Search

BackgroundIn this single-arm study, the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy were evaluated in patients with resectable esophageal squamous cell carcinoma (ESCC).MethodsThis 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.ResultsFrom 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).ConclusionsThe 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 RegistrationChiCTR2100048917.

Additional file 1.

Additional file 1. Translation Methodology Questionnaire.

Additional file 1: Supporting Information 1. Search Strategy. Supporting Information 2. Data Extraction.

Additional file 4. Survey presented to participants in round 1 of the Delphi.

Additional file 2. Instructions for translating files related to the GASTROS Delphi Survey.

Additional file 3. Outcomes for translation.

Additional file 1 Supplementary Table 1. Patient demographics. Supplementary Fig. 1. Experimental outline and flow cytometry gating strategy and staining controls. Supplementary Fig. 2. ex vivo TCM from distinct gastrointestinal adenocarcinoma types induced differential effects on LPS-induced DC maturation. Supplementary Fig. 3. ex vivo TCM from distinct gastrointestinal adenocarcinoma types induced differential effects on unstimulated DC marker levels. Supplementary Fig. 4. in vitro TCM of 2Gy-irradiated cell lines from gastrointestinal cancers induced significant inhibition of DC markers compared to mock irradiation. Supplementary Fig. 5. ex vivo TCM of 2Gy-irradiated TME from gastrointestinal cancers inhibited DC markers compared to mock irradiation

Background & Aims\ud Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.\ud \ud Methods\ud We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.\ud \ud Results\ud We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).\ud \ud Conclusions\ud We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Summary 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 100 for 4.5%; in responder’s hospitals procedures number was 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.