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Background Surgery is the primary treatment that can offer potential cure for gastric cancer, but is associated with significant risks. Identifying optimal surgical approaches should be based on comparing outcomes from well designed trials. Currently, trials report different outcomes, making synthesis of evidence difficult. To address this, the aim of this study was to develop a core outcome set (COS)—a standardized group of outcomes important to key international stakeholders—that should be reported by future trials in this field. Methods Stage 1 of the study involved identifying potentially important outcomes from previous trials and a series of patient interviews. Stage 2 involved patients and healthcare professionals prioritizing outcomes using a multilanguage international Delphi survey that informed an international consensus meeting at which the COS was finalized. Results Some 498 outcomes were identified from previously reported trials and patient interviews, and rationalized into 56 items presented in the Delphi survey. A total of 952 patients, surgeons, and nurses enrolled in round 1 of the survey, and 662 (70 per cent) completed round 2. Following the consensus meeting, eight outcomes were included in the COS: disease-free survival, disease-specific survival, surgery-related death, recurrence, completeness of tumour removal, overall quality of life, nutritional effects, and ‘serious’ adverse events. Conclusion A COS for surgical trials in gastric cancer has been developed with international patients and healthcare professionals. This is a minimum set of outcomes that is recommended to be used in all future trials in this field to improve trial design and synthesis of evidence. more...

Purpose The clinical significance of VEGF-A expression in gastric cancer (GC) has been reported with contradicting results. We analyzed the expression and clinical significance of VEGF-A in a wide Italian cohort of GC specimens. Methods VEGF-A expression was tested by immunohistochemistry in 507 patients with GC of all clinical stages. The impact of VEGF-A on overall survival (OS) was evaluated in conjunction with clinical and pathological parameters. Results In the Italian cohort we studied VEGF-A was not an independent prognostic factor neither at the univariate nor at multivariate analysis. Conclusions Although frequently expressed, in our study VEGF-A was not able to discriminate between groups of patients with different risk. more...

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. more...

The actual benefit of extended lymphadenectomy in terms of survival in the surgical treatment of gastric cancer is still a debated issue. The aim of this non-randomized prospective multicentre study was to evaluate long-term survival in a group of patients with involvement of the second level lymph nodes, which would not have been removed with a limited lymphadenectomy. From 1991 to 1997, 451 patients with primary gastric cancer underwent curative resection with extended lymphadenectomy in three italian surgical departments. Lymph node stations were removed and classified according to the rules of the Japanese Research Society for Gastric Cancer; in all cases, retrieval of the lymph nodes was performed by the surgeon on the fresh specimen. Metastases to lymph node stations 7-12 were found in 126 patients out of 451 (27.9%). A mean number of 13 +/- 9 positive lymph nodes (range: 1-42) was found in these cases. Lymph node stations 7 and 8 showed the highest incidence of metastases (61.1% and 44.4%, respectively). Morbidity and mortality rates were 17.1% and 2% in 451 cases treated by extended lymphadenectomy, and 21.4% and 3.2%, respectively, in 126 cases with involvement of second level lymph nodes. In this group of patients, the five-year survival rate was 32 +/- 4%. Multivariate analysis, identified depth of invasion (P0.0001, relative risk (RR) 2.4) and the number of positive lymph nodes (P0.001, RR 1.6) as significant predictors of a poor prognosis. Japanese-type extended lymphadenectomy is associated with low morbidity and mortality rates if performed in specialised centres. The incidence of metastases in lymph node stations removed with this technique is by no means negligible. This procedure could be beneficial as regards long-term survival even in patients with involvement of regional lymph nodes. more...

The aim of this multicenter longitudinal study was to evaluate the pattern of recurrence in patients submitted to potentially curative surgery for intestinal-type and diffuse-type gastric cancer. The study included 412 patients surgically treated at three Italian surgical departments, subdivided into 273 intestinal-type cases (group A) and 139 diffuse-type cases (group B). Recurrence of disease was found in 41% of group A cases and 65% of group B cases (p < 0.0001). The incidence of locoregional, hematogenous, and peritoneal recurrence was 20%, 19%, and 9% in group A, and 27%, 16%, and 34% in group B, respectively; the difference between the two groups was statistically significant for peritoneal recurrence (p < 0.0001). Multivariate analysis identified as prognostic variables lymph node status, depth of invasion, extent of lymphadenectomy, advanced age, and male gender in group A; depth of invasion, extent of lymphadenectomy, tumor size, and lymph node status, in group B. Whereas in group A the incidence of peritoneal recurrence was limited in all subgroups examined, in group B very high rates were observed in cases with infiltration of the serosa, involvement of second-level lymph nodes, or large tumor size. The notable difference in the risk of peritoneal recurrence between the intestinal and diffuse types should be taken into consideration in the therapeutic approach to gastric cancer. more...

The prognostic significance of the histological type in gastric cancer is still debated. The correlation between intestinal-diffuse type and tumor recurrence was investigated in a prospective multicentric study which collects the cases from three surgical Departments of Italy.Four-hundred and twelve patients who underwent a potentially curative resection between 1988 and 1995 were considered; 273 cases were classified as intestinal type (group A), and 139 cases as diffuse type (group B). Mixed cases were excluded from the study. All patients were included in a complete follow-up program for the early diagnosis of recurrence. Clinical, histopathological and surgical factors were examined for their influence on tumor recurrence by univariate and multivariate analysis.Recurrence rate was 41.4% in intestinal type, and 65.5% in diffuse type cases (p0.0001). In group A, multivariate analysis identified nodal status (p0.0001), depth of invasion (p0.005), lymph node dissection (D1 vs. D2-D4, p0.01), advanced age (p0.01) and male sex (p0.05) as significant prognostic factors. In group B, depth of invasion (p0.0005), lymph node dissection (p0.005), tumor size (p0.01) and nodal status (p0.05) resulted as significant variables; no preventive effect on tumor recurrence was found for D2 vs. D1 lymphadenectomy. Multivariate analysis performed on the totality of the cases demonstrated diffuse type as an independent predictor of poor prognosis (relative risk: 1.67, p0.001).Diffuse type of gastric cancer is an independent risk factor for tumor recurrence as compared with intestinal type; clinical and pathological variables play a different role as prognostic factors in the two histotypes. more...

The topic chosen by the Board of the Italian Society of Surgery for the 2013 annual Consensus Conference was gastric cancer. With this purpose, under the direction of 2 chairmen, 36 experts nominated by the Regional Societies of Surgery and by the Italian Research Group for Gastric Cancer (GIRCG) participated in an experts consensus exercise, preceded by a questionnaire and mainly held by telematic vote, in accordance with the rules of the Delphi method. The results of this Consensus Conference, presented to the 115th National Congress of the Italian Society of Surgery, and approved in plenary session, are reported in the present paper. more...

BackgroundAfter the REGATTA trial, patients with stage IV gastric cancer could only benefit from chemotherapy (CHT). However, some of these patients may respond extraordinarily to palliative chemotherapy, converting their disease to a radically operable stage. We present a single centre experience in treating peritoneal carcinomatosis from gastric cancer.MethodsAll patients with stage IV gastric cancer with peritoneal metastases as a single metastatic site operated at a single centre between 2005 and 2020 were included. Cases were grouped according to the treatment received.ResultsA total of 118 patients were considered, 46 were submitted to palliative gastrectomy (11 were considered M1 because of an unsuspected positive peritoneal cytology), and 20 were submitted to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) because of a p = 0.742).ConclusionsConversion surgery for peritoneal carcinomatosis from gastric cancer was associated with long survival and it should always be taken into consideration in this group of patients. more...

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. more...

Background. More than 50% of operable GEA relapse after curative-intent resection. We aimed at externally validating a nomogram to enable a more accurate estimate of individualized risk in resected GEA. Methods. Medical records of a training cohort (TC) and a validation cohort (VC) of patients undergoing radical surgery for c/uT2-T4 and/or node-positive GEA were retrieved, and potentially interesting variables were collected. Cox proportional hazards in univariate and multivariate regressions were used to assess the effects of the prognostic factors on OS. A graphical nomogram was constructed using R software’s package Regression Modeling Strategies (ver. 5.0-1). The performance of the prognostic model was evaluated and validated. Results. The TC and VC consisted of 185 and 151 patients. ECOG:PS > 0 (p < 0.001), angioinvasion (p < 0.001), log (Neutrophil/Lymphocyte ratio) (p < 0.001), and nodal status (p = 0.016) were independent prognostic values in the TC. They were used for the construction of a nomogram estimating 3- and 5-year OS. The discriminatory ability of the model was evaluated with the c-Harrell index. A 3-tier scoring system was developed through a linear predictor grouped by 25 and 75 percentiles, strengthening the model’s good discrimination (p < 0.001). A calibration plot demonstrated a concordance between the predicted and actual survival in the TC and VC. A decision curve analysis was plotted that depicted the nomogram’s clinical utility. Conclusions. We externally validated a prognostic nomogram to predict OS in a joint independent cohort of resectable GEA; the NOMOGAST could represent a valuable tool in assisting decision-making. This tool incorporates readily available and inexpensive patient and disease characteristics as well as immune-inflammatory determinants. It is accurate, generalizable, and clinically effectivex. more...

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. more...

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. more...

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. more...

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18&ndash, 1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2&ndash, 65.8) in arm A and 40.3% (95% CI: 28.9&ndash, 55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3&ndash, 72.2) and 53.9% (95% CI: 35.5&ndash, 69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group. more...

Background: The prognostic value of T subclassification in patients with gastric carcinoma has been just implemented in the new AJCC TNM staging system, which has reclassified T2a and T2b into T2 and T3 tumors, respectively. The aim of the present study was to validate the prognostic significance of the new T categorization within the frame of the latest TNM staging system. Methods: We retrospectively reviewed the records of 686 T2/T3 patients among 2155 subjects who underwent radical resection for gastric carcinoma at six Italian centers from 1988 through 2006. Results: Upon multivariate analysis, the new T categories, extent of lymph node dissection (D) and patient's age were retained by the survival model as independent prognostic factors. In particular, the death risk for patients with T3 tumors was higher than that of patients with T2 tumors (HR: 1.42, P = 0.005). Among the 686 patients previously classified as having T2 tumors, patients with T2 and T3 disease were 270 (39.4%) and 416 (60.6%), respectively. After a median follow-up of 55 months, the 5-year overall survival rates were 67.3% and 52.3% for patients with T2 and T3 tumors, respectively (P < 0.001). The survival advantage for the T2 as compared to T3 category was maintained even when N0 and N+ patients were separately considered (P = 0.0154 and P < 0.001, respectively). Conclusions: Our data confirm the prognostic difference between the newly proposed T2 and T3 categories, which should be implemented in the routine clinical practice to improve risk stratification of patients with gastric cancer. more...

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 more...

BACKGROUND: Duodenal fistula (DF) after gastrectomy continues to be a life-threatening problem. We performed a retrospective multicenter study analyzing the characteristics of DF after elective gastrectomy for malignant disease. METHODS: Three thousand seven hundred eighty-five patients who had undergone gastrectomy with duodenal stump in 11 Italian surgical units were analyzed. RESULTS: Sixty-eight DFs occurred, with a median frequency of 1.6% and a mortality rate of 16%. Complications were mainly septic but fistulas or bleeding of surrounding organs accounted for about 30%. Reoperation was performed in 40% of patients. We observed a correlation between mortality and age (hazard ratio 1.09; 95% CI 1.00-1.20) and serum albumin (hazard ratio 0.90; 95% CI 0.83-0.99). The appearance of further complications was associated with reoperation (P < 0.001) and death (P = 0.054), while the preservation of oral feeding was related to DF healing (P < 0.001). CONCLUSIONS: This paper represents the largest series ever published on DF and shows that its features have changed in the last 20 years. DF alone no longer leads to death and some complications observed in the past have disappeared, while new ones are emerging. Nowadays, medical therapy is preferred and surgery is indicated only in cases of abdominal sepsis or bleeding. more...

Aims The proportion between metastatic and examined lymph nodes (N-ratio) has been proposed as an independent prognostic factor in patients with gastric cancer. In the present work we validated the reliability of N-ratio in a large, multicenter series. Patients and methods We retrospectively reviewed the data of 1853 patients who underwent radical resection for gastric carcinoma. Survival of patients with >15 (Group-1, n = 1421) and those with ≤15 (Group-2, n = 432) lymph nodes examined was separately analyzed in order to evaluate the influence of lymph node dissection on disease staging. N-ratio categories (N-ratio 0, 0%; N-ratio 1, 1–9%; N-ratio 2, 10–25%; N-ratio 3, >25%) were determined by the best cut-off approach. Results At multivariate analysis, N-ratio (but not TNM N-category) was retained as an independent prognostic factor both in Group-1 and Group-2 (HR for N-ratio 1, N-ratio 2 and N-ratio 3 = 1.67, 2.96 and 6.59, and 1.56, 2.68 and 4.28, respectively). After a median follow-up of 45.5 months, the 5-year overall survival rates of TNM N0, N1 and N2 patients were significantly different in Group-1 vs Group-2. This was not the case when adopting the N-ratio classification, suggesting that a low number of excised lymph nodes can lead to patients being understaged using the N-category, but not N-ratio. Moreover, N-ratio identified subsets of patients with significantly different survival rates within TNM N1 and N2 categories in both groups. Conclusions N-ratio is a simple and reproducible prognostic tool that can stratify patients with gastric cancer, including those cases with limited lymph node dissection. These data support the rationale to propose the implementation of N-ratio into the current TNM staging system. more...

Purpose: To investigate whether the ratio between metastatic and examined lymph nodes (N ratio) is a better prognostic factor as compared with traditional staging systems in patients with gastric cancer regardless of the extension of lymph node dissection. Patients & Methods: We retrospectively reviewed the data of 1853 patients who underwent radical resection for gastric carcinoma at 6 Italian centers. Patients with >15 (group 1, n = 1421) and those with 25%) were determined by the best cut-off approach. Results: After a median follow-up of 45.5 months (range, 4-182 months), the 5-year overall survival of N0, N1, and N2 patients of group 1 versus group 2 was 83.4% versus 74.2% (P = 0.0026), 54.3% versus 44.3% (P = 0.018), and 32.7% versus 14.7% (P = 0.004), respectively, suggesting that a low number of excised lymph nodes can lead to the understaging of patients. N ratio identified subsets of patients with significantly different survival rates within NI and N2 stages in both groups. At multivariate analysis, the N ratio (but not N stage) was retained as an independent prognostic factor both in group I and group 2 (HR for N ratio 1, N ratio 2, and N ratio 3 = 1.67, 2.96, and 6.59, and 1.56, 2.68, and 4.28, respectively). In our series, the implementation of N ratio led to the identification of subgroups of patients prognostically more homogeneous than those classified by the TNM system. Conclusion: N ratio is a simple and reproducible prognostic tool that can stratify patients with gastric cancer also in case of limited lymph node dissection. These data may represent the rational for improving the prognostic power of current UICC TNM staging system and ultimately the selection of patients who may most benefit from adjuvant treatments. more...