Temporal expression profiles of microRNAs associated with acute phase of brain ischemia in gerbil hippocampus.

Neuroprotective therapeutic potential for restoring dysregulated microRNA (miRNA) expression has previously been demonstrated in a gerbil cerebral infarction model. However, since temporal changes in miRNA expression profiles following stroke onset are unknown, miRNAs proving to be useful therapeutic targets have yet to be identified. We evaluated cognitive function, hippocampal neuronal cell death, and microarray-based miRNA expression profiles at 5, 9, 18, 36, and 72 h after 5-min whole brain ischemia in gerbils. A decline in cognitive function occurred in parallel with increased neuronal cell death 36-72 h after ischemia. The Jonckheere-Terpstra test was used to analyze miRNA expression trends 5-72 h after ischemia. The expression levels of 63 miRNAs were significantly upregulated, whereas 32 miRNAs were significantly downregulated, monotonically. Of the 32 monotonically downregulated miRNAs, 18 showed the largest decrease in expression 5-9 h after ischemia. A subset of these dysregulated miRNAs (miR-378a-5p, miR-204-5p, miR-34c-5p, miR-211-5p, miR-34b-3p, and miR-199b-3p) could be associated with brain ischemia and neuropsychiatric disorders.

18F-THK5351 Positron Emission Tomography Clearly Depicted Progressive Multifocal Leukoencephalopathy After Mantle Cell Lymphoma Treatment.

An 84-year-old Japanese woman presented with left hemiplegia 8 months after completing chemotherapy for mantle cell lymphoma. Brain magnetic resonance imaging (MRI) revealed a hyperintense lesion extending from the right parietal lobe to the left parietal lobe. Compared with these MRI results, 18F-THK5351 PET revealed more extensive accumulation. A brain biopsy showed progressive multifocal leukoencephalopathy (PML). Immunohistochemistry and John Cunningham virus (JCV) DNA-polymerase chain reaction indicated JCV infection. Therefore, a diagnosis of PML was made. 18F-THK5351 PET, indicative of activated astrocytes, clearly depicted PML lesions composed of reactive and atypical astrocytes. 18F-THK5351 PET may capture fresh progressive PML lesions better than MRI.

Cytotoxic Lesions of the Corpus Callosum (CLOCC) Suggesting Exacerbation by Heterogeneous COVID-19 Booster Vaccination.

Cytotoxic lesions of the corpus callosum (CLOCC) is a disease entity associated with reversible lesions of the corpus callosum on magnetic resonance imaging (MRI). CLOCC is caused by a variety of etiologies, but CLOCC after vaccination is extremely rare. Four prior cases of CLOCC after the first dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine have been reported; these were localized to the splenium and showed early clinical and neuroradiological recovery. We experienced an unusual case in which a heterogeneous COVID-19 booster vaccination caused rather severe CLOCC damage. A 74-year-old Japanese woman presented with ataxia, high fever, and hearing loss several days after her third vaccination against COVID-19. This booster was an mRNA-1273 while her first and second vaccinations were both BNT162b2 type. SARS-CoV-2 real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis was negative, but serum SARS-CoV-2 S-IgG antibodies were elevated. Her cerebrospinal fluid (CSF) showed an elevated cell count and high levels of protein and interleukin-6 (IL-6). Brain MRI showed CLOCC spreading throughout the body of the corpus callosum. After the exclusion of other potential causes, the diagnosis of vaccination-related CLOCC was made. Six months later, recovery of clinical and MRI findings remained incomplete. It was suggested that the patient's CLOCC might have been caused by the increase in CSF IL-6 due to an enhanced immune response from the heterogeneous vaccination, resulting in more severe damage to the corpus callosum than usual.

Age­related brainstem degeneration through microRNA modulation in mice.

Histopathological changes occur in the brainstem during the early stages of Alzheimer's disease (AD), with the pathological changes of the brain lesions ascending progressively in accordance with the Braak staging system. The senescence­accelerated mouse prone 8 (SAMP8) mouse model has been previously used as a model of age­dependent neurodegenerative diseases, including AD. In the present study, microRNAs (miRNAs) that were upregulated or downregulated in SAMP8 brainstems were identified using miRNA profiling of samples obtained from miRNA arrays. The preliminary stage of cognitive dysfunction was examined using male 5­month­old SAMP8 mice, with age­matched senescence­accelerated mouse resistant 1 mice as controls. A Y­maze alternation test was performed to assess short­term working memory and miRNA profiling was performed in each region of the dissected brain (brainstem, hippocampus and cerebral cortex). SAMP8 mice tended to be hyperactive, but short­term working memory was preserved. Two miRNAs were upregulated (miR­491­5p and miR­764­5p) and two were downregulated (miR­30e­3p and miR­323­3p) in SAMP8 brainstems. In SAMP8 mice, the expression level of upregulated miRNAs were the highest in the brainstem, wherein age­related brain degeneration occurs early. It was demonstrated that the order of specific miRNA expression levels corresponded to the progression order of age­related brain degeneration. Differentially expressed miRNAs regulate multiple processes, including neuronal cell death and neuron formation. Changes in miRNA expression may result in the induction of target proteins during the early stages of neurodegeneration in the brainstem. These findings suggest that studying altered miRNA expression may provide molecular evidence for early age­related neuropathological changes.

Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is an autosomal dominant genetic disorder caused by variants in the NF2 gene. Approximately 50% of NF2 patients inherit pathogenic variants, and the remainder acquire de novo variants. NF2 is characterized by development of bilateral vestibular schwannomas. The genetic background of Japanese NF2 cases has not been fully investigated, and the present report performed a genetic analysis of 14 Japanese NF2 cases and examined genotype-phenotype correlations. DNA samples collected from peripheral blood were analyzed by next-generation sequencing, multiplex ligation-dependent probe amplification analysis, and in vitro electrophoresis. Ten cases had pathogenic or likely pathogenic variants in the NF2 gene, with seven truncating variants and three non-truncating variants. The age of onset in all seven cases with truncating variants was < 20 years. The age of onset significantly differed among cases with truncating NF2 variants, non-truncating NF2 variants, and no NF2 variants. However, the clinical course of tumor growth and hearing deterioration were not predicted only by germline pathogenic NF2 variants. The rate of truncating variants was higher in the present study than that of previous reports. Genotype-phenotype correlations in the age of onset were present in the analyzed Japanese NF2 cases.

Possible critical region associated with late-onset spasms in 17p13.1-p13.2 microdeletion syndrome: a report of two new cases and review of the literature.

17p13.1-2 microdeletion syndrome is a congenital anomaly syndrome with characteristic facial features and multiple malformations. The prevalence of epilepsy with 17p13.1-2 microdeletion is low, with only one case reported for late-onset spasms. Late-onset spasms is one of the rare epilepsy syndromes and one of the developmental epileptic encephalopathies requiring urgent treatment. We experienced two cases of 17p13.1-2 microdeletion syndrome, one of which presented with epileptic spasms in cluster at 18 months of age. EEG showed symmetrical hypsarrhythmia during interictal periods and a paroxysmal fast wave superimposed on widespread slow waves during seizures, leading to the diagnosis of late-onset spasms. Another case had no epilepsy. Comparing the extent of deletion in the two cases with that of previous reports, the involvement of the USP6 gene was suspected. However, the accumulation of additional case reports is needed to confirm the genetic involvement in late-onset spasms.

Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Accelerated pubertal onset in short children with delayed bone age.

OBJECTIVES: Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. METHODS: The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010-2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979-1992). Individuals with the height standard deviation score <-1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. RESULTS: From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. CONCLUSIONS: Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

Nationwide survey of endogenous hyperinsulinemic hypoglycemia in Japan (2017-2018): Congenital hyperinsulinism, insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease).

AIMS/INTRODUCTION: We aimed to investigate the nationwide incidence, treatment details and outcomes of patients with endogenous hyperinsulinemic hypoglycemia (EHH), including those with transient/persistent congenital hyperinsulinism (CHI), insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease) in Japan. MATERIALS AND METHODS: A nationwide, questionnaire-based survey was carried out to determine the number of patients with EHH who were treated for hypoglycemia or hypoglycemia-related complications in 2017-2018. The questionnaires were sent to all hospitals in Japan with >300 beds, and with pediatric and/or adult clinics likely managing EHH patients. The secondary questionnaires were sent to obtain the patients' date of birth, sex, age at onset, treatment details and post-treatment outcomes. RESULTS: A total of 447 patients with CHI (197 transient CHI, 225 persistent CHI and 25, unknown histology), 205 with insulinoma (118 benign, 18 malignant and 69 unknown subtype), 111 with non-insulinoma pancreatogenous hypoglycemia syndrome (33 post-gastric surgery HH, 57 postprandial HH, 10 nesidioblastosis and 11 unknown subtype) and 22 with insulin autoimmune syndrome were identified. Novel findings included: (i) marked improvement in the prognosis of persistent CHI over the past 10 years; (ii) male dominance in the incidence of transient CHI; (iii) non-insulinoma pancreatogenous hypoglycemia syndrome emerging as the second most common form of EHH in adults; (iv) frequent association of diabetes mellitus with insulin autoimmune syndrome; and (v) frequent post-treatment residual hypoglycemia and impaired quality of life. CONCLUSIONS: The first nationwide, all age group survey of EHH showed the current status of each type of EHH disorder and the unmet needs of the patients.

Successful treatment of infantile-onset ACAD9-related cardiomyopathy with a combination of sodium pyruvate, beta-blocker, and coenzyme Q10.

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.

Orexin secretion abnormality involved in excessive somnolence in CNS lymphoma without hypothalamic lesions.

A 72-year-old woman developed excessive somnolence as one of the symptoms of diffuse large B-cell lymphoma in the central nervous system (CNS). Although somnolence might be caused by reduced orexin secretion associated with hypothalamic lesions, neither brain MRI nor 18F-fluorodeoxyglucose positron emission tomography identified hypothalamic lesions. However, the decreased cerebrospinal fluid (CSF) orexin levels recovered to near normal values with improvement of somnolence after chemotherapy. The alteration of CSF orexin levels suggested the involvement of potential hypothalamic lesions. Therefore, measurements of CSF orexin levels may be useful for understanding the pathological background of somnolence in CNS lymphoma without hypothalamic lesions.

Pregnancy outcome of Japanese patients with glucokinase-maturity-onset diabetes of the young.

AIMS/INTRODUCTION: Glucokinase-maturity-onset diabetes of the young (GCK-MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK-MODY to better formulate the management plan for this population. MATERIALS AND METHODS: The study participants were 34 GCK-MODY families whose members were diagnosed at Osaka City General Hospital during 2010-2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review. RESULTS: Birthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small-for-gestational age birthweight were found only in affected offspring born to insulin-treated women. CONCLUSIONS: In Japanese GCK-MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.

Importance of mediastinal screening-based observation during endoscopic ultrasound to examine gastrointestinal pathologies.

In all endoscopic ultrasound (EUS) examinations performed at our hospital, the heart, vasculature, and mediastinal lymph nodes from the esophagus are observed after checking for gastrointestinal pathologies. Since the introduction of EUS using a convex linear-array echoendoscope at our hospital in April 2015, EUS examinations have been performed in 371 cases for examining pancreaticobiliary diseases, submucosal tumors, and other pathologies during the 3-year period, till March 2018. We diagnosed 2 patients with asymptomatic cardiovascular disease while observing the mediastinum during EUS examination to examine identified pancreaticobiliary disease. No subjective symptoms associated with cardiovascular disease were observed and the respective conditions had not been identified previously in either case. One case involved a left atrial myxoma while the other involved a saccular aortic aneurysm in the thoracic aorta. A left atrial tumor resection and aortic replacement surgery were performed in each case. Their postoperative courses have been favorable. As cardiovascular diseases are often life-threatening, as in the present 2 cases, observational screening of the cardiovascular system from the esophagus should also be performed during EUS examinations just as the pharyngeal region is examined during upper gastrointestinal endoscopy.

Growth Hormone Treatment for Achondroplasia.

Achondroplasia (ACH) is the most common form of skeletal dysplasia causing rhizomelic, short-limb short stature. Short- and long-term clinical trials have been conducted with rhGH, with similar results across these studies. At supraphysiological dose of GH, height gain of 1-1.5 SDS on the population curve was observed during the first 1-3 years, which was then followed by a smaller increase in growth rate persisting for 5-6 years. These studies led to the approval of rhGH for ACH in Japan where rhGH has been used for 20 years at 0.05 mg/kg/day. Although the available data are still limited, compared to untreated controls, total gain in adult height has been greater in males than in females, reported at 3.5-8.0 cm and 2.8-4.2 cm, respectively. Serious adverse events have been rare although some were potentially life-threatening and need careful monitoring. These results should serve as a comparator for novel emerging treatments for ACH.

Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance.

BACKGROUND: Causative mutations cannot be identified in the majority of Asian patients with suspected maturity-onset diabetes of the young (MODY). OBJECTIVES: To elucidate the genetic basis of Japanese patients with MODY-like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. SUBJECTS: A total of 263 Japanese patients with early-onset, non-obese, MODY-like diabetes mellitus referred to Osaka City General Hospital for diagnosis. METHODS: Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation-positive and mutation-negative patients were further analyzed for clinical features. RESULTS: Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation-positive patients did not have affected parents and 8.2% were in the overweight range (body mass index [BMI] >85th percentile). HOMA-IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation-positive patients. Compared with mutation-positive patients, mutation-negative patients were significantly older (P = 0.003), and had higher BMI percentile at diagnosis (P = 0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation-negative patients (P = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation-negative patients with paternal inheritance (P = 0.0106). CONCLUSIONS: Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin-resistance are common in Japanese patients with mutation-positive MODY. A significant fraction of mutation-negative patients had features of early-onset type 2 diabetes common in Japanese, and non-Mendelian inheritance needs to be considered for these patients.

Chromosome 6q24-related diabetes mellitus.

Chromosome 6q24-related diabetes mellitus is the most common cause of transient neonatal diabetes (TNDM), accounting for approximately two-thirds of all TNDM cases. Patients with 6q24-TNDM develop insulin-requiring diabetes soon after birth, followed by the gradual improvement and eventual remission of the disorder by 18 mo of age. The most important clinical feature of affected patients is a small-for-gestational age (SGA) birth weight, which reflects the lack of insulin in utero. It is believed that 6q24-TNDM is caused by the overexpression of the paternal allele of the imprinted locus in chromosome 6q24, which contains only two expressed genes, PLAGL1 and HYMAI. Identified mechanisms include: (1) duplication of the paternal allele, (2) paternal uniparental disomy, and (3) hypomethylation of the maternal allele. Many patients with TNDM relapse after puberty. Relapsed 6q24-related diabetes is no longer transient and typically occurs in non-obese patients who are autoantibody negative. Thus, these patients possess features indistinguishable from those of maturity-onset diabetes of the young (MODY). Conversely, it has been shown that not all patients with 6q24-related diabetes have a history of TNDM. 6q24-related diabetes should therefore be considered as one of the differential diagnoses for patients with MODY-like diabetes, especially when they are SGA at birth.

Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability.

Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically. Seven affected members displayed pure spastic paraplegia. Impression of genetic anticipation was observed in the family, including tendency of earlier age-at-onset and increasing severity in subsequent generations. Genetic analysis revealed a heterozygous intronic variant, c.303+2T > A, in REEP1, which segregated with disease, and was also identified in one unaffected member. The variant causes exon 4 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through nonsense mediated mRNA decay (NMD). Our study demonstrated further evidence of allelic heterogeneity in SPG31, mutant REEP1 mRNA dosage effects through NMD and intra-familial phenotype variability.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia.

OBJECTIVES: To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. SUBJECTS: A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. METHODS: The levels of biochemical markers (glucose, insulin, ß-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. RESULTS: Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (<.5) µU/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 µmol/L, and those of FFA were 270.5 and 2660 µmol/L, respectively. For patients after 5 months, cutoffs of insulin >1.25 µU/mL, BHB < 2000 µmol/L, and FFA < 1248 µmol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. CONCLUSIONS: After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry.

Octreotide, a long-acting somatostatin analog, has been used for treating hypoglycemia caused by congenital hyperinsulinism (CHI). However, octreotide has not been evaluated in clinical trials and has not been approved in any developed country. We aimed to test the efficacy and safety of octreotide for diazoxide-unresponsive CHI through a combination of a single-arm, open-label clinical trial (SCORCH study) and an observational study to collect data on the clinical course of patients treated off-label in Japan (SCORCH registry). In the SCORCH study, 5 patients were stabilized (blood glucose > 45 mg/dL) by hypertonic glucose infusion, and treated by continuous subcutaneous octreotide infusion at a dose of 5-25 µg/kg/day. Continuous blood glucose monitoring was performed between -24 and +48 hours. In 3 patients, a clinically meaningful rise in blood glucose was achieved and therapy was continued. The glucose infusion was gradually decreased and stopped after 5, 11, and 174 days, respectively. In one case, remission of CHI was reached after 606 days and octreotide was discontinued. The SCORCH registry included 19 diazoxide-unresponsive patients treated by subcutaneous octreotide, by continuous infusion or multiple daily injections. Of the 17 patients treated with hypertonic glucose infusion, the infusion rate was reduced after 4 weeks to less than 50% in 11 patients (64.7%) and stopped in 9 (52.9%). During the combined observation period of 695.4 patient-months in both studies, no severe adverse events related to octreotide were observed. In conclusion, subcutaneous octreotide injection was effective and well tolerated in the majority of patients with diazoxide-unresponsive CHI.