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Western blot analysis was performed to determine the effect of trastuzumab after 24h of treatment in N87-TR cells and their control cell line.

Top differentially regulated coding genes in N87-TR1, N87-TR2, N87-TR3, and N87-TR4 trastuzumab-resistant gastric cancer cell lines compared with NCI-N87 control cell line.

Supplementary Materials and Methods

Purpose: The majority of gastric cancer patients who achieve an initial response to trastuzumab-based regimens develop resistance within 1 year of treatment. This study was aimed at identifying the molecular mechanisms responsible for resistance.Experimental Design: A HER2+-trastuzumab sensitive NCI-N87 gastric cancer orthotopic nude mouse model was treated with trastuzumab until resistance emerged. Differentially expressed transcripts between trastuzumab-resistant and sensitive gastric cancer cell lines were annotated for functional interrelatedness by Ingenuity Pathway Analysis software. Immunohistochemical analyses were performed in pretreatment versus posttreatment biopsies from gastric cancer patients receiving trastuzumab-based treatments. All statistical tests were two-sided.Results: Four NCI-N87 trastuzumab-resistant (N87-TR) cell lines were established. Microarray analysis showed HER2 downregulation, induction of epithelial-to-mesenchymal transition, and indicated fibroblast growth factor receptor 3 (FGFR3) as one of the top upregulated genes in N87-TR cell lines. In vitro, N87-TR cell lines demonstrated a higher sensitivity than did trastuzumab-sensitive parental cells to the FGFR3 inhibitor dovitinib, which reduced expression of pAKT, ZEB1, and cell migration. Oral dovitinib significantly (P = 0.0006) reduced tumor burden and prolonged mice survival duration in N87-TR mouse models. A higher expression of FGFR3, phosphorylated AKT, and ZEB1 were observed in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatment biopsies.Conclusions: This study identified the FGFR3/AKT axis as an escape pathway responsible for trastuzumab resistance in gastric cancer, thus indicating the inhibition of FGFR3 as a potential strategy to modulate this resistance. Clin Cancer Res; 22(24); 6164–75. ©2016 AACR.

Quality of Life (QoL) after extensive head and neck resections is of paramount importance, especially after pharyngolaryngectomy or pharyngolaryngoesophagectomy where complex digestive tract reconstruction is required (with gastric pull-up or colon transposition). Tracheodigestive puncture (TDP) is the only vocal restoration option in this group of patients. The aim of this study is to evaluate postoperative complications, vocal outcomes, voice-related and swallowing-related QoL after secondary TDP in this cohort of patients.A retrospective study was conducted in the tertiary referral center of Verona Hospital between June 2014 and June 2020. Patient demographics, clinical and surgical data were assessed. Speech objective and subjective evaluation was performed. QoL was assessed with Voice Handicap Index-10 (VHI-10) and M.D. Anderson Dysphagia Inventory (MDADI) questionnaires.Seven patients met the inclusion criteria, but two had died before questionnaires were administered. No intraoperative complications were noted after TDP surgery. There were delayed complications in four cases (57.1%) and all were treated with restoration. Intelligible voice was restored in all patients. Maximum phonation time and maximal voice intensity recorded were 5.42 ± 3.27 s and 65.20 ± 5.45 dB, respectively. Acceptable average VHI-10 and MDADI scores were obtained in all patients.Secondary TDP performed after gastric pull-up or colon transposition reconstructions are feasible and effective procedures. An intelligible voice was restored in all patients, with satisfactory patient-perceived voice-related and dysphagia-related quality-of-life outcomes.

Introduction. RCTs support neoadjuvant chemoradiotherapy (nCRT) followed by surgery in Locally Advanced Esophago-Gastric Junction (LA-EGJ) adenocarcinoma. However, RCTs are performed in highly controlled settings with limited representativeness of real-life patients (RLS). Aim: To compare the outcomes in RLS and clinical trial settings. Methods. The outcomes of RLS, which comprised 125 patients consequently treated for LA-EGJ adenocarcinoma between 2012 and 2017, were compared with the phase II trial (PIIS), performed on 65 patients from 2003 to 2011. Results. About half of RLS (51.2%) were treated with nCRT according to VR-protocol, 20.8% with standard-CRT according to CROSS/Al-Sarraf, 20% with CT alone. pCR was 36.8%, 28.6% and 9.1% after VR-protocol, standard-CRT, and chemotherapy respectively (p=0.082), while three-year overall survival (OS) was 58.6% (95% CI 43.2-71.1%), 32.8% (14.6-52.4%) and 44.8% (21.3-65.9%) respectively (p=0.030). With respect to PIIS, RLS had a higher proportion of cN+ (94% versus 54%; p

The incidence of esophagogastric junctional adenocarcinoma (EGJ) has been steadily increasing over the last 30 years, especially in Western countries. Surgical and oncological treatment of these malignancies are still debated, in particular in case of true junctional cancer (Siewert type II tumors). The aim of the study is to compare different approaches to EGJ cancers in high volume centers around the world. We administered a survey to 39 international opinion leaders, working in high volume centers, with a minimum of 50 gastrectomies and 20 esophagectomies performed as first operator. The survey was structured in the form of clinical case scenarios, created to focus on different peculiar issues in the management of Siewert type II tumors. The main fields of investigation were the oncological approach of these malignancies (i.e. choice and type of neoadjuvant treatment) and the preferred surgical strategy. Our first finding was that almost 80% of responders would choose a neoadjuvant treatment even in cT2N0 patients, fearing probably the low accuracy of the clinical staging. Secondly, 60% of surgeons would prefer chemotherapy over chemoradiotherapy in locally advanced Siewert II tumors, regardless of histological subtype and nodal diffusion. As for the surgical strategy, we reported a strong preference (75% of responders) for two-field esophagectomy, over three-field esophagectomy (11%) and total extended gastrectomy (14%). However, in case of signet-ring cell carcinoma, up to 20% of surgeons would prefer an extended total gastrectomy, to avoid a distal positive margin. Our survey confirms that the management of Siewert type II tumors is greatly debated, even among experts of the field, and it needs to be tailored on the patient and tumor characteristics. Even so, we observed a trend towards the choice of chemo over chemoradiotherapy for any histological subtype. When operating on Siewert type II tumors, a thoracic approach is considered necessary by most of responders.

Optimal surgical treatment for Siewert type II esophagogastric junction adenocarcinoma is debated. The aim of this study was to compare transhiatal extended gastrectomy (TEG) and transthoracic esophagectomy (TTE). Patients with Siewert type II tumors who underwent a resection by TEG or TTE in two centers (Erasmus University Medical Center, Rotterdam, and University of Verona) between 2014 and 2019 were identified. To limit selection bias, patients were matched for baseline characteristics and compared with a multivariable logistic regression model. Some 159 patients treated by TEG (60 patients, 37.7%) or TTE (99 patients, 62.3%) were included. Patients in the TEG group were older, had less tumor invasion of the esophagus, and were more often excluded from neoadjuvant therapy. Post-operative morbidity was comparable (P = 0.88), while 90-day mortality was higher after TEG (90-day mortality 10.0% in TEG group vs. 2.0% in TTE group P = 0.01). R0 resection was achieved in 83.3% of patients after TEG and in 97.9% after TTE (P

Background: Delayed gastric emptying (DGE) is a common complication after esophagectomy with gastric tube reconstruction. It is still unclear whether a pyloric drainage procedure might reduce the r...

Italian Research Group for Gastric Cancer (GIRCG), during the 2013 annual Consensus Conference to gastric cancer, stated that laparoscopic or robotic approach should be limited only to early gastric cancer (EGC) and no further guidelines were currently available. However, accumulated evidences, mainly from eastern experiences, have supported the application of minimally invasive surgery also for locally advanced gastric cancer (AGC). The aim of our study is to give a snapshot of current surgical propensity of expert Italian upper gastrointestinal surgeons in performing minimally invasive techniques for the treatment of gastric cancer in order to answer to the question if clinical practice overcome the recommendation. Experts in the field among the Italian Research Group for Gastric Cancer (GIRCG) were invited to join a web 30-item survey through a formal e-mail from January 1st, 2020, to June 31st, 2020. Responses were collected from 46 participants out of 100 upper gastrointestinal surgeons. Percentage of surgeons choosing a minimally invasive approach to treat early and advanced gastric cancer was similar. Additionally analyzing data from the centers involved, we obtained that the percentage of minimally invasive total and partial gastrectomies in advanced cases augmented with the increase of surgical procedures performed per year (p = 0.02 and p = 0.04 respectively). It is reasonable to assume that there is a widening of indications given by the current national guideline into clinical practice. Propensity of expert Italian upper gastrointestinal surgeons was to perform minimally invasive surgery not only for early but also for advanced gastric cancer. Of interest volume activity correlated with the propensity of surgeons to select a minimally invasive approach.

Gastrectomy for gastric cancer is still performed in Western countries with high morbidity and mortality. Post-operative complications are frequent, and effective diagnosis and treatment of complications is crucial to lower the mortality rates. In 2015, a project was launched by the EGCA with the aim of building an agreement on list and definitions of post-operative complications specific for gastrectomy. In 2018, the platform www.gastrodata.org was launched for collecting cases by utilizing this new complication list. In the present paper, the Italian Research Group for Gastric Cancer endorsed a collection of complicated cases in the period 2015–2019, with the aim of investigating the clinical pictures, diagnostic modalities, and treatment approaches, as well as outcome measures of patients experiencing almost one post-operative complication. Fifteen centers across Italy provided 386 cases with a total of 538 complications (mean 1.4 complication/patient). The most frequent complications were non-surgical infections (gastrointestinal, pulmonary, and urinary) and anastomotic leaks, accounting for 29.2% and 17.3% of complicated patients, with a median Clavien–Dindo score of II and IIIB, respectively. Overall mortality of this series was 12.4%, while mortality of patients with anastomotic leak was 25.4%. The clinical presentation with systemic septic signs, the timing of diagnosis, and the hospital volume were the most relevant factors influencing outcome.

Bleeding from the thoracic aorta is potentially fatal in patients with advanced esophageal cancer (AEC). Esophageal malignancy is the third most common cause of aortoesophageal fistula, after thoracic aortic aneurysm and ingestion of foreign body. The involvement of aortic wall often contraindicates chemoradiotherapy (CRT) treatment, thus reducing life expectancy of these patients. Thoracic endovascular aortic repair (TEVAR) is a well-described mini-invasive technique that can be also applied for coverage of the aortic lumen in case of invasion by esophageal cancer. Only few cases have been published with this atypical indication. Between 2016 and 2018, in our tertiary hospital 3 patients affected by AEC involving the thoracic aorta were treated by means of prophylactic TEVAR. All procedures were uneventful, and all patients were reconsidered fit for preoperative or definitive CRT.

Laparoscopic D2 gastrectomy is a demanding procedure which can be safely performed by expert upper gastrointestinal surgeons with advanced laparoscopic skills. This procedure struggles to be accepted, specifically for locally advanced gastric cancer, because the real compliance to D2 dissection during laparoscopic gastrectomy is still a matter of debate, in particular in patients with bulky nodes and/or patients who underwent neoadjuvant therapy.

Siewert III cancer, although representing around 40% of esophagogastric junction (EGJ) cancers and being the EGJ cancer with worst prognosis, does not have a homogenous treatment. According to TNM 8th ed., they are considered gastric cancers. Our aim was to consolidate the current literature on the indications and treatment options for Siewert III adenocarcinoma. A review of the literature was performed in order to better delineate treatment indications (according to stage, surgical margins, type of lymphatic spread and lymphadenectomy) and treatment strategy. The treatment of Siewert III cancer requires a total gastrectomy and distal esophagectomy, with 5 cm of clear proximal and distal margins and a D2 abdominal and inferior mediastinal lymphadenectomy. Multimodal treatments are indicated in all locally advanced and node positive Siewert III patients and surgical principles remain unaltered after multimodal treatments. Siewert III cancers are gastric cancers with some peculiarities and require dedicated studies and deserve more consideration in the current literature, especially because their treatment is particularly challenging.

In Western countries, perioperative complications severely affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates. In 2015 the European project “Complications after gastrectomy for cancer” was launched. The first step was the setup of a standardized list of 27 complications, with clinical definitions. The second step was the retrospective collection of consecutive gastrectomies performed in 2017–2018 at participating European centers, including clinical, oncological and surgical data, and outcome measures at hospital discharge, 30 and 90 days postoperatively. Eventually, data on 1349 gastrectomies were entered into an international database and then analyzed. The overall incidence of complications was 29.8%. The most frequent complications were non-surgical infections (23%), anastomotic leak (9.8%), other postoperative abnormal fluid from drainage and/or abdominal collections (9.3%), pleural effusion (8.3%), postoperative bleeding (5.6%). In-hospital, 30-day, and 90-day mortality were 3.2%, 3.6%, and 4.5%, respectively. Actions are therefore needed to limit the incidence and to effectively treat the most frequent and most lethal complications.

Over the last decade, laparoscopic gastrectomy has gradually gained popularity as a surgical option for early gastric cancer, especially in Eastern countries, with most of the evidence coming from Korea and Japan. After the publication of two large-scale Eastern trials, laparoscopic distal gastrectomy proved to be a safe alternative to open surgery for stage I distal gastric cancer when performed by experienced surgeons. This evidence can be roughly transposed to high-volume Western centers, paying attention to some subgroups of patients. Conversely, laparoscopic total gastrectomy proved to be a complex procedure especially due to the technical issue of esophagojejunal anastomosis, and concerns regarding its surgical safety should be considered when planning surgical strategies for each individual patient. Few data are available on the benefit of robotic gastrectomy for cancer: despite increased costs and operation time, no significant improvement was observed in estimated blood loss, rates of open conversion and postoperative outcomes compared to the laparoscopic approach. While the development of even more conservative surgery, such as pylorus-preserving or proximal gastrectomy, is an urgent need in Korea and Japan, these are far from becoming part of clinical practice in the West, where most newly diagnosed gastric cancers are at advanced stages.

The correct technique for accurate upper gastrointestinal endoscopy has some key points: preparation of the patient, use of anti-peristaltic agents and mapping of the entire stomach. Systematic protocols to explore the entire gastric mucosa have been proposed to reduce the risk of missing lesions, but a worldwide standardized protocol is still lacking. For a correct diagnosis of superficial neoplastic lesions, white light imaging (WLI) together with chromoendoscopy showed a higher accuracy compared to WLI alone. High-definition endoscopy with the combination of narrow band imaging has been used to better characterize early lesions. However, biopsy specimens and histological examination remain essential for assessing the presence of pre-neoplastic lesions or early gastric adenocarcinoma and guaranteeing the correct therapeutic pathway. Moreover, due intra-tumor heterogeneity also in the case of advanced gastric cancer a biopsy protocol should be conceptualized in order to obtain the most accurate tumor representation, crucial in an era of target therapy. A well-performed endoscopy is instrumental for both an accurate diagnosis and appropriate treatment.

Background Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in 20–40% of cases. The present study investigated the recurrence pattern and predictive factors of recurrence after pCR in patients with esophageal cancer. Methods In this study, 427 patients received preoperative treatment for either esophageal squamous cell carcinoma (SCC) or adenocarcinoma at Verona University Hospital between 2000 and 2018. Of these, 145 patients (34%) achieved a pCR. Long-term prognosis, recurrence pattern, and risk factors for relapse in pCR patients were analysed. Results During a median follow-up of 52 months, 37 relapses (25.5%) occurred, mostly at distant level (n = 28). Nearly all locoregional relapses (8/9) were detected in SCC cases. The 5-year overall survival and cancer-related survival were 71.7% (95% confidence interval [CI] 62.6–78.9%) and 77.5% (95% CI 68.5–84.2%) respectively. Male sex, higher body mass index, and cT4 were significant risk factors for recurrence at univariate analysis. The multivariate analysis confirmed the role of cT4 as predictor of recurrence only in SCCs. Conclusions Esophageal cancer recurs in about one-fourth of pCR cases. A fair number of local recurrences occurs in SCCs, but the main problem is the systemic disease control. According to our analysis, SCCs patients with cT4 stage have an increased risk to recur, so they should be managed differently by a personalized approach in terms of adjuvant treatment and follow-up.

Simple Summary Chemoradiotherapy according to CROSS regimen is the standard of care for locally advanced esophageal cancer. The studies conducted on this topic have demonstrated the benefits of this type of treatment particularly for squamocellular cancers. Its application for adenocarcinoma has evidenced different results and few studies have investigated its role for adenocarcinomas of esophagogastric junction. Our intent is to evaluate the relation between pathological (yp) stage after CROSS regimen followed by surgery for adenocarcinoma of cardia and overall (OS) and disease-free survival (DFS) in a retrospectively analyzed group of patients. Sites of relapse after surgery were also analyzed. Our results evidenced no differences in term of OS and DFS according to different pathological response after chemoradiotherapy and surgery. Further analyses could be performed to identify the histological and molecular characteristics of these tumors and predict the efficacy of systemic therapy identifying patients who can most benefit from this type of treatment. Abstract Background:After the results reported by the “Chemoradiotherapy for esophageal Cancer Followed by Surgery Study” (CROSS) trial, neo-adjuvant chemoradiotherapy became the standard treatment for locally advanced cancers of esophagus and gastroesophageal junction (GEJ). Excellent results were reported for squamocellular carcinomas (SCCs). Since the advent of the CROSS regimen, the results of surgery for esophageal adenocarcinomas (EAC) have cast some doubts about its efficacy on overall survival (OS) even in the presence of local response. This study evaluated the relation between pathological (yp) stage after CROSS regimen followed by surgery for adenocarcinoma of cardia and overall (OS) and disease-free survival (DFS). Sites of relapse after surgery were also analyzed. Methods: Patients submitted to the CROSS regimen for locally advanced EAC of the cardia followed by transthoracic esophagectomy were analyzed. Actuarial OS and DFS were analyzed and stratified according to yp stage. The site of relapse, distal and local, was also analyzed. Results: The study included 132 patients. The 50-month OS and DFS were 45% and 6.7%, respectively. No differences emerged analyzing OS according to yp stage. Time to relapse was significantly longer for yp Stage I and II, and for yp N0, compared with yp N+. Recurrence occurred in 48 cases (36.3%) with a 9 months median time to relapse. Local and distal relapse were 10 (7.5%) and 38 (28.7%) cases, respectively (p ≦ 0.001). Conclusions: Pathological stage after CROSS regimen does not relate to OS and DFS. Time to recurrence is significantly longer for yp Stages I and II and ypN0. Chemoradiotherapy in a neoadjuvant setting may influence the site of relapse, significantly reducing local recurrences.

The treatment of leak after esophageal and gastric surgery is a major challenge. Over the last few years, endoscopic vacuum therapy (E-VAC) has gained popularity in the management of this life-threatening complication. We reported our initial experience on E-VAC therapy as rescue treatment in refractory anastomotic leak and perforation after gastro-esophageal surgery. From September 2017 to December 2019, a total of 8 E-VAC therapies were placed as secondary treatment in 7 patients. Six for anastomotic leak (3 cervical, 1 thoracic, 2 abdominal) and 1 for perforation of the gastric conduit. In 6 cases, E-VAC was placed intracavitary; while in the remaining 2, the sponge was positioned intraluminal (one patient was treated with both approaches). A total of 60 sponges were used in the whole cohort. The median number of sponge insertions was 10 (range: 5–14) with a median treatment duration of 41 days (range: 19–49). A complete healing was achieved in 4 intracavitary (67%) and in 1 intraluminal (50%) E-VAC. We observed only one E-VAC-related complication: a bleeding successfully managed endoscopically. E-VAC therapy seems to be a safe and effective tool in the management of leaks and perforations after upper GI surgery, although with longer healing time when it is used as secondary treatment.

Due to the difficulties in the intra-thoracic esophagogastric anastomosis creation, totally minimally invasive Ivor Lewis esophagectomy (MIE) did not encountered a large diffusion, preferring hybrid techniques or cervical anastomosis. Robot-assisted minimally invasive esophagectomy (RAMIE) has gained popularity due to an easy reproducibility of the open anastomotic technique. In this feasibility study, we described the RAMIE technique introduced in our Center, providing innovative details for a mechanical end-to-end anastomosis. With patient in prone position, esophagectomy is conducted through the meso-esophagus plan. Robotic hand-sewn purse-string is realized above Azygos vein. A 4-cm thoracotomy in the fifth intercostal space is performed by enlarging the trocar incision. The tubulization is performed to create an access pouch for the introduction of the circular stapler. After the creation of the end-to-end anastomosis, the access pouch is resected and a robotic over-sewn is realized. From January 2020 until July 2020, ten patients were enrolled. No restriction in term of age, BMI, ASA grade or previous surgery were applied. Median operative time was 700 min. R0 resection was achieved in all cases with a good lymph node harvesting. No anastomotic leak or stricture were observed. One chyle leak was treated conservatively. Median length of stay was 8 days and 90 days mortality was 0%. This study evidenced how robotic surgery allowed us to perform the same anastomosis of our open technique with good oncological results and morbidity and length of stay comparable with our previous results. Of note, longer operative time has been recorded. Further studies after the completion of the learning curve are necessary to address more definite conclusions.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved., Objective: Utilizing a standardized dataset based on a newly developed list of 27 univocally defined complications, this study analyzed data to assess the incidence and grading of complications and evaluate outcomes associated with gastrectomy for cancer in Europe. Summary background data: The absence of a standardized system for recording gastrectomy-associated complications makes it difficult to compare results from different hospitals and countries. Methods: Using a secure online platform (www.gastrodata.org), referral centers for gastric cancer in 11 European countries belonging to the Gastrectomy Complications Consensus Group recorded clinical, oncological, and surgical data, and outcome measures at hospital discharge and at 30 and 90 days postoperatively. This retrospective observational study included all consecutive resections over a 2-year period. Results: A total of 1349 gastrectomies performed between January 2017 and December 2018 were entered into the database. Neoadjuvant chemotherapy was administered to 577 patients (42.8%). Total (46.1%) and subtotal (46.4%) gastrectomy were the predominant resections. D2 or D2+ lymphadenectomy was performed in almost 80% of operations. The overall complications' incidence was 29.8%; 402 patients developed 625 complications, with the most frequent being nonsurgical infections (23%), anastomotic leak (9.8%), other postoperative abnormal fluid from drainage and/or abdominal collections (9.3%), pleural effusion (8.3%), postoperative bleeding (5.6%), and other major complications requiring invasive treatment (5.6%). The median Clavien-Dindo score and Comprehensive Complications Index were IIIa and 26.2, respectively. In-hospital, 30-day, and 90-day mortality were 3.2%, 3.6%, and 4.5%, respectively. Conclusions: The use of a standardized platform to collect European data on perioperative complications revealed that gastrectomy for gastric cancer is still associated with heavy morbidity and mortality. Actions are needed to limit the incidence of, and to effectively treat, the most frequent and most lethal complications.

Gastric conduit perforation is a life-threatening complication after esophagectomy and currently there is no consensus about its optimal management. Endoscopic vacuum therapy (E-VAC) is a promising technique for the treatment of leaks and perforations after upper gastro-intestinal surgery. We report the case of a 65 years-old male patient who underwent an Ivor Lewis esophagectomy for esophago-gastric junction adenocarcinoma. He referred to our Emergency Department for septic shock and right hydropneumothorax. We performed an emergency thoracoscopy with intraoperative esophagogastroduodenoscopy which showed a pre-pyloric perforation of the gastric conduit. The perforation was initially treated with unsuccessful primary surgical closure and subsequently by means of E-VAC, firstly placed intraluminal and then intracavitary. With the latter technique, we assisted to a progressive clinical improvement until the definitive healing of the perforation. To our knowledge, this is the first case of a gastric tube perforation after esophagectomy successfully treated with E-VAC.

Background:Prognosis of patients affected by metastatic esophageal–gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.Methods:The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib.Discussion:Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance.Protocol number:CRC2017_02EudraCT Number:2017-004522-14

Background Boerhaave’s syndrome (BS) is a rare life-threating condition with poor prognosis. Unfortunately, due to its very low incidence, no clear evidences or definitive guidelines are currently available: in detail, surgical strategy is still a matter of debate. Most of the case series reports thoracic approach as the most widely used; conversely, transhiatal abdominal management is just described in sporadic case reports. In our center, the laparoscopic approach has been adopted for years: in the present study, we aim to show his feasibility by reporting the outcomes of the largest clinical series available to date. Methods Clinical records of patients admitted for BS to the General and Upper GI Surgery Division of Verona from February 2014 to December 2019 were retrospectively collected. Clinico-pathological characteristics, preoperative workup, surgical management, and outcomes were analyzed. Results Seven patients were admitted; epigastric/thoracic pain and vomiting were the most frequent symptoms at diagnosis. Laboratory findings were not specific; conversely, radiological imaging always revealed abnormal findings: particularly, CT had excellent sensitivity in detecting signs of esophageal perforation. All but one case had diagnostic workup and received surgery within 24 h. Every patient had laparoscopic transhiatal direct suture and gastric valve; 2 patients (28.6%) also needed a thoracoscopic toilette. Postoperative complications occurred in 4 patients (57%), but in only two of them (29%), the complication was severe according to Clavien-Dindo classification (both received thoracentesis or thoracic drainage for pleural effusion). Of note, no cases of postoperative esophageal leak were recorded. Postoperative mortality was 14% due to one patient who died for cardiovascular complications. Most of the patients (71.4%) were admitted to ICU after surgery (average length, 8.8 days); mean hospital stay was 14.7 days. No patients had readmissions. Conclusions To our knowledge, this is the largest case series reporting laparoscopic management of BS. We show that laparoscopy is a safe and feasible approach associated with a shorter length of hospital stay when compared with clinical series in which thoracic approach had been chosen. Of note, laparoscopic management would be easily adopted by surgical centers treating benign gastro-esophageal junction entailing a proper management more widely.

Background and ObjectiveThe aim of this study was to assess the ability of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) to provide functional information useful in predicting pathological response to an intensive neoadjuvant chemo-radiotherapy (nCRT) protocol for both esophageal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) patients.Material and MethodsEsophageal carcinoma (EC) patients, treated in our Center between 2014 and 2018, were retrospectively reviewed. The nCRT protocol schedule consisted of an induction phase of weekly administered docetaxel, cisplatin, and 5-fluorouracil (TCF) for 3 weeks, followed by a concomitant phase of weekly TCF for 5 weeks with concurrent radiotherapy (50–50.4 Gy in 25–28 fractions). Three 18F-FDG PET/CT scans were performed: before (PET1) and after (PET2) induction chemotherapy (IC), and prior to surgery (PET3). Correlation between PET parameters [maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)], radiomic features and tumor regression grade (TGR) was investigated.ResultsFifty-four patients (35 ADC, 19 SCC; 48 cT3/4; 52 cN+) were eligible for the analysis. Pathological response to nCRT was classified as major (TRG1-2, 41/54, 75.9%) or non-response (TRG3-4, 13/54, 24.1%). A major response was statistically correlated with SCC subtype (p = 0.02) and smaller tumor length (p = 0.03). MTV and TLG measured prior to IC (PET1) were correlated to TRG1-2 response (p = 0.02 and p = 0.02, respectively). After IC (PET2), SUVmean and TLG correlated with major response (p = 0.03 and p = 0.04, respectively). No significance was detected when relative changes of metabolic parameters between PET1 and PET2 were evaluated. At textural quantitative analysis, three independent radiomic features extracted from PET1 images ([JointEnergy and InverseDifferenceNormalized of GLCM and LowGrayLevelZoneEmphasis of GLSZM) were statistically correlated with major response (p < 0.0002).Conclusions18F-FDG PET/CT traditional metrics and textural features seem to predict pathologic response (TRG) in EC patients treated with induction chemotherapy followed by neoadjuvant chemo-radiotherapy. Further investigations are necessary in order to obtain a reliable predictive model to be used in the clinical practice.

Coronavirus Disease-19 (COVID-19) outbreak has significantly burdened healthcare systems worldwide, leading to reorganization of healthcare services and reallocation of resources. The Italian Society for Study of Esophageal Diseases (SISME) conducted a national survey to evaluate changes in esophageal cancer management in a region severely struck by COVID-19 pandemic. A web-based questionnaire (26 items) was sent to 12 SISME units. Short-term outcomes of esophageal resections performed during the lockdown were compared with those achieved in the same period of 2019. Six (50%) centers had significant restrictions in their activity. However, overall number of resections did not decrease compared to 2019, while a higher rate of open esophageal resections was observed (40 vs. 21.7%; P = 0.034). Surgery was delayed in 24 (36.9%) patients in 6 (50%) centers, mostly due to shortage of anesthesiologists, and occupation of intensive care unit beds from intubated COVID-19 patients. Indications for neoadjuvant chemo (radio) therapy were extended in 14% of patients. Separate COVID-19 hospital pathways were active in 11 (91.7%) units. COVID-19 screening protocols included nasopharyngeal swab in 91.7%, chest computed tomography scan in 8.3% and selective use of lung ultrasound in 75% of units. Postoperative interstitial pneumonia occurred in 1 (1.5%) patient. Recovery from COVID-19 pandemic was characterized by screening of patients in all units, and follow-up outpatient visits in only 33% of units. This survey shows that clinical strategies differed considerably among the 12 SISME centers. Evidence-based guidelines are needed to support the surgical esophageal community and to standardize clinical practice in case of further pandemics.

Background The present study aimed to better define the usefulness of F-FDG PET/CT in predicting pathological tumor response (PTR) and survival in patients with noncardia gastric cancer treated with preoperative chemotherapy. Methods Seventy-one patients were recruited in 6 Italian centers. The SUV of F-FDG PET/CT was measured at baseline and after treatment, and the difference (dSUV) was computed. The association between PET indexes and PTR, assessed by the Becker score, was evaluated by nonparametric regression. The discriminant power of PET indexes with respect to the absence of PTR (Becker 2/3) was studied by receiver operating characteristic (ROC) curve and synthesized by the area under the curve (ROC-AUC). Results dSUV allowed to partially discriminate between absence/presence of PTR, when expressed as either absolute value (ROC-AUC, 0.73; 95% confidence interval, 0.59-0.87) or percentage (ROC-AUC, 0.74; 95% confidence interval, 0.59-0.89). However, only extreme values of percent dSUV were really informative. All 7 patients whose F-FDG uptake had increased despite preoperative treatment showed no tumor regression at pathologic examination. Seven of the 10 patients whose metabolic response had been 70% or greater had complete or nearly complete pathologic tumor regression (Becker score 1a or 1b). The metabolic response of the remaining 54 patients, which ranged between 0% and 70%, did not permit to reliably forecast pathologic tumor regression. Survival significantly decreased with increasing Becker score but was unaffected by metabolic response. Conclusions The present study suggests that F-FDG PET/CT has limited usefulness in predicting cancer regression. The lack of metabolic response in serial measurements indicates the probable ineffectiveness of preoperative treatment.

Enhanced recovery protocols (ERP) have demonstrated their efficacy after esophagectomy and gastrectomy but little is known about their feasibility and safety in elderly patients. Patients submitted to Ivor-Lewis esophagectomy or gastrectomy for cancer between January 2016 and June 2019 were divided into three age groups: young-age group, YG (≤ 65 years, n = 130); middle-age group, MG (66–74 years, n = 101); old-age group, OG (≥ 75 years, n = 74). The groups were compared for adherence to our ERP, morbidity and mortality rates. After esophagectomy, adherence to ERP was comparable between the three groups, overall morbidity was higher in OG, without statistically significant difference, while the incidence of cardiac complications was significantly higher in OG (p = 0.02). After gastrectomy, OG presented a lower adherence to urinary catheter removal and to early mobilization. No difference in overall morbidity rate was observed (p = 0.13). The median length of stay was comparable both after esophagectomy (p = 0.075) and gastrectomy (p = 0.07). Multivariable analysis showed that age ≥ 75 years was not associated with a higher risk of ERP failure either after esophagectomy (p = 0.59) or after gastrectomy (p = 0.83). After esophagectomy, the risk of failure of the ERP program was higher for patients with ASA grade 3–4 (p = 0.03) and for those with postoperative complications (p

Background To review the available clinical data about the value of Indocyanine Green (ICG) fluorescence imaging for intraoperative detection of peritoneal carcinomatosis. Methods We conducted a systematic review, according to the PRISMA guidelines, for clinical series investigating the possible role of ICG fluorescence imaging in detecting peritoneal carcinomatosis during surgical treatment of abdominal malignancies. With the aim to analyze actual application in the daily clinical practice, papers including trials with fluorophores other than ICG, in vitro and animals series were excluded. Data on patients and cancer features, timing, dose and modality of ICG administration, sensitivity, specificity and accuracy of fluorescence diagnosis of peritoneal nodules were extracted and analyzed. Results Out of 192 screened papers, we finally retrieved 7 series reporting ICG-guided detection of peritoneal carcinomatosis. Two papers reported the same cases, thus only 6 series were analyzed, for a total of 71 patients and 353 peritoneal nodules. The investigated tumors were colorectal carcinomas in 28 cases, hepatocellular carcinoma in 16 cases, ovarian cancer in 26 cases and endometrial cancer in 1 case. In all but 4 cases, the clinical setting was an elective intervention in patients known as having peritoneal carcinomatosis. No series reported a laparoscopic procedure. Technical data of ICG management were consistent across the studies. Overall, 353 lesions were harvested and singularly evaluated. Sensitivity varied from 72.4 to 100%, specificity from 54.2 to 100%. Two series reported that planned intervention changed in 25 and 29% of patients, respectively. Conclusion Indocyanine Green based fluorescence of peritoneal carcinomatosis is a promising intraoperative tool for detection and characterization of peritoneal nodules in patients with colorectal, hepatocellular, ovarian carcinomas. Further prospective studies are needed to fix its actual diagnostic value on these and other abdominal malignancies with frequent spread to peritoneum.

Bleeding from the thoracic aorta is potentially fatal in patients with advanced esophageal cancer (AEC). Esophageal malignancy is the third most common cause of aorto-esophageal fistula (AEF), after thoracic aortic aneurysm and ingestion of foreign body. The involvement of aortic wall often contraindicates chemo-radiotherapy (CRT) treatment, thus reducing life expectancy of these patients. Thoracic endovascular aortic repair (TEVAR) is a well described mini-invasive technique that can be also applied for coverage of aortic lumen in case of invasion by esophageal cancer (EC). Only few cases have been published with this atypical indication. Between 2016 and 2018, in our tertiary hospital three patients affected by AEC involving the thoracic aorta were treated by means of prophylactic TEVAR (ProTEVAR). We did not observe procedure-related complications and all patients were reconsidered fit for preoperative or definitive CRT.

Aim our aim was to evaluate if CT could predict outcomes in terms of treatment in patient with caustic ingestion injury. Background and methods endoscopy has long been the gold standard for initial evaluation of caustic ingestion injury. Lately several studies suggested CT-scans to have an equal or even superior accuracy in emergency evaluation and prediction of esophageal stricture formation. Wishing to avoid complications of endoscopic procedures, new radiological grading system are being defined to supplement or replace the ones currently used. On the basis of the available evidence, we proposed a radiological 3 grade-score: grade I (well-defined visceral wall, homogenous post-contrastographic enhancement, no wall/perivisceral fat tissue edema), grade IIA (thickened and hypointense mucosa with post-contrastographic enhancement, wall/perivisceral fat tissue edema), grade IIB (necrotic mucosa with slight post-contrastographic external wall enhancement), grade III (transmural necrosis, defined by two of three between: lack of post-contrastografic wall enhancement, not defined visceral wall, blurred perivisceral fat tissue). Retrospectively we collected patients’ CT-scans which were reviewed by a radiologist, two senior surgeons and six resident surgeons; CT-scans performed within 48 hours after the ingestion were considered significant. We also tracked patients’ clinical history and compared the outcomes. Results of 50 patients that were admitted in our division in the last 10 years, we reviewed CT-scans of 23 patients; 15 were performed within 48 hours after the caustic ingestion. From the analysis of the data we observed that clinicians scored similarly, especially for grades I and III. Of these patients, 26,6 % had elective surgery (I: 0%; IIA: 0%; IIB: 75%; III: 25%), 20 % underwent emergency surgery (I: 0%; IIA: 33%; IIB: 0%; III: 66%), 53,4 % had conservative management (I: 25%; IIA: 12,5%; IIB: 37,5%; III: 25%). For what concerns the effectiveness of the score, we found high negative predictive value for grade I (all patients were treated conservatively), although highest grade had good specificity (0,86) regarding the needs of reconstructive surgery. Conclusion our radiological classification seems a worthwhile tool at the two extreme grades; on the contrary, for intermediate scores is still necessary an endoscopic-integrated approach to define which treatment achieve.

Background In dedicated centres ERAS (Enhanced Recovery After Surgery) programs have been successfully applied after esophageal surgery. However, some concerns have been raised about the feasibility of these protocols in elderly patients. Methods We retrospective reviewed 72 patients submitted to Ivor-Lewis esophagectomy in our Institution, during the period 2015-2017. We divided the patients into two groups: 47 patients (65,3%) were Results The two groups were not different in terms of overall morbidity rate (53,2% in YG vs 60,0% in EG p= 0,6) and pulmonary complications rate (70,2% in YG vs 72,0% in EG, p= 1). EG showed a higher cardiac complications rate (3,5% in YG vs 26,7% in EG, p=0,001). We did not report 90-days mortality. We did not observe differences in adherence to the following ERAS steps: pre-operative carbohydrate load administration (78,7% in YG vs 76,0% in EG, p=0,7), ward transfer on POD 0 (61,7% in YG vs 48,0% in EG, p=0,32), removal of naso-gastric tube on POD 1 (87,2% in YG vs 96,0% in EG, p=0,4), resume of liquid diet on POD 1 (55,3% in YG vs 56,0% in EG, p=1), urinary catheter removal on POD 2 (61,7% in YG vs 48,0% in EG, p=0,3), fully mobilization on POD 3 (63,8% in YG vs 52,0% in EG, p=0,4), resume of soft diet on POD 4 (72,3% in YG vs 68,0% in EG, p=0,7), discharge on POD 7 (48,9% in YG vs 40,0% in EG, p=0,6). Median day of discharge was POD 8 for both groups (p= 0,8). Conclusions In high-volume centres ERAS protocols can be safely applied to elderly patients undergoing esophagectomy.