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Peritoneal mesothelioma (PeM) is an aggressive tumor with limited treatment options. The current study aimed to evaluate the value of next generation sequencing (NGS) of PeM samples in current practice. Foundation Medicine F1CDx NGS was performed on 20 tumor samples. This platform assesses 360 commonly somatically mutated genes in solid tumors and provides a genomic signature. Based on the detected mutations, potentially effective targeted therapies were identified. NGS was successful in 19 cases. Tumor mutational burden (TMB) was low in 10 cases, and 11 cases were microsatellite stable. In the other cases, TMB and microsatellite status could not be determined. BRCA1 associated protein 1 (BAP1) mutations were found in 32% of cases, cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2) mutations in 16%, and ataxia-telangiectasia mutated serine/threonine kinase (ATM) in 11%. Based on mutations in the latter two genes, potential targeted therapies are available for approximately a quarter of cases (i.e., protein kinase inhibitors for three NF2 mutated tumors, and polyADP-ribose polymerase inhibitors for two ATM mutated tumors). Extensive NGS analysis of PeM samples resulted in the identification of potentially effective targeted therapies for about one in four patients. Although these therapies are currently not available for patients with PeM, ongoing developments might result in new treatment options in the future.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC. METHODS: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment. RESULTS: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation. CONCLUSIONS: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells wa

Background: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. An earlier population-based study found that the majority of Dutch patients do not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in two expert centers. We reviewed treatment patterns at these centers, to assess the impact of centralization of MPM care in the Netherlands. Methods: Data from all patients referred to the Dutch MPM expert centers from 2014 to 2020, were retrospectively collected. Descriptive statistics regarding referrals, patient and tumor characteristics, and treatment patterns were provided. Population-based incidence rates were provided by the Netherlands Cancer Registry. Results: From 2014 to 2020, 78 patients were referred to the Dutch Mesothelioma expert centers, of whom 32 were female (41%). From 2014 to 2017, 27 patients were referred, whereas 51 patients were referred from 2018 to 2020. This represents about 24% and 61% of the estimated population incidence, respectively. Treatment patterns were comparable between both periods. Between 2014 and 2018, 33% of patients underwent surgery, 44% systemic therapy, and 22% received best supportive care (BSC), while this was 29%, 37%, and 33% respectively from 2018 to 2020. Conclusion: Centralization of care for patients with MPM resulted in an increase of annual referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. This might be considered a first important step towards better treatment for patients with this fatal disease.

Introduction: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure.This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993.Materials and methods: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry.Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR).Treatment pattern and Kaplan-Meier overall survival analyses were performed.Results: In total, 12 168 patients were included in the study.For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01).Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01).From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%).Overall, 62.2% of patients received no antitumour treatment.The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%).The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001).Conclusion: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups.The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time.The majority of patients do not receive treatment though and prognosis is still poor.

Introduction Malignant peritoneal mesothelioma (MPM) is a rare, aggressive tumour arising primarily from the peritoneum. The only potentially curative treatment is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the majority of patients are not eligible to undergo this treatment. The benefit of systemic treatment for these patients is limited at the cost of considerable morbidity. Hence, there is a need for appropriate palliative treatment options for patients with MPM. As MPM rarely disseminates outside the abdominal cavity, these patients might benefit from local treatment. A higher, more effective dose of chemotherapy can directly be delivered at the site of the disease. Systemic uptake will be limited, likely resulting in less toxicity. The aim of the INTERACT MESO trial is to determine the maximum tolerable dose of intraperitoneal paclitaxel monotherapy in patients with MPM. Secondary endpoints are to assess safety and toxicity, feasibility and the pharmacokinetic profile of this treatment. Methods and analysis The INTERACT MESO trial is a prospective, open-label, single-centre, phase I study with a classic three-plus-three dose escalation design. The study population consists of adult patients with primary MPM, without extra-abdominal disease, who are not eligible to undergo CRS-HIPEC. According to standard of care work-up for CRS-HIPEC, patients will undergo diagnostic laparoscopy to determine the feasibility of CRS-HIPEC. In case CRS-HIPEC is not considered feasible, a peritoneal port-a-cath (PAC) system will be placed. Through this PAC, 8-16 weekly cycles of intraperitoneal chemotherapy will be administered. Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO, The Hague, The Netherlands) and the Medical Research Ethics Committee (METC, Rotterdam, The Netherlands) have granted permission to carry out this study protocol. The results of this trial will be submitted for publi

Objectives: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with postoperative gastroparesis and ileus. In 2015, our practice shifted from using percutaneous gastrostomy tubes (PGT), to nasogastric tubes (NGT) for prophylactic gastric decompression after CRS-HIPEC. This study aimed to compare these methods for length of stay (LOS) and associated complications. Methods: Patients that underwent CRS-HIPEC for peritoneal metastases from colorectal cancer between 2014 and 2019 were included. Cases were grouped based on receiving NGT or PGT postoperatively. Multivariable linear regression determined the independent effect of decompression method on LOS, thereby adjusting for confounders. Results: In total, 179 patients were included in the analyses. Median age was 64 years [IQR:54–71]. Altogether, 135 (75.4%) received a NGT and 44 (24.6%) received a PGT. Gastroparesis occurred significantly more often in the PGT group (18.2 vs. 7.4%, p=0.039). Median LOS was significantly shorter for patients with a NGT (15 [IQR:12–19] vs. 18.5 [IQR:17–25.5], p<0.001). PGT was independently associated with longer LOS in multivariable analysis (Beta=4.224 [95%CI 1.243–7.204]). There was no difference regarding aspiration, pneumonia and postoperative mortality between groups. Conclusions: NGT should be preferred over PGT for gastric decompression after CRS-HIPEC as it is associated with fewer gastroparesis and shorter LOS.