Open versus laparoscopic gastrectomy for advanced gastric cancer: a propensity score matching analysis of survival in a western population-on behalf of the Italian Research Group for Gastric Cancer.

BACKGROUND: Oncologic outcomes after laparoscopic gastrectomy for advanced gastric cancer in the West have been poorly investigated. The aim of the present study was to compare survival outcomes in patients undergoing curative-intent laparoscopic and open gastrectomy for advanced gastric cancer in several centres belonging to the Italian Research Group for Gastric Cancer. METHODS: Data of patients operated between 2015 and 2018 were retrospectively analysed. Propensity Score Matching was performed to balance baseline characteristics of patients undergoing laparoscopic and open gastrectomy. The primary endpoint was 3-year overall survival. Secondary endpoints were 3-year disease-free survival and short-term outcomes. Multivariable regression analyses for survival were conducted. RESULTS: Data were retrieved from 20 centres. Of the 717 patients included, 438 patients were correctly matched, 219 per group. The 3-year overall survival was 73.6% and 68.7% in the laparoscopic and open group, respectively (p = 0.40). When compared with open gastrectomy, laparoscopic gastrectomy showed comparable 3-year disease-free survival (62.8%, vs 58.9%, p = 0.40), higher rate of return to intended oncologic treatment (56.9% vs 40.2%, p = 0.001), similar 30-day morbidity/mortality. Prognostic factors for survival were ASA Score ≥ 3, age-adjusted Charlson Comorbidity Index ≥ 5, lymph node ratio ≥ 0.15, p/ypTNM Stage III and return to intended oncologic treatment. CONCLUSIONS: Laparoscopic gastrectomy for advanced gastric cancer offers similar rates of survival when compared to open gastrectomy, with higher rates of return to intended oncologic treatment. ASA score, age-adjusted Charlson Comorbidity Index, lymph node ratio, return to intended oncologic treatment and p/ypTNM Stage, but not surgical approach, are prognostic factors for survival.

Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer.

BACKGROUND: Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer. METHODS: A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool. RESULTS: Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Laurén histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I-II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001). CONCLUSION: MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.

Validation of two prognostic models for recurrence and survival after radical gastrectomy for gastric cancer.

BACKGROUND: Prognostic models from Korea and Italy have been developed that predict overall survival and cancer recurrence respectively after radical gastrectomy for gastric cancer. The aim of this study was to validate the two models in independent patient cohorts, and to evaluate which factors may explain differences in prognosis between Korean and Italian patients with gastric cancer. METHODS: Patients who underwent radical gastrectomy for gastric cancer between January 2000 and December 2004 at Seoul National University Hospital and at eight centres in Italy were included. Discrimination of the models was tested with receiver operating characteristic (ROC) curves and calculation of area under the curve (AUC). Calibration was evaluated by plotting actual survival probability against predicted survival probability for the Korean nomogram, and actual against predicted risk of recurrence for the Italian score. RESULTS: Some 2867 and 940 patients from Korea and Italy respectively were included. The Korean nomogram achieved good discrimination in the Italian cohort (AUC 0·80, 95 per cent c.i. 0·77 to 0·83), and the Italian model performed well in the Korean cohort (AUC 0·87, 0·85 to 0·89). The Korean nomogram also achieved good calibration, but this was not seen for the Italian model. Multivariable analyses confirmed that Italian ethnicity was an independent risk factor for cancer recurrence (odds ratio (OR) 1·72, 1·31 to 2·25; P < 0·001), but not for overall survival (OR 1·20, 0·95 to 1·53; P = 0·130). CONCLUSION: Both prognostic models performed fairly well in independent patient cohorts. Differences in recurrence rates of gastric cancer may be partially explained by ethnicity.

Assessment of a tumor bank: a thirty years experience of the University of Siena (Italy).

Tumor biobank plays a pivotal role in cancer biomedical research. The collection of a high variety of biological samples, including DNA, RNA, tissues, cells, blood, plasma and other body fluids, represents a necessary step to plan new strategies in the improvement of oncological patient care. Since 1985, a consolidated experience in biobanking management has been developed at the University of Siena (Italy). During these years, some information about clinico-pathology, surgery and a high number of human bispecimens have been collected. Herein, we described our experience in sampling management to improve the cancer research and the patient care.

EBV persistence in gastric cancer cases conventionally classified as EBER-ISH negative.

BACKGROUND: The Epstein-Barr virus (EBV) causes various B-cell lymphomas and epithelial malignancies, including gastric cancer (GC) at frequencies ranging from 5 to 10% in adenocarcinomas (ADK) to 80% in GC with lymphoid stroma (GCLS). Using high-sensitivity methods, we recently detected EBV traces in a large cohort of EBV-negative B-cell lymphomas, suggesting a hit-and-run mechanism. METHODS: Here, we used routine and higher-sensitivity methods [droplet digital PCR (ddPCR) for EBV segments on microdissected tumour cells and RNAscope for EBNA1 mRNA] to assess EBV infection in a cohort of 40 GCs (28 ADK and 12 GCLS). RESULTS: ddPCR documented the presence of EBV nucleic acids in rare tumour cells of several cases conventionally classified as EBV-negative (ADK, 8/26; GCLS, 6/7). Similarly, RNAscope confirmed EBNA1 expression in rare tumour cells (ADK, 4/26; GCLS, 3/7). Finally, since EBV induces epigenetic changes that are heritable and retained after complete loss of the virus from the host cell, we studied the methylation pattern of EBV-specifically methylated genes (Timp2, Eya1) as a mark of previous EBV infection. Cases with EBV traces showed a considerable level of methylation in Timp2 and Eya1 genes that was similar to that observed in EBER-ISH positive cases and greater than cases not featuring any EBV traces. CONCLUSIONS: These findings suggest that: (a) EBV may contribute to gastric pathogenesis more widely than currently acknowledged and (b) indicate the methylation changes as a mechanistic framework for how EBV can act in a hit-and-run manner. Finally, we found that the viral state was of prognostic significance in univariate and multivariate analyses.

Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer.

BACKGROUND: MicroRNAs are tiny non-coding small endogenous RNAs that regulate gene expression by translational repression, mRNA cleavage and mRNA inhibition. The aim of this study was to investigate the hypermethylation of miR-34b/c and miR-148a in colorectal cancer, and correlate this data to clinicopathological features. We also aimed to evaluate the hypermethylation of miR-34b/c in faeces specimens as a novel non-invasive faecal-DNA-based screening marker. METHODS: The 5-aza-2'-deoxycytidine treatment and methylation-specific PCR were carried out to detect the hypermethylation of miR-34b/c and miR-148a. RESULTS: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110. In 75% (21 out of 28) of faecal specimens we found a hypermethylation of miR-34b/c while only in 16% (2 out of 12) of high-grade dysplasia. In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features. However, a trend with female gender and advanced age was found, P=0.083. We also observed a trend to lower survival rate in patients with miR-148a hypermethylation with 10-year survival probability: 48 vs 65%, P=0.561. CONCLUSIONS: These findings show that aberrant hypermethylation of miR-34b/c could be an ideal class of early screening marker, whereas miR-148a could serve as a disease progression follow-up marker.

Changing clinical and pathological features of gastric cancer over time.

BACKGROUND: The aim of the present multicentre observational study was to evaluate potential changes in clinical and pathological features of patients with gastric cancer (GC) treated in a 15-year interval. METHODS: A centralized prospective database including clinical, surgical, pathological and follow-up data from 2822 patients who had resection of a primary GC was analysed. The analysis focused on three periods: 1991-1995 (period 1), 1996-2000 (period 2) and 2001-2005 (period 3). Surgical procedure, pathological classification and follow-up were standardized among centres. RESULTS: The number of resections decreased from 1024 in period 1 to 955 and 843 in periods 2 and 3 respectively. More advanced stages and a smaller number of intestinal-type tumours of the distal third were observed over time. Five-year survival rates after R0 resection (2320 patients) did not change over time (overall: 56·6 and 51·2 per cent in periods 1 and 3; disease-free: 66·8 and 61·1 per cent respectively). Decreases in survival in more recent years were related particularly to more advanced stage, distal tumours and tumours in women. Multivariable analysis showed a lower probability of overall and disease-free survival in the most recent interval: hazard ratio 1·22 (95 per cent confidence interval 1·06 to 1·40) and 1·29 (1·06 to 1·58) respectively compared with period 1. Recurrent tumours were more frequently peritoneal rather than locoregional. CONCLUSION: Overall and disease-free survival rates after R0 resection of GC were unchanged over time.

Heterotopic pancreatic tissue in the gallbladder. Two case reports and brief review of the literature.

Heterotopic pancreas tissue in the gallbladder is a rare benign condition with no clinical relevance and found incidentally in most cases. Only 28 cases of heterotopic pancreas are reported until 2007 in the worldwide literature. The preoperative diagnosis is very hard, so that it could be considered in differential diagnosis with other benign and malignant disease of gallbladder and biliary tree. The surgical approach for the excision of a undefined lesion and the histological identification is a correct procedure in suspect case. We report 2 cases of heterotopic pancreatic tissue of the gallbladder.

[Treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. / Trattamento della carcinosi peritoneale mediante citoriduzione chirurgica e chemioipertermia intraperitoneale.

Pinto Peritoneal carcinomatosis (PC) had for long been regarded as a terminal disease, characterized by a very poor survival and worthy of being treated with palliative therapy only. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising additional treatment option for patients with peritoneal carcinomatosis, resulting in recently published series enable to obtain long-term survival. In spite of the need for more high quality studies, there is now a consensus among many international experts about the use of this new strategy as gold standard for treating with intent of cure selected patients with PC. We summarized the present status and possible future progress of this treatment modality, in particular outlining its rationale, current practice and general outcomes.

Familial gastric cancer and Li-Fraumeni syndrome.

Gastric cancer occurs in some familial diseases with inherited cancer predisposition. Genetic factors have been correlated with the hereditary diffuse gastric cancer and other familial gastric cancer conditions as hereditary non-polyposis colorectal cancer and Li-Fraumeni syndrome. The present study was aimed at searching for germ line mutations of TP53 gene in familial gastric cancer with cluster for Li-Fraumeni syndrome or Li-Fraumeni-like syndrome. Twenty-three pedigrees with characteristics for Li-Fraumeni-like syndrome were identified. DNA of the proband was sequenced using polymerase chain reaction/single-strand conformation polymorphism. Among these 23 cases, no germ line mutation of TP53 was identified, while two single-nucleotide polymorphisms were identified in four patients. In our area, in which a high rate of familial aggregation was demonstrated, the lack of germ line mutation of TP53 together with the infrequency of mutation of E-cadherin gene seem to limit the role of genetic predisposition in the development of gastric cancer.

Gastrointestinal stromal tumors (GIST): a proposal of a "CT-based predictive model of Miettinen index" in predicting the risk of malignancy.

PURPOSE: To identify the predictors of malignancy on CT for the evaluation of gastrointestinal stromal tumors (GIST) by correlating CT findings with the mitotic index in order to propose a "CT-based predictive model of Miettinen index." METHODS: One radiologist and one resident in radiology with 14- and 4-year experience in oncological field reviewed the CT findings of 42 patients by consensus, with respect to lesion site, size, contour, tumor growth pattern, enhancing pattern, degree of enhancement of tumor, percentage of tumor necrosis, mesenteric fat infiltration, ulceration, calcification, regional lymphadenopathy, direct invasion to adjacent organs, and distant metastasis. All parameters were correlated with the mitotic index evaluated at histopathological analysis following surgery. Normality of variables was evaluated using Shapiro-Wilk test. Pearson's correlation test was used to assess the interaction between variables. The diagnostic accuracy percentage of tumor necrosis was measured by receiver operating characteristic (ROC) analysis for detecting whether the number of mitosis per 50 high-power fields was > 5. RESULTS: A significant statistical correlation was found between percentage of tumor necrosis and the mitotic index (p < 0.005), dimension, and location of the tumor. CONCLUSION: CT could be an accurate technique in the prediction of malignancy of GIST in a CT risk assessment system, based on the location of the tumor, its size, and the percentage of tumor necrosis.

Indexes of surgical quality in gastric cancer surgery: experience of an Italian network.

BACKGROUND: Short-term results of gastric cancer surgery vary remarkably worldwide, and international surgical quality criteria are urgently needed. To contribute to defining these criteria, we reviewed short-term results of gastrectomy for gastric cancer in three centers of the Italian Research Group for Gastric Cancer, with an average of 24.7, 29.5, and 18 gastrectomies per year. METHODS: Between 1988 and 2002, 1,032 patients underwent gastrectomy for gastric cancer in Verona, Siena, and Padua. D1, D2, and D3 lymphadenectomy were performed, respectively, in 228, 584, and 220 cases. RESULTS: The median number of retrieved lymph nodes was 14 (interquartile range 9-18.75) after D1, 29 (21-38) after D2, and 46.5 (37-57) after D3. Fewer than 15 nodes were retrieved in 54.5%, 6.2%, and 1.4% of cases undergoing, respectively, D1, D2, and D3. Adjacent organ removal was rare during D1 (splenectomy: 6.1%, splenopancreasectomy: 1.8%), and quite common during D3 (11.4%, 11.4%). Forty patients (3.9%) died postoperatively. Neither postoperative morbidity nor mortality was significantly associated with extension of lymphadenectomy. CONCLUSION: We conclude that at least D2 lymphadenectomy is necessary to achieve adequate disease staging (>or=15 nodes retrieved). Spleen and pancreas tail are more frequently removed during D3, but this removal is not associated with higher postoperative morbidity or mortality.

Elastofibroma dorsi: three cases of personal experience.

Elastofibroma dorsi is a rare, slow growing, soft tissue lesion, which occurs mainly in elderly women, typical located in the infrascapular region. This lesion is characterized by a poorly defined solid mass of fibro-elastic and fatty tissue, enlarging into intermuscular spaces. Elastofibroma may simulate an aggressive behaviour, and differential diagnosis with malignant tumors is sometimes difficult. Surgical resection is generally recommended in symptomatic lesions or in the suspicion of malignancy. We report our experience of three cases of elastofibroma, two of which typically located in the infrascapular region and one located in the supra-clavicle fossa, atypical site never reported so far.

Mayer-Rokitansky-Küster-Hauser syndrome presenting as vaginal atresia: report of two cases.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) is characterized by Müllerian duct structures agenesis: the vagina atresia is the commonest variant. There can be some anomalies associated, such as renal, skeletal, spine malformations and others. Patients with MRKH can show different presentation from newborn period to adolescence. We report our experience in treatment of the vaginal atresia presenting in two young girls as a sign of MRKH syndrome.

Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family.

AIMS: Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations. METHODS: The entire coding region of the CDH1 gene and all intron-exon boundaries were analyzed by direct sequencing in the 14 families fulfilling the IGCLC criteria. E-cadherin immunohistochemical expression was evaluated on tumour as well as normal formalin-fixed paraffin embedded tissues. RESULTS: A novel germline missense mutation was found. It was a single C-->T substitution in exon 8, resulting in a transition of CCG-->CTG (C1118T; Pro373Leu) demonstrated in the proband and her brother. At immunohistochemical analysis, the staining intensity was reduced and considered weakly positive (15%). CONCLUSIONS: The first CDH1 germline mutation of an Italian family is herein reported. The present missense mutation has never been described so far.

Pseudoaneurysm of the splenic artery fistulized in the stomach and associated to a pancreatic pseudocyst: case report.

A case of pseudoaneurysm of the splenic artery fistulized in the stomach and associated to a pancreatic pseudocyst is presented. A diabetic and alcoholist 40-year-old man was referred for gastrointestinal bleeding. Esophagogastro-duodenoscopy showed a tumefaction of the little gastric curve and a gastric bleeding fistula. A computed tomography demonstrated a pseudoaneurysm of the splenic artery fistulized in the stomach and associated to pancreatic pseudocyst. Marsupialization of the pancreatic pseudocyst, ligature of the splenic artery, splenectomy and closure of the gastric bleeding fistula were performed. There were no postoperative complications and the follow-up showed no other complications. Aneurysms and pseudoaneurysms of the splenic artery are very frequent, generally asymptomatic (70% of the cases) and in half of the cases they are occasionally diagnosticated. The bleeding of pseudoaneurysm for rupture or fistulization is a very rare and serious complication associated to a high percentage of mortality.

Predicting recurrence after curative resection for gastric cancer: External validation of the Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system.

BACKGROUND: Most nomograms for Gastric Cancer (GC) were developed to predict overall survival (OS) after curative resection. The Italian Research Group for Gastric Cancer (GIRCG) prognostic scoring system (PSS) was designed to predict the recurrence risk after curative treatment based on pathologic tumor stage and treatment performed (D1-D2/D3 lymphadenectomy). This study was carried out to externally validate the GIRCG's PSS. PATIENTS AND METHODS: Adopting the same criteria used by GIRCG to build the PSS, 185 patients with GC operated with curative intention were selected. The median follow-up period was 77.8 months (1.93-150.8) for all patients and 102.5 months (60.9-150.8) for patients free of disease. The NRI (net reclassification improvement) was calculated to estimate the overall improvement in the reclassification of patients using the PSS in place of the TNM stage system. RESULTS: GC recurrence occurred in 70 (37.8%) patients. The mean time to recurrence was 22.2 (range 1.9-98.1) months. For patients with recurrence, the gain in the proportion of reclassification was 0.257 (p < 0.001), indicating an improvement of 26%. For patients without recurrence, the gain in the proportion of reclassification was -0.122 (p < 0.001), indicating a worsening of 12%. The NRI calculated was 0.135 (p = 0.0527). CONCLUSION: The GIRCG's PSS, which predicts the likelihood of recurrence after radical surgical treatment for GC, is more accurate than TNM system to predict recurrence mainly for high-risk patients. Yet, the PSS does not have the same effectiveness for low-risk patients, overestimating the chance of recurrence occurs even for disease-free patients.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Surgical management of advanced gastric cancer: An evolving issue.

Worldwide, gastric cancer represents the fifth most common cancer and the third leading cause of cancer deaths. Although the overall 5-year survival for resectable disease was more than 70% in Japan due to the implementation of screening programs resulting in detection of disease at earlier stages, in Western countries more than two thirds of gastric cancers are usually diagnosed in advanced stages reporting a 5-year survival rate of only 25.7%. Anyway surgical resection with extended lymph node dissection remains the only curative therapy for non-metastatic advanced gastric cancer, while neoadjuvant and adjuvant chemotherapies can improve the outcomes aimed at the reduction of recurrence and extension of survival. High-quality research and advances in technologies have contributed to well define the oncological outcomes and have stimulated many clinical studies testing multimodality managements in the advanced disease setting. This review article aims to outline and discuss open issues in current surgical management of advanced gastric cancer.

Extended lymphadenectomy in elderly and/or highly co-morbid gastric cancer patients: A retrospective multicenter study.

BACKGROUND: Gastrectomy with extended lymphadenectomy is considered the gold standard treatment for advanced gastric cancer, with no age- or comorbidity-related limitations. We evaluated the safety and efficacy of curative gastrectomy with extended nodal dissection, verifying survival in elderly and highly co-morbid patients. METHODS: In a retrospective multicenter study, we examined 1322 non-metastatic gastric-cancer patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January 2000 to December 2009. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) according to age and the Charlson Comorbidity Score were analyzed in relation to the extent of lymphadenectomy. RESULTS: Postoperative morbidity was 30.4%. Complications were more frequent in highly co-morbid elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were similar (29.9% and 33.2%, respectively), they increased following D2 in highly co-morbid elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0% vs. 37.6% in D1, p < 0.001 and 72.6% vs. 58.1% in D1, p < 0.001, respectively) in all patients. In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs. 21.2% in D1, p = 0.008 and 47.5% vs. 30.6% in D1, p = 0.001, respectively), although it was present only in DSS when highly co-morbid elderly patients were considered. CONCLUSION: Extended lymphadenectomy confirmed better survival rates in gastric cancer patients. Due to high postoperative complication rate and no significant improvement of the OS, D1 lymphadenectomy should be considered in elderly and/or highly co-morbid gastric cancer patients.