Efficacy and Safety of Long-Term Administration of Esomeprazole in Japanese Pediatric Patients Aged 1-14 Years with Chronic Gastric Acid-Related Disease.

Purpose: To evaluate prolonged esomeprazole use in Japanese pediatric patients for reflux esophagitis (RE) maintenance therapy and prevention of gastric (GU) and/or duodenal ulcers (DU) while using non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: This multicenter, open-label, parallel-group, phase III study (NCT03553563) included patients who were administered esomeprazole according to body weight (10 mg/day [Groups 1 and 3] and up to 20 mg/day [Groups 2 and 4] for patients weighing 10-20 kg and ≥20 kg, respectively). Efficacy outcomes for Groups 1 and 2 (maintenance therapy for healed RE) and Groups 3 and 4 (prevention of long-term NSAID/LDA use-associated GU/DU) were the presence/absence of RE relapse and GU/DU recurrence, respectively. Results: Esomeprazole as maintenance therapy was associated with a low RE recurrence rate, independent of body weight or dosage. Recurrence rates of RE were 0.0% and 5.3% for Groups 1 and 2, respectively. In patients previously diagnosed with GU and/or DU due to long-term NSAID/LDA use, the recurrence rates of GU/DU during weeks 0-32 were 11.1% and 0.0% in Groups 3 and 4, respectively. Conclusion: Long-term use of 10- or 20-mg, once-daily esomeprazole demonstrated a favorable benefit-risk balance in preventing RE and suppressing recurrence of GU and/or DU secondary to NSAID or LDA therapy in Japanese pediatric patients. No new safety concerns were identified. Esomeprazole may be a viable option for managing RE and preventing GU and DU in Japanese pediatric patients.

Successful Allogeneic Hematopoietic Cell Transplantation for Patients with IL10RA Deficiency in Japan.

BACKGROUND: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. METHODS: We retrospectively analyzed patients with IL10RA deficiency in Japan. RESULTS: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. CONCLUSION: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250).

Current Pediatric Endoscopy Training Situation in the Asia-Pacific Region: A Collaborative Survey by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition Endoscopy Scientific Subcommittee.

Purpose: To date, there is no region-specific guideline for pediatric endoscopy training. This study aimed to illustrate the current status of pediatric endoscopy training in Asia-Pacific region and identify opportunities for improvement. Methods: A cross-sectional survey, using a standardized electronic questionnaire, was conducted among medical schools in the Asia-Pacific region in January 2024. Results: A total of 57 medical centers in 12 countries offering formal Pediatric Gastroenterology training programs participated in this regional survey. More than 75% of the centers had an average case load of <10 cases per week for both diagnostic and therapeutic endoscopies. Only 36% of the study programs employed competency-based outcomes for program development, whereas nearly half (48%) used volume-based curricula. Foreign body retrieval, polypectomy, percutaneous endoscopic gastrostomy, and esophageal variceal hemostasis, that is, sclerotherapy or band ligation (endoscopic variceal sclerotherapy and endoscopic variceal ligation), comprised the top four priorities that the trainees should acquire in the autonomous stage (unconscious) of competence. Regarding the learning environment, only 31.5% provided formal hands-on workshops/simulation training. The direct observation of procedural skills was the most commonly used assessment method. The application of a quality assurance (QA) system in both educational and patient care (Pediatric Endoscopy Quality Improvement Network) aspects was present in only 28% and 17% of the centers, respectively. Conclusion: Compared with Western academic societies, the limited availability of cases remains a major concern. To close this gap, simulation and adult endoscopy training are essential. The implementation of reliable and valid assessment tools and QA systems can lead to significant development in future programs.

Clinical outcomes of endoscopic detachable snare ligation for colonic diverticular hemorrhage: Multicenter cohort study.

OBJECTIVES: The hemostatic mechanism of endoscopic detachable snare ligation (EDSL) for colonic diverticular hemorrhage (CDH) is similar to that of endoscopic band ligation, which is effective and safe. However, because reports on EDSL are scarce, we conducted a two-center cohort study to evaluate its effectiveness. METHODS: This study analyzed 283 patients with CDH treated with EDSL at two Japanese hospitals between July 2015 and November 2021. Patient characteristics and clinical outcomes were retrospectively evaluated. A Kaplan-Meier analysis was performed to evaluate the cumulative probability of rebleeding after EDSL. A Cox proportional hazards regression analysis was performed to compare the effects of complete and incomplete ligation on rebleeding. RESULTS: The initial hemostasis success and early rebleeding rates were 97.9% and 11.0%, respectively. The time to hemostasis after identification of the bleeding site and total procedure time were 9 min and 44 min, respectively. Red blood cell transfusion was required for 32.9% of patients. The median hospital length of stay after EDSL was 5 days. The complete ligation rate of the early rebleeding group was significantly lower than that of the group without early rebleeding (P < 0.01). The 1-year cumulative rebleeding rate with EDSL was 28.2%. Complete ligation was associated with decreased cumulative rebleeding after EDSL (P < 0.01). One patient experienced colonic diverticulitis; however, colonic perforation was not observed. CONCLUSION: Complete ligation is associated with reduced short-term and long-term rebleeding. EDSL could be valuable for CDH because of its low rebleeding rate and the absence of serious adverse events.

Evaluation of Deficient Nutrients in Infants and Toddlers Mainly Taking Amino Acid-Based Elemental Formulas: An Exploratory Study.

INTRODUCTION: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). METHODS: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. RESULTS: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 µg/dL vs. 9.3 µg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 µg/mL vs. 12.0 µg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher's ratio (p < 0.01). CONCLUSION: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Correction: Impact of the Coronavirus Disease 2019 Pandemic on Pediatric Gastrointestinal Endoscopy: A Questionnaire-based Internet Survey of 162 Institutional Experiences in Asia Pacific.

[This corrects the article on p. 291 in vol. 26, PMID: 38025493.].

Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1.

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.

Prognosis of pediatric ulcerative colitis after infliximab failure: A multicenter registry-based cohort study.

BACKGROUND AND AIM: Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC. METHODS: A prospective cohort study of pertinent cases enrolled in the Japanese Pediatric Inflammatory Bowel Disease Registry between 2012 and 2020 was conducted to determine outcomes for pediatric UC patients who received IFX but required its discontinuation during follow-up (IFX failure). RESULTS: Of the 301 pediatric UC patients in the registry, 75 were treated with IFX; in 36 of these, IFX was discontinued during follow-up. Severity of UC at onset and absence of concomitant immunomodulator therapy were significant risk factors for IFX failure (P = 0.005 and P = 0.02, respectively). The cumulative colectomy rate after IFX failure was 41.3% at 1 year and 47.5% at 2 years. Colectomy was significantly more frequent when IFX was discontinued before June 1, 2018, than when IFX was discontinued later (P = 0.013). This difference likely involves availability of additional biologic agents for treatment of UC beginning in mid-2018 (P = 0.005). CONCLUSION: In pediatric UC patients, approximately 50% underwent colectomy during a 2-year interval following IFX failure. Prognosis after IFX failure appeared to improve with availability of new biologic agents and small-molecule drugs in mid-2018.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Impact of the Coronavirus Disease 2019 Pandemic on Pediatric Gastrointestinal Endoscopy: A Questionnaire-based Internet Survey of 162 Institutional Experiences in Asia Pacific.

Purpose: The impact of coronavirus 2019 (COVID-19) on gastrointestinal (GI) endoscopy procedures in adults has been reported, with a drastic reduction in the number of procedures. However, there are no sufficient data regarding the impact on pediatric GI endoscopy. Here, we aimed to report that impact in the Asia-Pacific region. Methods: A questionnaire-based internet survey was conducted from June to November 2021 among pediatric endoscopy institutions in the Asia-Pacific region, with each institution providing a single response. Overall, 25 questions focused on the impact of the number of procedures conducted, the usage of personal protective equipment (PPE), and endoscopy training programs during the pandemic. Results: A total of 162 institutions across 13 countries in the Asia-Pacific region participated in the study, and 133 (82.1%) institutions underwent procedure changes since the emergence of COVID-19. The number of esophagogastroduodenoscopy and ileocolonoscopy procedures decreased in 118/133 (88.7%) and 112/133 (84.2%) institutions, respectively. Endoscopy for patient with positive COVID-19 in an emergency or urgent cases still carried out in 102/162 (62.9%) institutions. Screening of COVID-19 for all patients before endoscopy was done across 110/162 (67.9%) institutions. PPE recommendations varied among institutions. Pediatric gastrointestinal endoscopy training programs were discontinued in 127/162 (78.4%) institutions. Conclusion: This study reports the impact of the COVID-19 pandemic on pediatric gastrointestinal endoscopy in the Asia-Pacific region. There has been a significant reduction in the number of endoscopic procedures and relevant training programs.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Anxiety, Depression, and Quality of Life in Parents of Adolescents with Inflammatory Bowel Disease: A Longitudinal Study.

Purpose: The parents of adolescents with inflammatory bowel disease may experience impaired mental health and quality of life. This longitudinal study aimed to verify whether the mental health and quality of life of the parents of adolescents with inflammatory bowel disease declined when their children had active disease. Methods: Sociodemographic data, parental anxiety, depression, and quality of life were analyzed using validated questionnaires for each variable. After the baseline survey, the second and follow-up surveys were conducted at 3 and 12 months, respectively. The active disease group comprised eight parents whose children had active disease during the baseline and second surveys. The remission group comprised 14 parents whose children remained in remission during both surveys. The improved group comprised nine parents whose children experienced active disease at baseline and remission during the second survey. Parental mental health and quality of life were compared among the groups. Results: Significantly higher levels of anxiety were observed in the active disease group in all surveys (p<0.050). Although depression levels and quality of life did not differ significantly among the three groups, pairing the active disease group with other groups showed some large effect sizes. Conclusion: Parents tended to experience decreased mental health and quality of life when their adolescents experienced active inflammatory bowel disease. Consequently, our hypothesis was partially verified. Therefore, parents need support when their children have active disease; this finding highlights the need for parental support systems.

Anticoagulation against portal vein thrombosis reduces mortality and liver cirrhosis-related complications: A propensity score-matched study.

AIM: Portal vein thrombosis (PVT) is one of the common complications of liver cirrhosis. Although anticoagulation contributes to thrombus resolution and is considered the first-choice treatment, its impact on patients' prognosis is still controversial. This study aimed to clarify the benefit of anticoagulation on mortality, liver function, and the incidence of liver cirrhosis-related complications in cirrhotic PVT patients. METHODS: We conducted a multicenter retrospective review in which we included 78 eligible patients with PVT out of 439. After propensity score matching, 21 cirrhotic PVT patients were included in each one of the untreated control and anticoagulation groups. RESULTS: Overall survival was significantly improved in the anticoagulation group compared with the control group (p = 0.041), along with PVT size reduction (53.3% vs. 108.2%, p = 0.009). At the time of CT follow-up, the anticoagulation group showed a lower ALBI score (p = 0.037) and its prevalence of massive ascites was significantly lower (p = 0.043) compared with the control group. The incidence of overt encephalopathy was also lower in the anticoagulation group (p = 0.041). The cumulative incidence of bleeding events did not differ significantly between the two groups. CONCLUSIONS: Anticoagulation improves the survival of patients with cirrhotic PVT. Preserved liver function and reduced risks of cirrhosis-related complications under the treatment may have contributed to a better prognosis. Given its efficacy and safety, anticoagulation is worth initiating in patients with PVT.

Predictors of Small Bowel Transit Time for Capsule Endoscopy in Children with Inflammatory Bowel Disease.

Purpose: The development of assistive devices has allowed for the performance of capsule endoscopy in children. Anticipating the capsule's transit time could affect the efficacy of the investigation and potentially minimize the fasting period. This study determined the predictors of small bowel transit time for small-bowel capsule endoscopy in children and adolescents with inflammatory bowel disease. Methods: We retrospectively examined children and adolescents with inflammatory bowel disease who underwent capsule endoscopy by the age 18 at a Japanese tertiary care children's hospital. Small bowel transit time predictors were analyzed using multiple regression with explanatory variables. Results: Overall, 92 patients, aged 1-17 years, with inflammatory bowel disease (63 Crohn's disease and 29 ulcerative colitis cases) were examined for factors affecting small bowel transit time. In the simple regression analysis, diagnosis, age, height, weight, serum albumin, general anesthesia, and small intestine lesions were significantly associated with small bowel transit time. In the multiple regression analyses, serum albumin (partial regression coefficient: -58.9, p=0.008), general anesthesia (partial regression coefficient: 127, p<0.001), and small intestine lesions (partial regression coefficient: 30.1, p=0.037) showed significant associations with small bowel transit time. Conclusion: Hypoalbuminemia, the use of general anesthesia for endoscopic delivery of the capsule, and small intestine lesions appeared to be predictors of prolonged small bowel transit time in children and adolescents with inflammatory bowel disease. Expecting the finishing time may improve examination with a fasting period reduction, which benefits both patients and caregivers.

Attenuated Expression of SLCO2A1 Caused by DNA Methylation in Pediatric Inflammatory Bowel Disease.

BACKGROUND: SLCO2A1 encodes a prostaglandin (PG) transporter, and autosomal recessive pathogenic variants of this gene cause chronic enteropathy associated with SLCO2A1. It is unclear whether a heterozygous pathogenic variant of SLCO2A1 has a role in the pathogenesis of other types of inflammatory bowel disease (IBD). In this study, we investigated the possible involvement of a local epigenetic alteration in SLCO2A1 in patients with a heterozygous pathogenic variant. METHODS: We conducted whole-exome sequencing of samples from 2 sisters with suspected monogenic IBD. In addition, we performed bisulfite sequencing using DNA extracted from their small and large intestine samples to explore epigenetic alterations. RESULTS: A heterozygous splicing site variant, SLCO2A1:c.940 + 1G > A, was detected in both patients. To explore the possible involvement of epigenetic alterations, we analyzed protein and messenger RNA expression of SLCO2A1, and observed attenuated SLCO2A1 expression in the inflamed lesions of these patients compared with that in the control individuals. Furthermore, bisulfite sequencing indicated dense methylation in the promoter region of SLCO2A1 only in the inflamed lesions of both patients. The urinary PG metabolite levels in these patients were comparable to those in patients with chronic enteropathy associated with SLCO2A1 and higher than those in the control individuals. We found considerably higher levels of the metabolites in patient 1, who showed more severe symptoms than patient 2. CONCLUSIONS: Local DNA methylation attenuated SLCO2A1 expression, which may evoke local inflammation of the mucosa by the unincorporated PG. These findings may improve our understanding of the epigenetic mechanisms underlying IBD development.

We observed attenuated expression of SLCO2A1 caused by DNA methylation in inflamed lesions of patients with suspected monogenic inflammatory bowel disease. This finding prompted us to understand the important roles of genetic and epigenetic alterations in the development of inflammatory bowel disease.

Development of an action plan for acute food protein-induced enterocolitis syndrome in Japan.

Reports of food protein-induced enterocolitis syndrome (FPIES) in Japan have been increasing. However, the disease itself and the treatment options are poorly understood by both patients and medical professionals. The objective of this study is to develop an action plan for acute FPIES in Japan. We prepared a single-sheet action plan that describes the management of acute FPIES episodes for caregivers on one side and medical professionals on the reverse side. To evaluate the content of the action plan, we distributed a questionnaire to caregivers of patients with FPIES and to physicians who would encounter patients with FPIES. Changes to the FPIES action plan were made based on the feedback from the participants. The Delphi method was utilized to finalize the action plan. The participants of the initial survey found the action plan to be useful but the process for determining severity to be impractical. After discussion, the authors made appropriate improvements. By the Delphi method, consensus was reached on the revised FPIES action plan. In conclusion, this Japanese FPIES action plan was created by physicians from multiple subspecialties and caregivers of patients with FPIES. The action plan may improve the management of acute FPIES reactions in the Japanese community.