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Background: The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods. Digital drug assignment (DDA) is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers, targets, and targeted agents. DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial. The aim of this study was to evaluate the utility of DDA in pediatric oncology., Methods: Between 2017 and 2020, 103 high-risk pediatric cancer patients (< 21 years) were involved in our precision oncology program, and samples from 100 patients were eligible for further analysis. Tissue or blood samples were analyzed by whole-exome (WES) or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support. Finally, a molecular tumor board (MTB) evaluated the results to provide therapy recommendations., Results: Of the 100 cases with comprehensive molecular diagnostic data, 88 yielded WES and 12 panel sequencing results. DDA identified matching off-label targeted treatment options (actionability) in 72/100 cases (72%), while 57/100 (57%) showed potential drug resistance. Actionability reached 88% (29/33) by 2020 due to the continuous updates of the evidence database. MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases (78%). The approved therapies had significantly higher aggregated evidence levels (AELs) than dismissed therapies. Filtering of WES results for targeted panels missed important mutations affecting therapy selection., Conclusions: DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers. Knowledgebase updates enable automatic interpretation of a continuously expanding gene set, a "virtual" panel, filtered out from genome-wide analysis to always maximize the performance of precision treatment planning., (© 2023. The Author(s).)

The Hungarian Pediatric Oncology Network provides centralized treatment and population-based registration for cases of childhood cancer since 1973. We collected and analized data on late mortality, secondary malignancies and cardiac diseases in survivors (> 5 years) of childhood cancer to evaluate long-term risks. We extracted all solid tumour cases (3,650 followed up for 5-39.3 years, diagnosis: 1973-2008) from the database of the Hungarian Childhood Cancer Registry and checked against the Population Registry. Among the 301 patients who died after 5 years (8.2%) the most common causes of death were progression of primary cancer (52.5%), secondary malignancies (16%) and cardiovascular diseases (8%). Late mortality rates (SMR, total: 35,006 pyrs) showed highly elevated risk of death (SMR: 10.7 95% CI 9-12.4) for the second 5 years of follow up and moderately elevated risk for 10-year survivors (SMR: 3.5 95% CI 3-4.1). Marked differences were detected in the pattern of causes of death between diagnostic groups of primary cancer; with highest risks beyond 10 years for CNS tumours, Hodgkin disease, osteosarcoma and advanced stage neuroblastoma. The longstanding mortality risk for 5-year survivors underlines the need for tailored long-term follow-up and monitoring of late consequences according to the context of different primary diseases of childhood cancer.

The aim of this study was to compare the quality of life and school success of adolescent survivors and their classmates. A survey was conducted among 21 cancer survived 12-18-year-old children and 95 of their classmates by using questionnaires covering (a) characteristics of the quality of life; (b) characteristics of the learning process; and (c) level of the fear of cancer recurrence. Significant difference was found in the field of physical and emotional functions but contrary to expected, the members of the control group reported lower values than survivor children. Those children that were teased because of cancer made friends hardly and got involved in social programs with more difficulty. With reference to the level of development of school motivation and the use of learning strategies, it was experienced a significant difference between the two groups only in the field of planning. Our results show that the better the survived children's general quality of life is the better results they achieve at school. Their learning achievement is influenced to a much bigger extent by social functions than their physical disadvantages.

Background: Late nephrotoxicity among childhood cancer survivors is poorly documented., Methods: We investigated 115 patients and 86 controls assessing serum cystatin C concentration (CysC), urinary N-acetyl-beta-D-glucosaminidase activity (NAG), and microalbuminuria. Proteinuria was quantified and electrophoresis performed. Polymorphism of the angiotensin convertase enzyme (ACE) gene was determined by genomic PCR., Results: CysC was elevated in Wilms tumor (WT) patients. Gross proteinuria was observed in 30 patients including three patients with progressive proteinuria who improved on ACE-inhibitor treatment. Neither patients with proteinuria nor the entire study population differed from controls with respect to ACE polymorphism. Pathologically elevated urinary NAG was noted in 38% of leukemia/lymphoma, 54% of solid tumor, 20% of WT survivors. A similar distribution of pathological microalbuminuria was found., Conclusions: Mild-to-moderate subclinical glomerular and tubular damage can be identified in many childhood cancer survivors. However, most patients experience some spontaneous recovery from acute nephrotoxicity., ((c) 2004 Wiley-Liss, Inc.)