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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.

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.

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.

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.

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.

Introduction:\ud Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.\ud \ud Methods:\ud A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.\ud \ud Results:\ud A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.\ud \ud Conclusions:\ud SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

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Introduction Children and young adults diagnosed with malignant mesothelioma may have unique genetic characteristics. In this study, we evaluated for the presence of the anaplastic lymphoma kinase (ALK) translocations in these patients. Methods In a prospective study of mesothelioma natural history ( ClinicalTrials.gov number NCT01950572 ), we assessed for the presence of the ALK translocation in patients younger than 40 years, irrespective of the site of disease. The presence of this translocation was assessed by means of fluorescence in situ hybridization (FISH). If the patients tested positive for the ALK translocation, both immunohistochemistry and RNA sequencing were performed on the tumor specimen. Results Between September 2013 and December 2018, 373 patients were enrolled in the mesothelioma natural history study, of which 32 patients were 40 years old or younger at the time of their mesothelioma diagnosis. There were 25 patients with peritoneal mesothelioma, five with pleural mesothelioma, one with pericardial mesothelioma, and one with bicompartmental mesothelioma. Presence of an ALK translocation by FISH was seen in two of the 32 patients (6%) with mesothelioma. Both patients, a 14-year-old female and a 27-year-old male, had peritoneal mesothelioma and had no history of asbestos exposure, prior radiation therapy, or predisposing germline mutations. Neither had detectable ALK expression by immunohistochemistry. RNA sequencing revealed the presence of an STRN fusion partner in the female patient but failed to identify any fusion protein in the male patient. Conclusions Young patients with peritoneal mesothelioma should be evaluated for the presence of ALK translocations. Presence of this translocation should be assessed by FISH and these patients could potentially benefit from tyrosine kinase inhibitors targeting ALK.

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Introduction Detailed guidelines regarding the use of radiation therapy for malignant pleural mesothelioma (MPM) are currently lacking because of the rarity of the disease, the wide spectrum of clinical presentations, and the paucity of high-level data on individual treatment approaches. Methods In March 2017, a multidisciplinary meeting of mesothelioma experts was cosponsored by the U.S. National Cancer Institute, International Association for the Study of Lung Cancer Research, and Mesothelioma Applied Research Foundation. Among the outcomes of this conference was the foundation of detailed, multidisciplinary consensus guidelines. Results Here we present consensus recommendations on the use of radiation therapy for MPM in three discrete scenarios: (1) hemithoracic radiation therapy to be used before or after extrapleural pneumonectomy; (2) hemithoracic radiation to be used as an adjuvant to lung-sparing procedures (i.e., without pneumonectomy); and (3) palliative radiation therapy for focal symptoms caused by the disease. We discuss appropriate simulation techniques, treatment volumes, dose fractionation regimens, and normal tissue constraints. We also assess the role of particle beam therapy, specifically, proton beam therapy, for MPM. Conclusion The recommendations provided in this consensus statement should serve as important guidelines for developing future clinical trials of treatment approaches for MPM.

Surgical intervention plays an important role in the diagnosis, staging, and treatment of malignant pleural mesothelioma (MPM) and can be applied with curative or palliative intent. The overall aim of surgery should be, as in any oncologic surgery, the macroscopic complete resection (MCR) of the tumor. Most importantly, the majority of patients with the diagnosis of MPM should be appropriately staged and initially evaluated in a multidisciplinary setting, including medical oncology, radiation oncology, and surgery after histologic diagnosis. Surgical staging, including determination of the histologic subtype and lymph node status, as well as clinical staging with positron-emission tomography-computer tomography scan and determination of cardiopulmonary reserve are crucial. Herein, we summarize the role of surgical resection, specifically macroscopic complete resection, performed as extrapleural pneumonectomy or extended pleurectomy/decortication in multimodality treatment settings and advocate for optimal patient selection for one or the other procedure. In addition, the roles of surgery in diagnosis of MPM and in palliative care are discussed.

Introduction There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Methods Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative ( Results A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. Conclusion These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti–PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.

INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a “transitional” (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin – stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a signicant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 – 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 – 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

Introduction Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. Methods The current de facto standard for the assessment of mesothelioma tumor response, "modified RECIST" (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented "modified RECIST 1.1 for mesothelioma" response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. Results These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. Conclusion Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.

Introduction Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) Src Tyr419 . Results For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-Src Tyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) ( p = 0.004). A decrease in p-Src Tyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [ p = 0.03]), suggesting that p-Src Tyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy ( p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

Introduction Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and relatively chemoresistant and radioresistant malignancy with limited therapeutic options. Our objective was to investigate the prevalence of programmed death ligand 1 (PD-L1) and the characteristics of the immune environment in this disease. Methods A total of 99 archival tumors from advanced-stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories, and 87 of them were profiled for immune gene expression by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and phosphoinisitide-3-kinase pathways. Results PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells or the infiltrating immune cells. Gene expression analysis suggested that MPM is an inflamed tumor type and can be classified into three different subgroups on the basis of the different expression profiles of immune-related genes, of which two groups showed varying degrees of expression of immune-related genes. Overall, these molecular findings suggest that these subgroups of MPM associated with PD-L1 positivity and expression of immune-related genes accounting for 60% of MPMs represent a candidate subtype that may respond to cancer immunotherapy. Conclusions These data suggest that 60% of patients with MPM characterized by either PD-L1 expression or an inflamed status are attractive candidates for cancer immunotherapeutic options.

Introduction BRCA1 associated protein1 (BAP1) is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A, and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM. Methods Expression of BAP1 isoforms was detected by quantitative polymerase chain reaction in MPM and normal mesothelium cell lines and tumor and nontumor samples. Histone H2A ubiquitination levels were analyzed by Western blot after acidic extraction of core histones. Subcellular localization of BAP1 isoforms was examined by immunofluorescence. MPM cell survival in response to poly(adenosine diphosphate–ribose) polymerase (PARP) and dual phosphoinositide 3–kinase (PI3K)–mammalian target of rapamycin (mTOR) inhibitors was analyzed by in vitro assays. Results We have identified a novel alternative splice isoform of BAP1 (BAP1Δ) that misses part of the catalytic domain. Cells transfected with BAP1Δ showed reduced deubiquitinating activity compared with full-length BAP1. The expression of BAP1Δ transcript is more abundant in nontumor than in tumor samples. MPM cell lines expressing more than 20% of BAP1Δ are more sensitive to olaparib (a PARP1 inhibitor) cytotoxicity, and this sensitivity is enhanced when olaparib treatment is combined with GDC0980 (a dual PI3K-mTOR inhibitor), which induces downregulation of BRCA1. Conclusions These observations suggest that BAP1Δ does regulate DNA damage response and influences drug sensitivity. It might therefore be relevant to investigate whether patients with high expression of BAP1Δ may be responsive to PARP/PI3K-mTOR inhibitors.

© 2017 International Association for the Study of Lung Cancer Introduction In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential. Methods S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme. Results A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7). Conclusions Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

Introduction Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicity. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) with previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D). Methods We analyzed 209 patients who underwent P/D and adjuvant RT (131 who received CONV and 78 who received IMPRINT) for MPM between 1974 and 2015. The primary end point was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing risks analysis was performed for local failure-free survival and progression-free survival. Univariate analysis and multivariate analysis were performed with relevant clinical and treatment factors. Results The median age was 64 years, and 80% of the patients were male. Patients receiving IMPRINT had significantly higher rates of the epithelial histological type, advanced pathological stage, and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 versus 12.3 months, p = 0.001). Higher Karnofsky performance score, epithelioid histological type, macroscopically complete resection, and use of chemotherapy/IMPRINT were found to be significant factors for longer OS in multivariate analysis. No significant predictive factors were identified for local failure or progression. Grade 2 or higher esophagitis developed in fewer patients after IMPRINT than after CONV (23% versus 47%). Conclusions Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicity in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events.

INTRODUCTION: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. MATERIAL AND METHODS: We used mate-pair (n=22), RNA (n=28) and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. RESULTS: We observed that inter- or intra-chromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient’s circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. DISCUSSION: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.