Management of elderly ulcerative colitis in Japan Management of elderly ulcerative colitis in Japan

Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2) Abstract Background The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn’s disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596). Methods Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6 months with ADA (40 mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, “continue” (Con) or “discontinue” (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52 weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety. Results Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group. Conclusion Continuation of thiopurines > 6 months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

Initial- and re-treatment effectiveness of glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C virus-genotype 1/2/3 infections Abstract Background Glecaprevir and pibrentasvir (GLE/PIB) are potent antiviral agents for hepatitis C virus (HCV) pan-genotypic infections; however, their clinical effectiveness and safety remain limited in the real-world. This study aimed to evaluate viral responses and the safety of GLE/PIB for patients with chronic HCV-1/2/3 infections during both initial- (Arm A) and re-treatment (Arm B) with all-oral direct-acting antiviral agents (DAAs). Methods This prospective-observational cohort study included Japanese patients with chronic HCV-1/2/3 infections (n = 271: 183 in Arm A and 83 in Arm B), who had started receiving GLE/PIB. Primary end point was a sustained virological response (SVR) rate at week 12 (SVR12) after the end of GLE/PIB treatment (EOT). Results SVR12 was achieved by 99.4% of patients (180/181: modified intention-to-treat (mITT) analysis excluding 2 patients lost to follow-up) in Arm A. One patient with an HCV-3b infection who discontinued at week 8 failed to achieve SVR12. SVR12 was achieved by 97.7% of patients (85/87: mITT excluding 1 patient lost to follow-up) in Arm B. Virological relapse occurred in 2 patients with HCV-1b, presenting common 5 loci of resistance-associated substitutions (RASs) including A92 RASs in the NS5A lesion at baseline. Any adverse events (AEs) (grade ≥ 3) occurred in 8 patients (3.0%). 8 patients (3.0%) discontinued due to AEs, however, all of them achieved SVR12. Conclusions Initial and re-treatment with GLE/PIB are effective and safe for Japanese patients with HCV-1/2/3 in real-life settings. Further studies are required to elucidate the mechanism underlying treatment failures of GLE/PIB to completely eradicate HCV worldwide.

Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations Abstract This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.

Preceding endoscopic submucosal dissection for T1 colorectal carcinoma does not affect the prognosis of patients who underwent additional surgery: a large multicenter propensity score-matched analysis Abstract Background We analyzed the influence of preceding endoscopic submucosal dissection (ESD) on the prognosis of patients with T1 colorectal carcinoma (CRC) after additional surgery using propensity-score matching. Methods 1638 consecutive patients with T1 CRC were retrospectively identified between January 1998 and December 2016 at the Hiroshima GI Endoscopy Research Group. We assessed 602 patients with 602 T1 CRC who underwent additional surgery after ESD (n = 216) or surgery alone (n = 386). The enrolled patients were treated according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016, and were defined as non-endoscopically curable (non-e-curable) when they did not satisfy its curative criteria. We analyzed the pathological characteristics and the prognosis of non-e-curable patients using propensity-score matching between the additional surgery after ESD and surgery alone groups. Results There were no cases of recurrence and lymph node metastasis among the e-curable patients. The rate of lymph node metastasis and recurrences in the non-e-curable patients were 10.8% and 2.6%, respectively. After propensity-score matching, there were no significant differences in the 5-year overall survival rates (96.9% vs. 92.0%), 5-year disease-free survival rates (96.7% vs. 96.7%) and 5-year disease-specific survival rates (100% vs. 98.6%) after treatment of T1 CRCs between the 2 groups in non-e-curable patients. Conclusions Preceding ESD with histological en bloc resection for patients with T1 CRC did not affect their oncologic behavior adversely after additional surgery.

Impact of the Charlson Comorbidity Index on the treatment strategy and survival in elderly patients after non-curative endoscopic submucosal dissection for esophageal squamous cell carcinoma: a multicenter retrospective study Abstract Background In elderly patients with superficial esophageal squamous cell carcinoma (ESCC), the optimal treatment strategy after non-curative endoscopic submucosal dissection (ESD) remains unclear. We aimed to evaluate the validity of additional treatments after non-curative ESD and post-ESD survival predictors in elderly patients with ESCC. Methods Elderly patients (age > 75 years) treated with ESD for ESCC between January 2010 and July 2014 at six tertiary referral hospitals in Japan were retrospectively investigated and stratified according to lymph node metastasis risk, based on histological findings (high-risk factors: positive lymphovascular invasion, submucosal invasion, and positive/indeterminate vertical margin) and post-ESD treatment strategy: group A (287 patients; low risk), group B (41 patients; high risk, without additional treatment), and group C (32 patients; high risk, with additional treatment). We evaluated 3- and 5-year overall survival and disease-specific survival, and prognostic factors for post-ESD survival. Results At a median follow-up of 38, 40, and 49 months, respectively, there was 1 esophageal cancer-related death in group A, 1 in group B, and none in group C, whereas 22, 9, and 3 patients in groups A, B, and C died of other diseases. The groups differed significantly in overall survival (92.4%; 87.6%; 93.4%, p = 0.022), although not in disease-specific survival (99.4%; 96.3%; 100%, p = 0.217). On multivariate analysis, Charlson Comorbidity Index (CCI) ≥ 2 was the only independent risk factor for post-ESD death (hazard ratio 7.92; 95% confidence interval 3.42–18.3; p < 0.001). Conclusions A follow-up strategy without additional treatment after ESD for ESCC may be acceptable in high-risk elderly patients, especially for CCI ≥ 2.

Prospective study of early chronic pancreatitis diagnosed based on the Japanese diagnostic criteria Abstract Background Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas. Early diagnosis and intervention, before CP becomes established and irreversible, are essential to improve the long-term outcomes. The world’s first diagnostic criteria for early CP were proposed in Japan in 2009, but their clinical utility remains elusive. This study aimed to clarify whether patients with early CP progress to definite CP. Methods This is a multicenter, prospective study. Patients diagnosed as having early CP according to the Japanese diagnostic criteria were prospectively followed for 2 years. Clinical profiles including symptoms, drinking and smoking status, laboratory data, imaging findings and treatments were analyzed. Results Among the 83 patients who completed the 2-year follow-up period, four (4.8%) patients progressed to definite CP. The diagnosis of 48 (57.8%) patients was unchanged, and that of 31 (37.3%) patients was downgraded. All the four progressive patients were male, alcohol-related, smokers (3 current and 1 ever), and continued drinking. Comparison of the clinical profiles between the progression group (n = 4) and non-progression group (n = 79) revealed that etiology (alcohol-related), smoking status and presence of acute pancreatitis episodes were associated with the progression to definite CP. Conclusions The Japanese diagnostic criteria could identify some patients before the progression to definite CP, while the majority of the patients did not progress. Trial registration number: UMIN000015992.

Sarcopenia in cirrhosis: from pathogenesis to interventions Abstract Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation. The pathogenesis of sarcopenia is multifactorial and results from an imbalance between protein synthesis and breakdown. Nutritional, metabolic, and biochemical abnormalities seen in chronic liver disease alter whole body protein homeostasis. Hyperammonemia, increased autophagy, proteasomal activity, lower protein synthesis, and impaired mitochondrial function play an important role in muscle depletion in cirrhosis. Factors including cellular energy status, availability of metabolic substrates (e.g., branched-chain amino acids), alterations in the endocrine system (insulin resistance, circulating levels of insulin, insulin-like growth factor-1, corticosteroids, and testosterone), cytokines, myostatin, and exercise are involved in regulating muscle mass. A favored atrophy of type II fast-twitch glycolytic fibers seems to occur in patients with cirrhosis and sarcopenia. Identification of muscle biological abnormalities and underlying mechanisms is required to plan clinical trials to reverse sarcopenia through modulation of specific mechanisms. Accordingly, a combination of nutritional, physical, and pharmacological interventions might be necessary to reverse sarcopenia in cirrhosis. Moderate exercise should be combined with appropriate energy and protein intake, in accordance with clinical guidelines. Interventions with branched chain amino acids, testosterone, carnitine, or ammonia-lowering therapies should be considered individually. Various factors such as dose, type, duration of supplementations, etiology of cirrhosis, amount of dietary protein intake, and compliance with supplementation and exercise should be the focus of future large randomized controlled trials investigating both prevention and treatment of sarcopenia in this patient population.

Dose–response relationship between cigarette smoking and risk of ulcerative colitis: a nationwide population-based study Abstract Background Former cigarette smokers are at risk of developing ulcerative colitis (UC). However, the impact of smoking behavior on the occurrence of UC according to the amount smoked remains elusive. We aimed to determine the relationship between smoking behavior and the risk of UC development. Methods We conducted a retrospective population-based cohort study using the National Health Insurance Service database in South Korea. From January 2009 to December 2012, 23,235,771 individuals over 18 years of age who underwent a national health examination were enrolled and followed until 2016. All study participants were divided into the following 3 groups: nonsmokers, former smokers, and current smokers. The primary endpoint was newly developed UC. Results Compared with nonsmokers, the risk of UC development was significantly higher in former smokers [adjusted hazard ratio (aHR) 1.83; 95% confidence interval (CI) 1.73–1.95] but significantly lower in current smokers (aHR 0.92; 95% CI 0.87–0.98). Among current smokers, individuals who stopped smoking after the baseline evaluation had a significantly higher risk of UC development than those who continued to smoke (aHR 2.42; 95% CI 2.10–2.80). The risk of UC development among former smokers was significantly associated with smoking amount and duration. Among current smokers, however, the risk of UC development was not correlated with the cumulative lifetime smoking exposure. The preventive effect of current smoking on UC development was observed only in men (aHR 0.90; 95% CI 0.84–0.96). Conclusions Compared with nonsmokers, former smokers have a significantly higher risk of UC development that may be proportional to the cumulative smoking exposure.

Genomic landscape of epithelium with low-grade atypia on gastric cancer after Helicobacter pylori eradiation therapy Abstract Background Gastric cancer may develop after successful eradication of Helicobacter pylori, although the incidence is lower than in non-eradicated individuals. We previously reported the appearance of characteristic epithelium with low-grade atypia (ELA) on the surface of gastric cancer after H. pylori eradication. However, whether ELA originates from cancer after re-differentiation or from the non-cancerous surrounding mucosa is unknown. Methods We isolated ELA regions from 10 early gastric cancer patients and analyzed the nucleotide sequences for 90 oncogenes and 35 fusion oncogenes, comparing them with counterpart cancer tissue, normal gastric mucosa, and blood cell-derived DNA. Somatic mutations in each tissue were identified by comparing them with the sequences from whole blood-derived DNA. Result Gene alterations were observed in nine of the ten patients, and up to 42 and 70 somatic mutations were seen in cancer and ELA samples, respectively. Common mutations shared between cancer and ELA tissues were found in eight of these nine patients. In contrast, common mutations between non-cancer mucosa and ELA were only detected in one patient, who also had common mutation between cancer and ELA. ELA-specific nucleotide substitutions were seen in seven patients. In contrast, cancer-specific substitutions were only found in two patients. 18 out of 19 amino acid substitutions present in cancer tissue were also identified in ELA. These results suggest that ELA originated from cancer tissue and accumulated further nucleotide substitutions. Conclusions Differential diagnosis of ELA and normal mucosa should be carefully performed to prevent misdiagnosis of ELA as normal mucosa with atypia.