Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Efficacy and safety of nivolumab with ipilimumab for recurrent malignant pleural mesothelioma after primary surgical intervention.

BACKGROUND: Treatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery. METHODS: Treatment comprised 360 mg nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 6 weeks, both administered intravenously. Both were discontinued for progressive disease or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), post-treatment survival, progression-free survival (PFS), and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Survival analysis was estimated using a Kaplan-Meier plot. Feasibility analysis was performed using the National Cancer Institute Common Terminology Criteria for AEs version 5.0. RESULTS: Forty-one patients received nivolumab with ipilimumab for recurrent MPM after primary curative-intent surgery (median follow-up, 10.4 months; median treatment, 5.1 months). Overall, 18 patients exhibited partial response, 13 exhibited stable disease, and 10 had documented progressive disease. ORR and DCR were 43.9 and 75.6%, respectively. The 12-month post-treatment survival rate and PFS rate were 74.2 and 40.0%, respectively (median survival, not calculated; median PFS, 7.3 months). Further, 47 AEs were reported in 29 patients (70.7%), including grade 3-4 AEs in 14 patients (34.1%). Grade 4 hepatobiliary disorders were observed in 2 patients and grade 4 neutropenia was observed in 1. CONCLUSION: Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Optimal surgery for resectable malignant pleural mesothelioma in the setting of multimodality treatment.

The surgical treatment of malignant pleural mesothelioma (MPM) involves procedures to achieve macroscopic complete resection, depending on the patient's condition. We reviewed the evolution of surgical approaches for resectable MPM. Since surgery is no more than a single step in the set of processes in multimodality treatment (MMT), we concluded that these procedures should give precedence to lung preservation and minimize resection whenever possible. Postoperative quality of life must be prioritized when the patient can receive appropriate adjuvant therapy.

Complications and Predictive Factors for Air Leak > 10 Days with Neoadjuvant Chemotherapy Followed by Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

BACKGROUND: A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D). OBJECTIVE: The aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D. METHODS: Data on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak > 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses. RESULTS: Of 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien-Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3-12.7; p = 0.02) remained the only variable predicted for AL10. CONCLUSIONS: Recent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.

Clinicopathological features of radiological early malignant pleural mesothelioma with no apparent tumor or pleural thickening.

BACKGROUND: We occasionally encounter malignant pleural mesothelioma (MPM) of no apparent tumor or pleural thickening that is radiological early MPM. This study aimed to examine the clinicopathological outcomes of radiological early MPM. METHODS: Patients with MPM treated with neoadjuvant chemotherapy and planned surgery at the time of diagnosis between July 2004 and December 2019 were retrospectively examined. Pretreatment maximal pleural thickness of all patients was measured on chest computed tomography. We extracted and investigated the patients who exhibited a lack of pleural thickening or visible tumor, which was defined as radiological early MPM. Survival was analyzed by the Kaplan-Meier method. RESULTS: Of 296treated patients, 16 (5.4%) exhibited radiological early MPM. Fourteen (87.5%) of these patients underwent pleurectomy/decortication and 2 (12.5%) underwent extrapleural pneumonectomy. Pathological stage T1 disease was diagnosed in 14 (87.5%) patients; 2 (12.5%) exhibited pulmonary parenchymal invasion (pathological stage T2). Lymphatic invasion was detected in only 1 patient. Lymph node metastases and vascular invasion were not detected. Median follow-up was 42 months. Median progression-free survival and median overall survival were 40.7 and 56.1 months, respectively. The 3-year progression-free survival and overall survival rates were 84.8% and 83.6%, respectively. CONCLUSIONS: Radiological early MPM occurs in approximately 1 of every 20 patients treated with neoadjuvant chemotherapy and surgery planned at the time of diagnosis in an experienced center. Radiological early MPM was associated with early pathological stage and long-term survival.

The utility of 68F-FDG PET/CT for evaluation of tumor response to immune checkpoint inhibitor therapy and prognosis prediction in patients with non-small-cell lung cancer.

OBJECTIVE: To compare three fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (EORTC criteria and PERCIST) and computed tomography (CT) (RECIST1.1) for response evaluation and prognosis prediction in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI) monotherapy. SUBJECTS AND METHODS: Forty NSCLC patients underwent 18F-FDG PET/CT scans at baseline and after 4 to 8 cycles of nivolumab or pembrolizumab. Therapeutic response was evaluated according to EORTC criteria, PERCIST, and RECIST1.1,then concordance among those was assessed using Cohen's κ coefficient. Progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. RESULTS: The number of complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) were 8/10/4/18 for EORTC criteria and 9/9/4/18 for PERCIST. Using RECIST1.1, those of CR/PR/SD/PD were 4/10/12/14. Although there was high concordance between PERCIST and EORTC (92.5% of patients; κ=0.924), that between PERCIST and RECIST1.1 was substantial (65.0%; κ=0.560) and that between EORTC and RECIST1.1 (65.0%; κ=0.574). After a median 23.2 months (range 7.2 to 51.8 months), 32 patients had documented progression and 24 patients died from NSCLC. According to both PET and CT, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and OS than PMD or PD patients (EORTC: P<0.0001 and P<0.0001, respectively, PERCIST: P<0.0001 and P=0.0001, respectively, RECIST1.1: P<0.0001 and P<0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatment 18F-FDGPET/CT scans was significantly associated with progression. Highest SUVmax (P<0.0001), total MTV (P=0.0062), total TLG (P<0.0001), highest SULpeak (P<0.0001), and total TLGL (P<0.0001) on post-ICI treatment 18F-FDG PET/CT scans were also were significantly associated with progression. Moreover, the change rate of highest SUVmax (P<0.0001), total metabolic tumor volume (MTV) (P<0.0001), total lesion glycolysis(TLG) (P<0.0001), highest SULpeak (P<0.0001), total TLGL (P<0.0001), size (P=0.0012), EORTC (P<0.0001), PERCIST (P<0.0001), and RECIST 1.1 (P<0.0001) on two PET/CT scans were significantly associated with progression. A multivariate analysis confirmed the change rate of total MTV (P=0.034), and total TLGL (P=0.0027), EORTC (P=0.018), PERCIST (P=0.045), and RECIST1.1 (P=0.0037) as independent negative PFS predictors. CONCLUSION: Both 18F-FDG PET (EORTC criteria and PERCIST) and CT (RECIST1.1) after 4 to 8ICI monotherapy cycles are accurate for evaluation of tumor response and predicting prognosis in NSCLC patients.

Initial evaluation of nivolumab in patients with post-operative recurrence of malignant pleural mesothelioma.

BACKGROUND: Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting. METHODS: This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1-14 months), and median of 8 cycles (range: 2-32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed. CONCLUSION: Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.

Physical function and health-related quality of life in the convalescent phase in surgically treated patients with malignant pleural mesothelioma.

PURPOSE: According to reports, patients with lung cancer have decreased pulmonary function and exercise capacity after surgery. However, to date, physical function and health-related quality of life (HRQOL) after surgery for malignant pleural mesothelioma (MPM) have not been evaluated in detail in the convalescent phase. This study aimed to assess physical function and HRQOL of MPM patients following pleurectomy/decortication (P/D) in the convalescent phase. METHODS: The study included 16 male MPM patients who underwent P/D between September 2014 and August 2016. Physical function was assessed based on handgrip and knee extensor strengths, the six-minute walk distance (6MWD), and pulmonary function, including forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). HRQOL was assessed using the Medical Outcome Study 36-item Short Form Health Survey (SF-36). The assessment was performed preoperatively, postoperatively, and 1-year after surgery. RESULTS: The 6MWD, FVC, and FEV1 values 1-year postoperatively improved significantly compared with baseline (P < 0.05 all). Additionally, the scores of six of the eight SF-36 domains were significantly improved 1 year after P/D: physical functioning, body pain, general health, vitality, social functioning, and mental health (all P < 0.05). 6MWD, FVC, and FEV1 were correlated with vitality, mental health, and physical functioning (P < 0.05 all). CONCLUSIONS: Patients with MPM who underwent P/D showed improved physical function and HRQOL compared with postoperative values in the convalescent phase. Physicians, nurses, and rehabilitation staff should note these findings, which may provide insight into the development of customized rehabilitation strategies in the convalescent phase for such patients.

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma.

We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable- SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification.

INTRODUCTION: The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group. METHODS: Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models. RESULTS: Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015). CONCLUSIONS: Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.

Physical function and health-related quality of life in patients undergoing surgical treatment for malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare cancer that affects the thin cell wall lining of internal organs and structures. Studies have shown that patients with lung cancer have decreased pulmonary function and exercise capacity after pneumonectomy. However, to date, physical function and health-related quality of life (HRQOL) in surgically treated MPM patients have not been evaluated in detail. The aim of this study was to assess physical function and HRQOL of MPM patients following pleurectomy/decortication (P/D). METHODS: The subjects were 22 MPM patients (20 men and 2 women) who completed P/D between December 2013 and March 2015. Physical function was assessed using handgrip strength and knee extensor strength tests, the 6-min walk distance (6MWD), and pulmonary function tests, including forced expiratory vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). HRQOL was assessed using the Medical Outcome Study 36-item Short Form Health Survey (SF-36). RESULTS: The handgrip strength (P < 0.05), 6MWD, FVC, and FEV1 values following P/D decreased significantly compared to baseline (P < 0.001 for each comparison). Additionally, scores of three of the eight SF-36 domains were significantly lower following P/D: physical functioning (P < 0.001), body pain (P = 0.002), and vitality (P = 0.005). 6MWD correlated role physical (P < 0.05) and vitality (P < 0.01). Significant correlations were also observed between FEV1 and physical functioning (P < 0.05) and social functioning (P < 0.05). CONCLUSION: Patients with MPM who completed P/D have decreased physical function and HRQOL. Following surgery, exercise capacity and pulmonary function decreased more than limb muscle strength. Physicians, nurses, and rehabilitation staff should note these findings, which may provide insight into the development of customized rehabilitation strategies for patients with MPM who completed P/D.

Post-recurrence chemotherapy for mesothelioma patients undergoing extrapleural pneumonectomy.

BACKGROUND: Additional chemotherapy is often not feasible in patients with recurrent malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), due to deteriorated cardiopulmonary reserve. We thus examined the feasibility and efficacy of additional chemotherapy in patients with recurrent MPM after EPP. METHODS: A retrospective review was conducted of 59 consecutive patients who underwent bi-/tri-modal treatment with induction chemotherapy, EPP, and radiation therapy from July 2004 to August 2013 at Hyogo College of Medicine (Nishinomiya, Japan). RESULTS: Of 59 patients, 39 (male/female = 31/8, right/left = 15/24, pathological stage I/II/III/IV = 1/7/23/3, bi-/tri-modality = 27/12) relapsed at a median age of 62 (range 37-71) years. The median time to recurrence after EPP was 11.6 months. Of the 39 relapsed patients, 12 received best supportive care alone, six started but discontinued chemotherapy, and the remaining 21 (53%) completed more than three cycles of intravenous chemotherapy. The median survival time after EPP was significantly longer in 21 patients who received additional chemotherapy than in 18 patients who did not (39.2 vs. 12.2 months, P = 0.009). CONCLUSIONS: Additional systemic chemotherapy was successfully administered in more than 50% of relapsed patients after bi-/tri-modal treatment, which included EPP, and resulted in a longer survival in comparison with best supportive care alone.

Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial).

PURPOSE: 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). METHODS: 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. RESULTS: 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 %. CONCLUSION: This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

Current surgical strategies for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. The main components of multimodality treatment include surgery, chemotherapy, and radiation therapy. Surgery remains controversial. Two procedures are currently offered: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). The recent scientific literature suggests that P/D is a well-tolerated procedure, with the potential of becoming a default procedure in multimodality regimens. However, the precise treatment schemes and surgical procedures are yet to be established. In our study, we review the advantages and disadvantages of EPP and P/D, summarize the post-EPP and post-P/D observations (including mortality, morbidity, and median survival time), and discuss the choice of surgical technique (EPP vs. P/D). Moreover, we highlight the aspects of the multimodality treatments that are offered to MPM patients, including chemotherapy, radiotherapy, intensity-modulated radiation therapy, and other types of therapy.

[LEGACIES OF SURGERY FOR TUBERCULOSIS AND SUCCESSION TO THE NEXT GENERATION].

A symposium entitled "Legacies of surgery for tuberculosis and succession to the next generation" was held at the 89th annual meeting of The Japanese Society for Tuberculosis in Gifu. The purpose of the symposium was to look back at the history of surgery for tuberculosis and development of surgical techniques. The contribution of those techniques to the next generation was also discussed. Many unique and universal techniques such as segmentectomy, thoracoplasty, muscle flap plombage, greater omental plom- bage, open window thoracotomy, cavernostomy, and decortication have matured during a long history. Based on the development of antituberculous drugs, surgery seems to have a less important role. However, surgical techniques are still required for multi-drug resistant tuberculosis and non- tuberculous mycobacteriosis. Core techniques are apjlied in the surgery for many thoracic diseases, such as lung cancer, mycosis, pyothorax, and mesothelioma. This manuscript summarizes the presentations.

[PLEURECTOMY/DECORTICATION].

Malignant pleural mesothelioma (MPM) is a very aggressive tumor with poor prognosis. Unlike other solid malignancies, the aim of surgery for MPM is cytoreductive rather than radical. Surgery is performed as multimodality therapy in MPM, combining extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). An en-bloc resection of the pleura, lung, diaphragm, and pericardium is performed in EPP. P/D is a lung-sparing procedure that removes the pleura alone without the lung parenchyma. P/D is less invasive and preserves greater cardiopulmonary function compared with EPP, which leads to good postoperative quality of life (QOL). Tumor recurrence is more frequent after P/D, but it is possible to perform additional treatment because cardiopulmonary function is preserved and QOL is maintained. P/D is a feasible curative surgical treatment for MPM, and it will be performed more frequently in Japan.

Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.

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.

Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level.

Malignant mesothelioma (MM) is an asbestos-related malignancy arising from surface serosal cells of pleural and peritoneal cavities. Somatic mutations of BRCA1 associated protein-1 (BAP1) gene were recently found in MM as well as in uveal melanoma and kidney cancer among the Caucasian and Japanese people. However, frequency of mutations varies among the reported studies, which might be due to presence of undetected gross rearrangements of BAP1 gene that might escape detection by sequencing strategy. We investigated the presence and frequency of gross genomic rearrangements in the BAP1 gene by multiplex ligation-dependent probe amplification (MLPA) in 17 Japanese cases of MM tumors. We found five tumors with partial deletion of BAP1 gene; each tumors displayed partial deletion of exons 1-4 (MM39), exons 1-5 (MM48), exons 11-17 (MM57), exons 1-15 (MM19) and exons 1-16 (MM21). Two tumors (MM34, MM14) had biallelic deletion and four tumors (MM29, MM35, MM45 and MM56) had monoallelic deletion of entire BAP1 gene. Therefore, MLPA analysis revealed large gene rearrangements of BAP1 gene in 65% of MM (11/17). Unusually high frequency of large deletions indicates that the 3p21 chromosomal region surrounding BAP1 gene is structurally unstable. MLPA was useful in characterizing both monoallelic and biallelic deletion of BAP1 gene precisely at exon level.

[Current surgical therapy for malignant pleural mesothelioma].

Malignant pleural mesothelioma (MPM) is a rare tumor and associated with very poor prognosis. The median survival time( MST) was 8.9 months for those treated by palliative care only. For a radical treatment, total removal of the tumor is the main therapy as well as other solid tumors, but these diffuse and infiltrate growth pattern of tumor make it difficult. The MST was 13 months for patients treated by surgery only. On the other hand, MST using pemetrexed/cisplatin was 12.1 months. There are negative opinions for invasive surgical treatment such as extrapleural pneumonectomy (EPP). Currently surgical treatment of mesothelioma is conducted as part of the multidisciplinary treatment combined with chemotherapy and radiation therapy.

Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM).

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.