10-year follow-up results of the European Achalasia Trial: a multicentre randomised controlled trial comparing pneumatic dilation with laparoscopic Heller myotomy.

OBJECTIVE: As achalasia is a chronic disorder, long-term follow-up data comparing different treatments are essential to select optimal clinical management. Here, we report on the 10-year follow-up of the European Achalasia Trial comparing endoscopic pneumodilation (PD) with laparoscopic Heller myotomy (LHM). DESIGN: A total of 201 newly diagnosed patients with achalasia were randomised to either a series of PDs (n=96) or LHM (n=105). Patients completed symptom (Eckardt score) and quality-of-life questionnaires, underwent functional tests and upper endoscopy. Primary outcome was therapeutic success defined as Eckardt score <3 at yearly follow-up. Secondary outcomes were the need for retreatment, lower oesophageal sphincter pressure, oesophageal emptying, gastro-oesophageal reflux and the rate of complications. RESULTS: After 10 years of follow-up, LHM (n=40) and PD (n=36) were equally effective in both the full analysis set (74% vs 74%, p=0.84) and the per protocol set (74% vs 86%, respectively, p=0.07). Subgroup analysis revealed that PD was superior to LHM for type 2 achalasia (p=0.03) while there was a trend, although not significant (p=0.05), that LHM performed better for type 3 achalasia. Barium column height after 5 min at timed barium oesophagram was significantly higher for patients treated with PD compared with LHM, while other parameters, including gastro-oesophageal reflux, were not different. CONCLUSIONS: PD and LHM are equally effective even after 10 years of follow-up with limited risk to develop gastro-oesophageal reflux. Based on these data, we conclude that PD and LHM can both be proposed as initial treatment of achalasia.

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as "benign." However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. SIGNIFICANCE: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Optimal Predictors of Postoperative Complications After Gastrectomy: Results from the Procalcitonin and C-reactive Protein for the Early Diagnosis of Anastomotic Leakage in Esophagogastric Surgery (PEDALES) Study.

BACKGROUND: The aim of this study was to define whether procalcitonin (PCT) is an earlier and more accurate predictor than C-reactive protein (CRP) for anastomotic leakage (AL) and major infective complications (MICs). METHODS: This was a prospective multicentric observational study conducted in three Italian centers, including all patients undergoing gastrectomy from May 2016 to April 2021. The endpoint was the assessment of the discrimination and accuracy achieved by the PCT and CRP values measured from POD1 to POD7 for predicting the occurrence of AL and MICs. Accuracy was assessed by calculating the area under the receiver operating curve (AUROC) values and Youden's statistics. Two charts were created for risk stratification during the postoperative course. RESULTS: The rate of AL was 4.6%, with a median day of occurrence on POD5 (range 3-26). The overall rate of major infective complications was 19.9%, with a median day of occurrence on POD6 (range 2-30). PCT showed a significant association with AL on POD6 and POD7 and a significant association with MICs on POD2, while CRP values showed a significant association with AL on POD4 and a significant association with MICs on POD1. No difference in the prediction of AL was observed between PCT and CRP, while CRP was found to be a superior predictor of major infective complications on POD5 (p = 0.024) and POD7 (p = 0.035). CONCLUSIONS: PCT was not superior to CRP as an early predictor of AL and major infective complications after gastrectomy. CRP should be used as the reference screening postoperative marker.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in multimodal therapy for patients with oligometastatic peritoneal gastric cancer: a randomized multicenter phase III trial PIPAC VEROne.

Objectives: Peritoneal carcinomatosis is the most frequent site of metastases in patients with gastric cancer. Current standard treatment is palliative systemic chemotherapy with very poor prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) resulted in long-term benefits in selected patients. Among patients with peritoneal carcinomatosis, a distinctive subset is oligometastatic disease which is characterized by low metastatic burden. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a recent technique of intraperitoneal chemotherapy used in combination with systemic chemotherapy with promising results. Methods: PIPAC VER-One is a prospective, randomized, multicenter phase III clinical trial that aims to evaluate the effectiveness of the use of PIPAC in combination with systemic chemotherapy in patients with gastric cancer and synchronous positive peritoneal cytology and/or limited peritoneal metastases (peritoneal cancer index [PCI] ≤6). Patients will be randomized into two arms: arm A (control) treated with standard systemic chemotherapy and arm B (experimental) treated with a bidirectional scheme including PIPAC and systemic chemotherapy. Results: Primary endpoint is the secondary resectability rate. Secondary endpoints are: overall survival (OS), pregression-free survival (PFS), disease-free survival (DFS), histological response assessed both on primary tumor and peritoneal lesions, quality of life (QoL), complication rate (CTCAE v5), and incremental cost-effectiveness ratios (ICER). Conclusions: The role of PIPAC in multimodal treatment for oligometastatic gastric cancer will be investigated in this trial.

Development of the PERI-Gastric (PEritoneal Recurrence Index) and PERI-Gram (Peritoneal Recurrence Index NomoGRAM) for predicting the risk of metachronous peritoneal carcinomatosis after gastrectomy with curative intent for gastric cancer.

BACKGROUND: A model that quantifies the risk of peritoneal recurrence would be a useful tool for improving decision-making in patients undergoing curative-aim gastrectomy for gastric cancer (GC). METHODS: Five Italian centers participated in this study. Two risk scores were created according to the two most widely used pathologic classifications of GC (the Lauren classification and the presence of signet-ring-cell features). The risk scores (the PERI-Gastric 1 and 2) were based on the results of multivariable logistic regressions and presented as nomograms (the PERI-Gram 1 and 2). Discrimination was assessed with the area under the curve (AUC) of receiver operating curves. Calibration graphs were constructed by plotting the actual versus the predicted rate of peritoneal recurrence. Internal validation was performed with a bootstrap resampling method (1000 iterations). RESULTS: The models were developed based on a population of 645 patients (selected from 1580 patients treated from 1998 to 2018). In the PERI-Gastric 1, significant variables were linitis plastica, stump GC, pT3-4, pN2-3 and the Lauren diffuse histotype, while in the PERI-Gastric 2, significant variables were linitis plastica, stump GC, pT3-4, pN2-3 and the presence of signet-ring cells. The AUC was 0,828 (0.778-0.877) for the PERI-Gastric 1 and 0,805 (0.755-0.855) for the PERI-Gastric 2. After bootstrap resampling, the PERI-Gastric 1 had a mean AUC of 0.775 (0.721-0.830) and a 95%CI estimate for the calibration slope of 0.852-1.505 and the PERI-Gastric 2 a mean AUC of 0.749 (0.693-0.805) and a 95%CI estimate for the slope of 0.777-1.351. The models are available at www.perigastric.org . CONCLUSIONS: We developed the PERI-Gastric and the PERI-Gram as instruments to determine the risk of peritoneal recurrence after curative-aim gastrectomy. These models could direct the administration of prophylactic intraperitoneal treatments.

Personalized therapeutic strategies in HER2-driven gastric cancer.

BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas.

PURPOSE: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents. EXPERIMENTAL DESIGN: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX). RESULTS: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. CONCLUSIONS: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.See related commentary by Openshaw et al., p. 2964.

Upper GI training of young surgeons: a reality full of hurdles. An international survey.

OBJECTIVE: Anecdotal evidence suggests that the training of young surgeons in Upper GI is not homogeneous across the world. This survey aimed to investigate the different training programs and the level of satisfaction of young surgeons with their surgical and scientific education pathway. DESIGN: A multiple-choice and single best answer format questionnaire was sent to 36 Upper GI chairs from international referral centres and then forwarded to young surgeons (attending physician less than 40 years old). The same questionnaire containing 5 main topics (demographics, residency, fellowship, academic research and activities, manual skill improvement) was posted online on a Surveymonkey website. SETTING: San Luigi University Hospital, Orbassano (Turin), Italy; Tertiary University Hospital. RESULTS: Fourteen replies were received from colleagues in 36 referral centres (39% response rate) and 65 voluntary answers from the survey monkey platform. During residency training, only 43% of residents had a specific training in upper GI tract surgery, which was characterized by a small number of interventions performed both with trainer scrubbed and unscrubbed. Fellowship programmes were undertaken by 49% of participants and 64% spent this training period abroad. Operative experience was reported by nearly all respondents with only 27% performing > 10 gastrectomies and only 11% performing > 10 oesophagectomies with the trainer scrubbed. The majority attended less than 10 meetings (58%), and 70% of them published less than 5 papers. CONCLUSIONS: The present survey reveals that the young surgeons of the twenty-first century face many hurdles during their surgical training. Overall, the surgical education settings are limited for both practical and scientific training for upper GI trainees. As a result, it is not possible to train in upper GI surgery to a level of competent independent practice.

Ileocecal valve syndrome and vitamin b12 deficiency after surgery: a multicentric prospective study.

Patients undergoing colon resection are often concerned about their functional outcomes after surgery. The primary aim of this prospective, multicentric study was to assess the intestinal activity and health-related quality-of-life (HRQL) after ileocecal valve removal. The secondary aim was to evaluate any vitamin B12 deficiency. The study included patients undergoing right colectomy, extended right colectomy and ileocecal resection for either neoplastic or benign disease. Selected items of GIQLI and EORTC QLQ-CR29 questionnaires were used to investigate intestinal activity and HRQL before and after surgery. Blood samples for vitamin B12 level were collected before and during the follow-up period. The empirical rule effect size (ERES) method was used to explain the clinical effect of statistical results. Linear mixed effect (LME) model for longitudinal data was applied to detect the most important parameters affecting the total score. A total of 158 patients were considered. Applying the ERES method, the analysis of both questionnaires showed clinically and statistically significant improvement of HRQL at the end of the follow-up period. Applying the LME model, worsening of HRQL was correlated with female gender and ileum length when using GIQLI questionnaire, and with female gender, open approach, and advanced cancer stage when using the EORTC QLQ-CR29 questionnaire. No significant deficiency in vitamin B12 levels was observed regardless of the length of surgical specimen. In our series, no deterioration of HRQL and no vitamin B12 deficiency were found during the follow-up period. Nevertheless, warning patients about potential changes in bowel habits is mandatory. In our series, no deterioration of HRQL and no vitamin B12 deficiency were found during the follow-up period. Nevertheless, warning patients about potential changes in bowel habits is mandatory.

Correction to: Ileocecal valve syndrome and vitamin b12 deficiency after surgery: a multicentric prospective study.

One of the co-author Eliana Cagnazzo has been incorrectly published. The correct co-author name has been copied below.

Intraoperative angiography with indocyanine green to assess anastomosis perfusion in patients undergoing laparoscopic colorectal resection: results of a multicenter randomized controlled trial.

BACKGROUND: Insufficient vascular supply is one of the main causes of anastomotic leak in colorectal surgery. Intraoperative indocyanine-green (ICG) angiography has been shown to provide information on tissue perfusion, identifying a well-perfused location for colonic and rectal transections, and thus possibly reducing the leak rate. Aim of this study was to evaluate the usefulness of intraoperative assessment of anastomotic perfusion using ICG angiography in patients undergoing left-sided colon or rectal resection with colorectal anastomosis. METHODS: This randomized trial involved 252 patients undergoing laparoscopic left-sided colon and rectal resection randomized 1:1 to intraoperative ICG or to subjective visual evaluation of the bowel perfusion without ICG. The primary aim was to assess whether ICG angiography could lead to a reduction in anastomotic leak rate. Secondary outcomes were possible changes in the surgical strategy and postoperative morbidity. RESULTS: After randomization, 12 patients were excluded. Accordingly, 240 patients were included in the analysis; 118 were in the study group, and 122 in the control group. ICG angiography showed insufficient perfusion of the colic stump, which led to extended bowel resection in 13 cases (11%). An anastomotic leak developed in 11 patients (9%) in the control group and in 6 patients (5%) in the study group (p = n.s.). CONCLUSIONS: Intraoperative ICG fluorescent angiography can effectively assess vascularization of the colic stump and anastomosis in patients undergoing colorectal resection. This method led to further proximal bowel resection in 13 cases, however, there was no statistically significant reduction of anastomotic leak rate in the ICG arm. CLINICAL TRIAL: ClinicalTrials.gov NCT02662946.

How Should We Measure the Quality of Lymphadenectomy for Gastric Cancer? Anatomical Versus Numerical Criterion.

AIM: To compare anatomical with numerical criterion to measure the quality of lymphadenectomy for gastric cancer. PATIENTS AND METHODS: We analyzed 447 gastric cancer patients with resectable tumor stage (R0 resection) with at least 16 examined lymph nodes. RESULTS: Of 447 patients, 82.6% underwent D2 lymphadenectomy for a median of total examined lymph nodes of 28. The 7-year disease-specific survival rate for the whole sample was 71.4%. Survival was significantly different between patients treated with D2 and D1 lymphadenectomy (77.4% versus 44.3%; p < 0.001) and between patients with total examined lymph nodes ≥ 28 and < 28 (74.5% versus 62.3%; p = 0.041). Anatomical criterion significantly differentiated 7-year survival in patients stratified according to a numerical parameter. CONCLUSION: We should still consider the anatomical criterion as the best item to measure the quality of lymphadenectomy for gastric cancer.

Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia.

BACKGROUND: Pneumatic dilation and laparoscopic Heller's myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. METHODS: In a multicenter, randomized trial, we compared POEM with LHM plus Dor's fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of -12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. RESULTS: A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor's fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], -8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, -0.75 mm Hg; 95% CI, -2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, -4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. CONCLUSIONS: In this randomized trial, POEM was noninferior to LHM plus Dor's fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.).

A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell-Intrinsic Transcriptional MSI Traits.

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

Incidence and treatment of mediastinal leakage after esophagectomy: Insights from the multicenter study on mediastinal leaks.

BACKGROUND: Mediastinal leakage (ML) is one of the most feared complications of esophagectomy. A standard strategy for its diagnosis and treatment has been difficult to establish because of the great variability in their incidence and mortality rates reported in the existing series. AIM: To assess the incidence, predictive factors, treatment, and associated mortality rate of mediastinal leakage using the standardized definition of mediastinal leaks recently proposed by the Esophagectomy Complications Consensus Group (ECCG). METHODS: Seven Italian surgical centers (five high-volume, two low-volume) affiliated with the Italian Society for the Study of Esophageal Diseases designed and implemented a retrospective study including all esophagectomies (n = 501) with intrathoracic esophagogastric anastomosis performed from 2014 to 2017. Anastomotic MLs were defined according to the classification recently proposed by the ECCG. RESULTS: Fifty-nine cases of ML were recorded, yielding an overall incidence of 11.8% (95%CI: 9.1%-14.9%). The surgical approach significantly influenced the occurrence of ML: the proportion of leakage was 10.5% and 9% after open and hybrid esophagectomy (HE), respectively, and doubled (20%) after totally minimally invasive esophagectomy (TMIE) (P = 0.016). No other predictive factors were found. The 30- and 90-d overall mortality rates were 1.4% and 3.2%, respectively; the 30- and 90-d leak-related mortality rates were 5.1% and 10.2%, respectively; the 90-d mortality rates for TMIE and HE were 5.9% and 1.8%, respectively. Endoscopy was the first-line treatment in 49% of ML cases, with the need for retreatment in 17.2% of cases. Surgery was needed in 44.1% of ML cases. Endoscopic treatment had the lowest mortality rate (6.9%). Removal of the gastric tube with stoma formation was necessary in 8 (13.6%) cases. CONCLUSION: The incidence of ML after esophagectomy was high mainly in the TMIE group. However, the general and specific (leak-related) mortality rates were low. Early treatment (surgical or endoscopic) of severe leaks is mandatory to limit related mortality.

Enhanced Recovery After Surgery (ERAS) Pathway in Esophagectomy: Is a Reasonable Prediction of Hospital Stay Possible?

OBJECTIVE: To assess whether perioperative variables or deviation from enhanced recovery after surgery (ERAS) items could be associated with delayed discharge after esophagectomy, and to convert them into a scoring system to predict it. SUMMARY BACKGROUND DATA: ERAS perioperative pathways have been recently applied to esophageal resections. However, low adherence to ERAS items and high rates of protocol deviations are often reported. METHODS: All patients who underwent esophagectomy between April 2012 and March 2017 were managed with a standardized perioperative pathway according to ERAS principles. The target length of stay was set at eighth postoperative day (POD). All significant variables at bivariate analysis were entered into a logistic regression to produce a predictive score. An initial validation of the score accuracy was carried out on a separate patient sample. RESULTS: Two hundred eighty-six patients were included in the study. Multivariate regression analysis showed that American Society of Anesthesiology score ≥ 3, surgery duration > 255 min, "nonhybrid" esophagectomy, and failure to mobilize patients within 24 h from surgery were associated with delayed discharge. The logistic regression model was statistically significant (P < 0.001) and correctly classified 81.9% of cases. The sensitivity was 96.6%, and the specificity was 17.6%. The prediction score applied to 23 patients correctly identified 100% of those discharged after eighth POD. CONCLUSIONS: The results of this study seem to be clinically meaningful and in line with those from other studies. The initial validation revealed good predictive properties.

Self-Expanding Metal Stents for the Treatment of Post-Surgical Esophageal Leaks: A Tertiary Referral Center Experience.

BACKGROUND/AIMS: The study aimed to evaluate the effectiveness and safety of self-expanding metal stents (SEMS) in the management of post-surgical esophageal leaks. METHODS: Retrospective data of consecutive patients with a post-surgical esophageal leak treated by means of a metal stent between January 2008 and December 2014 at the Humanitas Research Hospital (Milan, Italy) were extracted from a prospectively maintained register of SEMS used for benign indications, such as post-surgical benign esophageal strictures and/or leaks. The primary outcome of the study was to assess the rate of successful leak closure and to identify the variables associated with its achievement. As a secondary outcome, we evaluated the overall safety of SEMS placement and the efficacy and safety for different types of SEMS in this specific setting of patients. Leak resolution was documented with endoscopic and/or imaging studies. In the case of leak persistence, further attempts of esophageal stenting were carried out at the discretion of both endoscopists and surgeons. RESULTS: A total of 49 patients were included in the study (men 41 of 49, 83.7%, mean age 62.4 ± 11.9). One patient was excluded from analysis, because of death 1 day after stent insertion due to worsening of pre-existing mediastinitis. A total number of 82 stents were placed (mean number of stents per patient: 1.7) in 49 patients: 35 patients (71.4%) received a partially covered SEMS (PCSEMS) as the first stent positioned, while the remaining 14 (28.6%) received a fully covered SEMS (FCSEMS); but 1 patient (2%) died following stent insertion; therefore, data regarding therapeutic success were available for 48 patients. Stents were left in place for a mean period of 21.9 ± 15.2 days. Leak closure after the first stent placement was achieved in 22 of 48 (45.8%) patients. Of the 26 patients with failure of index stent placement, 18 patients underwent further stenting attempts (69.2%), and secondary closure of leak was achieved in 7 (38.9%) of these 18 patients. Thus, the overall success rate was 60.5% (29 of 48). On the basis of stent type, the success rate was 57.1% (8 of 14) for FCSEMS and 64.7% (22 of 34) for PCSEMS. Logistic regression analysis did not find any significant association between successful leak closure and analyzed variables. Overall mortality was 13.0%. Complication rate was 38.8% (19 of 49 patients). CONCLUSION: The use of SEMS is an effective and safe option for post-surgical esophageal leaks, with no evidence of any significant influence of stent type on outcome.

Rituximab Treatment Prevents Lymphoma Onset in Gastric Cancer Patient-Derived Xenografts.

Patient-Derived Xenografts (PDXs), entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer. More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV) positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas. The ability of grafted samples to develop lymphomas did not correlate with patient outcome, nor with the histotype, the lymphocyte infiltration level, or the EBV status of the original gastric tumor, impeding from foreseeing lymphoma onset. Interestingly, lymphoma development was significantly more frequent when primary rather than metastatic samples were grafted. Notably, the development of such lympho-proliferative disease could be prevented by a short rituximab treatment upon mice implant, without negatively affecting gastric carcinoma engraftment. Due to the high frequency of human lymphoma onset, our data show that a careful histologic analysis is mandatory when generating gastric cancer PDXs. Such care would avoid misleading results that could occur if testing of putative gastric cancer therapies is performed in lymphoma PDXs. We propose rituximab treatment of mice to prevent lymphoma development in PDX models, averting the loss of human-derived samples.

Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG).

BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer-specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1-16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A-type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

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.