Surgical approach to right colon cancer: From open technique to robot. State of art

Improvement in genetic characterization of Colon Cancer (CC) patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are receptor tyrosine kinases (RTKs) whose role in CC need to be better investigated. We have analysed 37 CC patients using the Ion AmpliSeq™ Comprehensive Cancer Panel (CCP). We have confirmed the somatic nature of RET variants through Sanger sequencing and assessed RET activation status and protein expression by immunofluorescence and western-blot analyses. We have used RET mutant expression vectors to evaluate the effect of selected mutations in HEK293 cells by performing proliferation, migration and clonogenic assays. Among the 409 cancer-related genes included in the CCP we have focused on the RTKs. Overall, we have observed 101 different potentially damaging variants distributed across 31 RTK genes in 28 patients. The most frequently mutated RTKs were FLT4, ROS1, EPH7, ERBB2, EGFR, RET, FGFR3 and FGFR4. In particular, we have identified 4 different somatic variants in 10% of CC patients in RET proto-oncogene. Among them, we have demonstrated that the G533C variant was able to activate RET by promoting dimer formation and enhancing Y1062 phosphorylation. Moreover, we have demonstrated that RET G533C variant was able to stimulate anchorage-dependent proliferation, migration and clonogenic cell survival. Notably, the effects induced by the RET G533C variant were abolished by vandetanib. The discovery of pathogenic variants across RTK genes in 75% of the CC patients under analysis, suggests a previously underestimated role for RTKs in CC development. The identification of a gain-of-function RET mutation in CC highlights the potential use of RET in targeted therapy.

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

Choledocholithiasis occurs in 10-15% of patients with cholecystolithiasis. Despite the existence of many therapeutic options for the treatment of cholecystocholedocholithiasis, a sequential treatment in which pre-operative ERCP is combined with intraoperative cholangiography (IOC) and laparoscopic cholecystectomy (LC), is the most commonly accepted strategy. However, use of IOC in the "splitting treatment" of cholecystocholedocholithiasis is controversial. The aim of the present study is to investigate the utility of IOC in detecting residual stones in patients undergoing LC in the sequential treatment of common biliary duct or gallbladder stones. Patients were recruited retrospectively among those who underwent IOC during LC, performed as second stage in the sequential treatment for cholecystocholedocholithiasis between 2010 and 2016. Demographic and clinical data were obtained from CPT codes at Ospedale Monaldi A.O.R.N dei Colli Naples, Italy. Data obtained from all pre-operative ERCP analyses were recorded, including cholangiogram findings and performance of sphincterotomy. Statistical analysis was carried out using the IBM SPSS Statistic 19.0 software package. Between January 2010 and December 2016 575 patients (343 males, 242 females) underwent IOC during LC for symptomatic cholecystitis due to cholelithiasis. Among patients accrued for the study, 143 underwent preoperative ERCP for suspicion of common biliary duct stones. At the time of pre-operative ERCP, 123 were found to have common biliary duct stones while 20 (15%) presented negative ERCP. Complete removal of stones was accomplished in 119 patients. Among these patients, 13 had residual common biliary duct stones diagnosed by IOC (11%). Two patients underwent laparoscopic bile duct revision and, last, two patients were referred for ERCP at a later point. It is of note that all patients who presented residual stones by IOC had undergone pre-operative sphincterotomy. This study demonstrates that IOC is particularly effective in detecting residual stones in patients undergoing LC in sequential treatment of common biliary duct and/or gallbladder stones, and may be used on a routine basis in the sequential treatment of cholecystocholedocholithiasis.