The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%–100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC)

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence

Past, present and future of adjuvant HIPEC in patients at high risk for colorectal peritoneal metastases

EDITORIA

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma

Introduction: Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity. Methods: Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo. Results: Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls. Conclusions: SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM