James I. Geller

Relapse occurs in 10%–20% of children with hepatoblastoma and is associated with inferior outcomes, yet standardized management remains limited. Defining risk factors and relapse patterns, as well as the role of surgery, particularly transplantation, is critical to optimizing survival. A retrospective review was performed of patients aged 0–18 years diagnosed with hepatoblastoma from 2007 to 2024. Demographics, tumor characteristics, treatment course, relapse patterns, and outcomes were collected. Analyses included univariable and multivariable logistic regression, Kaplan–Meier survival estimation, and log‐rank testing. Among 135 patients, 98 (72.6%) achieved remission without relapse, 32 (23.7%) relapsed, and 5 (3.7%) experienced primary progression without remission. Older age, PRETEXT (pretreatment extent of disease) IV, metastatic disease at diagnosis, and macrovascular invasion were associated with relapse on univariable analysis, but only older age remained independently associated with relapse (adjusted odds ratio 1.27 per year, 95% confidence interval 1.05–1.53); PRETEXT IV and metastatic disease were not significantly associated with overall survival. Lung‐only relapse demonstrated favorable survival (100% alive), whereas combined liver and lung or extrahepatic relapse had poorer outcomes (40%–44% alive), although survival did not differ significantly across relapse sites ( p = 0.15). Of 54 liver transplant recipients, 44 underwent upfront transplantation, and 10 underwent salvage transplantation, with no significant difference in overall survival ( p = 0.90), although the salvage group was small. Relapse or progression after upfront transplantation occurred in 27% of recipients; lung‐only relapse again conferred favorable survival. Long‐term survival is achievable in relapsed hepatoblastoma, particularly for isolated pulmonary relapse. Older age, likely a surrogate for adverse tumor biology, was associated with relapse but did not preclude survival when aggressive multimodal therapy was used. Salvage transplantation achieved durable survival in selected patients and should be considered for unresectable intrahepatic relapse when extrahepatic disease is absent or controlled.

Objective: To determine whether the number of lymph nodes (LNs) sampled, LN positivity, and LN density impact event-free survival (EFS) or overall survival (OS) in patients with favorable histology Wilms tumor (FHWT). Background: LN sampling is a core component of the surgical staging used to assign appropriate therapy in FHWT. LN sampling has also been independently associated with decreased recurrence and improved survival in FHWT. Methods: Patients with stage I to III FHWT enrolled on the Children’s Oncology Group AREN03B2 study with upfront nephrectomy, confirmed LN sampling, and available follow-up and treatment data were included. Cox proportional hazards models with restricted cubic splines were used to visualize the effects of each continuous LN variable on the outcome. Results: A total of 2310 patients met the inclusion criteria. Among stage I to III LN-negative patients, the number of LNs sampled was associated with OS ( P =0.001) but did not impact EFS or vary by stage. In stage III LN-positive patients, neither the number of positive LNs nor LN density was associated with EFS or OS. EFS was significantly worse in stage III patients with LN-positive disease (LN-negative 4 y EFS: 93.7%, LN-positive 4 y EFS: 87.2%; P =0.0079), but OS did not differ significantly (LN-negative 4 y OS: 97.0%, LN-positive 4 y OS: 96.8%; P =0.61). Conclusion: While this analysis confirmed the negative prognostic impact of LN positivity on EFS and the association of OS and the number of LN sampled, these findings strongly underscore the need for standardized approaches to nodal sampling in FHWT. Such standardization is ongoing in current COG renal tumor trials.

Supplementary Figure 1. Inhibition of the cohesin ring by JQ1 inhibits proliferation of HepG2 and Huh6 cells.

Supplementary Figure 2. A diagram showing the presence of CEGRs/ALCDs in genes that were strongly downregulated by JQ1 in HepG2 and Huh6 cells.

The pediatric and adolescent liver cancers, hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC), respectively, are dangerous diseases requiring aggressive surgery, when feasible, and nontargeted toxic chemotherapy for a chance of cure due to insufficient knowledge of underlying molecular mechanisms. We have previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called cancer-enhancing genomic regions or aggressive liver cancer domains (CEGR/ALCD). In FLC, the fusion DNAJB1-PKAc (J-PKAc) oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this study, we found that all members of the cohesin ring—CTCF, Rad21, SMC1, SMC3, and STAG1—and β-catenin–TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin–TCF4–p300 complex, is detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces the proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific J-PKAc fusion oncogene.Implications:These studies provide evidence that J-PKAc–β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.

PURPOSE: Molecular biomarkers are increasingly used for risk stratification, particularly in up-front surgery settings (Children's Oncology Group trials), whereas in preoperative chemotherapy setting, the ongoing International Society of Pediatric Oncology (SIOP)-Renal Tumor Study Group-2016 UMBRELLA study aims to validate selected biomarkers for future risk-adapted treatment strategies. This systematic review summarizes all literature on the prognostic value of these biomarkers. MATERIALS AND METHODS: A systematic literature review (PubMed and Embase; up to January 2025) included studies with ≥50 de novo Wilms tumors (WTs). Eligible biomarkers included copy number variations; 1q gain, 1p and/or 16q loss of heterozygosity (LOH)/loss, 12 gain, 14q loss, 22 loss, 11p15 LOH/loss of imprinting (LOI), and structural somatic variants ( TP53 [and/or 17p loss], MYCN , FBXW7 , WT1 , WTX , SIX1/SIX2 , DROSHA , DGCR8 , AMER1 , CTNNB1 , GPC3 , MLLT1 , DICER1 , DIS3L2 ). Outcome included relapse-free survival, event-free survival (EFS), and overall survival (OS). Risk of bias was assessed with quality in prognosis studies tool. RESULTS: Low-bias multivariable/stratified analyses identified 1q gain as worse EFS and 1p and/or 16q LOH/loss as worse EFS/OS prognostic factors, in up-front nephrectomy settings. Preoperative chemotherapy settings revealed similar trends with lacking significance. TP53 and MYCN were adverse prognostic in univariate analyses. No prognostic data were available for the remaining variants. CONCLUSION: 1q gain and 1p and/or 16q LOH/loss emerge as independent prognostic biomarkers in up-front nephrectomy settings. Evidence remains limited in preoperative chemotherapy settings, particularly when using SIOP-oriented treatment algorithms. Prognostic value of TP53 , MYCN , and 11p15 LOH/LOI warrants further validation in both settings. This highlights the need for adequately powered prospective studies, specifically in the preoperative chemotherapy setting, to establish reliable molecular biomarkers.

Background: Translocation morphology renal cell carcinoma (tRCC) accounts for nearly half of all pediatric RCC cases. Biological study AREN14B4-Q aimed to characterize the molecular landscape of tRCC using samples acquired from patients enrolled in the Children’s Oncology Group Risk Classification and Biobanking study AREN03B2. Methods: From 2006 to 2014, patients <30 yr old with renal tumors were prospectively enrolled in AREN03B2, a Central IRB-approved biobanking study. All pediatric RCC cases underwent a detailed central pathology review and molecular diagnostics to accurately classify RCC subtypes. Samples with confirmed tRCC and appropriate informed consent were identified with adequate tissue for RNA and DNA extraction, along with germline DNA, for whole-genome sequencing (WGS), RNA sequencing, and DNA methylation analyses. Results: From 41 patients, high-quality samples allowed for 18 tumors and non-tumor DNA to be analyzed via WGS, 19 via DNA methylation, and 36 RNA samples via transcriptome sequencing. Consistent with and extending clinical cytogenetic findings, WGS and fusion transcript analyses confirmed very few additional mutations beyond the tRCC translocation. No recurrent genomic copy number gains/losses were found. RNA and WGS analyses enabled sub-classification of tRCC, closely aligning with the different TFE3 fusion partners. DNA methylation analyses demonstrated less tRCC sub-stratification compared with RNA analyses. Pathways activated in tRCC were involved in epithelial differentiation, extracellular matrix organization, apoptosis, immune regulation, signal transduction, and angiogenesis. Conclusions: Arrested epithelial differentiation is the overarching driver in tRCC and is strongly correlated with the specific subclasses of fusion transcript generated by the genetic translocation TFE fusion partner. Negative regulation of apoptosis, increased M2 macrophage expression, and enhanced angiogenesis also appear to be functional features of tRCCs, as are increased expression of matrix metalloproteinases, PI3K-AKT/mTOR/MAPK signaling, and mitochondrial metabolism, highlighting potential therapeutic options beyond direct targeting of the oncogenic driver fusions.

PURPOSE: Children with favorable histology Wilms tumor (FHWT) with pulmonary metastases have inferior outcomes compared with those with localized disease. We evaluated the impact of pulmonary tumor burden within subgroups of similarly treated children with stage IV FHWT. METHODS: Children with FHWT with pulmonary-only metastasis enrolled in AREN0533 were included. Lung nodule response assessment, by chest computed tomography after two cycles of vincristine/dactinomycin/doxorubicin (Regimen DD-4A) chemotherapy, identified rapid complete responses (RCRs) and slow incomplete pulmonary nodule responses (SIRs). Event-free survival (EFS) and overall survival (OS) were compared by number and size of pulmonary metastases within two cohorts: (1) RCR treated with additional DD-4A without lung radiation therapy (RT) and (2) SIR treated with the original three drugs plus cyclophosphamide/etoposide (Regimen M) with lung RT. The multivariable Cox proportional hazards model for EFS and OS stratified by treatment assessed the impact of the number and size of pulmonary metastases adjusted for tumor 1q gain. RESULTS: AREN0533 enrolled 288 children with stage IV pulmonary-only metastases, of whom 251 met inclusion criteria for outcome analyses. In the RCR cohort (n = 105), EFS and OS were not significantly different based on the number of lung metastases, whereas size of pulmonary metastases was significantly associated with EFS ( P = .022), but not OS. In the SIR cohort (n = 146), EFS and OS did not differ by the number or size of lung metastases. In multivariable models, neither number nor size of lung metastases was significantly associated with EFS or OS although 1q gain was significant (EFS P = .0015; OS P = .039) after adjustment for these factors. CONCLUSION: 1q gain is a superior prognostic indicator to pulmonary tumor burden in patients with FHWT with pulmonary-only metastasis.

Background: The Pediatric Oncology Group P9262 Phase 2 study of single‐agent paclitaxel demonstrated one complete response (CR), one partial response (PR), and four with stable disease (SD) among 15 patients with recurrent Wilms tumor (WT). Based on this activity, paclitaxel‐containing regimens have been used as salvage therapy for treatment‐refractory WT. We conducted a multi‐institutional retrospective study to further characterize the clinical activity of paclitaxel‐containing regimens in recurrent WT.Methods: Twelve institutions submitted anonymized data from patients with relapsed WT treated with paclitaxel. Response after one or two cycles of a paclitaxel‐containing regimen was reported according to Response Evaluation Criteria in Solid Tumors.Results: Twenty‐eight patients with a median age at diagnosis of 5.5 years (range: 3 months to 31.9 years) were reported. Twenty had non‐anaplastic WT; eight had diffuse anaplasia (DA). Stage at diagnosis was I (n = 1), II (n = 1), III (n = 11), IV (n = 14), and V (n = 1). Patients received a mean of 8.5 anticancer drugs (range: 6–12) before paclitaxel, including eight who received high‐dose therapy/stem cell transplant. Paclitaxel (n = 13) or nab‐paclitaxel (n = 15) were predominantly administered in combination with other agents, most commonly doxorubicin and/or gemcitabine. Eleven of 26 patients with measurable disease had a partial response (7 = non‐anaplastic; 4 = DA), four had stable disease, and 11 had progressive disease. Two patients without measurable disease maintained a complete response for 12 and 16 months. The mean duration without progression was 7.6 months (range: 1–35 months).Conclusions: Paclitaxel‐containing regimens appear to be active against heavily pretreated WT with either non‐anaplastic or DA histology. Prospective studies are warranted to formally evaluate the efficacy of paclitaxel‐based therapies.

Introduction: Perlman syndrome is a rare autosomal recessive overgrowth disorder with a predisposition to Wilms tumor, caused by biallelic variants in DIS3L2. The majority of patients die in infancy due to respiratory and/or renal failure, limiting the reports of patients surviving into childhood.Methods: Exome sequencing was performed in the proband and her older brother. A younger sibling subsequently underwent targeted variant analysis. RNA sequencing was utilized to investigate the functional impact of the missense variant.Results: Three siblings presented at birth with fetal macrosomia, dysmorphic facial features, and facial hypotonia. The proband had early speech delay and was diagnosed with Wilms tumor at 3 years old. Her brothers both had developmental delay presenting within the first year of life. Genetic testing identified compound heterozygous variants in DIS3L2 (NM_152383.5): c.127C>T (p.Arg43Ter) (paternal)/c.2381G>A (p.Arg794His) (maternal).Conclusion: Our findings expand the genetic and clinical spectrums associated with Perlman syndrome and increase the understanding of the phenotype observed in childhood. They also support consideration of genetic testing for Perlman syndrome in individuals and sibships with macrosomia, developmental delay, and characteristic facial dysmorphisms, with or without the presence of Wilms tumor.