Fleifil et al. recently reported the DNAJB1::PRKACA fusion in 70% of hepatoblastomas (HB), suggesting its diagnostic relevance beyond fibrolamellar carcinoma (FLC). Here, an international consortium re-examined this claim using 225 independent assays across 148 HB samples from five institutions. We found no evidence of the DNAJB1::PRKACA fusion in any HB case, in contrast to 286/290 FLC samples. These findings demonstrate that the fusion remains specific to FLC and underscore the need for rigorous validation before clinical interpretation of molecular findings in pediatric liver tumors.

OBJECTIVES:Sodium thiosulfate (STS) has recently been approved as an otoprotectant for systemic use in pediatric cancer patients receiving cisplatin treatment for localized, nonmetastatic solid tumors by the Food and Drug Administration, European Medicines Agency, and Medicines and Healthcare Products Regulatory Agency. While incorporating STS into the current standard of care pediatric practice, questions about uniform, timely, and safe administration are raised that may benefit from additional guidance. DESIGN:Recognizing that advancing clinical practice presents multiple challenges, an international onco-ototoxicity prevention task force, including experts in pediatric oncology, audiology, and pharmacology, was established to identify potential barriers to the implementation of otoprotection and to offer practical solutions for clinical services for children exposed to cisplatin, based on available evidence, as well as consensus where data are less robust. This task force held several online meetings and a working group session at the annual SIOPE meeting in Milan in May 2024, where the challenges for implementing STS were outlined and addressed. RESULTS:Nine key challenges were identified, including, for example, the timing of both cisplatin infusion and STS administration, the optimal integration of STS into existing treatment protocols, potential drug interactions, and relevant economic considerations. CONCLUSION:In this article, we propose practical steps to address these challenges, informed by the existing literature and expert opinion, incorporating recommendation statements from the international onco-ototoxicity prevention task force on behalf of the SIOP Supportive Care Network, to facilitate the implementation of STS in children with localized, nonmetastatic disease.

BACKGROUND:Pediatric hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC) have historically been studied on prospective trials in aggregate with hepatoblastoma (HB). It is now recognized that both HCC and FLC have unique histologies, characteristic genomics, and a more aggressive clinical course than HB. It is anticipated that data analyzed from patients treated on previously conducted international trials will inform current and future approaches to the study of these rare diseases. METHODS:The Children's Hepatic tumors International Collaboration houses data from clinical trials conducted by three global consortia as well as international registries. Data from patients with HCC or FLC who were enrolled on historic trials designed for patients with HB were analyzed for patient demographics, disease characteristics, treatment, and outcomes. RESULTS:The authors identified 236 patients with pediatric HCC or FLC who were enrolled on trials conducted in the United States, Europe, and Japan. As anticipated, HCC and FLC predominantly affected adolescent patients, and outcomes were generally related to extent of disease and resectability. Independent of histology, upfront resection (p = .004) predicted superior survival, likely reflecting the inadequacies of systemic agents to control disease. Outcomes were comparable across studies, with a 5-year survival rate of 36%, independent of chemotherapy received. Survival was equivalent for patients with HCC and FLC after 7-year follow-up. CONCLUSIONS:Treatment of pediatric HCC and FLC remains challenging. The current results support risk-stratification methods currently under study prospectively and the independent study of these tumors in the future.

Cisplatin-induced hearing loss (CIHL) in pediatric cancer patients is an irreversible and highly prevalent adverse effect with a devastating impact on quality of life. Sodium thiosulfate (STS) has recently been approved for systemic administration as an otoprotective agent in children. However, implementation of systemic STS has its challenges, and there is currently limited evidence to support local STS for children. This review investigates the potential value of locally administered otoprotective agents other than STS with a focus on future pediatric implementation. We conducted a systematic review on the efficacy and safety of locally applied non-STS otoprotective agents in in vivo settings. This included a summary of investigated drug delivery methods and administration routes. We identified 70 preclinical and eight clinical studies. Agents were categorized based on their biological mechanisms: anti-inflammatory, chemical deactivators, calcium blockers, biologicals, and miscellaneous mechanisms. Preclinical studies investigated 45 different agents. Dexamethasone and N-acetylcysteine were identified as efficacious agents recurrently and progressed to clinical trials. Dexamethasone was investigated in three randomized clinical trials (RCTs) and three non-randomized clinical studies and showed statistically significant but not clinically relevant benefit in two trials. N-acetylcysteine was investigated in two clinical trials and one RCT and was minimally effective in the RCT and in one clinical study. Our review did not identify available studies of local alternative otoprotective agents that could reliably replace systemic STS in terms of safety and efficacy for pediatric patients. Further research on the optimal dosage, delivery method, and timing of otoprotective agents is needed.

Pediatric adrenocortical tumors (pACTs) are rare neoplasms with limited biomarkers for risk stratification. Two DNA methylation-based molecular subtypes (A1 and A2) previously identified using data from the International Pediatric Adrenocortical Tumor Registry cohort were strongly associated with outcome, with A1 linked to poor prognosis and A2 to indolent disease. The objective of the current study was to validate the prognostic utility of pACT molecular subtypes in the clinical trial cohort from the Children’s Oncology Group ARAR0332 protocol (ClinicalTrials.gov: NCT00304070, registration date: 3/15/2006). A DNA-methylation-based neural-network classifier trained on 60 reference samples was used to assign ARAR0332 samples to A1, A2, or normal adrenal classes. The class assignments were correlated with clinical variables, genomic features, and survival outcomes. Among ARAR0332 samples, 11 (22%) were classified as A1 and 38 (78%) as A2. A1 tumors were associated with older age, metastatic disease, Cushing syndrome, and CTNNB1 mutations, while A2 tumors presented in younger patients (mean 4.1 years) and in patients who more often exhibited virilization. A1 tumors had significantly worse 5-year event-free survival and overall survival compared to A2 tumors. In patients with non-metastatic tumors, methylation class remained a significant predictor of risk even after adjusting for clinical stage and histopathologic risk class as defined by Wieneke criteria. Taken together, our findings suggest integration of methylation class with clinical stage and histopathologic features could improve risk stratification on future risk-adapted clinical trials.

Abstract Purpose: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies. Patients and Methods: Patients with TP53 wild-type malignancies were enrolled in a monotherapy arm (solid/central nervous system tumors) or a combination arm with cytarabine (acute leukemia). Monotherapy dosing used the Targeted-Agent Continual Reassessment Method design for dose escalation. Pharmacodynamic assessment included serum macrophage inhibitory cytokine-1 (MIC-1) as a biomarker of p53 activation. Circulating tumor DNA (ctDNA) was analyzed for emergent TP53 mutations. Results: Twenty-two patients enrolled; 20 received treatment (17 monotherapy and 3 combination). The most common diagnosis was Ewing sarcoma (n = 5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and 1 patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLT occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30- to 50-fold by 24 hours after dose at dose levels 2 to 4, confirming on-target p53 activation. Among 19 response-evaluable patients, 1 partial remission occurred in a patient with relapsed acute lymphoblastic leukemia on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample. Conclusions: ALRN-6924 was well tolerated in children, with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and the evaluation of higher dose levels.

OBJECTIVE:To evaluate the impact of surgical guidelines on the management of children with hepatoblastoma. BACKGROUND:The Children's Oncology Group study AHEP0731 was the first pediatric cooperative group trial to propose guidelines for the surgical management of children with hepatoblastoma. METHODS:AHEP0731 enrolled children with hepatoblastoma between 2009 and 2018. Surgical guidelines were based upon radiographic extent of disease (PRETEXT, POST-TEXT). Planned non-real-time central review of imaging was completed at diagnosis and after two, four, and six cycles of chemotherapy to determine guideline adherence. Resection rate, event-free survival (EFS), overall survival (OS), and complications were compared between guideline adherent and nonadherent groups. RESULTS:Of 226 enrolled patients, 221 were evaluable of whom 205 (93%) underwent definitive surgical resection. Guideline adherence for protocol recommended timing of resection was 65% (133/205). The nonadherent group included 44/205 (21%) patients who underwent early resection and 28/205 (14%) patients who underwent late resection or late transplantation. Eighty-five patients met criteria for early referral to a liver transplant center, of whom 55 (65%) were referred within the recommended timeframe. Twelve patients received liver transplants outside of surgical guidelines. There were no significant differences in EFS, OS, or complication rates between adherent and nonadherent groups. CONCLUSIONS:Implementation of surgical guidelines, in combination with effective chemotherapy and radiologic staging, produced a higher rate of definitive tumor resection compared to historical trials. Nonadherence with surgical guidelines resulted in liver transplantation in some patients for whom partial hepatectomy might have been an option.

PURPOSE:Individuals with Li-Fraumeni syndrome (LFS) are at risk of developing cancer in multiple organs and therefore require a multimodal screening program. We assessed the performance of annual whole-body noncontrast magnetic resonance imaging (WBMRI) in early cancer detection for individuals with LFS. METHODS:Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual noncontrast WBMRI. Clinical findings on WBMRI, follow-up studies, biopsies, and cancer incidence were prospectively assessed. RESULTS:One hundred sixty-two participants with LFS (127 adult, 35 pediatric) underwent 477 WBMRIs; 119 (73%) underwent three or more. The median age at enrollment was 37 years; 75% of participants were female. Classic or Chompret diagnostic criteria for LFS were met for 68.5% of participants. Follow-up studies for findings on WBMRI were pursued for 55.6% of participants. Biopsies were performed in 18% of participants; 39.5% of 38 biopsies confirmed a cancer diagnosis. The rate of follow-up interventions decreased with consecutive WBMRIs. During the study period, of 37 cancers diagnosed in 33 participants, 15 (40.5%) were diagnosed by WBMRI; 86% (13 of 15) were asymptomatic, localized cancers treated with curative intent. The 22 cancers not diagnosed on WBMRI included five sarcomas; one each of adrenocortical, lung, thyroid, and renal cell carcinomas; and 13 cancers that WBMRI would not be expected to detect. CONCLUSION:Annual WBMRI contributes substantially to the detection of asymptomatic localized cancers among individuals with LFS and is best used in conjunction with a multimodality approach endorsed by LFS guidelines. Our study highlights the need for further research to enhance early detection and interception of cancer in LFS.

Hepatoblastoma is the most common primary liver cancer in children, with an incidence of approximately 1.5 cases per million children per year. Most cases are sporadic, typically presenting at a median age of 18 months, with only 5% occurring after 4 years of age. Clinical presentation often includes an abdominal mass and, less commonly, abdominal pain, weight loss, jaundice and precocious puberty. Low birth weight is a significant risk factor, along with genetic conditions such as Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18. Screening protocols for hepatoblastoma are recommended for children with predisposing conditions. Medical imaging is crucial for hepatoblastoma diagnosis and staging, with abdominal ultrasonography being the initial modality of choice, followed by abdominal contrast MRI for detailed evaluation and monitoring. Chest computer tomography is indicated to evaluate potential lung metastases. The Pretreatment Extent of Disease (PRETEXT) system is employed for hepatoblastoma staging and for guiding treatment strategies such as surgical resection and chemotherapy. Patients with advanced hepatoblastoma may require liver transplantation. Advancements in surgery and chemotherapy have improved survival rates, with 5-year survival rates exceeding 80-90% in localized disease. However, challenges remain in treating individuals with high-risk and metastatic hepatoblastoma. Ongoing research into treatment stratification, the introduction of novel therapies, including targeted and immune therapies, and the application of otoprotectants are essential to address refractory or recurrent hepatoblastoma and to increase the overall survival of patients. Long-term quality of life and the management of treatment-related sequelae are becoming increasingly important as survival rates improve.

Malignant liver tumors affecting children and adolescents are rare. In order to adequately study liver tumors occurring in this patient population and establish a more uniform approach to therapy, the three primary liver tumor consortia, SIOPEL (mainly European), COG (mainly North American) and JCCG (Japan), in concert, designed an international prospective clinical trial [PHITT (Paediatric Hepatic International Tumour Trial)/COGAHEP1531/JPLT4 – to be referred to as PHITT from this point forth] for the study of hepatoblastoma and hepatocellular carcinoma in children and adolescents. Recruitment to PHITT has recently concluded. The major results from this trial will be published in the next 2–3 years, therefore in the interim, we sought to provide a consensus statement on evidence-based chemotherapy guidance for hepatoblastoma and hepatocellular carcinoma of all stages.

Romiplostim for chemotherapy-induced thrombocytopenia (CIT) is not well-studied in children. This single-center retrospective cohort study describes 24 pediatric patients with solid tumors who initiated romiplostim a median of 5 months into chemotherapy (range: 0-14 months) at a median maximum dose of 6.5 µg/kg (range: 1-10). A minority of patients achieved a decrease in cycle delays (30%) or dose reductions (13%). A comparative cohort, which did not receive romiplostim, had no difference in cycle delays (p = 0.42) or dose reductions (p > 0.99). There were no adverse events. Romiplostim was safe in children with solid tumors, but requires further prospective study of efficacy.

BACKGROUND:Hypercalcemia is rarely observed in pediatric patients with cancer. However, rare cases of renal insufficiency and osteoporosis have been reported as severe consequences. Published literature focuses predominantly on hypercalcemia in pediatric hematologic malignancies, precluding causative associations with solid tumor disease histology or tumor characteristics. METHODS:In this retrospective cohort analysis, we identified 39 patients (aged < 21 years) diagnosed and hospitalized with a solid tumor and prolonged hypercalcemia over the span of 25 years at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Hypercalcemia was defined as a sustained serum calcium of at least 11.5 mg/dL for more than 1 week. Disease characteristics, clinical symptoms, management, and outcome were analyzed. RESULTS:The median age for patients in this cohort was 2.3 years, and the majority of patients had a diagnosis of neuroblastoma, rhabdoid tumor, hepatoblastoma, or rhabdomyosarcoma. The 39 patients experienced 45 episodes of hypercalcemia, with a median peak serum calcium level (corrected for albumin) of 13.1 mg/dL. The median time from tumor diagnosis to a hypercalcemic episode was 5.4 months, suggesting that disease-directed therapy, tumor progression, or organ dysfunction may have contributed. Peak ionized calcium was not significantly associated with bone or bone marrow involvement, nor with metastatic disease. CONCLUSIONS:This work describes the largest retrospective series of pediatric patients with solid tumors and hypercalcemia to date. Hypercalcemia was most frequently reported for a small subset of diseases, suggesting that disease histology, biology, and the intensive therapeutic interventions required to treat these diseases may be contributing to hypercalcemic risk.

AIMS:Hepatocellular adenomas (HCAs) are rare in children and often arise in distinct clinical contexts, despite sharing classification frameworks with adult cases. This series evaluates the clinicopathologic features of HCAs in patients 21 years or younger, highlighting phenotype-genotype correlations and the clinical relevance of molecular testing. METHODS AND RESULTS:27 HCAs from 26 patients (69% female; mean age: 16.2 years) were analyzed. Based on morphology and immunohistochemistry (IHC), most cases were unclassified (46%), followed by inflammatory (35%), HNF1A-inactivated (15%) and β-catenin-activated (4%) subtypes. Most patients (69%) had multifocal disease. In addition to classic risk factors such as oral contraceptive use and obesity, 35% had a history of neoplasm and 15% had glycogen storage disease. Next-generation sequencing was performed on 13 HCAs; germline testing was available in 1 patient with familial adenomatous polyposis. While molecular testing had limited impact on reclassification, it was valuable in cases with ambiguous IHC profiles and in guiding management of patients with atypical or syndromic presentations by excluding variants associated with malignant potential. CONCLUSIONS:Paediatric HCAs arise in diverse clinical contexts and may require individualized treatment planning. While histologic and immunophenotypic evaluation is sufficient in most cases, molecular profiling adds value in diagnostically challenging scenarios and may help guide management decisions.

10501 Background: Individuals with LFS are at risk for developing cancer in multiple organs and therefore require a multimodal cancer screening program. We assessed the performance of annual WBMRI in early cancer detection for individuals with LFS. Methods: Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual non-contrast WBMRI. Clinical findings on WBMRI, follow-up studies, and biopsies were prospectively assessed. Cancer incidence during the study period and up to 18 months after WBMRI was evaluated. Results: 162 eligible participants (pts) with LFS (127 adult, 35 pediatric) underwent a total of 477 WBMRIs; 119 (73%) underwent 3 or more. Median age at enrollment was 37 years; 75% of pts were female. Classic or Chompret diagnostic criteria for LFS were met for 66% (84/127) of adult and 77% (27/35) of pediatric pts. Follow-up studies for findings on WBMRI were pursued for 61.4% (78/127) of adult and 34.3% (12/35) of pediatric pts. Biopsies were performed without complication in 18% (29/162) of pts with 39.5% of 38 biopsies confirming a cancer diagnosis. The percentage of pts requiring follow-up studies or biopsies decreased with consecutive WBMRIs (Table 1). During the study period, 37 cancers were diagnosed in 33 pts (27 adults, 6 children); 26 of these pts were alive at the time of data cut off. Fifteen of 37 cancers (40.5%) were asymptomatic cancers diagnosed by WBMRI; 86% (13/15) of these (in 12 patients) were localized and treated with curative intent, including 3 lung cancers and 4 pelvic/abdominal sarcomas. Ten of these 12 pts remain alive at the time of last follow-up. The 22 cancers not diagnosed on WBMRI included five sarcomas, and one each of adrenocortical, lung, thyroid and renal cell carcinoma as well as cancers not likely to be detected on WBMRI (4 breast/chest wall, 3 endoluminal, 3 hematologic, and 3 metastatic recurrences). Conclusions: Annual WBMRI contributes substantially to detection of asymptomatic localized cancers among individuals with LFS but interval cancers remain common. Our study highlights limitations of WBMRI and the need for further research to enhance early detection and interception of cancer in LFS. Sequence of WB-MRI scans and timing of follow-up studies, biopsies, and cancer diagnoses. WB-MRI scan number # pts evaluated # pts with follow-up studies n (%) # pts with biopsiesn (%) # pts dx with ca by WBMRI n (%) # ca dx based on WBMRI n # pts with interval ca dxn (%) # interval ca dx by other means or symptoms (not detected on WBMRI) n 1 162 60 (37.0) 20 (12.3) 6 (3.7) 7 8 (4.9) 8 2 143 38 (26.6) 12 (8.4) 6 (4.2) 6 7 (4.9) 9 3 119 21 (17.6) 3 (2.5) 0 (0) 0 3 (2.5) 3 4 33 5 (15.2) 1 (3.0) 1 (3.0) 1 2 (6.1) 2 5 11 1 (9.1) 0 (0) 1 (9.1) 1 0 (0) 0 6 5 1 (20) 0 (0) 0 (0) 0 0 (0) 0 7 3 1 (33.3) 0 (0) 0 (0) 0 0 (0) 0 pts: participants, ca: cancer, dx: diagnosed.

AIMS:Hepatoblastoma is the most common primary malignant tumour of the liver diagnosed in children and its incidence is increasing worldwide. Ongoing international clinical trials and scientific collaborative efforts are attempting to standardize the diagnosis, risk stratification and management of young patients diagnosed with this rare cancer, which includes surgical resection of the tumour. Here we report the international consensus-based dataset for the pathology reporting of hepatoblastoma resection specimens. The dataset was developed under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of international pathology and cancer organizations. METHODS AND RESULTS:According to the ICCR's guidelines for dataset development, an international expert panel including paediatric pathologists and a paediatric oncologist specialized in liver tumours developed a set of core and non-core data items for hepatoblastoma resection specimens based on critical review and discussion of current evidence available. Members of the panel were specialists working in tertiary paediatric hospitals, central reviewers for international paediatric liver tumours consortia and/or involved in paediatric liver tumour trials expert committees. Commentaries were provided to support each data item, explaining the rationale for selecting them as a 'core' or 'non-core' elements, their clinical relevance and highlighting potential areas of lack of evidence, including clinical, macroscopic, microscopic and ancillary testing considerations. The hepatoblastoma dataset was finalized and ratified following international public consultation and is published on the ICCR website for wide implementation. CONCLUSION:This is the first international dataset developed by an international expert panel for reporting hepatoblastoma resection specimens aimed to promote high-quality, standardized pathology reporting of these rare paediatric liver tumours. The adoption and implementation of this hepatoblastoma data set, freely available worldwide on the ICCR website (www.iccr-cancer.org/data-sets), will facilitate accurate reporting and enhance the consistency of data collection, support retrospective and inform prospective research and ultimately help to improve clinical outcomes of children with hepatoblastoma.

BACKGROUND:Cisplatin-induced hearing loss (CIHL) remains a significant complication of pediatric cancer treatment. We evaluated the feasibility, safety, and trends of the efficacy of intratympanic injections of sustained-exposure dexamethasone thermosensitive gel (OTO-104) for otoprotection. PROCEDURE:In this multisite randomized phase 2 trial (NCT02997189), patients aged 0.5-21 years with newly diagnosed cancer treated with cisplatin were eligible. Participants' ears were randomized to receive up to three intratympanic injections of 0.2 mL OTO-104 in one ear and no treatment contralaterally. OTO-104 was administered by an otolaryngologist within 72 hours preceding each cisplatin cycle. Feasibility was determined by the successful administration of intended doses. Treatment-emergent adverse events (TEAEs) and outcomes were monitored by physical examination, concurrent medications, otoscopy, tympanometry, and audiometry. RESULTS:From January 6 to September 26, 2017, 18 doses of OTO-104 were administered to 11 evaluable participants across 5 centers (range, 1-14 years; 9 neuroblastoma and 2 osteosarcoma) via intratympanic injection (9) or tympanostomy tube (2). Sixteen injections were paired with other procedural sedations and two were performed awake; all injections were successfully delivered. The median interval between OTO-104 and cisplatin was 14 hours (range, 7-64). Clinically insignificant tympanic scabs were noted in five participants; no middle ear changes were observed. There were three otologic TEAEs (two transient mild-moderate otalgia [related] and one hypoacusis [unrelated]) and no related non-otologic TEAEs. CIHL developed similarly in treated versus untreated ears; the trial was terminated early. CONCLUSIONS:Although dexamethasone at this dose was not otoprotective, these results suggest that intratympanic injection may be safe, feasible, and a viable delivery platform for testing other otoprotectants.

Hepatoblastoma is the most common primary liver cancer in children, with an incidence of approximately 1.5 cases per million children per year. Most cases are sporadic, typically presenting at a median age of 18 months, with only 5