Language：English   Publisher：Pediatric Blood and Cancer  

Programs allowing access to investigational drugs and off-label drug use for serious diseases have often been applied to pediatric cancers. A clinical study conducted under the Japanese “Patient-Proposed Healthcare Services” evaluated the efficacy and safety of dabrafenib plus trametinib in children with BRAF V600 mutant glioma (jRCTs071210071). This study successfully provided unapproved and off-label medications to four enrolled patients, two with low-grade glioma and two with high-grade glioma (median age: 10.5 years), until regulatory approval. The timeframe and data collection from such access programs need to be optimized for pediatric patients in accordance with the healthcare system of each nation.

DOI： 10.1002/pbc.31510

Web of Science

Scopus

PubMed

Language：English   Publisher：Early Human Development  

Background: Many studies have indicated an association between maternal occupational exposure to hazardous agents, such as anticancer drugs and ionizing radiation, and an increased risk of adverse pregnancy outcomes, including stillbirths or miscarriages and physical abnormalities in offspring. However, the effects of recent advancements in protective measures to reduce these risks have not been clarified. Aim To investigate the current impact of parental occupational exposure to anticancer drugs and ionizing radiation on stillbirths or miscarriages as well as physical abnormalities under the circumstances of the developed safety protocols. Methods: This cohort study utilized The Japan Environment and Children's Study dataset, which included 96,606 fetuses born between January 2011 and March 2014. This study focused on the association between occupational exposure to these agents during pregnancy and the incidence of stillbirths or miscarriages and physical abnormalities in offspring, employing Poisson regression models for adjusted relative risk. Results: From the study population, 471 cases of stillbirths or miscarriages and 4493 infants with physical abnormalities were identified. Fisher's exact tests indicated no significant differences in fetal loss or physical abnormalities between the exposure groups. A multivariable analysis also found no significant association between maternal exposure to anticancer drugs and ionizing radiation and these adverse outcomes. Conclusion: Under improved safety measures, maternal occupational exposure to anticancer drugs and ionizing radiation does not significantly affect the occurrence of stillbirths or miscarriages and physical abnormalities in offspring. These findings highlight the critical role of current safety practices and indicate lower reproductive risks with proper precautions.

DOI： 10.1016/j.earlhumdev.2025.106195

Web of Science

Scopus

PubMed

Language：English   Publisher：Pediatric Research  

Background: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study aimed to examine whether such occupational exposure increased the risk of childhood cancer in offspring. Methods: We used the dataset of the Japan Environment and Children’s Study, a nationwide birth cohort involving over 100,000 mother–child pairs. Information was obtained via successive questionnaires that were completed until the child turned 1 year of age. The parents were asked whether they occupationally handled medical agents during pregnancy. Results: A total of 26 infants developed neoplasms: neuroblastoma, leukemia, and brain tumor. The incidence of neuroblastoma was significantly higher in infants whose mothers were exposed to radiation (3/2142: 140.1 per 100,000 population) than in those who were not (12/90,384: 13.3 per 100,000 population). Multivariable regression analyses revealed a close association between maternal irradiation and the development of neuroblastoma (adjusted incident rate ratio: 10.68 [95% confidence interval: 2.98‒38.27]). Conclusions: The present study demonstrated, for the first time, a potential association between maternal occupational exposure and the occurrence of neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results. Impact: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study examined the association between such occupational exposure and offspring’s cancers that developed until the age of 1 year. Maternal exposure to ionizing radiation was associated with infantile neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results.

DOI： 10.1038/s41390-021-01634-z

Scopus

PubMed

Language：English   Publisher：Pediatric Blood and Cancer  

Background: Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). Methods: We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Results: Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020–2023, n = 58) than in the pre-DF era (31% vs. 13%, p =.04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p =.04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p <.01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p =.01) and juvenile myelomonocytic leukemia (OR = 8.98, p =.04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Conclusions: Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

DOI： 10.1002/pbc.31331

Web of Science

Scopus

PubMed

Language：English   Publisher：Blood Advances  

Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

DOI： 10.1182/bloodadvances.2023010080

Web of Science

Scopus

PubMed

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

小児がんの細胞起源は胎児期にあり、職業性曝露を含む妊産婦の様々な環境因子への曝露が影響している可能性が指摘されている。抗がん剤や電離放射線への職業性曝露が、流産などの胎児期のリスクになることが報告されているが、小児がん発症との関連については一定の見解が得られていなかった。今回私たちは、妊娠中の母親の職業性の医療用物質曝露が小児がんのリスクになることを前向きコホートで初めて示した。妊娠中の母親の職業性曝露対策が、こどもの発がん予防に寄与する可能性があると考えられた。(著者抄録)

Language：Japanese   Publisher：(有)科学評論社