Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

Background: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study.

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.

45,X/46,XY mosaicism: Clinical manifestations and long term follow-up.

45,X/46,XY chromosomal mosaicism presents a range of clinical manifestations, including phenotypes from Turner syndrome through genital abnormalities to apparently unaffected phenotypic males; however, the full clinical spectrum has not yet been fully delineated since prior studies on the clinical phenotype and associated risk of gonadal tumors included small cohorts and limited follow-up. To better describe the clinical manifestations and long-term outcome of patients with 45,X/46,XY mosaicism. We conducted a retrospective chart review of patients with 45,X/46,XY from three health centers (Hospital for Sick Children and Mount Sinai Hospital in Canada, and University of Pittsburgh Medical Center in United States).

Myeloproliferative Neoplasm Driven by in an Adolescent with Recent History of Burkitt Leukemia.

gene fusion is a rare genetic rearrangement in a variety of malignancies, including myeloproliferative neoplasms (MPN), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Here, we report the case of a 16-year-old male diagnosed with a MPN, 7 months post-completion of treatment for Burkitt leukaemia. RNA sequencing analysis confirmed the presence of an fusion transcript, with an intact, in-frame tyrosine-kinase domain.

Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia.

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset.

Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome.

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome.

Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

Background: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease.

Practice patterns of prenatal and perinatal testing in Canadian cytogenetics laboratories.

Objective: To survey patterns of practice in Canadian cytogenetics laboratories and evaluate whether newer technologies have influenced testing algorithms for the detection of common aneuploidies and other genomic imbalances in the prenatal and perinatal settings.

Methods: Cytogenetics laboratories across Canada were invited to participate in two patterns-of-practice surveys: one in 2016 and one in 2019. They were asked to identify the prenatal and perinatal specimen types tested at their facility and which testing methods were used for initial testing and for follow-up.

Pediatric fibromyxoid soft tissue tumor with PLAG1 fusion: A novel entity?

The classification of undifferentiated soft tissue tumors continues to evolve with the expanded application of molecular analysis in clinical practice. We report three cases of a unique soft tissue tumor in young children (5 months to 2 years old) displaying a purely fibromyxoid histology, with positive staining for desmin and CD34. In two cases, RNA sequencing detected a YWHAZ-PLAG1 gene fusion, while in the third case, a previously unreported EEF1A1-PLAG1 fusion was identified.

First report of t(5;11) KMT2A-MAML1 fusion in de novo infant acute lymphoblastic leukemia.

Infant acute lymphoblastic leukemia (ALL) comprises 2.5%-5% of pediatric ALL with inferior survival compared to older children. A majority of infants (80%) with ALL harbor KMT2A gene rearrangement, which portends a poor prognosis.

Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia.

Clinical management and risk stratification of B-lymphoblastic leukemia/ lymphoma (B-ALL/LBL) depend largely on identification of chromosomal abnormalities obtained using conventional cytogenetics and Fluorescence In Situ Hybridization (FISH) testing. In the last few decades, testing algorithms have been implemented to support an optimal risk-oriented therapy, leading to a large improvement in overall survival. In addition, large scale genomic studies have identified multiple aberrations of prognostic significance that are not routinely tested by existing modalities.

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups.

Genetic diversity in alveolar soft part sarcoma: A subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors.

Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis. The disease-defining molecular event characterizing the diagnosis of ASPS is the ASPSCR1-TFE3 fusion gene. Following identification of an index case of ASPS with a novel TFE3 fusion partner, we performed a retrospective review to determine whether this represents an isolated event.

Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group.

Hyperdiploidy with greater than 50 chromosomes is usually associated with favorable prognosis in pediatric acute lymphoblastic leukemia (ALL), whereas hypodiploidy with ≤43 chromosomes is associated with extremely poor prognosis. Sometimes, hypodiploidy is "masked" and patients do not have a karyotypically visible clone with ≤43 chromosomes. Instead, their abnormal karyotypes contain 50-78 or more chromosomes from doubling of previously hypodiploid cells.

An aggressive central giant cell granuloma in a pediatric patient: case report and review of literature.

Background: Central giant cell granulomas are benign tumours of the mandible, presenting in children and young adults. Divided into non- and aggressive subtypes, the aggressive subtype is relatively rare and can occasionally progress rapidly, resulting in significant morbidity.

Case Presentation: We present a case of an aggressive central giant cell granuloma (CGCG) in a six year-old female.

Immunohistochemistry for ATRX Can Miss ATRX Mutations: Lessons From Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood with a median age of presentation of 17 months. A common theme in high-risk neuroblastoma is maintenance of telomeres, one mechanism for which involves alternate lengthening of telomeres (ALT) associated with ATRX gene mutations. Mutations are believed to result in loss of ATRX protein, and therefore immunohistochemistry is used to detect mutations.

MYCN Amplified Relapse Following Resolution of MYCN Nonamplified 4S Neuroblastoma With Placental Involvement: A Case Report and Review of the Literature.

Congenital neuroblastoma with placental involvement is exceptionally rare, but mortality is high. Detailed examination of placenta including MYCN amplification and segmental chromosomal aberrations should be performed in all suspected cases, as it is noninvasive and readily available. Maternal dissemination has not been reported.

Aggressive embryonal rhabdomyosarcoma in a 3-month-old boy: A clinical and molecular analysis.

Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy.

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between , a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when fusions arise by studying the whole genomes of Ewing sarcomas.