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Simple Summary: Fusion oncoprotein DNAJB1-PKAc was found only in adolescent patients with fibrolamellar HCC. Expression of the fusion kinase in FLC patients causes the formation of fibrotic lamellar structures, increased proliferation, and massive alterations in transcriptome profiling that drive FLC disease. In this paper, we identified cancer cells expressing the DNAJB1-PKAc in 1–3-year-old children with pediatric liver cancers and children with biliary atresia. The expression of DNAJB1-PKAc enhances the development of pediatric liver cancers by bringing fibrolamellar-specific disorders, by increasing the rate of proliferation, and by increasing resistance to chemotherapy. Expression of DNAJB1-PKAc in patients with biliary atresia correlates with an increased expression of oncogenes. Background and Aims: Hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC) are the most common liver malignancies in children and young adults. FLC oncogenesis is associated with the generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). J-PKAc has been found in 90% of FLC patients' tumors but not in other liver cancers. Since previous studies of J-PKAc were performed with adolescent patients, we asked if young children may express J-PKAc and if there are consequences of such expression. Methods: The biobank of the pediatric HBL/HCN-NOS specimens was examined by QRT-PCR, Western blots, RNA-Seq, and immunostaining with fusion-specific antibodies. Results: J-PKAc is expressed in 70% of the HBL/HCN-NOS patients. RNA-Seq analysis revealed that HBL tumors that do not have cells expressing J-PKAc show elevated expression of the membrane attack complex (MAC), which eliminates cells expressing J-PKAc. The fusion-positive HBL/HCN-NOS samples have several signaling pathways that are different from fusion-negative HBLs. Upregulated pathways included genes involved in the G1 to S transition and in liver cancer. Downregulated pathways included over 60 tumor suppressors, the CYP family, and the SLC family. The repression of these genes involves J-PKAc-β-catenin-TCF4-mediated elevation of the HDAC1-Sp5 pathway. The identified upregulated and downregulated pathways are direct targets of the fusion kinase. The J-PKAc kinase is also detected in livers of 1-year-old children with biliary atresia (BA). Conclusions: J-PKAc is expressed in both HBL tumor and BA liver samples, contributing to the development of HBL and creating a transcriptome profiling consistent with the potential development of liver cancer in young patients. [ABSTRACT FROM AUTHOR]

The objective of this study is to report the long‐term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event‐free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre‐specified groups. Two hundred and twenty‐two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8‐year EFS was 75% (95% confidence interval: 69%–83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow‐up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post‐chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: A retrospective review of patients treated for retinoblastoma who developed a non-pineoblastoma second primary malignant neoplasm (SPMN) was performed. Methods: The demographics, clinical features and treatments for retinoblastoma, pathologic types of non-pineoblastoma second primary malignant neoplasm (SPMN), intervals between the retinoblastoma diagnosis and treatment and diagnosis of non-pineoblastoma SPMN, treatment provided for the SPMN, and the survival outcomes of the patients were evaluated. Results: Of 550 patients treated initially for retinoblastoma, this series used the 15 (2.7) that developed a non-pineoblastoma SPMN, 14 of which (93.3%) had been treated for bilateral retinoblastoma. All patients had carried a germline mutations in the RB1 gene. The median time from retinoblastoma diagnosis to SPMN diagnosis was 19.0 years (extremes 3.4 and 39.4 years). Six of the fifteen patients died during the follow-up of their SPMN. The median interval between initial retinoblastoma diagnosis and death in the 6 patients who died of their SPMN was 18.8 years (extremes 6.2 and 34.6 years) and between diagnosis of the SPMN and death was 1.2 years (extremes 0.25 and 4 years). Discussion: Of the patients who had been treated with External Beam Radiotherapy (EBRT), 13 developed a SPMN within the previously irradiated field. [ABSTRACT FROM AUTHOR]

Background: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5‐year event‐free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk‐adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH‐1). Patients who had stage II/III disease received regimen I with RT. Methods: Four‐year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage‐appropriate chemotherapy. Results: Eighty‐two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4‐year EFS rate was 82.7% (95% confidence interval [CI], 74.8%–91.4%) for AREN0321 and 89.6% (95% CI, 81.3%–98.7%) for AREN03B2 only (p =.28). When combining studies, the 4‐year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%–100.0%), 93.4% (95% CI, 86.4%–100.0%), 82.8% (95% CI, 74.1%–92.6%), and 58.3% (95% CI, 34%–100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. Conclusions: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin‐containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced‐stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365). The results of this study indicate that treatment of clear cell sarcoma of the kidney can be risk‐adapted based on disease stage, radiotherapy should be omitted for patients with stage I disease if lymph nodes are sampled, and patients with stage IV disease appear to benefit from a carboplatin‐containing regimen. With treatment according to the Children's Oncology Group AREN0321 study, most relapses occurred within 3 years, and the most common sites of recurrence were in the central nervous system. [ABSTRACT FROM AUTHOR]

Background: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD‐4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS‐5, were reviewed. Methods: Combined outcomes for patients with EPM from NWTS‐5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS‐5. Prognostic factors were explored in the pooled cohort. Results: Forty‐seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS‐5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4‐year event‐free survival (EFS) of 77.3% (95% CI, 70.8–84.4) and 4‐year overall survival of 88.9% (95% CI, 83.9–94.2). Four‐year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6–89.4) vs 64.9% (95% CI, 51.7–82.2) on NWTS‐5; hazard ratio, 0.64, p =.26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. Conclusions: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. Clinical trial registration: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611. Pooled outcomes across three studies of patients with favorable histology Wilms tumor and extrapulmonary metastases revealed 4‐year event‐free survival of 77.3% and overall survival of 88.9%, with no statistical differences seen between patients on AREN0533 compared with those on NWTS‐5. Missing details on local management of metastatic sites informs a critical need for better data capture in future studies to optimize local control strategies and chemotherapy regimens for this higher‐risk favorable histology Wilms tumor patient group. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is the standard therapy for end-stage liver disease in pediatric patients with biliary atresia (BA), congenital and metabolic conditions, and for an unresectable malignant tumor like hepatoblastoma (HB). BA is the leading indication for pediatric liver transplantation, while HB is the most common childhood liver cancer. Despite improved outcomes through advanced surgical techniques and novel immunosuppression, pediatric liver transplantation (pLT) is complicated by post-transplant infections., Methods: A retrospective review was performed of pLT recipients at Cincinnati Children's Hospital Medical Center (CCHMC) and stratified patients by underlying disease to assess impact on post-transplant infectious events., Results: BA patients were youngest at pLT (12.5 months; p < 0.001) compared to other disease cohorts (HB 30.8, other 43.7). All HB patients received organs from deceased donors. In the year following pLT, 93% of the patients experienced at least one infectious event (IE). HB patients had the highest mean number of IE across disease groups (5.5 IE/patient vs. BA 4.5, other 4.0; p = 0.055), with significantly more patients with fever and neutropenia (p < 0.001) and EBV infections (p = 0.012). HB patients were more likely to develop IE earlier after pLT than non-HB groups (p = 0.013), especially Clostridioides difficile (p < 0.01) and fever and neutropenia (p < 0.01). Despite having variable IE experiences, 1-and-5-year survival across disease groups were similar., Conclusions: IE were frequently observed in HB patients after pLT, possibly related to pre-and-postoperative chemotherapy and associated neutropenia. Underlying disease may help inform targeted infection-related patient management following pLT., (© 2025 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: In the fifth National Wilms Tumor Study, patients received vincristine and dactinomycin (VA) without radiation for stage I focal anaplastic Wilms tumor (FAWT) and VA plus doxorubicin (DD4A) and radiation for stage II-IV FAWT. Four-year event-free survival (EFS) and overall survival (OS) for stage I FAWT were 67.5% and 88.9% and for stage IV FAWT were 61.4% and 71.6%, respectively. Therapy intensification for stage I and IV FAWT was evaluated as secondary objectives in AREN0321., Methods: Central review in the AREN03B2 Renal Tumors Classification, Biology, and Banking Study confirmed patient stage and tumor histology. Patients were then enrolled in AREN0321 and received DD4A with radiation for stage I-III FAWT and vincristine, doxorubicin, cyclophosphamide, carboplatin, and etoposide (UH-1/revised UH-1) with radiation for stage IV FAWT. Outcomes of patients with FAWT who were treated in AREN0321 (n = 25) and in AREN03B2 (n = 20) treated as per AREN0321 were analyzed., Results: In the pooled data analysis from AREN0321 and AREN03B2, 4-year EFS and OS were both 100% for stage I-II FAWT (n = 21), 82.4% (95% CI, 66.1%-100%) and 87.8% (95% CI, 73.4%-100%) for stage III FAWT (n = 17), respectively, and both 85.7% (95% CI, 63.3%-100%) for stage IV FAWT (n = 7). Four patients enrolled in AREN0321 had events: treatment failure occurred in three patients with stage III FAWT, and one treatment-related death was observed in a patient with stage IV FAWT following revised UH-1. No EFS or OS events occurred in patients with FAWT enrolled in AREN03B2 only., Conclusions: Patients with stage I and II FAWT have outstanding survival when treated with DD4A and radiation. Intensification of therapy may have improved survival for stage IV FAWT, albeit with an increased toxicity risk., (© 2025 American Cancer Society.)

Ototoxicity is among the adverse events related to cancer treatment that can have far-reaching consequences and negative impacts on quality-of-life for cancer patients and survivors of all ages. Ototoxicity management (OtoM) comprises the prevention, diagnosis, monitoring, and treatment, including rehabilitation and therapeutic intervention, of individuals who experience hearing loss, tinnitus, or balance/vestibular difficulties following exposures to ototoxic agents, including platinum chemotherapy (cisplatin, carboplatin) and cranial radiation. Despite the well-established physical, socioeconomic, and psychological consequences of hearing and balance dysfunction, there are no widely adopted standards for clinical management of cancer treatment-related ototoxicity. Consensus recommendations and a roadmap are needed to guide development of effective and feasible OtoM programs, direct research efforts, address the needs of caregivers and patients at all stages of cancer care and survivorship. Here we review current evidence and propose near-term to longer-term goals to advance OtoM in five strategic areas: (1) beneficiary awareness, empowerment, and engagement, (2) workforce enhancement, (3) program development, (4) policy, funding, and sustainability, and (5) research and evaluation. The goal is to identify needs and establish a roadmap to guide worldwide adoption of standardized OtoM for cancer treatment and improved outcomes for patients and survivors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/ WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future., Competing Interests: Conflict of Interest Statement: The authors have no conflicts of interest to declare.