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PurposeTreatment 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 methodsWe 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). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.ResultsThe most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.ConclusionsDespite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.

Simple Summary: Genomic rearrangements are chromosomal abnormalities that alter the arrangement of genes and are important for diagnosing multiple cancer types and guiding therapy selection. However, current diagnostic tests may not detect all genomic rearrangements. Hi-C sequencing is a promising new method for detecting genomic rearrangements. First, we examined whether Hi-C can detect known genomic rearrangements in pediatric leukemia and sarcoma specimens. Next, we evaluated whether Hi-C can detect genomic rearrangements that were not found using standard diagnostic testing. Hi-C showed complete agreement with other diagnostic methods in identifying known rearrangements. Hi-C also detected previously unknown genomic rearrangements in 5/11 pediatric leukemia cases that could impact diagnosis, prognosis, or treatment choices. These data suggest Hi-C could be beneficial for medical diagnostic testing of pediatric cancers, but more extensive clinical validation is needed. 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. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows. [ABSTRACT FROM AUTHOR]

Objective: Ameloblastomas are a group of relatively common odontogenic tumors that frequently originate from the dental epithelium. These tumors are aggressive in nature and present as slow‐growing painless cortical expansion of the jaw. Histologically, the follicular and plexiform subtypes constitute two‐thirds of solid/multicystic ameloblastomas. The objective of this study was to understand the genetic architecture of follicular and plexiform ameloblastomas using deep whole‐exome sequencing. Methods: Archived formalin‐fixed paraffin‐embedded tissue blocks of follicular (n = 4) and plexiform (n = 6) ameloblastomas were retrieved and genomic DNAs were isolated from the tumor tissue dissected from the formalin‐fixed paraffin‐embedded block. The exomes were enriched using the Integrated DNA Technologies Exome Research Panel (IDT, Coralville, IA) and paired‐end sequencing was completed on an Illumina NovaSeq 6000 with an average output of 20 GB of data resulting in a mean coverage of 400×. Variant analysis was completed using custom‐developed software: Rapid Understanding of Nucleotide variant Effect Software and variant integration and knowledge interpretation in genomes. Results: Our analyses focused on examining somatic variants (gnomAD minor allele frequency ≤1%) in genes found on an Food and Drug Administration ‐approved clinical cancer sequencing panel (FoundationOne®CDx). In follicular tumors, variants (>20% of the reads) were identified in BRAF, KMT2D, and ABL1 genes. In plexiform tumors, variants (>20% of the reads) were identified in ALK, BRAF, KRAS, KMT2D, SMO, KMT2A, and BRCA2 genes. Enrichment analysis showed a significant role of DNA repair genes in the development of these tumors. Conclusion: The variants identified in follicular and plexiform ameloblastomas were enriched in DNA‐repair genes. The observed genetic heterogeneity in these ameloblastomas may contribute to the aggressive nature and recurrence risk of these tumors. [ABSTRACT FROM AUTHOR]

Benign and malignant neoplasms in CRJS have been noted, but only one patient thus far has presented with desmoplastic medulloblastoma, and the tumor's histologic and genetic features were not further enumerated.[3] Here, we describe a second patient with desmoplastic medulloblastoma associated with CRJS. Targeted therapy for patients with CRJS would be beneficial, but mouse studies of current SMO inhibitors show association with permanent defects in bone development.[6] Ongoing research of SHH pathway inhibitors could hold exciting potential for treatment of medulloblastoma and CRJS patients, decreasing long-term sequelae of conventional management. Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the sonic hedgehog-patched-GLI pathway. [Extracted from the article]

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. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of 5 days of azacitidine treatment immediately prior to the start of chemotherapy on day 6, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was well-tolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells demonstrated decreased DNA methylation in 87% of samples tested following 5 days of azacitidine treatment. Event-free survival was similar to that in prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of peripheral blood mononuclear cells in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.