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Background: Diesel exhaust exposure and cancer other than the lungs have been limitedly investigated., Aims: To conduct a systematic review and meta-analysis on the association between occupational exposure to diesel exhaust and gastrointestinal cancers., Methods: Two researchers performed a systematic literature review to identify all cohort studies on occupational exposure to diesel exhaust and risk of cancers other than lung. Of the 30 retained studies, 10 reported risk estimates for oesophageal, 18 on gastric, 15 on colon and 14 on rectal cancer. We performed random-effects meta-analyses to calculate summary relative risks (RRs) and 95% confidence intervals (CIs) for ever-exposure to diesel exhaust., Results: We calculated summary RR = 1.08 (95% CI 0.97-1.21, P heterogeneity = 0.06) for oesophageal, 1.06 (95% CI 0.99-1.14, P < 0.001) for gastric, 0.98 (95% CI 0.96-1.00, P = 0.453) for colon, and RR = 1.04 (95% CI 0.97-1.11, P = 0.013) for rectal cancer. Drivers showed an association with oesophageal (RR = 1.26, 95% CI 0.99-1.62), gastric (RR = 1.20, 95% CI 0.91-1.59) and rectal cancer (RR = 1.41, 95% CI 1.13-1.75); machine operators with oesophageal (RR = 1.09, 95% CI 1.00-1.20) and gastric (RR = 1.15, 95% CI 1.10-1.20) and handlers with oesophageal cancer (RR = 1.95, 95% CI 1.23-3.09). Studies from Europe revealed an association with gastric cancer while those from North America did not (P < 0.05). No difference was found by quality score except for gastric cancer, where high-quality studies but not low-quality ones showed increased risk (P heterogeneity = 0.04). There was no evidence of publication bias., Conclusions: An increased but insignificant risk of oesophageal, gastric and rectal, but not colon cancer, was suggested in workers exposed to diesel exhaust. Residual confounding cannot be excluded., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal cancers worldwide. Most ESCC patients are diagnosed at an advanced stage; however, current research on in vivo animal models accurately reflecting their clinical presentation is lacking. Alcohol consumption is a major risk factor for ESCC and has been used in several disease models for disease induction. In this study, we used 4-nitroquinoline-1-oxide in combination with ethanol to induce an in vivo ESCC mouse model. Esophageal tissues were stained with hematoxylin and eosin for histopathological examination and lesion scoring. In cellular experiments, cell adhesion and migration invasion ability were observed using phalloidin staining, cell scratch and transwell assays, respectively, and the expression of epithelial-mesenchymal transition-related markers was detected using quantitative reverse transcription polymerase chain reaction and western blotting. The results showed that ethanol-exposed mice lost more weight and had an increased number of esophageal nodules. Histological examination revealed that the lesion scores of the ethanol-exposed esophageal samples were significantly higher than those of the unexposed esophageal samples. Furthermore, ethanol-exposed esophageal cancer samples had more severe lesions with infiltration of tumor cells into the muscularis propria. In vitro cellular experiments showed that ethanol exposure induced cytoskeletal microfilament formation, promoted cell migration invasion elevated the expression of N-cadherin and Snail, and decreased the expression of E-cadherin. In conclusion, ethanol exposure exacerbates ESCC, promotes tumor cell infiltration into the muscularis propria, and could be an effective agent for establishing innovative models of invasive carcinoma., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this work., (Copyright © 2024. Published by Elsevier Inc.)

Background: A recent epidemiological study systematically screened 250 prescription medications for associations with oesophageal cancer risk, using Scottish data, and identified an increased risk with use of prednisolone and warfarin. We investigated whether oral prednisolone or warfarin use was associated with increased oesophageal cancer risk., Methods: A case-control study was conducted within the Clinical Practice Research Datalink. In the primary analysis oesophageal cancer cases were identified from linked cancer registry records. Up to 5 cancer-free controls were matched to each case (based upon sex, birth year, GP practice and year of GP registration). Prednisolone and warfarin medications were identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression after adjusting for covariates including demographics, comorbidities and medication use., Results: There were 4552 oesophageal cancer cases and 22,601 matched control participants. Overall, there was no evidence of an increased risk of oesophageal cancer with oral prednisolone use (unadjusted OR=1.16 95% CI 1.06, 1.27 and adjusted OR=0.99 95% CI 0.89, 1.11) or warfarin use (unadjusted OR=1.12 95% CI 0.99, 1.28 and adjusted OR=1.08 95% CI 0.92, 1.27)., Conclusions: In this large population-based study, oral prednisolone and warfarin were not associated with oesophageal cancer risk., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The effect of human 8-Oxoguanine DNA Glycosylase (hOGG1) on exogenous chemicals in esophageal squamous cell carcinoma (ESCC) remain unclear. The study plans to determine hOGG1 expression levels in ESCC and possible interactions with known environmental risk factors in ESCC., Material and Methods: We analyzed levels of exposure to urinary nitrosamines in volunteers from high and low prevalence areas by GC-MS. And we performed the interaction between hOGG1 gene and nitrosamine disinfection by-products by analyzing hOGG1 gene expression in esophageal tissues., Results: In ESCC, nitrosamine levels were significantly increased and hOGG1 mRNA expression levels were significantly decreased. There was a statistically significant interaction between reduced hOGG1 mRNA levels and non-tap drinking water sources in ESCC. The apparent indirect association between ESCC and NMEA indicated that 33.4% of the association between ESCC and NMEA was mediated by hOGG1., Conclusion: In populations which exposed to high levels of environmental pollutants NDMA, low expression of hOGG1 may promote the high incidence of esophageal cancer in Huai'an. hOGG1 may be a novel mediator in nitrosamine-induced esophageal tumorigenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new therapeutic strategies. However, the model is time-consuming and malignant tumor incidences are low. Here, we report the usage of multi-kinase inhibitor sorafenib as a tumor promoter to establish an efficient two-stage NMBzA-induced rat ESCC carcinogenesis model, resulting in increments of tumor incidences and shortened tumor formation times. By establishing the model and applying whole-genome sequencing, we discover that benign papillomas and malignant ESCCs harbor most of the "driver" events found in rat ESCCs (e.g. recurrent mutations in Ras family, the Hippo and Notch pathways and histone modifier genes) and the mutational landscapes of rat and human ESCCs overlap extensively. We generate tumor cell lines derived from NMBzA-induced papillomas and ESCCs, showing that papilloma cells retain more characteristics of normal epithelial cells than carcinoma cells, especially their exhibitions of normal rat cell karyotypes and inabilities of forming tumors in immunodeficient mice. Three-dimensional (3-D) organoid cultures and single cell RNA sequencing (scRNA-seq) indicate that, when compared to control- and papilloma-organoids, ESCC-organoids display salient abnormalities at tissue and single-cell levels. Multi-omic analyses indicate that NMBzA-induced rat ESCCs are accompanied by progressive hyperactivations of the FAT-Hippo-YAP1 axis and siRNA or inhibitors of YAP1 block the growth of rat ESCCs. Taken together, these studies provide a framework of using an effective rat ESCC model to investigate multilevel functional genomics of ESCC carcinogenesis, which justify targeting YAP1 as a therapeutic strategy for ESCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Air pollution has been increasingly linked to cancer risk. However, the genetic causality between air pollution and cancer risk remains poorly understood. To elucidate the potential roles of air pollution (NOx, NO 2 , PM 2.5 , PM course, and PM 10 ) in the risk of 18 specific-site cancers, large-scale genome-wide association studies with a novel Mendelian randomization (MR) method were employed. Our MR analyses revealed significant associations between certain air pollutants and specific types of cancer. Specifically, a positive association was observed between NOx exposure and squamous cell lung cancer (OR: 1.96, 95%CI: 1.07-3.59, p = 0.03) as well as esophageal cancer (OR: 1.002, 95%CI: 1.001-1.003, p = 0.005). Genetically predicted NO2 exposure was found to be a risk factor for endometrial cancer (OR 1.41, 95%CI: 1.03-1.94, p = 0.03) and ovarian cancer (OR: 1.49, 95%CI: 1.14-1.95, p = 0.0037). Additionally, genetically predicted PM2.5 exposure was associated with an increased risk of ER+ breast cancer (OR: 1.24, 95%CI: 1.03-1.5, p = 0.02) and ER- breast cancer (OR: 2.57, 95%CI: 1.05-6.3, p = 0.04). PM course exposure was identified as a risk factor for glioma (OR: 487.28, 95%CI: 13.08-18,153, p = 0.0008), while PM10 exposure exerted a detrimental effect on mesothelioma (OR: 114.75, 95%CI: 1.14-11,500.11, p = 0.04) and esophageal cancer (OR: 1.01, 95%CI: 1.007-1.02, p = 0.03). These findings underscored the importance of mitigating air pollution to reduce the burden of cancer and highlight the need for further investigations to elucidate the underlying mechanisms involved in these associations., Competing Interests: Declaration of competing interest The authors declare that the study was performed in the absence of the conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study aims to explore the mechanism of Liujunzi Decoction in the treatment of 4-nitroquinoline-N-oxide(4NQO)-induced esophageal cancer in mice. One hundred mice of 35-45 days were randomized into blank, model, and low-, medium-, and high-concentration(18.2, 36.4, and 54.6 g·kg~(-1), respectively) Liujunzi Decoction groups. The mice in other groups except the blank group had free access to the water containing 100 μg·mL~(-1) 4NQO for 16 weeks for the modeling of esophageal cancer. The mice in the Liujunzi Decoction groups were fed with the diets supplemented with corresponding concentrations of Liujunzi Decoction. The body weight and organ weights were weighed for the calculation of organ indexes. The pathological changes of the esophageal tissue were observed by hematoxylin-eosin(HE) staining. Ultra performance liquid chromatography-mass spectrometry(UPLC-MS/MS) was employed to collect metabolites from mouse serum samples, screen out potential biomarkers, and predict related metabolic pathways. Compared with the blank group, the model group showed decreased spleen and stomach indexes and increased lung, esophagus, and kidney indexes. Compared with the model group, Liujunzi Decoction groups had no significant changes in the organ indexes. The HE staining results showed that Liujunzi Decoction inhibited the invasive growth and cancerization of the esophageal cancer cells. A total of 9 potential biomarkers of Liujunzi Decoction in treating esophageal cancer were screened out in this study, which were urocanic acid, 1-oleoylglycerophosphoserine, 11-deoxy prostaglandin E1, Leu-Glu-Lys-Glu,(±) 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid, ureidosuccinic acid,(2R)-2,4-dihydroxy-3,3-dimethylbutanoic acid, kynurenic acid, and bicyclo prostaglandin E2, which were mainly involved in histidine, pyrimidine, alanine, aspartate, glutamate, pantothenate and tryptophan metabolism and coenzyme A biosynthesis. In summary, Liujunzi Decoction may exert the therapeutic effect on the 4NQO-induced esophageal cancer in mice by regu-lating the amino acid metabolism, inflammation, and immune function.

Background: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours., Methods: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed., Findings: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4)., Interpretation: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours., Funding: Akeso Biopharma., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests LS reports grants or contracts from Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Alphamab Oncology, Yaojie Ankang (Nanjing) Technology, Beigene, Qiyu Biotechnology (Shanghai), and BriSTAR Immunotech; consulting fees from Mingji Biopharmaceutical, Haichuang Pharmaceutical, and Herbour Biomed; and participated on a data safety monitoring board or advisory board from MSD, Merk, Bristol Myers Squibb, Boehringer Ingelheim, Sanofi, Roche, Servier, and AstraZeneca. WL, WS, ZMW, BL, and MX are Akeso employees. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background & Aims: Antibiotic exposure leads to changes in the gut microbiota. Our objective was to evaluate the association between antibiotic exposure and esophageal adenocarcinoma (EAC) risk., Methods: We performed a nested case-control study using data from the Veterans Health Administration from 2004 through 2020. The case group consisted of patients who received an incident diagnosis of EAC. For each case, up to 20 matched controls were selected using incidence density sampling. Our primary exposure of interest was any oral or intravenous antibiotic use. Our secondary exposures included cumulative number of days of exposure and classification of antibiotics by various subgroups. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (aORs) for the risk of EAC associated with antibiotic exposure., Results: The case-control analysis included 8226 EAC cases and 140,670 matched controls. Exposure to any antibiotic was associated with an aOR for EAC of 1.74 (95% confidence interval [CI], 1.65-1.83) vs no antibiotic exposure. Compared with no antibiotic exposure, the aOR for EAC was 1.63 (95% CI, 1.52-1.74; P < .001) for cumulative exposure to any antibiotic for 1 to 15 days; 1.77 (95% CI, 1.65-1.89; P < 0 .001) for 16 to 47 days; and 1.87 (95% CI, 1.75-2.01; P < .001) for ≥48 days, respectively (P for trend < .001)., Conclusion: Exposure to any antibiotic is associated with an increased risk of EAC, and this risk increases as the cumulative days of exposure increase. This novel finding is hypothesis-generating for potential mechanisms that may play a role in the development or progression of EAC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort., Patients and Methods: The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance., Results: 89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS., Conclusions: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation., (©2023 The Authors; Published by the American Association for Cancer Research.)

Ethanol is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the molecular mechanisms behind how ethanol promotes ESCC development remain poorly understood. In this study, ethanol-ESCC-associated target genes were constructed and screened using network pharmacology and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and bioinformatics analysis. A mouse ethanol-exposed esophageal cancer model was constructed with 4-nitroquinoline-1-oxide (4-NQO) to assess its survival and tumor lesion status, and the mechanism of ethanol-promoted ESCC lesions was verified by qRT-PCR and Western blotting. The results showed that 126 ethanol-ESCC crossover genes were obtained, which were significantly enriched in the PI3K/AKT signaling pathway. Bioinformatics results showed that the target genes TNF, IL6, IL1β and JUN were highly expressed in esophageal tumor samples and positively correlated with tumor proliferation and apoptosis genes, and the genetic information of these genes was mutated to different degrees. Animal model experiments showed that ethanol decreased the survival rate and aggravated the occurrence of esophageal cancer in mice. qRT-PCR showed that ethanol promoted the expression of TNF, IL6, IL1β and JUN mRNA in mouse esophageal tumor tissues, and Western blotting showed that ethanol promoted p-PI3K and p-AKT protein expression in mouse esophageal tumor tissues. In conclusion, ethanol promotes esophageal carcinogenesis by increasing the expression of TNF, IL6, IL1β and JUN and activating the PI3K/AKT signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in this work., (Copyright © 2023. Published by Elsevier Inc.)

Aims: There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. We aim to assess the association between weak opioids and cancers of the GI tract., Methods: A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n = 2432), gastric (n = 1443) and colorectal cancer (n = 8750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use., Results: There was no association between weak opioids and colorectal cancer (adjusted OR = 0.96, CI 0.90, 1.02, P = 0.15). There was an increased risk of oesophageal (adjusted OR = 1.16, CI 1.04, 1.29, P = 0.01) and gastric cancer (adjusted OR = 1.26, CI 1.10, 1.45, P = 0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR = 1.03 CI 0.86, 1.22, P = 0.76 and adjusted OR = 1.29 CI 1.02, 1.64, P = 0.04 respectively)., Conclusions: In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Betel nut chewing involves the chewing of areca nuts or betel quid (areca nuts wrapped in betel leaves), which is associated with an increased risk of esophageal squamous cell carcinoma (ESCC). Statins have anticancer properties. We investigated the association between statin use and ESCC risk in betel nut chewers., Methods: The study included 105 387 betel nut chewers matched statin users and nonusers. Statin use was defined as the use of ≥28 cumulative defined daily doses (cDDDs) of statin. The primary outcome was incidence of ESCC., Results: The incidence rate of ESCC was significantly lower in statin users than in nonusers (2.03 vs. 3.02 per 100 000 person-years). Statin users had a lower incidence rate ratio of 0.66 for ESCC (95% confidence interval [CI]: 0.43-0.85) relative to nonusers. After potential confounders were adjusted for, statin use was determined to be associated with a reduced risk of ESCC (adjusted hazard ratio [aHR], 0.68; 95% CI: 0.51-0.91). A dose-response relationship was observed between statin use and ESCC risk; the aHRs for statin use at 28-182 cDDDs, 183-488 cDDDs, 489-1043 cDDDs, and > 1043 cDDDs were 0.92, 0.89, 0.66, and 0.64, respectively., Conclusion: Statin use was revealed to be associated with a reduced risk of ESCC in betel nut chewers., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), found in pickled foods and in chlorinated water, has been used to induce malignant transformation and gastrointestinal cancer in rats. Helicobacter pylori (HP) is implicated in human gastric cancer and possibly also in esophageal cancer. These two agents - one chemical and the other biological - might act together to induce esophageal cancer. In this study, human esophageal epithelial cells (HEECs) were divided into four groups: HP, MNNG, HP + MNNG, and control. The HP-to-HEEC ratio was 100:1. Cells were exposed for 6 h and then passaged until malignant transformation. HEEC at early, intermediate, and late stages of malignant transformation were used for proliferation, cell-cycle, and invasion assays. The alkaline comet assay was performed and expression of proteins, including γ-H2AX and PAXX, was studied by western blotting, to explore DNA damage and repair processes. Measurements of cell morphology, soft-agar clone formation, and invasiveness, and a nude mouse xenograft model, were used to examine malignancy. The effect of HP was stronger than that of MNNG. The combination HP + MNNG exerted a stronger malignant transformation effect than either HP or MNNG alone. Mechanisms of this combined carcinogenesis may include promotion of cell proliferation, perturbation of the cell cycle, promotion of invasiveness, DNA double-strand break induction, or PAXX inhibition., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2023. Published by Elsevier B.V.)

As widespread environmental carcinogens causing esophageal carcinoma (EC), the effects of N-nitrosamines on human health hazards and accurate toxicity mechanisms have not been well-elucidated. In this study, we explored the tumorigenic mechanism of N-nitrosomethylbenzylamine (NMBA) exposure using both cell and rat models. It was found that NMBA (2 μM) exposure for 26 weeks induced malignant transformation of normal esophageal epithelial (Het-1A) cells. After then proteomics analysis showed that lipid metabolism disorder predominantly participated in the process of NMBA-induced cell malignant transformation. Further the integrated proteomics and lipidomics analysis revealed that the enhancement of fatty acid metabolism promoted the EC tumorigenesis induced by NMBA through facilitating the fatty acid-associated PPARα signaling pathway. The animal studies also revealed that accelerated fatty acid decomposition in the progression of NMBA-induced EC models of rats was accompanied by the activation of the PPARα pathway. Overall, our findings depicted the key dynamic molecular alteration triggered by N-nitrosamines, and provided comprehensive biological perspectives into the carcinogenic risk assessment of N-nitrosamines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A mouse model for esophageal squamous cell carcinoma (ESCC) is induced by oral administration of the carcinogen 4-nitroquinoline 1-oxide (4-NQO). There is not an objective method for determining histopathologic severity of disease in this model. We aim to create a clearly defined and easily applied scoring system that can quantify the severity of 4-NQO-induced murine ESCC. Fifteen wild-type C57BL/6J mice were treated with 4-NQO for 8 (n = 8) or 16 (n = 7) weeks, while the rest (n = 9) were treated with vehicle, as 8 weeks of 4-NQO typically results in dysplasia and 16 weeks in carcinoma. We identified histologic abnormalities of the esophagus in this model and developed metrics to grade severity of dysplasia, papillomas, and invasion. Scores were then calculated using quantitative digitized image analysis for measuring depth and extent of each feature within the entire sample. Each feature was also assigned a weight based on its relation to cancer severity. Histology scores were significantly different in the three groups, suggesting that this method can discriminate dysplasia from carcinoma. This model can be applied to any mouse treated with 4-NQO.

Background/aim: The earliest cellular and molecular biologic changes in the esophagus that lead to esophageal cancer were evaluated in a mouse model. We correlated numbers of senescent cells with the levels of expression of potentially carcinogenic genes in sorted side population (SP) cells containing esophageal stem cells and non-stem cells in the non-side population cells in the 4-nitroquinolone oxide (NQO)-treated esophagus., Materials and Methods: We compared stem cells with non-stem cells from the esophagus of mice treated with the chemical carcinogen 4-NQO (100 μg/ml) in drinking water. We also compared gene expression in human esophagus samples treated with 4-NQO (100 μg/ml media) to non-treated samples. We separated and quantitated the relative levels of expression of RNA using RNAseq analysis. We identified senescent cells by luciferase imaging of p16 +/LUC mice and senescent cells in excised esophagus from tdTOMp16+ mice., Results: A significant increase in the levels of RNA for oncostatin-M was found in senescent cells of the esophagus from 4-NQO-treated mice and human esophagus in vitro., Conclusion: Induction of OSM in chemically-induced esophageal cancer in mice correlates with the appearance of senescent cells., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: There is uncertainty whether long-term use of proton-pump inhibitors can cause gastric adenocarcinoma (GAC) and oesophageal adenocarcinoma (OAC). This study aimed to determine how discontinuation of long-term PPI therapy influences the risk of GAC and OAC., Methods: This population-based cohort study included all long-term users of PPI therapy in Sweden in 2005-2018 was based on Swedish nationwide health registry data. The exposure was discontinuation of long-term PPI therapy, defined as no dispensation of PPI following inclusion and used as a time-varying variable, compared to remaining on PPI. Main outcomes were GAC and OAC, while oesophageal squamous cell carcinoma (OSCC) was included as a comparison outcome. Incidence rate ratios (IRR) with 95% CI adjusted for age, sex, comorbidity, obesity, diabetes, hyperlipidaemia, NSAIDs/aspirin, and statins were calculated with Poisson regression., Results: Among 730,176 long-term PPI users (mean age 65.6 years, 58.4% females) with 4,210,925 person-years at risk (median 5.5 person-years), 439,390 (60.2%) discontinued PPIs. In total, 495 developed GAC, 598 OAC, and 188 developed OSCC. PPI discontinuation was associated with decreased risk of GAC (IRR 0.81, 95% CI 0.67-0.98) and OAC (IRR 0.80, 95% CI 0.68-0.96), but not OSCC (IRR 1.10, 95% CI 0.82-1.49) compared to continued PPI use. Stratified analyses showed decreased point estimates across most age categories and both sexes for GAC and OAC risk among participants discontinuing PPI therapy., Conclusion: Discontinuation of long-term PPI therapy may decrease the risk of GAC and OAC, suggesting that physicians should consider ceasing prescribing long-term PPI in patients without continued indication for its use., (© 2022. The Author(s).)

Background: To investigate the effect of tea consumption on the improvement of postoperative quality of life in male patients with esophageal squamous cell carcinoma (ESCC)., Methods: The quality of life information of 290 male patients with ESCC was collected. The time to deterioration and the number of events in each area of quality of life was calculated by time-to-deterioration (TTD) model. The association between postoperative tea drinking and postoperative quality of life in male ESCC patients was investigated using the Cox proportional risk model., Results: Postoperative tea-drinking patients experienced delayed TTD in multiple domains, including general health, physical, role, emotional, and cognitive function, fatigue, nausea and vomiting, dyspnea, loss of appetite, constipation, diarrhea, eating problems, difficulty swallowing, choking while swallowing saliva, dry mouth, taste difficulties, coughing, and speech problems. The multivariate Cox regression analysis showed that drinking tea after surgery improved quality of life, including physical function (HR = 0.722, 95% CI: 0.559-0.933), role function (HR = 0.740, 95% CI: 0.557-0.983), eating problems (HR = 0.718, 95% CI: 0.537-0.960), odynophagia (HR = 0.682, 95% CI: 0.492-0.945), trouble swallowing saliva (HR = 0.624, 95% CI: 0.444-0.877), coughing (HR = 0.627, 95% CI: 0.442-0.889) and speech problems (HR = 0.631, 95% CI: 0.441-0.903). Furthermore, the improvement was more significant in patients who drank tea before surgery and continued to drink tea after surgery., Conclusions: Postoperative tea drinking had a positive effect on delay in clinical deterioration and improvements in multiple functions and symptoms associated with ESCC in men., (© 2022. The Author(s).)

Squamous esophageal carcinoma is a common pathological type of esophageal carcinoma around the world. The prognosis of esophageal carcinoma is usually poor and diagnosed at late stages. Recently, research suggested that genomic instability occurred in esophageal cells during the development of esophageal squamous cell carcinoma (ESCC). Identifying prognostic and specific genomic characteristics, especially at the early hyperplasia stage, is critical. Mice were given 4-nitroquinoline 1-oxide (4NQO) with drinking water to induce esophageal cancer. The immortalized human esophageal epithelial cell line (NE2) was also treated with 4NQO. We performed histologic analyses, immunofluorescence, and immunohistochemical staining to detect DNA damage at different time points. Whole-exome sequencing was accomplished on the esophagus tissues at different pathological stages to detect single-nucleotide variants and copy number variation (CNV) in the genome. Our findings indicate that all mice were tumor-forming, and a series of changes from simple hyperplasia (ESSH) to intraepithelial neoplasia (IEN) to esophageal squamous cell carcinoma (ESCC) was seen at different times. The expression of γ-H2AX increased from ESSH to ESCC. In addition, mutations of the Muc4 gene were detected throughout the pathological stages. Furthermore, CNV burden appeared in the esophageal tissues from the beginning of ESSH and accumulated more in cancer with the deepening of the lesions. This study demonstrates that mutations caused by the early appearance of DNA damage may appear in the early stage of malignant tissue before the emergence of atypia. The detection of CNV and mutations of the Muc4 gene may be used as an ultra-early screening indicator for esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly cancers worldwide, especially in Eastern Asia. As a potential endocrine-disrupting chemical (EDC), perfluorooctane sulfonate (PFOS) can mimic estrogen, disturb the estrogen signals, and then cause various diseases. Although ESCC can be directly exposed to PFOS during food digestion, the effects and mechanisms of PFOS on the development of ESCC are still not well illustrated. This study showed that PFOS can promote the migration and invasion of ESCC cells. Further, PFOS treatment can increase the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, while decreasing the expression of E-Cadherin (E-Cad). Zeb1, an important transcription factor for cell motility, was essential for PFOS induced migration and invasion of ESCC cells. PFOS can increase the expression of Zeb1 via upregulation of its transcription and proteins stability. A-kinase interacting protein 1 (AKIP1) and ataxia-telangiectasia mutated (ATM) were responsible for PFOS induced transcription and proteins stability of Zeb1 in ESCC cells, respectively. Collectively, our data indicated that environmental exposure and body accumulation of PFOS might be an important risk factor for ESCC progression.

Background: The epidemiological evidence regarding the carcinogenicity of nitrate and sodium in drinking water is limited, partly because measuring the exposure at the individual level is complex. Most studies have used nitrate in water supplies as a proxy for individual exposure, but dietary intakes and other factors may contribute to the exposure. The present study investigates the factors associated with urinary nitrate and sodium in a high-risk area for esophageal and gastric cancers., Methods: For this cross-sectional study, we used data and samples collected in 2004-2008 during the enrollment phase of the Golestan Cohort Study from a random sample of 349 participants (300 individuals from 24 rural villages and 49 from the city of Gonbad), stratified by average water nitrate in their district, the source of drinking water, and the usual dietary intake of nitrate and sodium. Nitrate, sodium, and creatinine were measured in a spot urine sample collected at the time of interview. We used the provincial cancer registry data to calculate the cumulative incidence rates of esophageal and gastric cancers for each location through June 1, 2020, and used weighted partial Pearson correlation to compare the incidence rates with median urinary nitrate and sodium in each village or the city., Results: Among 349 participants (mean age±SD: 50.7 ± 8.6 years), about half (n = 170) used groundwater for drinking, and the use of groundwater was significantly more common in high-elevation locations (75.8%). The geometric mean of the creatinine-corrected urinary nitrate concentration was 68.3 mg/g cr (95%CI: 64.6,72.3), and the corresponding geometric mean for urinary sodium was 150.0 mmoL/g cr (95%CI: 139.6,161.1). After adjusting for confounders, urinary nitrate was associated with being a woman, drinking groundwater, and living in high-elevation locations, but not with estimated dietary intake. Urinary sodium concentration was significantly associated with monthly precipitation at the time of sampling but not with elevation or drinking water source. There were significant positive correlations between both median urinary nitrate and sodium in each location and esophageal cancer incidence rates adjusted for sex and age (r = 0.65 and r = 0.58, respectively, p < 0.01), but not with gastric cancer incidence., Conclusion: In a rural population at high risk for esophageal and gastric cancers, nitrate excretion was associated with living at a higher elevation and using groundwater for drinking. The associations between nitrate and sodium excretion with esophageal cancer incidence warrant future investigation., (Published by Elsevier Inc.)

Increasing evidence have revealed that epigenomic and genomic factors jointly contribute to the malignancy of esophageal squamous cell carcinoma (ESCC). However, little is known regarding how enhancers regulate tumor suppressors and drive the tumorigenesis of ESCC. Here, we characterized S100A14 as a tumor suppressor in ESCC and showed that S100A14 deficiency dramatically promoted 4-nitroquinoline-1-oxide (4NQO) -induced tumorigenesis of ESCC and shortened survival of mice. Intriguingly, we found that S100A14 expression was driven by enhancer, and disruption of enhancer decreased the S100A14 expression in ESCC. Mechanistic investigation showed that S100A14 deficiency triggered aberrant differentiated program. TP63, SOX2 and EP300 occupied the enhancer region of S100A14 gene locus and regulated the expression of S100A14. Consistently, S100A14 is downregulated in ESCC tissues compared with their corresponding adjacent normal tissues, and lower S100A14 expression predicts poorer overall survival. Collectively, disruption of enhancer-regulated S100A14 induces ESCC tumorigenesis and it acts as a critical driver of ESCC tumorigenesis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD + in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) accounts for the large majority of esophageal cancer cases worldwide. In this review, we examine the potential role of non-acidic fluid (NAF) exposure in ESCC carcinogenesis. Esophageal NAF consists of a mixture of salivary, esophageal, gastric, and duodenal fluids, containing inflammatory constituents such as digestive enzymes and bile acids that induce DNA damage, as well as known carcinogens such as acetaldehyde and N-nitrosamines. Exposure to NAF can occur in the setting of increased non-acid reflux, decreased gastric acidity, and decreased esophageal fluid clearance. Non-acid reflux has been associated with ESCC in small observational studies, and in animal models bile reflux can promote the development of ESCC. Associations have been found between increased ESCC risk and atrophic gastritis, a history of partial gastrectomy, and proton pump inhibitor use, all of which raise the pH of refluxate. Additionally, a minimally or non-acidic gastric environment contains an altered microbiome that can increase the production of acetaldehyde and N-nitrosamines. Esophageal motility disorders such as achalasia and opioid-induced esophageal dysfunction result in increased stasis and exposure to these potentially proinflammatory constituents of NAF. NAF may promote the development of ESCC via multiple mechanisms and is an understudied area of research., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to evaluate and compare nivolumab's cost-effectiveness with chemotherapy in patients with advanced esophageal squamous cell carcinoma from the Chinese healthcare system perspective. To this end, the researchers utilized a partitioned survival model with three mutually exclusive health stages. The characteristics of the patients used as inclusion and exclusion criteria in this model were the same as those used for patients with advanced esophageal squamous cell carcinoma in the ATTRACTION-3 study. The ATTRACTION-3 trial, which took place between January 7, 2016 and November 12, 2018, also yielded important clinical data. Data on medical and economic preferences were collected from real-world clinical practices. Costs, quality-adjusted life years, and incremental cost-effectiveness ratio were calculated for the two therapy options. The model uncertainty was investigated using a deterministic and probabilistic sensitivity analysis. When compared to chemotherapy, nivolumab was linked with an increase of 0.28 quality-adjusted life years with an increased cost of US$ 36,956.81 per patient in the base case analysis of a hypothetical sample of 419 patients. The incremental cost-effectiveness ratio in the deterministic sensitivity analysis was US$ 132,029.46/quality-adjusted life year, with a 48.02% probability of being cost-effective at willingness-to-pay thresholds of US$ 132,029.22/quality-adjusted life year. The incremental cost-effectiveness ratio remained greater than US$ 80,000/quality-adjusted life year in the deterministic sensitivity analyses. To be more cost-effective and remain below the threshold of 37,653 US$/quality-adjusted life year, which the Chinese population can afford, nivolumab's price would have to be lowered sharply by 53.50%. Nivolumab is clinically beneficial but not cost-effective when compared to chemotherapy. A substantial reduction in nivolumab's drug acquisition cost would be necessary to make it cost-effective for immunotherapy., 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 Lin, Liu, Chen, Wang and Chen.)

Background: Oesophageal adenocarcinoma is characterised by a strong male predominance. We aimed to test the hypothesis that menopausal hormonal therapy decreases the risk of oesophageal adenocarcinoma., Methods: This population-based cohort study included all women who used systemic menopausal hormonal therapy (exposed) in Sweden between 2005 and 2018. For each exposed participant, five randomly selected female age-matched non-users of menopausal hormonal therapy (unexposed) were included. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, smoking-related diagnoses, Helicobacter pylori eradication, use of non-steroidal anti-inflammatory drugs/aspirin, use of statins and hysterectomy., Results: The study included 296,964 users of menopausal hormonal therapy and 1,484,820 non-users. Ever-users of menopausal hormonal therapy had an overall decreased risk of oesophageal adenocarcinoma (HR 0.78, 95% CI 0.63-0.97), which remained unchanged after further adjustment for gastro-oesophageal reflux disease (HR 0.78, 95% CI 0.63-0.97) and obesity/diabetes (HR 0.79, 95% CI 0.63-0.98). Decreased HRs were indicated both in users of oestrogen only (HR 0.82, 95% CI 0.60-1.12) and oestrogen combined with progestogen (HR 0.75, 95% CI 0.56-1.00). The risk reduction was more pronounced in users younger than 60 years (HR 0.57, 95% CI 0.38-0.86)., Conclusions: Menopausal hormone therapy in women may decrease the risk of oesophageal adenocarcinoma., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Exposure to PM 2.5 pollution is a significant health concern and increases risks for cancers in China. However, the studies regarding the effect of PM 2.5 and esophageal cancer incidence (ECI) among urban-rural areas are limited. In this study, we examined the sex- and area-specific association between exposure to PM 2.5 and ECI, as well as explored the corresponding lag effects on ECI using a geographical weighted Poisson regression. We found significantly positive effect on ECI for males and females in different models, with the greatest increase of 1.44% (95% CI: 1.30%, 1.59%) and 2.42% (95% CI: 2.17%, 2.66%) in per 10 ug/m 3 increase of PM 2.5 for males and females at single year lag7 and lag4 after all covariates controlled, respectively. We also found that the long-term effect of PM 2.5 on ECI was relatively stable at all moving average year lags. Moreover, rural areas had higher ECI risks for males (0.17%) and females (0.64%) with longer lag period than urban areas. In addition, higher risks for both sexes appeared in north, northwestern, and east China. The findings indicated that long-term exposure to PM 2.5 was significantly associated with increased risks for ECI, which reinforce a comprehensive understanding for ECI related to PM 2.5 ., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We conducted a meta-analysis to quantitatively assess the association between asbestos exposure and esophageal cancer., Methods: We systematically collected articles from three electronic databases and calculated the pooled standardized mortality rate (SMR) from the meta-analysis. Subgroup analysis according to the type of asbestos exposure, follow-up years, sample size, industry classification, sex, and high-dose exposure was conducted., Results: From 242 studies, 34 cohort studies were included in our meta-analysis. Pooled SMR was positively associated with asbestos exposure and esophageal cancer (pooled SMR = 1.28; 95% confidence interval (CI) 1.19-1.38, p < 0.00001). In the subgroup analysis, (1) chrysolite, (2) four groups with follow-up over ten years, (3) the textile industry and shipyard, (4) both male and female, and (5) eight studies on highest asbestos exposure, all the subgroups showed significantly increased pooled SMRs., Conclusion: Asbestos exposure was significantly and positively associated with esophageal cancer, especially chrysolite. Considering the long latency period, we suggest that patients should be followed up for cancer, including esophageal cancer, for over ten years.

Background: Cancer stem cells (CSCs) are related to the patient's prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood., Methods: We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells., Results: ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model., Conclusions: ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment., (© 2021. The Author(s).)

The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N -methyl- N '-nitro- N -nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Rapid urbanization and industrialization in China have incurred serious air pollution and consequent health concerns. In this study, we examined the modifying effects of urbanization and socioeconomic factors on the association between PM 2.5 and incidence of esophageal cancer (EC) in 2000-2015 using spatiotemporal techniques and a quasi-Poisson generalized linear model. The results showed a downward trend of EC and high-risk areas aggregated in North China and Huai River Basin. In addition, a stronger association between PM 2.5 and incidence was observed in low urbanization group, and the association was stronger for females than males. When exposure time-windows were adjusted as 0, 5, 10, 15 years, the incidence risk increased by 2.48% (95% CI: 2.23%, 2.73%), 2.20% (95% CI: 1.91%, 2.49%), 2.18% (95% CI%: 1.92%, 2.43%), 1.87% (95% CI%:1.64, 2.10%) for males, respectively and 4.03% (95% CI: 3.63%, 4.43%), 2.20% (95% CI: 1.91%, 2.49%), 3.97% (95% CI: 3.54%, 4.41%), 3.06% (95% CI: 2.71%, 3.41%) for females, respectively. The findings indicated people in low urbanization group faced with a stronger EC risk caused by PM 2.5 , which contributes to a more comprehensive understanding of combating EC challenges related to PM 2.5 pollution., (Copyright © 2020 Elsevier Inc. All rights reserved.)

DNA repair system plays a crucial role in maintaining genomic integrity and stability and in protecting against cancer. Poly(ADP-ribose) polymerase 1 (PARP1) functions as a key enzyme in the base excision repair (BER) pathway. Single nucleotide polymorphism (SNP) that could affect the function or expression of PARP1 gene might be associated with the risk of cancer. This study was designed to evaluate the association between PARP1 SNPs and the susceptibility to esophageal squamous cell carcinoma (ESCC) in a population from Cixian, a high incidence region from northern China. In 574 ESCC patients and 577 controls, PARP1 rs1136410 and rs8679 SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method. Upper gastrointestinal cancer (UGIC) family history enhanced the risk of ESCC (the sex-, age- and smoking status-adjusted OR 1.355, 95% CI 1.071-1.715). Overall, rs1136410 and rs8679 SNPs did not modify the risk of ESCC. When stratified by sex, age, smoking status and UGIC family history, the rs1136410 C/C genotype was associated with an increased risk of ESCC in smokers compared to T/T or T/C genotype (the sex-, age- and UGIC family history-adjusted OR 1.696, 95% CI 1.032-2.787). In Cixian high incidence region from northern China, smokers with rs1136410 C/C genotype might have higher susceptibility to ESCC than those with T/T or T/C genotype. These high-risk individuals receiving periodic upper gastrointestinal fiber tests might facilitate early detection and early treatment of ESCC.

Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis., (Copyright © 2021 American Society for Microbiology.)

Habits such as smoking and alcohol drinking and existing esophageal malfunction are considered the main risk factors for esophageal carcinogenesis. Caustic ingestion of acidic or alkaline agents or strong irritants can induce severe esophageal corrosive injury and increase esophageal cancer risk. We studied the relationship between esophageal carcinoma and acute detergent or pesticide poisoning by using nationwide health insurance data. Methodology/Principle findings: We compared a pesticide/detergent intoxication cohort (N = 21,840) and an age- and gender-matched control cohort (N = 21,840) identified from the National Health Insurance Research Database between 2000 and 2011. We used the multivariable Cox proportional model to determine esophageal carcinoma risk. The overall incidence density of esophageal cancer was 1.66 per 10,000 person-years in the comparison cohort and 4.36 per 10,000 person-years in the pesticide/detergent intoxication cohort. The corresponding adjusted hazard ratio (HR) for esophageal cancer was 2.33 (95% confidence interval [CI] = 1.41-3.86) in the pesticide/detergent intoxication cohort compared with the control cohort. Patients with corrosive and detergent intoxication did not have a higher risk of esophageal cancer (adjusted HR = 0.98, 95% CI = 0.29-3.33) than those without pesticide/detergent intoxication. However, patients with pesticide intoxication had a significantly higher risk of esophageal cancer (adjusted HR = 2.52, 95% CI = 1.52-4.18) than those without pesticide/detergent intoxication. Conclusion: In the present study, after adjusting for conventional risk factors, we observed that pesticide intoxication could exert substantial effects through increased esophageal cancer risk. However, patients with detergent intoxication may not have an increased risk of esophageal cancer., Competing Interests: The authors have declared that no competing interests exist.

Cigarette smoking is a factor capable of inducing esophageal squamous cell carcinoma (ESCC). However, the biological pathways that are responsible for tumor development and are directly affected by cigarette smoking remain unknown. To explore the role of cigarette smoking in ESCC, we developed a long-term cigarette smoke extract (CSE) exposed cell model using the normal immortalized SHEE esophageal epithelial cell line, which would malignantly transform after long-term cultivation without carcinogens. CSE-exposed cells displayed higher malignancy and differently expressed several lncRNAs. Among them, H19, a lncRNA responsible for proliferation and invasion, was upregulated in CSE-exposed SHEE cells. In tumors from ESCC patients, H19 was significantly increased in smoking ESCC patients compared to non-smoking patients, and H19 was overexpressed and correlated with pathological tumor size in smokers. These results indicated that cigarette smoking lead to a different biological change from non-smoking induced ESCC and H19 related to cancer development during CSE-induced carcinogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The tumor immune microenvironment (TIME) has an important impact on response to cancer immunotherapy using immune checkpoint inhibitors. Specifically, an "infiltrated-excluded"/"cold" TIME is predictive of poor response. The antidiabetic agent metformin may influence anticancer immunity in esophageal squamous cell carcinoma (ESCC)., Experimental Design: We analyzed matched pre- and posttreatment ESCC specimens in a phase II clinical trial of low-dose metformin treatment (250 mg/day) to evaluate direct anti-ESCC activity and TIME reprogramming. Follow-up correlative studies using a carcinogen-induced ESCC mouse model were performed with short-term (1 week) or long-term (12 weeks) low-dose metformin (50 mg/kg/day) treatment., Results: In the clinical trial, low-dose metformin did not affect proliferation or apoptosis in ESCC tumors as assayed by Ki67 and cleaved caspase-3 immunostaining. However, metformin reprogrammed the TIME toward "infiltrated-inflamed" and increased the numbers of infiltrated CD8 + cytotoxic T lymphocyte and CD20 + B lymphocyte. Further, an increase in tumor-suppressive (CD11c + ) and a decrease in tumor-promoting (CD163 + ) macrophages were observed. Metformin augmented macrophage-mediated phagocytosis of ESCC cells in vitro . In the ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME toward an active state (e.g., reduction in CD4 + FoxP3 + regulatory T cells) and inhibited ESCC growth. In both humans and mice, metformin triggered AMPK activation and STAT3 inactivation, and altered the production of effector cytokines (i.e., TNFα, IFNγ, and IL10) in the immune cells., Conclusions: Low-dose metformin reprograms the TIME to an activated status and may be a suitable immune response modifier for further investigation in patients with ESCC., (©2020 American Association for Cancer Research.)

Lycopene, a natural carotenoid, has potential chemopreventive effects in many cancers. This study aimed to examine the effects of lycopene on regulating the inflammation and apoptosis of N-nitrosomethylbenzylamine(NMBzA) induced esophageal cancer in F344 rats. After the rats were fed normal diets containing different concentrations of lycopene for 25 weeks (10, 25, 50 mg/kg·d of lycopene, respectively), the incidence of tumors in the rats treated with lycopene was significantly lower than that in the simple exposed group (P < 0.05). The antioxidant activity of lycopene was exerted by measuring the levels of GSH-PX, SOD and MDA activity by oxidative stress kits. Furthermore, through western blotting analysis lycopene intervention was found to have significantly improved apoptosis cytokines by increasing the protein expression levels of PPARγ and caspase-3, and also significantly reduced inflammatory cytokines by decreasing the protein expression of NF-κB and COX-2 in the esophagus tissue, especially in the 25 mg/kg of lycopene intervention group (all P < 0.05). These results demonstrated that appropriate dose of lycopene intervention could inhibit the carcinogenesis of esophageal in F344 rats through the possible mechanisms of anti-inflammatory and pro-apoptosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Though therapy that promotes anti-tumor response about CD8 + tumor-infiltrating lymphocytes (TILs) has shown great potential, clinical responses to CD8 + TILs immunotherapy vary considerably, largely because of different subpopulation of CD8 + TILs exhibiting different biological characters. To define the relationship between subpopulation of CD8 + TILs and the outcome of antitumor reaction, the phenotype and function of CD103 + CD8 + TILs in esophageal squamous cell carcinoma (ESCC) were investigated. CD103 + CD8 + TILs were presented in ESCC, which displayed phenotype of tissue-resident memory T cells and exhibited high expression of immune checkpoints (PD-1, TIM-3). CD103 + CD8 + TILs were positively associated with the overall survivals of ESCC patients. This population of cells elicited potent proliferation and cytotoxic cytokine secretion potential. In addition, CD103 + CD8 + TILs were elicited potent anti-tumor immunity after anti-PD-1 blockade and were not affected by chemotherapy. This study emphasized the feature of CD103 + CD8 + TILs in immune response and identified potentially new targets in ESCC patients.

Context: Evidence has shown that essential nutrients are highly correlated with the occurrence of esophageal cancer (EC). However, findings from observational studies on the associations between dietary carbohydrate, salt consumption, and the risk of EC remain controversial., Objective: The aim of this study was to conduct a systematic review and meta-analysis to confirm the associations of dietary carbohydrate and salt consumption with EC risk., Data Source: Various electronic databases (PubMed, MEDLINE, Embase, Google Scholar, Cochrane Library, Chinese Electronic Periodical Services, and China Knowledge Resource Integrated) were searched up until January 31, 2019., Data Extraction: Data related to patient characteristics and study characteristics were extracted by 2 independent reviewers. The risk ratio reported as relative risk (RR) or odds ratio (OR) was extracted, and random-effects models were performed to estimate the summary risk ratio., Results: In total, 26 studies were included in this analysis, of which 12 studies, including 11 case-control studies and 1 cohort study, examined dietary carbohydrates, and 18 studies, including 16 case-control studies and 2 cohort studies, examined dietary salt. The pooled OR showed that dietary carbohydrate intake was inversely related to EC risk (OR = 0.62; 95% confidence interval [CI], 0.50-0.77), but positive correlations between dietary salt intake and the risk of EC were supported by the recruited case-control studies (OR = 1.97; 95% CI, 1.50-2.61) and cohort studies (RR = 1.04; 95% CI, 1.00-1.08)., Conclusions: Salt is an essential nutrient for body functions and biochemical processes. Providing health education and management regarding proper use of salt in daily foods and labeling the amount of sodium in manufactured products to reduce the risk of developing EC should be more appropriately performed in the general population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 69-year-old woman had been undergoing treatment with methotrexate for rheumatoid arthritis for 9 years. Because fever and right hypochondriac pain continued, she visited the nearby hospital. The enlargement of intraabdominal multiple lymph nodes was detected through abdominal computed tomography. Esophagogastroduodenoscopy showed a depressed lesion in the lower intrathoracic esophagus, and squamous cell carcinoma was diagnosed by a biopsy. Positron emission tomography-computed tomography showed a highly abnormal accumulation of lymph nodes, mainly in the upper abdomen, and some lymph nodes around the aorta. Suspecting methotrexate-lymphoproliferative disorder, we discontinued the oral administration of methotrexate. Multiple lymphadenopathy reduced by the withdrawal of the oral administration of methotrexate. We operated for esophageal cancer, and she was discharged on the 17th postoperative day. The postoperative pathological result showed moderately differentiated squamous cell carcinoma. Metastasis to the lymph nodes around the esophagus was observed, and the patient was diagnosed with T1b (SM3), N2 M0, Stage II cancer. Immunostaining showed enlarged lymph nodes composed of CD20-positive cells and with cells positive for EBV-encoded small RNA in situ hybridization. This case shows that patients with rheumatoid arthritis who are being administered methotrexate may have enlarged lymph nodes due to methotrexate-lymphoproliferative disorder.

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N -nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% ( P = 0.038) and miR-31 gene knockout abrogated development of ESCC ( P = 1 × 10 -6 ). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31 -/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Achalasia is characterized by impaired swallowing due to lower esophageal sphincter (LES) dysfunction and an increased risk of esophageal carcinoma. Aflatoxin is a known carcinogen. Esophageal retention is relieved by per oral endoscopic myotomy (POEM), which lowers the esophageal cancer risk. The present study determined whether aflatoxin is involved in the pathogenesis of achalasia or esophageal cancer. A total of 75 patients with achalasia were prospectively enrolled from a tertiary center. Aflatoxin levels in their esophageal contents were measured using ELISA, and esophageal mucosal specimens were immunohistochemically evaluated for Ki67 and p53 expression prior to and 3 months after POEM. The effect of aflatoxin on esophageal contractility was assessed using murine specimens. Aflatoxin was detected in 67 patients before POEM and only 2 patients after POEM. The number of Ki67‑ and p53‑immunopositive cells in the esophageal mucosa significantly decreased after POEM: [Ki67: 27.8% (95% confidence interval (CI), 25.98‑29.70) vs. 20.7% (95% CI, 19.78‑24.03), P=0.04 and p53: 2.14% (95% CI, 1.85‑2.41) vs. 1.45% (95% CI, 1.22‑1.68), P=0.03]. In vitro experiments revealed that 500 ng/ml aflatoxin significantly increased the amplitude (P<0.05) and frequency (P<0.05) of spontaneous LES contractions compared with the control group. These increases were blocked by co‑treatment with atropine sulfate (P<0.05), but not with a nitric oxide synthase inhibitor (P>0.05). Aflatoxin was found in most patients with achalasia and was eliminated following POEM. Reduced Ki67 and p53 expression after POEM indicated a decreased risk of carcinogenesis. Aflatoxin accumulation increased LES contractility via cholinergic signaling. Therefore, aflatoxin may maintain achalasia symptoms and increase esophageal cancer risk.

Background: Consumption of moldy food has previously been identified as a risk factor for esophageal squamous cell carcinoma (ESCC) in high-risk countries; however, what contributing roles these dietary carcinogenic mycotoxins play in the etiology of ESCC are largely unknown., Methods: A mycotoxin biomarker-incorporated, population-based case-control study was performed in Huaian area, Jiangsu Province, one of the two high-risk areas in China. Exposure biomarkers of aflatoxins (AF) and fumonisins (FN) were quantitatively analyzed using HPLC-fluorescence techniques., Results: Among the cases (n = 190), the median levels of AF biomarker, serum AFB 1 -lysine adduct, and FN biomarker, urinary FB 1 , were 1.77 pg/mg albumin and 176.13 pg/mg creatinine, respectively. Among the controls (n = 380), the median levels of AFB 1 -lysine adduct and urinary FB 1 were 1.49 pg/mg albumin and 56.92 pg/mg creatinine, respectively. These mycotoxin exposure biomarker levels were significantly higher in cases as compared to controls (p <  0.05 and 0.01, respectively). An increased risk to ESCC was associated with exposure to both AFB 1 and FB 1 (p <  0.001 for both)., Conclusions: Mycotoxin exposure, especially to AFB 1 and FB 1 , was associated with the risk of ESCC, and a greater-than-additive interaction between co-exposures to these two mycotoxins may contribute to the increased risk of ESCC in Huaian area, China.

People of north-eastern states of India consume raw areca-nut (RAN) and lime which could lead to oral, esophageal and gastric cancers. However, the incidence of these cancers are significantly lesser in those who consume pieces of Potentilla fulgens root along with RAN. Since evaluation of anticancer role, if any, of P. fulgens on RAN-mediated genetic alterations in human is difficult because of other compounding factors, this study was undertaken in mice to focus on gastric carcinogenesis since ad libitum administration of RAN extract with lime in drinking water induced stomach cancer due to greater exposure of its lining. A total of 160 mice were used at different time points and either methanol extract of P. fulgens roots (PRE) or mixture of four compounds of ethyl-acetate fraction (EA-mixture) was mixed with mice feed. Histological studies revealed that RAN + lime induced cancer in all the mice and interestingly only 20% developed cancer when PRE/EA-mixture was provided along with RAN + lime. Higher frequency of precocious anaphase and over expression of p53 and Securin genes were significantly reduced by PRE/EA-mixture. Thus PRE/EA-mixture mitigates the RAN-induced tumor-initiating process in stomach by maintaining expression of tumor suppressor and check-point genes under control.

The Huai'an area in Jiangsu Province of East China is an endemic region of esophageal cancer (EC). The regional heterogeneity of EC suggests that the levels of potential carcinogens might vary throughout the environment. It has been suggested that the most likely carcinogens related to EC are a group known as the N-nitrosamines. In this study, we measured the concentrations of nine nitrosamines in drinking water and human urine in two areas in China, one with a high incidence of EC (Huai'an) and one with a low incidence (Nanjing). Among the nine target analytes, N-nitrosodi-n-propylamine (NDPA), N-nitrosodibutylamine (NDBA), N-nitrosopyrrolidine (NPyr), N-nitrosodiethylamine (NDEA) and N-nitrosomorpholine (NMor) occurred at higher concentrations in drinking water in the high incidence area. Inhabitants from the high incidence area also had urinary excretions with significantly higher concentrations of NDEA, NDBA, N-nitrosopiperidine (NPip) and N-nitrosodiphenylamine (NDPhA). These findings indicated that people in the high EC incidence area were exposed to higher levels of nitrosamines. However, the association between the incidence of EC and nitrosamines exposure will need to be evaluated in more detail., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: There is increasing interest in the potential association between proton pump inhibitors (PPIs) and the risk of gastric and oesophageal cancer, yet the effect of duration of treatment needs clarification., Methods: This Swedish population-based cohort study assessed the influence of time since initiation of PPI treatment on the risk of gastric and oesophageal cancer, presented as standardised incidence ratios and 95% confidence intervals., Results: The risk of gastric and oesophageal cancer during the first year was 7-10 times higher than the background population, and remained 24-202% increased without any decrease over time after the first year., Conclusion: PPI use was associated with an increased risk of gastric and oesophageal cancer and the risk remained increased over follow-up. These results support our original hypothesis that use of PPIs may be a risk factor for gastric and oesophageal cancer in the general population of maintenance users, independent of underlying indications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)