Greg Tiao

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.

In 2024, we published a paper which described the identification of the fusion DNAJB1::PRKACA kinase in young patients with aggressive hepatoblastoma (HBL) and with biliary atresia (BA). In our study, we used sensitive molecular and cellular techniques and found that about 70% of our analyzed HBL samples showed varying levels of DNAJB1::PRKACA expression. In total, 15–20% of those fusion-positive HBL samples had DNAJB1::PRKACA levels comparable to those observed in FLC, whereas the remaining samples exhibited lower kinase levels. Palaz et al. analyzed five HBL datasets and one BA RNA-Seq dataset with Arriba and found no DNAJB1::PRKACA fusion transcript. Based on their analysis, the authors concluded that DNAJB1::PRKACA is not expressed in HBL patients. They further stated that the identification of DNAJB1::PRKACA fusion in either HBL or BA requires orthogonal molecular validation to confirm the fusion event at the DNA or RNA level. Therefore, we conducted Sanger sequencing on RT-PCR products from several fusion-positive HBL samples and three BA samples. Both HBL and BA cases showed the presence of the DNAJB1::PRKACA fusion transcript, identical to that detected in FLC. These results verify that DNAJB1::PRKACA is present in some HBL and BA patients, as has already been demonstrated using sensitive molecular and cellular techniques. Arriba analysis of current RNA-Seq data may not be sensitive enough for detecting low DNAJB1::PRKACA levels in HBL cases, especially if they are mixed with fusion-negative HBL specimens. Thus, we found that several independent methods, such as immunoanalysis and RT-PCR sequencing, effectively detect DNAJB1::PRKACA in HBL and BA cases. Our study also highlights that detecting low levels of DNAJB1::PRKACA requires individual analysis of HBL and BA patients within the same study, using FLC as the control.

Arif and colleagues commented on our paper Fleifil et al. “DNAJB1-PKAc is expressed in Young Patients with Pediatric Liver Cancers and Enhances Carcinogenic Pathways” published in Cancers in 2024. In our paper, we examined expression of DNAJB1::PRKACA (DNAJB1-PKAc or J-PKAc) in the Bio Bank of HBL (Hepatoblastoma) and HCN-NOS (Hepatocellular Malignant Neoplasm, Not Otherwise Specified) tissue samples collected at CCHMC during the last five years. Our data demonstrated that DNAJB1::PRKACA was detected in approximately 70% of HBL/HCN-NOS patients, with varying expression levels. In the commentary, the authors reviewed their earlier data and found no evidence of the fusion DNAJB1-PKAc expression within their cohorts of HBL specimens. Based on these data, the authors stated that “…DNAJB1::PRKACA remains specific to fibrolamellar carcinoma among liver tumors and caution against its use as a diagnostic marker for hepatoblastoma without rigorous validation in external cohorts.” After reviewing the commentary, we are offering a response outlined below.

Paediatric oncology surgeons play a crucial role in diagnosing, staging, and treating malignant solid tumors. In recent years, many solid tumour protocols have advocated for a more tailored surgical approach to both the primary tumour site and metastatic disease. The integration of Minimally Invasive Surgery (MIS) into paediatric oncology practice has gained popularity over the past few decades. While the benefits of MIS are well established in non-oncologic surgery, its role in paediatric solid tumours is still evolving and, in many cases, lacks high-quality evidence. These IPSO-MIS guidelines guidelines aim to provide practical surgical recommendations for diverse clinical scenarios, addressing the needs of both High-Income Countries (HICs) and Low- and Middle-Income Countries (LMICs). The contributing authors represent both settings, ensuring a comprehensive and inclusive perspective. We hope that these guidelines will contribute to improving outcomes for children with cancer worldwide.

The role of the minimally invasive surgery in the management of paediatric liver tumours Alyssa Stetson1, Gloria Gonzalez2,3 and Greg M Tiao1 1Departmen

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.

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 generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). The 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 ex-press the J-PKAc, and if there are consequences of such expression. Methods: Bio Bank of the pediatric HBL/HCN-NOS specimens were examined by QRT-PCR, Western Blot, RNA-Seq and by Immunostaining with fusion-specific antibodies. Results: J-PKAc is expressed in 70% of 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 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-beta-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 years 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 potential development of liver cancer in young patients.