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Despite the increasing availability of comprehensive next generation sequencing (NGS), its role in characterizing pediatric hematologic malignancies remains undefined. We describe findings from comprehensive genomic profiling of hematologic malignancies at a pediatric tertiary care center. Patients enrolled on a translational research protocol to aid in cancer diagnosis, prognostication, treatment, and detection of cancer predisposition. Disease-involved samples underwent exome and RNA sequencing and analysis for single nucleotide variation, insertion/deletions, copy number alteration, structural variation, fusions, and gene expression. Twenty-eight patients with hematologic malignancies were nominated between 2018-2021. Eighteen individuals received both germline and somatic sequencing; two received germline sequencing only. Germline testing identified patients with cancer predisposition syndromes and non-cancer carrier states. Fifteen patients (15/18, 83%) had cancer-relevant somatic findings. Potential therapeutic targets were identified in seven patients (7/18, 38.9%); three (3/7, 42.9%) received targeted therapies and remain in remission an average of 47 months later. [ABSTRACT FROM AUTHOR]

Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation. [ABSTRACT FROM AUTHOR]

This document is a corrigendum for an article titled "Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors." The corrigendum addresses an error in the legend for Figure 1, where the tumor models were mistakenly referred to as xenografts instead of syngeneic models. The corrected legend clarifies that the study used syngeneic tumor models. The authors apologize for the error and state that it does not affect the scientific conclusions of the article. [Extracted from the article]

North American members in the genus Radiolucina are reviewed. A lectotype for the type species, Radiolucina amianta, is designated and descriptions and illustrations are provided. A description of a new species, Radiolucina jessicae, from the west coast of Mexico is presented. Key diagnostic species characteristics are outlined and compared among members of the genus. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and limited treatment options. Bulk genomic characterization of ACC has not yielded obvious therapeutic or immunotherapeutic targets, yet novel therapies are needed. We hypothesized that elucidating the intratumoral cellular heterogeneity by single nuclei RNA sequencing analyses would yield insights into potential therapeutic vulnerabilities of this disease. In addition to characterizing the immune cell and fibroblast landscape, our analyses of single nuclei gene expression profiles identified an adrenal cortex cell cluster exhibiting a program of replication stress and DNA damage response in primary and metastatic ACC. In vitro assessment of replication stress and DNA damage response using an ACC cell line and a series of newly-derived hormonally active patient-derived tumor organoids revealed ATR sensitivity. These findings provide novel mechanistic insight into ACC biology and suggest that an underlying dependency on ATR may be leveraged therapeutically in advanced ACC.

Background: Identifying germline predisposition in CNS malignancies is of increasing clinical importance, as it contributes to diagnosis and prognosis, and determines aspects of treatment. The inclusion of germline testing has historically been limited due to challenges surrounding access to genetic counseling, complexity in acquiring a germline comparator specimen, concerns about the impact of findings, or cost considerations. These limitations were further defined by the breadth and scope of clinical testing to precisely identify complex variants as well as concerns regarding the clinical interpretation of variants including those of uncertain significance., Methods: In the course of conducting an IRB-approved protocol that performed genomic, transcriptomic and methylation-based characterization of pediatric CNS malignancies, we cataloged germline predisposition to cancer based on paired exome capture sequencing, coupled with computational analyses to identify variants in known cancer predisposition genes and interpret them relative to established clinical guidelines., Results: In certain cases, these findings refined diagnosis or prognosis or provided important information for treatment planning., Conclusions: We outline our aggregate findings on cancer predisposition within this cohort which identified 16% of individuals (27 of 168) harboring a variant predicting cancer susceptibility and contextualize the impact of these results in terms of treatment-related aspects of precision oncology., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.