Faculty Bibliography

Molecular classification has improved diagnosis and treatment for patients with malignant gliomas. However, classification has relied on individual assays that are both costly and slow, leading to frequent delays in treatment. Here, we propose the use of DNA methylation, as an emerging clinical diagnostic platform, to classify gliomas based on major genomic alterations and provide insight into subtype characteristics. We show that using machine learning models, DNA methylation signatures can accurately predict somatic alterations and show improvement over existing classifiers. The established Unified Diagnostic Pipeline (UniD) we develop is rapid and cost-effective for genomic alterations and gene expression subtypes diagnostic at early clinical phase and improves over individual assays currently in clinical use. The significant relationship between genetic alteration and epigenetic signature indicates broad applicability of our approach to other malignancies.

PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.

Purpose/UNASSIGNED:Second primary (SP) neoplasms of the central nervous system (CNS) among cancer survivors are devastating but poorly understood processes. The absolute risk, or true incidence, of developing an SP CNS tumor among cancer survivors is not well characterized. Methods and Materials/UNASSIGNED:Patients diagnosed with cancer between 1975 and 2016 were queried using the Surveillance, Epidemiology, and End Results Program. Cumulative incidence rates (CIRs) were estimated using competitive risk analysis. The effects of covariates were assessed using multivariate competitive risk regression. Results/UNASSIGNED: = 7e-5). Conclusions/UNASSIGNED:The risk of developing a second primary CNS neoplasm is elevated in patients with a prior CNS cancer independent of treatment history. The association between cranial radiation therapy and risk for subsequent cancers may be limited to the pediatric population.

PURPOSE/OBJECTIVE:American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS:was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS:. RECOMMENDATIONS/CONCLUSIONS:is conditionally recommended.Additional information is available at www.asco.org/neurooncology-guidelines.

Purpose: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature. Results: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.

Radiation therapy has long been a critical modality of treatment of patients with central nervous system tumors, including primary brain tumors, brain metastases, and meningiomas. Advances in radiation technology and delivery have allowed for more precise treatment to optimize patient outcomes and minimize toxicities. Improved understanding of the molecular underpinnings of brain tumors and normal brain tissue response to radiation will allow for continued refinement of radiation treatment approaches to improve clinical outcomes for brain tumor patients. With continued advances in precision and delivery, radiation therapy will continue to be an important modality to achieve optimal outcomes of brain tumor patients.

Background/UNASSIGNED:We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods/UNASSIGNED:= 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results/UNASSIGNED:had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions/UNASSIGNED:Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.