Oesophageal adenocarcinoma (OAC) is the 7th most common cancer in the United Kingdom (UK) and remains a significant health challenge. This study presents a proteomic analysis of seven OAC donors complementing our previous neoantigen identification study of their human leukocyte antigen (HLA) immunopeptidomes. Our small UK cohort were selected from donors undergoing treatment for OAC. We used label-free mass spectrometry proteomics to compare OAC tumour tissue to matched normal adjacent tissue (NAT) to quantify expression of 3552 proteins. We identified differential expression of a number of proteins previously linked to OAC and other cancers including common markers of tumourigenesis and immunohistological markers, as well as enrichment of processes and pathways relating to RNA processing and the immune system. Our findings also offer insight into the role of the protein stability in the generation of an OAC neoantigen we previously identified. These results provide independent corroboration of existing oesophageal adenocarcinoma biomarker studies that may inform future diagnostic and therapeutic research.

BACKGROUND:Prehabilitation is safe, feasible and may improve a range of outcomes in patients with oesophago-gastric cancer (OGC). Recent studies have suggested the potential of prehabilitation to improve body composition, sarcopenia and physical fitness, reduce surgical complications and improve quality of life. Despite this, prehabilitation services are not offered throughout all OGC centres in the UK. Where prehabilitation is offered, delivery and definitions vary significantly, as do funding sources and access. METHODS:A professional association endorsed series of consensus meetings were conducted using a modified Delphi process developed by the Peri-Operative Quality Initiative (POQI) to identify and refine consensus statements relating to the development and delivery of prehabilitation services for OGC patients. Participants from a variety of disciplines were identified based on a track record of published studies in the field of prehabilitation and/or practice experience encompassing prehabilitation of OGC patients. Approval from the POQI board was obtained and independent supervision provided by POQI. RESULTS:A total of 20 statements were developed and agreed by 26 participants over a preliminary meeting and 2 semi-structured formal POQI meetings. Ten research themes were identified. In the case of one statement, consensus was not reached and the statement was recorded and developed into a research theme. A strong recommendation was made for the majority of the consensus statements (17 of 20). DISCUSSION:Consensus statements encompassing the interventions and outcomes of prehabilitation services in oesophago-gastric cancer surgery have been developed to inform the implementation of programmes.

Objective: The aim of this study was to develop a predictive model for overall survival after esophagectomy using pre/postoperative clinical data and machine learning. Summary Background Data: For patients with esophageal cancer, accurately predicting long-term survival after esophagectomy is challenging. This study investigated survival prediction after esophagectomy using a Random Survival Forest (RSF) model derived from routine data from a large, well-curated, national dataset. Methods: Patients diagnosed with esophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales who underwent an esophagectomy were included. Prediction models for overall survival were developed using the RSF method and Cox regression from 41 patient and disease characteristics. Calibration and discrimination (time-dependent area under the curve) were validated internally using bootstrap resampling. Results: The study analyzed 6399 patients, with 2625 deaths during follow-up. Median follow-up was 41 months. Overall survival was 47.1% at 5 years. The final RSF model included 14 variables and had excellent discrimination with a 5-year time-dependent area under the receiver operator curve of 83.9% [95% confidence interval (CI) 82.6%–84.9%], compared to 82.3% (95% CI 81.1%—83.3%) for the Cox model. The most important variables were lymph node involvement, pT stage, circumferential resection margin involvement (tumor at < 1 mm from cut edge) and age. There was a wide range of survival estimates even within TNM staging groups, with quintiles of prediction within Stage 3b ranging from 12.2% to 44.7% survival at 5 years. Conclusions: An RSF model for long-term survival after esophagectomy exhibited excellent discrimination and well-calibrated predictions. At a patient level, it provides more accuracy than TNM staging alone and could help in the delivery of tailored treatment and follow-up.

Despite advances in medical treatment, oesophageal cancer remains a lethal condition with a 5-year survival of around 15%. Broadly, there are two main subtypes of oesophageal cancer, squamous cell carcinoma (OSCC) and adenocarcinoma (OAC). OSCC usually affects the middle third of the oesophagus and is associated with smoking, alcohol and low socio-economic status. OAC affects the lower third of the oesophagus and is associated with gastro-oesophageal reflux disease. The UK has the highest incidence of OAC in the world and it is rising. Treatment may be curative or palliative. Curative treatment for advanced disease consists of perioperative chemotherapy or chemoradiotherapy followed by surgery. In the UK the most common operation is a two-phase Ivor–Lewis oesophagectomy. Increasingly surgery is carried out by a robotic or minimally invasive approach. Modern management has reduced the morbidity and mortality of the perioperative period but progress in long-term survival has been slow. Enhanced perioperative patient pathways and stratified therapies (according to characteristics of the tumour at the molecular level) offer the promise of further improvements. On-going clinical trials are assessing the role of novel therapies in the treatment of oesophageal cancer.

Abstract Background: Esophageal adenocarcinoma (EAC) is usually resistant to cytotoxic therapies and immunotherapies have gained little traction. Cancer-associated fibroblasts (CAF) are a major stromal cell population in the EAC tumor microenvironment associated with prognosis and treatment outcomes. Recent evidence suggests that cancer cell phenotypes related to EMT may determine CAF heterogeneity, but the molecular and cellular biology that underlies myofibroblast fate in EAC is not well understood. Methods: To obtain the most comprehensive profile of CAF heterogeneity in EAC, we performed histopathologic, single-cell RNA sequencing and transcriptomic analyses on 28 samples from 26 patients and prognostic validation using two EAC cohorts from genomic consortia. Results: Combining histologic and molecular profiles revealed five CAF phenotypes, including three myofibroblast phenotypes, associated with EMT-related signatures in EAC cells and cellular interactions that promote tumor progression and metastasis. We identified a specific myofibroblast subtype (CAF5) in close proximity to cancer cells and tumor vasculature with exclusive expression of TRPA1, offering a potential therapeutic vulnerability. We reconstructed CAF differentiation trajectories from esophagus-resident universal fibroblasts to identify candidate genes central to the CAF phenotype, and used this knowledge to construct a combined EMT-myofibroblast four gene signature (GSN, ATF1, ZEB2 and POSTN) that was highly prognostic in EAC and several other solid tumors. Conclusions: This study stratifies EAC patients into two prognostic groups and reports important data supporting a cancer – CAF signalling axis, promoting myofibroblastic differentiation, that may inform more effective treatment strategies.

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

Oesophageal adenocarcinoma (OAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T-cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.

Single-nuclei RNA sequencing allows single cell-based analysis in frozen tissue, ameliorating cell recovery biases associated with enzymatic dissociation methods. The authors present two optimized methods for isolating and sequencing nuclei from esophageal tissue using a commercial EZ and citric acid (CA)-based method. Despite high endogenous RNase activity, these protocols produced libraries of expected fragment length (average length EZ: 745 bp; CA: 1232 bp) with comparable complexity (median Transcript/Gene number, EZ: 496/254; CA: 483/256). CA nuclei showed a higher proportion of ribosomal gene reads, potentially reflecting co-isolation of nuclei and adherent ribosomes. The authors identified 11 cell lineages in the combined datasets, with differences in cell type recovery between the two methods, providing utility dependent on experimental needs.

There are two main types of Oesophageal Cancer, Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ACA). SCC usually affects the middle third of the oesophagus and is associated with smoking, alcohol and low socio-economic status. ACA affects the lower third of the oesophagus and is associated with gastro-oesophageal reflux disease. The UK has the highest incidence of ACA in the world and it is rising. Treatment may be palliative or curative. Curative treatment for advanced disease consists of Neo-adjuvant chemotherapy or chemoradiotherapy followed by surgery. In the UK the most common operation is a two-phase Ivor-Lewis oesophagectomy. Increasingly surgery is carried out with a minimally invasive approach. Modern management has reduced the morbidity and mortality of the peri-operative period but progress in long-term survival has been slow. Enhanced peri-operative patient pathways and stratified therapies (according to characteristics of the tumour at the molecular level) offer the promise of further improvements. On-going clinical trials are assessing the role of monoclonal antibodies in the treatment of oesophageal cancer.

Background: Esophageal cancer is increasingly common and carries a poor prognosis. The optimal treatment modality for locally advanced cancer is unknown, with current guidance recommending either neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) followed by surgery. There is a lack of adequately powered trials comparing CT against CRT. We retrospectively compared CT versus CRT using a propensity score weighting approach. Methods: Demographic, disease, treatment and outcome data were retrieved from a local database for patients who received neoadjuvant CT or CRT followed by surgery. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach. Groups were assessed for differences in postoperative outcomes and survival. Kaplan-Meier and non-parametric tests were used to compare survival and outcome data as appropriate. Results: Data for 284 patients were retrieved. Following IPTW groups were well matched. No significant differences were seen for postoperative complications (CT 64.9% vs. CRT 63.3%, p = 0.807), including major complications (24.0% vs. 23.6%, p = 0.943) and anastomotic leak (7.8% vs. 5.6%, p = 0.526). Significantly higher rates of clinical regression and complete pathological response were seen following CRT (p = 0.002 for both). Rates of R0 resection were higher with CRT, CT 79.1% vs. CRT 93.1%, p = 0.006. There was no difference between groups for overall or disease-free survival. Conclusion: This study suggests that the significant improvements in local tumour response seen after neoadjuvant CRT compared to CT may not translate to different survival outcomes. However, it must be stressed that adequately powered prospective trials are still lacking. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.