Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans.

Detection of H3F3A K27M or BRAF V600E in liquid biopsies of brain tumor patients as diagnostic and monitoring biomarker: impact of tumor localization and sampling method.

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management.

Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.

Background: Diffuse hemispheric glioma, H3 G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these 2 oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization, and consequently validate a targeted therapy approach.

Real-World Performance of Integrative Clinical Genomics in Pediatric Precision Oncology.

Despite significant improvement in the survival of pediatric patients with cancer, treatment outcomes for high-risk, relapsed, and refractory cancers remain unsatisfactory. Moreover, prolonged survival is frequently associated with long-term adverse effects due to intensive multimodal treatments. Accelerating the progress of pediatric oncology requires both therapeutic advances and strategies to mitigate the long-term cytotoxic side effects, potentially through targeting specific molecular drivers of pediatric malignancies.

Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma.

Background: Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients.

Epithelial metabolism as a rheostat for intestinal inflammation and malignancy.

The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis.

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial.

Importance: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.

Objective: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).

Design, Setting, And Participants: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis.

Proof-of-Concept for Liquid Biopsy Disease Monitoring of -Amplified Group 3 Medulloblastoma by Droplet Digital PCR.

Background: Liquid biopsy diagnostic methods are an emerging complementary tool to imaging and pathology techniques across various cancer types. However, there is still no established method for the detection of molecular alterations and disease monitoring in MB, the most common malignant CNS tumor in the pediatric population. In the presented study, we investigated droplet digital polymerase chain reaction (ddPCR) as a highly sensitive method for the detection of amplification in bodily fluids of group 3 MB patients.

The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location.

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation.

Viral infections in pediatric brain tumor patients treated with targeted therapies.

Background: Brain tumors are the most common solid malignancies and the leading cause of cancer-related mortality in children. While numerous studies report on viral infections in children with hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking.

Objectives/study Design: We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021.

Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors.

Purpose: Numerous acute effects of chemotherapeutics on kidney function are well described. However, data on the long-term effects of chemotherapy in the growing population of childhood central nervous system (CNS) tumor survivors is limited. We aimed to evaluate the kidney function of a cohort of long-term CNS tumor survivors treated with different standard chemotherapeutic regimens.

The metabolic nature of inflammatory bowel diseases.

Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism.

Recovery of ameliorates hepatic steatosis in experimental alcohol-related liver disease.

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged.

Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness.

Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed.

Interleukin-11 drives human and mouse alcohol-related liver disease.

Objective: Alcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD.