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Reasons for structural and outcome differences in esophageal cancer surgery in Western Europe remain unclear. This questionnaire study aimed to identify differences in the organization of esophageal cancer surgical care in Western Europe. A cross-sectional international questionnaire study was conducted among upper gastrointestinal (GI) surgeons from Western Europe. One surgeon per country was selected based on scientific output and active membership in the European Society for Diseases of the Esophagus or (inter)national upper GI committee. The questionnaire consisted of 51 structured questions on the structural organization of esophageal cancer surgery, surgical training, and clinical audit processes. Between October 2021 and October 2022, 16 surgeons from 16 European countries participated in this study. In 5 countries (31%), a volume threshold was present ranging from 10 to 26 annual esophagectomies, in 7 (44%) care was centralized in designated centers, and in 4 (25%) no centralizing regulations were present. The number of centers performing esophageal cancer surgery per country differed from 4 to 400, representing 0.5-4.9 centers per million inhabitants. In 4 countries (25%), esophageal cancer surgery was part of general surgical training and 8 (50%) reported the availability of upper GI surgery fellowships. A national audit for upper GI surgery was present in 8 (50%) countries. If available, all countries use the audit to monitor the quality of care. Substantial differences exist in the organization and centralization of esophageal cancer surgical care in Western Europe. The exchange of experience in the organizational aspects of care could further improve the results of esophageal cancer surgical care in Europe., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Objective: To determine the impact of operative approach [open (OE), hybrid minimally invasive (HMIE), and total minimally invasive (TMIE) esophagectomy] on operative and oncologic outcomes for patients treated with curative intent for esophageal and junctional cancer., Background: The optimum oncologic surgical approach to esophageal and junctional cancer is unclear., Methods: This secondary analysis of the European multicenter ENSURE study includes patients undergoing curative-intent esophagectomy for cancer between 2009 and 2015 across 20 high-volume centers. Primary endpoints were disease-free survival (DFS) and the incidence and location of disease recurrence. Secondary endpoints included among others R0 resection rate, lymph node yield, and overall survival (OS)., Results: In total, 3199 patients were included. Of these, 55% underwent OE, 17% HMIE, and 29% TMIE. DFS was independently increased post-TMIE [hazard ratio (HR): 0.86 (95% CI: 0.76-0.98), P = 0.022] compared with OE. Multivariable regression demonstrated no difference in absolute locoregional recurrence risk according to the operative approach [HMIE vs OE, odds ratio (OR): 0.79, P = 0.257; TMIE vs OE, OR: 0.84, P = 0.243]. The probability of systemic recurrence was independently increased post-HMIE (OR: 2.07, P = 0.031), but not TMIE (OR: 0.86, P = 0.508). R0 resection rates ( P = 0.005) and nodal yield ( P < 0.001) were independently increased after TMIE, but not HMIE ( P = 0.424; P = 0.512) compared with OE. OS was independently improved following both HMIE (HR: 0.79, P = 0.009) and TMIE (HR: 0.82, P = 0.003) as compared with OE., Conclusion: In this European multicenter study, TMIE was associated with improved surgical quality and DFS, whereas both TMIE and HMIE were associated with improved OS as compared with OE for esophageal cancer., Competing Interests: M.I.v.B.H. is a consultant for Alesi Surgical, BBraun, Johnson & Johnson, Medtronic and Viatris, and received research grants from Stryker (all fees paid to the institution). The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD)., Methods: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD., Results: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18 F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended., Discussion: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment., Competing Interests: Declaration of Competing Interest Dr. van Laarhoven reports a consultant or advisory role: Amphera, Anocca, Astellas, AstraZeneca, Beigene, Boehringer, Daiichy-Sankyo, Dragonfly, MSD, Myeloid, Servier; Research funding, medication supply, and/or other research support: Auristone, Incyte, Merck, ORCA, Servier; Speaker role: Astellas, Beigene, Benecke, BMS, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Springer, Travel Congress Management B.V. Dr. Muijs reports institutional grants from: Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, KWF, all outside the submitted work. Dr. van Hillegersberg has a consulting and advisory role at Intuitive Surgical, Medtronic, Olympus and J&J Ethicon. Dr. de Manzoni reports personal fees from Lilly, outside the submitted work. Dr. Gani reports travel grants from Elekta and departmental research cooperation, outside the submitted work. Dr. Smyth is supported by the NIHR Biomedical Research Centre at Oxford (the views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health) and resports personal fees/grants from: Astra Zeneca, Beigene, BMS, Amal Therapeutics, Amgen, Daiichi Sankyo, Merck, Servier, Novartis, Pfizer, Roche, and Zymeworks, all outside the submitted work. Dr. Haj Mohammad reports consulation fees from: Merck, BMS, Eli Lilly, Astra Zeneca, and research funding from Servier, all outside the submitted work. Dr. Adenis reports grants and personal fees from Bayer, personal fees and non-financial support from MSD, personal fees from: BMS, Novartis, Pierre-Fabre, non-financial support from Servier, grants from Sanofi, all outside the submitted work. Dr. Lordick reports grants from: BMS and Gilead, personal fees from: Amgen, Astellas, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Elsevier, Incyte, Merck, MSD, Roche, Servier, all outside the submitted work. Dr. Slingerland reports an advisory role at BMS and Lilly. Dr. van Berge Henegouwen received researcher-initiated grant from Stryker and is consultant for Alesi Surgical, Johnson and Johnson, Medtronic, BBraun and Viatris. Dr Nilsson reports advisory roles for BMS and Medtronic. Dr. Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc; and also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Dr. Tabernero declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. Dr. Nieuwenhuijzen reports advisory/speaker roles from Medtronic and Lilly. All remaining authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic oropharyngeal dysphagia (COD) and aspiration after esophageal cancer surgery may have clinical significance; however, it is a rarely studied topic. In a prospective cross-sectional observational study we comprehensively evaluated the nature, severity, and impact of COD, its predictors, and the impact of the surgical approach and site of anastomosis. Forty participants were recruited via purposive sampling from the (Irish) National Center between November 2021 and August 2022. Swallow evaluations included videofluoroscopy [Dynamic Imaging Grade of Swallowing Toxicity v2 (DIGESTv2), MBS Impairment Profile, Penetration-Aspiration Scale)]. Functional Oral Intake Scale (FOIS) identified oral intake status. The patient reported outcome measures of swallowing, and Quality of Life (QL) included EAT-10 and MD Anderson Dysphagia Inventory (MDADI). Fourteen (35%) participants presented with COD on DIGESTv2 and 10% had uncleared penetration/aspiration. Avoidance or modification of diet on FOIS was observed in 17 (42.5%). FOIS was associated with pharyngeal dysphagia (OR = 4.05, P = 0.046). Median (range) EAT-10 and MDADI Composite results were 3(0-30) and 77.9(60-92.6), respectively. Aspiration rates significantly differed across surgical groups (P = 0.029); only patients undergoing transhiatal surgery aspirated. Survivors of esophageal cancer surgery may have COD that is undiagnosed, potentially impacting swallow-related QL. Given the small number of aspirators, further research is required to determine whether aspiration risk is associated with surgical approach. A FOIS score below 7 may be a clinically useful prompt for the MDT to refer for evaluation of COD following curative intent surgery. These data present findings that may guide preventive and rehabilitative strategies toward optimizing survivorship., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Background: Oesophageal cancer, in particular adenocarcinoma, has a strong male predominance. However, the impact of patient sex on operative and oncologic outcomes and recovery of health-related quality of life is poorly documented, and was the focus of this large multicentre cohort study., Methods: All consecutive patients who underwent oncological oesophagectomy from 2009 to 2015 in the 20 European iNvestigation of SUrveillance after Resection for Esophageal cancer study group centres were assessed. Clinicopathologic variables, therapeutic approach, postoperative complications, survival and health-related quality of life data were compared between male and female patients. Multivariable analyses adjusted for age, sex, tumour histology, treatment protocol and major complications. Specific subgroup analyses comparing adenocarcinoma versus squamous cell cancer for all key outcomes were performed., Results: Overall, 3974 patients were analysed, 3083 (77.6%) male and 891 (22.4%) female; adenocarcinoma was predominant in both groups, while squamous cell cancer was observed more commonly in female patients (39.8% versus 15.1%, P < 0.001). Multivariable analysis demonstrated improved outcomes in female patients for overall survival (HRmales 1.24, 95% c.i. 1.07 to 1.44) and disease-free survival (HRmales 1.22, 95% c.i. 1.05 to 1.43), which was caused by the adenocarcinoma subgroup, whereas this difference was not confirmed in squamous cell cancer. Male patients presented higher health-related quality of life functional scores but also a higher risk of financial problems, while female patients had lower overall summary scores and more persistent gastrointestinal symptoms., Conclusion: This study reveals uniquely that female sex is associated with more favourable long-term survival after curative treatment for oesophageal cancer, especially adenocarcinoma, although long-term overall and gastrointestinal health-related quality of life are poorer in women., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Esophagectomy is an exemplar of complex oncological surgery and is associated with a relatively high risk of major morbidity and mortality. In the modern era, where specific complications are targeted in prevention and treatment pathways, and where the principles of enhanced recovery after surgery are espoused, optimum outcomes are targeted via a number of approaches. These include comprehensive clinical and physiological risk assessment, specialist perioperative care by a high-volume team, and multimodal inputs throughout the patient journey that aim to preserve or restore nutritional deficits, muscle mass and function., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Oesophagogastric adenocarcinomas (OAC) are poor prognosis, obesity-associated cancers which may benefit from natural killer (NK) cell-based immunotherapies. Cellular immunotherapies encounter two key challenges to their success in OAC, namely recruitment to extratumoural tissues such as the omentum at the expense of the tumour and an immunosuppressive tumour microenvironment (TME) which can hamper NK cell function. Herein, we examined approaches to overcome the detrimental impact of obesity on NK cells and NK cell-based immunotherapies. We have demonstrated that NK cells migrate preferentially to the chemotactic signals of OAC patient-derived omentum over tumour in an ex vivo model of immune cell migration. We have identified CX3CR1 modulation and/or tumour chemokine profile remodelling as approaches to skew NK cell migration towards tumour. We also report targetable immunosuppressive facets of the obese OAC TME which dampen NK cell function, in particular cytotoxic capabilities. These data provide insights into approaches to therapeutically overcome key challenges presented by obesity and will inform superior design of NK cell-based immunotherapies for OAC., (© 2024. The Author(s).)

Background: A conditional survival nomogram was developed at a single high-volume center to predict 5-year overall survival for esophageal cancer patients after neoadjuvant chemoradiation and esophagectomy. The aim of this study was to externally validate the nomogram in a cohort of patients with esophageal adeno- or squamous cell carcinoma from another high-volume center., Methods: Consecutive patients with an esophageal adeno- or squamous cell carcinoma who had undergone esophagectomy after being treated with preoperative chemoradiation between 2004 and 2016 were selected from a prospectively maintained institutional database. The level of discrimination for prediction of 5-year overall survival was quantified by Harrell's C statistic. Calibration of the conditional survival nomogram was visualized by plotting predicted 5-year survival and observed 5-year survival for comparison., Results: Of the 296 patients examined, the probability of 5-year overall survival directly after surgery was 45% and increased to 51%, 68%, 78%, and 89% for each additional year survived. The predicted 5-year overall survival differed from the observed survival, with a calibration slope of 0.54, 0.55, 0.59, 0.73, and 1.09 directly after surgery and 1, 2, 3, and 4 years of survival after surgery, respectively. The nomogram's discrimination level for 5-year survival was moderate, with a C statistic of 0.65 compared to the 0.70 reported in the original study., Conclusion: The nomogram model has moderate predictive discrimination and accuracy, supporting its applicability to external cohorts to predict conditional survival. Further validation studies should empirically assess the model for predictive performance., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently)., Methods: Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m 2 epirubicin on day 1 plus intravenous 60 mg/m 2 cisplatin or intravenous 130 mg/m 2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m 2 fluorouracil daily or oral 625 mg/m 2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m 2 fluorouracil, 85 mg/m 2 oxaliplatin, 200 mg/m 2 leucovorin, and 50 mg/m 2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m 2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452., Findings: Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years., Interpretation: Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise., Funding: Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute., Competing Interests: Declaration of interests SRP reports support for the present manuscript from Cancer Research UK; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Jabar Al Ahmed Hospital, Kuwait City, Kuwait; support for attending meetings or travel from the Ministry of Health Kuwait. MAL reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from AstraZeneca; participation on a data safety monitoring board or advisory board for Servier and Agios; other financial or non-financial interests (educational grant to institution from Roche and being principal investigator on clinical trials for MSD, Basilea, Exilexis, Astellas, Daichii Sancho, and Zymeworks). SC reports support for attending meetings or travel from MSD, Pfizer, and Roche. GOG reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca and AbbVie. IP reports support for the present manuscript from Health Research Board, Irish Cancer Society, and Oesophageal Cancer Fund to Cancer Trials Ireland. RR reports consulting fees from Servier; payment or honoraria for educational events from Bristol-Myers Squibb and Servier; support for attending meetings from Servier Laboratories; and advisory board fees from Servier Laboratories. SF reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Servier. GP reports support for the present manuscript from the French National Cancer Institute; grants or contracts from the French National Cancer Institute; consulting fees from Bristol-Myers Squibb, Astellas, and Nestle; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from the European Society for Medical Oncology; and support for attending meetings or travel from Metronic. DO'T reports honoraria for lectures and speaker bureaus from Ipsen, Novartis, Wyeth Ledrele, and AstraZeneca; support for attending meetings or travel from Ipsen, Novartis, and AstraZeneca; and unpaid leadership roles in other board, society, committee or advocacy groups (European Neuroendocrine Tumour Society Board). RM reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bayer, Sanofi, Janssen, MSD, Pfizer, Novartis, Clovis, Astellas, Ipsen, and Bristol-Myers Squibb, and support for attending meetings from Pfizer, Janssen, Roche, and Ipsen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aimed to compare clinicopathologic, oncologic, and health-related quality of life (HRQL) outcomes following neoadjuvant chemoradiation (nCRT) and chemotherapy (nCT) in the ENSURE international multicenter study., Background: nCT and nCRT are the standards of care for locally advanced esophageal cancer (LAEC) treated with curative intent. However, no published randomized controlled trial to date has demonstrated the superiority of either approach., Methods: ENSURE is an international multicenter study of consecutive patients undergoing surgery for LAEC (2009-2015) across 20 high-volume centers (NCT03461341). The primary outcome measure was overall survival (OS), secondary outcomes included histopathologic response, recurrence pattern, oncologic outcome, and HRQL in survivorship., Results: A total of 2211 patients were studied (48% nCT, 52% nCRT). pCR was observed in 4.9% and 14.7% ( P <0.001), with R0 in 78.2% and 94.2% ( P <0.001) post nCT and nCRT, respectively. Postoperative morbidity was equivalent, but in-hospital mortality was independently increased [hazard ratio (HR)=2.73, 95% CI: 1.43-5.21, P= 0.002] following nCRT versus nCT. Probability of local recurrence was reduced (odds ratio=0.71, 95% CI: 0.54-0.93, P =0.012), and distant recurrence-free survival time reduced (HR=1.18, 95% CI: 1.02-1.37, P =0.023) after nCRT versus nCT, with no difference in OS among all patients (HR=1.10, 95% CI: 0.98-1.25, P =0.113). On subgroup analysis, patients who underwent R0 resection following nCT as compared with nCRT had improved OS (median: 60.7 months, 95% CI: 49.5-71.8 vs 40.8 months, 95% CI: 42.8-53.4, P <0.001)., Conclusions: In this European multicenter study, nCRT compared with nCT was associated with reduced probability of local recurrence but reduced distant recurrence-free survival for patients with LAEC, without differences in OS. These data support tailored patient-specific decision-making in the overall approach to achieving optimum outcomes in LAEC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of this study was to explore oncologic outcomes of transhiatal gastrectomy (THG) or transthoracic esophagectomy (TTE) for neoadjuvantly treated gastroesophageal junction (GEJ) Siewert type II adenocarcinomas, a multinational, high-volume center cohort analysis was undertaken., Background: Neoadjuvant radiochemotherapy or perioperative chemotherapy (CTx) followed by surgery is the standard therapy for locally advanced GEJ. However, the optimal surgical approach for type II GEJ tumors remains unclear, as the decision is mainly based on individual experience and assessment of operative risk., Methods: A retrospective analysis of 5 prospectively maintained databases was conducted. Between 2012 and 2021, 800 patients fulfilled inclusion criteria for type II GEJ tumors and neoadjuvant radiochemotherapy or CTx. The primary endpoint was median overall survival (mOS). Propensity score matching was performed to minimize selection bias., Results: Patients undergoing THG (n=163, 20.4%) had higher American Society of Anesthesiologists (ASA) classification and cT stage ( P <0.001) than patients undergoing TTE (n=637, 79.6%). Neoadjuvant therapy was different as the THG group were mainly undergoing CTx (87.1%, P <0.001). The TTE group showed higher tumor regression ( P =0.009), lower ypT/ypM categories (both P <0.001), higher nodal yield ( P =0.009) and higher R0 resection rate ( P =0.001). The mOS after TTE was longer (78.0 vs 40.0 months, P =0.013). After propensity score matching a higher R0 resection rate ( P =0.004) and mOS benefit after TTE remained ( P =0.04). Subgroup analyses of patients without distant metastasis ( P =0.037) and patients only after neoadjuvant chemotherapy ( P =0.021) confirmed the survival benefit of TTE. TTE was an independent predictor of longer survival., Conclusion: Awaiting results of the randomized CARDIA trial, TTE should in high-volume centers be considered the preferred approach due to favorable oncologic outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Visceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity., Methods and Results: Visceral adipose conditioned media (ACM) from both early and late-stage OGJ patients significantly altered T cell activation status, upregulating co-stimulatory marker CD27 on T cells. ACM from both early and late-stage OGJ patients significantly altered immune checkpoint expression profiles downregulating immune checkpoints (ICs) on the surface of dual Th1/17-like and Th17-like cells and upregulating ICs on the surface of Th1-like cells and Treg cells. ACM derived from early-stage OGJ patients but not late-stage OGJ patients increased IFN-γ production by T cells. The addition of immune checkpoint blockers (ICBs) did not increase IFN-γ production by T cells in the presence of late-stage ACM, collectively highlighting the dichotomous immunostimulatory effect of early-stage ACM and immune-inhibitory effect of late-stage ACM. Interestingly, ACM from early-stage OGJ patients was more pro-inflammatory than ACM from late-stage patients, reflected by decreased levels of IL-17A/F, TNF-α, IL-1RA and IL-5., Conclusion: The ACM-induced upregulation of ICs on T cells highlights a therapeutic vulnerability that could be exploited by ICBs to harness anti-cancer immunity and improve clinical outcomes for OGJ patients. Schematic workflow - (A) visceral adipose tissue was taken from OAC patients at time of surgery and cultured for 72 h in media. (B) The harvested ACM was co-cultured with healthy donor PBMCs that were concurrently activated with anti-CD3/28 for 48 h and T cell immunophenotyping was carried out by flow cytometry. Key findings - (A) Early and late stage ACM enhanced a Th1-like phenotype and upregulated CTLA-4 on Th1-like cells. A Th17-like phenotype was also enhanced in addition with a Treg-like phenotype. CTLA-4 and PD-L1 were upregulated on the surface of Treg-like cells. (B) ICB-attenuated IL-17 production by T cells. However, ACM attenuated ICB-mediated reduction in IL-10 production by T cells. Higher levels of pro-inflammatory factors were found in early stage ACM compared with late stage ACM., (© 2023. The Author(s).)

The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers. Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed. Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined. Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30 + and NKp46 + NK cells and increased frequencies of TIGIT + , FasL + and TRAIL + NK cells. Frequencies of IFN-γ-producing NK cells increased while frequencies of TIM-3 + NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30 + NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT. Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells. However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation. In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients., (© 2022. The Author(s).)

Competing Interests: Conflict of interest: None declared

Objective: To determine the impact of surveillance on recurrence pattern, treatment, survival and health-related quality-of-life (HRQL) following curative-intent resection for esophageal cancer., Summary Background Data: Although therapies for recurrent esophageal cancer may impact survival and HRQL, surveillance protocols after primary curative treatment are varied and inconsistent, reflecting a lack of evidence., Methods: European iNvestigation of SUrveillance after Resection for Esophageal cancer was an international multicenter study of consecutive patients undergoing surgery for esophageal and esophagogastric junction cancers (2009-2015) across 20 centers (NCT03461341). Intensive surveillance (IS) was defined as annual computed tomography for 3 years postoperatively. The primary outcome measure was overall survival (OS), secondary outcomes included treatment, disease-specific survival, recurrence pattern, and HRQL. Multivariable linear, logistic, and Cox proportional hazards regression analyses were performed., Results: Four thousand six hundred eighty-two patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy, 45.5% IS). At median followup 60 months, 47.5% developed recurrence, oligometastatic in 39%. IS was associated with reduced symptomatic recurrence (OR 0.17 [0.12-0.25]) and increased tumor-directed therapy (OR 2.09 [1.58-2.77]). After adjusting for confounders, no OS benefit was observed among all patients (HR 1.01 [0.89-1.13]), but OS was improved following IS for those who underwent surgery alone (HR 0.60 [0.47-0.78]) and those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58-0.89]). IS was associated with greater anxiety ( P =0.016), but similar overall HRQL., Conclusions: IS was associated with improved oncologic outcome in select cohorts, specifically patients with early-stage disease at presentation or favorable pathological stage post neoadjuvant therapy. This may inform guideline development, and enhance shared decision-making, at a time when therapeutic options for recurrence are expanding., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Esophageal cancer has a notably high recurrence rate with a paucity of robust evidence in defining the optimal surveillance strategy. The surveillance protocol at our institution comprises of annual esophagogastroduodenoscopy (OGD) from years 1 to 5 postoperatively. This study aims to evaluate the implementation of the endoscopic surveillance at our center and ascertain the value of endoscopy in detecting local recurrence after esophagectomy. A retrospective cohort review of all patients (320 patients) who underwent esophagectomy between 2013 and 2018 was conducted. The local esophageal cancer database and corresponding OGD reports were accessed to obtain data on demographics, operation details, local recurrence, and endoscopy performed. 1086 OGDs were performed between 2014 and 2020, broadly categorized to surveillance and symptomatic OGDs; 555 and 531, respectively. Surveillance OGDs detected four asymptomatic local recurrences, of which only one was treated with curative intent. Symptomatic OGDs resulted in a higher yield for the detection of local recurrence compared with surveillance endoscopy; 5% versus 0.7%, with overall median time-to-recurrence of 11.5 months (95% confidence interval 9-17). Of local recurrences, 85.7% occurred within the first 2 years postoperatively. The proportion of endoscopic findings differed between intensive and ad hoc surveillance cohorts for strictures, esophagitis, Barrett's esophagus, and sloughing. Thirteen patients were diagnosed with histologically confirmed Barrett's with no subsequent local recurrences. Surveillance endoscopy had a low positive yield rate with subsequent minimal survival benefits. Therefore, it is prudent to consider an alternative protocol that focuses on the period with the highest risk of recurrence and symptom presentation., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Despite the fact that health information is now more accessible than ever, knowledge gaps remain between patients and healthcare providers (HCPs). To date, the patients' need for information following a diagnosis of oesophageal cancer has not been adequately met., Purpose: The purpose of this study was to identify why knowledge gaps exist between oesophageal cancer patients and HCPs and how to address them., Methods: Purposive sampling of a group of people living with and after oesophageal cancer who had participated in a priority-setting partnership where 45% of questions from patients had existing evidence-based answers. A 7-set question series was developed for use in a patient/HCP focus group in addition to 11 individual phone interviews with survivors of oesophageal cancer. Qualitative semistructured interviews were conducted to explore oesophageal cancer patients' access to information. The data was analysed thematically, which involved coding all patient transcripts before identifying and reviewing key themes., Results: The three primary themes that emerged were as follows: opportunity (HCP team factors and relationship development), ability (patient factors) and priority (pacing of information delivery)., Conclusion: Effective communication between patients and HCPs was identified as an integral component of the enhancement of patient knowledge. HCPs should continue to refine and improve methods of information delivery and encourage conversations regarding information preferences., (© 2022. The Author(s).)

Anastomotic leak (AL) is a severe complication after esophagectomy. Clinical presentation of AL is diverse and there is large practice variation regarding treatment of AL. This study aimed to explore different AL treatment strategies and their underlying rationale. This mixed-methods study consisted of an international survey among upper gastro-intestinal (GI) surgeons and focus groups with expert upper GI surgeons. The survey included 10 case vignettes and data sources were integrated after separate analysis. The survey was completed by 188 respondents (completion rate 69%) and 6 focus groups were conducted with 20 international experts. Prevention of mortality was the most important goal of primary treatment. Goals of secondary treatment were to promote tissue healing, return to oral feeding and safe hospital discharge. There was substantial variation in the preferred treatment principles (e.g. drainage or defect closure) and modalities (e.g. stent or endoVAC) within different presentations of AL. Patients with local symptoms were treated by supportive means only or by non-surgical drainage and/or defect closure. Drainage was routinely performed in patients with intrathoracic collections and often combined with defect closure. Patients with conduit necrosis were predominantly treated by resection and reconstruction of the anastomosis or by esophageal diversion. This mixed-methods study shows that overall treatment strategies for AL are determined by vitality of the conduit and presence of intrathoracic collections. There is large variation in preferred treatment principles and modalities. Future research may investigate optimal treatment for specific AL presentations and aim to develop consensus-based treatment guidelines for AL after esophagectomy., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Objective: To analyze the spectrum of Centers for Disease Control and Prevention (CDC)-defined pneumonia after esophageal cancer surgery., Summary Background Data: Pneumonia is commonly documented after esophageal cancer surgery, and reducing its incidence is central to both ERAS development and to the evidence-base for minimally invasive approaches. The existing definitions of pneumonia based on hospital acquired pneumonia classifications may be suboptimal in this context and merits strict academic scrutiny., Methods: Patients (2013-2018) treated with curative intent by open surgery were studied. Pneumonia was defined per the CDC definition. Risk factors and associations were analyzed, as was the implications of positive cultures. Multivariable logistic regression examined independently predictive factors of pneumonia and oncologic outcomes., Results: Of 343 patients, 56 (16%) had defined pneumonia, 22 (39%) with positive cultures. Preoperative respiratory disease predicted pneumonia ( P = 0.043). Neoadjuvant therapy was significantly ( P = 0.004) associated with culture negative pneumonia, and age ( P = 0.001) with culture positive pneumonia. In multivariable analysis, pneumonia was associated ( P < 0.05) with respiratory comorbidity, tumor site, and neoadjuvant chemoradiation. Pneumonia did not impact on overall survival (P = 0.807)., Discussion: CDC-defined pneumonia occurred in 16% of cases. Culture-negative pneumonia accounted for 61% of cases and was significantly associated with neoadjuvant chemoradiation. Pneumonia as currently defined seems to represent a spectrum of etiology and severity in the post-esoph-agectomy patient, with infection per se rarely proven, suggesting a need to reevaluate its definition, severity classification, and preventive and treatment strategies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The FLOT protocol and the CROSS trimodality regimen represent current standards in the management of locally advanced esophageal adenocarcinoma. In the absence of published Randomised Controlled Trial data, this propensity-matched comparison evaluated tolerance, toxicity, impact on sarcopenia and pulmonary physiology, operative complications, and oncologic metrics., Methods: Two hundred and twenty-two patients, 111 in each arm, were included from 2 high-volume centers. Computed tomography-measured sarcopenia, and pulmonary function (forced expiratory volume in first second/forced vital capacity/diffusion capacity for carbon monoxide) were compared pretherapy and posttherapy. Operative complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria, and severity per Clavien-Dindo. Tumor regression grade and R status were measured, and survival estimated per Kaplan-Meier., Results: A total of 83% were male, cT3/cN+ was 92%/68% for FLOT, and 86%/60% for CROSS. The full prescribed regimen was tolerated in 40% of FLOT patients versus 92% for CROSS. Sarcopenia increased from 16% to 33% for FLOT, and 14% to 30% in CROSS ( P <0.01 between arms). Median decrease in diffusion capacity for carbon monoxide was -8.25% (-34 to 25) for FLOT, compared with -13.8%(-38 to 29), for CROSS ( P =0.01 between arms). Major pathologic response was 27% versus 44% for FLOT and CROSS, respectively ( P =0.03). In-hospital mortality, respectively, was 1% versus 2% ( P =0.9), and Clavien Dindo >III 22% versus 27% ( P =0.59), however, respiratory failure was increased by CROSS, at 13% versus 3% ( P <0.001). Three-year survival was similar at 63% (FLOT) and 60% (CROSS) ( P =0.42)., Conclusions: Both CROSS and FLOT resulted in equivalent survival. Operative outcomes were similar, however, the CROSS regimen increased postoperative respiratory failure and atrial fibrillation. Less than half of patients received the prescribed FLOT regimen, although toxicity rates were acceptable. These data support clinical equipoise, caution, however, may be advised with CROSS in patients with greatest respiratory risk., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Postoperative pulmonary complications (PPCs) represent the most common complications after esophageal cancer surgery. The lack of a uniform reporting nomenclature and a severity classification has hampered consistency of research in this area, including the study of interventions targeting prevention and treatment of PPCs. This systematic review focused on RCTs of clinical interventions used to minimize the impact of PPCs. Searches were conducted up to 08/02/2021 on MEDLINE (OVID), CINAHL, Embase, Web of Science, and the COCHRANE library for RCTs and reported in accordance with PRISMA guidelines. A total of 339 citations, with a pooled dataset of 1,369 patients and 14 RCTs, were included. Heterogeneity of study design and outcomes prevented meta-analysis. PPCs are multi-faceted and not fully understood with respect to etiology. The review highlights the paucity of high-quality evidence for best practice in the management of PPCs. Further research in the area of intraoperative interventions and early postoperative ERAS standards is required. A consistent uniform for definition of pneumonia after esophagectomy and the development of a severity scale appears warranted to inform further RCTs and guidelines., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Visceral obesity (VO) and metabolic syndrome (MetS) are risk factors for esophageal adenocarcinoma (EAC); however, their impact on operative and oncological outcomes is unclear. The aim of this study was to determine the incidence of VO and MetS among patients with EAC, and to assess their independent impact on operative and oncological outcomes. A total of 454 consecutive patients undergoing treatment with curative intent were studied. Total, subcutaneous, visceral fat area (VFA), and lean body mass (LBM) were measured by computed tomography pretreatment, with VO defined as VFA >163.8cm2 for men and 80.1cm2 for women. MetS was defined per the ATPIII definition. Multivariable logistic and Cox proportional hazards regression were utilized to determine independent predictors of oncologic and operative outcomes. A total of 227 patients (50.0%) had VO. A total of 134 (30%) overall had MetS, 44% in the VO cohort. VO was associated with Barrett's esophagus (P = 0.002) and lower cT (P = 0.006) and cN stage (P = 0.011), and improved disease-specific (P = 0.021) and overall survival (P = 0.012). No survival benefit existed for patients with VO who also had MetS. For operative complications, neither VO nor MetS increased the severity of complications, or mortality. However, VO was significantly (P = 0.035) associated with anastomotic leak and pneumonia (P = 0.037). MetS alone did not increase complication risk. VO increases specific major operative complications with no increase in mortality. VO improved survival, mainly relating to earlier stage disease; however, co-existent MetS abrogated this benefit. These seemingly paradoxical outcomes highlight manageable and potentially targetable perioperative challenges in the context of an overall favorable oncologic vista., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Oesophageal adenocarcinoma (OAC) is an aggressive cancer with a five-year survival of <15%. Current chemotherapeutic strategies only benefit a minority (20-30%) of patients and there are no methods available to differentiate between responders and non-responders. We performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on albumin/IgG-depleted and non-depleted plasma samples from 23 patients with locally advanced OAC prior to treatment. Individuals were grouped based on tumour regression (TRG) score (TRG1/2/3 vs TRG4/5) after chemotherapy, and differentially abundant proteins were compared. Protein depletion of highly abundant proteins led to the identification of around twice as many proteins. SWATH-MS revealed significant quantitative differences in the abundance of several proteins between the two groups. These included complement c1q subunit proteins, C1QA, C1QB and C1QC, which were of higher abundance in the low TRG group. Of those that were found to be of higher abundance in the high TRG group, glutathione S-transferase pi (GSTP1) exhibited the lowest p-value and highest classification accuracy and Cohen's kappa value. Concentrations of these proteins were further examined using ELISA-based assays. This study provides quantitative information relating to differences in the plasma proteome that underpin response to chemotherapeutic treatment in oesophageal cancers. SIGNIFICANCE: Oesophageal cancers, including oesophageal adenocarcinoma (OAC) and oesophageal gastric junction cancer (OGJ), are one of the leading causes of cancer mortality worldwide. Curative therapy consists of surgery, either alone or in combination with adjuvant or neoadjuvant chemotherapy or radiation, or combination chemoradiotherapy regimens. There are currently no clinico-pathological means of predicting which patients will benefit from chemotherapeutic treatments. There is therefore an urgent need to improve oesophageal cancer disease management and treatment strategies. This work compared proteomic differences in OAC patients who responded well to chemotherapy as compared to those who did not, using quantitative proteomics prior to treatment commencement. SWATH-MS analysis of plasma (with and without albumin/IgG-depletion) from OAC patients prior to chemotherapy was performed. This approach was adopted to determine whether depletion offered a significant improvement in peptide coverage. Resultant datasets demonstrated that depletion increased peptide coverage significantly. Additionally, there was good quantitative agreement between commonly observed peptides. Data analysis was performed by adopting both univariate as well as multivariate analysis strategies. Differentially abundant proteins were identified between treatment response groups based on tumour regression grade. Such proteins included complement C1q sub-components and GSTP1. This study provides a platform for further work, utilising larger sample sets across different treatment regimens for oesophageal cancer, that will aid the development of 'treatment response prediction assays' for stratification of OAC patients prior to chemotherapy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting., Aim: To immunophenotype OAC patients' immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability., Methods: In the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients' IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination of in vitro and ex vivo models. Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay. Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies. Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay., Results: We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT) in vitro and ex vivo in OAC. There were two distinct subcohorts with one demonstrating significant upregulation of ICs and the contrary in the other cohort. Increasing IC expression post RT was associated with a more aggressive tumour phenotype and adverse features of tumour biology. The use of anti-PD-1 and anti-PD-L1 immunotherapies in combination with radiation resulted in a significant and synergistic reduction in viability of both radiosensitive and radioresistant OAC cells in vitro. Interleukin-21 (IL-21) and IL-31 significantly increased, with a concomitant reduction in IL-23 as a consequence of 4 Gray radiation. Similarly, radiation induced an anti-angiogenic tumour milieu with reduced expression of vascular endothelial growth factor-A, basic fibroblast growth factor, Flt-1 and placental growth factor., Conclusion: The findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: In this single-arm study, the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy were evaluated in patients with resectable esophageal squamous cell carcinoma (ESCC)., Methods: This study included patients with ESCC of clinical stages II-IVA who underwent surgery within 4 to 6 weeks after completing treatment with pembrolizumab (200 mg) combined with a conventional chemotherapy regimen (3 cycles). The safety and efficacy of this combination treatment were evaluated as primary endpoints of the study., Results: From April 2019 to August 2020, a total of 18 patients (including 14 men) were enrolled, of whom 13 patients progressed to surgery. Postoperative pathology revealed a major pathological response (MPR) in 9 cases (9/13, 69.2%) and a pathological complete response (pCR) in 6 cases (6/13, 46.2%). Five patients (5/18, 27.8%) experienced serious treatment-related adverse events (AEs) of grades 3-4. At the time of data cutoff (Mar 25, 2022), the shortest duration of follow-up was 17.8 months. Programmed death-ligand 1 (PD-L1) expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT) (r=-0.55, P=0.08). Changes in counts of CD68 + macrophage between pre- and post-treatment specimens were weakly correlated with RVT (r=0.71; P=0.07), while a positive correlation was observed between postoperative forkhead box P3-positive (Foxp3) + T cells/CD4 + Tcells ratios and RVT (r=0.84, P = 0.03)., Conclusions: The combination of neoadjuvant immunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment (TME). It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials (RCTs)., Trial Registration: ChiCTR2100048917., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Duan, Shao, Pan, Liu, Dong, Zhang, Tong, Feng, Wang, Wang, Newman, Sarkaria, Reynolds, De Cobelli, Ma, Jiang and Yan.)

Objective: To determine the incidence, risk factors, and consequences of AKI in patients undergoing surgery for esophageal cancer., Summary of Background Data: Esophageal cancer surgery is an exemplar of major operative trauma, with well-defined risks of respiratory, cardiac, anastomotic, and septic complications. However, there is a paucity of literature regarding AKI., Methods: consecutive patients undergoing curative-intent surgery for esophageal cancer from 2011 to 2017 in 3 high-volume centers were studied. AKI was defined according to the AKI Network criteria. AKI occurred if, within 48 hours postoperatively, serum creatinine rose by 50% or by 0.3 mg/dL (26.5 μmol/L) from preoperative baseline. Complications were recorded prospectively. Multivariable logistic regression determined factors independently predictive of AKI., Results: A total of 1135 patients (24.7%:75.3% female:male, with a mean age of 64, a baseline BMI of 27 kg m-2, and dyslipidemia in 10.2%), underwent esophageal cancer surgery, 85% having an open thoracotomy. Overall in-hospital mortality was 2.1%. Postoperative AKI was observed in 208 (18.3%) patients, with AKI Network 1, 2, and 3 in 173 (15.2%), 28 (2.5%), and 7 (0.6%), respectively. Of these, 70.3% experienced improved renal function within 48 hours. Preoperative factors independently predictive of AKI were age [P = 0.027, odds ratio (OR) 1.02 (1.00-1.04)], male sex [P = 0.015, OR 1.77 (1.10-2.81)], BMI at diagnosis [P < 0.001, OR 1.10 (1.07-1.14)], and dyslipidemia [P = 0.002, OR 2.14 (1.34-3.44)]. Postoperatively, AKI was associated with atrial fibrillation (P = 0.013) and pneumonia (P = 0.005). Postoperative AKI did not impact survival outcomes., Conclusion: AKI is common but mostly self-limiting after esophageal cancer surgery. It is associated with age, male sex, increased BMI, dyslipidemia, and postoperative morbidity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The emergence of the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the coronavirus disease COVID-19 has impacted enormously on non-COVID-19-related hospital care. Curtailment of intensive care unit (ICU) access threatens complex surgery, particularly impacting on outcomes for time-sensitive cancer surgery. Oesophageal cancer surgery is a good example. This study explored the impact of the pandemic on process and short-term surgical outcomes, comparing the first wave of the pandemic from April to June in 2020 with the same period in 2019., Methods: Data from all four Irish oesophageal cancer centres were reviewed. All patients undergoing resection for oesophageal malignancy from 1 April to 30 June inclusive in 2020 and 2019 were included. Patient, disease, and peri-operative outcomes (including COVID-19 infection) were compared., Results: In 2020, 45 patients underwent oesophagectomy, and 53 in the equivalent period in 2019. There were no differences in patient demographics, co-morbidities, or use of neoadjuvant therapy. The median time to surgery from neoadjuvant therapy was 8 weeks in both 2020 and 2019. There were no significant differences in operative interventions between the two time periods. There was no difference in operative morbidity in 2020 and 2019 (28% vs 40%, p = 0.28). There was no in-hospital mortality in either period. No patient contracted COVID-19 in the perioperative period., Conclusions: Continuing surgical resection for oesophageal cancer was feasible and safe during the COVID-19 pandemic in Ireland. The national response to this threat was therefore successful by these criteria in the curative management of oesophageal cancer., (© 2021. Royal Academy of Medicine in Ireland.)

The incidence of oesophageal cancer, in particular adenocarcinoma, has markedly increased over the last four decades with adenocarcinoma becoming the dominant subtype in the West, and mortality rates are high. Nevertheless, overall survival of patients with oesophageal cancer has doubled in the past 20 years, with earlier diagnosis and improved treatments benefiting those patients who can be treated with curative intent. Advances in endotherapy, surgical approaches, and multimodal and other combination therapies have been reported. New vistas have emerged in targeted therapies and immunotherapy, informed by new knowledge in genomics and molecular biology, which present opportunities for personalised cancer therapy and novel clinical trials. This review focuses exclusively on the curative intent treatment pathway, and highlights emerging advances., (© 2021. The Author(s).)

Background: Esophageal adenocarcinoma (EAC) has a poor prognosis; predictive markers of prognosis would facilitate advances in personalized therapy. C-reactive protein (CRP) and CRP-based scores are increasingly recommended across oncology; however, their role and value in EAC is unclear. This systematic review and meta-analysis examined CRP cut-point and scores and how they may best be applied in predicting survival in EAC., Methods: A systematic literature search was conducted in EMBASE, Medline, Web of Science, Cochrane, Scopus and CINAHL databases, from inception to 1st October 2020. Studies reporting data from adults with EAC including adenocarcinoma of the gastro-esophageal junction (AEG), pre-treatment CRP or CRP-based score and Hazard Ratio (HR) for survival were included. QUIPS tool assessed risk of bias. Meta-analysis was undertaken., Results: A total of 819 records were screened. Eight papers were included, with data for 1475 people. CRP cut-points ranged from 2.8 to 10 mg/L. The Glasgow Prognostic Score (GPS) and modified GPS were the most commonly reported scores. On meta-analysis, elevated preoperative GPS/mGPS was significantly associated with worse overall survival (hazards ratio [HR] 1.81, 95% confidence interval [CI] 1.25-2.62, p = 0.002); results were similar in subgroup analyses of multimodal treatment, M0 disease, and R0 resection., Conclusions: This is the first review to evaluate comprehensively the evidence for CRP and CRP-based scores in EAC. Meta-analysis demonstrated that elevated preoperative GPS or mGPS was significantly associated with reduced overall survival in EAC, including AEG. There is insufficient evidence to support use of CRP alone. Future studies should examine GPS/mGPS in EAC prospectively, alone and combined with other prognostic markers., (© 2021. Society of Surgical Oncology.)

Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression., (© 2022. The Author(s).)

Objective: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors., Background: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood., Patients and Methods: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool., Results: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities.Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97-1.65), low mood (OR 1.42; 95% CI 1.15-1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18-1.59). The areas under the curves for the development and validation datasets were 0.81 ± 0.02 and 0.82 ± 0.09 respectively., Conclusion: Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients., Methods: Systemic immunity in 11 EAC patients was phenotyped immediately prior to esophagectomy (POD-0) and post-operatively (POD)-1, 3, 7 and week 6. Longitudinal serological profiling was conducted by ELISA. The frequency of circulating lymphocytes, activation status, immune checkpoint expression and damage-associated molecular patterns was assessed by flow cytometry., Results: The frequency of naïve T-cells significantly increased in circulation post-esophagectomy from POD-0 to POD-7 (p<0.01) with a significant decrease in effector memory T-cells by POD7 followed by a subsequent increase by week 6 (p<0.05). A significant increase in activated circulating CD27 + T-cells was observed from POD-0 to POD-7 (p<0.05). The percentage of PD-1 + and CTLA-4 + T-cells peaked on POD-1 and was significantly decreased by week 6 (p<0.01). There was a significant increase in soluble PD-1, PD-L2, TIGIT and LAG-3 from POD-3 to week 6 (p<0.01). Increased checkpoint expression correlated with those who developed metastatic disease early in their postoperative course. Th1 cytokines and co-stimulatory factors decreased significantly in the immediate post-operative setting, with a reduction in IFN-γ, IL-12p40, IL-1RA, CD28, CD40L and TNF-α. A simultaneous increase was observed in Th2 cytokines in the immediate post-operative setting, with a significant increase in IL-4, IL-10, IL-16 and MCP-1 before returning to preoperative levels at week 6., Conclusion: Our study highlights the prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if administered in the immediate neoadjuvant setting. Consequently, this body of work paves the way for further studies and appropriate trial design is needed to further interrogate and validate the use of ICI in the multimodal treatment of locally advanced disease in the neoadjuvant and adjuvant setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Donlon, Davern, Sheppard, O’Connell, Dunne, Hayes, Mylod, Ramjit, Temperley, Mac Lean, Cotter, Bhardwaj, Butler, Conroy, O’Sullivan, Ravi, Donohoe, Reynolds and Lysaght.)

Background: Dysphagia is prevalent in oesophageal cancer with significant clinical and psychosocial complications. The purpose of this study was i) to examine the impact of exercise-based dysphagia rehabilitation on clinical and quality of life outcomes in this population and ii) to identify key rehabilitation components that may inform future research in this area., Methods: Randomised control trials (RCT), non-RCTs, cohort studies and case series were included. 10 databases (CINAHL Complete, MEDLINE, EMBASE, Web of Science, CENTRAL, and ProQuest Dissertations and Theses, OpenGrey, PROSPERO, RIAN and SpeechBITE), 3 clinical trial registries, and relevant conference abstracts were searched in November 2020. Two independent authors assessed articles for eligibility before completing data extraction, quality assessment using ROBINS-I and Downs and Black Checklist, followed by descriptive data analysis. The primary outcomes included oral intake, respiratory status and quality of life. All comparable outcomes were combined and discussed throughout the manuscript as primary and secondary outcomes., Results: Three single centre non-randomised control studies involving 311 participants were included. A meta-analysis could not be completed due to study heterogeneity. SLT-led post-operative dysphagia intervention led to significantly earlier start to oral intake and reduced length of post-operative hospital stay. No studies found a reduction in aspiration pneumonia rates, and no studies included patient reported or quality of life outcomes. Of the reported secondary outcomes, swallow prehabilitation resulted in significantly improved swallow efficiency following oesophageal surgery compared to the control group, and rehabilitation following surgery resulted in significantly reduced vallecular and pyriform sinus residue. The three studies were found to have 'serious' to 'critical' risk of bias., Conclusions: This systematic review highlights a low-volume of low-quality evidence to support exercise-based dysphagia rehabilitation in adults undergoing surgery for oesophageal cancer. As dysphagia is a common symptom impacting quality of life throughout survivorship, findings will guide future research to determine if swallowing rehabilitation should be included in enhanced recovery after surgery (ERAS) programmes. This review is limited by the inclusion of non-randomised control trials and the reliance on Japanese interpretation which may have resulted in bias. The reviewed studies were all of weak design with limited data reported., (© 2022. The Author(s).)

SSIs represent common infection-related morbidity following major surgery. Modern care bundles have been established as prophylactic measures aimed at preventing SSI occurring postoperatively. SSI incidence and data on common culprit pathogens post-esophagectomy for cancer have not been previously reported. Patients (2013-2018) treated with curative intent were studied. SSI was defined as per the Center for Disease Control (CDC) definition. A care bundle pathway following the National Institute for Clinical Excellence (NICE) guidelines for prevention of SSIs was introduced in 2013 and was audited quarterly. Risk factors and associations of SSIs were analyzed, as was the prevalence of isolated pathogens. Multivariable logistic regression examined independently predictive factors of SSIs and oncologic outcomes. Of 343 patients, 34 (9.9%) developed a postoperative SSI, with a median (range) of 8 (6-17). Quarterly audit carried out over 6 years showed no significant annual variance or trend. The most prevalent pathogen cultured was Methicillin-sensitive Staphylococcus aureus (MSSA) in nine patients (32%) followed by Candida albicans (29%), Escherichia coli (14%), and Enterococcus faecium (11%). SSI was significantly associated with pneumonia (P = 0.001), respiratory failure (P = 0.014), atrial fibrillation (P = 0.004), anastomotic leak (P < 0.001), and in-hospital blood transfusions (P = 0.031). SSI did not impact the overall survival (P = 0.951). SSI rates can be maintained at less than 10% using strict care bundles and regular audit. The most common culprit pathogen is gram-positive MSSA representing 32% of cases. These data are novel and may represent a modern benchmark for SSI post-open esophagectomy for cancer. This study highlights the incidence and associations of SSI post-esophageal cancer surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes., Study Design: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology., Results: 175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%., Conclusion: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Colonic interposition is rarely used as an oesophageal replacement after resection, as the preferred use of stomach involves less anastomoses and lower risks of major complications. The functional outcome from the colonic conduit is also unpredictable. This report documents the spectrum of experience of a high-volume oesophageal centre, highlighting indications, techniques and functional outcomes. A retrospective review was undertaken of a prospective database from 2012 to 2016. Four of 252 (1.5%) cases in this time period utilised colon interposition. Two cases were for gastric conduit necrosis following oesophageal cancer resections, one for caustic ingestion with both an oesophago-bronchial fistula and gastric injury, and one for a primary oesophageal malignancy in a patient whom previously had a total gastrectomy. All patients had either a retrosternal or posterior mediastinal isoperistaltic right colon conduit placed. Two of three cancer patients are alive and disease free at 3 and 5 years, respectively. Surviving patients are weight stable and tolerating a normal diet. Both report excellent quality of life using validated assessment tools. Colonic interposition is rarely required in modern oesophageal practice, but with this technique good long-term nutritional and functional outcomes can be obtained. It is required in the armamentarium of a specialist centre, and training given its rarity may require novel approaches such as simulation and cadaveric-based training., (© 2020. Italian Society of Surgery (SIC).)

Surgery for benign esophageal diseases may be complex, requiring specialist training, but currently, unlike oncologic surgery, it is not centralized. The aim of the study was to explore the opinion of European surgeons on the centralization of surgery for benign esophageal diseases. A web-based questionnaire, developed through a modified Delphi process, was administered to general and thoracic surgeons of 33 European surgical societies. There were 791 complete responses (98.5%), in 59.2% of respondents, the age ranged between 41 and 60 years, 60.3% of respondents worked in tertiary centers. In 2017, the number of major surgical procedures performed for any esophageal disease by respondents was <10 for 56.5% and >100 for 4.5%; in responder's hospitals procedures number was <10 in 27% and >100 in 15%. Centralization of surgery for benign esophageal diseases was advocated by 83.4%, in centers located according to geographic/population criteria (69.3%), in tertiary hospitals (74.5%), with availability of advanced diagnostic and interventional technologies (88.4%), in at least 10 beds units (70.5%). For national and international centers accreditation/certification, criteria approved included in-hospital mortality and morbidity (95%), quality of life oriented follow-up after surgery (88.9%), quality audits (82.6%), academic research (58.2%), and collaboration with national and international centers (76.6%); indications on surgical procedures volumes were variable. The present study strongly supports the centralization of surgery for benign esophageal diseases, in large part modeled on the principles that have underpinned the centralization of cancer surgery internationally, with emphasis on structure, process, volumes, quality audit, and clinical research., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Ninety-day mortality rates after esophagectomy are an indicator of the quality of surgical oncologic management. Accurate risk prediction based on large data sets may aid patients and surgeons in making informed decisions., Objective: To develop and validate a risk prediction model of death within 90 days after esophagectomy for cancer using the International Esodata Study Group (IESG) database, the largest existing prospective, multicenter cohort reporting standardized postoperative outcomes., Design, Setting, and Participants: In this diagnostic/prognostic study, we performed a retrospective analysis of patients from 39 institutions in 19 countries between January 1, 2015, and December 31, 2019. Patients with esophageal cancer were randomly assigned to development and validation cohorts. A scoring system that predicted death within 90 days based on logistic regression β coefficients was conducted. A final prognostic score was determined and categorized into homogeneous risk groups that predicted death within 90 days. Calibration and discrimination tests were assessed between cohorts., Exposures: Esophageal resection for cancer of the esophagus and gastroesophageal junction., Main Outcomes and Measures: All-cause postoperative 90-day mortality., Results: A total of 8403 patients (mean [SD] age, 63.6 [9.0] years; 6641 [79.0%] male) were included. The 30-day mortality rate was 2.0% (n = 164), and the 90-day mortality rate was 4.2% (n = 353). Development (n = 4172) and validation (n = 4231) cohorts were randomly assigned. The multiple logistic regression model identified 10 weighted point variables factored into the prognostic score: age, sex, body mass index, performance status, myocardial infarction, connective tissue disease, peripheral vascular disease, liver disease, neoadjuvant treatment, and hospital volume. The prognostic scores were categorized into 5 risk groups: very low risk (score, ≥1; 90-day mortality, 1.8%), low risk (score, 0; 90-day mortality, 3.0%), medium risk (score, -1 to -2; 90-day mortality, 5.8%), high risk (score, -3 to -4: 90-day mortality, 8.9%), and very high risk (score, ≤-5; 90-day mortality, 18.2%). The model was supported by nonsignificance in the Hosmer-Lemeshow test. The discrimination (area under the receiver operating characteristic curve) was 0.68 (95% CI, 0.64-0.72) in the development cohort and 0.64 (95% CI, 0.60-0.69) in the validation cohort., Conclusions and Relevance: In this study, on the basis of preoperative variables, the IESG risk prediction model allowed stratification of an individual patient's risk of death within 90 days after esophagectomy. These data suggest that this model can help in the decision-making process when esophageal cancer surgery is being considered and in informed consent.

Chyle leakage from the thoracic duct or cisterna chyli is a relatively rare complication of oesophageal cancer surgery. The majority of cases settle with conservative measures, but high volume leaks may be refractory and result in significant morbidity and require intervention with reoperation or embolization. In the experience of this high-volume centre over the last decade, 3 (0.5%) patients required reoperation and ligation of the thoracic duct; for the so-called type III leaks, interventional radiological approaches were not considered. This article is built around two recent cases, where interventional radiology to embolize and disrupt complex fistulae was successfully performed. The lessons from this experience will change practice at this centre to initial lymphangiography with a view to embolization or disruption of thoracic duct and cisterna chyli leaks as first line therapy for type III chyle leaks, with surgery reserved for where this fails., (© 2020. Royal Academy of Medicine in Ireland.)

The global obesity epidemic is contributing to increased prevalence of diseases fuelled by chronic inflammation, including cancer. Oesophageal adenocarcinoma (OAC) is an obesity-associated malignancy with increasing prevalence, dismal prognosis, and severely dysregulated immune processes. We previously reported that αβ T cells migrate to omentum and liver in OAC and contribute to inflammation in these tissues. Here, we assessed the tissue distribution and phenotype of gamma/delta (γδ) T cells in the blood, omentum, liver and tumour of OAC patients. Our data show that the Vδ1 and Vδ3 subsets of γδ T cells are most prevalent in omentum and liver of OAC patients. Furthermore, γδ T cells are predominantly pro-inflammatory in these tissues, and co-express IFN-γ and IL-17. Moreover, γδ T cells exhibit cytotoxic capabilities in OAC omentum and liver. This study provides the first indication that γδ T cells contribute to obesity-associated inflammation in OAC and might be exploited therapeutically., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Oesophageal cancer (OC) is an inflammation-associated malignancy linked to gastro-oesophageal reflux disease, obesity and tobacco use. Knowledge of the microenvironment of oesophageal tumours is relevant to our understanding of the development of OC and its biology, and has major implications for understanding the response to standard therapies and immunotherapies, as well as for uncovering novel targets. In this context, we discuss what is known about the TME in OC from tumour initiation to development and progression, and how this is relevant to therapy sensitivity and resistance in the two major types of OC. We provide an immunological characterisation of the OC TME and discuss its prognostic implications with specific comparison with the Immunoscore and immune-hot, -cold, altered-immunosuppressed and -altered-excluded models. Targeted therapeutics for the TME under pre-clinical and clinical investigation in OCs are also summarised. A deeper understanding of the TME will enable the development of combination approaches to concurrently target the tumour cells and TME delivering precision medicine to OC patients., (© 2021. The Author(s), under exclusive licence to Cancer Research UK.)

Purpose of Review: This review examines current developments and controversies in the multimodal management of oesophageal cancer, with an emphasis on surgical dilemmas and outcomes from the surgeon's perspective., Recent Findings: Despite the advancement of oncological neoadjuvant treatments, there is still no consensus on what regimen is superior. The majority of patients may still fail to respond to neoadjuvant therapy and suffer potential harm without any survival advantage as a result. In patients who do not respond, adjuvant therapy is still often recommended after surgery despite any evidence for its benefit. We examine the implications of different regimens and treatment approaches for both squamous cell cancer and adenocarcinoma of the oesophagus., Summary: The efficacy of neoadjuvant treatment is highly variable and likely relates to variability of tumour biology. Ongoing work to identify responders, or optimize treatment on an individual patient, should increase the efficacy of multimodal therapy and improve patient outcomes., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Research investigating exercise interventions in oesophagogastric cancer survivors is sparse, and the outcomes are varied. The aim of this systematic review is to identify the domains and outcomes reported in exercise interventions in oesophagogastric cancer survivors to be included in a Delphi study, with a view to informing the development of a core outcome set (COS)., Methods: EMBASE, PubMed, CINHAL, Cochrane Library, SCOPUS, and PEDro were searched up to March 2020 using a predefined search strategy. The outcomes identified during data extraction were categorised using the core areas outlined in the OMERACT Filter 2.0., Results: Fourteen domains and 63 outcomes were identified. The most frequently reported outcomes were in the domains of quality of life using the EORTC-QLQ-C30 questionnaire and the relevant disease-specific modules (100%), exercise capacity/fitness/physical function (100%), anthropometrics (83.33%), physical activity (66.67%), and biomarker analysis (50%)., Conclusion: This systematic review quantifies and describes the domains and outcomes examined in exercise interventions in oesophagogastric cancer survivors. Some inconsistency exists within the domains and outcomes used, and little attention was given to nutritional or economic endpoints. In order to develop a COS, a Delphi consensus process with key stakeholders is needed to identify the relevant domains and outcomes for inclusion.

Purpose: To investigate patients' perspectives of their physical recovery in the first six months post oesophago-gastric cancer surgery., Materials and Methods: Semi-structured interviews were held at St James's Hospital, Dublin, with participants who were 4 weeks to 6 months post-oesophagectomy/gastrectomy. Interviews were an average of 14 min and included questions pertaining to physical recovery post-oesophagectomy/gastrectomy. Interviews were audio-taped, transcribed verbatim, and analyzed by thematic analysis., Results: Twenty participants (mean age 63.35(7.50) years) were recruited. Four themes were identified: i) challenges of recovery and impact on physical activity, ii) facilitators of, and barriers to, returning to physical activity, iii) physical challenges of returning to pre-operative societal roles, iv) recommendations for health services on measures which may enhance the return to physical activity. Post-operative barriers to physical activity included dietary issues, continuing treatments, pain, breathlessness, muscle weakness, fatigue, and anxiety. Participants identified that strategies such as a gradual return to activities, rest, and family support facilitated return to physical activity. Participants highlighted the need for i) greater physiotherapy input, ii) psycho-social support, and iii) fatigue management may aid physical recovery., Conclusions: Following oesophago-gastric cancer surgery, patients experience physical and psychosocial difficulties which can hamper recovery, but many of which are amenable to rehabilitative intervention. Accordingly, rehabilitative measures throughout the early stages of recovery require investigation.Implications for RehabilitationCurative treatment for oesophageal and gastric cancer is associated with significant risk of post-operative morbidity, resulting in a myriad of physical and nutritional challenges which may impact on post-operative physical recovery.Greater provision of physiotherapy services to counteract physical impairments post oesophago-gastric cancer surgery is required.Physical recovery may also be aided through the enhanced provision of other supportive care services such as fatigue management and psychological support.

Objectives: Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance., Methods: Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-β, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments., Results: This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors., Conclusions: Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Improved cure rates in esophageal cancer care have increased focus on health-related quality of life (HRQL) in survivorship. To optimize recovery after esophagectomy, particularly nutritional well-being, a personalized multidisciplinary survivorship clinic was established at this center. Assessments at 6 and 12 months postoperatively include validated European Organization for the Research and Treatment of Cancer (EORTC) symptom and health-related quality of life (HRQL) questionnaires, functional status review, anthropometry, and biochemical screening for micronutrient deficiencies. 75 patients, at a mean age of 63 years, 84% male, 85% with adenocarcinoma, and 73% receiving multimodal therapy were included. Mean preoperative body mass index (BMI) was 27.5 (4.3) kg m -2. 6- and 12-month assessments were completed by 66 (88%) and 37 (93%) recurrence-free patients, respectively. Mean body weight loss at 6 months was 8.5 ± 6.6% and at 12 months 8.8 ± 7.3%. Of the 12-month cohort, micronutrient deficiency was present in 27 (79.4%) preoperatively and 29 (80.6%) after 1 year (P = 0.727), most commonly iron deficiency (preoperative: 16 [43.2%] and postoperative: 17 [45.9%] patients, P = 0.100). 26 (70.3%) of these patients also had clinically significant dumping syndrome persisting to 12 months after surgery. We describe a novel follow-up support structure for esophageal cancer patients in the first year of survivorship. This may serve as an exemplar model with parallel application across oncological care., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)