Maurizio Degiuli

Morbidity and mortality after D2 gastrectomy for gastric cancer: results of the Italian Gastric Cancer Study Group prospective multicenter surgical study.

PURPOSE To investigate whether pancreas preservation together with a strict quality-control system could ameliorate the outcome of D2 resections for gastric cancer in Western patients. PATIENTS AND METHODS Italian patients with potentially curable proven adenocarcinoma of the stomach were registered from nine general and/or university hospitals in the area of Turin, Northern Italy. The study was performed according to the guidelines of the Japanese Research Society for Gastric Cancer (JRSGC). A strict quality-control system was guaranteed by a supervising surgeon of the reference center, who had stayed at the National Cancer Center Hospital, Tokyo, to learn the standard D2 gastrectomy. The standard procedure entailed removal of the level 1 and 2 lymph nodes. During total gastrectomy, the pancreas was preserved according to the Maruyama technique. RESULTS Between May 1994 and December 1996, 191 eligible patients were entered onto the study. The mean number of lymph nodes removed was 39. The overall morbidity rate was 20.9%. Surgical complications were observed in 16.7% of patients. Reoperation was necessary in six patients and was always successful. The overall hospital mortality rate was 3.1%; it was higher after total gastrectomy (7.46%) than after distal gastrectomy (0.8%). The average length of hospital stay was 17 days. CONCLUSION Given that postoperative morbidity and mortality rates are favorably comparable with those reported after the Western standard gastrectomy, the more extensive Japanese procedure with pancreas preservation can be regarded as a safe radical treatment of gastric cancer for selected Western patients treated in experienced centers.

Extended lymph node dissection for gastric cancer: results of a prospective, multi-centre analysis of morbidity and mortality in 118 consecutive cases

This study reports interim data on post-operative morbidity, hospital mortality and duration of hospital stay of Italian patients undergoing extended lymph-node dissection combined with a pancreas-preserving technique for gastric cancer. Of the 218 patients admitted to one of eight general and/or university hospitals in North Italy, 118 were enrolled in the trial. Eligible patients presented with proven primary adenocarcinoma of the stomach without clinical evidence of distant, peritoneal and/or liver metastasis, or metastasis in para-aortic and retropancreatic nodes at intraoperative biopsy. Patients underwent the extended procedure as described by the Japanese Research Society for the Study of Gastric Cancer, following the Maruyama pancreas-preserving technique. A strict quality control system was used to ensure the performance of a standard surgical treatment. A surgeon of the reference centre (M.D.), who stayed at the National Cancer Center Hospital in Tokyo to learn the D2 technique from a specialist Japanese surgeon, became the trial supervisor and assisted each surgeon in all the Italian participating centres. The patients were staged according both to the TNM system and to the General Rules for the Gastric Cancer Study in Surgery and Pathology. Post-operative surgical complications developed in 21 patients (17.8%). The non-surgical complication rate was 2.5%. Reoperation was necessary in six patients (5%), all of whom survived. The 30-day mortality rate for the eligible group was 2.5%. The overall hospital mortality was the same. Total gastrectomy was associated with a slightly higher operative mortality (4.5% vs 1.3%). Only one patient died from an anastomotic leak. The rate of leakages was higher after total than after distal gastrectomy (15.9 vs 5.4%); the association of splenectomy and pancreatectomy worsened the morbidity rate. D2 lymphadenectomy with pancreas-preserving technique, when performed at experienced centres, seems a feasible and safe technique for the radical treatment of gastric cancer in selected Western patients.

Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: Profile comparison.

A dendritic cell‐based cancer vaccine has recently received Food and Drug Administration approval in the USA based on its ability to prolong the survival of prostate cancer patients with advanced disease. However, tumor‐mediated immunosuppressive mechanisms might represent an obstacle to optimal performance of this therapy. We have recently shown that monocytes from the blood of prostate cancer patients can fully mature to dendritic cells only after the tumor is removed. Here, we have tested the hypothesis that these tumor‐driven monocytes correspond to the recently described subset of CD14+HLA‐DRlow immunosuppressor cells.

Gastric cancer: Current status of lymph node dissection

D2 procedure has been accepted in Far East as the standard treatment for both early (EGC) and advanced gastric cancer (AGC) for many decades. Recently EGC has been successfully treated with endoscopy by endoscopic mucosal resection or endoscopic submucosal dissection, when restricted or extended Gotodas criteria can be applied and D1+ surgery is offered only to patients not fitted for less invasive treatment. Furthermore, two randomised controlled trials (RCTs) have been demonstrating the non inferiority of minimally invasive technique as compared to standard open surgery for the treatment of early cases and recently the feasibility of adequate D1+ dissection has been demonstrated also for the robot assisted technique. In case of AGC the debate on the extent of nodal dissection has been open for many decades. While D2 gastrectomy was performed as the standard procedure in eastern countries, mostly based on observational and retrospective studies, in the west the Medical Research Council (MRC), Dutch and Italian RCTs have been conducted to show a survival benefit of D2 over D1 with evidence based medicine. Unfortunately both the MRC and the Dutch trials failed to show a survival benefit after the D2 procedure, mostly due to the significant increase of postoperative morbidity and mortality, which was referred to splenopancreatectomy. Only 15 years after the conclusion of its accrual, the Dutch trial could report a significant decrease of recurrence after D2 procedure. Recently the long term survival analysis of the Italian RCT could demonstrate a benefit for patients with positive nodes treated with D2 gastrectomy without splenopancreatectomy. As nowadays also in western countries D2 procedure can be done safely with pancreas preserving technique and without preventive splenectomy, it has been suggested in several national guidelines as the recommended procedure for patients with AGC.

Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET -amplified gastroesophageal xenopatient cohort

Amplification of the MET oncogene occurs in 2–4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although in vitro studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a MET-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high MET amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line. In vitro experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy—even in the absence of EGFR genetic alterations—induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.

The first European Union Network of Excellence for Gastric Cancer conference, Rome, Italy, April 2008

and somatic mutations of the APC gene are observed in 20%–40% of gastric adenomas, 6% of patients with intestinal metaplasia, and more than 50% of intestinaltype gastric cancers. The molecular biology of Helicobacter infection and the development of gastric cancer has been established. Progression to neoplasia appears to be a balance between apoptosis and proliferation. The Fas antigen pathway of apoptosis seems to be suppressed with persisting Helicobacter infection facilitating the Fas pathway for proliferation. There is differential expression of Fas ligands between intestinaland diffuse-type cancer, supporting distinct mechanisms of malignant transformation. The catalogue of gene alterations is growing rapidly. Multiple genetic and epigenetic alterations are involved over the course of the multistep conversion of normal cells to cancer. Identifi cation of specifi c genetic pathways may predict prognosis and infl uence treatment selection. Scarpa described data from DNA analysis showing how cases of microsatellite instability have a better prognosis than those with microsatellite stability. In addition, cancers which are positive on immunohistochemistry for the APC gene have a better prognosis than those with negative expression. DNA extraction, polymerase chain reaction PCR-RNA extraction, microsatellite assays, and microarray techniques are among the variety of techniques to facilitate this rapidly developing area of knowledge.

Complications after gastrectomy for cancer: Italian perspective

Surgery for gastric cancer is associated with significant major morbidity and an estimated mortality rate of about 5%. A reliable comparison of post-operative outcomes is hampered by the lack of a clear, universally recognized, definition of the most frequent complications. This paper reports the final results of a project launched by the Italian Research Group for Gastric Cancer in September 2015, whose goal was to propose a comprehensive list of surgical-related, gastric cancer-specific complications, with their definitions. The project was carried out through a multicentric, mainly web-based, consensus of experts. The proposed list, following assessment and validation by a group of experts of the European Chapter of the International Gastric Cancer Association, will form the basis for implementing a “Complications Recording Sheet” that can be disseminated worldwide for proper and reliable post-operative assessment.

Updates on Surgical Management of Advanced Gastric Cancer: New Evidence and Trends. Insights from the First International Course on Upper Gastrointestinal Surgery—Varese (Italy), December 2, 2011

Between the Ninth International Gastric Cancer Congress (IGCC) in South-Korea (Seoul, 2011) and the Tenth IGCC in Italy (Verona, 2013), the Insubria University organized the First International Course on Upper Gastrointestinal Surgery (Varese, December 2, 2011), with the patronage of Italian Research Group for Gastric Cancer (IRGGC) and the International Gastric Cancer Association (IGCA). The Course was intended to be a comprehensive update and review on advanced gastric cancer (GC) staging and treatment from well-known international experts. Clinical, research, and educational aspects of the surgeon’s role in the era of stage-adapted therapy were discussed. As highlighted in the meeting, in this final document we summarize and thoroughly analyze (with references only for well-acquired randomized control trials) the new and old open problems in surgical management of advanced GC.

Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake

AIM To investigate the neoadjuvant chemotherapy (NAC) effect on the survival of patients with proper stomach cancer submitted to D2 gastrectomy. METHODS We proceeded to a review of the literature with PubMed, Embase, ASCO and ESMO meeting abstracts as well as computerized use of the Cochrane Library for randomized controlled trials (RCTs) comparing NAC followed by surgery (NAC + S) with surgery alone (SA) for gastric cancer (GC). The primary outcome was the overall survival rate. Secondary outcomes were the site of the primary tumor, extension of node dissection according to Japanese Gastric Cancer Association (JGCA) performed in both arms, disease-specific (DSS) and disease-free survival (DFS) rates, clinical and pathological response rates and resectability rates after perioperative treatment. RESULTS We identified a total of 16 randomized controlled trials comparing NAC + S (n = 1089) with SA (n = 973) published in the period from January 1993 - March 2017. Only 6 of these studies were well-designed, structured trials in which the type of lymph node (LN) dissection performed or at least suggested in the trial protocol was reported. Two out of three of the RCTs with D2 lymphadenectomy performed in almost all cases failed to show survival benefit in the NAC arm. In the third RCT, the survival rate was not even reported, and the primary end points were the clinical outcomes of surgery with and without NAC. In the remaining three RCTs, D2 lymph node dissection was performed in less than 50% of cases or only recommended in the “Study Treatment” protocol without any description in the results of the procedure really perfomed. In one of the two studies, the benefit of NAC was evident only for esophagogastric junction (EGJ) cancers. In the second study, there was no overall survival benefit of NAC. In the last trial, which documented a survival benefit for the NAC arm, the chemotherapy effect was mostly evident for EGJ cancer, and more than one-fourth of patients did not have a proper stomach cancer. Additionally, several patients did not receive resectional surgery. Furthermore, the survival rates of international reference centers that provide adequate surgery for homogeneous stomach cancer patients’ populations are even higher than the survival rates reported after NAC followed by incomplete surgery. CONCLUSION NAC for GC has been rapidly introduced in international western guidelines without an evidence-based medicine-related demonstration of its efficacy for a homogeneous population of patients with only stomach tumors submitted to adequate surgery following JGCA guidelines with extended (D2) LN dissection. Additional larger sample-size multicentre RCTs comparing the newer NAC regimens including molecular therapies followed by adequate extended surgery with surgery alone are needed.

Intraoperative air leak test reduces the rate of postoperative anastomotic leak: analysis of 777 laparoscopic left-sided colon resections

BackgroundThe evidence supporting the use of the air leak test (ALT) after laparoscopic left-sided colon resection (LLCR) to test the colorectal anastomosis (CA) integrity aiming at reducing the rate of postoperative CA leakage (CAL) is not conclusive. The aim of this study was to challenge the use of ALT after elective LLCR.MethodsIt is a retrospective analysis of a prospectively collected database including all patients undergoing elective LLCR with primary CA and no proximal bowel diversion between January 1996 and June 2017. The decision to perform the ALT was based on the individual surgeon routine practice. A multivariate analysis was performed to identify independent risk factors for CAL.ResultsA total of 777 LLCR without proximal diversion were included in the analysis: the CA was tested in 398 patients (ALT group), while intraoperative ALT was not performed in 379 patients (No-ALT group). The two groups were similar in demographic characteristics, indication, and type of procedure. Intraoperative ALT was positive in 20 (5%) patients: a stoma was created in 14 (70%) patients, while 6 (30%) patients had a suture repair alone. Overall, postoperative CAL occurred in 32 patients (4.1%): the postoperative CAL rate was lower in ALT patients (2.5% vs. 5.8%, p = 0.025). A reoperation was needed in 87.5% of cases. No CAL occurred in the 20 patients with intraoperative positive ALT. Multivariate analysis showed that ASA score 3–4 (OR 5.39, 95% CI 2.53–11.51, p < 0.001) and male sex (OR 3.96, 95% CI 1.66–9.43, p = 0.002) were independent risk factors for postoperative CAL, while intraoperative ALT independently reduced the postoperative CAL rate (OR 0.40, 95% CI 0.18–0.88, p = 0.022).ConclusionIntraoperative ALT allows to detect AL defects after LLCR that can be effectively managed intraoperatively, leading to a significant lower risk of postoperative CAL.