Utility of Abdominal Drain in Gastrectomy (ADiGe) Trial: study protocol for a multicenter non-inferiority randomized trial.

BACKGROUND: Prophylactic use of abdominal drain in gastrectomy has been questioned in the last 15 years, and a 2015 Cochrane meta-analysis on four RCTs concluded that there was no convincing evidence to the routine drain placement in gastrectomy. Nevertheless, the authors evidenced the moderate/low quality of the included studies and highlighted how 3 out of 4 came from Eastern countries. After 2015, only retrospective studies have been published, all with inconsistent results. METHODS: ADiGe (Abdominal Drain in Gastrectomy) Trial is a multicenter prospective randomized non-inferiority trial with a parallel design. It aimed to verify whether avoiding routine use of abdominal drain is burdened with complications, particularly an increase in postoperative invasive procedures. Patients with gastric cancer, scheduled for subtotal or total gastrectomy with curative intent, are eligible for inclusion, irrespective of previous oncological treatment. The primary composite endpoint is reoperation or percutaneous drainage procedures within 30 postoperative days. The primary analysis will verify whether the incidence of the primary composite endpoint is higher in the experimental arm, avoiding routine drain placement, than control arm, undergoing prophylactic drain placement, in order to falsify or support the null hypothesis of inferiority. Secondary endpoints assessed for superiority are overall morbidity and mortality, Comprehensive Complications Index, incidence and time for diagnosis of anastomotic and duodenal leaks, length of hospital stay, and readmission rate. Assuming one-sided alpha of 5%, and cumulative incidence of the primary composite endpoint of 6.4% in the control arm and 4.2% in the experimental one, 364 patients allow to achieve 80% power to detect a non-inferiority margin difference between the arm proportions of 3.6%. Considering a 10% drop-out rate, 404 patients are needed. In order to have a balanced percentage between total and subtotal gastrectomy, recruitment will end at 202 patients for each type of gastrectomy. The surgeon and the patient are blinded until the end of the operation, while postoperative course is not blinded to the patient and caregivers. DISCUSSION: ADiGe Trial could contribute to critically re-evaluate the role of prophylactic drain in gastrectomy, a still widely used procedure. TRIAL REGISTRATION: Prospectively registered (last updated on 29 October 2020) at ClinicalTrials.gov with the identifier NCT04227951 .

Lymphadenectomy for gastric cancer at European specialist centres.

BACKGROUND AND AIMS: The aim of this project was to evaluate the current practice of D2 in Europe. MATERIALS AND METHODS: In the first part of the study, 18 European high volume gastric cancer centres completed a questionnaire, designed to evaluate their preferred lymphadenectomy in a series of clinical scenarios. Surgeon compliance with international guidelines for lymphadenectomy was evaluated. In the second part, information on 381 gastrectomies performed for primary gastric cancer by participating surgeons from January to December 2015, was retrospectively collected. RESULTS: Surgical choice in clinical scenarios was affected by tumour stage and to a lesser extent, site and histotype. In particular, in early gastric cancer with diffuse histology D2 was recommended by >70% of surgeons, while this percentage dropped to 44% in intestinal histotypes. When surgeons selected a D2 dissection, the procedure was rarely fully compliant with the Japanese guidelines. In the review of gastrectomy experience an adequate number of nodes (≥15 nodes) was retrieved in 97% after D2. The number of retrieved nodes varied with median values ranging from 17 to 35 (p < 0.001) after D2. D2/D2+ was more frequently performed in mixed (80%) and diffuse (78%) cases than in intestinal cases (69%) (p = 0.016). CONCLUSIONS: Although an adequate lymphadenectomy was achieved in almost all cases in dedicated centres, there is still variation in the number of retrieved nodes. Tumor histology largely affects surgeon's choice as regards the extent of lymphadenectomy; however, the role of histology in planning surgical procedures needs to be verified in prospective trials.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

Mid-transverse colon cancer and extended versus transverse colectomy: Results of the Italian society of surgical oncology colorectal cancer network (SICO CCN) multicenter collaborative study.

INTRODUCTION: Transverse colon cancer (TCC) is poorly studied, and TCC cases are often excluded from large prospective randomized trials because of their complexity and their potentially high complication rate. The best surgical approach for TCC has yet to be established. The aim of this large retrospective multicenter Italian series is to investigate the advantages and disadvantages of both hemicolectomy and transverse colectomy in order to identify the best surgical approach. MATERIALS AND METHODS: This was a retrospective cohort study of patients with mid-transverse colon cancer treated with a segmental colon resection or an extended hemicolectomy (right or left) between 2006 and 2016 in 28 high-volume (more than 70 procedures/year) Italian referral centers for colorectal surgery. RESULTS: The study included 1529 patients, 388 of whom underwent a segmental resection while 1141 underwent an extended resection. A higher number of complications has been reported in the segmental group than in the extended group (30.1% versus 23.6%; p 0.010). In 42 cases the main complication was the anastomotic leak (4.4% versus 2.2%; p 0.020). Recovery outcomes also showed statistical differences: time to first flatus (p 0.014), time to first mobilization (p 0.040), and overall hospital stay (p < 0.001) were significantly shorter in the extended group. Even if overall survival were similar between the groups (95.1% versus 97%; p 0.384), 3-year disease-free survival worsened after segmental resection (78.1% versus 86.2%; p 0.001). CONCLUSIONS: According to our results, an extended right colon resection for TCC seems to be surgically safer and more oncologically valid.

Lessons learned from 227 biological meshes used for the surgical treatment of ventral abdominal defects.

PURPOSE: The advantages of biological meshes for ventral hernia repair are still under debate. Given the high financial cost, the proper indications for biological meshes should be clarified to restrict their use to properly selected patients. METHODS: A retrospective database was instituted to register all cases of abdominal wall defect treated with biological meshes from 1/2010 to 3/2016. RESULTS: A total of 227 patients (mean age: 64 years) whose ventral abdominal defects were reconstructed with a biological mesh were included in the study. Patients were divided according to the 2010 four-level surgical-site complication risk grading system proposed by the Ventral Hernia Working Group (VHWG): Grade 1 (G1, 12 cases), Grade 2 (G2, 68 cases), Grade 3 (G3, 112 cases), and Grade 4 (G4, 35 cases). The surgical site complication rate was higher in patients with one or more risk factors (33.6% vs 19% in patients with no risk factors) (P = 0.68). Statistically significant risk factors associated with the onset of one or more postoperative surgical site complications included: diabetes, coronary artery disease, immunosuppression, and obesity. Recurrence was more common in patients with surgical site complications and mainly associated with infection (38.9%) and wound necrosis (44.4%), and in cases of inlay positioning of the mesh (36%). CONCLUSIONS: Due to their high costs, biological mesh should not be used in G1 patients. In infected fields (G4), they should only be used if no other surgical solution is feasible. There is a clear need to prospectively evaluate the performance of biological meshes.

Perianastomotic drainage in Ivor-Lewis esophagectomy, does habit affect utility? An 11-year single-center experience.

Anastomotic leakage (AL) is a deadly complication after Ivor-Lewis esophagectomy. The use of an anastomotic drainage (AD), to diagnose and to potentially treat the leakage, is still a widespread practice. At present, scientific literature is lacking in this topic and its use is based on each center experience. We performed a retrospective analysis of 239 consecutive patients who underwent an Ivor-Lewis esophagectomy in our Department from 01/01/2006 to 31/12/2017. Until 28/02/2014, a transthoracic anastomotic drainage was routinely placed in 119 patients (anastomotic-drain group). Drainage removal was planned on POD 5 after the resume of oral intake. In the remaining 120 cases, no drainage was placed (no anastomotic-drain group). We compared the two groups to assess whether the anastomotic drainage had an impact on the timing of the anastomotic leakage diagnosis and treatment. In our series, we observed 9 anastomotic leaks in the first group (7.6%) and 3 in the second one (2.5%). In the anastomotic-drain group, median time for leak diagnosis was 10 days, and notably, in seven cases, the anastomotic drainage was already removed. Considering all the patients who experienced an AL, a re-operation was mandatory in one case, while endoscopic treatment was chosen for five cases and conservative treatment was adopted in three cases. The median hospital length of stay in these patients was 31 days. In the no anastomotic-drain group, one patient with anastomotic leakage was treated conservatively and discharged after 34 days. The other two cases were re-operated and an esophageal prosthesis was placed in both cases, and these patients were discharged, respectively, on POD 28 and POD 38. Concluding, the role of the anastomotic drain in Ivor-Lewis esophagectomy is still unclear. There is a shortage of the literature on this topic and our experience shows that the anastomotic drain has a limited sensibility in AL diagnosis and cannot replace the clinical signs and symptoms. Moreover, the drain it is often removed before the leakage becomes visible. In selected patients with a less severe leak, the anastomotic drain can be an effective treatment, but often a percutaneous drainage, it is an effective alternative choice. In severe dehiscence with sepsis, a reoperation remains the mainstay to control the mediastinal contamination and to eventually treat the leakage.

The impact of experience on short- and long-term outcomes on gastric ESD: a western series.

Endoscopic submucosal dissection (ESD) represents the standard of care for early gastric cancer in Eastern countries. Nevertheless, in the West, this procedure is not widespread. Aim of the study was to confirm the feasibility and the efficacy of ESD in the West. A total of 60 ESD were performed between January 2005 and December 2014 by two expert endoscopists. The analysis, based on a retrospective collected database, was conducted by dividing the study period in three subgroups. Clinical and technical outcomes have been compared. Rates of complete, curative and en bloc resection did not significantly change among the study periods. Three cases of perforation occurred (5%), one in each period. The operation time significantly decreased from the second to the third period (p < 0.001). When adjusting for gender, tumor size and site in multivariable analysis, operation time decreased by nearly 90 min from the first to the second period, and by more than 3 h from the first to the last period. The median follow-up was 33 months. No cases of local or lymphnodal recurrence were detected during the study period. One patient presented a synchronous lesion, whilst four metachronous lesions have been discovered after a median follow-up of 11 months. Our experience supports the feasibility and safety of ESD in the West, if an adequate learning curve is accomplished. Long-term outcomes are comparable to the Eastern series.

Enhanced recovery protocol in esophagectomy, is it really worth it? A cost analysis related to team experience and protocol compliance.

Application of enhanced recovery protocols (ERP) in esophageal surgery seems to lead an advantage in terms of length of hospital staying and outcomes, but only few data exist on its cost effectiveness. Previous literature analyzed pre- and post-ERP groups, finding a cost reduction with the introduction of the pathway. We aimed to study the influence on costs of accumulating experience and compliance in an ERP group. Seventy-one patients have been treated at our institution from January 2014 to June 2017 with our ERP for Ivor-Lewis esophagectomy. Direct costs were divided into subcategories and were analyzed as a function of calendar year and compliance. Factor affecting costs were searched. Univariable analysis highlighted a significant reduction in costs over time. Increase in compliance led to a progressive cost reduction for each ERP item completed (€14 852-€11 045). While age was not found to significantly influence the cost (p = 0.341), complications seemed to nullify the effect of experience: the median was €11 507 in uncomplicated patients, and increased to €13 791 in Clavien-Dindo 3-4 (CD3-4) patients. Compliance and CD3-4 remained significant also in multivariable analysis, accomplished by quantile regression, while year of surgery lost its significance. Our results evidence how accumulating experience in ERP led to a cost reduction over time, which was mainly mediated by an increase in compliance. Indeed, compliance was the main factor in reducing ERP cost while CD3-4 complications were the most important factor in cost increasing, nullifying the benefit of compliance.

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.

Enhanced recovery after surgery protocol in patients undergoing esophagectomy for cancer: a single center experience.

This article is about an emerging issue in esophageal surgery: enhanced recovery after surgery (ERAS) Few data are published in literature and its safety and feasibility is still debated. The focus of our paper is on the feasibility of an ERAS protocol for esophagectomy (including both the Ivor-Lewis and McKeown procedure) in a high volume center comparing to a standard perioperative protocol. We introduced a novelty item on this type of surgery: resume of oral feeding in the first postoperative day. We analyzed the dropout rate for each item and the postoperative morbidity. We studied 39 patients operated in the Upper GI division of Verona University Hospital between January 2013 and August 2014; 22 patients (ERAS group) were studied in a perspective way while 17 patients (standard group) were studied retrospectively. The enhanced recovery protocol included intraoperative fluid management, time of extubation after surgery, intensive care unit discharge, drains and nasogastric tube management, mobilization of the patient, oral food intake. We compared the results between the two groups in term of hospital stay, postoperative morbidity and mortality. We also calculated the percentage completion of the protocol, evaluating patient drop-out rates for each of the items. Patients showed an improvement in the ERAS group in terms of earlier extubation, earlier intensive care unit discharge (p < 0.01), earlier thoracic drain, urinary catheter (p < 0.01) and nasogastric tube removal (p = 0.02), earlier mobilization (p < 0.01), and resume of oral feeding (p < 0.01). Median length of hospital stays in the ERAS group was 9 days while in the standard group was 10 days (p = 0.23). Postoperative morbidity and mortality were comparable between the two groups. This study shows the feasibility and safety of an ERAS protocol for esophageal surgery in a high-volume center. These data strengthen the literature results on this argument calling for larger sample size studies.

Genetic prediction of long-term survival after neoadjuvant chemoradiation in locally advanced esophageal cancer.

Candidate genes involved in DNA repair, 5-fluorouracil metabolism and drug detoxification were genotyped in 124 patients receiving neoadjuvant chemoradiation treatment for locally advanced esophageal cancer and their predictive role for long-term relapse-free survival (RFS) and cancer-specific survival (CSS) were evaluated. A panel including MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC, defined as high-risk genotypes, discriminated subgroups with significantly different outcomes. When the panel was combined with histology, patients split into two subsets with 5-year RFS and CSS rates of 65% vs 27% (hazard ratio (HR) 3.0, P<0.0001) and 69% vs 31% (HR 2.9, P<0.0001), respectively. Combining the 5-single-nucleotide polymorphism (5-SNP) panel with pathological response defined two major informative risk classes with 5-year PFS and CSS rates of 79.4% vs 17.7% (HR 6.71, P<0.0001) and 79.3% vs 26.3% (HR 6.25, P<0.0001), respectively. This classification achieved a sensitivity of 79%, a specificity of 85.4% and an accuracy of 81.8%.

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.

Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis.

In this study, we evaluated whether the presence of genetic alterations detected by next generation sequencing may define outcome in a prognostically-selected and histology-restricted population of resected gastric cancer (RGC). Intestinal type RGC samples from 34 patients, including 21 best and 13 worst prognostic performers, were studied. Mutations in 50 cancer-associated genes were evaluated. A significant difference between good and poor prognosis was found according to clinico-pathologic factors. The most commonly mutated genes in the whole population were PIK3CA (29.4%), KRAS (26.5%), TP53 (26.5%) MET (8.8%), SMAD4 (8.8%) and STK11 (8.8%). Multiple gene mutations were found in 14/21 (67%) patients with good prognosis, and 3/13 (23%) in the poor prognosis group. A single gene alteration was found in 5/21 (24%) good and 6/13 (46%) poor prognosis patients. No mutation was found in 2/21 (9.5%) and 4/13 (31%) of these groups, respectively. In the overall series, ß-catenin expression was the highest (82.4%), followed by E-Cadherin (76.5%) and FHIT (52.9%). The good prognosis group was characterized by a high mutation rate and microsatellite instability. Our proof-of-principle study demonstrates the feasibility of a molecular profiling approach with the aim to identify potentially druggable pathways and drive the development of customized therapies for RGC.

Description and analysis of clinical pathways for oesophago-gastric adenocarcinoma, in 10 European countries (the EURECCA upper gastro intestinal group - European Registration of Cancer Care).

AIMS: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group. METHODS: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared. RESULTS: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services. CONCLUSION: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience.

TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

BACKGROUND: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor ß activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. METHODS: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT-PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. RESULTS: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively). CONCLUSIONS: The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.

Impact of super-extended lymphadenectomy on relapse in advanced gastric cancer.

BACKGROUND: In gastric cancer the incidence of loco-regional recurrences decreases when lymphadenectomy is expanded from D1 to D2. The present study aimed at evaluating whether the pattern of recurrence in advanced gastric cancer (AGC) is further modified when lymphadenectomy is expanded from D2 to D3. METHODS: 568 patients undergoing curative gastrectomy for AGC (274 D2 and 294 D3) were considered; none of them received preoperative chemotherapy. MantelHaenszel test of homogeneity was used to verify whether the relation between extension of lymphadenectomy and recurrence varied as a function of each risk factor considered. The impact of D2 and D3 on relapse was further investigated by multivariable logistic regression model. RESULTS: Cumulative incidence of recurrence did not significantly differ after D2 and after D3 in the whole series (45.3% vs 46.3%; p = 0.866). However, the association between recurrence and extension of lymphadenectomy was significantly affected by histology (Mantel-Haenszel test of homogeneity: p = 0.007). The risk of recurrence was higher after D3 than after D2 (45.1% vs 35.3%) in the intestinal histotype while the pattern was reversed in the mixed/diffuse histotype (48.3% vs 61.5%). This pattern was confirmed in multivariable logistic regression: the interaction between histology and extension of lymphadenectomy was highly significant (p = 0.004). In particular, cumulative incidence of locoregional recurrences was higher in the diffuse histotype after D2, while being higher in the intestinal histotype after D3. CONCLUSIONS: D3 reverses the negative impact of diffuse histotype on relapses, especially on locoregional recurrences. Therefore D3 could be considered a valid therapeutic option in histotype-oriented tailored treatment of AGC.

[Spectrum of laparoscopic surgery for gastric tumors]. / Spektrum der laparoskopischen Chirurgie bei Magentumoren.

Minimally invasive operative procedures are increasingly being used for treating tumors of the upper gastrointestinal tract. While minimally invasive surgery (MIS) has become established as a standard procedure for benign tumors and gastrointestinal stromal tumors (GIST) based on current studies, the significance of MIS in the field of gastric cancer is the topic of heated debate. Until now the majority of studies and meta-analyses on gastric cancer have come from Asia and these indicate the advantages of MIS in terms of intraoperative blood loss, minor surgical complications and swifter convalescence although without any benefits in terms of long-term oncological results and quality of life. Unlike in Germany, gastric cancer in Asia with its unchanged high incidence rate, 50 % frequency of early carcinoma and predominantly distal tumor localization is treated at high-volume centres. Due to the proven marginal advantages of MIS over open resection described in the published studies no general recommendation for laparoscopic surgery of gastric cancer can currently be given.

VEGF-A clinical significance in gastric cancers: immunohistochemical analysis of a wide Italian cohort.

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.

Neoadjuvant concurrent chemoradiotherapy for locally advanced esophageal cancer in a single high-volume center.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is now considered the standard of care by many centers in the treatment of both squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus. This study evaluates the effectiveness of a neoadjuvant CRT protocol, as regards pathological complete response (pCR) rate and long-term survival. METHODS: From 2003 to 2011, at Upper G.I. Surgery Division of Verona University, 155 consecutive patients with locally advanced esophageal cancers (90 SCC, 65 adenocarcinoma) were treated with a single protocol of neoadjuvant CRT (docetaxel, cisplatin, and 5-fluorouracil with 50.4 Gy of concurrent radiotherapy). Response to CRT was evaluated through percentage of pathological complete response (pCR or ypT0N0), overall (OS) and disease-related survival (DRS), and pattern of relapse. RESULTS: One hundred thirty-one patients (84.5 %) underwent surgery. Radical resection (R0) was achieved in 123 patients (79.3 %), and pCR in 65 (41.9 %). Postoperative mortality was 0.7 % (one case). Five-year OS and DRS were respectively 43 and 49 % in the entire cohort, 52 and 59 % in R0 cases, and 72 and 81 % in pCR cases. Survival did not significantly differ between SCC and adenocarcinoma, except for pCR cases. Forty-nine patients suffered from relapse, which was mainly systemic in adenocarcinoma. Only three out of 26 pCR patients with previous adenocarcinoma developed relapse, always systemic. CONCLUSIONS: This study suggests that patients treated with the present protocol achieve good survival and high pCR rate. Further research is necessary to evaluate whether surgery on demand is feasible in selected patients, such as pCR patients with adenocarcinoma.

A clinical-biological risk stratification model for resected gastric cancer: prognostic impact of Her2, Fhit, and APC expression status.

BACKGROUND: To obtain a prognostic stratification model for resected gastric cancer patients. PATIENTS AND METHODS: Clinicopathological and molecular data (expression of Cdx2, Apc, ß-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios. RESULTS: Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P < 0.0001) and OS (21.4% and 82.0%, P < 0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P < 0.0001) and OS (6.1%, 34.6%, and 86.5%, P < 0.0001). CONCLUSIONS: A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.