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Purpose: In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery are accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. To gain a better survival, benefit especially for stage III patients in comparison with CF therapy, a three-arm phase III trial (neoadjuvant setting: CF vs. CF + radiation vs. DOC+CF [DCF]) is ongoing. We have aggressively performed DCF therapy for stage III or IV patients since October 2014. We herein review the outcomes of DCF therapy., Methods: We retrospectively reviewed the cases of 27 patients with stage III or IV EC (male, n = 24; female, n = 3; median age, 70.0 years) who received DCF therapy., Results: The response rate was 48.1%. Downstaging was achieved over the course of treatment in 14 patients (51.9%). Twenty-six patients transitioned to surgery, with 25 receiving R0 resection. DCF-treated patients who achieved downstaging showed significantly longer relapse-free survival (RFS) than those without downstaging (p = 0.0002). DCF-treated patients with a grade ≥ 1b histological effect showed significantly longer RFS than those with a grade < 1b effect (p = 0.0282). The multivariate analysis showed that downstaging was the only factor significantly associated with RFS in DCF-treated patients., Conclusions: DCF therapy for stage ≥ III esophageal carcinoma is both feasible and effective. These findings suggest that downstaging and the histological effect might predict the effects of DCF therapy for EC.

Background: Neoadjuvant chemoradiotherapy (nCRT), followed by surgery, is the current standard of care for patients with locally advanced esophageal squamous cell carcinoma. However, up to 30% of the patients do not respond to nCRT. Hence, a simple, cost-effective marker to predict response before initiation of nCRT is needed. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic marker in various cancers. However, its role as a predictive marker in patients with esophageal SCC planned for nCRT has not been prospectively analyzed., Materials and Methods: All consecutive patients with locally advanced (T1N1 and T2-T4a with or without nodal involvement) SCC planned for nCRT (CROSS protocol) followed by esophagectomy with total two field lymphadenectomy between December 2013 and December 2019 were included in this prospective analytical cohort study. NLR was calculated 1 week before starting the nCRT and was correlated with the histopathological response [Mandard tumor regression grade (TRG)]., Results: Of the 216 patients with esophageal cancer evaluated during the study period, 57 patients with SCC who fulfilled the inclusion criteria were included. A good pathologic response (TRG 1 and 2) to nCRT was seen in 28 (49.1%) patients. Using a ROC curve, the optimal cutoff value of pretherapy NLR for predicting good pathologic response was 2.33. With an NLR cutoff value of 2.33, 53.3% of patients had a good pathologic response to nCRT compared with 47.6% patients with NLR ≥ 2.33 (P = 0.77)., Conclusion: In patients with locally advanced esophageal SCC, NLR is not a useful marker to predict pathologic response to nCRT.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK 2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm 2 , SD 620.7; placebo: +307.8 Ki67+ cells/mm 2 , SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype ( TFF2, MUC5B ) and certain cancer-associated markers ( REG3A, PAX9, MUC1 ), and decreased expression of intestinal markers MUC2, FABP1, FABP2 , and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK 2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK 2 receptor antagonist did not have obvious chemopreventive effects., (©2021 American Association for Cancer Research.)

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention., (© The Author(s) 2019. Published by Oxford University Press.)

Purpose: The optimal treatment for locally advanced GEJ and cardia adenocarcinoma is controversial. Several studies have shown that treating these patients with neoadjuvant chemoradiotherapy followed by surgery leads to survival benefits, and there are also studies that have declared conflicting results. It seems that there is still room for discussion. We calculated the survival rates and pathologic responses in our patients with characteristics which we mentioned above., Methods: Patients with locally advanced, non-metastatic GEJ and cardia adenocarcinomas (only patients with Siewert's type I and II), who were referred to Imam Khomeini hospital (Institute of cancer) between 2005 and 2014 and received neoadjuvant chemoradiation and underwent surgery were enrolled in this retrospective cohort study. Evaluations were done every 3 months., Results: Thirty-two patients enrolled in this study. Median follow up time was 23 months (Reverse Kaplan-Meier method). The rates of 1-year survival, 2-year survival, 3-year survival, 4-year survival, and 5-year survival were 75%, 52%, 52%, 37%, and 37%, respectively. No local recurrences occurred among patients; however, four patients experienced distal recurrence in the following locations: two cases (6.3%) in the liver, one case (3.1%) in the lung, and one case (3.1%) in the peritoneum. The rate of complete pathologic response (T 0 N 0 ) was 21.9%., Conclusions: Neoadjuvant chemoradiation in patients with locally advanced GEJ and cardia adenocarcinoma will lead to a survival benefit.

Aims: Vitamin C plays a role in chemoprevention in cancer treatment, and Vitamin C modulates many regulators of inflammation in in vitro studies. The aim of this study is to assess the effect of Vitamin C supplementation with neoadjuvant chemoradiation in esophageal adenocarcinoma on the nuclear factor-kappa B (NF-κB) and associated cytokines., Materials and Methods: A total of 20 patients undergoing multimodal treatment for esophageal adenocarcinoma were randomized to receive Vitamin C (1000 mg/day) orally for 4 weeks or no supplementation. Pre- and post-Vitamin C endoscopic biopsies were used for the study of NF-κB activity and cytokine analysis., Results: NF-κB activity along with cytokines was activated in the cancer tissue pretreatment. Down-regulation in NF-κB activity was observed in 25% of cases, two from the Vitamin C arm posttreatment. There was a significant reduction in cytokines levels in the cancer group, and this effect was more pronounced in the Vitamin C group (P < 0.05)., Conclusions: Vitamin C supplementation had a mild protective effect in modulating of regulators of inflammation and carcinogenesis. Further studies with larger numbers of endpoints are needed to evaluate its effect on modulation of chemoradiation responses., Competing Interests: None