At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Most patients with advanced colorectal cancer (CRC) eventually develop resistance to systemic combination therapy. miR-195-5p and miR-497-5p are downregulated in CRC tissues and associated with drug resistance. Sensitization to 5-FU, oxaliplatin, and irinotecan by transfection with miR-195-5p and miR-497-5p mimics was studied using cell viability and clonogenic assays in cell lines HCT116, RKO, DLD-1, and SW480. In addition, proteomic analysis of transfected cells was implemented to identify potential targets. Significantly altered proteins were subjected to STRING (protein-protein interaction networks) database analysis to study the potential mechanisms of drug resistance. Cell viability analysis of transfected cells revealed increased sensitivity to oxaliplatin in microsatellite instable (MSI)/P53 wild-type HCT116 and RKO cells. HCT116 transfected cells formed significantly fewer colonies when treated with oxaliplatin. In sensitized cells, proteomic analysis showed 158 and 202 proteins with significantly altered expression after transfection with miR-195-5p and miR-497-5p mimics respectively, of which CHUK and LUZP1 proved to be coinciding downregulated proteins. Resistance mechanisms of these proteins may be associated with nuclear factor kappa-B signaling and G1 cell-cycle arrest. In conclusion, miR-195-5p and miR-497-5p replacement enhanced sensitivity to oxaliplatin in treatment naïve MSI/P53 wild-type CRC cells. Proteomic analysis revealed potential miRNA targets associated with the cell-cycle which possibly bare a relation with chemotherapy sensitivity.

CD276 can discriminate between tumor derived and normal CECs (circulating endothelial cells). We evaluated whether CD276⁺CEC is a clinically relevant biomarker to predict response to palliative systemic therapy in patients with metastatic colorectal cancer (mCRC). Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial (NCT01792934). At baseline and after three cycles of 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, CECs were measured by flowcytometry (CD34⁺CD45^negCD146⁺DNA⁺; and CD276⁺). A clinically relevant cut-off value of (CD276⁺)CECs was determined as 100% sensitivity (and 80% specificity in 95% confidence interval) identifying patients with progressive disease within 6 months. There were 182 baseline samples and 133 follow up samples available for analysis. CEC and CD276⁺CEC counts significantly increased during treatment from 48 to 90 CEC/4 mL (p = 0.00) and from 14 to 33 CD276⁺CEC/4 mL (p = 0.00) at baseline and at first evaluation, respectively. CEC and CD276⁺CEC counts were not predictive for poor response (area under the curve (AUC) 0.53 for CEC and AUC 0.52 for CD276⁺CEC). Despite numerical changes during therapy, CEC and CD276⁺CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC.