Japanese Pediatric Patients Research Articles

Establishment of Reference Values for Estimated Kidney Volume Using Ultrasonography in Japanese Pediatric Patients

Establishment of Reference Values for Estimated Kidney Volume Using Ultrasonography in Japanese Pediatric Patients

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

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). 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. 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. 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.

Is initial unilateral revascularization acceptable in pediatric patients with bilateral moyamoya disease with mild contralateral hemodynamic disturbance?

Although asymmetrical vascular involvement between hemispheres is common in pediatric patients with bilateral moyamoya disease, whether hemispheres with mild vascular changes and hemodynamic impairment require immediate surgical revascularization or whether they can be observed until disease progression remains unclear. The authors evaluated the long-term outcomes of their strategy to initially perform unilateral surgery and withhold surgery to the contralateral hemispheres with mild vascular changes and hemodynamic impairment. The authors retrospectively evaluated Japanese pediatric patients (onset age ≤ 15 years) diagnosed with bilateral sporadic moyamoya disease who underwent unilateral revascularization. The authors investigated whether the patient underwent additional collateral surgery and the incidence of ischemic events during follow-up. They also compared visual assessments of arterial spin labeling (ASL) images obtained before initial surgery, before additional contralateral surgery, and at last follow-up. Overall, 30/47 patients (63.8%) experienced progression of hemodynamic impairment in the contralateral hemisphere and underwent additional surgery. The age at initial surgery of the patients who needed additional contralateral surgery was significantly younger than that of the patients who did not require contralateral surgery (mean [SD] 7.0 [3.0] years vs 9.8 [2.6] years, p = 0.002). One patient (age 4 years) developed ischemic stroke before admission for preoperative evaluation 2 months after novel symptom onset, and another patient (age 6 years) experienced ischemic stroke in the contralateral hemisphere while discontinuing antiplatelet agents before surgery; both patients fully recovered from the neurological deficits. In contralateral hemispheres that required additional surgery, the ASL visual assessment scores significantly decreased before the additional contralateral surgery compared to those obtained before the initial surgery (p = 0.008). In pediatric patients with bilateral moyamoya disease, withholding surgery for hemispheres with mild vascular changes and hemodynamic impairment is generally safe. Younger patients were more likely to experience contralateral progression and require additional surgery, so close follow-up is needed. ASL imaging is useful for detecting and following the progression of hemodynamic impairment in conservatively treated hemispheres.

A multicohort platform trial to improve drug access for pediatric cancer patients in Japan: The PARTNER trial (NCCH2220).

TPS10079 Background: In Japan, there are no pediatric regulations that encourage drug development for pediatric cancer, such as Pediatric Investigation Plans (PIPs) which are mandated in Europe, or the RACE Act in the U.S. Therefore, there are fewer early-phase clinical trials and approved drugs for pediatric cancer than in Western countries. In addition, because there is no rapid compassionate use program, there are delays when using an unapproved drug. According to a report from the Japanese cancer genome profiling (CGP) testing data center, C-CAT, 51.3% of pediatric patients with solid tumors had targetable genetic abnormalities. However, only 5.8% of them had access to the recommended molecular targeted therapy (Tanimura K. et al., presented at the Japanese Society of Pediatric Hematology and Oncology annual meeting 2022). Thus, Japanese pediatric patients with relapsed or refractory solid tumors have limited access to novel drugs, even if they have druggable mutations. Therefore, we designed a platform study (NCCH2220, PARTNER trial) to rapidly deliver molecularly targeted drugs based on CGP testing. Methods: This study has two objectives: first, to administer some drugs to pediatric patients that are not approved for pediatric cancer in Japan. These drugs have been shown to be safe in pediatric patients in foreign countries and are expected to be effective. Second, to evaluate the safety and efficacy of the drug in Japanese pediatric patients and, if necessary, its pharmacokinetics. These data will be used for potential future regulatory filings. This is an open-label, multicenter, multicohort study. Eligible patients are aged 0–29 years with diseases having no standard therapy, which are refractory, or when there is intolerance to standard therapy. The study drug must be recommended for the patient by CGP testing or approved for pediatric use for their disease in the U.S. or Europe, or approved in Japan for use in adults only. The drugs are used as monotherapy in the study. The study schedules follow a master protocol. Up to 30 patients can be enrolled in each cohort. The primary endpoint is the incidence of dose-limiting toxicity in each cohort. The secondary endpoints are the incidence of adverse events, the overall response rate, and, if necessary, the pharmacokinetics in each cohort. As of January 2024, the study had five treatment cohorts with the following agents: imatinib, pazopanib, ruxolitinib, trametinib, and atezolizumab. Additional cohorts will be added. We started planning the study in November 2022, and enrollment began on January 18, 2024. This platform trial has enabled us to deliver drugs to patients more quickly and efficiently than by conducting individual early-phase trials for each drug. Clinical trial information: jRCTs031230544 .

Population Pharmacokinetic Analysis of Selumetinib and Its N-desmethyl Metabolite in Japanese and Non-Japanese Pediatric Patients with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Background. Selumetinib, a mitogen-activated protein kinase kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at a body surface area (BSA)-based dose of 25 mg/m2 twice daily. The objective of this population pharmacokinetic analysis was to evaluate ethnic sensitivity in the pharmacokinetics of selumetinib and N-desmethyl selumetinib between Japanese and non-Japanese pediatric patients. Methods. This population pharmacokinetic analysis was based on data from 80 pediatric patients enrolled in two clinical trials, one conducted in Japan and one conducted in the United States, comprising 12 Japanese participants and 68 non-Japanese participants. Both clinical trials used BSA-based dosing schemes. A two-compartment model with first-order elimination and sequential zero-order and first-order delayed absorption for selumetinib, combined with a one-compartment model with first-order elimination for N-desmethyl selumetinib, was used for this analysis. Ethnic sensitivity in pharmacokinetics was evaluated by covariate modeling and comparison of model-predicted exposures. Results. Covariate modeling showed that BSA had a clinically relevant impact on the pharmacokinetics of selumetinib. None of the other investigated covariates, such as race, had a significant impact. The predicted exposure in Japanese and non-Japanese patients showed a considerably overlapping distribution, and no clinically relevant difference in exposure was apparent. Conclusions. These findings support the use of the same BSA-based dosing regimen for Japanese and non-Japanese pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. Subsequent to this analysis, selumetinib was approved at the BSA-based dose of 25 mg/m2 in Japan, which is consistent with the recommended dosage and administration in other regions and countries. This analysis used data from trial registered with NCT04495127, and NCT01362803.

Efficacy and safety of dupilumab with concomitant topical corticosteroids in Japanese pediatric patients with moderate-to-severe atopic dermatitis: A randomized, double-blind, placebo-controlled phase 3 study

BackgroundWe investigated the efficacy and safety of dupilumab in Japanese patients aged ≥6 months to <18 years old with moderate-to-severe atopic dermatitis not adequately controlled with existing therapies. MethodsIn this randomized, double-blind, phase 3 study, patients received dupilumab (n = 30) or placebo (n = 32) with concomitant topical corticosteroids for 16 weeks, then all patients received dupilumab from 16 to 52 weeks. The primary endpoint was the proportion of patients with ≥75% improvement in Eczema Area and Severity Index (EASI) score from baseline (EASI-75) to Week 16. Key secondary endpoints included changes in EASI score, proportion of patients with investigator global assessment (IGA) scores of 0/1, and changes in worst daily itch numerical rating scale (NRS) scores (evaluated in patients aged ≥6 to <12 years [n = 35]). ResultsAt Week 16, more patients achieved EASI-75 with dupilumab than placebo (43.3% vs 18.8%; P = 0.0304), and the least squares mean (LSM) difference in percent change in EASI scores at Week 16 of dupilumab vs placebo was –39.4% (P = 0.0003). However, no significant difference in the proportion of patients achieving IGA scores of 0/1 at Week 16 with dupilumab versus placebo were seen (10.0% vs 9.4%; P = 0.8476). The percent change in worst daily itch NRS scores at Week 16 was higher with dupilumab (LSM difference: –33.3%; nominal P = 0.0117). Dupilumab was well tolerated; no new safety signals were identified. ConclusionsDupilumab showed consistent efficacy and was well tolerated in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis previously insufficiently controlled with existing therapies.

Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children

BackgroundMembranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses.MethodsIn this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients.ResultsOut of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5–8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up.ConclusionsMost patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Early diagnosis and treatments in childhood are associated with better prognosis in patients with familial hypercholesterolemia

Abstract Objective The early diagnosis and treatment initiation for children with familial hypercholesterolemia (FH) has been recommended in guidelines. However, there is limited data on the impact of early treatments on the prognosis of children with FH. To investigate if the early initiation of lipid-lowering therapies among Japanese pediatric patients with FH reduced the occurrence of cardiovascular disease (CVD) events in them. Methods We retrospectively investigated the occurrence of CVD events (myocardial infarction, unstable angina, or coronary artery revascularization) in patients with FH (N = 1050, male/female = 490/560), including 106 children below 20 years. We compared a variety of phenotypes, including genetic backgrounds, other complications, LDL cholesterol, medical therapies, and their prognoses between the patients’ diagnoses before the age of 20 years (children, mean age = 15 years) and after that age (adults, mean age = 52 years). Overall, 290 patients (27.6%) had a history of prior CVD events. Results The median follow-up duration was 12.6 [9.5–17.9] years. The baseline LDL cholesterol level, 239 mg/dL, dropped to 112 mg/dL with the treatments. The Achilles tendon thickness was significantly lower in children than that of adults (7.2 vs. 8.9 mm, P &amp;lt; 0.001). Over the follow-up duration, 119 CVD events were observed. Importantly, no CVD event was observed in children despite their median LDL cholesterol level at follow-up being significantly higher than that of adults (122 vs. 111 mg/dL, P &amp;lt; 0.001). Conclusion The likelihood of CVD events in those with FH diagnosed and treated in childhood is low.

Incidence of neurocutaneous melanosis in Japanese pediatric patients with congenital melanocytic nevi

Neurocutaneous melanosis (NCM) is a rare, non-hereditary neurocutaneous disorder characterized by excessive melanocytic proliferation in the skin and central nervous system. As no major studies have covered the incidence of NCM among Japanese patients with congenital melanocytic nevi (CMN), we prospectively investigated the incidence of NCM among Japanese patients who underwent initial treatment for CMN. The relationship of CMN and NCM was also investigated. Japanese pediatric patients with CMN under 1 year of age were included between January 2020 and November 2022, and all patients underwent brain MRI to check for NCM in this study. NCM lesions were most frequently seen in the amygdala, followed by the cerebellum, brainstem, and cerebral hemispheres. NCM was diagnosed on brain MRI in 31.6% of the 38 patients with CMN and in 25.0% of patients with no prior examination or treatment. Distribution and size of CMN, number of satellite nevi, rugosity and nodules were strongly associated with the existence of NCM, and these findings may guide a future registry study with a large cohort of CMN patients.

Validation of the Conventional Trauma and Injury Severity Score and a Newly Developed Survival Predictive Model in Pediatric Patients with Blunt Trauma: A Nationwide Observation Study.

To date, there is no clinically useful prediction model that is suitable for Japanese pediatric trauma patients. Herein, this study aimed to developed a model for predicting the survival of Japanese pediatric patients with blunt trauma and compare its validity with that of the conventional TRISS model. Patients registered in the Japan Trauma Data Bank were grouped into a derivation cohort (2009-2013) and validation cohort (2014-2018). Logistic regression analysis was performed using the derivation dataset to establish prediction models using age, injury severity, and physiology. The validity of the modified model was evaluated by the area under the receiver operating characteristic curve (AUC). Among 11 predictor models, Model 1 and Model 11 had the best performance (AUC = 0.980). The AUC of all models was lower in patients with survival probability Ps < 0.5 than in patients with Ps ≥ 0.5. The AUC of all models was lower in neonates/infants than in other age categories. Model 11 also had the best performance (AUC = 0.762 and 0.909, respectively) in patients with Ps < 0.5 and neonates/infants. The predictive ability of the newly modified models was not superior to that of the current TRISS model. Our results may be useful to develop a highly accurate prediction model based on the new predictive variables and cutoff values associated with the survival mortality of injured Japanese pediatric patients who are younger and more severely injured by using a nationwide dataset with fewer missing data and added valuables, which can be used to evaluate the age-related physiological and anatomical severity of injured patients.

The disease burden of pediatric patients with atopic dermatitis in Japan.

Atopic dermatitis (AD) is a chronic skin condition that is associated with significant patient burden and decreased health-related quality of life (HRQoL). We report results of the real-world Epidemiology of Children with Atopic Dermatitis Reporting on their Experience study in Japanese pediatric patients, focusing on the impact of AD severity on disease burden. Children and adolescents aged 6 months to 17 years (or their caregivers/parents) completed an online survey between September 26, 2018, and March 5, 2019. Patients with diagnosed AD (i.e., met International Study of Asthma and Allergies in Childhood criteria and had a self-reported AD diagnosis) were evaluated for disease severity using the Patient-Oriented Eczema Measure (POEM). Impact of AD severity on AD symptoms (itching, pain, and sleep disturbance), disease flares, atopic comorbidities, healthcare resource utilization, school days missed, and HRQoL were assessed. Of 5702 Japanese pediatric patients, 547 had diagnosed AD and were included in this analysis. Based on POEM scores, AD severity was clear/mild in 346 patients (63.3%), moderate in 177 (32.5%), and severe in 24 (4.4%). Across all age groups (i.e., less than 6, 6-11, and 12-17 years), increased AD severity was associated with increased AD symptom severity, number of flares, atopic comorbidities, healthcare resource utilization, and school absences, as well as worsened HRQoL. This population-based study of Japanese children and adolescents showed that greater AD severity had a high impact on disease burden.

Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open-label study.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

1465-P: Identification of GCK Gene Variants and Clinical Characterization in Japanese Pediatric MODY2 Cases

Maturity-onset diabetes of the young (MODY) is traditionally characterized by early onset and a heterogeneous autosomal dominant form of inheritance. MODY2 may be common in the Japanese, but the difference in clinical characteristics compared to Europeans and Americans remains unclear. Here, we examined the characteristics in Japanese pediatric patients diagnosed with MODY2. We retrospectively reviewed the diagnostic data of Japanese MODY2 patients diagnosed at our hospital between 2009 and 2022. Genetic screening for MODY2 was performed by direct sequencing followed by multiplex ligation amplification assays. We identified 20 missense mutations in 25 patients and 2 nonsense mutations in 2 patients. We detected 5 deletions in 6 patients. The mean age at diagnosis was 10 years (range 2-14 years), the mean BMI percentile was 46.2%, with none being obese. Mean HbA1c was 6.54%. A glucose tolerance test was performed on 29 patients, 15 of whom were diabetic (7 were diabetic at fasting, 5 were diabetic at 120 min, 3 were diabetic at both) and 14 of borderline diabetes (IFG + IGT: 11, IFG: 2, and IGT: 1). The average glucose tolerance test values were 121.6 mg/dL at 0 min and 182.2 mg/dL at 120 min. No correlation was found between age at onset and plasma glucose value at 0 and 120 min. Reportedly, MODY2 causes a slight increase in post-load blood glucose levels, however the difference between 120 min and 0 min was 56.0 mg/dL (−32 to 140). A negative correlation was observed between 0 min and 120 min blood glucose levels. HOMAIR average was 1.85, 27% of which patients were 2.5 or higher; HOMA-β average was 37.0%, 39% of which showed &amp;lt;30%; and insulinogenic index averaged 0.63, 25% of which showed &amp;lt;0.4, indicating decreased initial insulin secretion. In this study, it is suggested that in Japanese MODY2 cases, glucose sensor dysfunction due to GCK gene mutation causes decreased initial insulin secretion. Disclosure R.Katashima: None. S.Yoshida: None. Y.Watanabe: None. M.Moritani: None. I.Yokota: None.

434 Efficacy and safety of crisaborole ointment, 2%, in Chinese and Japanese pediatric patients aged 2–17 years with mild-to-moderate atopic dermatitis

Abstract Atopic dermatitis (AD) is a common, chronic immuno-inflammatory skin disorder that commonly arises during childhood. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. This study aims to evaluate the efficacy and safety of crisaborole ointment, 2%, in pediatric Chinese and Japanese patients aged 2–17 years with mild-to-moderate AD. This post hoc analysis of a double-blind, vehicle-controlled, phase 3 study (CrisADe CLEAR; NCT04360187) evaluated the safety and efficacy of crisaborole in Chinese and Japanese patients aged ≥2 years with mild-to-moderate AD (involving ≥5% treatable body surface area). Patients were randomly assigned 2 : 1 to receive crisaborole or vehicle, respectively, twice-daily for 28 days. In this analysis, subgroups consisting of Chinese and Japanese patients aged 2–6 years, 2–11 years, and 12–17 years from the overall population were assessed. Efficacy endpoints included percent change from baseline in Eczema Area and Severity Index (EASI) total score at Day 29, improvement in Investigator’s Static Global Assessment (ISGA) score [score of 0 (clear) or 1 (almost clear)] at Day 29, success per ISGA (score of 0 or 1 with a ≥2-grade improvement from baseline) at Day 29, and change from baseline in Peak Pruritus Numerical Rating Scale (PP-NRS; used with permission from Regeneron Pharmaceuticals, Inc., and Sanofi) score at Week 4 (patients ≥12 years only). Safety was also assessed. Of 391 patients in the overall study, 93 were aged 2–6 years, 99 were aged 7–11 years, and 40 were aged 12–17 years. A greater reduction in percent change from baseline in EASI total score at Day 29 was shown in crisaborole- vs. vehicle-treated patients for patients aged 2–6 years and the overall population, with comparable reductions in other age subgroups (ClinicalTrials.gov, NCT04360187). Patients in the crisaborole group vs. the vehicle group had higher rates of ISGA improvement (age 2–6 subgroup) and success per ISGA (age 12–17 subgroup); comparable response rates were seen in other age subgroups (ClinicalTrials.gov, NCT04360187). Patients who received crisaborole showed a greater reduction vs. those who received vehicle in change from baseline in PP-NRS score at Week 4 in the overall population, with a comparable reduction seen in patients aged ≥12 years (ClinicalTrials.gov, NCT04360187). Crisaborole-treated patients in the overall population and each age subgroup had consistent but comparable improvement in all primary and key secondary efficacy endpoints. In patients aged 2–6 years, 55.4% and 62.2% of those who received crisaborole and vehicle, respectively, experienced all-cause treatment-emergent adverse events (TEAEs). All-cause TEAEs occurred in 52.2% and 34.4% of patients aged 7–11 years who received crisaborole and vehicle, respectively; in the aged 12–17 years subgroup, 36% and 40% of patients who received crisaborole and vehicle experienced all-cause TEAEs, respectively. The TEAEs occurring in ≥1% of patients across all subgroups included atopic dermatitis and treatment-related application site pain. Application site pain was most frequently reported in the face and neck. Most TEAEs were mild. There were no new safety findings. Crisaborole was effective and well tolerated in Chinese and Japanese patients aged 2–17 years with mild-to-moderate AD.

Quality of life and physical/psychosocial factors in children and adolescents with orthostatic intolerance

BackgroundOrthostatic intolerance (OI), which is common in children and adolescents, negatively impacts their quality of life (QOL) due to physical symptoms that limit work, school, and daily activities. The purpose of this study is to explore the association of physical and psychosocial factors with QOL scores in children and adolescents with OI.MethodsA cross sectional observational study was conducted. The study participants included 95 Japanese pediatric patients of age 9–15 years who were diagnosed with OI from April 2010 to March 2020. The QOL scores and the QOL T-scores of children with OI assessed using the KINDL-R questionnaire at the initial visit were compared with conventional normative data. The associations of physical and psychosocial factors with the QOL T-scores were examined using multiple linear regression.ResultsPediatric patients with OI had significantly lower QOL scores than healthy children in both elementary (50.7 ± 13.5 vs. 67.9 ± 13.4, p < 0.001) and junior high schools (51.8 ± 14.6 vs. 61.3 ± 12.6, p < 0.001). This finding was observed in the physical, mental, self-esteem, friends, and school domains. Total QOL scores were significantly associated with school nonattendance (β = − 3.2, 95% confidence interval [CI] = − 5.8 to − 0.5, p = 0.022) and poor relationship with school (β = − 5.0, 95% CI = − 9.8 to − 0.4, p = 0.035).ConclusionsThese results suggest that the assessment of QOL, including both physical and psychosocial aspects, especially school factors, needs to be implemented earlier in children and adolescents with OI.

Altered serum levels of platelet-derived growth factor receptor β and cluster of differentiation 13 suggest a role for pericytes in West syndrome

BackgroundPericytes play a role in the maintenance of the blood–brain barrier and neuroinflammation, attracting attention as to whether they are also involved in the pathogenesis of epilepsy.This study aimed to explore the relationship between West syndrome and pericytes. MethodsEighteen Japanese pediatric West syndrome patients and nine controls aged 2 years or younger were retrospectively enrolled in this study. We assessed theserumlevels of pericyte markers, serum PDGFRβ (platelet-derived growth factor receptorβ),CD13 (aminopeptidase N), and 27 cytokines in 17 pediatric patients with West syndrome and the control group. ResultsPatients with West syndrome exhibited significantly increased CD13 and decreased PDGFRβ levels, compared with controls but not serum cytokine levels. These values did not differ significantly between symptomatic and idiopathic West syndrome. ConclusionPericytes might be implicated in the pathogenesis of West syndrome.

Impact of the Family and Household Environment on Pediatric Atopic Dermatitis in Japan.

Pediatric atopic dermatitis (AD) can negatively impact the family quality of life (QoL). We report data from the real-world Epidemiology of Children with Atopic Dermatitis Reporting on their Experience (EPI-CARE) study in Japanese pediatric patients, focusing on disease impact on family QoL. Children and adolescents aged 6 months to <18 years completed an online survey between September 2018-December 2019. The impact of disease severity on family QoL and its effect on parents' time were assessed using the dermatitis family impact (DFI) questionnaire. The impact of a family history of allergic conditions, current residency, second-hand smoke exposure, and household pets on AD prevalence and severity was also assessed. Family QoL decreased as AD severity increased, particularly in families with children aged <6 years; but had the greatest impact on sleep and tiredness in families with children aged <12 years. Parents spent at least 4.6 h/week caring for children <6 years, including those with mild symptoms. Most children (>80%) had a family history of allergic conditions; AD prevalence was increased in those exposed to second-hand smoke or household pets. This study demonstrated that pediatric AD in Japanese individuals has negative impacts on family QoL and that family and household environments can influence pediatric AD prevalence.

Lidocaine–epinephrine–tetracaine（LET）を使用した小児の創傷処理に関する記述的研究(A case series of anaesthetic efficacy of lidocaine, epinephrine, and tetracaine (LET) for wound management in children)

【目的】Lidocaine–epinephrine–tetracaine（LET）は，多くは小児における創傷処理の表面麻酔に使用されている。LETはリドカインの局所注射麻酔と比較しても効果に遜色がないことが示されているが，本邦におけるLETを使用した創傷処理に関する報告は限られている。そこで当院救急外来におけるLETを使用した小児の創傷処理の現状と有効性，副作用に関して調査した。【対象】本報告はカルテレビューに基づく単施設記述研究である。2018年4月1日から2021年3月31日までの期間に当院救急外来を受診した15歳以下の患者で，LETを使用し創傷処理を行った患者群を対象とした。調査項目は年齢，性別，創部の長さ，部位，局所注射麻酔もしくは鎮静鎮痛（procedural sedation and analgesia: PSA）の追加の有無，有害事象の有無とした。【結果】対象患者は312人で，LETのみで創傷処理を完遂できた症例は262例（84%），LETと局所注射麻酔を併用した症例は35例（11%），LETとPSAを併用した症例は10例（3%），LET，局所注射麻酔，PSAを併用した症例は5例（2%）であった。本報告において有害事象は0例（0%）であった。【結語】LETでの創傷処理は適切な鎮痛効果かつ少ない有害事象で施行可能と考えられる。 Introduction: A combination of lidocaine, epinephrine, and tetracaine (LET) is often used for surface anaesthesia in wound management in children. Several studies, mainly from the United States, showed that LET is as effective as lidocaine infiltration. However, reports on the LET are scarce in Japan. Therefore, this study evaluated the efficacy and safety of LET during wound management in children at the emergency department in Japan. Methods: This single–center retrospective descriptive study included pediatric patients (age ≤15) treated with wounds using the LET from April 2018 to March 2021. We collected data on patients' age and sex, length, and site of the wound, use of additional lidocaine infiltration, procedural sedation and analgesia (PSA), and adverse events. Results: A total of 312 patients were included in this study. Wound treatment was completed with only LET in 262 cases (84%), LET and lidocaine infiltration in 35 cases (11%), LET and PSA in 10 cases (3%), LET, lidocaine infiltration, and PSA in 5 cases (2%). Moreover, no adverse events were reported. Conclusion: Using the LET during wound management could be effective and safe in Japanese pediatric patients. 小児にとって救急外来を受診することは非常に大きなストレスを伴う経験であると言われている 1。さらに痛みを伴う創傷処置では恐怖や不安がいっそう強くなる。それにより医療者と患者の間で信頼関係を構築できず，泣いたり暴れてしまうことで治療に非協力的になり処置に難渋することも少なくない 1。救急外来での小児の創傷処理への対応は施設によって違いがあるが，患者は自ら上手く訴えられないことが多く，痛みや恐怖を取り除く配慮が必要になる 2, 3。その一方で小児の痛みに対する治療はしばしば未介入のままにされてしまうことや，対応が不十分であることが指摘されており，小児の痛みの訴えは過小評価される傾向にある 4, 5。不十分な疼痛管理は，処置時の恐怖や苦痛といった短期的な影響だけでなく，長期的にも神経系の発達や将来の痛みに対する反応にも影響を与えると言われている 5ため，疼痛や苦痛を最小限にする努力が重要と言える。1980年代には小児の鎮痛薬の使用が成人と比較し極端に少ないという事実が多く報告された 5。このような報告が増えたことで小児の疼痛管理の重要性が認知され様々な方法が考案され，今日では多くの種類の薬物療法や非薬物療法が使用できるようになり小児の痛みや不安を最小限にする努力がなされるようになってきた 5。 救急外来の創傷処理において表面麻酔は針を使わずに麻酔を行うことができ，注射の痛みや針そのものに対する恐怖を軽減させる方法の一つである。1980年にtetracaine–epinephrine–cocaine（TEC）が効果的な表面麻酔として初めて報告され，北米などを中心に広く使用されるようになったが，コカインの副作用の懸念がありコカインを含まない表面麻酔が発展してきた。Lidocaine–epinephrine–tetracaine（LET）は，リドカイン（lidocaine），エピネフリン（epinephrine），テトラカイン（tetracaine）の合剤で，欧米において1990年代頃から創傷処理における小児の表面麻酔として使用されている 6, 7, 8。LETはコカインを含まずTECと比較し安全でコストが安いことが知られている 8。 LETはリドカインの局所注射麻酔と比較しても効果に遜色がないことが示されているが 9, 10, 11，本邦ではLETに用いられる各薬剤が塗布薬としての使用承認を得ていないため，本邦におけるLETを使用した創傷処理に関する安全性や有効性に関する報告は限られている。そこで今回，独自にLETを作成し救急外来におけるLETを使用した小児の創傷処理の現状と有効性，有害事象に関して報告する。 なお，LETの使用に関しては，先進医療・保険適用外医療用の倫理委員会（東京ベイ浦安市川医療センター倫理審査委員会，受付番号：10 平成24年12月6日）にて承認を得ている。この論文は個人情報保護法に基づいて匿名化がなされている。 方法はカルテレビューに基づく単施設記述研究である。本研究の対象は，2018年4月1日から2021年3月31日の3年間で，当院救急外来を受診した15歳以下でLETを使用し創傷処理を行った患者である。創傷処理とは保険収載上の「縫合処理」と同様，縫合もしくはステイプラーで処理を行った患者のみを対象とした。洗浄のみの患者や，テープ固定を行った患者は除外している。LETの使用に関しては診療医がLETによる麻酔が適切と判断し，保護者の同意が得られた患者とした。保護者の同意は当院で独自に作成した説明書（補足図1）を用い同意を得た。 調査項目は年齢（新生児：生後28日以内，乳児：1歳未満，幼児：1歳以上6歳未満，小児：6歳以上），性別，創部の長さと深さ（表皮，皮下組織，真皮，筋層以下），部位（顔面，頭部，四肢，その他：耳介，背部），受傷機転（転倒，物や人に衝突し受傷したもの，転落，切創），既往歴の有無（発達障害や自閉症スペクトラム障害など），局所注射麻酔もしくは処置時の鎮静（procedural sedation and analgesia: PSA）の追加の有無，処置の方法（縫合もしくはステイプラー），処置者（初期臨床研修医，外部病院救急科専攻医，当院救急科専攻医，指導医），有害事象の有無とした 10, 12。深さに関しては，カルテ記載もしくはカルテに取り込まれた創部写真で判断した。有害事象は，先行研究 7と同様にアレルギー，皮膚炎，アナフィラキシーとした。局所注射麻酔の追加の判断は患者に痛みの程度を聞き，口頭での表出が困難な例では縫合時の表情から痛みが強いと臨床医が判断した場合に追加した。また，苦痛が強い，安静が保てないなど処置の完遂に支障を来すと考えられた場合も臨床医の判断でPSAを導入して創傷処理を完遂した。臨床医の判断については，痛みの程度について部門内で統一されたスケールや担当医に定められた事前学習はなく，個々の判断に依存していた。 LETの組成と施行手順は以下の通りである。本邦には欧米と同濃度の薬剤がないため組成はリドカイン2%（5mL），エピネフリン0.05%（5mL），テトラカイン0.5%（50mg）を混合したものを使用した。混合した液体は遮光の瓶に入れ冷所保存とし，保存期間は作成してから28日間とした。当院でのLETの使用方法は過去の報告に準拠し，創部に接着できるサイズのガーゼにLET液を通常1〜3mL程度を浸し，防水素材で被覆を行ったうえで約30分後に創傷処理を行った 6。 統計解析にはRを使用した。統計処理として，連続変数はマン・ホイットニーのU検定，2値のカテゴリー変数はフィッシャーの正確検定を用い，有意水準はP < 0.05とした。 対象期間中，312例が当院救急外来でLETを使用し創傷処理を行った。年齢中央値4歳［四分位範囲（interquartile range: IQR）2.0–5.5］，男性203人（65%），創部の長さの中央値は1.5cm（IQR 1.0–2.0）であった。 LETのみで創傷処理を完遂した症例は262例（84%），LETと局所注射麻酔を併用した症例は35例（11%），LETとPSAを併用した症例は10例（3%），LET，局所注射麻酔，PSAを併用した症例は5例（2%）であった。 各処置別の年齢中央値，性別，創部の長さの中央値，部位の内訳の詳細は表の通りである（Table 1）。 Age (year), median (IQR) Sex, male, n (%) Length of injury (cm), median (IQR) Face (n = 260) Scalp (n = 27) Extremity (n = 19) Other (n = 6) LETのみで創傷処理を完遂した症例の年齢中央値は4歳（IQR 2.8–5.0）であったが，LETのほかにPSAを必要とした症例の年齢中央値は3.5歳（IQR 2.3–9.8），LETのほかに局所注射麻酔とPSAを必要とした症例の年齢中央値は3.0歳（IQR 1.0–4.0）であった。その他の部位に含まれる耳介や背部の創傷処理の際に，6例中3例はLETに加えPSA，もしくは局所注射麻酔とPSAの両方を行っていた。 年齢，創部の深さ，受傷機転，処置者別のそれぞれのLETのみで創傷処理の完遂数と完遂率（%）は表の通りで有意な差は認めなかった（Table 2）。 Overall (n = 312) LET only (n = 262) LET ± LI ± PSA (n = 50) 年齢，創部の大きさや深さ，受傷機転，処置者によって，LETのみでの創傷処理の完遂率に統計学的に有意差が出るか検証した結果は表の通りである（Table 2）。 発達障害，自閉症スペクトラムなどの既往歴がある患者は本報告には含まれていなかった。 ステイプラーで創傷処理を行った患者は312例中10例で，全例が頭部挫創もしくは切創であった。追加で局所注射麻酔やPSAを必要とした症例は0例であった。 LETによるアレルギーなどの有害事象は312例中0例であった。 本報告において312例中262例（84%）が追加の局所注射麻酔やPSAを使用することなく，LETのみを使用し創傷処理を完遂することができた。追加の局所注射麻酔やPSAを使用しなかった患者のうち，部位別内訳では顔面や頭部の処置が多く，262例中242例（93%）を占めた。本報告ではLETによる重篤な有害事象は認めなかった。 顔面や頭部の処置で多く用いられた理由としては，顔面はより患者の視野に近く恐怖心を惹起しやすく医療者がLETによる効果を期待して選択しやすいことに加えて，顔面や頭部は血流が豊富で体幹部や四肢よりも麻酔の効果が得られやすいためLETの効果が高いことが知られている点 12や，小児は転倒による頭部外傷が多いことからそもそも小児の創傷処理は頭部や顔面の頻度が高いこと 13などが考えられる。 LETのみでの完遂率は，欧米の先行研究の75～90%と比較し同等の完遂率であった 9, 14, 15。LETの鎮痛効果を比較検討した論文において組成濃度はリドカイン2〜4%，エピネフリン0.05〜0.1%，テトラカイン0.5〜2%と違いがある（Table 3） 16, 17, 18。本報告で使用したLET製剤はリドカイン2%，エピネフリン0.05%，テトラカイン0.5%であり，本邦で作成しうる最大濃度のLET製剤となっている。先行研究間で患者の年齢層や評価方法に違いがあるが，最終的に得られたLETのみでの創傷処理の完遂率は同様の結果であり，本邦で使用可能な製剤で作成するLETも創傷処理の鎮痛方法として有効であることが示唆される結果であった。 Years of publication Age (Average) LETの効果を検証するうえでは年齢，創部の大きさや深さ，受傷機転，患者因子，処置の方法，処置者など多因子が関係していることが予想される。年齢層別の結果では，先行研究 9で6歳未満と6歳以上でLETの効果を比較しているが有意差は認めていない。本報告でもLETのみでの創傷処理を完遂した割合は幼児84%，小児82%とほぼ同じで先行研究と同様の結果であった。一方で，乳児は3例中すべてLETのみで処置を完遂できているが，乳児は痛みをうまく表出できない。啼泣が激しければ痛みを強く感じているのかと考える手がかりにはなるが，恐怖などでも啼泣するため痛みの評価が難しい。また抑えて処理をすることができる年齢であるため痛みの管理が不十分であっても早く処置を完了することを優先する心理が働く。そのため痛みが十分管理できて完遂できたのかそうでなかったが完遂したのかは判別が難しい。年齢，創部の大きさや深さ，受傷機転，処置者の違いによって，LETのみでの創傷処理の完遂率に統計学的に有意差が出るか検証したが，明らかな有意差は認めなかった（Table 2）。 患者の因子として発達障害，自閉症スペクトラムなどが背景にある患者は，指示が入らず処置が困難になる可能性があるが，本報告には含まれていなかった。 ステイプラーで創傷処理を行った患者は312例中10例で，全例が頭部挫創もしくは切創であった。本報告では全例LETのみで処置を完遂できている。ステイプラーは頭部挫創や切創の良い適応で，縫合と比較し簡易に短時間で創傷処理が可能な点が利点である 8。一方でLETは毛髪のために頭部外傷の疼痛管理には不向きとされている。にもかかわらず今回はステイプラーによる処置ではLETのみで処理を完遂できた割合が高かった。短時間で創傷処理が可能なため，疼痛緩和が不十分だったとしても創傷処理が行われていた可能性はあるが今後の検証が必要な領域であることが示唆された。 追加で注射麻酔やPSAを使用した創部の特徴として，若年であることや耳介などの末端部，背部などの体幹部が含まれている点が挙げられる。若年患者はLETの処置そのものでも暴れてしまうことがあること，痛みの表出が困難であることや処置への理解が乏しいことから，たとえLETによって痛みがコントロールされていたとしても医療者が追加の注射麻酔やPSAが必要と判断することが影響したかもしれない。その他にも末端部，四肢や体幹部に関しては麻酔の効果がやや低下するとの報告があり 15，LETの効果が十分に得られなかった可能性もある。 LETなどの表面麻酔によるアレルギー反応などの有害事象は非常に稀であり，今回も有害事象は認められなかった。局所注射麻酔よりも頻度は少ないと言われ 14，安全性に関しても先行研究と同等の結果であった。加えて，追加で局所麻酔を要する創であったとしてもLETにより注射麻酔の痛みは軽減されているという報告もある 16。そう考えるとLETのみで処置の完遂が困難と思われる創部においても局所麻酔の痛みを軽減する目的であらかじめLETで表面麻酔しておくことも有用と考えられた。 LETのみでは処置を完遂できない場合に備え，追加の局所麻酔やPSAなどのバックアッププランを準備，精通しておくことが重要である。前述の通りLETによる有害事象は稀であり，創傷処理の際にまずLETを行うことを検討してみてもよいと考える。そうすることでほかの鎮痛・鎮静薬の使用頻度の減少につながる可能性がある。 本報告をきっかけに本邦にてLETを使用した創傷処理の有用性がさらに認知され，救急外来における小児の創傷処理の際の局所麻酔の選択肢の一つとして考慮されることを期待する。 本報告には複数の限界がある。第一に単施設研究であり，ほかに子供の対応に慣れた医療者を配備できる施設においては麻酔方法を含めた子供への関わりが異なるため一般化できない可能性がある。 第二にLET処置後の局所注射麻酔やPSAの追加処置の必要性は医師の判断に依存している。追加処置を判断する際の判断は，救急外来に常駐する6年目以上の救急科医師と合議しているが，visual analogue scale（VAS）などのスケールによる客観的な痛みの定量的評価ができていないため，個々の症例で追加処置の適応基準に差があった可能性がある。また，本来は満足度を調査すべきであるが，小児であり表出が困難な年齢も含まれるため今回は検証できていない。 第三にLETの効果を検証するうえでは単一の因子だけでなく，多因子が関係することが予想されるが，今回収集されたデータだけではサンプルサイズが少なく，多変量解析を行うことができなかった。今後さらなる研究が必要になる。 第四にLET，注射麻酔，PSA以外の未測定の因子の存在がある。例としてはスマートフォンやタブレット端末を利用した動画使用の有無，子供対応専用の人員配備，子供の発達や理解度などは本報告では測定できておらず，これらの因子が麻酔方法の選択に影響を与えた可能性がある。 最後に後方的にカルテの記録を参照しているためアレルギーなどの有害事象の有無は実際の症状よりもカルテ記載に依存している点などが挙げられる。 当院救急外来でLETを使用した小児312例の創傷処理の現状について報告した。小児の創傷処理の鎮痛方法として有効かつ安全であることが示された。 本稿のすべての著者に規定された利益相反はない。 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Dose Rationale of Nasal Glucagon in Japanese Pediatric Patients with Diabetes Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation.

Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns. The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation. We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to <8, 8 to <12, and 12 to <18 years. Treatment success was defined as an increase in blood glucose to ≥70 or ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon. The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that >99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues. This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients

IntroductionThe pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. MethodsThe phase 2 trial enrolled Japanese pediatric patients (age 1–17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. ResultsFollowing administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. ConclusionsThe results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.