[Small intestinal mucormycosis associated with acute myeloid leukemia: a case report].

The patient was a man in his 70s. During the treatment for acute myeloid leukemia, abdominal pain and bloody stools appeared. A diagnosis of small intestinal ileus was made by computed tomography scan. Treatment with an ileus tube did not improve his condition, and enteroscopy revealed the presence of ileal ulcers. Based on histological examination, small intestinal mucormycosis was suspected, and thus, antifungal drugs were administered. However, the patient developed perforated peritonitis and underwent small intestine resection. He was finally diagnosed with small intestinal mucormycosis with the help of the resected specimen. The gastrointestinal form of mucormycosis rarely occurs, and small intestinal lesions are very rare. Enteroscopy was helpful in its diagnosis and treatment.

Prognostic impact of clinical outcome after endoscopic gastroduodenal stent placement for malignant gastric outlet obstruction: a multicenter retrospective cohort study using a time-dependent analysis.

Background: Endoscopic gastroduodenal stent (GDS) placement is widely used as a safe and effective method to rapidly improve gastrointestinal symptoms of malignant gastric outlet obstruction (MGOO). While previous studies reported the utility of chemotherapy after GDS placement for prognosis improvement, they did not fully address the issue of immortal time bias. Objectives: To examine the association between prognosis and clinical course following endoscopic GDS placement, using a time-dependent analysis. Design: Multicenter retrospective cohort study. Methods: This study included 216 MGOO patients who underwent GDS placement between April 2010 and August 2020. Data of patient baseline characteristics, including age, gender, cancer type, performance status (PS), GDS type and length, GDS placement location, gastric outlet obstruction scoring system (GOOSS) score, and history of chemotherapy before GDS were collected. The clinical course following GDS placement was evaluated by GOOSS score, stent dysfunction, cholangitis, and chemotherapy. A Cox proportional hazards model was used to identify prognostic factors after GDS placement. Stent dysfunction, post-stent cholangitis, and post-stent chemotherapy were analyzed as time-dependent covariates. Results: Mean GOOSS scores before and after GDS were 0.7 and 2.4, respectively, with significant improvement after GDS placement (p < 0.001). The median survival time after GDS placement was 79 [95% confidence interval (CI): 68-103] days. In multivariate Cox proportional hazards model with time-dependent covariates, PS 0-1 [hazard ratio (HR): 0.55, 95% CI: 0.40-0.75; p < 0.001], ascites (HR: 1.45, 95% CI: 1.04-2.01; p = 0.028), metastasis (HR: 1.84, 95% CI: 1.31-2.58; p < 0.001), post-stent cholangitis (HR: 2.38, 95% CI: 1.37-4.15; p = 0.002), and post-stent chemotherapy (HR: 0.01, 95% CI: 0.002-0.10; p < 0.001) significantly affected prognosis after GDS placement. Conclusion: Post-stent cholangitis and tolerability to receive chemotherapy after GDS placement influenced prognosis in MGOO patients.

Fatty acid-driven modifications in T-cell profiles in non-alcoholic fatty liver disease patients.

BACKGROUND: The interaction between T-cells/fatty acids involved in non-alcoholic fatty liver disease (NAFLD) and liver fibrosis progression is poorly understood. In this study, we conducted a comprehensive analysis of T-cell profiles of NAFLD patients to better understand their relationship with fatty acids and relevance to liver fibrosis. METHODS: We analyzed the differences in T-cell profiles of peripheral blood mononuclear cells (PBMCs) between 40 NAFLD patients and 5 healthy volunteers (HVs), and their relationship with liver fibrosis stage or progression. Moreover, we analyzed the relationship between T-cell profiles and fatty acid compositions in vivo, and changes in T-cell profiles after treatment with fatty acids in vitro. RESULTS: T-cell profiles of NAFLD patients were different from those of HVs. The CD25+CD45+CD4+ T-cell frequency was increased in NAFLD patients with high liver fibrosis stage and progression, and this indicated immune activation. Despite such a state of immune activation, the PD1+CD4+ T-cell frequency was decreased in the same patients group. The PD1+CD4+ T-cell frequency had a significantly negative correlation with the serum fatty acid composition ratio C16:1n7/C16:0. Moreover, the PD1+CD4+ T-cell frequency was significantly decreased by in vitro treatment with fatty acids. In addition, its rate of frequency change was significantly different between C16:0 and C16:1n7 and decreased by artificially increasing the C16:1n7/C16:0 ratio. CONCLUSIONS: The analysis of PBMCs in NAFLD patients showed that T-cell profiles were different from those of HVs. And, it suggested that fatty acids modified T-cell profiles and were involved in liver fibrosis in NAFLD patients.

Efficacy of Vonoprazan for 48-Week Maintenance Therapy of Patients with Healed Reflux Esophagitis.

AIMS: We aimed to evaluate the efficacy of vonoprazan (VPZ) as maintenance therapy for healed reflux esophagitis (RE). METHODS: We enrolled 74 patients diagnosed with RE with frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score ≥8 after at least 8 weeks of treatment with standard proton pump inhibitors (PPIs). These patients were switched to VPZ 20 mg for 4 weeks. We also enrolled 71 patients with no endoscopic evidence of erosive esophagitis who received maintenance therapy with VPZ 10 mg for 48 weeks. The primary end point was the proportion of patients who maintained healed RE refractory to PPIs after 48 weeks of maintenance therapy with on demand 10 mg VPZ. Secondary assessment included the proportion of patients with symptomatic nonrelapse at 48 weeks. RESULTS: Fifty patients successfully completed 48-week maintenance therapy. Maintenance therapy with VPZ 10 mg prevented the relapse of esophageal mucosal breaks in 43 (86.0%) of 50 patients at 48 weeks. During the 48-week maintenance therapy, symptomatic nonrelapse rate for acid reflux-related symptom score of FSSG and acid reflux score of Gastrointestinal Symptom Rating Scale at 48 weeks were 70.0 and 72.0%, respectively. No serious adverse events were reported during the study. CONCLUSION: VPZ 10 mg is clinically effective for maintenance of healed RE for 48 weeks.

Serum C16:1n7/C16:0 ratio as a diagnostic marker for non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: Accurate diagnosis of non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD) is clinically important. Therefore, there is a need for easier ways of diagnosing NASH. In this study, we investigated the serum fatty acid composition and evaluated the possibility of using the serum fatty acid composition as a diagnostic marker of NASH. METHODS: The subjects were 78 NAFLD patients (non-alcoholic fatty liver [NAFL]: 30, NASH: 48) and 24 healthy individuals. Fatty acids extracted from the liver tissue and serum were identified and quantified by gas chromatography. In addition, we evaluated the relationship between serum and liver tissue fatty acid composition, patient background, and liver histology. The diagnostic performance of NASH was evaluated by calculating the area under the receiver operating characteristic (AUROC). RESULTS: The results of the fatty acid analysis showed the C16:1n7/C16:0 ratio to have the strongest correlation between serum and liver tissue (r = 0.865, P < 0.0001). The serum C16:1n7/C16:0 ratio in the NASH group was higher compared with that in the NAFL group (P = 0.0007). Evaluation of the association of the serum C16:1n7/C16:0 ratio with liver histology revealed significant correlation with lobular inflammation score, ballooning score, and fibrosis score. The AUROC for predicting NASH in all NAFLD patients was 0.7097. The AUROC was nearly equivalent even when the study subjects were restricted to patients with a fibrosis score ≤ 2 only (AUROC 0.6917). CONCLUSION: Measuring the serum C16:1n7/C16:0 ratio may be an effective non-invasive method for diagnosing NASH, particularly in its early stages.

[Effect of Japanese Traditional Medicine, Ninjin-Youei-To(TJ-108), on the Quality of Life of Patients with Non-Small Cell Lung Cancer Receiving Outpatient Chemotherapy].

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy, and thus, it is very important to maintain the quality of life(QOL)of these patients. Ninjin-Youei-To(TJ-108), a Japanese traditional medicine, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-108 in patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate factors influencing the QOL of these patients, we administered a QOL questionnaire,"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs"(QOL-ACD)to 15 patients with non-small cell lung cancer. Factors related to the overall QOL scores and other categories indicating"activity","physical condition","psychological condition","social relationship", and"face scale" were analyzed. No significant decrease in each of the evaluated factors was observed in this study.

Efficacy of vonoprazan for 24-week maintenance therapy of patients with healed reflux esophagitis refractory to proton pump inhibitors.

The aim of the present study was to evaluate the efficacy of a potassium-competitive acid blocker (P-CAB), vonoprazan, for the maintenance therapy of healed reflux esophagitis (RE). A total of 60 patients were enrolled in this open-label, single-center, prospective study. All patients were diagnosed with RE with a frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score ≥8 following treatment with standard proton pump inhibitors (PPIs) for a minimum of 8 weeks. Standard PPI treatment was switched to vonoprazan 20 mg once daily for 4 weeks. A total of 52 patients, who had no endoscopic evidence of erosive esophagitis following vonoprazan treatment, received maintenance therapy with vonoprazan 10 mg once daily for 24 weeks. Symptoms were evaluated using the FSSG and Gastrointestinal Symptom Rating Scale (GSRS). Upper gastrointestinal endoscopies were performed following 24 weeks of maintenance therapy. The primary endpoint was to determine the proportion of patients who exhibited maintenance of healed RE refractory to PPIs following 24 weeks of maintenance therapy with vonoprazan 10 mg once daily. Secondary endpoints included evaluation of the proportion of patients with symptomatic non-relapse at 24 weeks. Maintenance therapy with vonoprazan 10 mg once daily prevented relapse of esophageal mucosal breaks in 37/43 (86.0%) patients at 24 weeks. However, the number of patients with symptomatic relapse was 1 (1.9%) and 4 (7.7%) at 4 and 8 weeks, respectively. A total of 4 patients were withdrawn due to loss to follow-up. At the end of the 24-week maintenance period, the symptomatic non-relapse rate for acid reflux-associated and dysmotility symptom FSSG scores were 86.5 and 80.8%, respectively. Furthermore, the symptomatic non-relapse rate for reflux, abdominal pain, indigestion, diarrhea, and constipation GSRS scores at 24 weeks were 86.5, 80.8, 75.0, 71.2 and 76.9%, respectively. No serious adverse events were reported during the study. The mean gastrin level was 1,059 pg/ml. In conclusion, the results of the present study indicate that vonoprazan 10 mg once daily is effective for 24-week maintenance therapy of healed RE refractory to PPIs.

Light alcohol consumption has the potential to suppress hepatocellular injury and liver fibrosis in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The modest consumption of alcohol has been reported to decrease the incidence of fatty liver or prevalence of steatohepatitis. In this study, we investigated the effect of light alcohol consumption on liver function and gene expression in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: The study group was formed of 178 patients diagnosed with non-alcoholic fatty liver disease, subclassified into two groups for analysis based on the daily alcohol consumption: non-alcohol group and light alcohol consumer group (≤20 g of ethanol/day). Clinical characteristics, liver histological features, gene expression, comprehensively analyzed using microarrays (BRB-Array tools), and molecular network were evaluated and compared between the two groups. RESULTS: No significant differences in steatosis or inflammation score were noted among the groups. However, the ballooning and fibrosis scores were significantly lower in the light alcohol consumer group than in the non-alcohol group. Gene expression analysis revealed a marked inhibition of the pathways involved in the immune response in the light alcohol group compared to that in the non-alcohol group. CONCLUSIONS: Light alcohol consumption might suppress activity of non-alcoholic steatohepatitis by reducing gene expression levels involved in the immune response. This inhibition in gene expression was associated with a lowering of liver fibrosis and hepatocellular injury.

Cellular Immune Responses for Squamous Cell Carcinoma Antigen Recognized by T Cells 3 in Patients with Hepatocellular Carcinoma.

BACKGROUND & AIMS: Squamous cell carcinoma antigen recognized by T cells 3 (SART3), a tumor-associated antigen expressed in many cancers, functions in tumor rejection. In this study, we investigated its usefulness as an immunotherapeutic target in hepatocellular carcinoma (HCC). METHODS: The expression of SART3 in hepatoma cell lines and HCC tissues was investigated by immunofluorescence and immunohistochemical analyses. Two peptides derived from SART3 (SART3109 and SART3315) were used for immunological analysis. T-cell responses were investigated by interferon-gamma (IFN-γ) enzyme-linked immunospot and cytotoxic T lymphocyte (CTL) assays using peripheral blood mononuclear cells (PBMCs) in 47 patients, and tumor-infiltrating lymphocytes in 8 of 47 patients with HCC. The safety of immunotherapy using a SART3-derived peptide was investigated by vaccinations of SART3109 in 12 patients with HCC (trial registration: UMIN000005677). RESULTS: The immunofluorescence and immunohistochemical analyses showed that SART3 was expressed in six HCC cell lines, and in HCC tissues including of alpha-fetoprotein-negative individuals. SART3-specific CTLs were generated by stimulating PBMCs with the peptides, and they showed cytotoxicity against HCC cells expressing the protein. Of the 47 HCC patients, 25.5% and 10.6% showed significant responses to SART3109 and SART3315, respectively. The infiltration of SART3109-specific IFN-γ-producing CTLs into the tumor site was confirmed. In the vaccination study, no severe adverse events were observed, and the peptide-specific CTLs were newly induced in four of five patients tested. CONCLUSIONS: SART3 is an immunotherapeutic candidate, and peptides from this antigen may be applied in HCC immunotherapy. TRIAL REGISTRATION: UMIN000005677.

Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and lipid metabolism. Recent studies have suggested that the quality of fat accumulated in the liver is associated with the development of nonalcoholic steatohepatitis (NASH). In this study, we investigated the fatty acid composition in liver tissue and its association with the pathology in NAFLD patients. METHODS: One hundred and three patients diagnosed with NAFLD [simple steatosis (SS): 63, NASH: 40] were examined and their hepatic fatty acids were measured using gas chromatography. In addition, relationships between the composition and composition ratios of various fatty acids and patient backgrounds, laboratory test values, histology of the liver, and expression of fat metabolism-related enzymes were investigated. RESULTS: The C16:1n7 content, the C16:1n7/C16:0 and C18:1n9/C18:0 ratios were increased and the C18:0/C16:0 ratio was decreased in the NASH group. The C18:0/C16:0 and C18:1n9/C18:0 ratios were associated with the steatosis score in liver tissue, and the C16:1n7/C16:0 ratio was associated with the lobular inflammation score. The expressions levels of genes: SCD1, ELOVL6, SREBP1c, FAS and PPARγ were enhanced in the NASH group. In multivariate analysis, the C18:0/C16:0 ratio was the most important factor that was correlated with the steatosis score. In contrast, the C16:1n7/C16:0 ratio was correlated with lobular inflammation. CONCLUSION: The fatty acid composition in liver tissue and expression of genes related to fatty acid metabolism were different between the SS and NASH groups, suggesting that the acceleration of fatty acid metabolism is deeply involved in pathogenesis of NASH.

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial.

AIMS/HYPOTHESIS: The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. METHODS: We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA(1c)) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. RESULTS: Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA1c and was associated with a significant increase in hepatic long-chain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. CONCLUSIONS/INTERPRETATION: Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000005250. FUNDING: The study was funded by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and research grants from MSD.