-intracellulare complex (MAC), Group II : 6 with M. kansasii) by aerosol inhalation cine-scintigraphy. In most of the patients, the MCT was abnormally slow both in the main bronchus and in the trachea, while in healthy controls the transport of the inhaled aerosol in the bronchus and the trachea were rapid and smooth. In both groups, the tracheal MCT was impaired in two thirds of the patients, while the MCT in the main bronchus was impaired in all except one in Group I and in two thirds in Group II. The results indicate that the grade of bronchial impairment was higher in MAC than in M. kansasii infections. In atypical mycobacteriosis, especially in MAC infections, such impairment of MCT could be closely related to the disruption of local defence mechanisms in the airways.

A 58-year-old woman, not having any history of pulmonary tuberculosis, was admitted to our hospital to examine a tender lump in her right breast. A breast echogram disclosed a well-defined hypoechoic mass lesion, indicating a pyogenic breast abscess. The patient underwent incision, drainage and resection of the tumor under local anesthesia. Histological findings of the resected tumor revealed epitheloid cell granulomas with caseous necrosis in mammary glands, suggesting tuberculosis of the breast. After operation, treatment with isoniazid, rifampisin and ethambutol hydrochloride was begun. After one year, she had complete healing without any indication of recurrence. During the last 10 years, 12 cases of tuberculosis of the breast have been reported. Their ages ranged from 28 to 84 years with an average of 42.8 years. Only one cases had a past history of tuberculosis and in the other cases tuberculosis of the breast was considered to be a primary disease. Axillary lymph-nodes involvement and formation of pyogenic breast abscess occurred in each 7 cases. Acid-fast bacilli were demonstrated in 25% of the reported cases. The histological findings of resected specimens and punch biopsy revealed epitheloid cell granulomas with caseous necrosis in 11 of 12 cases. Seven of 11 cases were treated with combination of surgery and antituberculous chemotherapy. © 1995, JAPANESE SOCIETY FOR TUBERCULOSIS. All rights reserved.

A 46-years-old male was admitted to our hospital because of productive cough and infiltrates on the chest roentgenogram. The patient had a history of left upper bullectomy ten years prior to the admission. The CT scan of the chest on admission showed infiltrates with cavitation in the left apex and multiple bullae in almost whole lung. Microscopical examination of smears of sputum and bronchoalveolar lavage fluid revealed acid-fast bacilli. They were identified as Mycobacterium szulgai by DNA-DNA hybridization method. The patient was treated with isoniazid, streptomycin and rifampicin. After treatment for about a month, the culture of sputum converted to negative for M. szulgai. After about three months hospitalization, the infiltrates decreased and the cavity wall became thin, and no recurrence sign has been observed after the discharge. There are a few case reports of pulmonary infection due to M. szulgai associated with bullous disease of the lung in Japan.

We investigated the responsiveness of peripheral blood lymphocytes (PBLs) from patients with M. avium-intracellulare complex (MAC) infection to the stimulation with PPDs by measuring their IFN-γ producing ability. PBLs were ohtained from MAC patients at active stage (culture-positive after three-month chemotherapy), those at inactive stage (culture-negative for three months after or during chemotherapy), and healthy donors. PPDs used were PPD-S prepared from M. tuberculosis, PPD-B from M. intracellulare, and PPD-Y from M. kansasii. PBLs from active MAC patients did not produce IFN-γ to a significant extent by stimulation with any of three PPDs, while PBLs from inactive MAC patients showed higher responses to each PPD compared to those from active patients. In inactive MAC patients, the maximal response was observed to PPD-B among three PPDs. On the other hand, PBLs from healthy controls produced different levels of IFN-γ in response to three different PPDs, and their response was most remarkable to PPD-S. These results indicated that the responsiveness of patients' PBLs to PPDs was impaired during active stage of MAC infection and restored on recovery from the disease.

We investigated lectin binding to normal bronchus and lung, metaplastic bronchial epithelium, and 42 cases of primary non-small cell lung carcinoma consisting of 23 squamous cell carcinomas and 19 adenocarcinomas. Fresh frozen sections were stained with 6 fluorescein isothiocyanate (FITC) -conjugated lectins of Dolichos biflorus (DBA), Ulex europaeus (UEA-I), Ricinus communis (RCA-I), Triticum vulgare (WGA), Canavalia ensiformis (ConA), Arachis hypogaea (PNA) and a microphotometer was used for objective evaluation of the fluorescence intensity. UEA-I, RCA-I, WGA, ConA, and PNA with the neuraminidase treatment (PNA · N (+)) were bound to most nontumorous bronchial and lung tissues, metaplastic bronchial epithelium, and lung carcinomas. However, the binding pattern of UEA-I differed from those of RCA-I, WGA, ConA, and PNA · N (+) in terms of localization of its binding sites. DBA was bound to nontumorous and metaplastic bronchial epithelium, bronchial glands, and a part of the bronchiolar epithelium and alveolar septum, but not to alveolar epithelium. The positivity of DBA binding to lung carcinomas was 61.9% (adenocarcinoma, 84.2% squamous cell carcinoma, 43.5%) the positivity of adenocarcinoma being significantly higher than that of squamous cell carcinoma. These results suggest that DBA is an important lectin for the analysis of differences of carbohydrate structures in cell surface membrane between nontumorous bronchus, lung, and the different histological types of non-small cell lung carcinomas. © 1994, The Japan Lung Cancer Society. All rights reserved.

A survey on the nutritional status and cell-mediated immune function of 47 hospitalized patients with active pulmonary tuberculosis and healthy controls was conducted. In the patients group: 1) Anthropometric measurements, such as %ideal body weight (%IBW), %arm circum ference (%AC), %arm muscle circumference (%AMC) and %triceps skin fold (%TSF), were significantly reduced. 2) Visceral proteins including serum albumin (Alb), transferrin (Tf), prealbumin (PA) and retinol binding protein (RBP) were significantly reduced. 3) The imbalance of plasma amino acids, which was characterized by the depression of Fischer ratio, a molar ratio of branched chain amino acids (BCAA) to aromatic amino acids (AAA), was observed. Fischer ratio was significantly correlated with anthropometric measurements (YDIBW, %AC and %AMC). Delayed-type hypersensitivity to DNCB (2, 4-dinitrochlorobenzene) and iymptiocyte transformation to phytohemagglutinin (PHA) and concanavalin A (Con A) were significantly impaired in the patients group, whereas NK cell activity was higher than that of controls. Alb, PA, RBP and Fischer ratio were significantly lower in the patients with reduced DNCB reaction than in those with normal responses. Lymphocyte transformation was signifcantly correlated with Fischer ratio, and NK cell activity was significantly correlated with Alb, PA, RBP. These data may suggest that the imbalance of plasma amino acids represented by the reduction of Fischer ratio and the depletion of visceral proteins are closely related to the impairment of lymphocyte function in the patients with active pulmonary tuberculosis. Copyright © 1994, The Japan Neurosurgical Society. All rights reserved.

The present authors investigated the utility and mechanism of long-term chemotherapy with erythromycin (EM) in the treatment of chronic lower respiratory tract infections. In parallel, we found that EM-clarithromycin (CAM) possesses properties as a biological response modifier (BRM), stimulating the activities of natural killer cells and producing various cytokines. Given these characteristics of CAM, investigations were performed on the effects of CAM on the survival of lung cancer patients receiving long-term administration of CAM. The subjects were 50 inpatients with primary lung cancer not indicated for surgical operation. They consisted of 43 males and 7 females, 41-82 years of age (64.5±9.8). Patients received concomitant application of radiotherapy with chemotherapy including CDDP after discharge, they were allocated randomly into a CAM administration group and nonadministration group at their initial visit to the outpatient clinic, and subsequent survival times were compared between the two groups. Survival rate data were analyzed using the Kaplan-Meier method and differences between the two groups were compared by the generalized Wilcoxon method and LongranK method. There were no significant differences between the two groups in terms of age, sex, stage, tissue type, basic treatment or efficacy rate. Results indicated that the survival curves of patients with small cell cancer were not significantly different between the two groups, but the 50% survival time of patients with non-small cell cancer was 930 days in the CAM administration group and 299 days in CAM non-administration group, indicating significant prolongation of survival in the CAM administration group (p=0.003). In conclusion, CAM was suggested to have potential as a BRM in eliciting prolongation of survival time in patients with lung cancer. © 1994, Japanese Society of Chemotherapy. All rights reserved.

マイコプラズマ肺炎6例に気管支鏡, 気管支肺胞洗浄(BAL), エロソール吸入シネシンチグラフィ(AICS)を施行し, 気道病変とこれに伴う粘液線毛輸送機構障害とを臨床的に検討した。気管支鏡検査では全例両側気管支粘膜の発赤, 腫脹などの炎症所見がみられ, 5例に膿性粘調な分泌物貯留を認めた。生検病理組織像では気管支上皮細胞傷害と気管支, 細気管支, 胞隔炎の所見が得られた。気管支肺胞洗浄液(BALF)所見では総細胞数とリンパ球・好中球比率の増加とを認めた。AICSによる粘液線毛輸送機構の検討では発症後約1ヵ月の時点で4例中3例に強い障害が認められ, 発症後約3ヵ月の時点でも粘液線毛輸送機構障害が遷延した症例も存在した。以上からマイコプラズマ肺炎には広汎で強い気道障害の存在することが明らかとなった。

A 66-year-old man was admitted with small cell carcinoma of the lung (T2, N2, MO, stage III A), accompanied by SVC syndrome. With chemo- and radiotherapy, the SVC syndrome temporarily improved, but recurred. Because the SVC syndrome wasthought to be refractory to these therapeutic modalities, a Gianturco expandable metallic stent (EMS) was inserted into the stenotic SVC. Immediately, many symptoms related to SVC syndrome, edema of the face and upper extremities and dyspnea, improved. A month after placement of the EMS he died of pneumonia but without any side effects induced by the EMS. Autopsy demonstrated that there were no thromboses over the EMS, which was covered with white sheets composed of proliferating intima. © 1993, The Japan Lung Cancer Society. All rights reserved.

症例は重喫煙歴のある70歳,男性。咳漱,喀痰を主訴として近医を受診し,胸部X線写真にて左肺門部腫瘤影を指摘され,喀痰細胞診において編平上皮癌を検出したため,精査,加療囲的で当院入院,気管支鏡検査では左B^<1+2>と右中葉支,下幹分岐部に一部表層浸潤を伴う結節隆起型の腫瘤,右上幹の各分岐部の肥厚,左B^6の完全閉塞を認めた。これら4病巣の生検病理組織所見は上皮内癌を含む扁平上皮癌であり,各腫瘍組織間に連続性はなく,リンパ節および遠隔転移もないことから原発性四重多発肺癌と診断した。CDDP,VDS,MMCの気管支動脈内注入と全身化学療法2コースとを施行し,治療後の気管支鏡検査では視診および病理組織学的に腫瘍の消失を認めた。左B^6の腫瘤影に放射線照射を併用し陰影消失し退院,治療開始後3年以上経過した現在まで再発の兆候なく生存中である。

夏型過敏性肺炎の3症例で, 気管支肺胞洗浄(BAL)法を中心に2∿3年間の経時的変化を観察した。1. 有症時にはBALFの細胞所見は総細胞数, リンパ球と好中球比率の増加, リンパ球CD4/CD8比の低下がみられた。2. 冬・春期および無症状夏期には上記所見は正常化傾向がみられたが, リンパ球比率は依然高値であった。3. ステロイド剤治療を行った1例ではリンパ球比率は他所見と共に正常に復したが, 中止にて再び異常を呈した。4. 家の改築や転居により再発は抑制され, CD4/CD8比のゆるやかな改善があり, 真菌抗体価も低下するが, リンパ球比率は依然高値を持続した。

症例は57歳, 男性。主訴は喘鳴と労作時呼吸困難。右上葉の肺結核合併肺扁平上皮癌cT_1N_1M_0 stage IIの診断で昭和63年10月3日右上葉およびS^6a部分切除術を施行した。平成元年2月下旬より喘鳴と労作時呼吸困難が出現したため5月1日再入院。胸部X線写真では右中葉の含気は低下し, 気管支鏡検査では右中間気管支幹と中葉支は著明に狭窄し底幹入口部には表面平滑な隆起を認めた。気管支造影, 肺動脈造影および換気・血流シンチグラフィ, エロソール吸入シンチグラフィの結果から残存気管支の変形, 狭窄により右肺に広汎で強い換気, 血流障害の生じていることが示されたため, 7月17日右中下葉切除術を施行した。本例では右上葉およびS^6a部分切除により中葉が上後方へと牽引され中葉支が屈曲し著明な狭窄をきたしたとともに, 下葉枝の上方伸展および下方屈曲により底幹入口部付近で気管支軟骨が折り畳まれ隆起を生じたものと考えられた。

A 72-year-old woman was admitted to our hospital with exertional dyspnea (Hugh-Jones III). Chest X-ray films showed right pleural effusion and pleural biopsy revealed pleural carcinomatosis (adenocarcinoma). Despite the intrathoracic administration of MMC and OK-432, an encapsulated pleural effusion remained and pulmonary lymphangitic carcinomatosis developed. Subsequently, a subcutaneous tumor that showed cancer cell infiltration became palpable at the site where the intrathoracic catheter had been inserted, and diffuse subcutaneous swelling extended over the right side of the trunk with right axillary lymphadenopathy. CT scans of the chest and abdomen showed a network of high density lesions in the subcutaneous tissue of the trunk. These physical and CT findings suggested diffuse subcutaneous infiltration of adenocarcinoma. Although systemic chemotherapy with CBDCA and VP-16 was performed, she died of respiratory failure. Autopsy findings revealed that the tumor was a poorly differentiated adenocarcinoma that originated from the right lower lobe, and both direct tumor infiltration from the pleura and the chest wall into the subcutaneous tissue and cutaneous lymphangitic carcinomatosis caused the diffuse subcutaneous swelling. © 1992, The Japan Lung Cancer Society. All rights Reserved.

西日本地区の30施設の共同研究 [西日本肺癌手術の補助化学療法研究会] によりMMC+tegafur (A群) とMMC+UFT (B群) の2群による術後補助化学療法の比較試験 (randomizedcontrolledstudy) を実施し, 両群間の生存期間, 無再発期間, および副作用について検討した.絶対的治癒または相対的治癒切除の腺癌を対象とし, 224例が集積され, 適格率は80.8%であった.背景因子, 投薬状況に群間差は認めず, 3年生存率, 健存率にも群間差は認めなかった.しかし, 相対的治癒切除例やIII期症例ではB群が良好であり, N2症例では有意の差でB群が良好であった.

気管支鏡を用いた内視鏡的治療法の一つとして, 気管, 気管支の腫瘍性狭窄, 閉塞に対して99.5%エタノール(純エタノール)局注療法を試みた。対象は肺癌7例, 転移性肺癌, 気管癌, 多発性気管乳頭腫各1例の計10例であった。有効症例は10例中6例(60%)であり, 肺癌症例のうち1例は有効, 3例は一時有効で, 他3例は無効であった。転移性肺癌症例は無効であったが, 気管癌, 気管乳頭腫症例では有効であった。有効例での腫瘍の発育は主にポリープ状であり, 無効例では浸潤性狭窄を呈していた。副作用は軽度の咳嗽以外認められなかった。以上から, 気管支鏡下純エタノール局注療法は, 適応をある程度限定すれば, 他療法の制限をともなう悪性腫瘍症例においても姑息的, 対症的治療法としてQOLの改善に有用であると考えた。

ヒート・プローブ法の気管支鏡への応用について検討した。1)基礎的検討 : ヒート・プローブ法の剖検気管標本に対する検討では, 膜様部, 軟骨間部においては90Jまでは直接の影響がほぼ軟骨線維層にとどまり, 軟骨上においては150Jまでは直接の影響が粘膜下組織にとどまっていた。2)臨床応用 : (1)肺癌症例において, 癌の浸潤部位の生検後の出血に対して, ヒート・プローブ法は有効であった。(2)気管癌症例にヒート・プローブ法を用いたところ, 加熱一週後では浮腫, 不整, 発赤などの炎症所見がみられ, 二週後では炎症はやや瘢痕化していたが, 部分的に癌組織が残存していた。以上, ヒート・プローブ法は, 気管支鏡下においても比較的安全に用いることができ, 止血法として有効であった。

A 80-year-old male had complained of cough and general fatigue. The chest roentogenogram showed a mass shadow in right S3. Fiberoptic bronchoscopy revealed a white necrotic polypoid tumor obstructing the orifice of right B3. Right upper lobectomy and lymph node dissection was performed. Histological examination of the resected specimen showed that the tumor was composed of mesenchymal chondrosarcoma and moderately differentiated squamous cell carcinoma. Since these two were separate, this case was considered double lung carcinoma. In spite of postoperative chemotherapy, he died of metastatic brain tumor, pneumonia and DIC after six months. Autopsy revealed multiple skin neurofibromatous lesions, and that the mesenchymal chondrosarcoma did not originate from bones or soft tissue. Metastases to the cerebrum, small intestine and mesenteric lymph nodes were recognized. We reported a rare double lung carcinoma associated with multiple neurofibromatosis. © 1989, The Japan Lung Cancer Society. All rights reserved.

We assessed the clinical efficacy of sulbactam·ampicillin (SBT·ABPC) in a study of 19 patients with respiratory tract infections. The drug was administered by intravenous infusion in a dose of 1.5g twice a day. Those detected included H.influenzae in 10 patients, S.pneumoniae in 8, B.catarrhalis in 2, H.parahaemolyticus in 2, K.pneumoniae in 1 and Peptostreptococcus in 1. In 5 patients the organisms detected by transtracheal aspiration together with other organisms. 1) Efficacy was judged to be excellent in 2 patients, good in 16 and poor in 1, the efficacy rate being 94.7%. 2) The organisms were all eradicated except H.influenzae (1 strain) and K.pneumoniae (1 strain). 3) Nausea as a side effect was observed in 1 patient, but no abnormal laboratory findings were observed. From these findings, we believe this drug to be useful in the treatment of respiratory tract infections. © 1988, Japanese Society of Chemotherapy. All rights reserved.

アスベスト曝露に起因する悪性胸膜中皮腫は予後不良の難治性腫瘍であり、標準的治療法は未だ確立されていない。本研究では、悪性胸膜中皮腫に対して、次世代シーケンサーを用いた遺伝子発現解析を実施し、分子標的治療薬のターゲットとなる遺伝子変異を探索した。細胞株および胸膜腫瘍組織に共通して認められた遺伝子変異の中で、癌幹細胞の生存と増殖に関与するNOTCH1およびFBXW7、他疾患の原因遺伝子とされるTSC1およびBRCA2は、新規の治療標的となり得る可能性が示唆された。 今後、これらの遺伝子や癌幹細胞を標的とした悪性胸膜中皮腫に対する新しい治療法の開発が期待される。

兵庫医科大学で採取した悪性中皮腫(以下中皮腫)細胞・組織のゲノムを解析し、1p、3p21、4q、9p21、16p13、22qの欠損を見いだした。9p21ではCDKN2A・2B(p15-16)が全ての中皮腫細胞で両アレル欠損、22qではNF2遺伝子が80%の中皮腫細胞で欠損していた。新規のヘテロ欠損領域として3p21.1-21.31を見出し、上皮型に特異的であった。この領域にあるセマフォリン遺伝子群は発現低下し、アンタゴニストのVEGFA発現は増加し、VEGF優位の状況であることが示された。さらに上皮型中皮腫のほぼ全例(15/16)に、この領域のBAP1遺伝子の両アレル欠損もしくは1アレル欠損+/-他アレルの変異を見出し、免疫染色にてもBAP1(-)を確認した。また患者さんの正常ゲノム検索の結果、BAP1変異は体細胞レベルの変異であった。以上より、CDKN2A・2B欠損は全ての中皮腫の、BAP1欠損・変異は上皮型中皮腫の分子マーカーとなること、特にBAP1シグナル系の再活性化が上皮型中皮腫の治療の分子標的となる可能性が示された。