Esophageal Adenocarcinoma Research Articles

Abstract A030: Polycomb repressive complex 2 (PRC2) mediates the epigenetic regulation of cancer-associated fibroblasts in esophageal cancer

Abstract Cancer-associated fibroblasts (CAFs) are a heterogenous cell population that can promote esophageal cancer progression through multiple molecular mechanisms including increased cancer cell proliferation and migration, immunosuppression, and therapeutic resistance. Despite the divergence of CAFs from normal fibroblasts with regards to phenotype and functions, CAFs rarely exhibit widespread genetic alterations. Instead, it is proposed that CAFs are regulated at the epigenetic level. Our objective is to delineate this epigenetic regulation of CAFs in esophageal cancer. Ultimately, we aim to identify the epigenetic regulatory complexes that mediate CAF heterogeneity and pro-tumorigenic functions. To this end, we completed RNA-seq and ATAC-seq on fibroblasts isolated from esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC) and non-cancerous esophageal tissue. Enrichment analysis identified the polycomb repressive complex 2 (PRC2) as a potential regulator of ESCC and EAC CAFs. PRC2 catalyzes the methylation (mono-, di- or tri-) of lysine 27 on histone 3 (H3K27me1/2/3) resulting in transcriptional repression. Inhibition of two key proteins of PRC2 (EZH2 and SUZ12) through either pharmacological or genetic modulation, altered expression of multiple CAF phenotype related proteins and inhibited CAF functions including CAF proliferation. Ongoing studies, using co-cultures of fibroblasts and tumor cells, seek to identify if inhibition of PRC2 can prevent the initial transition of normal esophageal fibroblasts into CAFs. Importantly, we are conducting in vivo studies to determine if selective PRC2 inhibition in CAFs can inhibit esophageal tumor progression with specific focus on primary tumor growth and metastatic spread. In summary, initial studies have identify that PRC2 complex mediates CAF phenotype and functions, and we aim to establish the larger impact of these CAF specific effects on esophageal cancer. Citation Format: Karen J. Dunbar, Raul Navaridas Fernandez de Bobadil, Katherine M. Cunningham, Emily Esquea, Gizem Efe, Anil K. Rustgi. Polycomb repressive complex 2 (PRC2) mediates the epigenetic regulation of cancer-associated fibroblasts in esophageal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A030.

Oesophageal cancer.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Abstract PR003: ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma

Abstract Background: Esophageal adenocarcinoma (EAC) has a low 5-year survival rate and limited options for targeted therapies. Circulating tumor (ct)DNA isolated from liquid biopsies could help monitor patients to personalize treatment decisions. However, ctDNA studies in EAC remain sparse, and significant knowledge gaps exist in our understanding of ctDNA emission in response to therapy. The goal of this study was 1) to conduct a multimodal, longitudinal analysis of plasma cell free (cf)DNA in EAC patients and 2) to better understand the biology of ctDNA release during drug treatment. Methods: 1) A total of 189 longitudinal blood samples were collected from 41 EAC patients throughout treatment. cfDNA was isolated from baseline and post-neoadjuvant chemo samples for targeted deep sequencing alongside white blood cell controls. Shallow whole-genome sequencing was conducted on cfDNA for ichorCNA and fragmentomics analysis. 2) To dynamically monitor ctDNA fluctuations during EAC treatment, cfDNA was isolated from all other timepoints for digital (d)PCR quantification of the mutations identified from sequencing. ctDNA release kinetics were studied in vitro using three cell lines (OE19, FLO-1, A549), as well as our newly established cisplatin resistant model of OE19. ctDNA was analyzed by Qubit, dPCR, and Bioanalyzer. Annexin-V/PI flow cytometry was used to assess percentages of apoptotic and necrotic cells to correlate ctDNA to release mechanism. Results: 1) Sequencing has been completed for 21/41 patients and is ongoing for 20/41 patients. In the first 21 patients, somatic mutations were found in potential EAC driver genes, such as KRAS, TP53, ACVR2A, NOTCH1, and APC. Interestingly, in one patient’s cfDNA sample sequenced post neoadjuvant chemo, a novel mutation emerged in FBXW7, representing a potential resistance driver. ichorCNA tumor fraction (TF) values overall were low, and when using the recommended 0.03 TF estimate cutoff, there were significantly larger baseline TF values in metastatic (stage IVB) patients than those with localized disease (stage III) (p<0.05). 2) In vitro viable cancer cell numbers correlated to ctDNA levels, as measured by qubit and dPCR analysis. Additionally, cisplatin and 5-FU chemo treatments led to larger ctDNA release in all cells. ctDNA emission kinetics correlated to cytotoxicity (apoptosis and necrosis as shown through flow cytometry), with higher levels of ctDNA released by cisplatin-sensitive vs. resistant cells (p<0.05). Additionally, cisplatin treatment caused a shift in average ctDNA fragment size, with larger fragments observed during treatment, corresponding to an increased proportion of necrotic cells. Conclusions: This study reveals that multimodal cfDNA analysis can successfully be used in EAC patients to monitor treatment response and potentially identify resistance mechanisms. Moreover, in vitro models demonstrated a correlation of ctDNA emission and fragment length with chemo-cytotoxicity, shedding light on the release kinetics of DNA from cancer cells. Citation Format: Alexandra Bartolomucci, Laura Kienzle, Sarah Tadhg Ferrier, Lisa-Monique Edward, Jeffrey Bruce, Kwang-Bo Joung, Stephenie Prokopec, Wotan Zeng, Abirami Sharma, Kyle Dickinson, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo Ferri, Trevor J. Pugh, Julia V. Burnier. ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR003.

Abstract B001: ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR003) of the Conference Program/Proceedings. Citation Format: Alexandra Bartolomucci, Laura Kienzle, Sarah Tadhg Ferrier, Lisa-Monique Edward, Jeffrey Bruce, Kwang-Bo Joung, Stephenie Prokopec, Wotan Zeng, Abirami Sharma, Kyle Dickinson, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo Ferri, Trevor J. Pugh, Julia V. Burnier. ctDNA release kinetics and fragmentation to monitor treatment response and resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B001.

OGC SO13 - Recurrence Patterns after Minimally Invasive vs. Left Thoracoabdominal Oesophagectomy for distal oesophageal and junctional adenocarcinomas

Abstract Background Oesophageal cancer is a leading cause of cancer-related death worldwide, with oesophagec-tomy being the primary treatment for curable disease. This study compares loco-regional and distal disease recurrence patterns between minimally invasive oesophagectomy (MIO) and left thoracoabdominal oesophagectomy (LTAO) using a matched dataset. The definition of loco-regional recurrence remains unclear in the literature. In this study, loco-regional recur-rence is categorised as recurrence in the oesophageal bed, anastomosis, or local nodes in the mediastinum and upper abdomen. Method Patients from 2014 to 2021 were identified and followed until 31/12/2023. Data on MIOs and LTAO were collected from a prospectively maintained database. Gastroesophageal junction and distal oesophagus adenocarcinomas were included, and all received neoadjuvant chemotherapy. Out of 302 eligible patients, 104 were successfully matched. The primary outcome was overall cancer recurrence. Categorical variables were compared using chi-square tests, and non-parametric contin-uous variables with Mann-Whitney U tests. Propensity score matching, accounted for baseline differences. Logistic regression generated propensity scores for age, gender, and tumour stage. Operative approach was the dependant variable. The groups were then selected using ‘nearest neighbour’ matching. Results The study compared 52 cases each of LTAO and MIO. Postoperative complications were similar, LTAO (58%) and MIO (52%) P=0.554. The R0 resection rate was higher in LTAO (90%) compared to MIO (81%) P=0.163. Recurrence was significantly higher in LTAO (42%) than MIO (23%) P=0.037. Local recurrence rates were 15% for LTAO and 8% for MIO P=0.22. Distant recurrence was 35% for LTAO and 21% for MIO P=0.111. Notably, peritoneal recurrence was significantly higher in LTAO (12%) P=0.012. There was no difference in median time to recurrence. Mortality rate was similar: 38% for LTAO and 35% for MIO P=0.684. Conclusion The study found that while postoperative complications and mortality rates were similar between LTAO and MIO, LTAO had a significantly higher overall recurrence rate and notably higher peritoneal recurrence. There was no significant difference in median time to recurrence between the two groups. These findings suggest that MIO may be associated with better long-term outcomes in terms of recurrence.

Travel to High-Volume Centers and Survival After Esophagectomy for Cancer.

Ongoing efforts have encouraged the regionalization of esophageal adenocarcinoma treatment to high-volume centers (HVCs). Yet such centralization has been linked with increased patient travel burden and reduced postoperative continuity of care. To determine whether traveling to undergo esophagectomy at HVCs is linked with superior overall survival compared with receiving care locally at low-volume centers (LVC). This cohort study considered data for all patients diagnosed with stage I through III esophageal adenocarcinoma in the 2010-2021 National Cancer Database. Patients were stratified based on distance traveled to receive care and the annual esophagectomy volume at the treating hospital: the travel-HVC cohort included patients in the top 25th percentile of travel burden who received care at centers in the top volume quartile, and the local-LVC cohort represented those in the bottom 25th percentile of travel burden who were treated at centers in the lowest volume quartile. Data were analyzed from July 2023 to January 2024. The primary end points were overall survival at 1 year and 5 years. Secondary end points included perioperative outcomes and factors linked with traveling to receive care. Of 17 970 patients, 2342 (13%) comprised the travel-HVC cohort, and 1969 (11%), the local-LVC cohort. The median (IQR) age was 65 (58-71) years; 3748 (87%) were male and 563 (13%) were female. After risk adjustment and with care at local LVCs as the reference, traveling to HVC was associated with superior survival at 1 year (hazard ratio for mortality [HR], 0.69; 95% CI, 0.58-0.83) and 5 years (HR, 0.80; 95% CI, 0.70-0.90). Stratifying by stage, traveling to HVCs was associated with comparable outcomes for stage I disease but reduced mortality for stage III (1-year HR, 0.72; 95% CI, 0.60-0.87; 5-year HR, 0.83; 95% CI, 0.74-0.93). Further, traveling to HVC was associated with greater lymph node harvest (β, 5.08 nodes; 95% CI, 3.78-6.37) and likelihood of margin-negative resection (adjusted odds ratio, 1.83; 95% CI, 1.29-2.60). Traveling to HVCs for esophagectomy was associated with improved 1-year and 5-year survival compared with receiving care locally at LVCs, particularly among patients with locoregionally advanced disease. Future studies are needed to ascertain barriers to care and develop novel targeted pathways to ensure equitable access to high-volume facilities and high-quality oncologic care.

Abstract PR017: A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition

Abstract Immune checkpoint inhibitors (ICI) are increasingly used as first line of treatment in a range of cancer types, owing to their efficacy and advantageous toxicological profile. Currently, PD-L1 expression and tumor mutation burden (TMB) are the most common biomarkers to select patients for ICI treatment, yet response to ICI remains highly variable between patients, necessitating more accurate early predictors of treatment response. Circulating cell-free DNA (cfDNA) originates from dying cells throughout the body, each molecule carrying unique epigenetic features of its cell-type of origin. Most studies on cfDNA focus on tumor-derived fragments for diagnostics or minimal residual disease detection. However, variations in the contribution of immune cells and other stromal cell populations could provide important clues to classify a tumor with respect to treatment. To address this, we collected tumor and adjacent normal tissue as well as cfDNA from the blood of 33 patients enrolled in the LUD2015-005 trial in which ICI were administered to patients with non-resectable esophageal adenocarcinoma (EAC) for four weeks, before adding standard-of-care chemotherapy (ICI+CTX). For each patient, we took samples at diagnosis, before ICI+CTX, during and at the end of treatment. Tissue and cfDNA samples were sequenced using TET-Assisted Pyridine-borane Sequencing (TAPS), a method recently developed in Oxford which provides genome-wide high-depth, base- resolution DNA methylation and mutation information from low-input samples. We then selected a representative set of high-purity tumor tissue samples and combined them with whole- genome TAPS data from 9 healthy blood cell types and 5 gastrointestinal tissues to generate a GI-specific atlas of cell-type specific methylation. This atlas allows us to accurately quantify the contribution of tumor and 14 healthy cell types to the cfDNA collected from each patient at each timepoint. Strikingly, the presence of T-cell derived cfDNA at time of diagnosis (tDNA) is a strong positive predictive marker of overall survival (p=0.0024). In contrast, the fraction of tumor-resident T-cells, estimated by either bulk tissue TAPS or RNA sequencing, correlated only weakly with treatment response in this cohort, indicating that T-cell activity is more accurately captured by tDNA. Furthermore, we find that patients with a combination of high TMB and high tDNA have an 80% 2-year survival probability, as opposed to below 25% for others, suggesting that tDNA is derived from T-cells actively engaging tumor cells with high neoantigen load. In summary, we demonstrate that T-cell turnover, as reflected in differential methylation in a set of marker regions spanning only 24kb, is a promising biomarker of treatment response, especially when combined with neoantigen load: in the presented cohort, all but one long-term survivors (alive at last follow up > 3 years after diagnosis) were tDNA positive with high TMB. This demonstrates the power of cfDNA composition analysis for risk stratification in ICI treatment. Citation Format: Phil Xie, Zohar Etzioni, Chun-Xiao Song, Richard P Owen, Mark R Middleton, Xin Lu, Benjamin Schuster-Boeckler. A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR017.

OGC SO21 - Role of Staging Laparoscopy on oesophageal and junctional cancer management

Abstract Background Staging laparoscopy and peritoneal cytology is currently recommended as a staging tool required for oesophageal and gastro-oesophageal junction (OGJ) adenocarcinomas. However, evidence is variable regarding the utility of this investigation, leading to heterogenous practice in the UK. With improved staging sensitivity of CT and PET imaging and inclusion of routine MDT discussion for upper GI cancer patients, staging laparoscopy may not be necessary for all patients with oesophago-gastric cancer, and in fact may delay their treatment. We thus aimed to assess the impact of staging laparoscopy on the treatment algorithm of patients with oesophago-gastric cancer. Method All staging laparoscopies undertaken between January 2022 and March 2024 were identified from our surgical database. Patients were included if they had oesophago-gastric adenocarcinoma, with a plan for curative treatment. Data collected included age, gender, location of primary tumour, CT/PET staging, laparoscopy findings, impact on treatment intention, neoadjuvant treatment, and final histology. Primary outcome was incidence of positive microscopic or macroscopic peritoneal disease for oesophageal and OGJ malignancy. Results 127 patients were identified - 69 (55%) oesophageal, 25 (20%) GOJ, and 32 (24.4%) gastric cancer. 1/70 (1.4%) patient diagnosed endoscopically with oesophageal cancer had positive peritoneal disease, which was suspected due to pre-operative imaging findings of ascites and suspicions of linitis plastica. Of patients diagnosed with GOJ cancer, 4/25 patients (16%) had peritoneal disease present. None of the 39 patients with oesophageal/junctional tumours with clinical T1-2 disease were found to have peritoneal disease on staging laparoscopy. 6/32 (19%) patients with gastric cancer were found to have unexpected peritoneal disease present. Conclusion This study found minimal impact staging laparoscopy has on the management of primary oesophageal cancers. Consideration can be made of limiting staging in oesophageal cancer to patients with suspicious findings on CT/PET imaging. For GOJ tumours, there may be a role for limiting staging laparoscopy for Siewert 1 tumours to T3/4 tumours based on CT/PET findings. Importantly, accurate identification on primary endoscopy of the location of the tumour in relation to the gastro-oesophageal junction is necessary to help guide ongoing management.

BN SO63 - A systematic review of Hiatus Hernia classifications

Abstract Background Hiatus hernias (HH) are common, an important cause of symptoms, and a strong risk factor for complications and oesophageal dysplasia and adenocarcinoma. However, there is a lack of consensus as to how they should be classified. This has significant implications for benchmarking and standardising practice, as well as generating and answering research questions. The aim of this review was to systematically identify and appraise what classification systems have been described, and to identify any novel approaches to HH classifications and their association with treatment outcomes. Method We undertook a systematic review of the PubMed and EMBASE databases on the 17th January 2023. Inclusion criteria were any studies containing a HH classification described within adults. Exclusion criteria were studies not in English, animal studies and case reports. Results 847 articles were identified. 245 were included, with a further 9 studies identified that tested a novel approach to classifying HH against surgical outcomes. Most classification systems (64.9%) were anatomical, but with significant variation as regards stratification of size of the hernia, and its contents (primarily the proportion of herniated stomach). A small number of classifications described endoscopic, manometry, symptomatic and intra-operative classifications. There was considerable heterogeneity in the definitions used for larger HH. The quality of studies comparing classifications with outcomes was limited; however, some possible associations were reported based on anatomical and physiological parameters. Conclusion We found a wide range of HH classification systems. These were mainly anatomical and based on the traditional type I-IV system. Whilst the evidence is limited, it seems likely that other components (anatomical and physiological) may have utility in better classifying HH and guiding treatment, standardisation and research.

OGC SO41 - Omentopexy Technique in Robotic Assisted Minimally Invasive Oesophagectomy

Abstract Background Laparoscopic omentopexy has been shown to reduce the rates of post-oesophagectomy diaphragmatic hernia (PODH) in a retrospective cohort study in a UK specialist centre. We aimed to demonstrate the technique during robotic-assisted minimally invasive oesophagectomy (RAMIE) with video capture. Method The Versius (CMR Surgical) robotic system was used in the abdominal stage of RAMIE performed on a 63 year old male with a poorly differentiated oesophageal adenocarcinoma. No previous abdominal surgery had been performed on this patient. Video capture was used to record this part of the procedure. Results Ports were inserted in standard configuration to allow fashioning of a gastric conduit. Following this the greater omentum was secured to the anterior abdominal wall around the jejunostomy site. No immediate complications were observed. Conclusion The Versius system can be used to successfully perform omentopexy with standard port positioning. Omentopexy was successfully performed with no immediate complications, did not significantly prolong procedural time and may reduce risk of PODH. The authors support the use of this technique in robotic-assisted surgery for reducing risk of PODH and support further work to validate this technique in cohort studies.

OGC SO43 - Management of oesophageal adenocarcinoma in the Covid-19 Pandemic – What have we learnt?

Abstract Background The management of oesophageal adenocarcinoma in the UK has been standardised to neoadjuvant chemotherapy followed by surgery. However, during the early phase of the Covid-19 pandemic, oesophagectomy was considered to be too high risk, and alternative treatment options were explored . In our unit, patients were offered definitive chemoradiotherapy with a view to performing salvage oesophagectomy if there was residual disease or disease recurrence. Method We retrospectively screened all patients referred to the UGI MDT between March 2020 to February 2021. Patients included were those with first diagnosis of oesophageal carcinoma, on the curative pathway, planned neoadjuvant FLOT chemotherapy and oesophagectomy then converted to definitive CRT (dCRT). Data collected were patient demographics, cancer staging and cancer outcomes including progression to salvage surgery, disease free survival and overall survival at 1 year and 3 years post treatment. Results Ten patients with distal or junctional adenocarcinoma were included. Median age at diagnosis was 70.5 years. Five patients had T3 or T4 disease. All patients had N0 disease. After one year, one patient had undergone salvage surgery for residual disease and two for recurrent disease. One other patient was unfit for surgery and not offered salvage surgery. At three years, only two patients had no disease recurrence. Nine of 10 patients were alive at one year and seven alive at three years. Conclusion The Covid-19 pandemic was an unusual event in our most recent history that influenced the way we managed patients with oesophageal adenocarcinoma. Little data exists as to what alternative treatments were effective. Our limited data indicates that dCRT may be used as an alternative to surgery in a subgroup of patients – although disease recurrence was common, 3-year survival was high (70%). Our data appears to be comparable to 3-year survival in our own unit and that reported in NOCGA 2024 (63%). Nevertheless, these numbers are small and thus require further study.

Esophageal adenocarcinoma models: a closer look

Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer with significant morbidity and mortality rates worldwide. Despite advancements in tumor models, the underlying cellular and molecular mechanisms driving EAC pathogenesis are still poorly understood. Therefore, gaining insights into these mechanisms is crucial for improving patient outcomes. Researchers have developed various models to better understand EAC and evaluate clinical management strategies. However, no single model fully recapitulates the complexity of EAC. Emerging technologies, such as patient-derived organoids and immune-competent mouse models, hold promise for personalized EAC research and drug development. In this review, we shed light on the various models for studying EAC and discuss their advantages and limitations.

Neuroendocrine differentiation and serotonin expression in oesophageal adenocarcinomas after neoadjuvant therapy: correlation with clinicopathological features and outcome.

Oesophageal adenocarcinoma (EAC) is a glandular or mucinous epithelial malignancy that can show immunohistochemical evidence of neuroendocrine differentiation (NED) and express the hormone serotonin. The objective of this study was to correlate the presence of NED and serotonin with clinicopathological characteristics and patient outcome after neoadjuvant chemoradiation. A retrospective cohort of patients treated between 2002 and 2021 was established and included 218 oesophagectomy specimens with residual tumour. Representative full-face sections of tumour were stained for synaptophysin, chromogranin-A and serotonin by immunohistochemistry, and staining results were correlated with disease-free survival (DFS) and overall survival (OS). In total, 129 (59%) tumours showed evidence of NED, defined as immunohistochemical expression of synaptophysin or chromogranin-A, while 40 (18%) showed evidence of NED and expressed serotonin. Patients with neuroendocrine-positive tumours had significantly shorter median OS compared to those with neuroendocrine-negative tumours (22.5 versus 48.8 months, P = 0.006), but similar median DFS (13.3 versus 17.8 months, P = 0.34). Using Cox regression, the association between NED and OS was significant in univariate [hazard ratio (HR) = 1.68, 95% confidence interval (CI) = 1.16-2.45] and multivariate (HR = 1.65, 95% CI = 1.08-2.52) analysis. Patients with serotonin-expressing tumours had similar median OS (21.7 versus 25.9 months, P = 0.24) and DFS (7.3 versus 15.6 months, P = 0.12) compared to those with NED but lacking serotonin. Using Cox regression, serotonin expression was associated with reduced OS in univariate (HR = 1.62, 95% CI = 1.06-2.47) but not multivariate (HR = 1.03, 95% CI = 0.64-1.65) analysis. Our findings support NED as independent predictor of OS in EAC after neoadjuvant chemoradiation. While a subset of tumours with NED expressed serotonin, this did not provide additional prognostic information.

Targeting c-MET for Endoscopic Detection of Dysplastic Lesions Within Barrett's Esophagus Using EMI-137 Fluorescence Imaging.

Esophageal cancer (EC) carries a poor prognosis with 5-year overall survival of less than 20%. Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). The aim of this study was to investigate the ability of EMI-137, a mesenchymal-epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in BE. c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus (GEO) datasets, tissue microarrays and BE biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy (FME) was performed in a mouse model of Barrett's-like metaplasia and dysplasia (L2-IL1β). Tumors and organs-of-interest were evaluated through ex vivo fluorescence imaging. MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in BE and EAC compared to normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 h post injection decreasing by more than 50% on co-injection of a 10-fold molar excess of unlabeled EMI-137. The target-to background ratio (TBR) at 3 h p.i. for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. FME of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within BE with a TBR of 1.9 in vivo, and greater than 2 in ex vivo fluorescence imaging. EMI-137 accumulates in dysplastic lesions within BE and in c-MET positive EAC. EMI-137 imaging has potential as a screening and surveillance tool for patients with BE and as a means to detecting dysplasia and EAC.

Association between sulfur microbial diet and the risk of esophageal cancer: a prospective cohort study in 101,752 American adults

BackgroundSulfur microbial diet (SMD) is a dietary pattern closely related to the intestinal load of sulfur-metabolizing microbes in humans. Diet and microbes may play an important role in the carcinogenesis of esophagus. However, epidemiological studies on SMD and esophageal cancer (EC) risk are scarce. Here, we evaluated this association based on a large American cohort.MethodsIn the cohort of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a SMD score was calculated to evaluate participants’ compliance of SMD pattern, with higher scores presenting greater adherence. Cox hazards regression model was used to explore the association between the SMD score and the incidence of EC, esophageal squamous cell carcinoma (ESCC), and esophageal adenocarcinoma (EA). Subgroup analyses were conducted to figure out potential modifiers interacting with SMD on EC. Sensitivity analyses were used to testify the robustness of our main result.ResultsAmong 101,752 participants, 154 EC cases, consisted of 41 ESCC cases and 97 EA cases, were identified with mean follow-up of 8.9 years. In the fully adjusted model, the highest versus the lowest quartiles of the SMD score were found to be associated with an increased risk of EC and ESCC (EC: HRQ4 vs. Q1: 1.64; 95% CI: 1.05, 2.56; P = 0.016 for trend; ESCC: HRQ4 vs. Q1: 2.37; 95% CI: 1.02, 5.47; P = 0.031 for trend), while not significantly associated with increases risk of EA (HRQ4 vs. Q1: 1.41; P = 0.144 for trend). The main result remained through a series of sensitivity analyses. Subgroup analyses showed a stronger association between SMD and EC in participants with no regular consumption of aspirin (HRQ4 vs. Q1: 1.90; 95% CI: 1.04, 3.47) than in those using aspirin regularly (HRQ4 vs. Q1: 1.37; 95% CI: 0.71, 2.66) (P = 0.008 for interaction).ConclusionAdherence to the SMD pattern may be associated with increased risks of EC and ESCC, particularly for EC in individuals who do not regularly consume aspirin.

Current Standards and Controversies in Multidisciplinary Management of Locoregional Gastroesophageal Junction Tumors.

There has been controversy in the management of gastroesophageal (GE) junction cancers with pre-operative chemoradiation and peri-operative chemotherapy as accepted practices. We aim to assess and compare the defining trials establishing current standards of care and discuss future directions seeking to further improve patient-centered outcomes in GE junction cancers. Over the last two decades, several large Phase III randomized trials have been conducted including GE junction cancers, showing superiority of 1) pre-operative chemoradiation over surgery (CROSS) and 2) peri-operative chemotherapy with FLOT over CROSS without radiotherapy (FLOT 4). While NEO-Aegis suggested equipoise between the CROSS vs. peri-operative chemotherapy, the recently presented ESOPEC trial demonstrated superiority of peri-operative FLOT versus CROSS in esophagus and GE junction adenocarcinomas. Based on the ESOPEC trial, peri-operative chemotherapy with FLOT appears to be a preferred regimen for patients with resectable GE junction adenocarcinomas in patients able to receive FLOT. There is evidence in support of other practices, such as induction chemotherapy, pre-operative chemoradiation, definitive chemoradiation for those not fitting ESOPEC criteria. Chemoradiation ± chemotherapy with non-operative intent represents a promising strategy for patients seeking organ preservation, and ongoing studies will better define its feasibility and long-term outcomes.

Factors influencing the cost-effectiveness of radiofrequency ablation for Barrett's esophagus with low-grade dysplasia in Australia.

Endoscopic eradication therapy using radiofrequency ablation (RFA) is considered an acceptable alternative to surveillance monitoring for Barrett's esophagus with low-grade dysplasia (LGD). This study aimed to estimate whether RFA for LGD is cost-effective and to determine which factors influence cost-effectiveness. A Markov model was developed to estimate the incremental cost per quality-adjusted life year (QALY) gained for RFA compared with endoscopic surveillance. An Australian longitudinal cohort study (PROBE-NET) provides the basis of the model. Replacing surveillance with RFA yields 10 fewer cases of HGD and 9 fewer esophageal adenocarcinoma (EAC)-related deaths per 1000 patients' treatment, given on average 0.192 QALYs at an additional cost of AU$9211 (€5689; US$6262) per patient (incremental cost-effectiveness ratio AU$47,815 per QALY). The model is sensitive to the rate of EAC from LGD health state, the utility values, and the number of RFA sessions. Hence, the incremental benefit ranges from 0.080 QALYs to 0.198 QALYs leading to uncertainty in the cost-effectiveness estimates. When the cancerous progression rate of LGD falls <0.47% per annum, the cost-effectiveness of RFA becomes questionable. RFA treatment of LGD provides significantly better clinical outcomes than surveillance. The additional cost of RFA is acceptable if the LGD to EAC rate is >0.47% per annum and no more than three RFA treatment sessions are provided. Accurate estimates of the risk of developing EAC in patients with LGD are needed to validate the analyses.

More May Not Be Better: Comparison of Oncologic Outcomes Following Induction Chemotherapy Plus Chemoradiation and Chemoradiation Alone for Esophageal Adenocarcinoma.

The oncologic benefit of induction chemotherapy (IC) before chemoradiation (CRT) compared to CRT alone for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma is not well defined. We hypothesized that IC with CRT would improve survival and pathologic complete response rate compared to CRT alone. A retrospective review of patients with biopsy proven esophageal or GEJ adenocarcinoma treated with preoperative CRT and IC + CRT and surgical resection from 2007 to 2023 at a single institution was performed. First order outcomes were overall survival and pathologic complete response rate; secondary outcomes included disease-free survival and distant metastasis failure. Subgroup analyses were conducted based on baseline characteristics and tumor-specific features. Survival analysis was performed with Kaplan-Meier curves with log-rank tests and Cox regression analysis. Of 205 patients that met inclusion criteria, 76 (38%) patients underwent IC + CRT. There were no significant differences in demographic or tumor-specific characteristics between the two cohorts. There were no differences in the median overall survival between CRT and IC + CRT groups (47 months vs. not reached, p = 0.194). The rate of pathologic complete response in the overall cohort was 22%; IC + CRT was not associated with higher complete tumor response than CRT alone (20% vs. 23%, p = 0.557). There were no significant differences in any of the secondary outcomes between the two treatment paradigms. We could not detect added oncologic benefit in survival or pathologic complete response with IC over CRT alone for resectable esophageal and GEJ cancer. Biomarker driven prospective studies exploring the optimal perioperative treatment regimens are warranted.

Definition and Predictors of Early Recurrence in Neoadjuvantly Treated Esophageal and Gastroesophageal Adenocarcinoma: a Dual-Center Retrospective Cohort Study.

BACKGROUND: Early recurrence after esophagectomy is often used as a surrogate for aggressive tumor biology and treatment failure. However, there is no standardized definition of early recurrence, and predictors for early recurrence are unknown. Therefore, we aimed to define an evidence-based cutoff to discriminate early and late recurrence and assess the influence of neoadjuvant treatment modalities for patients with esophageal or gastroesophageal-junction adenocarcinoma (EAC). This dual-center retrospective cohort study included patients who underwent esophagectomy for stage II-III EAC after neoadjuvant treatment with chemotherapy using 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) or radiochemotherapy according to the Chemoradiotherapy for Esophageal Cancer followed by Surgery Study (CROSS)protocol from 2012 to 2022. The optimal cutoff for early versus late recurrence was calculated by using the most significant difference in survival after recurrence (SAR). Multivariable logistic regression was used to identify variables associated with early recurrence. Of 334 included patients, 160 (47.9%) were diagnosed with recurrence. Most patients had systemic (60.5%) or multiple sites of recurrence (21.1%), whereas local-only recurrence (9.2%) and carcinomatosis (9.2%) were rare. The optimal interval between surgery and recurrence for distinguishing early and late recurrence was 18 months (median SAR: 9.1 versus 17.8 months, p = 0.039) with only 24% of recurrences diagnosed after the calculated cutoff. Advanced pathologic tumor infiltration (ypT3-4, p = 0.006), nodal positivity (p = 0.013), poor treatment response (>10% residual tumor, p = 0.015), and no adjuvant treatment (p = 0.048) predicted early recurrence. Early recurrence can be defined as recurrent disease within 18 months. Hallmarks for early recurrence are poor response to neoadjuvant therapy with persisting advanced disease. In those patients, adjuvant therapy and closer follow-up should be considered.

Tumor-Infiltrating Lymphocytes in Resected Esophageal and Gastric Adenocarcinomas Do Not Correlate with Tumor Regression Score After Neoadjuvant Chemotherapy: Results of a Case-Series Study.

Background/Objectives: Adenocarcinomas of the esophagogastric junction and stomach present clinical entities with significant cancer-related morbidity and mortality, often requiring multimodal treatments. Preoperative chemotherapy, mainly the FLOT regimen, is increasingly being utilized in the neoadjuvant setting for the treatment of these malignancies, with varying degrees of tumor response. Methods: We conducted a retrospective, single-institution review on 75 patients operated on for adenocarcinoma of the esophagogastric junction and stomach after neoadjuvant FLOT. We investigated whether tumor response correlates with disease response in lymph nodes examined on surgical specimens. We also investigated the role of tumor-infiltrating lymphocytes (TILs) in correlation with primary tumor response and disease response in lymph nodes on pathological specimens. Results: Our results suggest that TILs correlate in a differential manner with regards to primary tumors versus lymph nodes, thus suggesting that there are different biologic processes in place. Conclusions: Our results provide unique evidence on tumor-infiltrating lymphocytes in the adenocarcinoma histology of the esophagogastric junction and stomach and might be important for further studies.