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Primary pericardial mesothelioma (PPM) has no accepted standard-of-care treatment options with management and outcomes often extrapolated from diffuse pleural mesothelioma. Disease-specific research is needed to better define PPM. We report our institutional experience with PPM highlighting the potential role for multimodality therapy.Patients with PPM diagnosed by a multidisciplinary team of medical oncologists, thoracic surgeons, thoracic pathologists, and radiologists between January 2011 and January 2022 were followed to February 2022. Clinicopathologic features and treatment outcomes were annotated. Overall survival (OS) was defined from the date of pathologic diagnosis.The median age at diagnosis of the 12 patients identified with having PPM was 51 (range: 21-71) years old. Most patients were of female sex (n = 8; 67%), 75% of the samples were epithelioid (n = 9), and 25% were nonepithelioid (two sarcomatoid and one biphasic). Most cases (92%, 11 of 12) had expression of at least two mesothelial markers on immunohistochemistry. The median OS of the cohort was 25.9 months. Five patients had an OS greater than 12 months; four of whom received pericardial radiation. Three of the patients who received radiation did so as part of a trimodality approach (surgical resection, adjuvant chemotherapy, and radiation); the OS for patients who received trimodality therapy was 70.3 months versus 8.2 months for those who did not.PPM represents a distinct disease with no universally accepted treatment options. Our findings suggest that trimodality therapy may improve outcomes in selected patients with PPM.

Well-differentiated papillary mesothelial tumor (WDPMT, formerly called well-differentiated papillary mesothelioma) is a morphologically distinctive lesion composed of expansile papillae with a myxoid core covered by a single layer of generally bland mesothelial cells. Whether some WDPMT are precursors of invasive mesothelioma is uncertain, and this question is confounded by shallow biopsies of ordinary diffuse mesotheliomas that have superficial areas resembling WDPMT as well as by misinterpretation of some cases of mesothelioma in situ. Genetic analyses on a very small number of published cases of peritoneal WDPMT have shown a variety of mutations/copy number losses that do not overlap at all with those that are found recurrently in invasive mesotheliomas. The newly described entity of mesothelioma in situ usually appears as a single layer of mesothelial cells that have lost BAP1 by immunostaining, but sometimes is papillary and produces a morphologic mimic of WDPMT. We propose that, at least in the peritoneal cavity where most WDPMT occur, there are two morphologically identical but functionally distinct lesions: one is true WDPMT, a process that is probably benign, and the other is papillary mesothelioma in situ with the configuration of WDPMT. For that reason immunostaining for BAP1, and if necessary MTAP or CDKN2A FISH, should always be performed on cases with the appearance of WDPMT. It is possible, but speculative, that the small number of reports in the literature which describe invasive mesothelioma arising from WDMPT are actually describing invasive mesothelioma arising from mesothelioma in situ that looks like WDPMT.

As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n = 15), low-grade serous carcinoma (n = 1), well-differentiated papillary mesothelial tumors (WDPMTs; n = 2), and mesothelioma (n = 12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5 cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8 patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5 cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.

Frequency of PD-L1 expression and the role of immunotherapy in malignant peritoneal mesothelioma (MPM) have not been well characterized. The purpose of this study was to determine PD-L1 expression in patients with MPM and perform an exploratory analysis for associations between PD-L1 and its biological behavior in MPM.Tumor samples were collected from patients undergoing surgical interventions between January 2018 and June 2020. Specimens were stained with anti-PD-L1 antibodies (Dako 22c3) and positivity was determined by tumor proportion score (TPS) or combined positive score (CPS) being ≥1%.Twenty one samples were obtained from 21 patients. Sixteen of 21 (76%) samples were CPS positive and 9 of 21 (43%) were TPS positive. Three samples had more aggressive biphasic/sarcomatoid histology and a high CPS and TPS (CPS: 3, 75, 95%; TPS: 2, 60, 90%). On an exploratory analysis, as the CPS or TPS threshold increased, there was a trend towards worse survival.MPM has a high frequency of PD-L1 expression, which may be associated with more aggressive tumor biology. These data provide the foundation for continued evaluation of checkpoint inhibition in patients with MPM.

Malignant pleural mesothelioma is an asbestos-related disease with poor survival. The prognostic role of histologic subtype is well established. Some studies (without a biological hypothesis) suggested that higher asbestos lung burden is associated with reduced survival.We selected subjects from two series of necropsies: residents in Brescia province (North-West Italy) and workers (or persons living with them) employed in the Monfalcone shipyards (North-East Italy). Asbestos fibers and asbestos bodies in lung samples were counted using a scanning electron and an optical microscope, respectively. Separately in the two series, we analyzed median survival time and fitted multivariable Cox regression models (adjusted for sex, period and age at diagnosis, and histopatholocical diagnosis) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for three levels of asbestos fiber counts (reference:1 million fibers/g of dry lung tissue).We analyzed 185 necropsies, 83 in Brescia and 102 in Monfalcone. Despite a much higher lung burden in Monfalcone patients, median survival was slightly shorter in Brescia (8.3 mo) than in Monfalcone (10.2 mo). In Brescia, medium (1.0-9.9) and high (10+) fiber burden HRs were 0.91 (95% CI: 0.54-1.53) and 1.23 (95% CI: 0.41-3.70), respectively. In Monfalcone, the corresponding HRs were 1.18 (95% CI: 0.59-2.35) and 1.63 (95% CI: 0.77-3.45), respectively.No relationship between asbestos lung burden and survival was found. Histologic subtype was the strongest prognostic determinant.

Our goal was to evaluate the diagnostic value of DNA methylation analysis in combination with machine learning to differentiate pleural mesothelioma (PM) from important histopathological mimics.DNA methylation data of PM, lung adenocarcinomas, lung squamous cell carcinomas and chronic pleuritis was used to train a random forest as well as a support vector machine. These classifiers were validated using an independent validation cohort including pleural carcinosis and pleomorphic variants of lung adeno- and squamous cell carcinomas. Furthermore, we performed differential methylation analysis and used a deconvolution method to estimate the composition of the tumor microenvironment.T-distributed stochastic neighbor embedding clearly separated PM from lung adenocarcinomas and squamous cell carcinomas, but there was a considerable overlap between chronic pleuritis specimens and PM with low tumor cell content. In a nested cross validation on the training cohort, both machine learning algorithms achieved the same accuracies (94.8%). On the validation cohort, we observed high accuracies for the support vector machine (97.8%) while the random forest performed considerably worse (89.5%), especially in distinguishing PM from chronic pleuritis. Differential methylation analysis revealed promoter hypermethylation in PM specimens, including the tumor suppressor genes BCL11B, EBF1, FOXA1, and WNK2. Deconvolution of the stromal and immune cell composition revealed higher rates of regulatory T-cells and endothelial cells in tumor specimens and a heterogenous inflammation including macrophages, B-cells and natural killer cells in chronic pleuritis.DNA methylation in combination with machine learning classifiers is a promising tool to reliably differentiate PM from chronic pleuritis and lung cancer, including pleomorphic carcinomas. Furthermore, our study highlights new candidate genes for PM carcinogenesis and shows that deconvolution of DNA methylation data can provide reasonable insights into the composition of the tumor microenvironment.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.METHODS: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234).RESULTS: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01).CONCLUSIONS: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.

Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma.We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (CBetween July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean CFurther refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.Epizyme.

Randomised controlled trials (RCTs) with systemic therapies for patients with pre-treated mesothelioma have reported equivocal efficacy results and generated a degree of clinical uncertainty about the choice of active treatment in this poor prognosis malignancy.To compare the effectiveness and safety and weigh the benefit of different systemic treatments in patients with pre-treated mesothelioma by systematic review, meta-analysis and network meta-analysis of RCTs. Full-text articles and abstracts were searched on PubMed, EMBASE, Cochrane Library and oncology conferences proceedings from 2005 through November 2021 for phase 2 and 3 RCTs. The protocol was submitted to the PROSPERO registry. Reporting followed the PRISMA guideline. Outcomes of interest were overall survival (OS) and progression-free (PFS), grade ≥3 treatment-related (Tr) adverse events (AEs), Tr-deaths and Tr-AEs leading to treatment discontinuation.Nine trials at low risk of bias by Cochrane Collaboration's methodology were included, encompassing 2789 patients. Five studies showed PFS benefit in the experimental treatment. In two studies, OS was prolonged by immunotherapy (versus placebo) or by adding an antiangiogenic agent to chemotherapy. Reported Tr-AE were lower with single-agent anti-PD1 compared with chemotherapy or placebo. The meta-analysis revealed a beneficial global effect on OS and PFS from experimental treatments (HR 0.86, 95% CI 0.77-0.96, p = 0.0083 and HR 0.79, 95% CI 0.72-0.86, p 0.001), that for the PFS significantly favoured the comparison with non-active treatments (HR 0.73, 95% CI 0.66-0.81, p 0.001). Younger patients (i.e. 65-70 years) appeared to benefit the most in OS (HR 0.71, 95% CI 0.55-0.92, p = 0.04). The risk of serious Tr-AEs and Tr-deaths was not significantly increased by experimental treatments (RR 1.38, 95% CI 0.81-2.35, p = 0.24 and RR 2.07, 95% CI 0.69-6.24, p = 0.19, respectively) that instead increased TrAEs leading to treatment discontinuation (RR 2.9, 95% CI 1.44-6.08, p = 0.003). The network meta-analysis did not identify any superior treatment in PFS.For patients with pre-treated MPM, single-agent anti-PD1 or chemotherapy ± the antiangiogenic agent can be considered active and safe systemic therapeutic options, particularly for younger patients.

To understand the geographic distribution of and area-level factors associated with malignant mesothelioma incidence and survival in Australia.Generalised linear models and Bayesian spatial models were fitted using population registry data. Area-level covariates were socioeconomic quintile, remoteness category and state or territory. The maximised excess events test was used to test for spatial heterogeneity.There was strong evidence of spatial differences in standardised incidence rates for malignant mesothelioma but survival was uniformly poor. Incidence rates varied by state or territory and were lower in remote areas. Patterns in the geographic distribution of modelled incidence counts for malignant mesothelioma differed substantially from patterns of standardised incidence rates.Geographic variation in the modelled incidence counts of malignant mesothelioma demonstrates varying demand for diagnostic and management services. The long latency period for this cancer coupled with migration complicates any associations with patterns of exposure, however some of the geographic distribution of diagnoses can be explained by the location of historical mines and asbestos-related industries.

International audience; Background: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. Patients and methods: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of = 3 years after discontinuation. Conclusions: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Prediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters.Baseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators.468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/mThe prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM.

Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

BAP1 is a tumor suppressor gene implicated in DNA repair and cell growth. Individuals with germline BAP1 mutations are at a significantly increased risk for developing many different cancers including malignant mesothelioma, uveal melanomas, cutaneous melanomas and renal clear cell carcinomas. Meningiomas with absent BAP1 expression have been reported to be more aggressive and present often with rhabdoid features. Here, we report the co-occurrence of pleural mesotheliomas and meningiomas in patients with germline BAP1 mutations. We describe the cancer history, family pedigrees, clinical management, and outcomes of four BAP1 germline mutation carrier families with a history of malignant mesothelioma and meningioma.

Primary pericardial mesothelioma is a rare malignancy of the mesothelial lining of the pericardium. This study aimed to evaluate the clinical characteristics and survival outcomes of these patients using a United States population-based cancer database. We queried the Surveillance, Epidemiology, and End Results program (1973-2015). Primary pericardial mesothelioma patients with complete follow-up data were included, and primary pleural mesothelioma patients were identified as controls. Propensity-score matching was used to balance individual characteristics. Kaplan-Meier analysis and log-rank tests were performed to compare overall survival. Forty-one primary pericardial mesothelioma and 15,970 primary pleural mesothelioma patients were identified. Before matching, when compared to the pleural mesothelioma counterparts, primary pericardial mesothelioma patients were younger (median 57 vs 73 years, P0.001), more likely to be female (46.3% vs 20.2%, P0.001), more likely to be nonwhite (24.4% vs 8.4%, P = 0.001), and less likely to have been diagnosed in the most recent study decade (2006-2015, 34.1% vs 43.5%, P = 0.002). The overall 1- and 2-year survival rates were 22.0% and 12.2%, with a median survival of 2 months (IQR: 1-6). After 1:2 nearest neighbor propensity-score matching, 38 pericardial mesothelioma and 76 matched pleural mesothelioma cases were identified. The 2 matched groups had comparable baseline characteristics, including age, sex, race, year of diagnosis, histological type, and cancer history. Compared to their pleural mesothelioma counterparts, primary pericardial mesothelioma patients were less likely to receive chemotherapy (23.7% vs 50.0%, P = 0.01) and had worse overall survival (median survival: 2 vs 10 months, log-rank P = 0.006). Primary pericardial mesothelioma has worse survival outcomes than pleural mesothelioma, with a median survival of only 2 months. These patients should seek care from experienced multidisciplinary teams at tertiary care centers that handle high volumes of mesothelioma patients.

Introduction Peritoneal malignant mesothelioma is an extremely rare tumor and is a difficult diagnosis to be made on cytology alone. We report 3 cases where the cytologic features were misdiagnosed as carcinoma/lymphoma but histopathology and immunohistochemistry (IHC) established the diagnosis of malignant mesothelioma. Clinical details Case 1 was a 60-year-old man with multiloculated ascites and omental caking. Peritoneal fluid was reported as malignant on cytology but was misclassified as adenocarcinoma. Case 2, a 45-year-old man with ascites and peritoneal nodularity, radiologically mimicking peritoneal carcinomatosis, was also reported positive for malignancy on ascitic fluid cytology. Fine-needle aspiration (FNAC) from omental fat revealed signet ring cells, thus misleading to cytologic diagnosis of adenocarcinoma. Case 3 was a 63-year-old man with perisplenic mass with extensive omental caking and peritoneal nodularity that was also suspected to be peritoneal carcinomatosis on radiology. FNAC smears from perisplenic mass showed sheets of plasmacytoid cells. On cytology, the differential diagnoses offered were neuroendocrine tumor or non-Hodgkin lymphoma. The diagnosis of malignant mesothelioma was established only after IHC on histopathologic sections in all these cases. None of our patients had history of prior asbestos exposure. Conclusion In such clinical scenarios, with radiology suggesting peritoneal carcinomatosis, the cytologic features need corroboration by IHC/fluorescence in situ hybridization on cell block or biopsy to correctly identify malignant mesothelioma and differentiate it from metastatic carcinomatous deposits and benign mesothelial proliferation.

Background Overall survival (OS) for malignant pleural mesothelioma (MPM) in vulnerable subgroups remains poorly understood with scarce data available to guide treatment decisions. The study describes real-world detailed treatment patterns and outcomes of patients with advanced MPM overall and specifically in elderly and poor performance status (PS) patients. Methods Retrospective chart review was performed for all patients with histologically confirmed MPM seen at University Health Network/Princess Margaret Cancer Centre (UHN-PM). Results A total of 667 patients with MPM were identified and 304 advanced-disease MPM (aMPM) patients had continuing care at U HN- P M (UP-cohort). In the UP-cohort, 77% of patients received ≥ one line of systemic treatment. Systemic therapy trial participation was 39%. Patients not treated with systemic therapy (29%) were more likely to be ≥ 75 years and PS ≥ 2. Median OS was 15.3 months (95%CI 13.6-18.3), with longer survival in treated vs. untreated patients (17.4 vs. 10.6 months; P = .01). Longer survival with systemic treatment was seen in patients ≥75 years (12.7 vs. 6.6 months) and patients with poor PS (9.1 vs. 5.9 months). Median progression-free-survival (PFS) and OS for patients treated with second-line therapy was poor (3.0 and 8.9 months, respectively). Discussion In our real-world analysis of patients with aMPM treated at an academic referral centre, systemic treatment was given to the majority of patients and benefit was seen even in the elderly and poor PS patients frequently underrepresented in clinical trials. Trial participation was potentially facilitated by the formation of a dedicated multidisciplinary MPM clinic.

Mesothelial tumors are classified into benign or preinvasive tumors, and mesotheliomas. The benign or preinvasive group includes adenomatoid tumors, well-differentiated papillary mesothelial tumors, and mesothelioma in situ. Malignant tumors are mesotheliomas and can be localized or diffuse. Histological classification of invasive mesotheliomas into three major subtypes-epithelioid, sarcomatoid, and biphasic is prognostically important. It also plays a significant role in the treatment decisions of patients diagnosed with this deadly disease. Grading and subtyping of epithelioid mesotheliomas have been one of the major changes in the recent WHO classification of pleural tumors. Mesothelioma in situ has emerged as a precisely defined clinico-pathologic entity that for diagnosis requires demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH. The use of these two biomarkers improves the diagnostic sensitivity of effusion specimens and limited tissue samples and is valuable in establishing the diagnosis of epithelioid mesothelioma. In this review, recent changes in the histologic classification of pleural mesothelioma, importance of ancillary diagnostic studies, and molecular characteristics of mesotheliomas are discussed.

Malignant pleural mesothelioma is a rare tumor arising from the pleural mesothelial cells. Imaging plays a crucial role in the diagnosis, staging, and management of patients with mesothelioma. Accurate staging to stratify patients into homogeneous groups is required to evaluate the effectiveness of multimodality therapeutic regimens. CT and PET/CT are recommended for the initial staging of MPM. MRI adds value to further assess invasion of the tumor into the diaphragm, chest wall, and mediastinum. This review will discuss pearls and pitfalls in the imaging of mesothelioma with emphasis on the roles of CT, MRI, and PET/CT.

Background: no phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.Methods: this was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.Findings: between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52–0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.Interpretation: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.Funding: Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb.

Case Presentation A 57-year-old man with history of stage IIIB right-sided malignant pleural mesothelioma was admitted from his oncologist’s office for progressive dyspnea of two weeks duration. He had associated dyspnea at rest and a new dry cough. He denied sputum production, hemoptysis, or fevers, but he did endorse chills, fatigue, and weight loss. The patient was a veteran of the Navy and had extensive international travel in his 20s. He had never been incarcerated and denied any sick contacts or recent travels. He had received a diagnosis of mesothelioma 11 months earlier after presenting to his physician’s office with complaints of shortness of breath on exertion. Initial imaging revealed a large right-sided pleural effusion with irregular pleural thickening. He underwent right-sided thoracoscopy, and the pleural biopsy result was consistent with epithelioid mesothelioma. Because of invasion of his seventh rib, he was not a candidate for surgery and underwent palliative radiation and chemotherapy with cisplatin, pemetrexed, and bevacizumab. He was undergoing his eighth cycle of chemotherapy at the time of presentation.

Background With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with the routine use of positron emission tomography (PET). Methods We performed a retrospective review of our prospectively maintained database from February 2014 to May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of the staging evaluation before surgery. Results Of 187 patients (71% men, 80% epithelial) who underwent DL during staging, 76% proceeded to surgery; 22% were unresectable at exploratory thoracotomy and 78% underwent resection (pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). Also, 89% had a PET computed tomography (CT), and 11% had a preoperative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based on the pathologic findings at DL the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%. Conclusions PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of the preoperative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging before surgery.

Objectives Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with antimitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models. Methods Human MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models. Results TTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor. Conclusion This research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatin-induced DNA damage is repaired via the FA-BRCA pathway.

The prognostic impact of tumour grading, cytological and architectural patterns and stromal features in diffuse pleural malignant epithelioid mesothelioma (MEM) has been partly studied but not correlated to molecular features. We performed a retrospective study on 92 MEM in our department in order to assess the prognostic role of architectural and stromal patterns, especially tumour to stroma ratio. Secondly, based on The Cancer Genome Atlas (TCGA) database, we analysed the differentially expressed genes in prognostic groups of interest. Our results showed that tumour grading, tumour to stroma ratio and predominant pattern were related to overall survival, p≤0.001, p=0.01 and p=0.001, respectively. In univariate analysis, for high grade tumours hazard ratio (HR) was 4.75 (2.47-9.16), for stroma poor tumours HR=0.016, for predominant tubular or tubulopapillary pattern HR=0.044. In multivariate analysis, high grade tumours were related to overall survival [HR=3.09 (1.50-6.35), p=0.002] and predominant tubular or tubulopapillary pattern [HR=0.56 (0.32-0.99), p=0.045]. In TCGA analysis, after grading of diagnostic slides, we showed that KRTDAP and CXRCR1 expression was higher in low grade tumours, unlike PDZD7 and GPR176 expression which was higher in high grade tumours. FAM81B had a higher expression in stroma poor tumours. We did not find any differentially expressed genes in the architectural patterns group. Our work suggests that tumour grading is an important parameter in MEM with an underlying genomic basis. The role of tumour to stroma ratio needs to be investigated and might also have a genomic basis.

Objectives Second-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM. Materials and Methods We performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups. Results Of the 176 patients with MPM, the median age was 75 years (IQR: 69–79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (1 1 5) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34–0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively. Conclusion In this “real-world” population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy.

BACKGROUND: Current risk stratification for patients with malignant pleural mesothelioma based on disease stage and histology is inadequate. For some individuals with early-stage epithelioid tumours, a good prognosis by current guidelines can progress rapidly; for others with advanced sarcomatoid cancers, a poor prognosis can progress slowly. Therefore, we aimed to develop and validate a machine-learning tool—known as OncoCast-MPM—that could create a model for patient prognosis. METHODS: We did a retrospective study looking at malignant pleural mesothelioma tumours using next-generation sequencing from the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We collected clinical, pathological, and routine next-generation sequencing data from consecutive patients with malignant pleural mesothelioma treated at the Memorial Sloan Kettering Cancer Center (New York, NY, USA), as well as the MSK-IMPACT data. Together, these data comprised the MSK-IMPACT cohort. Using OncoCast-MPM, an open-source, web-accessible, machine-learning risk-prediction model, we integrated available data to create risk scores that stratified patients into low-risk and high-risk groups. Risk stratification of the MSK-IMPACT cohort was then validated using publicly available malignant pleural mesothelioma data from The Cancer Genome Atlas (ie, the TCGA cohort). FINDINGS: Between Feb 15, 2014, and Jan 28, 2019, we collected MSK-IMPACT data from the tumour tissue of 194 patients in the MSK-IMPACT cohort. The median overall survival was higher in the low-risk group than in the high-risk group as determined by OncoCast-MPM (30·8 months [95% CI 22·7–36·2] vs 13·9 months [10·7–18·0]; hazard ratio [HR] 3·0 [95% CI 2·0–4·5]; p

We aimed to explore the feasibility of 2D and 3D radiomics signature based on the unenhanced computed tomography (CT) images to predict BRCA1-associated protein 1 (BAP1) gene mutation status for malignant pleural mesothelioma (MPM) patients.74 patients with MPM were retrospectively enrolled (22 mutant BAP1, 52 wild-type BAP1 demonstrated by Sanger sequencing). The radiomic features were extracted respectively from the 2D and 3D segmentation of unenhanced pre-treatment CT images, and the dataset was randomly divided into training (n = 51) and test (n = 23) sets for radiomics model development and internal validation. The synthetic minority over-sampling technique (SMOTE) was used for data balancing in the training set. 2D or 3D features were sequentially selected by ICC 0.8, correlation analysis (cut-value 0.7), univariate analysis or univariate logistic regression (LR), which were involved into multivariate LR for LR model construction. Following the comparison of the 2D and 3D models by the ROC analysis and Delong test for AUC, the calibration and clinical utility of 2D and 3D models were evaluated.3D radiomic features showed better ICCs compared with 2D in both intra- (P0.001) and inter-observer (P 0.001) analysis. 3D radiomic model based on selected features developed from a balanced training dataset presented a favorable predictive performance with AUC of 0.786 and 0.768 in the training and test sets, respectively. The predictive performance of 3D model was superior to 2D model (1 feature) both in the training (AUC 0.786 vs. 0.683, P = 0.036) and the test (AUC 0.768 vs.0.652, P = 0.441) set. The calibration curve and decision curves also indicate a better BAP1 prediction performance and clinical benefit for 3D model than that of 2D model.The developed unenhanced CT-based 3D radiomics signature is potential as a noninvasive marker for predicting BAP1 mutation status.

The aim of adoptive T-cell therapy is to promote tumor-infiltrating immune cells following the transfer of either tumor-harvested or genetically engineered T lymphocytes. A new chapter in adoptive T-cell therapy began with the success of chimeric antigen receptor (CAR) T-cell therapy. T cells harvested from peripheral blood are transduced with genetically engineered CARs that render the ability to recognize cancer cell-surface antigen and lyse cancer cells. The successes in CAR T-cell therapy for B-cell leukemia and lymphoma have led to efforts to expand this therapy to solid tumors. Herein, we discuss the rationale behind the preclinical development and clinical trials of T-cell therapies in patients with malignant pleural mesothelioma. Furthermore, we highlight the ongoing investigation of combination immunotherapy strategies to synergistically potentiate endogenous as well as adoptively transferred immunity.

Malignant pleural mesothelioma (MPM) is often associated with a poor prognosis and options for the treatment of this disease are few. To date, the important role of the immune microenvironment in modifying the disease natural history is well established. The programmed cell death pathway (PD-1/PD-L1) limits the T lymphocyte activation in peripheral tissues when an inflammatory response occurs, and controls the tumour immune escape. PD-L1 is broadly expressed in several malignant tumours and associated with poor clinical outcomes. Thus, the aim of our study is to investigate the potential role of PD-L1 expression in MPM prognosis. Biopsy samples from 198 patients diagnosed with MPM were examined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) to evaluate PD-L1 protein and gene expression. For PD-L1 protein expression we consider at least 5% membranous staining as positive. Gene expression levels were calculated with ΔΔCt method. Positive expression of PD-L1 by IHC was correlated with worse overall survival (OS; p=0.0225) in MPM patients. PD-L1 positive status was correlated with worse OS in the subgroup of patients with ECOG score

Malignant pleural effusion is common in mesothelioma. We report a case of viscous recurrent malignant mesothelioma pleural effusion. The viscosity was due to the presence of hyaluronic acid and resulted in prolonged drainage time. The use of intrapleural hyaluronidase significantly reduced fluid viscosity and drainage duration. No adverse reactions were noted. This novel case highlights the feasibility and safety of the use of intrapleural hyaluronidase in the management of hyaluronic acid-rich viscous malignant pleural effusion.

Study design A retrospective, single-center, case series Introduction Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm with poor prognosis. The combined cisplatin/pemetrexed regimen is the only regimen currently approved by the FDA. Immunotherapy with checkpoint inhibitors and other therapeutics are quickly becoming the preferred second-line therapy following incorporation into clinical practice guidelines in 2018 as a salvage therapy. Purpose of the study: To describe the use of PD-1/PD-L1 targeted therapy to manage MPM. Methods Retrospective chart review of patients with MPM treated at a single institution with pembrolizumab or nivolumab was performed. Clinical and pathologic information were extracted and clinical response rate and other outcomes were assessed. Results Twelve patients received pembrolizumab, and two patients received nivolumab. Patients were 43% male (6 out of 14), 64% non-Hispanic white (9 out of 14), and 93% epithelioid histological subtype (13 out of 14). Prior to immunotherapy, 36% had received surgical resection (5 out of 14), 36% had received radiotherapy (5 out of 14), and 93% received platinum-pemetrexed based chemotherapy (13 out of 14). Objective response rate was 21% (0 CR and 3 PRs), and disease control rate was 43% (3 PRs and 3 SDs). Time to progression ranged from Conclusion Based on this small series, real-world PD-1/PD-L1 targeted therapy appears to be a promising treatment for patients with MPM who have disease progression on systemic chemotherapy, consistent with small single arm clinical trials. Further investigation with multicenter, prospective longitudinal cohorts and/or randomized clinical trials may help identify which patients have the largest magnitude of benefit.

Objectives Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. Materials and methods Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. Results A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p Conclusions Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.

Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury.We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 μmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days.Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P .001), intraoperative cisplatin administration (odds ratio, 3.12; P .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models.Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.

Aim Conformational forms of the epidermal growth factor receptor (EGFR) are pro‐tumorigenic. The prevalence and impact of conformational forms of EGFR in malignant mesothelioma (MM) is unknown. We investigated expression of EGFR and conformational forms of EGFR by immunohistochemistry using EGFR-targeting monoclonal antibodies (mAb). In addition, EGFR gene amplification was investigated by fluorescent in-situ hybridization (FISH). Findings were correlated with survival. Methods Patients treated between 1988 and 2014 were identified from the thoracic surgery database of the Austin Hospital, Melbourne, Australia. Tissue microarrays (TMAs) were constructed, subjected to wild type (wt) EGFR IHC staining and FISH analysis. Conformational and mutation forms of EGFR were detected by IHC using mAb806, and LMH-151 which detects EGFRVIII. `H-scores` were derived and EGFR expression correlated with survival by Kaplan-Meier and log rank analysis. Results WtEGFR expression was seen in 93 % (299/321) of cases with overexpression (defined as an H-score ≥200) seen in more than half of cases (64 %). EGFR overexpression in MM was seen more commonly in the epithelioid subtype. EGFR overexpression was not associated with true EGFR amplification, although multiple copies were appreciated in samples with polysomy. EGFR expression did not correlate with survival. A conformational form of EGFR associated with EGFR dysregulation was found in 8.2 % of cases, and patients with these tumors had a trend towards a poorer outcome. No cases of the EGFRVIII mutation were identified. Conclusion MM consistently demonstrated high expression of EGFR, with a subset of tumors showing conformational EGFR forms consistent with EGFR dysregulation, but withoutEGFR amplification or EGFR VIII mutation. wtEGFR expression did not influence survival. The impact of EGFR conformation on survival warrants further investigation.

Treatment planning for malignant pleural mesothelioma is a challenging task due to the relatively large size of the target and the need to spare critical organs that overlap with or are within the target volume. We aimed to develop a knowledge-based model using RapidPlan (RP) for patients with 2 intact lungs.Data from 57 patients treated with volumetric modulated arc therapy were chosen for training the dose estimation model at a single dose level. The prescription dose was 50.4 Gy in 1.8 Gy fractions. The model was validated on 23 new patients by comparing the clinical plan to the RP. Time taken to plan the RP was compared with that for the clinical plan.For similar target coverage and plan inhomogeneity, RP significantly improved the sparing of the contralateral lung, heart, stomach, esophagus, and ipsilateral kidney. On average, the contralateral lung V5 Gy and V10 Gy were reduced by 13.9% (P.001) and 7.9% (P.001), respectively. The mean heart dose was reduced by 5 Gy (P.001) and V30 Gy by 9.1% (P.001). Mean dose to the stomach and esophagus were both reduced by 5 Gy (P.001), and the ipsilateral kidney V18 Gy by 4.1% (P.001). Mean total lung dose was reduced by 0.8 Gy with RP, which enabled an increase in prescription dose by 1 fraction Absolute volume of ipsilateral lung was adequately spared by both techniques, while sparing of all other organs, namely the cord, liver, and bowel, was not compromised with RP. Time taken with RP was 20 minutes, 45 seconds versus at least 4 hours for an experienced treatment planner.The RP model for malignant pleural mesothelioma showed improved sparing of critical organs with a reduced treatment planning time and increased prescription dose.

Background In selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy. Trial Design The NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial ( ClinicalTrials.gov identifier, NCT04177953 ). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life. Conclusion This prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.

No standard treatment option is available for patients with unresectable malignant pleural mesothelioma (MPM) progressing after upfront chemotherapy. We aimed to explore the role of focal radiotherapy (FRT) as a treatment modality for oligo-progressive MPM.In this retrospective study, consecutive patients pretreated with ≥1 lines of chemotherapy were included. Oligo-progressive MPM was defined as an unresectable disease with radiological progression at ≤3 sites according to a chest-abdominal contrast-enhanced computed tomography. Patients were treated with either stereotactic body radiotherapy (SBRT, ≥5 Gy per fraction) or hypo-fractionated radiotherapy (hypoRT,5 Gy per fraction). Time to further systemic therapy (TFST) and local control (LC) after FRT were the primary endpoints. Biologically effective dose (BED) was calculated using three different alpha/beta models (1.5 Gy, 3 Gy and 10 Gy).From April 2006 to March 2019, 37 patients were treated on 43 pleural lesions; 16/37 (43 %) had undergone upfront multimodality treatment (MMT) including surgery. FRT was given in 22/37 (59.5 %) after one line of chemotherapy. SBRT was delivered for 26/43 lesions (60.5 %), hypoRT for 17/43 (39.5 %). Median TFST was 6 months (95 % CI 4.9-7.1). LC at 6 months and 1 year was 84 % and 76 %, respectively. Median TFST was longer in patients treated after 1 vs1 line of chemotherapy (9 vs 4 months, p = 0.001) and in patients pretreated with MMT (6 vs 3 months, p = 0.021). Six-month LC was better in patients treated with a BED 100 using alpha/beta 1.5 and 3. No ≥ G3 acute or late toxicities were reported.FRT was feasible in selected patients with oligo-progressive MPM, allowing delay of further systemic therapies, with no severe toxicity. FRT was more effective when performed at progression after one line of systemic therapy. Our results suggest a radio-resistant behavior of MPM.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age

Summary Background A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol. Methods In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2, with histologically proven, resectable, cT1–3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov , NCT00797719 . Findings Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2–12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3–4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4–61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3–74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]). Interpretation Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period. Funding Princess Margaret Hospital Foundation Mesothelioma Research Fund.

In recent years, there has been a shift from extrapleural pneumonectomy (EPP) toward pleurectomy/decortication (P/D) as the preferred surgical technique. However, we occasionally encounter difficult cases wherein visceral pleurectomy requires conversion to EPP from P/D. We sought to clarify the preoperative risk factors and clinical outcomes associated with conversion to EPP. We compared and analyzed conversion to EPP and P/D between September 2012 and December 2019. Conversion to EPP was decided in case of diffuse tumor invasion to the pulmonary parenchyma or due to failure of decortication. Univariable regression analysis was performed to determine the association of preoperative variables with conversion to EPP. Survival was analyzed by the Kaplan-Meier method and log-rank test. Of the 181 patients who underwent intended P/D, 145 (80.1%) patients underwent P/D and 18 (9.9%) patients underwent conversion to EPP. The sum of 3-level pleural thickness (P0.001), maximum of 3-level pleural thickness (P = 0.006), and clinical T stage (P0.001) demonstrated association with conversion to EPP. Overall survival and progression-free survival were significantly worse in the conversion to EPP group (median overall survival, 29.2 months vs 57.0 months [P = 0.008]; median progression-free survival, 15.3 months vs 23.2 months [P = 0.005]. Our data show that approximately 1 of every 10 patients with P/D intention converted to EPP. Preoperative pleural thickness and clinical T stage may be risk factors associated with conversion to EPP. The survival rate of conversion to EPP was worse than that of P/D.

Aim Severe neurological and endocrine toxicities are well recognised adverse events of immune checkpoint inhibitors. However, the underlying pathophysiology is poorly understood, and classical circulating markers are often non-informative, making it difficult to obtain a precise diagnosis and to initiate timely and effective treatment. Here we investigated immune-modulating activity in the plasma of a mesothelioma patient who developed fatal neuroendocrine toxicity characterised by insulin-dependent diabetes, hypophisitis and a myasthenia-like syndrome while on treatment with the dual PD1 and TIM3 blockade. Methods We used an in vitro functional assay for unbiased detection of plasma dendritic cell–modulating activity, followed by cytokine quantification by the Cytokine Bead Array. Results Immunosuppressive treatment as per established guidelines could not prevent the fatal outcome. Patient's plasma contained a dendritic cell–stimulating activity that induced specific markers (CD25+) compatible with T-helper 17 stimulation. Consistently, elevated levels of interleukin 17 (IL17A), but no other cytokines, were identified in the patient's plasma but not in controls (healthy volunteers and patients treated with immunotherapy without neuroendocrine toxicities). Conclusion If confirmed in larger series, these data suggest IL17 as a candidate diagnostic and therapeutic target in the management of high-grade neuroendocrine immune-related adverse events.

Background Detection of homozygous deletion of the p16 gene (CDKN2A) by fluorescence in situ hybridization (FISH) has been investigated as an ancillary technique in the diagnosis of malignant mesothelioma. Method This retrospective study reviewed the results of all p16 FISH tests performed at a regional mesothelioma centre from February 2012 to November 2019 in cases of possible mesothelioma to examine the diagnostic utility of this test as well as patients characteristics and survival in p16 FISH positive mesothelioma versus p16 FISH negative mesothelioma. Results P16 FISH testing was requested in 216 pathological samples in the study period. The test failure rate was 4% (10/216). Median time from request to result was 10 days (IQR 7–13, range 1–30). The sensitivity, specificity, NPV and PPV were 60 %, 100 %, 39 % and 100 % respectively. There were no false positive results and this genetic aberration was only detected in cases of mesothelioma. The prevalence of p16 FISH positive mesothelioma was higher in cytological specimens compared to histological specimens (75 % vs 58 %, p = 0.03) and lower in women compared to men (33 % vs 66 %, p = 0.003). P16 FISH positive mesothelioma was associated with significantly worse survival (median overall survival 285 vs 339 days, p = 0.0018). This remained significant after adjusting for confounding variables (OR 4.4, 95 %CI 1.84–11.14, p = 0.001). Conclusions In this study, 60 % of mesotheliomas harbour a homozygous deletion of CDKN2A and can be accurately, reliably and efficiently identified by p16 FISH testing. This test can be embedded within routine practice in mesothelioma pathways to enhance diagnostic accuracy.

Within a larger national malignant pleural mesothelioma cohort, we identified 43 patients with unusually long survival times. This study aimed to evaluate the diagnostic accuracy in this subgroup, and the diagnosis was confirmed to be correct in most cases. In addition, we searched for clinical factors related to the prolonged survival time. Introduction: Malignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival. Materials and Methods: Forty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists. Results: Our study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time. Conclusion: We confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors. (C) 2020 Elsevier Inc. All rights reserved.

Despite multiple diagnostic toolkits, the diagnosis of diffuse malignant pleural mesothelioma relies primarily on proper histologic assessment. The definitive diagnosis of diffuse malignant pleural mesothelioma is based on the pathologic assessment of tumor tissue, which can be obtained from core biopsy sampling, pleurectomy, or other more extensive resections, such as extrapleural pneumonectomy. Given its rarity and overlapping microscopic features with other conditions, the histologic diagnosis of diffuse malignant pleural mesothelioma is challenging. This review discusses the pathologic features and the differential diagnosis of diffuse malignant pleural mesothelioma, including select diagnostic pitfalls.

Extended pleurectomy and decortication (ePD) is a difficult operation performed for the surgical resection of malignant pleural mesothelioma that can achieve a macroscopic complete resection with preservation of the lung. With lower perioperative mortality, similar long-term survival, and better tolerance in patients with lower performance status, ePD has become the preferred operation rather than extrapleural pneumonectomy despite lack of a direct comparison. As ePD has become more popular, international collaboration is underway to create surgical guidelines based on collection of operative data. These efforts will improve the safety and standardization of this operation.

Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.