Successful classification of clinical pediatric leukemia genetic subtypes via structural variant detection using HiFi long-read sequencing.

Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort.

Evaluation of Hi-C Sequencing for Detection of Gene Fusions in Hematologic and Solid Tumor Pediatric Cancer Samples.

Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed.

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed -rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of failure to achieve remission, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies.

Evaluation of Hi-C sequencing for the detection of gene fusions in hematologic and solid pediatric cancer samples.

Unlabelled: HiC sequencing is a DNA-based next-generation sequencing method that preserves the 3D conformation of the genome and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate HiC as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens previously positive for clinically significant genomic rearrangements. Archived specimen types tested included viable and nonviable frozen leukemic cells, as well as formalin-fixed paraffin-embedded (FFPE) tumor tissues.

Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads.

Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy.

Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631.

We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.

Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children's Oncology Group cohort trials.

Background: Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status.

Methods: Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Children's Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis.

Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy.

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting.

MicroRNA Content of Ewing Sarcoma Derived Extracellular Vesicles Leads to Biomarker Potential and Identification of a Previously Undocumented EWS-FLI1 Translocation.

Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing.

Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric -Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531.

Purpose: We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with -rearranged (-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 (NCT01407757).

Methods: Patients with -r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners.

Anaplastic Lymphoma Kinase Inhibitor in Treatment of Inflammatory Myofibroblastic Tumor of the Tongue in Infancy.

Inflammatory myofibroblastic tumors (IMTs) are rare in neonates. IMTs of the tongue are also very rare in infancy, with only 1 case reported in this age group. The mainstay of therapy has traditionally been surgery, which can be devastating to surrounding structures and negatively impact prognosis.

Overcoming Wnt-β-catenin dependent anticancer therapy resistance in leukaemia stem cells.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-β-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress.

Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.

Patients And Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL).

Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib.

Background: The treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children is challenging and new treatment options are needed. Bortezomib is a proteasome inhibitor with activity in pediatric acute lymphoblastic leukemia. Adding bortezomib to standard reinduction chemotherapy in relapsed and refractory pediatric ALL has produced very good response rates in prior studies.

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma.

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol.

Precision Medicine in Pediatric Cancer: Current Applications and Future Prospects.

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities.

Combined heparin/acid citrate dextrose solution A anticoagulation in the Optia continuous mononuclear cell protocol for pediatric lymphocyte apheresis.

Collecting a sufficient number of T-cells is a critical first step in the production of chimeric antigen receptor (CAR)-T cells. Herein, we report a successful implementation of anticoagulation with combined heparin and acid citrate dextrose solution A (ACD-A) for the continuous mononuclear cell (CMNC) protocol on the Spectra Optia in a 20-month-old, 7.5 kg patient with refractory acute lymphoblastic leukemia for manufacture of tisagenlecleucel, a CAR-T cell therapy.

Parental Perceptions of Obesity and Obesity Risk Associated With Childhood Acute Lymphoblastic Leukemia.

The prevalence of obesity and related comorbidities in survivors of childhood acute lymphoblastic leukemia (ALL) is well established and ranges anywhere from 29% to 69% depending on the study. We sought to explore the awareness of parents of survivors of childhood ALL regarding the increased risk of obesity and their perceptions regarding the overall health of their child. One hundred twenty-one parents of 99 survivors of pediatric ALL completed surveys regarding perceptions of obesity risk in survivors.