Phase II study of axitinib in patients with -related schwannomatosis and progressive vestibular schwannomas.

Background: Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS).

Methods: Eligible patients were age > 5 years with a clinical diagnosis of -related schwannomatosis (-SWN) and at least one volumetrically measurable, progressive VS.

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification.

DNA methylation-based classification is integral to contemporary neuro-oncological diagnostics, as highlighted by the current World Health Organization (WHO) classification of central nervous system (CNS) tumors. We introduce the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.

Effect of bevacizumab on non-target intracranial meningiomas and non-vestibular schwannomas in NF2-related schwannomatosis: NF104.

Purpose: Bevacizumab treatment is associated with imaging and hearing responses in progressive vestibular schwannoma (VS) caused by NF2-related schwannomatosis (NF2-SWN). However, its effect on co-existing intracranial non-vestibular schwannomas (NVS) and meningiomas is unclear.

Methods: We retrospectively analyzed tumor volumes of non-target intracranial NVS and meningiomas in patients with NF2-SWN and progressive VS who were prospectively treated with bevacizumab for two years on the Neurofibromatosis Clinical Trials Consortium (NFCTC) trial NF104 (NCT01767792).

Improving Global Access to Genomic Profiling in Rare Pediatric Cancers.

Purpose: To address financial barriers that limit access to genomic profiling and precision medicine, philanthropy-supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system tumors.

Experimental Design: Tumor DNA or cerebrospinal fluid (CSF)-derived ctDNA was analyzed using the MSK-IMPACT assay, supplemented by targeted RNA panel sequencing in select cases.

Financial toxicity in pediatric and adolescent neurosurgical oncology.

Background: Financial toxicity (FT) encompasses the negative impact of medical costs on patients. In-depth analysis of FT in pediatric and adolescent neurosurgical oncology has not been performed. The aim of this study was to determine the incidence of FT in this population.

A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis.

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap.

FOXR2 activation is not exclusive of CNS neuroblastoma.

Background: FOXR2 activation is regarded as pathognomonic for CNS neuroblastoma (NB). However, a comprehensive understanding of the landscape for CNS tumors exhibiting FOXR2 activation is lacking.

Methods: Histopathologic, molecular, imaging, and clinical data of 42 CNS tumors with FOXR2 overexpression identified through screening institutional datasets and published institutional cases were analyzed.

A multi-institutional retrospective cohort of adult-onset medulloblastoma in the modern era.

Background: Adult onset medulloblastoma (aMB) is a rare tumor with limited available evidence. We present a large multi-institutional retrospective cohort of aMB patients treated in the modern era, with an emphasis on understanding the role of chemotherapy at initial diagnosis.

Methods: We included 267 consecutive patients with aMB treated at 7 different institutions from 2000-present, controlling for chemotherapy regimen and cycles received.

Phase 2 trial of veliparib, local irradiation, and temozolomide in patients with newly diagnosed high-grade glioma: a Children's Oncology Group study.

Background: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.

Methods: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations, compared to patient-level data from historical cohorts with closely matching clinical and molecular features.

Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation.

Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis.

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas.

Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

Background: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.

Leptomeningeal disease in histone-mutant gliomas.

Background: The 2016 WHO classification described a subtype of midline gliomas harboring histone 3 (H3) K27M alterations, and the 2021 edition added a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. The incidence and clinical behavior of leptomeningeal disease (LMD) in these patients is not well defined.

Methods: Retrospective study of patients with H3-altered gliomas diagnosed from 01/2012 to 08/2021; histone mutations were identified through next-generation sequencing (NGS) of tumor biopsy and/or cerebrospinal fluid (CSF).

Slipped capital femoral epiphyses: A major on-target adverse event associated with FGFR tyrosine kinase inhibitors in pediatric patients.

Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long-term safety data are limited, and serious toxicities unique to pediatrics may emerge. In a retrospective analysis of patients less than 18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n = 7), we observed slipped capital femoral epiphyses in three of seven patients along with increased linear growth velocity.

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

Background: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS).

Methods: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months.

Phase II study of everolimus for recurrent or progressive pediatric ependymoma.

Background: Preclinical studies have suggested that mTOR pathway signaling may be a potential therapeutic target for childhood ependymoma.

Methods: A phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that mTOR pathway inhibition would result in tumor responses for children with recurrent and/or progressive ependymomas.

Treatment of Pediatric Low-Grade Gliomas.

Purpose Of Review: Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy.

Current Role and Future Potential of CSF ctDNA for the Diagnosis and Clinical Management of Pediatric Central Nervous System Tumors.

Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring.

Tapping into the genome: the role of CSF ctDNA liquid biopsy in glioma.

Liquid biopsy has emerged as a novel noninvasive tool in cancer diagnostics. While significant strides have been made in other malignancies using liquid biopsy for diagnosis, disease monitoring, and treatment selection, development of these assays has been more challenging for brain tumors. Recently, research in primary and metastatic brain tumors has begun to harness the potential utility of liquid biopsy-particularly using circulating tumor DNA (ctDNA).

YAP1-MAML2 fusion in a pediatric NF2-wildtype intraparenchymal brainstem schwannoma.

Biallelic inactivation of NF2 represents the primary or sole oncogenic driver event in the vast majority of schwannomas. We report on a four-year-old female who underwent subtotal resection of a right medullary intraparenchymal schwannoma. RNA sequencing revealed an in-frame fusion between exon 5 of YAP1 and exon 2 of MAML2.

Lack of complete response pretransplant is not associated with inferior overall survival for stage 4a metastatic retinoblastoma.

Background: Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC-ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre-ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival.

Procedure: We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC-ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24).