Search

Masticatory function is significantly lower in individuals with malocclusion than in those with normal occlusion. Although several studies suggest that masticatory function influences gastrointestinal digestive function, the relationship between malocclusion and gastrointestinal symptoms has not been studied extensively. We hypothesised that insufficient masticatory function would increase the functional burden of the stomach and have some influence on the gastrointestinal system. The purpose of this study was to investigate masticatory function and gastric emptying rate in subjects with malocclusion. Eleven healthy dentate female volunteers and eleven female patients with maloc-clusion underwent a 13C-acetate breath test with a liquid meal. Maximum 13 CO2 exhalation time ( Tmax) was compared statistically between both groups. Masticatory function was assessed by colour-changeable chewing gum. In addition, the frequency scale for the symptoms of gastroeso-phageal reflux disease ( FSSG) and questionnaires on food intake were given to both groups. The mean Tmax of the malocclusion group was significantly longer than that of the normal occlusion group ( P = 0·007). Masticatory performance, measured by colour-changeable gum and questionnaires, was significantly lower in the malocclusion group than in the normal occlusion group ( P = 0·023, P = 0·003). There was no significant difference in the FSSG results between the two groups ( P = 0·262). This study suggested that there was a correlation between malocclusion and gastric emptying function in women. [ABSTRACT FROM AUTHOR]

Background Metabolic syndrome and obesity are known risk factors for gastro-esophageal reflux disease (GERD), especially for erosive esophagitis. Although non-erosive reflux disease (NERD) is probably associated with obesity or other metabolic syndrome, there is little direct evidence to support this assertion. Methods Workers in Keio University who underwent a general health examination between September 2006 and August 2007 were enrolled. Reflux symptom questionnaires were administered and metabolic parameters were obtained. The severity of gastro-esophageal reflux (GER) was scored using a validated scale of videoesophagography. Key Results Two hundred and eighty-three subjects (243 men and 40 women; mean age 49.8 ± 6.9 years) with no radiographic evidence of erosive esophagitis were enrolled. The severity of GER was worse among men than among women, whereas the severity of reflux symptoms was worse among women. The severity of GER was associated with age and serum triglyceride levels in men, and with the serum low-density lipoprotein cholesterol levels in women. The severity of reflux symptoms, however, was not associated with metabolic parameters. There were more women than men with reflux symptoms but without GER (‘presumed’ functional heartburn group), compared with subjects with neither GER nor reflux symptoms. In men, the presence of both reflux symptoms and GER (‘presumed’ NERD group) was associated with the serum triglyceride levels. Conclusions & Inferences While NERD is associated with serum lipid levels, functional heartburn is not. The prevalence of GER was greater among men; conversely, the prevalence of functional heartburn was greater among women. [ABSTRACT FROM AUTHOR]

Abstract: Background/Aim: The Adacolumn selectively depletes granulocytes and monocytes/macrophages, which are thought to be part of the immunopathogenesis of ulcerative colitis. This work aims at evaluating the safety and clinical efficacy of the Adacolumn in patients with ulcerative colitis in large population-based data sets. Methods: The Adacolumn post marketing surveillance in Japan was undertaken on 697 patients in 53 medical institutions over 7 years from 29 October 1999 to 28 October 2006. Clinical efficacy and safety data were provided by patients’ physicians in the participating institutes. Results: Safety was evaluated in all the 697 patients and efficacy in 656 patients. At entry, 92% of the patients were on salicylates, 74% on prednisolone and only 9% on immunomodulators. Approximately 40% of patients had severe ulcerative colitis and over 70% had ulcerative colitis that was refractory to conventional medications. There was no serious adverse events; mild to moderate adverse events were seen in 7.7% of the patients. The overall response (remission or significantly improved) was 77.3%; the remission rate based on clinical activity index was 71.1%, while 17.1% remained unchanged and 5.6% worsened. Patients were subgrouped into severe, moderate and mild ulcerative colitis based on clinical activity index (n =578), the response rates were 63.2%, 65.7% and 80.4%, respectively (P <0.001). Endoscopic assessment of efficacy showed very significant mucosal healing, Matts’ endoscopic index improved from 3.2±0.04 to 2.1±0.7 (n =219, P <0.001); reduction in prednisolone dose (P <0.0001); leucocyte count (n =358, P <0.0001) and C-reactive protein (n =314, P <0.0001). Patients who received ≥6 Adacolumn sessions (n =319) did better than patients who received ≤5 sessions (n =188, P =0.004) and multivariate logistic regression analysis revealed that baseline granulocyte count was the strongest predictor of clinical response to Adacolumn (P =0.0191, odds ratio 1.151). Conclusion: This post marketing surveillance provides the largest ever efficacy and safety data on the Adacolumn therapeutic leucocytapheresis in patients with ulcerative colitis. As a non-pharmacologic treatment for patients with active ulcerative colitis most of whom were refractory to conventional drug therapy, the observed efficacy was very significant. Baseline granulocyte count was convincingly an independent predictor of clinical response. [Copyright &y& Elsevier]

For most patients with liver failure receiving maintenance renal replacement therapy (RRT), treatment with living-donor liver transplantation (LDLT) alone is indicated in Japan. We retrospectively reviewed patients who underwent LDLT while receiving RRT in our hospital. Three of the 5 patients who underwent LDLT while on RRT died during the first year after transplantation. The indications for liver transplantation in patients on RRT require careful examination. [ABSTRACT FROM AUTHOR]

Introduction: Behçet's disease (BD) with intestinal, neurological (NBD), and vascular (VBD) manifestations often leads to poor outcomes. Infliximab is approved for the treatment of intestinal BD, NBD, and VBD in Japan; however, evidence regarding its safety and effectiveness in these patients is limited. We conducted a 2-year post-marketing surveillance to evaluate the safety and effectiveness of infliximab in patients with intestinal BD, NBD, and VBD in Japan., Methods: This 2-year, multicenter, prospective, observational study included all patients with intestinal BD, NBD, or VBD, who had experienced an insufficient response to conventional therapies (e.g., glucocorticoids and immunosuppressants/immunomodulators), and initiated infliximab for the first time at participating medical institutions. The safety endpoints included adverse events and adverse drug reactions (ADRs), and the effectiveness endpoints included global improvement, and for patients with acute NBD, acute attacks., Results: Between October 2015 and August 2018, 255 patients (171 intestinal BD, 49 NBD, and 51 VBD; including 16 with two disease types) were enrolled from 133 medical centers and treated with infliximab. Adverse events, ADRs, and serious ADRs occurred in 100 (39.2%), 72 (28.2%), and 38 (14.9%) patients, respectively; incidences were generally similar across intestinal BD, NBD, and VBD groups. No new safety concerns were identified. At the final evaluation, 68.8% of patients with intestinal BD showed improvement, most patients with chronic progressive NBD and VBD had not worsened (100% and 91.7%, respectively), and 93.3% of patients with acute NBD had no new acute attacks during the observation period., Conclusion: These results confirmed the safety and effectiveness of infliximab in clinical practice in 255 patients with intestinal BD, NBD, and VBD. There were no new safety concerns., (© 2024. The Author(s).)

The excess mortality of coronavirus disease 2019 (COVID-19) solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOCs): Waves 1 to 3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1632 COVID-19-confirmed SOTRs included 1170 kidney, 408 liver, 25 lung, 20 heart, 1 small intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOCs transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1-12.5), 4.0 (1.5-10.6), 3.0 (1.3-6.7), 8.8 (5.3-14.5), and 21.9 (5.5-87.6) for Waves 1 to 3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set., Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model., Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors., Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Purpose: The volume of surgical services has significantly reduced globally due to the coronavirus disease 2019 (COVID-19) pandemic. This study evaluated the level of recovery in terms of the number of operations performed in Japan in 2021, based on nationwide periodic surveillance., Methods: Information on the weekly and annual volumes of 20 representative procedures in 6 surgical subspecialties in 2021 was extracted from the National Clinical Database. Statistical data for 2018 and 2019 (pre-pandemic era) were compared with those for 2020. Data on waves of infection, peak period, and high-prevalence areas (13 of 47 prefectures) were analyzed individually., Results: The volumes of the 10 procedures, including gastrectomy, hepatectomy, valve replacement and valve plasty, coronary artery bypass grafting, infrarenal abdominal aorta replacement, ventricular septal defect closure, lung lobectomy, inguinal hernia repair (age < 16 years old), and appendectomy (age < 16 years old), did not reach 95% of that in the pre-pandemic era. The most striking decline in the surgical volume of these 10 procedures was observed during the peak period of wave 5 in high-prevalence areas., Conclusion: This near-complete enumeration survey identified the polarization of 20 representative procedures in terms of resumption of surgical service after the pandemic., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: The current study was designed to analyze the impact of the COVID-19 pandemic on general thoracic surgeries in Japan., Methods: Changes in surgeries for lung cancer and metastatic lung tumors were evaluated based on National Clinical Database data regarding cancer screening., Results: In 2021, surgeries for primary lung cancer increased by 3.4% compared to 2020, which, given the increase from 2014 to 2019, indicates an overall 11.1% decrease. In contrast, surgeries for metastatic lung tumors in 2021 decreased by 5.8% compared to 2020, which, given the increase from 2014 to 2020, indicates an overall 9.2% decrease. Half of the primary diseases for metastatic lung tumor were cases of colorectal cancer. Low anterior resection procedures in 2020 decreased by 5.5% compared to 2019. Lung and colon cancer screening examinees in 2021 were increased compared to 2020; however, they still showed respective decreases of 11% and 9.0% compared to 2019., Conclusions: Surgeries for primary lung cancer still decreased substantially during the COVID-19 pandemic. The continued stagnation of screening was responsible for this decrease. Surgeries for metastatic lung tumors decreased profoundly, and the decrease in screening for primary tumors was responsible for this reduction. Our findings emphasize the significance of maintaining cancer screening efforts, even during a pandemic., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Objectives: Donor safety is paramount in living donor liver transplantation. However, there remains a risk of postoperative complications for some donors. Here, we provide a comprehensive assessment of donor morbidity by a single team with 17 years of experience at a single center., Materials and Methods: We retrospectively reviewed 453 donor hepatectomies of living donor liver transplants at Kumamoto University from August 2000 to March 2017. Posterior segment graft cases were excluded in this study., Results: The donors were classified by graft type as follows: right lobe (n = 173), left lobe (n = 149), and left lateral segment (n = 131). The overall complication rate was 29.8%, and the severe complication (Clavien-Dindo grade IIIa or higher) rate was 9.1%. The most frequent complication was bile leakage, with an overall incidence of 13.9% and severe incidence of 4.6%. Among the 3 types of graft, there were no significant differences in bile leakage with any Clavien-Dindo grade. However, upper gastrointestinal complications, such as a duodenal ulcer and gastric stasis, were related to left lobe donation., Conclusions: There were no significant differences in the incidence of postoperative donor complications, except upper gastrointestinal complications, among the 3 types of graft.

Background: The coronavirus disease 2019 (COVID-19) pandemic had adversely impacted cancer screening, diagnosis, and treatment. We investigated the change in medical resource, such as the intensive care unit use, and short-term outcomes after esophagectomy during the pandemic., Methods: Data of patients who underwent esophagectomy for esophageal cancer registered in the National Clinical Database (NCD) in Japan from January 2018 to December 2021 were analyzed. The time series change in the number of surgical cases; usage of intensive care unit; incidence of morbidity and mortality; standardized mortality and morbidity ratio (SMR) for 30-days mortality; surgical mortality; and morbidities for pneumonia, sepsis, unplanned intubation, and anastomotic leakage were evaluated., Results: The annual number of patients undergoing esophagectomy remained similar from 2018 to 2021. The negative impact of the pandemic on medical resources was strongly identified in the patients from an epidemic area where there is a higher cumulative number of infections per population as compared to all prefectures. The proportions of patients admitted to the intensive care unit were 91.4%, 93.0%, 91.6%, and 90.5% in 2018, 2019, 2020, and 2021, respectively. Moreover, 93.3%, 94.0%, 92.0%, and 90.9% patients who underwent surgery in an epidemic area were admitted to the intensive care unit in 2018, 2019, 2020, and 2021, respectively. However, the morbidity and mortality rates during the pandemic did not worsen according to the SMR values., Conclusions: Esophagectomy was performed during the pandemic despite limited medical resources by a systematic endeavor of the entire surgical department in Japan, without increasing the incidence rate of worse outcome., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Objective: Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). The objective of this study was to evaluate the long-term cost-effectiveness of tofacitinib versus current biologics, considering combinations of first-line (1L) and second-line (2L) therapies, from a Japanese payer's perspective in patients with moderate-to-severe active UC following an inadequate response to conventional therapy and in those who were naïve to biologics., Methods: A cost-effectiveness analysis was conducted during the time horizon specified in the Markov model, which considers a patient's lifetime as 60 years and an annual discount rate of 2% on costs and effects. The model compared tofacitinib with vedolizumab, infliximab, adalimumab, golimumab, and ustekinumab. The time of active treatment was divided into induction and maintenance phases. Patients not responding to their biologic treatment after induction or during the maintenance phase were switched to a subsequent line of therapy. Treatment response and remission probabilities (for induction and maintenance phases) were obtained through a systematic literature review and a network meta-analysis that employed a multinomial analysis with fixed effects. Patient characteristics were sourced from the OCTAVE Induction trials. Mean utilities associated with UC health states and adverse events (AEs) were obtained from published sources. Direct medical costs related to drug acquisition, administration, surgery, patient management, and AEs were derived from the JMDC database analysis, which corresponded with the medical procedure fees from 2021. The drug prices were adjusted to April 2021. Further validation through all processes by clinical experts in Japan was conducted to fit the costs to real-world practices. Scenario and sensitivity analyses were also performed to confirm the accuracy and robustness of the base-case results., Results: In the base-case, the treatment pattern including 1L tofacitinib was more cost-effective than vedolizumab, infliximab, golimumab, and ustekinumab for 1L therapies in terms of cost per quality-adjusted life year (QALY) gained (based on the Japanese threshold of 5,000,000 yen/QALY [38,023 United States dollars {USD}/QALY]). The base-case results demonstrated that the incremental costs would be reduced for all biologics, and decreases in incremental QALYs were observed for all biologics other than adalimumab. The incremental cost-effectiveness ratio (ICER) was found to be dominant for adalimumab; for the other biologics, it was found to be less costly and less efficacious. The efficiency frontier on the cost-effectiveness plane indicated that tofacitinib-infliximab and infliximab-tofacitinib were more cost-effective than the other treatment patterns. When infliximab-tofacitinib was compared with tofacitinib-infliximab, the ICER was 282,609,856 yen/QALY (2,149,157 USD/QALY) and the net monetary benefit (NMB) was -12,741,342 yen (-96,894 USD) with a threshold of 5,000,000 yen (38,023 USD) in Japan. Therefore, infliximab-tofacitinib was not acceptable by this threshold, and tofacitinib-infliximab was the cost-effective treatment pattern., Conclusion: The current analysis suggests that the treatment pattern including 1L tofacitinib is a cost-effective alternative to the biologics for patients with moderate-to-severe UC from a Japanese payer's perspective., (© 2023. The Author(s).)

Aim: The Japan criteria (Milan criteria + 5-5-500 rule) was established recently to select cirrhotic patients with hepatocellular carcinoma for liver transplantation. We evaluated factors associated with poor prognosis after liver transplantation and investigated whether a further extension of the criteria would be worthwhile., Methods: We retrospectively analyzed 86 patients who underwent liver transplantation for hepatocellular carcinoma at Kumamoto University Hospital since 2004; 69 patients (80.2%) met the Japan criteria (the JC IN group), and 17 patients (19.8%) did not (the JC OUT group)., Results: The 5-year cancer-specific survival rates of the JC IN group (92.2%) were significantly better than that of the JC OUT group (39.2%; P < .001). In univariable analysis, alfa-fetoprotein and des-gamma-carboxy prothrombin were significant independent factors associated with cancer-specific survival rates. According to the receiver operating characteristic curves, the cutoff values of alfa-fetoprotein and des-gamma-carboxy prothrombin that predicted hepatocellular carcinoma recurrence after liver transplantation were 756 ng/mL and 1976 mAU/mL, respectively. The JC OUT group was divided into 2 subgroups according to alfa-fetoprotein and des-gamma-carboxy prothrombin: low risk (alfa-fetoprotein level <756 ng/mL and des-gamma-carboxy prothrombin level <1976 mAU/mL) and high risk (alfa-fetoprotein level ≥756 ng/mL and/or des-gamma-carboxy prothrombin level ≥1976 mAU/mL). The 5-year cancer-specific survival rate in the low-risk group (67.5%) was significantly better than that in the high-risk group (0%; P < .001)., Conclusions: Alfa-fetoprotein levels of <756 ng/mL and des-gamma-carboxy prothrombin levels of <1976 mAU/mL may help identify cirrhotic patients with hepatocellular carcinoma who do not meet the Japan criteria but still benefit from liver transplantation., Competing Interests: DISCLOSURES 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 Inc. All rights reserved.)

Background: Although many transplant programs have been forced to suspend living donor transplants due to the emergence of coronavirus disease (COVID-19), there are relatively few real-time databases to assess center-level transplant activities. We aimed to delineate the actual impact of COVID-19 on living donor transplant programs and the resumption process in Japan., Methods: In a nationwide survey, questionnaires were sent to 32 liver transplant programs that had performed at least more than one case of living donor liver transplantation in 2019 and 132 kidney transplant programs that had performed more than one living donor kidney transplantation in 2018., Results: Thirty-one (96.9%) and 125 (94.7%) liver and kidney transplant programs responded, respectively. In the early pandemic period, 67.7% (21/31) of liver programs and 29.8% (37/125) of kidney programs were able to maintain transplant activities similar to those during the pre-pandemic period. After temporal suspension, 58.1% of kidney programs resumed their transplant activity after the number of local COVID-19 cases peaked. Establishing institutional COVID-19 screening, triage, and therapeutic management protocols was mandatory to resume transplant activity for 64.5% and 67.7% of liver and kidney programs, respectively. In the future wave of COVID-19, 67.7% of liver programs would be affected by institutional COVID-19 intensive care unit-bound patient numbers, and 55.7% of kidney programs would stop if hospital-acquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection spreads., Conclusions: THIS NATIONWIDE SURVEY REVEALED FOR THE FIRST TIME HOW LIVING DONOR LIVER AND KIDNEY: transplant programs changed in response to the COVID-19 pandemic in a country where living donor transplantations are predominant., (© 2022 Wiley Periodicals LLC.)

Background: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome., Methods: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion., Results: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425)., Discussion: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis., (© 2022. The Author(s).)

Background and Purpose: The spread of COVID-19 has restricted the delivery of standard medical care to surgical patients dramatically. Surgical triage is performed by considering the type of disease, its severity, the urgency for surgery, and the condition of the patient, in addition to the scale of infectious outbreaks in the region. The purpose of this study was to evaluate the impact of the COVID-19 pandemic on the number of surgical procedures performed and whether the effects were more prominent during certain periods of widespread infection and in the affected regions., Methods: We selected 20 of the most common procedures from each surgical field and compared the weekly numbers of each operation performed in 2020 with the respective numbers in 2018 and 2019, as recorded in the National Clinical Database (NCD). The surgical status during the COVID-19 pandemic as well as the relationship between surgical volume and the degree of regional infection were analyzed extensively., Results: The rate of decline in surgery was at most 10-15%. Although the numbers of most oncological and cardiovascular procedures decreased in 2020, there was no significant change in the numbers of pancreaticoduodenectomy and aortic replacement procedures performed in the same period., Conclusion: The numbers of most surgical procedures decreased in 2020 as a result of the COVID-19 pandemic; however, the precise impact of surgical triage on decrease in detection of disease warrants further investigation., (© 2021. The Author(s).)

Background and Aim: This study aimed to determine the efficacy and safety of vedolizumab treatment with or without concomitant immunomodulator use in Japanese patients with moderate-to-severe ulcerative colitis., Methods: Among enrolled patients in a phase 3 study conducted in Japan (clinicaltrials.gov, NCT02039505), data from patients allocated to 300-mg intravenous vedolizumab for induction and maintenance phases were used for this exploratory analysis. Efficacy endpoints were clinical response, clinical remission, and mucosal healing at week 10 and clinical remission and mucosal healing at week 60, and disease worsening and treatment failure during the maintenance phase., Results: At week 10, the differences in clinical response, clinical remission, and mucosal healing rates between the subgroups (those with concomitant immunomodulator use minus those without) were 0.7 (95% confidence interval: -14.3, 15.7), 3.3 (95% confidence interval: -8.5, 15.2), and 1.8 (95% confidence interval: -13.0, 16.5), respectively. At week 60, the differences in clinical remission and mucosal healing between the subgroups with and without concomitant immunomodulator use were 26.1 (95% confidence interval: -3.5, 55.6) and 29.9 (95% confidence interval: 1.4, 58.4), respectively. The proportions of patients without treatment failure at day 330 of the maintenance phase were 90.7% with concomitant immunomodulator use and 73.7% without. No marked differences in incidence of infections were observed between subgroups., Conclusions: This study suggested the possibility that concomitant immunomodulator use may be beneficial to maintain the clinical efficacy of vedolizumab., (© 2021 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes., Methods: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTG PBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4 + T lymphocytes with 6-thioguanine (6-TG)., Results: dTG PBMC was significantly higher in NUDT15 variants than in non-variants. dTG PBMC , but not 6-TGN RBC , negatively correlated with peripheral lymphocyte counts (r =  - 0.31 and  - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis., Conclusion: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation., (© 2021. Japanese Society of Gastroenterology.)

Background: Real-world big data studies using health insurance claims databases require extraction algorithms to accurately identify target population and outcome. However, no algorithm for Crohn's disease (CD) has yet been validated. In this study we aim to develop an algorithm for identifying CD using the claims data of the insurance system., Methods: A single-center retrospective study to develop a CD extraction algorithm from insurance claims data was conducted. Patients visiting the Kitasato University Kitasato Institute Hospital between January 2015-February 2019 were enrolled, and data were extracted according to inclusion criteria combining the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis codes with or without prescription or surgical codes. Hundred cases that met each inclusion criterion were randomly sampled and positive predictive values (PPVs) were calculated according to the diagnosis in the medical chart. Of all cases, 20% were reviewed in duplicate, and the inter-observer agreement (Kappa) was also calculated., Results: From the 82,898 enrolled, 255 cases were extracted by diagnosis code alone, 197 by the combination of diagnosis and prescription codes, and 197 by the combination of diagnosis codes and prescription or surgical codes. The PPV for confirmed CD cases was 83% by diagnosis codes alone, but improved to 97% by combining with prescription codes. The inter-observer agreement was 0.9903., Conclusions: Single ICD-code alone was insufficient to define CD; however, the algorithm that combined diagnosis codes with prescription codes indicated a sufficiently high PPV and will enable outcome-based research on CD using the Japanese claims database., Competing Interests: HM has received research grants from Japan Foundation for Applied Enzymology. TK has served as a speaker, a consultant or an advisory board member for Abbvie, Alfresa Pharma, Janssen Pharma, Takeda, Mitsubishi Tanabe Pharma, Pfizer, Mochida, and received research grants from Nippon Kayaku, EA Pharma, Otsuka Holdings, JIMRO, Abbie, Zeria. FT has received research grants from Mitsubishi Tanabe Pharma. TN are employees of JMDC Co. Ltd., holds shares in JMDC Co. Ltd. TaH has served as a speaker, a consultant or an advisory board member for Mitsubishi Tanabe Pharma, AbbVie GK, EA Pharma, Kyorin Pharma, JIMRO, Janssen Pharmaceutical, Mochida Pharmaceutical, Takeda Pharmaceutical, and received research grants from Alfresa Pharma, EA Pharma, Mitsubishi Tanabe Pharma, AbbVie GK, JIMRO, Zeria Pharmaceutical, Daiichi-Sankyo, Kyorin Pharmaceutical, Nippon Kayaku, Astellas Pharma, Takeda Pharmaceutical, Pfizer, Mochida Pharmaceutical. ToH has served as a speaker, a consultant or an advisory board member for Aspen Japan, Abbvie GK, Ferring, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Zeria, and received research grants from Abbvie, EA Pharma, JIMRO, Otsuka Holdings, Zeria, and received scholarship grants from Zeria. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The relationship of bidirectional sharing of information between physicians and patients to patient satisfaction with treatment decision-making for ulcerative colitis (UC) has not been examined. Here, we conducted a web-based survey to evaluate this relationship., Methods: Patients aged ≥ 20 years with UC were recruited from the IBD Patient Panel and Japanese IBD Patient Association. Patients completed our web-based survey between 11 May and 1 June 2020. The main outcomes were patient satisfaction (assessed by the Decision Regret Scale) and patient trust in physicians (assessed by the Trust in Physician Scale)., Results: In this study (n = 457), a structural equation modelling analysis showed that physician-to-patient and patient-to-physician information significantly affected patient satisfaction with treatment decision-making (standardised path coefficient: 0.426 and 0.135, respectively) and patient trust in physicians (0.587 and 0.158, respectively). Notably, physician-to-patient information had a greater impact. For patient satisfaction with treatment decision-making and patient trust in physicians, information on "disease" (indirect effect: 0.342 and 0.471, respectively), "treatment" (0.335 and 0.461, respectively), and "endoscopy" (0.295 and 0.407, respectively) was particularly important, and the level of this information was adequate or almost adequate. Patient-to-physician information on "anxiety and distress" (0.116 and 0.136, respectively), "intention and desire for treatment" (0.113 and 0.132, respectively), and "future expectations of life" (0.104 and 0.121, respectively) were also important for patient satisfaction with treatment decision-making and patient trust in physicians, but these concerns were not adequately communicated., Conclusions: Adequate physician-patient communication, especially physician-to-patient information, enhanced patient satisfaction with treatment decision-making for UC., (© 2021. The Author(s).)

Background and Aim: CT-P13, an infliximab (IFX) biosimilar, was approved for treatment of inflammatory bowel disease. However, no comparison with the originator IFX in this indication has been conducted in Japan where endemic levels of tuberculosis and hepatitis virus infection are not low. We evaluated the safety and efficacy in real-world data of CT-P13 and compared with originator IFX data in Japan., Methods: In a prospective post-marketing surveillance (PMS) study, patients who received CT-P13 in a 28-month period from January 2015 were followed up for 2 years. By conducting Japanese administrative database search (DBS) for the same period of PMS, data of the originator IFX including treatment persistence, tuberculosis incidence, and liver injury were analyzed retrospectively and compared with the corresponding PMS data of CT-P13., Results: CT-P13 persistence in PMS (n = 640) and IFX persistence in DBS (n = 4113) were almost similar between patients who switched from the originator and patients who continued on the originator, and also between the biologics-naïve patient groups. There were no differences in the incidences of tuberculosis and hepatic injury (Tuberculosis: 2 patients [0.31%] with CT-P13, 10 patients [0.24%] with the originator, P = 0.75; Hepatic injury: 18.5% with CT-P13, 15.4% with the originator, P = 0.22). Most of the patients with hepatic injury continued treatment in PMS and DBS at similar rates (80.8% vs 83.6%, P = 0.65)., Conclusion: The results of long-term PMS of CT-P13 compared with external reference data from an administrative database suggested that the biosimilar and its originator were comparably useful in real-world clinical practice., (© 2021 Nippon Kayaku Co., Ltd. Journal of Gastroenterology and Hepatology published by John Wiley & Sons Australia, Ltd and Journal of Gastroenterology and Hepatology Foundation.)

Background: Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab., Methods: We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092., Findings: Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions., Interpretation: Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account., Funding: Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests TK reports personal fees from Alfresa, Covidien, Eli Lilly, Ferring, Janssen, Kyorin, Mochida, Nippon Kyaku, Pfizer, Takeda, Thermo Scientific, AbbVie, Ajinomoto, Asahi Kasei Medical, Astellas, Celltrion, EA Pharma, Mitsubishi Tanabe, Zeria, Eisai, Gilead Sciences, and JIMRO; and grants from AbbVie, EA Pharma, Otsuka, Zeria, Kyorin, Mochida, Thermo Fisher Scientific, Alfresa, Nippon Kyaku, and Asahi Kasei Medical. SM reports grants from Takeda, Mitsubishi Tanabe, and Janssen. SN reports grants and personal fees from Mitsubishi Tanabe, AbbVie, Mochida; grants from EA Pharma, Kyorin, JIMRO, and Zeria; and personal fees from Janssen and Takeda. MN reports lecture fees from Mitsubishi Tanabe. THis reports grants and personal fees from EA Pharma, AbbVie, Pfizer, Mitsubishi Tanabe, JIMRO, Mochida, Kyorin, and Takeda; personal fees from Celgene, Janssen, and Nichi-lko; and grants from Daiichi-Sankyo. HN reports personal fees from AbbVie, Kissei, Kyorin, Mitsubishi Tanabe, Janssen, Takeda, Pfizer, Celgene, EA Pharma, Zeria, Mochida, Nippon Kayaku, and JIMRO; and grants from Hoya Group Pentax Medical, Boehringer Ingelheim, and Bristol Myers Squibb. KW reports grants and personal fees from Mitsubishi Tanabe and personal fees from Nippon Kayaku. TM reports personal fees from EA Pharma, AbbVie, Mitsubishi Tanabe, Takeda, Kyorin, Janssen, Mochida, Zeria, AstraZeneca, and Sekisui Medical; and personal fees and grants from Nippon Kayaku and Pfizer. TA reports personal fees from EA Pharma, Kissei, Mochida, and Mitsubishi Tanabe. YS reports grants and personal fees from AbbVie, Mitsubishi Tanabe, Mochida, and EA Pharma; personal fees from Zeria, Kyorin, and Janssen; and grants from JIMRO, Kissei, and Nippon Kayaku. MW reports grants and personal fees from Mitsubishi Tanabe, Takeda, Zeria, Nippon Kayaku, Mochida, AbbVie, EA Pharma, Pfizer, and Kissei; grants from Miyarisan, JIMRO, and Kyorin; and personal fees from Janssen, Celltrion, Celgene, Eli Lilly, and Gilead Sciences. THib reports personal fees from Aspen, Ferring, Gilead Sciences, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly, Nippon Kayaku, Pfizer, Kisse; and grants and personal fees from AbbVie, Janssen, JIMRO, Takeda, Zeria, Kyorin, Nichi-Iko, Mitsubishi Tanabe, and Mochida; and grants from Otsuka. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Intrahepatic cholangiocarcinoma had been considered a contraindication for liver transplantation because of poorer outcomes. However, incidental intrahepatic cholangiocarcinoma in the explanted liver has been reported because of the difficulty of obtaining an accurate diagnosis in cirrhotic livers on preoperative imaging., Methods: We conducted a nationwide survey to analyze the incidence of incidental intrahepatic cholangiocarcinoma and outcomes after liver transplantation, in Japan., Results: Forty-five of 64 institutions (70%) responded to our initial investigation. Between January 2001 and December 2015, 6627 liver transplantations were performed in these 45 institutions, with 19 cases (0.3%) of incidental intrahepatic cholangiocarcinoma reported from 12 transplant centers. Six cases were diagnosed as hepatocellular carcinoma preoperatively. The 1-, 3-, and 5-year recurrence-free survival rates were 79%, 45%, and 45%, respectively. Tumor recurrence after liver transplantation was found in 10 patients (53%). The 1-, 3-, and 5-year overall survival rates were 79%, 63%, and 46%, respectively., Conclusions: Intrahepatic cholangiocarcinoma at liver transplantation is associated with a high risk of recurrence and poor prognosis, even these tumors are detected incidentally in the explanted liver., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC., Methods: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0., Results: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM., Conclusions: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM., Clinical Trial Registry: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .

Background and Aim: To evaluate the onset of symptomatic response with vedolizumab in patients with moderate-to-severe ulcerative colitis in Japan., Methods: Patients were randomized to receive vedolizumab 300 mg or placebo at Weeks 0, 2, and 6. Mayo subscores were analyzed in patients with baseline stool frequency (SF) ≥1 and rectal bleeding (RB) ≥1. In patients with baseline SF ≥2 and RB ≥1, the proportion who achieved SF ≤1 and RB = 0 was determined., Results: Patients were randomized to vedolizumab (n = 164) or placebo (n = 82). Decrease from baseline in mean SF subscore was greater with vedolizumab versus placebo from Week 2 (-6.6%; 95% confidence interval [CI], -16.2, 3.0), with a greater difference in anti-tumor necrosis factor (TNF)α-naive patients (vedolizumab vs. placebo, -13.2%; 95% CI, -29.7, 3.3). Mean percentage decrease from baseline RB subscore was numerically greater with vedolizumab versus placebo from Week 6 in anti-TNFα-naive patients (-10.7%; 95% CI, -33.0, 11.5). More patients in the anti-TNFα-naive subgroup achieved SF ≤1 and RB = 0 with vedolizumab versus placebo at Week 2 (14.8%; 95% CI, 2.5, 27.0) and Week 6 (20.3%; 95% CI, 4.4, 36.2). Patients with SF ≤1 and RB = 0 at Week 2 had higher clinical response, clinical remission, and mucosal healing rates at Week 10 than those without., Conclusions: Our results indicate that vedolizumab induces a rapid symptomatic response, particularly in anti-TNFα-naive patients, and suggest that early symptomatic improvement predicts treatment response at Week 10 (NCT02039505)., (The Author(s). Published by S. Karger AG, Basel.)

Background and Aim: Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly-onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world-leading aging society., Methods: The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC-related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging., Results: The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = -0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5-6.5) and surgery (OR: 2.7, 95% CI, 0.98-7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99-2.0] and 2.3 [95% CI, 0.8-6.3], respectively)., Conclusion: Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Late-onset acute liver failure due to Wilson's disease (WD-ALF) is rare. A 44-year-old female patient presenting acute hepatic decompensation with extreme coagulopathy was transferred to our hospital for evaluation for liver transplantation (LT). Alveolar hemorrhage and Coombs-negative acute hemolysis occurred during workup. Mechanical ventilation, plasmapheresis, and hemodiafiltration with zinc and chelation were started immediately before placing the patient on the waitlist for deceased donor LT (DDLT), with a tentative diagnosis of WD-ALF using the Leipzig score and quick diagnostic criteria suggested by the Acute Liver Failure Study Group Registry. The peak MELD score was 40, and the revised version of King's score for WD was 13. Serum free copper levels and the patient's overall general condition were stabilized with artificial support systems, although triphasic wave on electroencephalogram and liver atrophy were noted. She successfully underwent emergent DDLT approximately 2 weeks after suffering from acute hemolysis and survived. The genetic tests confirmed mutations at 2 loci in the ATP7B gene and, therefore, the diagnosis of WD. This is the first and oldest patient reported in Japan to present late-onset WD-ALF that was successfully treated with emergent DDLT.

In this unprecedented COVID-19 pandemic, several key issues must be addressed to ensure safe treatment and prevent rapid spread of the virus and a consequential medical crisis. Careful evaluation of a patient's condition is crucial for deciding the triage plan, based on the status of the disease and comorbidities. As functionality of the medical care system is greatly affected by the environmental situation, the treatment may differ according to the medical and infectious disease circumstances of the institution. Importantly, all medical staff must prevent nosocomial COVID-19 by minimizing the effects of aerosol spread and developing diagnostic and surgical procedures. Polymerase chain reaction (PCR) screening for COVID-19 infection, particularly in asymptomatic patients, should be encouraged as these patients are prone to postoperative respiratory failure. In this article, the Japan Surgical Society addresses the general principles of surgical treatment in relation to COVID-19 infection and advocates preventive measures against viral transmission during this unimaginable COVID-19 pandemic.

Background and Aims: Patients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn's disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan., Methods: Patients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population., Results: A total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1)., Conclusions: There is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients., (© European Crohn’s and Colitis Organisation (ECCO) 2019.)

Background: Liver transplantation is the most suitable treatment option available for end-stage liver disease. However, some patients require retransplantation, despite medical advances that have led to improved survival. We aimed to compile a definitive, nationwide resource of liver retransplantation data in Japan, seeking to identify the predictors of patient survival posttransplantation., Methods: Questionnaires were sent to 32 institutions that had conducted 281 retransplantations before 2015., Results: Among the 265 patients included in this study (142 pediatric cases), the average age at primary transplantation was 23 years, and retransplantation was performed after an average of 1468 days. The main indication for retransplantation was graft rejection (95 patients). Living-donor liver transplantation accounted for 94.7% of primary transplantations and 73.2% of retransplantations. Patient survival at 1, 3, or 5 years did not differ by type of transplantation but was better for pediatric (70.8%, 68.3%, and 60.1%, respectively) than for adult (57.2%, 50.4%, and 45.2%, respectively) recipients (P = 0.0003). Small-for-size syndrome, retransplantation within 365 days, and inpatient status at retransplantation were significant predictors of poor survival in pediatric cases. Retransplantation within 365 days and conditions warranting retransplantation were significant predictors of poor survival in adult patients., Conclusions: In Japan, where >70% of retransplantations are performed using living donors, the indications and timing are different from those in previous reports from other countries, while maintaining comparable survival rates. Considering technical challenges, graft failure within 365 days should be thoroughly restricted to justify the use of living donor.

Background: Vedolizumab is a gut-selective humanized antibody that binds the α 4 β 7 integrin. We evaluated efficacy and safety of vedolizumab in Japanese patients with moderate-to-severe Crohn's disease (CD)., Methods: In this Phase 3, double-blind study (NCT02038920), 157 patients were randomized to receive intravenous vedolizumab 300 mg (n = 79) or placebo (n = 78) at Weeks 0, 2, and 6 (induction phase). Patients with CD activity index (CDAI)-70 response at Week 10 were randomized to receive vedolizumab 300 mg (n = 12) or placebo (n = 12) at Week 14, then every 8 weeks until Week 54 (maintenance phase). Primary endpoints were ≥ 100-point reduction in CDAI (CDAI-100 response) at Week 10 for induction, and clinical remission (CR: CDAI ≤ 150) at Week 60 for maintenance., Results: At Week 10, 26.6% of patients who received vedolizumab and 16.7% who received placebo achieved CDAI-100 response (odds ratio [OR] [95% confidence interval (CI)] 1.80 [0.82-3.96]; p = 0.145). At Week 60, 41.7% of vedolizumab-treated patients and 16.7% of placebo-treated patients achieved CR (OR [95% CI] 3.57 [0.53-23.95]; p = 0.178). The incidence of adverse events was similar in both treatment groups in both induction and maintenance phases. In patients without prior anti-TNFα exposure or with inadequate response to anti-TNFα, vedolizumab showed improved outcomes over placebo in the induction phase. Age might be a possible predictive factor of CR for future research., Conclusion: Vedolizumab showed a numerically greater efficacy versus placebo as induction therapy, but the difference was not statistically significant. Vedolizumab also showed a numerically greater efficacy in maintenance therapy, and was well tolerated.

Background: Bloodstream infection (BSI) is a life-threatening complication after living donor liver transplantation (LDLT). We aimed to explore the incidence and predisposing factors of BSI at our institution., Methods: We conducted a retrospective cohort analysis on all consecutive adults with BSI within 6 months after LDLT performed between 2005 and 2016. For antimicrobial prophylaxis, ampicillin/sulbactam, cefotaxime, and micafungin were administered. From 2011, methicillin-resistant Staphylococcus aureus (MRSA) carriers were decolonized using mupirocin ointment and chlorhexidine gluconate soap. Risk factors for BSI were identified by uni- and multivariate logistic regression., Results: Of a total of 106 LDLTs, 42 recipients (40%) suffered BSI. The BSI group demonstrated significantly higher in-hospital mortality rates compared with the non-BSI group (24% vs. 7%, P = .01). We identified MRSA carrier (odds ratio [OR], 19.1; P < .001), ABO incompatibility (OR, 2.9; P = .03), and estimated glomerular filtration rate <30 mL/min/1.73m 2 (OR, 15.8; P = .02) as independent risk factors for BSI. Decolonization treatment for MRSA carriers did not reduce the incidence of all-cause BSI but reduced the frequency of BSI caused by MRSA., Conclusion: To our knowledge, for the first time, MRSA carriers were revealed to be highly vulnerable to BSI after LDLT., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Kasai portoenterostomy (KP) is the primary procedure for biliary atresia (BA). However, due to reports of poor outcomes of KP, primary liver transplantation (LT) is preferred in selected cases. In Japan, primary LT is limited with no study reports details, particularly regarding the indications. We conducted the first nationwide survey to assess the status of primary LT in Japan., Methods: Questionnaires were sent to institutions where procedures other than KP were performed as the initial procedure for BA and registered to the Japan Biliary Atresia Registry. Parameters related to procedure selection were analyzed., Results: Of 2895 patients registered (1989-2013), primary LT (n = 15) or exploratory laparotomy (EL) followed by LT (n = 9) without KP was performed in 24 cases (0.8%). The main reason for primary LT was late diagnosis, and for EL followed by LT, lack of fibrous tissue at the porta hepatis (ο-type). The prognoses of LT without KP was good., Conclusion: Non-KP initial procedures were limited. Clear criteria regarding the timing of diagnosis or patient condition could not be determined. Reasons for not initially selecting KP varied, but late diagnosis was predominant. Further study is needed to create guidelines for the initial treatment of BA patients.

Background: Pediatric ulcerative colitis (UC) is typically more extensive and has a more active disease course than adult UC, and requires early treatment augmentation to achieve and maintain disease remission. The present study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe UC and inadequate response to existing treatment., Methods: This open-label, uncontrolled, multicenter, Phase 3 trial was conducted at 17 centers in Japan between April 2012 and September 2014. Pediatric patients (aged 6-17 years) diagnosed with moderate-to-severe UC received a treatment protocol comprising 5 mg/kg IFX at Weeks 0, 2, and 6, and Clinical Activity Index (CAI)-based responders at Week 8 also received treatment at 8-week intervals at Weeks 14 and 22, with a final evaluation at Week 30., Results: A total of 21 patients were treated in this study. IFX therapy rapidly improved clinical symptoms, and this effect was maintained for up to 30 weeks. Overall CAI-based remission rate was 42.9% and overall Pediatric Ulcerative Colitis Activity Index (PUCAI)-based remission rate was 19.0%. Median partial Mayo score was 6.0 at baseline and 4.0 at Week 30 (overall). Among the eight patients who underwent sigmoidoscopy, Mayo response was achieved at Week 30 (overall) in three patients (37.5%). Trough serum IFX concentrations in Week 8 CAI-based responders were maintained throughout the study period. Adverse events and serious adverse events were observed in 95.2 and 14.3% of patients, respectively., Conclusions: These results support the use of IFX in the treatment of pediatric patients with UC with inadequate response to existing treatment., Trial Registration: ClinicalTrials.gov, registration number: NCT01585155 .

Background: Survival benefit of liver resection for noncolorectal liver metastases (NCRLM) remains to be defined., Methods: This multicenter, retrospective cohort analysis included consecutive patients with NCRLM whose primary tumor and all metastases were treated with curative intent between 2000 and 2013. The primary endpoint was 5-year overall survival. Clinicopathological factors that affected prognoses were identified using multivariate Cox regression analyses and were included in a predictive model., Results: Data for 205 patients were analyzed. The three most common primary tumor sites were stomach (39%), pancreas (13%), and urinary tract (10%), with adenocarcinomas the main pathology (52%). R0 resection was achieved in 85%, and the overall survival at 5 years was 41%. In the multivariate analysis, synchronous liver metastases, R1/2 resection, and adenocarcinomas and other carcinomas (with gastrointestinal stromal tumors, neuroendocrine tumors G1/G2, and sarcomas set as the reference group) were independent negative indicators of overall survival. A predictive model effectively stratified the NCRLM patients into low-, intermediate-, and high-risk groups with overall 5-year survival rates of 63%, 38%, and 21%, respectively (P < 0.001)., Conclusions: Patients who underwent curative resection for metachronous disease and favorable tumor pathology are expected to have better survival in the NCRLM cohort., (© 2019 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs., Methods: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception., Results: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported., Conclusions: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Background: Combining a thiopurine with the human anti-tumour necrosis factor-α monoclonal antibody adalimumab for Crohn's disease [CD] treatment is controversial with regard to efficacy and safety. By conducting a subanalysis of a multicentre, randomised, prospective, open-label trial [the DIAMOND study, UMIN registration number 000005146], we studied the risk of discontinuation of thiopurine in combination with adalimumab., Methods: In the preceding DIAMOND study, we analysed the: [i] timing and reasons for dropout in the monotherapy group and combination group; [ii] risk factors for dropout in the combination group., Results: There was no significant difference in the dropout rate up to Week 52 between the monotherapy group and combination group [p = 0.325]. The main reason for study dropout was active CD in the monotherapy group, whereas it was adverse effects in the combination group [Fisher's exact test, p <0.001]. Kaplan-Meier analyses revealed significantly earlier dropout in the combination group [log-rank test, p = 0.001]. Multivariable analysis revealed low body weight to be a risk for dropout due to adverse effects in the combination group., Conclusions: Combination of azathioprine with adalimumab resulted in dropout in the early stage of the study due to side effects of azathioprine, in comparison with late dropout due to active CD in the adalimumab monotherapy group., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease that mainly affects the colon in young patients. Typical symptoms of UC are bloody diarrhoea and faecal urgency, which disturb the quality of life (QOL) of patients, and intractable UC leads to hospitalisation and colectomy. To improve relevant outcomes such as symptoms, QOL and colectomy, many clinical questions need to be resolved regarding what the ideal lifestyle, psychosocial burden and optimal practice patterns are. In this YOu and Ulcerative colitis: Registry and Social network (YOURS) study, we will investigate the effect of lifestyle, psychosocial factors and practice patterns on patient-reported outcomes (PRO), hospitalisation rate and colectomy rate in Japanese patients with UC., Methods and Analysis: For this prospective cohort study, we recruited 2006 patients from five hospitals (Tokyo and Chiba; May 2018-January 2019). Patients will be able to access their own data and compare them with summarised data from all patients on the website beyond the YOURS study. At baseline, patients will answer a questionnaire regarding lifestyle (diet, exercise, sleep and work), psychosocial factors (stress, depression and social support) and PRO (symptoms and QOL). Information on practice patterns (eg, medications, endoscopy frequency) will be collected from electronic medical records. Gaps between patients' needs and healthcare professionals' practice will be identified. Follow-up surveys will be conducted periodically for approximately 3 years. Research questions suggested by patients and healthcare professionals may be used in subsequent surveys. Results from the YOURS study will demonstrate optimal UC management strategies to improve relevant outcomes.The study was approved by the ethics committees of five investigational sites before starting the study. The results will be submitted to journals.UMIN000031995., Competing Interests: Competing interests: KM has received grants and personal fees from Sekisui Medical, AbbVie and Thermofisher Scientific, grants from Alfresa Pharma Corporation, personal fees from Mitsubishi-Tanabe Pharma, Eisai, Kyorin Pharmaceutical, Asahi Kasei Medical, Mochida Pharmaceutical, Kissei, Kyowa Hakko Kirin, Takeda Pharmaceutical, Covidien, Janssen Pharmaceutical, Pfizer, EA Pharma, Astellas, Zeria Pharmaceutical, Celltrion and JIMRO. JF is an employee of Takeda Pharmaceutical Company Limited and owns restricted stocks of Takeda Pharmaceutical Company Limited and GlaxoSmithKline. TH has received grants and personal fees from AbbVie GK, JIMRO Co., EA Pharma and Zeria Pharmaceutical, grants from Otsuka Pharmaceutical Co., personal fees from Mitsubishi-Tanabe Pharm, Kyorin Pharmaceutical, Janssen, Mochida Pharmaceutical, Takeda Pharmaceutical, Gilead Sciences, Celltrion, Nippon Kayaku, Kissei Pharmaceutical, Miyarisan Pharmaceutical, Ferring Pharmaceutical, Eli Lilly, Pfizer Japan and Nichi-Iko Pharmaceutical. MW has received grants and personal fees from Ajinomoto Pharma Co., Kyorin Pharmaceutical Co., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Eisai Co., Otsuka Pharma Co., Kyowa Hakko Kirin Co., Zeria Pharmaceutical Co., JIMRO Co., Asahi Kasei Kuraray Medical Co., EA Pharma Co., AbbVie GK, Astellas Pharma, Daiichi Sankyo Co., Chugai Pharmaceutical Co., Gilead Sciences, Nippon Kayaku Co., Mochida Pharmaceutical Co., Janssen Pharmaceutical K.K., Celltrion Healthcare Co., Pfizer Japan and Miyarisan Pharmaceutical Co.; grants from Toray Industries, MSD K.K., Bristol-Myers K.K., Taiho Pharmaceutical Co., Ayumi Pharmaceutical Co. and Shionogi & Co. and personal fees from Kissei Pharmaceutical Co., Nichi-Iko Pharmaceutical Co., Celgene and Novartis. TH has received grants and personal fees from Mitsubishi Tanabe Pharma, EA Pharma, AbbVie GK, JIMRO, Zeria, Kyorin Pharmaceutical, Takeda Pharmaceutical, Pfizer Japan and Mochida Pharmaceutical; grants from Asahi Kasei Kuraray Medical, Daiichi-Sankyo, Nippon Kayaku and Astellas; and personal fees from Celgene, Janssen Pharmaceutical and Nichi-Iko Pharmaceutical. SF has received lecture fees from Takeda Pharmaceutical Co., Chugai Pharmaceutical Co., Kyowa Hakko Kirin Co., Daiichi Sankyo Co., Bayer Yakuhin, Otsuka Pharmaceutical Co., Pfizer Japan and MSD K.K., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC)., Methods: Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase., Results: A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period., Conclusions: Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients., Trial Registration: ClinicalTrials.gov: NCT02039505., Competing Interests: Satoshi Motoya has received honoraria from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., and Takeda Pharmaceutical Co. Ltd.; and has received research grants from Pfizer Japan Inc., Janssen Pharmaceutical K.K., and from Takeda Pharmaceutical Co. Ltd. Kenji Watanabe has received honoraria from AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Janssen Pharmaceutical K.K.; has received research grants from EA Pharma Co. Ltd. and Takeda Pharmaceutical Co. Ltd.; has received scholarship grants from Astellas Pharma Inc., EA Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., AbbVie GK, Kyorin Pharmaceutical Co. Ltd. and JIMRO Co. Ltd.; and was a recipient of endowed chairs funded by AbbVie GK, EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, JIMRO Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Asahi Kasei Medical Co. Ltd. and Mochida Pharmaceutical Co. Ltd. Haruhiko Ogata has received honoraria from Takeda Pharmaceutical Co. Ltd.; and has received scholarship grants from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd. and Pfizer Japan Inc. Takanori Kanai has received honoraria Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Miyarisan Pharmaceutical Co. Ltd., AstraZeneca K.K. and Takeda Pharmaceutical Co. Ltd.; has received research grants from EN Otsuka Pharmaceutical Co. Ltd, Miyarisan Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Ezaki Glico Co. Ltd., Otsuka Pharmaceutical Co. Ltd. and Mitsubishi Tanabe Pharma Corporation; has received scholarship grants from AbbVie GK, Mochida Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Yakult Honsha Co. Ltd., Zeria Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Ono Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Eisai Co. Ltd. and JIMRO Co. Ltd.; and was a recipient of endowed chairs funded by Chugai Pharmaceutical Co. Ltd., AbbVie GK, UCB Japan Co. Ltd., Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., JIMRO Co. Ltd. and Mochida Pharmaceutical Co. Ltd. Toshiyuki Matsui has received honoraria from EA Pharma Co. Ltd., Ajinomoto Seiyaku, Abbvie GK, Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd. and Janssen Pharmaceutical K.K.; has received research grants from Takeda Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation and Otsuka Pharmaceutical Co. Ltd.; has received scholarship grants from Abbvie GK, Asahi Kasei Medical Co. Ltd., Astellas Pharma Inc., AstraZeneca K.K., EA Pharma Co. Ltd., Eisai Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co. Ltd. and Mochida Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by AbbVie GK, Asahi Kasei Medical Co. Ltd., Ajinomoto Seiyaku, Inflammatory Bowel Disease Advanced Clinical Treatment endowed chair, Regional/Emergency Medical Management endowed chair (Fukuoka), Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., EA Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Chugai Pharmaceutical Co. Ltd. Yasuo Suzuki has received honoraria from Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd. and Kyorin Pharmaceutical Co. Ltd.; and has received scholarship grants from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd. and Kissei Pharmaceutical Co. Ltd. Mitsuhiro Shikamura, Kenkichi Sugiura, Kazunori Oda, Tetsuharu Hori, and Takahiro Araki are employees of Takeda Pharmaceutical Co. Ltd. Mamoru Watanabe has received honoraria from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Ajinomoto Seiyaku, and Eisai Co. Ltd.; has received research grants from Kaken Pharmaceutical Co. Ltd., Alfresa Pharma Corporation and Eisai Co. Ltd.; has received scholarship grants from EA Pharma Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., MSD K.K., Daiichi Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Mochida Pharmaceutical Co. Ltd., Ayumi Pharmaceutical Corporation, Kissei Pharmaceutical Co. Ltd. and Miyarisan Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by Asahi Kasei Medical Co. Ltd., EA Pharma Co. Ltd., JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., AbbVie GK, Kyowa Hakko Kirin Co. Ltd., MSD K.K., Toray Industries, Inc., Chugai Pharmaceutical Co. Ltd., Gilead Sciences, Inc. and Fujirebio Inc. Toshifumi Hibi has received honoraria from Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, AbbVie GK, Zeria Pharmaceutical Co. Ltd., JIMRO Co. Ltd., EA Pharma Co. Ltd., Janssen Pharmaceutical K.K. and Pfizer Japan Inc.; has received scholarship grants from EA Pharma Co. Ltd., Nippon Kayaku Co. Ltd., Zeria Pharmaceutical Co. Ltd. and Mochida Pharmaceutical Co. Ltd.; and was a recipient of endowed chairs funded by Otsuka Holdings Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd. and EA Pharma Co. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background/aims: The small bowel is affected in more than half of patients with Crohn's disease (CD) at the time of diagnosis, and small bowel involvement has a negative impact on the long-term outcome. Many patients reportedly have active lesions in the small intestine even in patients in clinical remission. This study was performed to compare findings of magnetic resonance enterography (MRE) and ileocolonoscopy., Methods: A single-center retrospective study was conducted in 50 patients (60 imaging series) with CD, for whom MRE was additionally performed during the bowel preparation for subsequent ileocolonoscopy. Endoscopic remission was defined as a Simple Endoscopic Score for CD (SES-CD) of <5. MRE remission was defined as a Magnetic Resonance Index of Activity (MaRIA) score of <50. The time to treatment escalation was assessed by the log-rank test., Results: Importantly, 7 of 29 patients (24.1%) with endoscopic remission had a MaRIA score of ≥50. Both SES-CD and MaRIA correlated with the need for treatment escalation (P = 0.025, P = 0.009, respectively). MRE predicted the need for treatment escalation even in patients with endoscopic remission. Although no correlation was present between SES-CD and MaRIA score in patients with structuring/penetrating disease, or insufficient ileal insertion (<10cm), a high MaRIA score still correlated with the need for treatment escalation in stricturing or penetrating disease (P = 0.0306)., Conclusions: The MaRIA score predicts the need for treatment escalation even in patients with endoscopic remission, indicating that addition of MRE to conventional ileocolonoscopy alone can be a useful, noninvasive tool for monitoring CD especially in stricturing or penetrating disease., Competing Interests: T.H. received lecture fees from AbbVie Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., Janssen, JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Takeda Pharmaceutical, and ZERIA Pharmaceutical Co., Ltd. T.K. received lecture fees from AbbVie Inc., Ajinomoto Pharma, Asahi Kasei Medical, Astellas, Alfresa Pharma, Celltrion, EA Pharma Co., Ltd., Eisai Co., Ltd., Gilead Sciences, Janssen, JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Nippon Kayaku, Mochida Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Co., Ltd., and ZERIA Pharmaceutical Co., Ltd. T.K. received consulting fees from Alfresa Pharma, Covidien, Eli Lilly, Ferring Pharmaceuticals, Janssen, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Thermo Scientific. S.S. received grants from Japanese society for inflammatory bowel disease and Japan foundation for applied enzymology, but none of these grant funds were used for the present study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

Objectives: The prevalence of pediatric Crohn's disease (CD) is increasing in Japan and other countries, and many patients are unresponsive to or do not tolerate current treatment options. This study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe CD and inadequate response to existing treatment., Study Design: This was an open-label, uncontrolled, multicenter Phase 3 study conducted at nine sites in Japan between April 2012 and March 2015. Pediatric patients (aged 6-17 years) with moderate-to-severe CD were treated with IFX 5 mg/kg at Weeks 0, 2, and 6, and at 8-week intervals thereafter until Week 46, with final evaluation at Week 54. IFX dose was increased to 10 mg/kg in patients who showed loss of response to IFX from Week 14 onwards., Results: A total of 14 patients fulfilled eligibility criteria and were treated. Dose-escalation criteria were met by five patients who then received 10 mg/kg IFX. The remaining nine patients continued to receive an IFX dose of 5 mg/kg. IFX rapidly improved clinical symptoms and its effect was maintained for up to 54 weeks. Overall Pediatric Crohn's Disease Activity Index (PCDAI) response rate was 85.7%, and overall PCDAI remission rate was 64.3%. Three out of five patients who increased IFX dose regained PCDAI remission by retrieval of serum IFX concentration. Adverse events and serious adverse events occurred in 100.0% and 14.3% of patients, respectively. There was no substantial difference in the safety profiles of patients taking a constant dose of 5 mg/kg and those taking an increased dose of 10 mg/kg., Conclusions: These findings support the effective use of IFX in the treatment of pediatric patients with CD where other treatments have proven ineffective., Competing Interests: HT received consultancy fees from Mitsubishi Tanabe Pharma Corporation. SM received consultancy fees from AbbVie G.K., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical, Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., speaking fees from AbbVie G.K., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Mochida Pharmaceutical Co., Ltd., and research grants from EA Pharma Co., Ltd. and Pfizer Japan Inc. TM received consultancy fees from AbbVie G.K., EA Pharma Co., Ltd., and Mitsubishi Tanabe Pharma Corporation and research grants from EA Pharma Co., Ltd. and Mitsubishi Tanabe Pharma Corporation. NS, HY, MN, YS, KO, and KK are employees of Mitsubishi Tanabe Pharma Corporation. TH received consultancy fees from AbbVie G.K., EA Pharma Co., Ltd., Eli Lilly Japan K.K., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., lecture fees from AbbVie G.K., Celltrion Healthcare Co., Ltd., EA Pharma Co., Ltd., Ferring Pharmaceuticals Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JIMRO Co., Ltd, Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MIYARISAN Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd., and research grants from AbbVie G.K., EA Pharma Co., Ltd., JIMRO Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd. The other authors have no conflicts of interest. Funding for this research was provided by Mitsubishi Tanabe Pharma Corporation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background & Aims: We previously reported results from a prospective randomized controlled trial comparing the efficacy of adalimumab monotherapy versus combination with azathioprine for patients with Crohn's disease (CD) who were naive to biologics and thiopurines. We performed a subanalysis of data from this study to evaluate factors associated with endoscopic response and mucosal healing in study participants., Methods: We compared simple endoscopic scores for CD between patients with moderate to severe active CD randomly assigned groups that received adalimumab monotherapy (n = 85) or adalimumab in combination with azathioprine (n = 91), from June 2011 to June 2014 in Japan. We evaluated associations of simple endoscopic scores for CD with clinical factors and trough levels of adalimumab. Ultimately, 135 patients at Week 26 and 139 patients at Week 52 from 44 referral sites were analyzed for the present investigation., Results: The odds for endoscopic response were significantly higher in the combination group than in the monotherapy group at Week 26 (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.04-4.32) but not at Week 52 (OR, 1.50; 95% CI, 0.77-2.94). The odds of mucosal healing did not differ significantly between groups at Weeks 26 or 52. Simple endoscopic scores for CD at Week 0 was significantly associated with mucosal healing at Week 26 (OR, 0.80; 95% CI, 0.72-0.90) and at Week 52 (OR, 0.91; 95% CI, 0.84-0.99). Higher adalimumab trough level at Week 26 associated with mucosal healing at Week 52 (OR, 1.34; 95% CI, 1.14-1.58; P for trend = .001) and was significantly higher in patients with endoscopic response than in patients without endoscopic response at Weeks 26 and 52 (P < .001)., Conclusions: In a post hoc analysis of data from a randomized controlled trial of patients with moderate to severe CD, we found that adalimumab in combination with azathioprine increased trough levels of adalimumab. Higher trough levels of adalimumab associated with endoscopic response and mucosal healing at Weeks 26 and 52. UMIN registration No: 000005146., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Extracorporeal leukocytapheresis (LCAP) is effective for inducing remission of ulcerative colitis (UC). This retrospective observational study aimed to evaluate the clinical outcome at 1 year and identify risk factors for relapse of UC after LCAP., Methods: Patients with active UC treated with LCAP between 2010 and 2012 were enrolled from 54 medical facilities in Japan. Clinical data evaluated at 1 year after the last LCAP session included the incidence of relapse, 1-year cumulative relapse-free rate, risk factors for relapse, and history of re-induction treatment following relapse. Relapse was defined by the addition of treatment to induce remission. The primary endpoint was the 1-year cumulative relapse-free rate. Secondary endpoints were risk factors for relapse and outcomes of re-induction treatment after relapse., Results: For 314 patients, the 1-year cumulative relapse-free rate was 63.6%. Following LCAP, a Lichtiger clinical activity index (CAI) of 3 or 4 and high leukocyte count (cut-off value: 7790/mm 3 ) were associated with a greater risk of relapse. Intensive LCAP (≥4 sessions within the first 2 weeks) was associated with favorable long-term outcomes in corticosteroid-refractory patients. The response rate was 85.1% among 30 patients who required re-treatment with LCAP., Conclusions: The majority of patients (>60%) with UC treated with LCAP achieved clinical remission within 1 year and remained relapse-free. A higher Lichtiger CAI and leukocyte count following LCAP were risk factors for relapse. Re-induction therapy with LCAP was effective for relapse of UC.

Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn's disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.

Background: The 52-week safety and efficacy of adalimumab in Japanese patients with moderately to severely active ulcerative colitis were demonstrated in a placebo-controlled phase 2/3 trial. Data from patients who enrolled in the open-label extension study are presented., Methods: Remission and response per the full Mayo score (FMS) and the partial Mayo score (PMS), remission per the Inflammatory Bowel Disease Questionnaire (IBDQ) score, corticosteroid-free remission, and mucosal healing were assessed up to week 196 (week 208 for remission/response per PMS) of adalimumab treatment in patients who received one or more doses of adalimumab with use of a hybrid nonresponder imputation (hNRI) method. Nonresponder imputation was used for missing data up to the latest possible follow-up date for each patient, followed by observed case. Adalimumab trough concentrations were reported from week 52 to week 196 of treatment. Treatment-emergent adverse events were reported for all adalimumab-treated patients., Results: Two hundred sixty-six patients received adalimumab. At week 196 of treatment, remission and response rates per FMS, remission and response rates per PMS, remission rate per IBDQ score, mucosal healing rate, and corticosteroid-free remission rate were 19.2%, 32.2%, 22.5%, 32.5%, 33.1%, 30.5% (hNRI), and 40.5% (17/42; as observed), respectively. Serum adalimumab concentrations remained constant in patients receiving 40 mg every other week but increased in patients who underwent dose escalation. The safety profile was consistent with that in the 52-week study., Conclusions: The efficacy of adalimumab in Japanese patients with moderately to severely active ulcerative colitis was maintained for up to 4 years of treatment. No new safety signals were observed.

Background & Aim: Although inflammatory bowel disease (IBD) patients are at risk for metabolic bone disease, studies analyzing this correlation have identified various risk factors, including disease phenotype, age, sex and steroid therapy. Furthermore, few studies have assessed risk factors for bone loss in Japanese IBD patients. This study analyzed risk factors for metabolic bone disease in Japanese IBD patients., Methods: This cross-sectional study assessed 388 patients with IBD aged 20-50 years, including 232 with ulcerative colitis (UC) and 156 with Crohn's disease (CD). Bone mineral density of the femoral neck, total femur and lumbar spine was quantified by dual-energy X-ray absorptiometry. The blood concentrations of bone metabolism markers were measured. History of smoking and bone fracture, and nutritional intake were assessed using questionnaires., Results: Of the 388 patients with IBD, 78 (20.1%; UC, 17.2%; CD, 24.4%) had osteopenia and 17 (4.4%; UC, 3.4%; CD, 5.8%) had osteoporosis, as assessed by T-score. Bone mineral density of the lumbar vertebrae was lower in males than in females. Multivariate regression analysis showed that risk factors for bone loss in UC patients were male sex, low body mass index (BMI), high steroid dose and disease location. Risk factors for bone loss in CD patients were male sex and low BMI., Conclusion: Among Japanese patients with IBD, male sex and low BMI were associated with increased risk for metabolic bone disease. In addition, Steroid therapy shouldn't be indiscriminate in UC patients. These findings may help identify patients at particularly high risk of metabolic bone disease and may help implement appropriate therapies in a timely manner and improve long-term quality of life., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Behçet's disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçet's disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçet's disease who were refractory to corticosteroid and/or immunomodulator therapies., Methods: The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçet's-related symptoms., Results: Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed., Conclusions: Adalimumab is a potentially effective treatment for intestinal Behçet's disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.