Publications by authors named "Drew Pratt"

Article Synopsis
  • Papillary tumor of the pineal region (PTPR) is a rare and unique tumor characterized by specific molecular and histopathologic features, with limited prior research on its variations and clinical presentations.
  • In a study of 76 confirmed PTPR cases, researchers identified two main methylation groups (PTPR-A and PTPR-B) and further classified PTPR-B into two subtypes (B1 and B2) based on DNA methylation profiles and genomic variations.
  • Clinical outcomes revealed that nearly half of the patients experienced tumor progression, with significant differences in outcomes among the identified subtypes, highlighting the tumor's molecular diversity and potential for recurrence.
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  • Glioblastoma is a highly fatal brain tumor with chromosomal alterations affecting oncogenes and tumor suppressors, and research identified 6q27 as a poor prognostic marker.
  • Using a combination of CRISPR, transcriptomic data, and mouse models, the study explored Pde10a as a potential tumor suppressor in the 6q27 region and found its suppression leads to aggressive tumor behavior and treatment resistance.
  • Pde10a suppression was linked to enhanced PI3K/AKT signaling and a change in tumor cell characteristics, suggesting glioblastoma patients with Pde10a loss may have worse outcomes but might benefit from PI3K inhibitors.
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  • CNS embryonal tumors are diverse high-grade cancers, and recent advancements in profiling have identified new molecular subtypes, including those with the BRD4::LEUTX fusion.
  • A study characterized 9 cases of CNS tumors with this fusion, revealing key features such as young patient age, large tumor size, and spread to the cerebrospinal fluid, alongside distinct biological behaviors.
  • The tumors displayed high-grade characteristics and specific gene expressions, indicating a unique methylation signature that warrants further investigation through larger studies for a deeper understanding of this tumor type.
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Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.

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Article Synopsis
  • The review highlights the importance of molecular diagnostics in accurately diagnosing central nervous system tumors and identifying potential treatment targets.
  • Recent advances, especially the 2021 WHO Classification, show that over 100 tumor types are recognized, with molecular testing becoming essential for defining certain brain tumors, like IDH-mutant gliomas.
  • The integration of genetic and epigenetic information enhances diagnostic accuracy and reveals new tumor types, though challenges like cost and access still need addressing in implementing these technologies in routine practice.
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Unlabelled: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies.

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Recent studies exploring the impact of methylation in tumor evolution suggest that although the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Because changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and for jointly identifying lineage-informative CpG sites that harbor changes in methylation status that are retained along the lineage.

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Article Synopsis
  • Ependymomas are unusual tumors that typically contain pigments like melanin or lipofuscin; a case study reports on a pigmented ependymoma in a 46-year-old woman who experienced symptoms such as hearing loss and headaches.
  • The tumor, found in the fourth ventricle, showed distinct histological features, including pigmented cells resembling macrophages, and was ultimately diagnosed as a type of ependymoma with favorable characteristics.
  • A review of 17 cases indicates that pigmented ependymomas are predominantly seen in middle-aged patients, primarily located in the fourth ventricle, with a generally good prognosis, although one case resulted in patient death due to complications.
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Immature neuroectodermal tissue can be found in the ovary as part of an immature teratoma or as part of a teratoma with malignant neuroectodermal transformation. Such lesions may closely resemble central nervous system tumors, but their biologic similarity is unclear. We describe an 18-yr-old female who presented with abdominal pain caused by an ovarian mass with widespread metastases.

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Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M.

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Article Synopsis
  • Astroblastoma, -altered is a new classification of rare CNS tumors added by the WHO in 2021, characterized by unique DNA methylation patterns and specific genetic fusions but has variable histological features.
  • These tumors are most frequently found in children, especially females, and their clinical outcomes vary widely, with some patients facing multiple recurrences despite aggressive treatment while others do well after surgery alone.
  • The report details the cases of three female adults with these tumors, highlights the need for better clinical data collection, and suggests a standardized method for gathering neuropathological and patient-reported outcomes to enhance understanding of the tumor's clinical diversity.
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Purpose: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities.

Experimental Design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR).

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  • High-grade astrocytoma with piloid features (HGAP) is a newly identified glioma type classified by its unique global epigenetic signature and commonly associated with mutations in the MAPK pathway and other genetic alterations like CDKN2A/B deletions and ATRX mutations.
  • A study involving 144 patients with HGAP confirmed frequent CDKN2A/B deletions, ATRX mutations, and noted some cases with TP53 mutations or NTRK2 gene fusions, the latter being previously unreported.
  • Analysis revealed three distinct subtypes of HGAP based on DNA methylation patterns, with subtype gNF1 associated with Neurofibromatosis Type 1, specific tumor characteristics, and a potential trend towards
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Purpose: To highlight the clinical, neuroradiographic, neuropathologic, and molecular features of histologically identified neurocytoma in a pediatric cohort and highlight the evolving use methylation profiling in providing diagnostic clarity in difficult to diagnosis pediatric brain tumors.

Methods: Five consecutive children (ages 9-13, 2 girls 3 boys) were histologically diagnosed with neurocytoma at Rady Children's Hospital San Diego from 2012 to 2018. Clinical and molecular features were analyzed with regards to treatment course and outcome.

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Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas.

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Article Synopsis
  • Recent advancements in diagnosing central nervous system (CNS) tumors have led to a new classification system that integrates genetic and molecular data, improving alignment with clinical outcomes.
  • A newly identified glioma type, characterized by a unique DNA methylation signature, shares similarities with several other brain tumors and shows distinct genetic mutations.
  • Despite displaying high-grade features, this glioma type demonstrates better overall survival rates compared to glioblastoma, indicating its potential significance in treatment and prognosis.
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ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation.

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