Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia.

BACKGROUND: Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS: Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS: Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION: Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.

The first evidence for SLFN11 expression as an independent prognostic factor for patients with esophageal cancer after chemoradiotherapy.

BACKGROUND: Schlafen 11 (SLFN11) was recently identified as a dominant determinant of sensitivity to DNA-targeting agents including platinum-based drugs. SLFN11 also reportedly enhances cellular radiosensitivity. In this study, we examined the prognostic value of SLFN11 expression in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT), including the platinum derivative nedaplatin. METHODS: Seventy-three patients with ESCC who received dCRT were examined. SLFN11 expression was analyzed in pre-dCRT biopsies using immunohistochemistry and evaluated using a histo-score (H-score). Correlation between the H-score and overall survival was analyzed. An H-score ≥ 51 was provisionally defined as indicating high SLFN11 expression. Viability assays were performed using previously established isogenic human cell lines differentially expressing SLFN11 to test the usefulness of SLFN11 as marker of response to the dCRT regimen. RESULTS: High SLFN11 expression was independently associated with better prognosis in ESCC patients (hazard ratio = 0.295, 95% CI = 0.143-0.605, p = 0.001 for multivariate analysis). Kaplan-Meier survival curves showed that the prognostic value of high SLFN11 expression was most evident in patients at clinical stages II and III (p = 0.004). In in vitro study, SLFN11-proficient cells were highly sensitive to platinum derivatives compared to SLFN11-deficient cells. CONCLUSION: SLFN11 expression is an independent prognostic factor for ESCC patients treated with dCRT and a potential biomarker for treatment selection of ESCC. Examination of SLFN11 may be particularly useful for clinical Stage II-III patients who wish to choose dCRT (instead of surgery) to preserve esophageal function.

The effect of early trough level of infliximab on subsequent disease course in patients with Crohn disease: A prospective cohort study.

Decreased trough level of infliximab (TLI) is associated with diminished efficacy in patients with Crohn disease (CD). We examined whether TLI at 14 weeks subsequent to the start of infliximab (IFX) treatment would impact long-term clinical course.Serum IFX levels and antibodies to IFX (ATI) at 14 and 54 weeks after IFX administration were measured in 12 patients with mild to moderate CD. We examined patient background, clinical severity, blood test values, and the relationship between ATI and TLI up to 108 weeks.We compared the group with TLI < 3 µg/mL at 14 weeks (TLI(14) < 3 group) the group with TLI > 3 µg/mL (TLI(14) ≥ 3 group). Patients in the TLI(14) ≥ 3 group were significantly more likely to use immunomodulators before IFX treatment induction (P = .01). At 54 weeks, 2 cases of ATI production were observed in the TLI(14) < 3 group, but no ATI production was observed in the TLI(14) ≥ 3 group. TLI in the TLI(14) ≥ 3 group at 54 weeks was significantly higher than in the TLI(14) < 3 group (6.5 µg/mL vs 1.0 µg/mL; P < .01). Although CD activity index and serum albumin values in the TLI(14) ≥ 3 group at 14, 54, and 108 weeks significantly improved compared to baseline, these improvements were not observed in the TLI(14) < 3 group. The remission maintenance rate at 108 weeks evaluated with the Kaplan-Meier method was significantly higher in the TLI(14) ≥ 3 group than the TLI(14) < 3 group (100% vs 33.3%; P = .02).The TLI 14 weeks after IFX treatment in patients with CD affects long-term outcome.

Effect of ulcerative colitis duration on the usefulness of immunochemical fecal occult blood test result as a disease activity biomarker.

PURPOSE: The effects of ulcerative colitis (UC) duration on biomarker accuracy are unknown. We investigated the effects of UC duration on the predictive accuracy of biomarkers including immunochemical fecal occult blood test (FOBT, also known as FIT), prostaglandin E-major urinary metabolite (PGE-MUM), and C-reactive protein (CRP). METHODS: We divided 133 samples into groups based on disease duration. Clinical and endoscopic remission was defined as Lichtiger's clinical activity index (CAI) of ≤ 4, Mayo endoscopic subscore (MES) of 0, and UC endoscopic index of severity (UCEIS) of ≤ 1. RESULTS: FIT results were significantly correlated with all activity scores when the disease duration was < 4 years. When the disease duration was ≥ 4 years, FIT results were significantly correlated with the CAI and MES but not with UCEIS. When the disease duration was ≥ 5 years, FIT and CAI were significantly correlated, whereas FIT and MES or FIT and UCEIS did not show any correlation. When the duration was ≥ 4 years, PGE-MUM and CRP showed a significant correlation with CAI, MES, and UCEIS. Receiver operating characteristic curve analysis of biomarker data for predicting endoscopic remission showed that the accuracy of FIT was superior to that of PGE-MUM and CRP in the < 4-year group. CONCLUSIONS: FIT is an accurate biomarker reflecting the endoscopic score until 4 years in patients with UC. However, owing to the increased number of false negatives, the usefulness of FIT may decline after 4 years. Hence, evaluation of UC in combination with other biomarkers is recommended.

Prostaglandin E-major urinary metabolite versus fecal immunochemical occult blood test as a biomarker for patient with ulcerative colitis.

BACKGROUND: Prostaglandin E-major urinary metabolite (PGE-MUM) may be a novel biomarker for evaluating disease activity in ulcerative colitis (UC). We compared its usefulness to that of the fecal immunochemical occult blood test (FIT). METHODS: PGE-MUM and FIT measurements were performed of 92 urinary and fecal samples obtained from 60 patients with UC. Endoscopic activity was determined by Mayo endoscopic subscore (eMayo) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. RESULTS: PGE-MUM levels and FIT results showed a significant correlation with respect to eMayo (P <  0.001 and P < 0.001, respectively), and there was a significant difference in PGE-MUM values between the groups below eMayo1 and above eMayo2 (P = 0.012). Both biomarkers were significantly correlated with the UCEIS score (P < 0.001 and P < 0.001, respectively), and the PGE-MUM values were significantly different between groups below UCEIS1 and above UCEIS2 (P = 0.012). PGE-MUM and FIT were significantly correlated with eMayo in the group with a disease duration < 5 years (P = 0.041 and P < 0.001, respectively). Although PGE-MUM and eMayo differed significantly between groups over 5 years (P = 0.012), FIT was not correlated with eMayo (P = 0.101). CONCLUSIONS: PGE-MUM is useful as a biomarker as FIT for evaluating the endoscopic activity, particularly in long-term affected patients with UC.

A rectal neuroendocrine tumor in a patient with Crohn's disease: a case report and literature review.

Crohn's disease is recognized to increase the risk of gastrointestinal malignances. Adenocarcinoma is the most common malignancy in these patients. Association between Crohn's disease and adenocarcinoma in the small intestine has already been established, however, the association between neuroendocrine tumor and Crohn's disease remains uncertain. We report a 39-year-old man with Crohn's disease, who was diagnosed with NET in the rectum. He had suffered from fever and anal pain due to the anal fistula and abscess. The disease state was considered to be resistant to medical treatment. He underwent total proctocolectomy, small bowel resection, anal fistula drainage with ileostomy. Postoperative histology revealed a neuroendocrine tumor in the rectum. His postoperative course was uneventful, and he followed a good course under treatment with infliximab and mercaptopurine hydrate. This case highlights the need of careful observation of resected specimens in light of the possibility of NET, especially those with anal disorders.

High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy.

BACKGROUND: Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance. In this study, we investigated the influence of CD44v8-10 expression on the overall survival of esophageal squamous cell carcinoma (E-SCC) patients after definitive chemoradiotherapy (dCRT) and on radio-sensitivities of E-SCC cell lines treated with or without sulfasalazine, a CD44v8-10-xCT-GSH axis inhibitor. METHODS: Seventy-three patients with E-SCC who received dCRT were examined retrospectively. CD44v8-10 expression was analyzed immunohistochemically using paraffin-blocked pre-dCRT biopsy specimens obtained by esophagoscopy and was expressed as a histo-score (H-score). The relationship between the H-score and overall survival was analyzed. From human E-SCC cell lines (T.T, T.Tn, or Kyse-3650), we collected CD44v8-10High and CD44v8-10Low subpopulations using a cell sorter. Water-soluble tetrazolium salt-8 (WST), glutathione-SH (GSH) and ROS assays were performed to compare the effect of sulfasalazine on the radio-sensitivities of these subpopulations in T.Tn and Kyse-3650. RESULTS: High CD44v8-10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277-6.611, p = 0.011). In CD44v8-10High cells of each cell line, sulfasalazine decreased cellular GSH levels, resulting in increased radiation-induced ROS and reduced cell viability. In contrast, sulfasalazine had no significant effects in CD44v8-10Low cells. CONCLUSION: High CD44v8-10 expression was an independent prognostic factor in E-SCC patients treated with dCRT. CD44v8-10-xCT-GSH axis inhibition sensitized CD44v8-10High E-SCC cells to ROS-inducing treatments such as radiotherapy. Targeting CD44v8-10-xCT-GSH axis may improve the prognosis of post-dCRT E-SCC patients.

Improvement of gastroesophageal reflux disease in Japanese patients with spinal kyphotic deformity who underwent surgical spinal correction.

BACKGROUND AND AIM: Spinal kyphotic deformity occasionally results in gastroesophageal reflux disease (GERD). The effects of acid reflux on the esophagus in kyphotic patients are unclear, however, and it is unknown whether acid reflux, endoscopic GERD, and reflux-related symptoms improve following surgical spinal correction in these patients. Herein, we investigated the characteristics of GERD in kyphotic patients and the improvement in GERD following surgical correction. METHODS: In 48 patients with severe kyphotic deformity scheduled for surgical spinal correction, we conducted esophagogastroduodenoscopy, 24-h pH monitoring and three questionnaire surveys, including the frequency scale for the symptoms of GERD (FSSG). We repeated these measurements after surgical correction and compared pre- and post-surgery values. RESULTS: Of 48 patients, 70.8% [95% CI: 55.9-83.0%, 34/48] had endoscopically evaluated esophageal mucosal injury. Regarding pH before surgery, 64.9% (CI: 47.5-79.8%, 24/37) had abnormal acid reflux (intraesophageal pH < 4 more than 5% of the time). FSSG score was significantly associated with the severity of GERD, and the positive rate was 52.6% (CI: 35.8-69.0%, 20/38). Following surgical correction, esophageal mucosal injury improved endoscopically in 90% of patients, and median total FSSG score significantly decreased from 8 (0-30) to 5 (0-19) (P = 0.005). Regarding pH after surgery, prevalence of abnormal acid reflux decreased from 66.7% (95% CI: 41.0-86.7%) to 33.3% (95% CI: 13.3-59.0%) (P = 0.045). CONCLUSION: Surgical spinal correction in kyphosis patients improves not only kyphotic deformity-related disorders but also esophageal mucosal injury, abnormal acid reflux, and reflux-related symptoms.

Factors associated with healing of artificial ulcer after endoscopic submucosal dissection with reference to Helicobacter pylori infection, CYP2C19 genotype, and tumor location: Multicenter randomized trial.

BACKGROUND AND AIM: Healing speed of peptic ulcer is affected by a number of factors, including Helicobacter pylori (H. pylori) infection and intragastric pH. Acid inhibition exerted by proton pump inhibitors differs by CYP2C19 genotype. Herein, we investigated whether healing speed of artificial ulcers formed after endoscopic submucosal dissection (ESD) was influenced by H. pylori infection, CYP2C19 genotype, or other factors. METHODS: A total of 96 H. pylori-positive patients with gastric tumors scheduled for ESD were randomly assigned to receive eradication therapy for H. pylori before ESD (pre-ESD eradication) (n = 44) or after (post-ESD eradication) (n = 52). Patients received eradication therapy consisting of lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week. After ESD, lansoprazole 30 mg was given once daily for 8 weeks. Ulcer size was endoscopically measured on the next day and at 4 and 8 weeks after ESD. RESULTS: Mean reduction rate of artificial ulcer area in the pre-ESD eradication group was 94.7% ± 5.5% at 4 weeks, which was similar to that in the post-ESD eradication group (94.7% ± 6.7%, P = 0.987), irrespective of CYP2C19 genotype. In multivariate analyses, location of gastric tumor (middle and upper, odds ratio: 4.05, 95% CI: 1.620-10.230, P = 0.003) was a factor for 97% reduction of artificial ulcer area at 4 weeks post-ESD, but CYP2C19 genotype and H. pylori infection were not. CONCLUSION: Healing speed of ESD-induced artificial ulcer was affected by tumor location, but not by time of H. pylori eradication, resected size, or CYP2C19 genotype.

[A case of hemorrhage from varices of an interposed jejunum after choledochojejunostomy treated successfully by endoscopic injection using α-cyanoacrylate monomer].

A 73-year-old woman was admitted with gastrointestinal bleeding. She had undergone pylorus-preserving pancreaticoduodenectomy, hepaticojejunostomy and pancreatojejunostomy for pancreatic cancer a year earlier. Gastrointestinal endoscopy revealed bleeding from varices in an interposed jejunum. Enhanced CT showed an extrahepatic portal venous obstruction and cavernous transformation of the portal vein, which were complications of these operations. We performed endoscopic injection using α-cyanoacrylate monomer for the varices. After 4 treatments, the bleeding stopped. We concluded that endoscopic injection using α-cyanoacrylate monomer was effective and useful treatment for bleeding from hepatopetal varices, including cavernous transformation of the portal vein. This method is also useful in emergency situations.