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We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.

Retardation of growth and development is a well-known late effect after radiotherapy for pediatric patients. The goal of the study was to examine the effect of proton beam therapy (PBT) on the growth of muscles included in the irradiated area. The subjects were 17 pediatric patients (age ≤ 5 years) who received PBT with a treatment field including a muscle on only one side out of a pair of symmetrical bilateral muscles and had imaging evaluations for at least 1 year after PBT. The thicknesses of the irradiated and non-irradiated (contralateral) muscles were measured retrospectively on CT or MRI axial images collected before and after PBT. The change of thickness divided by the period (years) for each muscle was compared between the irradiated and contralateral sides. Correlations of muscle growth with irradiation dose and age at the start of treatment were also evaluated. The median observation period was 39.2 months. The measurement sites included the erector spinae (n = 9), gluteus maximus (n = 5) and rhomboids + trapezius (n = 3) muscles. The average changes in muscle thickness were 0.24 mm/year on the irradiated side and 1.19 mm/year on the contralateral side, showing significantly reduced growth on the irradiated side (P = 0.001). Younger patients had greater muscle growth. Irradiation dose was not significant, but muscle growth tended to decrease as the dose increased, and muscles irradiated at >50 Gy (RBE) showed little growth. These results show that muscle growth is affected by PBT and that long-term follow-up is needed to evaluate muscle growth retardation.

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. DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Twenty patients participated in this study. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Six pathogenic variants were found in five patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of BUB1B, LIG4, and MEN1. Two of the five patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. While this is the first report of the germline genetic analysis of Japanese children with RMS with detailed clinical information, 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.

PurposeWhilst proton beam therapy (PBT) for children with cancer is expected to reduce their comorbidities, to date only a limited number of studies have been published. To analyze the long-term comorbidity and health-related quality of life (HRQoL) of childhood cancer survivors (CCSs) after PBT, we conducted a questionnaire-based study.MethodsQuestionnaires were sent to CCSs who underwent PBT at the University of Tsukuba Hospital during the period from 1984 to 2020. Scores from 41 CCSs who did not undergo PBT (noPBT-CCSs) and from the general population were used for comparison.ResultsIn total, 110 individuals who underwent PBT participated in the study. Among them, 40 individuals were longitudinally analyzed. The range of change in the scores was significantly greater in the CCSs whose initial scores were low. Although the comorbidity levels were more severe, HRQoL tended to be better in the PBT-CCSs than in the noPBT-CCSs with central nervous system (CNS) or solid tumors, respectively. When compared with the general population, the psychosocial health summary scores and its components were not different in the noPBT-CNS-CCSs. On the other hand, the psychosocial health summary scores and/or at least one of the scores of emotional, social, and school functioning were significantly higher in the other CCSs groups.ConclusionsThe HRQoL scores of CCSs with low initial scores can be greatly changed over time. Appropriate psychosocial support for this population is warranted. PBT may avoid reduction in HRQoL in terms of the psychosocial functioning of CCSs with CNS tumors.

Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18 months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4 months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4 months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48 months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4 months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient’s AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia.

[Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4–93.3%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6543; 80.0% (95% CI: 75.7–83.6%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5–76.7%) vs. 40.2% (95% CI: 31.6–48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001). The rates of brain necrosis were 8–50% after PT and 0–4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings.

Background/Objectives: PBT enables precise targeting of tumors, which reduces side effects on surrounding organs, with particularly significant benefits for pediatric tumors. However, the efficacy of PBT compared to photon RT for pediatric medulloblastoma is unclear. A meta-analysis to assess the efficacy of PBT vs. photon RT for this disease was performed. Methods: Articles focusing on postoperative primary medulloblastoma from 1990 to 2022 were systematically reviewed and survival outcomes were extracted for medulloblastoma treated with PBT or photon RT. Meta-regression was used to identify predictive factors for treatment outcomes, including modality (PBT vs. photon RT), disease risk classification, gender, and age. Results: From 935 records, 18 articles were included (14 on photon RT, with 6 focusing on high-risk cases, and 4 on PBT). In standard-risk cases, the 1-, 3-, and 5-year overall survival (OS) rates were 95.5% (95% CI: 87.2–98.4%) vs. 96.7% (95% CI: 93.5–98.4%) (p = 0.1210); 89.8% (95% CI: 85.3–92.9%) vs. 88.0% (95% CI: 83.7–91.3%) (p = 0.5416); and 82.9% (95% CI: 76.6–87.6%) vs. 82.4% (95% CI: 77.2–86.5%) (p = 0.8313), respectively. For high-risk cases, the OS rates were 88.9% (95% CI: 85.5–91.6%); 73.6% (95% CI: 60.9–82.8%); and 68.6% (95% CI: 56.1–78.3%), respectively. The 1-, 3-, and 5-year progression-free survival (PFS) rates in standard-risk cases were 95.2% (95% CI: 91.8–97.2%) vs. 93.8% (95% CI: 89.4–96.5%) (p = 0.5275); 82.9% (95% CI: 77.3–87.2%) vs. 82.5% (95% CI: 80.1–84.7%) (p = 0.4294); and 79.6% (95% CI: 73.1–84.6%) vs. 77.0% (95% CI: 72.7–80.8%) (p = 0.3938), respectively. For high-risk cases, the PFS rates were 83.5% (95% CI: 77.0–88.3%); 64.8% (95% CI: 53.2–74.2%); and 60.4% (95% CI: 47.0–71.4%), respectively. Meta-regression analysis indicated no significant differences in 1- to 5-year OS and PFS between radiation modalities. Standard-risk cases were significantly associated with better OS and PFS. Younger age was significantly associated with 1- and 2-year OS and 1-year PFS, and male gender was significantly associated with 3-year OS and 3-year PFS. Conclusions: Postoperative irradiation for pediatric medulloblastoma using PBT has a therapeutic effect comparable to that of photon RT. This suggests that PBT is a useful option among RT modalities for medulloblastoma.

Proton beam therapy (PBT) is effective for pediatric tumors, but patients may require sedation and other preparations, which extend the treatment time. Pediatric patients were classified into sedation and non-sedation cases. Adult patients were classified into three groups based on irradiation from two directions without or with respiratory synchronization and patch irradiation. Treatment person-hours were calculated as follows: (time from entering to leaving the treatment room) × (number of required personnel). A detailed analysis showed that the person-hours required for the treatment of pediatric patients are about 1.4–3.5 times greater than those required for adult patients. With the inclusion of additional time for the preparation of pediatric patients, PBT for pediatric cases is two to four times more labor-intensive than for typical adult cases.

To compare late renal effects in pediatric and adult patients with malignancies after PBT involving part of the kidney. A retrospective study was conducted to assess changes in renal volume and function in 24 patients, including 12 children (1–14 years old) and 12 adults (51–80 years old). Kidney volumes were measured from CT or MRI images during follow-up. Dose-volume histograms were calculated using a treatment planning system. In children, the median volume changes for the irradiated and control kidneys were −5.58 (−94.95 to +4.79) and +14.92 (−19.45 to +53.89) mL, respectively, with a relative volume change of −28.38 (−119.45 to −3.87) mL for the irradiated kidneys. For adults, these volume changes were −22.43 (−68.7 to −3.48) and −21.56 (−57.26 to −0.16) mL, respectively, with a relative volume change of −5.83 (−28.85 to +30.92) mL. Control kidneys in children exhibited a marked increase in size, while those in adults showed slight volumetric loss. The percentage of irradiated volume receiving 10 Gy (RBE) (V10) and 20 Gy (RBE) (V20) were significantly negatively associated with the relative volume change per year, especially in children. The CKD stage based on eGFR for all patients ranged from 1 to 3 and no cases with severe renal dysfunction were found before or after PBT. Late effects on the kidneys after PBT vary among age groups. Children are more susceptible than adults to significant renal atrophy after PBT. V10 and V20 might serve as predictors of the degree of renal atrophy after PBT, especially in children. PBT has a minimal impact on deterioration of renal function in both children and adults.

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.