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Background: For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3., Methods: All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort)., Results: Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained., Conclusion: The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.

Background: The most common sites of malignant mesothelioma are the pleura and peritoneum, but little is known about the incidence, prognosis, or treatment of patients with disease in both cavities. Previous series suggest that multimodality treatment improves overall survival for pleural or peritoneal disease, but studies typically exclude patients with disease in both cavities. Despite limitations, this investigation is the only study to broadly examine outcomes for patients with malignant mesothelioma in both the pleural and peritoneal cavities., Methods: This study retrospectively examined 50 patients with both pleural and peritoneal mesothelioma treated with the intent to prolong survival. The primary end point was overall survival from the initial operative intervention., Results: The median overall survival was 33.9 months from the initial intervention. Female gender and intraperitoneal dwell chemotherapy were independent predictors of overall survival. Within 1 year after the initial diagnosis, second-cavity disease was diagnosed in 52% of the patients. The median time to the second-cavity diagnosis for those with a diagnosis 1 year after the initial diagnosis was 30 months., Conclusions: Well-selected patients with both pleural and peritoneal mesothelioma have a survival benefit over palliative treatment that is comparable with that seen in single-cavity disease. The presence of disease in both cavities is not a contraindication to multimodality treatment aimed at prolonging survival, whether the disease is diagnosed synchronously or metachronously. Patients with an initial diagnosis of single cavity disease are at the highest risk for identification of second-cavity disease within the first year after diagnosis.

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be associated with decreases in quality of life (QOL). Bowel-related QOL (BR-QOL) after CRS-HIPEC has not been previously studied. The objectives of the current study were to examine the effect of different types of bowel resection during CRS-HIPEC on overall QOL and BR-QOL., Methods: A prospective cohort study was performed. QOL data were collected using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR-29 questionnaires at 3, 6, and 12 months after CRS-HIPEC. Patients were divided into groups that underwent no bowel resection, non-low anterior resection (LAR) bowel resection, LAR, and LAR with stoma. Primary outcomes were global QOL and BR-QOL., Results: Overall, 158 patients were included in this study. Bowel resections were performed in 77% of patients, with 31% undergoing LAR. Global QOL was not significantly different between groups. LAR patients (with and without stoma) had significantly worse BR-QOL, embarrassment, and altered body image, with LAR + stoma patients having the largest impairments in these domains. Trends toward higher levels of impotence and anxiety were also seen in LAR patients. Although global QOL improved over time, impairments in BR-QOL and sexual and social function did not significantly improve over time., Conclusions: Although global QOL after CRS-HIPEC was not affected by the type of bowel resection, the use of LAR and ostomies was associated with clinically meaningful and persistent impairments in BR-QOL and related functional domains. Generic QOL questionnaires may not adequately capture these domains; however, targeted questionnaires in these patients may help improve QOL after CRS-HIPEC.

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.

Background and Objectives: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern., Methods: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018., Results: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m 2 BSA n = 36; 175 mg/m 2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m 2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%)., Conclusions: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies., (© 2019 Wiley Periodicals, Inc.)

Background: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. Recently, focus has shifted toward a more aggressive and multimodal treatment approach. This study aimed to assess the patterns of care and survival for MPM patients in the Netherlands on a nationwide basis., Methods: The records of patients with a diagnosis of MPM from 1993 to 2016 were retrieved from the Dutch Cancer Registry. Data regarding diagnosis, staging, treatment, and survival were extracted. Cox regression analyses and Kaplan-Meier survival curves were used to study overall survival., Results: Between 1993 and 2016, MPM was diagnosed for 566 patients. Overall, the prognosis was very poor (24% 1-year survival). The most common morphologic subtype was the epithelioid subtype (88%), followed by the biphasic (8%) and sarcomatoid (4%) subtypes. Surgical treatment has become more common in recent years, which most likely has resulted in improved survival rates. In this study, improved survival was independently associated with hyperthermic intraperitoneal chemotherapy (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.21-0.55) and surgery with adjuvant systemic chemotherapy (HR, 0.33; 95% CI, 0.23-0.48). Nonetheless, most patients (67%) do not receive any form of anti-cancer treatment., Conclusion: This study indicated that MPM still is a rare and fatal disease. The survival rates in the Netherlands have improved slightly in the past decade, most likely due to more aggressive treatment approaches and increased use of surgery. However, most patients still do not receive cancer-directed treatment. To improve MPM management, and ultimately survival, care should be centralized in expert medical centers.

Background: Malignant pleural mesothelioma (MPM) is a rare cancer with poor prognosis. As there is little information on the lived experience of MPM, our aim was to document the experience of MPM patients and their caregivers., Methods: Surveys for MPM patients and caregivers were developed from previous interviews with patients, caregivers, and health professionals, about treatments and decision-making. Participants were recruited from two hospitals, government compensation body, and support groups., Results: Survey responses were received from 78 MPM patients and 106 caregivers from January to September 2014., Patients: 85% male, median age 69 years, median time since diagnosis 15 months. Caregivers: median age 68, 91% female, 90% spouse of MPM patient, 95% bereaved. Most participants felt informed about treatment options but only 69% thought all treatment options were discussed. Chemotherapy was discussed most frequently (92-95%); ~80% had sufficient information for decision-making. Decision regarding chemotherapy was made by patient considering doctor's opinion (24%), doctor and patient equally (18%), and doctor (17%). Participants 'agreed'/'strongly agreed' that they made the right decision about chemotherapy (patients 81%, caregivers 60%), but 5% and 16%, respectively, regretted the decision. Most participants received 'sufficient' support (71%). A quarter reported seeing cancer nurse specialists. Palliative care referral: 31% patients, 85% caregivers. Caregivers would have liked to talk to someone by themselves (41%), more time with doctors (30%), psychological support (29%), and clearer information (31%). Bereaved caregivers requested grief counselling (39%) and post-death consultation with specialists (23-25%)., Conclusions: Satisfaction with treatment was high, but participants identified need for improved communication and quality information, discussion about all treatments, end-of-life assistance, and caregiver support after the patient's death.

Introduction : Malignant pleural mesothelioma (MPM) is a rare neoplasm with asbestos exposure as the dominant etiologic agent. Owing to the long latent period following exposure, MPM is often diagnosed late in life. Despite this, elderly patients are under-represented in clinical trials. To date, data regarding the tolerability and efficacy of anticancer treatments for elderly patients affected by MPM are still lacking. Areas covered : The current state-of-the-art of approved treatments employed in the treatment of MPM elderly patients is reviewed and discussed, with a look to emerging therapies. A structured search of bibliographic databases for peer-reviewed research literature and of main meeting abstracts using a focused review question was undertaken. Expert opinion : Even though the median age of MPM patients enrolled in the most recent experimental trials is increasing, no specific analysis has been reported so far in the elderly. Moreover, no data are available for the 'oldest of the elderly' (>75 years). Treatment of elderly patients with MPM is one of the major challenges to the clinician. There is a clear need of large, well-conducted retrospective studies and above all of prospective investigations in this patient population, both in the first-and in the second-line setting.

Background/aim: We performed multimodality therapy comprising preoperative chemotherapy, extrapleural pneumonectomy (EPP), and radiation therapy for patients with malignant pleural mesothelioma (MPM). Although multimodality therapy resulted in good prognosis, further improvement is required. Therefore, herein, we analysed the prognostic factors using surgical specimens and searched for suitable molecular targets to improve the prognosis after multidisciplinary treatment., Patients and Methods: Forty-six patients with MPM underwent multimodality therapy. Paraffin-embedded surgical samples were used for immunohistochemistry to evaluate the expression of phosphorylated (p-) AKT, extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and S6 ribosomal protein (S6RP)., Results: On univariate and multivariate analyses, significant differences were observed according to the histological type, pathological stage, and p-mTOR expression rate., Conclusion: The prognosis of MPM is affected by p-mTOR expression, suggesting that molecular-targeted treatment might be used during multimodal therapy for MPM., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The Mesothelioma and Radical Surgery Trial (MARS 2) aims to evaluate a surgical procedure by comparing chemotherapy and surgery against chemotherapy alone. The pilot study for MARS 2 evaluated the viability of recruitment. Challenges have been reported in conducting clinical research into thoracic surgical treatments and evidence is required to improve our understanding of patient experiences of trial procedures, trial treatments and the factors that influence participation., Methods: This longitudinal qualitative study was nested within the MARS 2 pilot. Semi-structured telephone interviews were conducted with 15 participants in the MARS 2 trial. Interviews were conducted post-randomisation, post-surgery (surgery arm) and at 6 and 12 months. Altogether, 41 interviews were carried out. The data were analysed using framework techniques., Results: Challenges were identified regarding the volume and complexity of information given to participants, and their understanding of clinical equipoise and randomisation. Factors influencing participation included having an opportunity to undergo surgery, a self-assessment of their ability to cope with trial treatments, maintaining a positive approach and altruism. Obstacles included the logistics of traveling for treatment in an unfamiliar setting. Negative consequences of trial participation included increased uncertainty amplified by multiple care providers and unclear transition arrangements after the trial., Conclusions: Participants' descriptions provided insights that have implications for care for mesothelioma trial patients. The need for healthcare staff to be alert to the potential for misunderstanding, particularly when presenting treatment options, was identified. Patients perceived and derived benefits from taking part in the trial but experienced some negative consequences. These should be anticipated and managed proactively., Trial Registration: ClinicalTrials.gov, NCT02040272 . Registered on 20 January 2014.

The study aim was to report survival and morbidity of all patients in Sweden with peritoneal mesothelioma treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as well as investigate whether the survival has increased on a population level since this treatment was nationalized 2011. Study data were collected from the Swedish HIPEC registry and the Swedish National Cancer Registry. All patients with peritoneal mesothelioma scheduled for CRS/HIPEC treatment in Sweden January 2011 to March 2018 were retrieved from the Swedish HIPEC registry. Clinicopathological and survival data were collected. For population-level analysis, all patients with diffuse malignant peritoneal mesothelioma (DMPM) were identified from the Swedish National Cancer Registry and data were retrieved from two separate 5-year time periods: 1999-2003 and 2011-2015. Thirty-two patients were accepted for CRS/HIPEC. Four were open/close cases. Two-year survival rate was 84% or 59% when excluding borderline peritoneal mesotheliomas (n = 17). Median overall survival was not reached. Grade III-IV Clavien-Dindo events occurred in 22% with no mortality. From the national cancer registry, 102 DMPM cases were retrieved: 40 cases between 1999 and 2003, and 62 cases between 2011 and 2015 (corresponding to an increase from 0.9 to 1.24/million/year, P = .04). Six patients (10%) received CRS/HIPEC in the second period. Median OS increased between periods from 7 to 15 months and 5-year survival from 14% to 29% (P = .03). Peritoneal mesothelioma of both borderline and DMPM subtypes undergoing CRS/HIPEC have good long-term survival. The incidence of DMPM in Sweden has increased. Overall survival has increased alongside the introduction of CRS/HIPEC, which may be a contributing factor., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express mesothelin, a tumor-associated antigen highly expressed in MPM. CRS-207 induces antitumor immune responses and increases susceptibility of neoplastic cells to immune-mediated killing., Patients and Methods: Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase Ib study. They received two priming infusions of 1 × 10 9 CFU CRS-207, followed by pemetrexed/cisplatin chemotherapy, and CRS-207 booster infusions. Primary objectives were safety and induction of immune response. Secondary/exploratory objectives included tumor response, progression-free survival (PFS), overall survival (OS), immune subset analysis, and gene-expression profiling of tumor., Results: Of 35 evaluable patients, 89% (31/35) had disease control with one complete response (3%), 19 partial responses (54%), and 10 stable disease (29%). The estimated median duration of response was 5.0 months (95% CI, 3.9-11.5). The median PFS and OS were 7.5 (95% CI, 7.0-9.9) and 14.7 (95% CI, 11.2-21.9) months, respectively. Tumor size reduction was observed post-CRS-207 infusion prior to chemotherapy in 11 of 35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed. IHC analysis of pre- and post-CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and natural killer cells, increased CD8:T reg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration., Conclusions: Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients., (©2019 American Association for Cancer Research.)

Introduction: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes., Methods: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution., Results: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors., Conclusions: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

Detailed guidelines pertaining to radiological assessment of malignant pleural mesothelioma are currently lacking due to the rarity of the disease, complex morphology, propensity to invade multiple planes simultaneously, and lack of specific recommendations within the radiology community about assessment, reporting, and follow-up. In March 2017, a multidisciplinary meeting of mesothelioma experts was co-sponsored by the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and the Mesothelioma Applied Research Foundation. One of the outcomes of this conference was the foundation of detailed, multidisciplinary consensus imaging and management guidelines. Here, we present the recommendations for radiologic assessment of malignant pleural mesothelioma in the setting of clinical trial enrollment. We discuss optimization of imaging parameters across modalities, standardized reporting, and response assessment within clinical trials., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Rationale: Nonexpandable lung is a recognized phenomenon that can create management challenges in patients with mesothelioma. Its prevalence and clinical importance are unknown. Objectives: The aim of this study was to describe the prevalence of nonexpandable lung and to evaluate whether there was any association between nonexpandable lung and survival in a clinical cohort of patients with mesothelioma. Methods: This was a prospective, observational cohort study of patients with mesothelioma who were seen in a single center between March 1, 2008, and August 3, 2017. Baseline characteristics were collected at diagnosis. Serial chest radiographs were assessed for the presence of pleural effusions and nonexpandable lung (defined as a lack of lung expansion after pleural aspiration or drainage). Patients were followed until they died or were censored on March 14, 2019. Results: Of 229 patients, 192 (82.7%) had a pleural effusion at presentation, and nonexpandable lung was observed in 64 of these 192 patients (33.3%). Breathlessness and cough were more frequent in patients with pleural effusions, especially in those with underlying nonexpandable lung, whereas chest pain was more prevalent in patients without effusions. Patients with pleural effusions, both with and without underlying nonexpandable lung, were more likely to have epithelioid or early-stage disease and to receive chemotherapy than patients with no pleural effusion. Nonexpandable lung was an independent risk factor for short survival, with a hazard ratio for mortality of 1.80 (95% confidence interval, 1.16-2.80) compared with patients without nonexpandable lung. The presence of a pleural effusion did not appear to be associated with a worse prognosis compared with patients with an effusion (adjusted hazard ratio, 1.86; 95% confidence interval, 0.93-3.72). Conclusions: This is the first study to describe the prevalence and clinical implications of nonexpandable lung in mesothelioma. It demonstrates that nonexpandable lung is a relatively common phenomenon that is associated with significant symptomatology and shorter survival. Keywords: mesothelioma; nonexpandable lung; pleural effusion.

The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27-specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.

Aim: This study evaluated the prognostic value of soluble mesothelin-related protein (SMRP) levels in pleural effusions (PE) from patients with pleural mesothelioma (MPM)., Patients and Methods: SMRP level in PE was tested using an enzyme-linked immunosorbent assay (ELISA) in 109 patients with MPM at diagnosis before any treatment. The Kaplan-Meier method and the Cox regression were applied to compare overall survival probabilities across tertile categories of SMRP level., Results: No significant differences in Kaplan-Meier overall survival probabilities among the SMRP categories were found. A statistically non-significant trend for increased death rate ratio (RR) was computed (p=0.327) when the higher (>46.5 nM, RR=1.38) and intermediate (8.5-46.5 nM, RR=1.18) SMRP categories were compared to the lower category (<8.5 nM, RR=1.00). Cox regression modelling including a restricted cubic spline showed a moderately rising non-linear trend in death rate., Conclusion: The SMRP level in PE does not appear to have prognostic significance and its detection is not recommended in routine clinical management of patients with MPM., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Current guidelines support cancer-directed surgery, chemotherapy, or active surveillance for clinical stages 1 to 3 of epithelial malignant pleural mesothelioma (MPM). Definitive chemotherapy is recommended for sarcomatoid/biphasic histologies. Our objective is to assess compliance with recommendations, measuring their impact on overall survival., Methods: The National Cancer Database participant user file (2004 to 2014) was queried for patients diagnosed with MPM clinical stages 1 to 3. Multivariable logistic regression model identified factors independently associated with guideline compliance. Kaplan-Meier analysis and Cox proportional hazards were used for overall survival comparison with histologic subgroup analysis., Results: A total of 3419 patients with clinical stages 1 to 3 met criteria for analysis and comprised epithelial (68.5%), sarcomatoid (17.2%), and biphasic subtypes (14.3%). Cancer-directed surgery was significantly underutilized in epithelial MPM, with 29.3% having no treatment. On multivariable analysis, insurance status and facility type were the strongest predictors of guideline compliance. High-volume hospitals were the most compliant with guidelines (odds ratio 3.58, 95% confidence interval (CI), 2.34 to 5.49, P < .001). Median survival estimates for no treatment, chemotherapy alone, surgery plus chemotherapy, and trimodal therapy were 10.2, 15.4, 21.1, and 21.7 months, respectively (log rank P < .001). In epithelial MPM, a significant increase in overall survival was observed in surgery plus chemotherapy (hazard ratio 0.62, 95% CI, 0.53 to 0.73, P < .001) and trimodality (hazard ratio 0.61, 95% CI, 0.49 to 0.76, P < .001; reference: no treatment)., Conclusions: There is a suboptimal compliance with national guidelines for the treatment of MPM, particularly in low-volume nonacademic settings. Adherence to recommended surgery-based multimodal therapy is associated with an overall survival improvement., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Trimodality therapy may prolong survival for patients with resectable malignant pleural mesothelioma. However, many patients are unable to complete therapy. We sought to identify risk factors for failing to complete adjuvant intensity-modulated radiation therapy after cytoreduction for malignant pleural mesothelioma., Methods: We performed a single-institution review of those who received an extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma from 2004 to 2017. Multivariable logistic regression was used to assess preoperative or intraoperative risk factors associated with failing to complete adjuvant intensity-modulated radiation therapy., Results: A total of 160 patients were identified, among whom 94 (59%) received an extrapleural pneumonectomy and 66 (41%) received a pleurectomy/decortication. Adjuvant intensity-modulated radiation therapy was completed among 105 patients (66%). Reasons for failing to complete adjuvant intensity-modulated radiation therapy included mortality (19), dose constraints (21), postoperative morbidity or delayed recovery (11), and refused or unknown status (4). On multivariable analysis, American Society of Anesthesiologists 3+ classification (P = .002) and smoking history (P = .022) were associated with failure to complete adjuvant intensity-modulated radiation therapy, whereas forced expiratory volume in 1 second 70% or less of predicted and pStage 4 (T4) were significant on univariable analysis only. Other factors, including extrapleural pneumonectomy or pleurectomy/decortication, margin status, age, and histology, were not associated with receiving adjuvant intensity-modulated radiation therapy., Conclusions: Many patients are unable to complete adjuvant intensity-modulated radiation therapy after cytoreduction. Failure to complete adjuvant intensity-modulated radiation therapy was associated with worse preoperative comorbidity, but not the type of surgery or margin status., (Copyright © 2019. Published by Elsevier Inc.)

Background: Malignant pleural mesothelioma (MPM) has a poor prognosis and heavy symptom burden. Here, we investigate health professionals' attitudes to management and decision-making in people with MPM., Methods: Survey questions were based on previous interviews with health professionals, MPM patients, and caregivers. Surveys were sent to specialist doctors and nurses who treat MPM., Results: Surveys were completed by 107 doctors and 19 nurses from January-September 2014. Most doctors were respiratory physicians (50%) or medical oncologists (35%). Overall, 90% of doctors estimated > 10% of eligible MPM patients did not receive chemotherapy; 43% estimated the rate was > 20%. Doctors believed clinical barriers to chemotherapy were clinician nihilism (70%); non-referral to medical oncology (49%); and lack of specialists in rural/regional areas (44%). Nurses perceived barriers as follows: delayed diagnosis (74%); non-referral to medical oncology (63%); lack of clinician knowledge (58%). Patient-related barriers were negative perception of chemotherapy (83%) and belief survival benefit not worthwhile (63%). Doctors' preference in decision-making was for the patient to make the decision while strongly considering the doctor's opinion (33%); equally with the doctor (29%); and using knowledge gained (23%). Nurses described their roles as providing patient support (100%); information (95%); intermediary (74%); and link to palliative care (74%). Overall, 95% believed they enabled better resource allocation and provided patients with holistic care (95%); clearer communication (89%); more time (89%); additional information (89%); timely referrals (89%)., Conclusions: Caring for patients with MPM is challenging and complex. Health care professionals believe under-utilisation of chemotherapy is occurring, primarily due to clinician nihilism and lack of medical oncology referral.

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleura of the thoracic cavity, followed by the peritoneum, pericardium, or tinea vaginalis testis. Malignant peritoneal mesothelioma (MPM) accounts for 10-15% of all mesotheliomas. The most significant risk factor for MPM is exposure to asbestos. There is no specific symptomatology, and imaging (computed tomography) and histopathology are crucial for diagnosis. There are no generally accepted guidelines for radical treatment of MPM. Previously, the prognosis of MPM patients was poor, with survival of up to 1 year. However, median survival of patients who are suitable candidates for radical therapy is currently 3-5 years. A combination of cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) is recommended in selected patients, while chemotherapy alone has insufficient efficacy. Systemic chemotherapy remains the only treatment option for patients who are unsuitable for CRS and HIPEC. In selected patients scheduled for or currently undergoing CRS and HIPEC, surgery may be performed in combination with systemic chemotherapy in the neoadjuvant or adjuvant setting; however, the benefit is unclear. There are no recommendations for follow-up of MPM patients after radical surgery. Existing guidelines for the pleural form (e.g., those issued by the European Society for Medical Oncology) do not specify the frequency or method of investigation. In the absence of specific serum markers, only CA 125 and mesothelin are generally available. Imaging methods include ultrasonography, computed tomography, and magnetic resonance imaging.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment., (© 2019 American Cancer Society.)

Background and Objectives: To review long-term survival outcomes of patients with Peritoneal metastasis (PM) who underwent colorectal cancer (CRS) and intraperitoneal chemotherapy (PIC)., Methods: Patients that underwent CRS, with or without PIC, from January 1996 to March 2018 at the Peritonectomy Unit of St. George Hospital, Sydney were retrospectively analyzed from a prospectively maintained database., Results: The study comprised of 1225 cases, including 687 females (56.1%) and 538 males (43.9%). Diagnoses included CRC (n = 363), followed by HAMN (n = 317), LAMN (n = 297), mesothelioma (n = 101), ovarian cancer (n = 55), and others including gastric, sarcoma, and neuroendocrine tumor (n = 92). The median OS, 5- and 10-year survivals for CRC were 35 months, 33% and 8%, respectively. Patients with LAMN, in relative to HAMN, experienced a higher median OS, 5- and 10-year survivals (248 months vs 63 months; 82% vs 52% and 59% vs 28%). The median OS for mesothelioma was 60 months with 5- and 10-year survivals of 48% and 19%, respectively. In ovarian cancer, the median OS was 30 months with 5- and 10-year survivals of 26% and 10%, respectively. For the remaining histological diagnoses, median OS and 5-year survival were 28 months and 27%, respectively., Conclusion: Our large-cohort data showed that CRS/PIC can provide long-term survival benefit to patients with PM of gastrointestinal and ovarian origin., (© 2019 Wiley Periodicals, Inc.)

In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination with ICP blocking antibodies. Cisplatin, oxaliplatin and pemetrexed are interesting chemotherapeutic agents to combine with immunotherapy given their immunomodulatory capacities. We looked into cisplatin and pemetrexed because their combination is used as first-line treatment of MPM. Additionally, the effect of the immunogenic chemotherapeutic agent, oxaliplatin, was also studied. Three different MPM cell lines were used for representation of both epithelioid and sarcomatoid subtypes. The desired inhibitory concentrations of the chemotherapeutic agents were determined with the SRB-assay. Allogeneic co-cultures of MPM cells with healthy donor peripheral blood mononuclear cells (PBMC) were set up to assess the effect of these chemotherapeutic agents on the expression of ICPs (PD-1, LAG-3, TIM-3) and their ligands (PD-L1, PD-L2, galectin-9). Cisplatin might be a promising treatment to combine with ICP blocking antibodies since our MPM cell lines were most susceptible to this stand-alone treatment. We found that the expression of ICPs and their ligands on both MPM cells and PBMC was mostly downregulated or unaltered when treated with chemotherapeutic agents, though no clear trend could be determined., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

Background: Clinical audit may improve practice in cancer service provision. The UK National Lung Cancer Audit (NLCA) collects data for all new cases of thoracic cancers., Aim: To collect similar data for our Victorian patients from six hospitals within the Victorian Comprehensive Cancer Centre and associated Western and Central Melbourne Integrated Cancer Service., Methods: We conducted a retrospective audit of all newly diagnosed patients with lung cancer and mesothelioma in 2013 across the six Victorian Comprehensive Cancer Centre/Western and Central Melbourne Integrated Cancer Service hospitals. The objectives were to adapt the NLCA data set for use in the Australian context, to analyse the findings using descriptive statistics and to determine feasibility of implementing a routine, ongoing audit similar to that in the UK. Individual data items were adapted from the NLCA by an expert steering committee. Data were collated from the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited for missing data., Results: Eight hundred and forty-five patients were diagnosed across the sites in 2013. Most were aged 65-80 (55%) and were male (62%). Most had non-small-cell lung cancer (81%) with 9% diagnosed with small cell lung cancer and 2% with mesothelioma. Data completeness varied significantly between fields. For those with higher levels of completeness, headline indicators of clinical care were comparable with NLCA data. The Victorian population seem to lack access to specialist lung cancer nurse services., Conclusion: Lung cancer care at participating hospitals appeared to be comparable with the UK in 2013. In future, prospective data collection should be harmonised across sites and correlated with survival outcomes. One area of concern was a lack of documented access to specialist nursing services., (© 2018 Royal Australasian College of Physicians.)

Background: The median age at diagnosis for malignant pleural mesothelioma (MPM) is approximately 72 years. Elderly patients pose unique management challenges because of the increased risk of therapy-related toxicities and mortality. Because there are no high-volume retrospective studies, prospective trials, or dedicated treatment recommendations for this population, this investigation addresses a major knowledge gap by examining national practice patterns and postoperative/survival outcomes in elderly MPM patients., Methods: The National Cancer Database was queried for patients aged ≥ 80 years with newly diagnosed nonmetastatic MPM. Multivariable logistic regression ascertained factors associated with observation and surgery. Kaplan-Meier analysis assessed overall survival (OS), and multivariable Cox proportional hazards modeling examined factors associated with OS. Survival was also calculated following propensity matching. Additionally, postoperative outcomes were evaluated in surgical patients., Results: Of 4526 patients, 2% received surgery and chemotherapy, 22% underwent chemotherapy alone, and 63% were observed. Respective median OS was 12.2, 9.5, and 4.1 months (p < 0.001). Differences between all groups persisted following propensity matching (all comparisons p < 0.05). For the 8% of patients who underwent specified definitive surgery (95% of whom received pleurectomy/decortication), 30- and 90-day mortality rates were 11.0% and 28.5%, respectively. The median length of postoperative hospitalization was 6 days, with 30-day readmission occurring in 7.5% of patients., Conclusions: The majority of elderly MPM patients in the US are observed, which was associated with poorer OS than chemotherapy and/or surgery. Although highly selected surgery/chemotherapy patients were associated with the longest OS, given the high biases in database studies and high perioperative mortality rates, careful patient selection for combined modality approaches in this population is imperative.

Background: Multimodality therapy with preoperative radiation (RT) followed by extrapleural pneumonectomy (EP) for patients with operable malignant pleural mesothelioma (MPM) has demonstrated encouraging results. At relapse, there are few data on the tolerance and efficacy of systemic therapies after prior multimodality therapy., Materials and Methods: We conducted a retrospective analysis of patients with relapsed MPM after RT and EPP ± adjuvant chemotherapy to determine overall survival (OS; date of relapse to death) and the proportion of patients that received systemic therapy and associated response rate (RR). OS was estimated using Kaplan-Meier method and potential prognostic variables were examined., Results: Fifty-three patients were included (2008-2016). Median OS was 4.8 months (median follow-up 4.4 months, range 0.03-34.8). Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, disease-free interval (DFI) <1 year, and hemoglobin ≤110 g/L at recurrence were associated with worse prognosis. Thirty-six percent of patients received any systemic therapy, whereas it was omitted in 62% because of poor PS. RR was 15% (0 complete responses, 15% partial responses) in 13 individuals with response-evaluable disease. Therapy was discontinued because of toxicity (6/15) or disease progression (5/15), and median number of cycles was four., Conclusion: Patients with relapsed MPM following RT and EPP, especially those with ECOG PS ≥2, DFI <1 year, and hemoglobin ≤110 g/L at recurrence, have poor prognosis and low RR to first-line systemic therapy. Earlier detection and novel diagnostic markers of relapse as well as potential neoadjuvant or adjuvant systemic therapy should be investigated in future studies., Implications for Practice: The results of this study have reinforced the importance of careful selection of appropriate candidates for this combined-modality approach and favor prompt detection of recurrence with early and regular postoperative imaging and biopsy of suspected relapsed disease along with rapid initiation of systemic therapy even in patients with very low burden of disease. Furthermore, with the emergence of new systemic agents targeting different histological subtypes of malignant pleural mesothelioma, histological sampling of recurrence could inform therapeutic decisions in the future., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Objective: Malignant pleural mesothelioma (MPM) is a cancer that primarily affects older adults. However this patient population is frequently under-represented in clinical studies. Therefore, we studied the impact of advancing age on treatment utilisation and clinical outcomes in an extensive series of minimally selected MPM patients., Materials and Methods: Patients with MPM receiving compensation from the New South Wales (NSW) Dust Diseases Authority (2002-2009) were assessed. They were categorised by age (<70 years, 70-80 years or > 80 years) and chi-square testing was used to assess the relationship between clinical and demographic variables, age, treatment and overall survival (OS)., Results: We identified 910 patients; 41% were aged <70 years, 40% were aged 70-80 years, and 19% were aged >80 years old. Median OS decreased with increasing age: 13.5 months in <70 years, 9.5 months in 70-80 years and 7.1 months in >80 years as did chemotherapy use (66%, 35% and 8% respectively). Radical surgical intervention, adjuvant, and palliative radiotherapy were less frequently used with advanced age. A Kaplan Meier analysis revealed that there was a significant survival advantage (p < .001) for patients <70 and 70-80 years receiving chemotherapy (16.8 vs 7.0 months; 13.9 vs 5.8 months respectively), but not for patients >80 years., Conclusion: Advancing age group of NSW patients with MPM was associated with reduced treatment utilisation and a decline in OS. Prospective studies are warranted to verify if current treatment guidelines are relevant for the older adults with MPM., (Copyright © 2019. Published by Elsevier Ltd.)

Malignant pleural mesothelioma (MPM) is a rare disease with a very poor prognosis. Previous studies have indicated that women experience longer survival compared with men. We analyzed 16 267 eligible patients (21.3% females) in the National Cancer Database to evaluate which clinical factors are independently predictive of longer survival. After adjusting for all covariates, survival was significantly better in females compared with males [HRadj: 0.81, 95% confidence interval (CI): 0.77-0.85]. Other factors significantly associated with better survival were younger age at diagnosis, higher income, lower comorbidity score, epithelial histology, earlier stage and receipt of surgical or medical treatment. After propensity matching, survival was significantly better for females compared with males [hazard ratio (HR): 0.86, 95% CI: 0.80-0.94]. After propensity matching within the epithelial group, survival remained significantly better for females compared with males (HR: 0.85, 95% CI: 0.74-0.97). This study adds information to the known significant gender survival difference in MPM by disentangling the effect of gender from the effect of age and histology, two known independent factors affecting survival. Circulating estrogen, present in young but not older women, and higher expression of the estrogen receptor beta in epithelial mesothelioma have been suggested to play a role in gender survival differences. These findings may lead to exploring new therapeutic options, such as targeting estrogen receptor beta, and considering hormonal therapy including estrogens for patients with otherwise limited prognosis., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction : Trimodality therapy (including surgery, chemotherapy and radiation therapy) represents an important management approach of early-stage malignant pleural mesothelioma (MPM). The oncological value, as well as the proper sequence of the three modalities, is still under investigations. Areas Covered : The article covers the timing of chemotherapy in the management plan with either a neoadjuvant approach or adjuvant approach. It evaluates also how to select patients for induction chemotherapy and how to assess the response to treatment. Expert Opinion : Management of patients with early-stage MPM must be completed in a multidisciplinary team in tertiary centers. Availability of newer prognostic and response assessment tools should facilitate the use of induction chemotherapy as well as the selection of patients who might benefit from radical surgery.

Malignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) represents a treatment option for peritoneal surface malignancies. Even if it has been reported that this new approach improved survival of selected patients, it is still associated with high morbidity and mortality rates., Methods: From October 1995 to December 2017, over 450 patients affected by peritoneal carcinomatosis (PC) underwent in our Institute CRS associated with HIPEC. For this preliminary analysis we considered 300 patients presenting PC of different origin: pseudomyxoma peritonei (PMP, N.=98), epithelial ovarian cancer (EOC, N.=87), peritoneal mesothelioma (DMPM, N.=49) and colorectal cancer (CRC, N.=66). Postoperative morbidity and mortality were studied in order to identify possible risk factors., Results: The morbidity rate was 36.3% in all procedures (109/300). According to the Clavien-Dindo Classification, 67 cases (22.3%) were associated with grade I-II complications and 35 cases (11.7%) with grade III-IV. Surgical and medical complication rates were 8.3% (25/300) and 11.3% (34/300), respectively. The mortality rate was 2.3%. Reoperation was needed in 28 patients (9.3%). The operative time, the number of anastomosis, of peritonectomy procedures, of visceral resections performed and the PCI value resulted the most statistically significant factors influencing postoperative morbidity and mortality., Conclusions: The risks of perioperative morbidity and mortality after CRS and HIPEC are analogous to any other major gastrointestinal surgery. CRS and HIPEC should remain a treatment option for highly-selected patients in whom a curative or life prolonging treatment is a pursuit and should be performed in high volume specialized institutions.

Introduction: Malignant peritoneal mesothelioma (MPM) is an uncommon but aggressive neoplasm and has a strong association with asbestos exposure. MPM has low survival rates of approximately 1 year even after (palliative) surgery and/or systemic chemotherapy. Recent advances in treatment strategies focusing on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have resulted in improved median survival of 53 months and a 5 year survival of 47%. However, recurrence rates are high. Current systemic chemotherapy in the adjuvant setting is of limited efficacy, while immunotherapy with dendritic cell based immunotherapy (DCBI) has yielded promising results in murine models with peritoneal mesothelioma and in patients with pleural mesothelioma., Methods and Analysis: The MESOPEC trial is an open-label single centre phase II study. The study population are adult patients with histological/cytological confirmed diagnosis of epithelioid malignant peritoneal mesothelioma., Intervention: 4 to 6 weeks before CRS-HIPEC a leukapheresis is performed of which the monocytes are used for differentiation to dendritic cells (DCs). Autologous DCs pulsed with allogeneic tumour associated antigens (MesoPher) are re-injected 8 to 10 weeks after surgery, three times biweekly. Additional booster vaccinations are given at 3 and 6 months.Primary objective is to determine the feasibility of administering DCBI after CRS-HIPEC in patients with malignant peritoneal mesothelioma. Secondary objectives are to assess safety of DCBI in patients with peritoneal mesothelioma and determine whether a specific immunological response against the tumour occurs as a result of this adjuvant immunotherapy., Ethics and Dissemination: Permission to carry out this study protocol has been granted by the Central Committee on Research Involving Human Subjects (CCMO in Dutch) and the Research Ethics Committee (METC in Dutch). The results of this trial will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NTR7060. EudraCT: 2017-000897-12; Pre-Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Combined modality treatment (CMT) for malignant pleural mesothelioma (MPM) remains a matter of debate regarding the choice of surgical procedure: extrapleural pneumonectomy (EPP) or pleurectomy/decortication., Methods: We performed a prospective interventional cohort study between 2003 and 2014. All consecutive patients with any histological MPM subtype, ≤70 years old, World Health Organization performance status ≤1, medically fit for pneumonectomy and stage cT1-2cN0-2cM0 (TNM7) or lower were included. Eligibility for CMT was discussed by the multidisciplinary tumour board. Our local CMT protocol consisted of induction chemotherapy, followed by EPP and hemithoracic radiotherapy. Induction chemotherapy consisted of 3 cycles of cisplatin (75 mg/m2 day 1) and pemetrexed (500 mg/m2 day 1), each administered once every 3 weeks. If non-progressive, EPP was performed followed by hemithoracic radiotherapy (most frequently, intensity-modulated radiotherapy; dose 54 Gy/1.8 Gy ± boost). Feasibility and long-term survival analyses were performed. Overall survival and disease-free survival (DFS) were calculated from histological confirmation of a diagnosis of MPM., Results: Out of 197 patients, 97 started with CMT (79 epithelioid, 15 mixed and 3 sarcomatoid tumours, based on histological analysis). Clinical TNM was IA (n = 9)/IB (n = 8)/II (n = 57)/III (n = 23). A total of 76 patients underwent surgery (EPP: n = 56; exploratory thoracotomy: n = 20). The in-hospital mortality rate was 3.6%. Out of 56 patients who underwent surgery, 47 completed the entire CMT protocol. The intent-to-treat median and 5-year OS were 22.4 [95% confidence interval (CI) = 15.5-27.9] months and 11.2% (95% CI = 6.9-23.4). In patients who completed the CMT protocol (n = 47), these values were 33.2 (95% CI = 23.0-45.0) months and 24.2% (95% CI = 13.4-43.8). The intent-to-treat median and 5-year DFS were 15.6 (95% CI = 14.0-17.3) months and 9.9% (95% CI = 5.1-19.2), 19.8 (95% CI = 16.8-27.7) months and 17.2% (95% CI = 8.6-34.1) in those who had the full CMT. The Cox proportional hazards model showed a significantly lower DFS in positive lymph nodes (HR 2.79, 95% CI=1.35-5.78; P=0.006). In 30 (64%) patients with epithelioid type MPM without positive lymph nodes (pN0) after EPP, the 5-year DFS was 27.0% (95% CI=14.1-51.7)., Conclusions: CMT with EPP for MPM is feasible, with an acceptable surgical mortality rate, and results in a 5-year survival rate of 24%. Careful patient selection (staging and physical performance) is extremely important., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Malignant pleural mesothelioma and malignant pleural effusions are a major therapeutic challenge, and are associated with impairment in quality of life and increased mortality. Advances in systemic therapies of malignant pleural mesothelioma have demonstrated limited clinical benefit and there is ongoing interest in intrapleural immunotherapies which have been demonstrated to be well tolerated overall with variable clinical responses. We have reviewed the literature to provide a comprehensive summary of novel intrapleural immunotherapeutic paradigms, including oncolytic virus therapy, gene-mediated cytotoxic immunotherapy, direct cytokine-mediated immunotherapies, innate immunomodulators and adoptive transfer of intrapleural chimeric antigen receptor T-cell therapy., Data Sources: A review of PubMed for original manuscripts and conference reports published between 1998 and 2018 pertaining to intrapleural immunotherapy, as well as examination of reference lists from reviewed manuscripts., Study Selection: Human clinical trials on intrapleural immunotherapies in subjects with malignant pleural mesothelioma or malignant pleural effusion were included in this review, including some relevant preclinical studies and anticipated ongoing trials reported on Clinicaltrials.gov., Results: Twenty-six clinical trials were identified, in addition to three trials currently in progress., Conclusion: Intrapleural immunotherapies for pleural malignancy have demonstrated promise with regard to generating durable tumor-specific immune responses with possible clinical benefits which merit further investigation as part of multimodal chemotherapeutic and immunotherapeutic regimens., (© 2019 John Wiley & Sons Ltd.)

Objectives: To assess the impact of short and long term outcomes of diaphragmatic interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC)., Methods: 1230 consecutive CRS/IPC procedures were preformed between 1996 and 2018 in Sydney, Australia. Redo procedures and incomplete cyto-reductions were excluded. Among these, 599 underwent diaphragmatic intervention. Preoperative heterogeneity was assessed for in 6 parameters and addressed with propensity score matching. CRS/IPC requiring diaphragmatic interventions were compared to CRS/IPC without diaphragmatic involvement. Ten perioperative outcomes were measured. Overall survival was assessed based on diagnosis type., Results: Intraoperative results revealed a significant increase in operative hours (7.85 vs. 7.28, p = 0.033). Transfusion requirements were insignificantly different. Postoperatively, increased grade III and IV complications (36% vs. 26%, p = 0.052) were noted. There was no difference with regards to intensive care stay, hospital length of stay, hospital death and return to theatre. In terms of respiratory specific complications, an increased incidence of pneumothorax (13% vs. 3%, p = 0.001) and pleural effusions (24% vs. 16%, p = 0.043) were noted, whilst the differences in pneumonia were insignificant. Overall survival revealed diaphragm interventions; did not affect survival outcomes in colorectal cancers (p = 0.750, RR = 1.077, CI 0.683-1.697) and increased relative risk in low-grade appendiceal mucinous neoplasms (p = 0.025, RR = 2.437, CI 1.121-5.298)., Conclusion: After our three-tiered research strategy, we conclude that despite the marginal increase in short term morbidity; diaphragmatic interventions do not decrease survival in colorectal cancers and diaphragmatic disease in LAMNs maybe an independent prognosticator of disease aggression., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Objectives: To characterize demographic features, clinical characteristics, and oncologic outcomes of mesothelioma of the testis., Methods: A population based search was performed using the National Cancer Institute's SEER 18 database. Patients diagnosed with malignant mesothelioma of the male genital organs from 1973 to 2015 were identified. Data on patient age, race, tumor laterality, histologic subtype, tumor extent, tumor size, tumor grade, treatment, cause of death, and survival months was collected. Primary outcomes were overall survival (OS) and disease-specific survival (DSS)., Results: A total of 113 patients with testicular mesothelioma were identified. The 5-year OS and DSS for all patients was 49% and 58%, and the 10-year OS and DSS was 33% and 45%, respectively. Biphasic mesotheliomas were associated with worse OS compared to general mesotheliomas and epithelioid subtypes (P = .043 and P = .039, respectively). Median survival time was not reached in patients with T1 disease while OS was 1.7 years and DSS was 1.8 years for patients with T4 disease (OS P = .002, DSS P <.001). Tumors greater than or equal to 4 cm were associated with worse OS and DSS (OS P = .025, DSS P = .047)., Conclusion: This rare malignancy has significant mortality, with poor survival associated with biphasic subtypes, higher disease stage, and a critical tumor size cutoff of 4 cm., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignant Mesothelioma is an uncommon tumor that usually presents with diffuse pleural involvement and carries a dismal prognosis. Rarely, however, it can present as a localized, circumscribed mass or focal pleural lesion without evidence of diffuse spread. We found four such cases in our database. Three patients had localized epithelioid malignant mesothelioma and one had localized sarcomatoid mesothelioma. These localized tumors are a potential diagnostic pitfall for the pathologists as well as radiologists, especially those practicing in a community setting. Herein we discuss the clinicopathologic features of our cases along with a review of literature., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Well differentiated papillary peritoneal mesothelioma (WDPPM) is a rare variant of mesothelioma which affects mainly women in the reproductive age. The disease may present multifocally and recur after primary resection. Our aim was to describe the outcomes of cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this disease., Methods: Patients with histological diagnosis of WDPPM were retrieved from the PSOGI registry. Demographical and clinical data were extracted as well as outcomes data (overall survival (OS) and recurrence free survival (RFS))., Results: We analyzed 45 patients for whom complete data was available. The majority of patients were women (n = 33, 73%) with a median age of 44 years. Preoperative chemotherapy (CT) was administered in 8 patients (18%). Median peritoneal carcinomatosis index was 9 (1-30), and complete cytoreduction was achieved in 69% of patients. There was one case (2%) of postoperative mortality, and 24% rate of severe morbidity. Overall, there were 4 deaths and 5 years OS was 80%. 8 patients (18%) had disease recurrence, all within 5 years from operation. On univariate analysis preoperative CT, high PCI and severe morbidity were associated with reduced RFS. On multivariate analysis, only preoperative CT (HR = 32.6, 95% CI: 2.39-446.2, p = 0.009) and high PCI (HR = 21.7, 95% CI: 1.11-425.7, p = 0.04) remained significant risk factors., Conclusions: WDPPM can be a lethal disease with substantial recurrence even after aggressive treatment. Patients presenting with extensive disease or disease recurrence after surgical excision are at increased risk for relapse. CRS + HIPEC can be safely applied to WDPPM in specialized centers., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature., Objective: We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry., Patients and Methods: All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed., Results: We report on 56 patients with a mean age of 52 years (range 21-74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0-33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified., Conclusions: Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

Background: Biphasic pleural mesothelioma (BPM) accounts for approximately 10% of all pleural mesothelioma. Our aim was to assess the clinical, radiologic, and pathologic factors impacting survival in BPM and to better identify patients most likely to benefit from active treatment., Methods: A 10-year retrospective review was made of 214 biopsy-proven BPM cases with minimum 2-year follow-up. Patients with insufficient tissue for analysis were excluded (n = 96). Clinical and pathologic factors were evaluated along with radiologic assessment of pleural thickness. Survival was measured from time of diagnosis. Univariable and multivariable predictors of survival were evaluated., Results: In all, 118 patients were included; 28 underwent pleurectomy/decortication, with 27 receiving additional modalities. Ninety patients underwent chemotherapy (n = 18) or radiotherapy alone (n = 9), 63 received combination therapy, and 27 received best supportive care. Median overall survival was 11.2 months (range, 0.3 to 36.2). At univariable analysis, pleurectomy/decortication (p = 0.0061), radiotherapy (p < 0.0001), and chemotherapy (p < 0.0001) were associated with superior survival when compared with best supportive care alone. Pleurectomy/decortication demonstrated 40% survival improvement compared with no surgery (p = 0.122). In a multivariable model, necrosis was negatively prognostic (hazard ratio 2.1, SE 0.76). Furthermore, increased sarcomatoid component was associated with worse survival without radiotherapy., Conclusions: BPM prognosis remains poor despite multimodality treatment. Anticancer treatment is associated with superior outcome in this nonrandomized retrospective series. Our findings suggest superior survival for patients with a lower proportion of sarcomatoid disease, with selective benefit of radiotherapy in higher proportions of sarcomatoid disease. When planning active treatment, the potential survival benefits require balancing against associated morbidity and recovery period., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis., Methods: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation., Results: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies., Conclusions: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Opinion Statement: Recent advances in immunology have extended into the mesothelioma field. To date, only Japan has given regulatory approval to salvage nivolumab in chemo-refractory mesothelioma patients. The USA has included in the NCCN guidelines that pembrolizumab (in programmed death ligand 1 (PD-L1) immunohistochemistry (IHC)-positive patients) and nivolumab with or without ipilimumab (whatever the PD-L1 status is) are accepted salvage therapies. Based on the growing body of literature, it is anticipated that checkpoint inhibitors will receive regulatory approval in the USA and Europe soon for salvage therapy. Additional research efforts will determine whether earlier stage patients and frontline unresectable patients will benefit from the addition of immunotherapy to their treatment regimens. The realm of biomarker research has lagged behind in mesothelioma. In general, mesothelioma has less tumor mutation burden than other malignancies. Most of the single-agent salvage checkpoint inhibitor trials have shown a trend correlating higher PD-L1 immunohistochemistry (IHC) with responses. However, survival data remains immature and a larger number of patient outcomes are needed to ascertain the value of PD-L1 IHC as a predictive biomarker. Incorporation of translational studies in all immunotherapy trials and especially window-of-opportunity resectable studies should be supported and instituted in all future mesothelioma trials.

Objectives: There are 2 main treatment paradigms recognized by the National Comprehensive Cancer Network for resectable malignant pleural mesothelioma (MPM): induction chemotherapy followed by resection (IC/R), and up-front resection with postoperative chemotherapy (R/PC). These paradigms are being compared in an accruing randomized phase II trial. In the absence of such completed trials, in this study we evaluated overall survival (OS) and postoperative outcomes of IC/R and R/PC., Methods: The National Cancer Database was queried for newly diagnosed epithelioid/biphasic MPM. Metastatic, node-positive, and/or cT4 disease was excluded, along with nondefinitive surgery and lack of chemotherapy. Multivariable logistic regression ascertained factors independently associated with induction chemotherapy delivery. Kaplan-Meier analysis was used to evaluate OS between cohorts; multivariable Cox proportional hazards modeling was used to assess factors associated with OS. Survival was also evaluated between propensity-matched populations. Last, postoperative outcomes were assessed between groups., Results: Overall, 361 patients (182 IC/R, 179 R/PC) were analyzed. Temporal trends revealed that IC/R is decreasing over time. Survival of the IC/R cohort was similar to that of R/PC patients (20.9 vs 21.7 months; P = .500); this persisted after propensity matching (20.8 vs 22.0 months; P = .270). However, patients who underwent IC/R experienced longer postoperative hospitalization (median 7 days vs 6 days; P = .001) and higher 30-day mortality (3.3% vs 0%; P = .020)., Conclusions: To our knowledge, this is the only comparative investigation of the 2 major management paradigms of operable MPM. IC/R regimens are decreasing over time in the United States. Although associated with survival similar to R/PC, IC/R might be associated with worse postoperative outcomes. Careful induction chemotherapy patient selection is thus highly recommended., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Malignant mesothelioma is a rare tumour, usually the result of asbestos exposure. Several cases of familial aggregation have been reported and recently shown to be associated with constitutional mutations of the BAP1 gene. BAP1 is a deubiquitinating enzyme implicated in several different cellular mechanisms such as the repair or differentiation of DNA. About a half of malignant mesotheliomas present a somatic, bi-allelic inactivation of BAP1, demonstrated by nuclear extinction on histochemistry. Constitutional alterations of BAP1 are extremely rare. Present in the heterozygous state they are transmitted as an autosomal dominant. They are associated with a risk of developing other tumours such as uveal and cutaneous melanomas, benign melanocytic tumours (melanocytic BAP1-mutated atypical intradermal tumour or MBAITS) and clear cell renal carcinomas. The causal link between mesothelioma and germinal mutations of BAP1 has still not been clearly identified. At present there is, in France, no consensus on recommendations for the management of patients with these mutations. This article is a synthesis of the literature on the functions of the BAP1 gene, the tumour risks related to its alteration and the follow up of patients bearing a constitutional mutation., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background and Objectives: The current standard of treatment for malignant peritoneal mesothelioma(MPM)is cytoreductive surgery(CRS)plus perioperative intraperitoneal or systemic chemotherapy(comprehensive treatment), The present study was performed to clarify the prognostic factors of PMP after comprehensive treatment., Methods: Among 63 patients with MPM, male and female patients were 34 and 29. CRSwas performed in 47 patients and complete cytoreduction(CC-0) was performed in 14(22%)patients. Mean numbers of resected peritoneal sectors and organs were 5.2(1-13), and 2.9(0- 9), respectively. Hyperthermic intraperitoneal chemoperfusion(HIPEC)was performed in 27 patients. Grade 1/2, Grade 3, and Grade 4 complications were experienced in 5, 6, and 3 patients, respectively. One patient died of sepsis, and the mortality rate was 2.3%. Independent prognostic factors for favorable prognosis were performance of HIPEC, peritoneal cancer index (PCI)score C12, no distant metastasis and histologic epithelial type. Relative risk of no HIPEC, PCI score B13, presence of distant metastasis and non epithelial type were 7.69, 22.1, 3.6 and 3.9, respectively., Conclusions: Risk factors for death after comprehensive treatment were no HIPEC, PCI score B13, and non epithelial type. However, only 11(17%)patients showed PCI score C12. Accordingly, PCI score should be reducedC12 before CRSby neoadjuvant chemotherapy.