Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Is blue light imaging without magnification satisfactory as screening for esophageal squamous cell carcinoma? Post-hoc analysis of multicenter randomized controlled trial.

OBJECTIVES: Narrow light observation is currently recommended as an alternative to Lugol chromoendoscopy (LCE) to detect esophageal squamous cell carcinoma (ESCC). Studies revealed little difference in sensitivity between the two modalities in expert settings; however, these included small numbers of cases. We aimed to determine whether blue light imaging (BLI) without magnification is satisfactory for preventing misses of ESCC. METHODS: This was a post-hoc analysis of a multicenter randomized controlled trial targeting patients at high risk of ESCC in expert settings. In this study, BLI without magnification followed by LCE was performed. The evaluation parameters included: (i) the diagnostic abilities of ESCC; (ii) the endoscopic characteristics of lesions with diagnostic differences between the two modalities; and (iii) the color difference between cancerous and noncancerous areas in BLI and LCE. RESULTS: This study identified ESCC in 49 of 699 cases. Of these cases, nine (18.4%) were missed by BLI but detected by LCE. In per-patient analysis, the sensitivity of BLI was lower than that of LCE following BLI (83.7% vs. 100.0%; P = 0.013), whereas the specificity and accuracy of BLI were higher (88.2% vs. 81.2%; P < 0.001 and 87.8% vs. 82.5%; P < 0.001, respectively). No significant endoscopic characteristics were identified, but the color difference was lower in BLI than in LCE (21.4 vs. 25.1; P = 0.003). CONCLUSION: LCE following BLI outperformed BLI in terms of sensitivity in patients with high-risk ESCC. Therefore, LCE, in addition to BLI, would still be required in screening esophagogastroduodenoscopy even by expert endoscopists.

Extraction and Fractionation of Human Gastric Mucins from Gastric Juice.

Mucin, a major component of the mucus, is considered to be one of the principal factors in the physiological defense mechanism of the gastrointestinal mucosa. Measuring the mucin content of human gastric mucus is a useful tool for the assessment of Helicobacter pylori (H. pylori) eradication or the involvement of mucus secretion in various gastroduodenal diseases. Here, we describe a methodology for the isolation of the mucin fraction from human gastric juice and the quantification of mucin.

Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer.

In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.

Helicobacter pylori Eradication Does Not Adversely Affect the Clinical Course of Gastric Cancer: A Multicenter Study on Screening Endoscopic Examination in Japan.

BACKGROUND: Since gastric cancers (GCs) detected after Helicobacter pylori (HP) eradication present with different morphological characteristics from conventional HP-positive GCs, delayed detection of early-stage GCs may be observed. This study aimed to investigate the clinical impact of HP eradication on diagnosing GC during screening endoscopy. METHODS: Eleven health checkup institutions in Japan participated in the present study. All GC cases newly diagnosed by screening endoscopy between January 2016 and December 2020 were included. After propensity score matching, multivariable regression analysis was performed to estimate the effect of HP eradication on deep tumor invasion among HP-eradicated and HP-positive GC cases. RESULTS: A total of 231 patients with GCs (134 HP-eradicated and 97 HP-positive cases) were enrolled. After propensity score matching, there were 81 cases in each group. The distribution of the depth of tumor invasion (pT1a, pT1b1, pT1b2, and pT2) between the HP-eradicated group and HP-positive group was similar (p = 0.82). In the propensity analysis, with HP-positive as the reference value, HP eradication was not significantly associated with T1b-T4-GCs and T1b2-T4-GCs, with odds ratios (95% confidence intervals) of 1.16 (0.48-2.81) and 1.16 (0.42-3.19), respectively. CONCLUSIONS: HP eradication does not adversely affect the clinical course of GCs, supporting the recommendation of HP eradication in screening programs to reduce the total number of GC cases without delaying diagnosis.

Background factors of idiopathic peptic ulcers and optimal treatment methods: a multicenter retrospective Japanese study.

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.

Iron overload in patients with Crohn's disease with short bowel syndrome who received long-term parenteral nutrition with trace elements.

Crohn's disease patients often need regular home parenteral nutrition (HPN) for intestinal failure due to multiple intestinal resections. Trace elements are necessary for long-term HPN but the requirement volume of iron is undetermined. We describe three patients with Crohn's disease with short bowel syndrome (SBS) who had iron overload as a result of long-term HPN including iron. Serum ferritin level was significantly decreased through depleting intravenous iron administration in all cases. One patient needed regular insulin injection and phlebotomy for diabetes mellitus due to hemochromatosis, and intravenous iron administration had a significant impact on the patient's health. Long-term routine intravenous iron administration should be cautious in SBS patients to avoid the overload.

Disproportionate cancer worries in ultra-short-segment Barrett's esophagus in Japan.

Objectives: Although Barrett's esophagus (BE), especially ultra-short-segment BE (USSBE), is very frequently diagnosed in Japan, how subjects feel about receiving a diagnosis of BE is unclear. We therefore prospectively investigated cancer worry in subjects who received a BE diagnosis. Methods: Self-administered questionnaires were sent to subjects who were diagnosed with BE at three health checkup institutes in Akita Prefecture, Japan. The cancer worry scale (CWS) was used to quantitatively assess the fear of developing cancer. The BE subjects were classified into USSBE <1 cm and non-USSBE ≥1 cm groups. Factors associated with the CWS were investigated using logistic regression analyses. Results: A total of 325 (31%) subjects, comprising 229 USSBE and 96 non-USSBE patients were included in this study. Compared with the USSBE group, the non-USSBE group had a significantly higher frequency of a history of a BE diagnosis and perception of carcinogenesis. However, the CWS was similar between the USSBE and non-USSBE groups, with a median CWS of 12.5 (3.75) versus 12.7 (3.65). A multivariate logistic regression analysis revealed that while positive reflux symptoms were significantly associated with a positive CWS, the BE length was not significantly associated with it, with an odds ratio (95% confidence interval) of 1.3 (0.75-2.2). Conclusions: A BE diagnosis promotes a similar level of worry about cancer among subjects, irrespective of the length of BE. In Japan, since USSBE poses a much lower cancer risk than non-USSBE, the former may frequently be associated with a disproportionate cancer worry relative to the latter. (UMIN000044010).

Peroral cholangioscopy for the evaluation of bile duct stricture in hepatocellular carcinoma on a preoperative examination.

Objective: Bile duct tumor thrombosis in hepatocellular carcinoma (HCC) is a relatively rare event with a poor prognosis. Furthermore, bile duct tumor thrombus in HCC may be misdiagnosed when only imaging modalities are used. The efficiency of peroral cholangioscopy (POCS) in evaluating bile duct lesions has been reported. Patients: We present three cases of HCC with bile duct strictures in which POCS was performed as a preoperative evaluation. Results: In these three cases, diagnosing whether the lesion was a bile duct tumor thrombus on CT and endoscopic retrograde cholangiopancreatography was difficult. We performed POCS in three cases and were able to diagnose the presence of bile duct tumor thrombus of HCC, including differentiation from extrinsic compression of the bile duct. Conclusion: POCS for HCC with bile duct features is useful for the preoperative diagnosis of bile duct tumor thrombus, especially in cases where the surgical procedure depends on the presence of bile duct tumor thrombus.

Clinical outcomes of endoscopic submucosal dissection for esophageal squamous cell carcinoma with esophageal varices: Multicenter retrospective study.

OBJECTIVES: Clinical outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) are obscure. We aimed to elucidate the clinical outcomes of ESD for ESCC with EVs in a multicenter, retrospective study. METHODS: We established a retrospective cohort of 30 patients with ESCC complicating EVs, who underwent ESD at 11 Japanese institutions. Rates of en bloc resection and R0 resection, procedure time, and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence, and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD. RESULTS: Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 min. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC. CONCLUSION: This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

Impact of functional status on development of Clostridioides difficile infection and increase in in-hospital mortality among antibiotic users.

INTRODUCTION: Functional status is one of the surrogates of advanced age, an established risk factor for Clostridioides difficile infection (CDI). We aimed to investigate the usefulness of functional status in the clinical management of CDI. METHODS: We enrolled all hospitalized adult patients receiving antibiotics from a retrospective hospital-based cohort in Japan between 2016 and 2020. Using the Barthel index (BI), which is an objective scale of functional status, we investigated the association of BI with developing CDI and its impact on in-hospital mortality in patients with CDI. RESULTS: We enrolled 17,131 patients with 100 cases of CDI. Multivariable analysis revealed that lower BI (≤ 25) was an independent risk factor for developing CDI (adjusted odds ratio, 4.11; 95% confidence interval, 2.62-6.46). Furthermore, a combination of BI and Charlson comorbidity index (CCI) showed an adjusted odds ratio of 36.40 (95% confidence interval, 17.30-76.60) in the highest-risk group. A high-risk group according to the combination of BI and CCI was estimated to have significantly higher in-hospital mortality in patients with CDI using the Kaplan-Meier method (p = 0.017). A combination of lower BI and higher CCI was an independent predictor of in-hospital mortality even in the multivariable Cox regression model (adjusted hazard ratio, 3.00; 95% confidence interval, 1.01-8.88). CONCLUSIONS: Assessment of functional status, especially combined with comorbidities, was significantly associated with developing CDI and may also be useful in predicting in-hospital mortality.

A new model to estimate duration of survival in patients with hepatocellular carcinoma with BCLC intermediate stage.

It is difficult to determine whether an individual therapy contributes to the elongation of survival because of the difficulty of organizing clinical research in patients who receive multiple treatments in HCC. We aimed to establish a new model of survival prediction in patients with intermediate stage HCC to establish standards in the recent and coming multi-MTA era. This analysis was prepared using a data set of 753 patients diagnosed HCC prior to 2017. Multiple regression analysis showed age, naïve or recurrence, the size of the largest tumor nodule, the number of nodules, total bilirubin, albumin and α-fetoprotein as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established a new predicted survival model. The survival duration can be predicted the proposed model; EXP (4.02580 + (- 0.0086253) × age + (- 0.34667) × (naïve/recurrence) + (- 0.034962) × (number of nodules) + (- 0.079447) × (the size of the largest nodule) + (- 0.21696) × (total bilirubin) + 0.27912 × (albumin) + (- 0.00014741) × (α-fetoprotein)) × (- natural logarithm(0.5))^0.67250. This model is useful for the planning and evaluating the efficacy of recent sequential therapies in multi-MTA era.

CCDC85A is regulated by miR-224-3p and augments cancer cell resistance to endoplasmic reticulum stress.

MicroRNAs (miRNAs) play pivotal roles in the tumor microenvironment. Here, we analyzed miRNAs in tumor stromal fibroblasts. Expression of miR-224-3p in cancer-associated fibroblasts (CAF) from scirrhous gastric cancer patients was lower than in normal fibroblasts (NF). Introduction of a miR-224-3p mimic attenuated migration and invasion of CAF. Coiled-coil domain containing 85A (CCDC85A), whose function in tumors is not understood, was the target gene of miR-224-3p. Immunohistological analysis revealed that CCDC85A is expressed to varying degrees by cancer cells and CAFs in gastric and pancreatic carcinomas. Downregulation of CCDC85A in cancer cells revealed that these cells are vulnerable to endoplasmic reticulum (ER) stress induced by thapsigargin or tunicamycin, which were ameliorated after addback of CCDC85A. Injection of NF-derived exosomes containing miR-224-3p into the xenograft tumor increased tumor shrinkage by cisplatin treatment. Mechanistically, CCDC85A associated with the molecular chaperone GRP78 and GRP94, thereby inhibiting association of these negative regulators of the unfolded protein response (UPR), leading to sustained activation of PERK and downstream eIF2〈 and ATF4 upon ER stress. These data suggest a novel miR-224-3p-mediated function for CCDC85A: protection from ER stress and cisplatin resistance.

[A case of severe inflammatory bowel disease triggered by vaccination with SARS-CoV-2 mRNA].

A 64-year-old woman received a third dose of SARS-CoV-2 mRNA vaccine. On the next day, she developed fever, diarrhea, and abdominal pain and had bloody stools. Total colonoscopy revealed deep ulceration on the whole colon. She was treated with corticosteroid and infliximab and her symptoms improved. She was diagnosed with severe enteritis resembling ulcerative colitis triggered by SARS-CoV-2 mRNA vaccination.