Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/blood-2023-189160

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DOI： 10.3324/haematol.2023.283636

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Hematology  

Acute graft-versus-host disease (aGVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and alternative therapies for patients showing inadequate response to steroids are limited. Vedolizumab, an anti-α4β7 integrin antibody widely used for treating inflammatory bowel diseases, has recently been studied in adult patients with steroid-refractory intestinal aGVHD. However, few studies have examined its safety and effectiveness in pediatric patients with intestinal aGVHD. We report the case of a male patient with intestinal late-onset aGVHD treated with vedolizumab. He underwent allogeneic cord blood transplantation for warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and developed intestinal late-onset aGVHD 31 months after transplantation. The patient was refractory to steroids; however, vedolizumab was initiated 43 months after transplantation (at the age of 7 years) and the symptoms of intestinal aGVHD were alleviated. Additionally, favorable endoscopic findings were observed, such as reduction of erosion and regenerative epithelial growth. We also evaluated the efficacy of vedolizumab in 10 patients with intestinal aGVHD (9 from the literature review and the present case). Six patients (60%) showed an objective response to vedolizumab. No serious adverse events were observed in any patients. Vedolizumab is a potential treatment option for steroid-refractory intestinal aGVHD in pediatric patients.

DOI： 10.1007/s12185-023-03590-2

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Language：English   Publisher：International Journal of Hematology  

Human leukocyte antigen (HLA) mismatched unrelated donor transplantation is associated with an increased risk of graft-versus-host disease, graft failure, and infection, which increases post-transplant morbidity and mortality. In this single-center retrospective study, outcomes were evaluated in 30 consecutive children who underwent bone marrow transplantation (BMT) from HLA 1 allele-mismatched (HLA 7/8-matched) unrelated donors with rabbit anti-thymocyte globulin (rATG) as graft-versus-host disease (GVHD) prophylaxis. The 3-year overall survival (OS), event-free survival (EFS), and GVHD-relapse-free survival rates were 91.7% (95% CI 70.5%–91.9%), 88.3% (95% CI 67.5%–96.1%), and 73.9% (95% CI 52.4%–86.8%), respectively. Grade II–IV and III–IV acute GVHD occurred in 10 (33%) and 2 (7.0%) patients, respectively. The 3-year cumulative incidence of chronic GVHD was 7.8%. No fatal viral infections occurred. The study results show the feasibility of HLA 7/8-matched unrelated BMT with ATG to achieve favorable outcomes and acceptable GVHD, especially for patients who lack a fully matched donor.

DOI： 10.1007/s12185-023-03571-5

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Language：English   Publisher：American Journal of Hematology  

DOI： 10.1002/ajh.26874

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Authorship：Lead author   Language：English   Publisher：Scientific Reports  

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

DOI： 10.1038/s41598-022-14161-6

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Language：English   Publisher：Cancer Medicine  

Background: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes. Methods: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity. Results: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1–9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3–4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity. Conclusions: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.

DOI： 10.1002/cam4.4529

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Language：English   Publisher：Journal of Hospital Infection  

In infants with immunodeficiency, rotavirus (RV) vaccines can be continuously excreted in stool. We analysed nosocomial infection with RV vaccine strain in immunodeficient paediatric patients. RV1 RNAs were detected in stool and serum samples from case A, who was vaccinated with RV1, and case B, who was not. PAGE analysis of serial stool samples of case A revealed several rearrangements of the RV genome. In case B, the only band pattern detected was the same as a rearrangement detected in case A at the same time. In summary, RV vaccination of infants with immunodeficiency poses a risk of nosocomial infections.

DOI： 10.1016/j.jhin.2021.12.009

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Language：English   Publisher：Cell Transplantation  

Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort (n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort (n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation (R2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.

DOI： 10.1177/09636897221143364

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