Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma.

Purpose: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM.

Patients And Methods: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ.

Increased SOX10, p16, and Cyclin D1 Immunoreactivity Differentiates MAP Kinase-activated Low-grade Gliomas From Piloid Gliosis.

Low-grade gliomas and reactive piloid gliosis can present with overlapping features on conventional histology. Given the large implications for patient treatment, there is a need for effective methods to discriminate these morphologically similar but clinically distinct entities. Using routinely available stains, we hypothesize that a limited panel including SOX10, p16, and cyclin D1 may be useful in differentiating mitogen-activated protein (MAP) kinase-activated low-grade gliomas from piloid gliosis.

Genomic profiling reveals SMARCA4 mutations are associated with shorter overall and intracranial progression free survival in melanoma brain metastasis patients.

Purpose: Melanoma brain metastases (MBMs) are a common, lethal complication of metastatic melanoma. Despite improvements in treatments, subsets of MBM patients experience rapid decline, and few prognostic biomarkers have been identified. An improved understanding of the molecular features specifically associated with MBM overall survival (OS) and intracranial progression free survival (PFS) could facilitate the development of more effective clinical management strategies.

Phase 1b/2 study of orally administered pexidartinib in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

Background: Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance.

Re-Irradiation Plus Pembrolizumab: A Phase II Study for Patients with Recurrent Glioblastoma.

Purpose: Radiotherapy may enhance antitumor immune responses by several mechanisms, including induction of immunogenic cell death. We performed a phase 2 study of pembrolizumab with re-irradiation in patients with recurrent glioblastoma.

Patients And Methods: Sixty patients with recurrent glioblastoma received pembrolizumab with re-irradiation alone (cohort A, bevacizumab-naïve; n = 30) or with bevacizumab continuation (cohort B, n = 30).

Multimodal deep learning improves recurrence risk prediction in pediatric low-grade gliomas.

Background: Postoperative recurrence risk for pediatric low-grade gliomas (pLGGs) is challenging to predict by conventional clinical, radiographic, and genomic factors. We investigated if deep learning (DL) of magnetic resonance imaging (MRI) tumor features could improve postoperative pLGG risk stratification.

Methods: We used a pretrained DL tool designed for pLGG segmentation to extract pLGG imaging features from preoperative T2-weighted MRI from patients who underwent surgery (DL-MRI features).

Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma.

Unlabelled: We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact.

Velcrin molecular glues induce apoptosis in glioblastomas with high and expression.

Background: Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNA(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines.

Measuring single-cell density with high throughput enables dynamic profiling of immune cell and drug response from patient samples.

Cell density, the ratio of cell mass to volume, is an indicator of molecular crowding and therefore a fundamental determinant of cell state and function. However, existing density measurements lack the precision or throughput to quantify subtle differences in cell states, particularly in primary samples. Here we present an approach for measuring the density of 30,000 single cells per hour with a precision of 0.

A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase.

Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease.

Noninvasive Molecular Subtyping of Pediatric Low-Grade Glioma with Self-Supervised Transfer Learning.

Purpose To develop and externally test a scan-to-prediction deep learning pipeline for noninvasive, MRI-based mutational status classification for pediatric low-grade glioma. Materials and Methods This retrospective study included two pediatric low-grade glioma datasets with linked genomic and diagnostic T2-weighted MRI data of patients: Dana-Farber/Boston Children's Hospital (development dataset, = 214 [113 (52.8%) male; 104 (48.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

Purpose: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM.

Experimental Design: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019.