Sialoblastoma and Hepatoblastoma in an Infant: A Case Report and Review of the Literature

: Sialoblastoma is a rare salivary gland tumor, diagnosed in the neonatal period or during infancy. Hepatoblastoma accounts for less than 1% of all pediatric malignancies. The co-occurrence of these two tumors is extremely uncommon. Here, we report a case of concurrent sialoblastoma and hepatoblastoma in an infant.

Spectrum of Pediatric Malignancies: An Observational Single Center Study from Western India

Cancer is a leading cause of death for children and adolescent worldwide. The cure rates in low middle-income countries are dismal (20%) in comparison to high income countries (80%). The first move is to assemble precise data on epidemiology of pediatric cancer across the country and its region wide variation. This study attempts to provide spectrum of pediatric malignancies from a tertiary care hospital in the state of Rajasthan, India. A total of 140 cases were studied retrospectively over a period of two years (April 2018-March 2020). Patients, 0-18 years of age that are diagnosed as a case of malignancy were included in this study. The records of these patients were retrieved and analyzed. Patients were stratified in 4 groups; 0-4 years, 5-9 years, 10-14 years and 15-18 years. Most of the patients fell in 15-18 year group (35.7%), followed by 5-9 year group (28.5%). Majority of cases, 67.8% were male. The male to female ratio is 2.1:1. Leukemia (40%) was the most common malignancy followed by lymphoma, retinoblastoma and malignant bone tumors. Acute lymphoblastic leukemia comprises majority (35/56) of leukemia. Retinoblastoma was predominant malignancy among <5-year children. In all other groups, leukemia was predominant. This study gauges the trend of pediatric malignancies at one of the largest tertiary care hospitals in Rajasthan, which is important in the planning and evaluation of health strategies. As we lack a dedicated pediatric cancer registry, such epidemiological studies play a significant part for this small but distinguished group of patients.

Therapy concepts in the context of precision medicine for pediatric malignancies—children are not adults

SummaryCancer remains the leading cause of death from disease among children beyond the age of one. Survival of pediatric patients with cancer has dramatically improved over the last decades but some tumors remain almost intractable and relapse is still associated with an infaust prognosis. Despite the heterogeneity of pediatric malignancies, most treatments include the same set of generic therapies. Optimizing delivery of conventional therapeutics has been the driving force behind continuous improvements but further escalation of conventional therapy is unlikely to improve outcomes. The limited success of targeted drugs in pediatric cancer patients, originally developed for cancers in adults, can be connected to the different etiology of tumors in children versus adults. In addition, many pediatric cancers lack reliable biomarkers, cannot be studied in large cohorts and only few available therapies target abberations specific for certain pediatric cancers.These observations have led to the establishment of pediatric precision-medicine programs. The major goal of these programs is to identify patient-tailored molecular treatment plans that will eventually improve quality of life and survival. Despite the initial euphemism, the impact of actionable matched treatments and the most adequate value-based genomics strategies are not yet well established. A non-competitive collaborative model based on pediatric cancer priorities and strong collaboration between academia, pharmaceutical companies and regulators is needed. In the near future, clinical trials need to focus on biologically defined patient subsets, in an even smaller patient population. A major collaborative effort between all associated groups will be necessary to ensure success of pediatric precision cancer medicine.

Using an integrated gene network technique to depict the genetic architecture of pediatric malignancies

Childhood malignancies have a mostly unknown genetic origin. It is critical, therefore, to develop fresh ways for deciphering the range of pediatric cancer genes. Statistical network modeling approaches have emerged as effective methods for inferring gene-disease associations and have been used to adult malignancies but not to pediatric malignancies. We used co-expression network analysis to get a multi-layer knowledge of pan-cancer transcriptome data from the Treehouse Childhood Cancer Initiative. Six modules were shown to be significantly correlated with pediatric tumor histotypes and to be functionally connected to developmental processes. Topological studies revealed that genes associated with childhood cancer propensity and prospective treatment targets were critical regulators of cancer-histotype-specific modules. A module with activities involved in DNA repair and cell cycle control was associated with several pediatric cancers. This canonical oncogenic module encapsulated the majority of the genes associated with pediatric cancer propensity and therapeutically actionable genes. The driver genes were co-expressed in a module associated with epigenetic and post-transcriptional processes in juvenile acute leukemias, indicating a key role for these pathways in the evolution of hematologic malignancies. This integrated pan-cancer analysis characterizes pediatric tumor-associated modules in detail and lays the groundwork for the investigation of new candidate genes implicated in juvenile carcinogenesis.

Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

The spectrum of mitochondrial DNA (mtDNA) mutations in pediatric central nervous system (CNS) tumors

Background We previously established the landscape of mitochondrial DNA (mtDNA) mutations in 23 subtypes of pediatric malignancies, characterized mtDNA mutation profiles among these subtypes, and provided statistically significant evidence for a contributory role of mtDNA mutations to pediatric malignancies. Methods To further delineate the spectrum of mtDNA mutations in pediatric CNS tumors, we analyzed 545 tumor-normal paired whole genome sequencing data sets from the Children’s Brain Tumor Tissue Consortium. Results Germline mtDNA variants were used to determine the haplogroup, and maternal ancestry, which was not significantly different among tumor types. Among 166 (30.5%) tumors we detected 220 somatic mtDNA mutations, primarily missense mutations (36.8%), as well as 22 loss-of-function mutations. Different pediatric CNS tumor subtypes had distinct mtDNA mutation profiles. The number of mtDNA mutations per tumor ranged from 0.20 (dysembryoplastic neuroepithelial tumor) to 0.75 (meningiomas). The average heteroplasmy was 10.7%, ranging from 4.6% in atypical teratoid/rhabdoid tumor (AT/RT) to 26% in diffuse intrinsic pontine glioma. High-grade gliomas had a significant higher number of mtDNA mutations per sample than low-grade gliomas (0.6 vs. 0.27) (p = 0.004), with almost twice as many missense mtDNA mutations per sample (0.24 vs. 0.11), and higher average heteroplasmy levels (16% vs. 10%). Recurrent mtDNA mutations may represent hotspots which may serve as biologic markers of disease. Conclusions Our findings demonstrate varying contributions of mtDNA mutations in different subtypes of CNS tumors. Sequencing the mtDNA genome may ultimately be used to characterize CNS tumors at diagnosis and monitor disease progression.

Comprehensive genomic and transcriptomic profiling of pediatric malignancies using the Tempus xT Next-Generation Sequencing Assay to identify clinically meaningful alterations.

e22002 Background: Our understanding of the genomic makeup of childhood cancers has accelerated over the past decade largely due to next-generation sequencing (NGS) utilized to identify genetic drivers, aid diagnostics and risk stratification, and detect therapeutic targets. Here, we present the genomic and transcriptomic landscape of pediatric malignancies tested with a broad NGS panel at a large commercial CLIA/CAP laboratory, Tempus Labs. Methods: We used the Tempus LENS platform to analyze DNA- and RNA-seq data from a cohort of 150 de-identified records of patients with pediatric cancer aged 0 to 18 years who underwent NGS with the Tempus xT platform. Results: The cohort included 139 solid tumors, 46 of which were central nervous system (CNS) tumors, and 11 hematologic malignancies. A total of 115 samples (77%) had at least one clinically meaningful pathogenic somatic variant detected, with TP53 variants being the most common (n=26; 17.3%). Gene fusions, most commonly EWSR1-FLI1 and KIAA1549-BRAF, were observed in 31 cases (20.7%). Matched tumor/normal testing revealed at least one incidental pathogenic germline variant in six patient records, with two cases harboring two distinct variants. Four cases had tumor mutational burdens (TMBs) greater than 10 mutations/megabase, including two that also exhibited high microsatellite instability (MSI). Conclusions: The Tempus xT tumor/normal-matched platform detects clinically meaningful genomic alterations in pediatric cancers important for diagnosis, prognosis, therapeutic target identification, and incidental germline findings. We continue to accumulate and structure data to meet the need for a large, accessible pediatric cancer clinical and molecular dataset. [Table: see text]