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Background Neoadjuvant chemoradiotherapy followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading and lymph node status helped to visualize individual tumor sensitivity to chemoradiotherapy, retrospectively. As the response to neoadjuvant chemoradiotherapy is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed. MicroRNAs are currently under investigation to serve as blood-based biomarkers. To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken. The aim of the study is to investigate the role of circulating miRNAs as biomarkers in those patients included in the TiMiSNAR Trial (NCT 03465982). This is a biomolecular substudy of TiMiSNAR Trial (NCT03962088). Methods All included patients in the TiMiSNAR Trial are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery, and after adjuvant chemotherapy whenever indicated. Discussion TiMiSNAR-MIRNA will evaluate the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pathological complete response. Moreover, the study will evaluate the role of liquid biopsies in the monitoring of treatment, correlate changes in expression levels of miRNA following complete surgical resection with disease-free survival, and evaluate the relation between changes in miRNA during surveillance and tumor relapse. Trial registration Clinicaltrials.gov NCT03962088. Registered on 23 May 2019.

Aims To investigate the survival benefit of extended lymphadenectomy (D2) in EGC patients in one European Institution. Methods A review was made of our prospective gastric database from January 1980 to December 2001. Of 527 patients with primary gastric adenocarcinoma, 119 with EGC underwent potentially curative resection (R0) with D2 lymphadenectomy. Results There were two post-operative deaths. Of the 117 evaluable cases, 96 were classified as N0 and 21 as N+, with metastases in the perigastric lymph nodes (level 1) in 13, and beyond this site (level 2) in eight. Five-year survival was 85.9 and 83.0% in N0 and N+ patients, respectively. During a median follow-up of 90 months, five of the eight patients with level 2 metastases died of recurrent disease and three were alive. The estimated survival benefit for 119 patients with EGC was 2.5% (3/119 cases). Conclusions In patients with EGC, metastases to level 2 are rare. Our results indicate that D2 lymphadenectomy has a limited survival benefit and that in these cases a less extensive lymphadenectomy (D1) could be performed.

Currently there is no reliable technique for predicting clinical or pathologic complete tumor response after radiochemotherapy (RCT) in patients with rectal cancer. We applied reverse phase protein microarray (RPMA) technology to find a signal pathway that may predict the response to preoperative treatment.Fifteen rectal cancer samples were collected during preoperative RCT. Seven patients had a good response to preoperative therapy (Mandard grade I-II) and 8 patients had a poor response (Mandard grade III-V). Using laser capture microdissection (LCM) and RPMA analysis, we measured the phosphorylation level of nearly 80 end points and analyzed the signaling pathways.We identified 4 signaling proteins whose phosphorylation levels were significantly different (P.05) between the good vs. poor responders; CHK2 and β-catenin were more highly phosphorylated in poor responders, whereas PDK1 and glycogen synthase kinase (GSK)-3α/β had lower phosphorylation levels in poor responders. Interestingly GSK-3α/β, β-catenin, and PDK1 are all present in the phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway.Based on our results, we hypothesize that the activating state of the PI3K-AKT pathway can stratify patients who could benefit most from neoadjuvant treatment. Moreover, identification of theranostic targets has the potential to pinpoint new therapeutic strategies for the nonresponsive population.

p53 Gene variants BstUI RFLP at codon 72 in exon 4, 16bp tandem repeat in intron 3 and MspI RFLP in intron 6, which code for two functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms.p53 genotype was assessed in 90 CRC patients, 321 age-matched controls and 322 centenarians.The p53 codon 72 arginine, the p53 16bp deletion, and the MspI RFLP were significantly more frequent in CRC patients in comparison to the controls and to the centenarians (odd ratio 1.44 and 1.93). In the CRC group, the BstUI RFLP polymorphism was the more frequent combination (62.2%), and it was significantly associated with highly infiltrating (p0.01), poorly differentiated (p0.01), and metastatic (p0.05) tumours. Our findings indicate that the p53 codon 72 polymorphisms are associated with a higher risk of CRC and are associated with more advanced and undifferentiated tumours.

BACKGROUND: The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS: The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS: All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value

Background and Objectives Low tumor expression of the p27Kip1 protein, which is involved in cell cycle control and apoptosis, is considered a negative prognostic factor in different types of cancer. The aim of this study was to evaluate the clinical and pathological significance of low p27Kip1 protein expression in patients who had undergone resection for gastric adenocarcinoma. Methods p27Kip1 protein was studied by immunohistochemistry in formalin-fixed tumor sections from 95 patients who underwent resection for gastric adenocarcinoma between 1991 and 1996. Based on the median value of protein expression, p27Kip1 protein expression was classified as low or high. Results Low p27Kip1 protein expression was significantly associated with tumor de-differentiation, increased penetration through the gastric wall, lymph node metastasis, and advanced tumor stage. In the group of 84 patients who underwent curative surgery, 5-year survival was 74% in cases with high p27Kip1 protein expression and 38% in those with low p27Kip1 protein expression (P