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ROC curves of Lee MSI signature predicting MSI genetic status in PDXs and TCGA samples cohorts.

MSI status transcriptional signature and GSEA analysis performed comparing MSI vs MSS samples

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking.Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models.Results: hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1–G2 grading, I and II tumor—node—metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments.Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. Clin Cancer Res; 20(6); 1502–12. ©2014 AACR.

Supplementary Methods

PDF file - 738K, ADDITIONAL MATERIALS AND METHODS, FIGURES AND TABLES Fig S1- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S2- hERG1 protein expression in GC primary samples. Figure S3- hERG1b characterization in primary GC. Fig S4- hERG1 protein expression in GC cell lines. Fig S5- hERG1USO protein expression in GC cell lines. Fig S6- Effects of the PI3K/Akt inhibition on VEGF-A secretion in AKG cells under normoxic conditions. Fig S7- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S8- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S9- VEGF-A and hERG1 expression in GC samples. Fig S10. Interaction analyses on OS between hERG1 and other clinical and pathological parameters (Forest Plot). Fig S11- Comparison between herg1a mRNA and hERG1A protein expression in GC samples. Table S1- Antibodies used for IHC experiments described in the main text. Table S2- Primer Sequences. Primers were used for methylation analysis and RQ-PCR. Table S3- Cell lines used in the experiments described in the main text. Table S4- hERG1 expression in AKG cells treated with alpha-hERG1 siRNAs and WAY hERG1 blocker. Table S5- VEGF-A and Kv 1.3 expression in AKG cells treated with alpha-hERG1 siRNAs, WAY hERG1 blocker and alpha-vegf-a siRNA. Table S6- Characteristics of patients excluded and included into the statistical analyses and distributions of clinical and pathological variables after multiple imputation of missing values.

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel “druggable” targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.Significance:This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.

Background: The coronavirus pandemic had a major impact in Italy. The Italian health system’s re-organization to face the emergency may have led to significant consequences especially in the diagnosis and treatment of malignancies. This study aimed to assess the impact of the pandemic in the diagnosis and treatment of gastric cancer in nine Gruppo Italiano RIcerca Cancro Gastrico (GIRCG) centers. Methods: All patients assessed for gastric adenocarcinoma at nine GIRCG centers between January 2019 and November 2020 were included. Patients were grouped according to the date of “patient 1’s” diagnosis in Italy: preCOVID versus COVID. Clinico-pathological and outcome differences between the two groups were analyzed. Results: A total of 632 patients were included in the analysis (205 in the COVID group). The cT4 weighted ratios were higher in 2020 from April to September, with the greatest differences in May, August and September. The cM+ weighted ratio was significantly higher in July 2020. The mean number of gastrectomies had the greatest reduction in March and May 2020 compared with 2019. The median times from diagnosis to chemotherapy, to complete diagnostic work-up or to operation were longer in 2019. The median time from the end of chemotherapy to surgery was 17 days longer in the preCOVID group. Conclusions: A greater number of advanced or metastatic cases were diagnosed after the spread of SARS-CoV-2 infection, especially after the “full lockdown” periods. During the pandemic, once gastric cancer patients were referred to one of the centers, a shorter time to complete the diagnostic work-up or to address them to the best treatment option was required.

BACKGROUND: To predict response to neoadjuvant chemotherapy (NAC) of gastric cancer (GC), prior to surgery, would be pivotal to customize patient treatment. The aim of this study is to investigate the reliability of computed tomography (CT) texture analysis (TA) in predicting the histo-pathological response to NAC in patients with resectable locally advanced gastric cancer (AGC). METHODS: Seventy (40 male, mean age 63.3 years) patients with resectable locally AGC, treated with NAC and radical surgery, were included in this retrospective study from 5 centers of the Italian Research Group for Gastric Cancer (GIRCG). Population was divided into two groups: 29 patients from one center (internal cohort for model development and internal validation) and 41 from other four centers (external cohort for independent external validation). Gross tumor volume (GTV) was segmented on each pre- and post-NAC multidetector CT (MDCT) image by using a dedicated software (RayStation), and 14 TA parameters were then extrapolated. Correlation between TA parameters and complete pathological response (tumor regression grade, TRG1), was initially investigated for the internal cohort. The univariate significant variables were tested on the external cohort and multivariate logistic analysis was performed. RESULTS: In multivariate logistic regression the only significant TA variable was delta gray-level co-occurrence matrix (GLCM) contrast (P=0.001, Nagelkerke R(2): 0.546 for the internal cohort and P=0.014, Nagelkerke R(2): 0.435 for the external cohort). Receiver operating characteristic (ROC) curves, generated from the logistic regression of all the patients, showed an area under the curve (AUC) of 0.763. CONCLUSIONS: Post-NAC GLCM contrast and dissimilarity and delta GLCM contrast TA parameters seem to be reliable for identifying patients with locally AGC responder to NAC.

Background: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama’s criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. Methods: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. Results: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5–8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). Conclusions: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.

Perioperative oncological treatment is currently the gold standard approach in Europe for Advanced Gastric Cancer patients. Unfortunately, patients dropping out due to worsening conditions has been frequently observed, but these data are seldomly considered and reported. To analyze frequency and propose solutions to support these patients, we reconsidered our results from the GASTRODOC randomized trial performed by [blinded for reviewers] and GIRCG on 91 patients. Thirty-four patients (37.4%) suspended chemotherapy and five (5.4%) did not reach surgery. Ten patients (11%) presented unacceptable toxicity related to gastrointestinal symptoms, six ended the treatment for investigator decision and six for progression, five patients withdrew their consent, five patients were excluded because of surgical complications and long hospitalization, and two patients died. Even though not significant, survival rates for patients who interrupted treatment in the whole trial were lower (5-year OS completed 64.6 vs. interrupted 41.8 p 0.07). Promptness in giving patient support for gastrointestinal symptoms, careful evaluation of anemia and patient nutritional status, and psychological programs from the beginning of the oncologic treatment may improve the final results.

Gastrectomy for gastric cancer is still performed in Western countries with high morbidity and mortality. Post-operative complications are frequent, and effective diagnosis and treatment of complications is crucial to lower the mortality rates. In 2015, a project was launched by the EGCA with the aim of building an agreement on list and definitions of post-operative complications specific for gastrectomy. In 2018, the platform www.gastrodata.org was launched for collecting cases by utilizing this new complication list. In the present paper, the Italian Research Group for Gastric Cancer endorsed a collection of complicated cases in the period 2015–2019, with the aim of investigating the clinical pictures, diagnostic modalities, and treatment approaches, as well as outcome measures of patients experiencing almost one post-operative complication. Fifteen centers across Italy provided 386 cases with a total of 538 complications (mean 1.4 complication/patient). The most frequent complications were non-surgical infections (gastrointestinal, pulmonary, and urinary) and anastomotic leaks, accounting for 29.2% and 17.3% of complicated patients, with a median Clavien–Dindo score of II and IIIB, respectively. Overall mortality of this series was 12.4%, while mortality of patients with anastomotic leak was 25.4%. The clinical presentation with systemic septic signs, the timing of diagnosis, and the hospital volume were the most relevant factors influencing outcome.

This study aimed to investigate which gastric cancer patients could benefit the most from staging laparoscopy.A retrospective cohort study was carried out, including 316 (216 cM- and 100 cM+) gastric cancer patients who had undergone staging laparoscopy between 2010 and 2020 in seven GIRCG centers. A model including easily-accessible clinical, biochemical and pathological markers was constructed to predict the risk of carcinomatosis. ROC curve and decision curve analyses were used to verify its accuracy and net benefit.In the cM-population staging laparoscopy could detect 67 cases who had peritoneal carcinomatosis or positive cytology, for a yield of 30.5%. In cM-patients, intestinal type tumors (0.25, 0.12-0.51; p = 0.002), cT4 tumors (2.18, 1.11-4.28; p = 0.023) and cancers of the lower third (0.31, 0.14-0.70; p = 0.004) were associated with the presence of peritoneal carcinomatosis and/or positive cytology. The ROC curve analysis of the model including the three variables showed an AUC of 0.75 (0.68-0.81, p lt; 0.001). The decision curve analyses showed that the model had a higher net benefit than the treating all strategy between threshold probabilities of 15 and 50%.Staging laparoscopy is a useful tool to address the patient with gastric cancer to the most adequate treatment. In cM-patients the assessment of the location of the tumor, the Lauren's histotype and the cT status may help in providing additional elements in indicating or not the use of staging laparoscopy.

Evidence against the use of prophylactic drain after gastrectomy are increasing and ERAS guidelines suggest the benefit of drain avoidance. Nevertheless, it is unclear whether this practice is still widespread. We conducted a survey among Italian surgeons through the Italian Gastric Cancer Research Group and the Polispecialistic Society of Young Surgeons, aiming to understand the current use of prophylactic drain. A 28-item questionnaire-based survey was developed to analyze the current practice and the individual opinion about the use of prophylactic drain after gastrectomy. Groups based on age, experience and unit volume were separately analyzed. Response of 104 surgeons from 73 surgical units were collected. A standardized ERAS protocol for gastrectomy was applied by 42% of the respondents. Most of the surgeons, regardless of age, experience, or unit volume, declared to routinely place one or more drain after gastrectomy. Only 2 (1.9%) and 7 surgeons (6.7%) belonging to high volume units, do not routinely place drains after total and subtotal gastrectomy, respectively. More than 60% of the participants remove the drain on postoperative day 4–6 after performing an assessment of the anastomosis integrity. Interestingly, less than half of the surgeons believe that drain is the main tool for leak management, and this percentage further drops among younger surgeons. On the other hand, drain’s role seems to be more defined for duodenal stump leak treatment, with almost 50% of the surgeons recognizing its importance. Routine use of prophylactic drain after gastrectomy is still a widespread practice even if younger surgeons are more persuaded that it could not be advantageous.

Background The present study provides a snapshot of Italian patients with peritoneal metastasis from gastric cancer treated by surgery in Italian centers belonging to the Italian Research Group on Gastric Cancer. Prognostic factors affecting survival in such cohort of patients were evaluated with the final aim to identify patients who may benefit from radical intent surgery. Methods It is a multicentric retrospective study based on a prospectively collected database including demographics, clinical, surgical, pathological, and follow-up data of patients with gastric cancer and synchronous macroscopic peritoneal metastases. Patients were surgically treated from January 2005 to January 2017. We focused on patients with macroscopic peritoneal carcinomatosis (PC) treated with upfront surgery in order to provide homogeneous evidences. Results Our results show that patients with peritoneal carcinomatosis cannot be considered all lost. Strictly selected cases (R0/R1 and P1 patients) could benefit from an aggressive surgical approach performing an extended lymphadenectomy and HIPEC treatment. Conclusion The main result of the study is that GC patients with limited peritoneal involvement can have a survival benefit from a surgery with “radical oncological intent”, that means extended lymphadenectomy and R0 resection. The retrospective nature of this study is an important bias, and for this reason, we have started a prospective multicentric study including Italian stage IV patients that hopefully will give us more answers.

Data on minimally invasive approaches for locally advanced gastric cancer were provided by KLASS-02 and CLASS-01: there are no differences between laparoscopic and open distal gastrectomy in 3-year overall and disease-free survival. Some concern still remains, however, regarding the applicability of such data in the West, since both these Eastern trials excluded patients receiving preoperative chemotherapy and cases with extensive/bulky nodes, which represent most Western patients with locally advanced gastric cancer. Concerns exist on laparoscopic total gastrectomy due to the technical issue of esophagojejunal anastomosis. The European multicenter STOMACH trial apparently resolved some of these doubts. In a post neoadjuvant setting, laparoscopic total gastrectomy and open surgery provided similar results in terms of retrieved nodes, as well as similar postoperative complication and 1-year survival rates. Late follow-up will provide the most crucial data; however, sample size was calculated for lymph node dissection, not for long-term survival. Moreover, we should consider that total gastrectomy with D2 lymphadenectomy might not be enough to treat locally advanced gastric cancer: splenectomy, bursectomy, D3 lymphadenectomy could be also indicated. Based on these considerations, providing evidence on the role of laparoscopic gastrectomy for locally advanced cases cannot be reduced to “OK, it is feasible”.

Surgery in metastatic gastric cancer may be sometimes required when oligometastatic patients are confirmed at re-staging after neoadjuvant treatment, or when palliative chemotherapy makes it possible allow to remove previously unresectable cancer. This second approach, defined as conversion surgery, has better results in comparison to simple oncologic treatment not only in liver metastases but also in patients with lymphatic metastases or carcinosis. Complete R0 resection is regarded as a significant prognostic factor also in conversion surgery, but in these patients the R0 resection must only consider the residual disease and not the initial volume. New oncologic drugs are proposed and the survival rates reported in the literature are promising; however, collaboration within a multidisciplinary team is the key point for this stage of the disease.

Over the last decade, laparoscopic gastrectomy has gradually gained popularity as a surgical option for early gastric cancer, especially in Eastern countries, with most of the evidence coming from Korea and Japan. After the publication of two large-scale Eastern trials, laparoscopic distal gastrectomy proved to be a safe alternative to open surgery for stage I distal gastric cancer when performed by experienced surgeons. This evidence can be roughly transposed to high-volume Western centers, paying attention to some subgroups of patients. Conversely, laparoscopic total gastrectomy proved to be a complex procedure especially due to the technical issue of esophagojejunal anastomosis, and concerns regarding its surgical safety should be considered when planning surgical strategies for each individual patient. Few data are available on the benefit of robotic gastrectomy for cancer: despite increased costs and operation time, no significant improvement was observed in estimated blood loss, rates of open conversion and postoperative outcomes compared to the laparoscopic approach. While the development of even more conservative surgery, such as pylorus-preserving or proximal gastrectomy, is an urgent need in Korea and Japan, these are far from becoming part of clinical practice in the West, where most newly diagnosed gastric cancers are at advanced stages.

D2 lymphadenectomy is the standard treatment for advanced gastric cancer. Careful dissection of each station allows better staging and survival.

Staging laparoscopy is a useful tool to adequately stage gastric cancer patients. It displayed a higher accuracy in detecting peritoneal involvement than computed tomography and positron emission tomography scans. The indications may vary across countries and different health systems, but there is a substantial agreement on performing staging laparoscopy in those patients needing neoadjuvant chemotherapy. It has been reported that the yield of staging laparoscopy ranges between 51.6–13.7%, confirming its importance in staging gastric cancer.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.

Background: To validate a nodal regression system for gastric cancer and to verify its impact on prognosis. Methods: This is an ancillary study which included 47 patients of the GASTRODOC trial. The dedicated pathologists of each Institute were invited to revise all the lymph nodes included in the surgical specimens in order to classify the regression according to the grading system proposed by Tsekrekos et al. The association of the nodal regression system and the clinico-pathological characteristics and prognosis were investigated. Results: According to the classification of Tsekrekos et al., there were 19 (40.4%) patients with grade a, 14 (29.8%) with grade b and 14 (29.8%) with grade c nodal regression. This regression system showed significant statistical associations with pathological N status (p < 0.001), residual tumor classification (p = 0.003) and Becker regression system (p = 0.011). At multivariable analysis only Tsekrekos’ grading regression system was significantly associated with the PFS (HR 10.1, 95% CI 1.3–75.5; p = 0.025). Conclusions: The analyzed nodal regression system is significantly associated with Becker's regression system and it has a strong correlation with prognosis.

Objectives: Written radiological report remains the most important means of communication between radiologist and referring medical/surgical doctor, even though CT reports are frequently just descriptive, unclear, and unstructured. The Italian Society of Medical and Interventional Radiology (SIRM) and the Italian Research Group for Gastric Cancer (GIRCG) promoted a critical shared discussion between 10 skilled radiologists and 10 surgical oncologists, by means of multi-round consensus-building Delphi survey, to develop a structured reporting template for CT of GC patients. Methods: Twenty-four items were organized according to the broad categories of a structured report as suggested by the European Society of Radiology (clinical referral, technique, findings, conclusion, and advice) and grouped into three “CT report sections” depending on the diagnostic phase of the radiological assessment for the oncologic patient (staging, restaging, and follow-up). Results: In the final round, 23 out of 24 items obtained agreement (≥ 8) and consensus (≤ 2) and 19 out 24 items obtained a good stability (p > 0.05). Conclusions: The structured report obtained, shared by surgical and medical oncologists and radiologists, allows an appropriate, clearer, and focused CT report essential to high-quality patient care in GC, avoiding the exclusion of key radiological information useful for multidisciplinary decision-making. Key Points: • Imaging represents the cornerstone for tailored treatment in GC patients. • CT-structured radiology report in GC patients is useful for multidisciplinary decision making.

Introduction: To compare outcomes of robotic gastrectomy (RG) performed during the learning curve (P1) with those after its completion (P2). Methods: In this retrospective study, all consecutive RG patients (n=92) performed between 2008 and 2018 were included. Primary outcome was conversion rate. Results: D2 lymphadenectomies were more common in P2 (41, 97.6%) than P1 (41, 82.0%) (p=0.019). Conversions were 11 (22%) in P1 versus 2 (4.8%) in P2 (p=0.006). Postoperative morbidity was comparable between the groups. Median hospital stay was significantly shorter in P2. The only factor significantly associated with conversion was P2 (odds ratio = 0.18; 95% confidence interval, 0.04–0.85; p=0.039). The 5-year overall survival in P1 was 79.6% versus 79.7% in P2 (p=0.373). Conclusions: The learning curve affected operative and postoperative outcomes: during the learning curve, conversion to open surgery was significantly more frequent, the number of D2 was higher and patients were discharged earlier.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved., Objective: Utilizing a standardized dataset based on a newly developed list of 27 univocally defined complications, this study analyzed data to assess the incidence and grading of complications and evaluate outcomes associated with gastrectomy for cancer in Europe. Summary background data: The absence of a standardized system for recording gastrectomy-associated complications makes it difficult to compare results from different hospitals and countries. Methods: Using a secure online platform (www.gastrodata.org), referral centers for gastric cancer in 11 European countries belonging to the Gastrectomy Complications Consensus Group recorded clinical, oncological, and surgical data, and outcome measures at hospital discharge and at 30 and 90 days postoperatively. This retrospective observational study included all consecutive resections over a 2-year period. Results: A total of 1349 gastrectomies performed between January 2017 and December 2018 were entered into the database. Neoadjuvant chemotherapy was administered to 577 patients (42.8%). Total (46.1%) and subtotal (46.4%) gastrectomy were the predominant resections. D2 or D2+ lymphadenectomy was performed in almost 80% of operations. The overall complications' incidence was 29.8%; 402 patients developed 625 complications, with the most frequent being nonsurgical infections (23%), anastomotic leak (9.8%), other postoperative abnormal fluid from drainage and/or abdominal collections (9.3%), pleural effusion (8.3%), postoperative bleeding (5.6%), and other major complications requiring invasive treatment (5.6%). The median Clavien-Dindo score and Comprehensive Complications Index were IIIa and 26.2, respectively. In-hospital, 30-day, and 90-day mortality were 3.2%, 3.6%, and 4.5%, respectively. Conclusions: The use of a standardized platform to collect European data on perioperative complications revealed that gastrectomy for gastric cancer is still associated with heavy morbidity and mortality. Actions are needed to limit the incidence of, and to effectively treat, the most frequent and most lethal complications.

Introduction: In a gastric cancer (GC) setting, phase II and III studies refer to an ideal patient population and only describe a specific category of patients. Older patients or those in poorer clinical condition are generally excluded from clinical trials. We aimed to evaluate therapeutic approaches to GC in a real-world setting at our institute (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori [IRST] IRCCS) over a 10-year period. Methods: A total of 621 consecutive patients with GC diagnosed between January 2000 and December 2009 were considered retrospectively. Among these, 573 with available information on stage of disease were included in the analysis. Demographic and clinical data were collected from paper or electronic medical records. Results: During the study period, 343 (59.8%) patients were diagnosed with GC stage 0 to IIIC (M0): of these, 118 patients had a relapse of disease. A total of 230 patients (40.2%) presented with metastatic disease at diagnosis. Older age was associated with less frequent administration of adjuvant chemotherapy (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.83–0.91); interaction between age and period (OR, 1.02; 95% CI, 1.01–1.03) and stage of disease at diagnosis (OR, 7.95; 95% CI, 3.71–17.1) were positively associated with administration of adjuvant chemotherapy. Older age (OR, 0.87; 95% CI, 0.84–0.90) and presence of comorbidity (OR, 0.46; 95% CI, 0.26–0.83) were associated with less frequent administration of palliative chemotherapy, whereas from 2000–2004 to 2005–2009, patients were more frequently treated with palliative chemotherapy overall (OR, 3.70; 95% CI, 2.01–6.81). Conclusions: Our results confirm that resection is the standard surgical approach to GC, and that chemotherapy is not widely used in adjuvant and metastatic settings. Older age and comorbidities are associated with nontreatment.

Background/Aim: This work explored the prognostic role of curative versus non-curative surgery, the prognostic value of the various localizations of metastatic disease, and the possibility of identifying patients to be submitted to aggressive therapies. Patients and Methods: Retrospective chart review of stage IV patients operated on in our institutions. Results: Two hundred and eighty-two patients were considered, 73.4% had a single metastatic presentation. In 117 cases, a curative (R0) resection of primary and metastases was possible, 75 received a R1 resection and 90 a palliative R2 gastrectomy. Surgery was integrated with chemotherapy in multiple forms: conversion therapy, HIPEC, neo-adjuvant and adjuvant treatment. Median overall survival (OS) of the entire cohort was 10.9 months, with 14 months for the R0 subgroup. There was no correlation between metastasis site and survival. At multivariate analysis, several variables associated with the lymphatic sphere showed prognostic value, as well as tumor histology and the curativity of the surgical procedure, with a worse prognosis associated with a low number of resected nodes, D1 lymphectomy, pN3, non-intestinal histology, and R+ surgery. Considering the subgroup of R0 patients, the variables pT, pN and D displayed an independent prognostic role with a cumulative effect, showing that patients with no more than 1 risk factor can reach a median survival of 33 months. Conclusions: Our data show that the possibility of effective care also exists for Western patients with stage IV gastric cancer.

Background The present study aimed to better define the usefulness of F-FDG PET/CT in predicting pathological tumor response (PTR) and survival in patients with noncardia gastric cancer treated with preoperative chemotherapy. Methods Seventy-one patients were recruited in 6 Italian centers. The SUV of F-FDG PET/CT was measured at baseline and after treatment, and the difference (dSUV) was computed. The association between PET indexes and PTR, assessed by the Becker score, was evaluated by nonparametric regression. The discriminant power of PET indexes with respect to the absence of PTR (Becker 2/3) was studied by receiver operating characteristic (ROC) curve and synthesized by the area under the curve (ROC-AUC). Results dSUV allowed to partially discriminate between absence/presence of PTR, when expressed as either absolute value (ROC-AUC, 0.73; 95% confidence interval, 0.59-0.87) or percentage (ROC-AUC, 0.74; 95% confidence interval, 0.59-0.89). However, only extreme values of percent dSUV were really informative. All 7 patients whose F-FDG uptake had increased despite preoperative treatment showed no tumor regression at pathologic examination. Seven of the 10 patients whose metabolic response had been 70% or greater had complete or nearly complete pathologic tumor regression (Becker score 1a or 1b). The metabolic response of the remaining 54 patients, which ranged between 0% and 70%, did not permit to reliably forecast pathologic tumor regression. Survival significantly decreased with increasing Becker score but was unaffected by metabolic response. Conclusions The present study suggests that F-FDG PET/CT has limited usefulness in predicting cancer regression. The lack of metabolic response in serial measurements indicates the probable ineffectiveness of preoperative treatment.

AIM To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up. METHODS We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics. RESULTS T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during long-term follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence. CONCLUSION The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up.

// Raefa Abou Khouzam 1 , Chiara Molinari 2 , Samanta Salvi 2 , Monica Marabelli 1 , Valeria Molinaro 1 , Donata Orioli 3 , Luca Saragoni 4 , Paolo Morgagni 5 , Daniele Calistri 2 , Guglielmina Nadia Ranzani 1 1 Department of Biology and Biotechnology, University of Pavia, Pavia, Italy 2 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 3 Institute of Molecular Genetics, Consiglio Nazionale delle Ricerche, Pavia, Italy 4 Pathology Unit, Morgagni-Pierantoni Hospital, Forli, Italy 5 Department of General Surgery, Morgagni-Pierantoni Hospital, Forli, Italy Correspondence to: Guglielmina Nadia Ranzani, email: guglielmina.ranzani@unipv.it Keywords: CDH1 transcripts, digital-PCR quantification, intestinal-type gastric cancer, normal gastric mucosa Received: October 04, 2016 Accepted: November 09, 2016 Published: November 16, 2016 ABSTRACT E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis -modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a , proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts ( P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1a transcript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a , corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.

CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value &lt, 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value &lt, 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10&ndash, 50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance, however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

Background: The aim of this study is to report the experience with conversion surgery from six Gruppo Italiano Ricerca Cancro Gastrico (GIRCG) centers, focusing our analysis on factors affecting survival and the risk of recurrence. Methods: A retrospective, multicenter cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2017. Data were extracted from a GIRCG database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-five resected M1 patients were included in the analysis. Reasons for being deemed unresectable at diagnosis were peritoneal involvement (PCI > 6) (n = 38, 84.4%), distant metastatic nodes (n = 3, 6.6%) and extensive liver involvement (n = 4, 8.8%). Median follow-up was 25months (IQR 9-50). Median overall survival from surgery was 15months and 1-, 3- and 5-year survivals were 57.2, 36.1 and 24%, respectively. Median progression-free survival was 12months with 1- and 3-year survival of 46.4 and 33.9%, respectively. At cox regression analysis the only independent prognostic factor for OS was the presence of more than one type of metastasis (HR 4.41, 95% CI 1.72–11.3, p = 0.002). A positive microscopic resection margin was the only risk factor for recurrence (HR 5.72, 95% CI 1.04–31.4, p = 0.045). Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. The main prognostic factor for these patients was the presence of more than one type of extra-gastric metastatic involvement.

BACKGROUND: The aim of this study was compare short- and long-term outcomes between robotic (RG) and standard open gastrectomy (OG). METHODS: This is a single-center propensity score-matched study including patients who underwent RG or OG for gastric cancer between 2008 and 2018. RESULTS: In total, 191 patients could be included for analysis. Of 60 RG patients, 49 could be matched. After matching, significant differences in baseline characteristics were no longer present. Operative time was significantly longer (451 min, IQR: 392-513) in the RG group than in the OG (262 min, IQR: 225-330) (P < .0001). No significant differences in postoperative complications between RG (n = 15, 30.6%) and OG (n = 15, 30.6%) were seen (P = 1.000). Overall survival was comparable between the groups. CONCLUSIONS: RG is feasible and safe. With regard to long-term oncologic outcomes, survivals in the RG group were similar to those in OG group.

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018, Background: Perioperative complications can affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates ranging between 10 and 40%. The absence of a standardized system for recording complications generates wide variation in evaluating their impacts on outcomes and hinders proposals of quality-improvement projects. The aim of this study was to provide a list of defined gastrectomy complications approved through international consensus. Methods: The Gastrectomy Complications Consensus Group consists of 34 European gastric cancer experts who are members of the International Gastric Cancer Association. A group meeting established the work plan for study implementation through Delphi surveys. A consensus was reached regarding a set of standardized methods to define gastrectomy complications. Results: A standardized list of 27 defined complications (grouped into 3 intraoperative, 14 postoperative general, and 10 postoperative surgical complications) was created to provide a simple but accurate template for recording individual gastrectomy complications. A consensus was reached for both the list of complications that should be considered major adverse events after gastrectomy for cancer and their specific definitions. The study group also agreed that an assessment of each surgical case should be completed at patient discharge and 90 days postoperatively using a Complication Recording Sheet. Conclusion: The list of defined complications (soon to be validated in an international multicenter study) and the ongoing development of an electronic datasheet app to record them provide the basic infrastructure to reach the ultimate goals of standardized international data collection, establishment of benchmark results, and fostering of quality-improvement projects.