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Background The details of gastrointestinal bleeding/ulcer in paediatric cancer patients treated with proton beam therapy have not been reported previously. Methods Patients aged 15 years or younger at the time of proton beam therapy and whose gastrointestinal tract was included in the irradiated field participated. Results A total of 124 patients participated in the study; their median age at irradiation was 5.4 years. Concurrent chemotherapies were vincristine–cyclophosphamide (16 patients), irinotecan-based treatment (16 patients), vincristine–cyclophosphamide–ifosfamide–etoposide (14 patients), other chemotherapy (27 patients) and no chemotherapy (51 patients). Gastrointestinal bleeding/ulcer occurred in four patients (3.2%), with no death due to the bleeding/ulcer. The sites of the gastrointestinal bleeding/ulcer were the stomach (two patients) and the duodenum (two patients). The ages of the four patients at PBT were 5.3, 13.8, 14.2 and 14.8 years, which were significantly older than those of patients without GI bleeding/ulcer (p = 0.017). The maximum irradiated doses to the GI tract in the four patients were 43.2, 45, 50.4 and 50.4 gray equivalent, respectively. The concomitant chemotherapy was vincristine–cyclophosphamide–ifosfamide–etoposide 3 and vincristine–cyclophosphamide 1. Weeks from proton beam therapy to bleeding/ulcer were 15, 20, 22 and 264. Discussion and conclusions Patients who developed gastrointestinal bleeding/ulcer were treated concurrently with vincristine–cyclophosphamide–ifosfamide–etoposide or vincristine–cyclophosphamide, and their ages were older than those of patients without gastrointestinal bleeding/ulcer. Bleeding occurred in the upper gastrointestinal tract in all the cases, and most cases occurred early and during chemotherapy. Upper gastrointestinal irradiation in older children undergoing intensive chemotherapy may increase the risk of developing gastrointestinal complications.

Introduction: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. Materials and Methods: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. Results: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. Discussion/Conclusion: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer-predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients’ peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

Gitelman syndrome (GS) is an autosomal recessive disorder characterized by alkalosis, hypokalemia, and hypomagnesemia. Although hundreds of genetic variants associated with GS have been reported, many of them are categorized as of uncertain significance in ClinVar. Here, we describe a pediatric GS patient from a three-generation family whose mother and maternal grandmother were asymptomatic. The proband was a 16-year-old Japanese girl with muscle weakness and continuous hypokalemic metabolic alkalosis. The patient, her mother, and her maternal grandmother were compound heterozygous for, and each expressing a different combination of, previously reported SLC12A3variants in GS patients. The mother and the maternal grandmother had no symptoms related to GS, and blood gas tests showed that the blood potassium levels and venous pH were within normal limits; however, the venous blood HCO3- levels were slightly elevated. The phenotypic effect of missense mutations is difficult to evaluate, and accumulation of genotypic data with accurate phenotyping, including those of “healthy” and “asymptomatic” individuals in various ethnic populations, will improve the genetic diagnosis of GS.

Childhood cancer survivors (CCSs) may have comorbidities including a long-term abnormality in the immune system. Immune reconstitution in CCSs after treatment for acute leukemia has been reported previously, while analyses of immune reconstitution in CCSs with solid tumors have been limited.Childhood cancer survivors who received chemotherapy for solid tumors and who visited University of Tsukuba Hospital between November 2019 and March 2021 were included the study. Peripheral blood was collected for flow cytometry analysis.Forty-nine samples from 35 CCSs (18 male, 17 female) were included in the study. High-dose chemotherapy and cerebral spinal irradiation were conducted in 14 CCSs (40%) and in five CCSs (14%), respectively. The median time between the completion of chemotherapy and the collection of the present samples was 15.0 months (range, 0-286 months). The total lymphocyte count, B cells, and CD8-positive T cells recovered to the normal range of controls (NR-CTLs) in 0 (0%), four (66.7%), and four (66.7%) of six samples at 0-3 months after the completion of chemotherapy, and in three (60%), four (80%), and three (60%) of five samples at 3-12 months after the completion of chemotherapy, respectively. Meanwhile, CD4-positive T cells remained lower than NR-CTLs in 0 (0%) of six samples, one (20%) of five samples, and seven (63.7%) of 11 samples at 0-3, 3-12 and 12-60 months after the completion of chemotherapy, respectively.Recovery to the NR-CTLs was rapidly achieved in B cells and CD8-positive T cells, while the recovery was slower and incomplete in CD4-positive T cells. Careful observation of infection in long-term follow-up clinics is needed.

A number of cases have been reported in recent years regarding the use of proton beam therapy to mitigate adverse events affecting important cranial organs in cases of rhabdomyosarcoma at parameningeal sites. However, few reports have described the use of proton beam therapy as urgent radiotherapy for parameningeal rhabdomyosarcoma with intracranial extension. We treated 3 patients diagnosed with parameningeal rhabdomyosarcoma extending into the cranium who were assessed at other hospitals as suitable for urgent radiotherapy and transferred to our hospital for proton beam therapy. These patients comprised 2 boys and 1 girl 6 to 12 years of age at diagnosis, and proton beam therapy was started on days 5, 11, and 23 after diagnosis, respectively. Patients with parameningeal rhabdomyosarcoma extending into the cranium can be transferred to institutions equipped to perform proton beam therapy. To minimize the interval to starting therapy, medical information should be shared with institutions capable of providing such therapy as soon as the possibility of intracranial soft-tissue sarcoma is recognized. Proton beam therapy is 1 option for radiotherapy in cases of intracranial rhabdomyosarcoma.

Background: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. Procedure: DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Results: Twenty patients participated in this study. The median age at diagnosis was 5.0 years. The male-to-female ratio was 3:2. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Five pathogenic variants were found in four patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of LIG4 and MEN1. Two of the four patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. This is the first report of germline cancer-related gene variants with detailed clinical information in Japanese children with RMS. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. Conclusions: When this is the first report of the germline genetic analysis of Japanese children with RMS, the frequency of the variant was almost equivalent to that of previous reports from Western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.