Rapid Tumor DNA Analysis of Cerebrospinal Fluid Accelerates Treatment of Central Nervous System Lymphoma.

Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Skull Base Tumors.

OBJECTIVE: This article reviews the presenting features, molecular characteristics, diagnosis, and management of selected skull base tumors, including meningiomas, vestibular schwannomas, pituitary neuroendocrine tumors, craniopharyngiomas, chordomas, ecchordosis physaliphora, chondrosarcomas, esthesioneuroblastomas, and paragangliomas. LATEST DEVELOPMENTS: Skull base tumors pose a management challenge given their complex location and, as a result, the tumors and treatment can result in significant morbidity. In most cases, surgery, radiation therapy, or both yield high rates of disease control, but the use of these therapies may be limited by the surgical accessibility of these tumors and their proximity to critical structures. The World Health Organization classification of pituitary neuroendocrine tumors was updated in 2022. Scientific advances have led to an enhanced understanding of the genetic drivers of many types of skull base tumors and have revealed several potentially targetable genetic alterations. This information is being leveraged in the design of ongoing clinical trials, with the hope of rendering these challenging tumors treatable through less invasive and morbid measures. ESSENTIAL POINTS: Tumors involving the skull base are heterogeneous and may arise from bony structures, cranial nerves, the meninges, the sinonasal tract, the pituitary gland, or embryonic tissues. Treatment often requires a multidisciplinary approach, with participation from radiation oncologists, medical oncologists, neuro-oncologists, and surgical specialists, including neurosurgeons, otolaryngologists, and head and neck surgeons. Treatment has largely centered around surgical resection, when feasible, and the use of first-line or salvage radiation therapy, with chemotherapy, targeted therapy, or both considered in selected settings. Our growing understanding of the molecular drivers of these diseases may facilitate future expansion of pharmacologic options to treat skull base tumors.

Study protocol for NeuroCARE: a randomised controlled trial of a psychological intervention for caregivers of patients with primary malignant brain tumours.

INTRODUCTION: Caregivers of patients with primary malignant brain tumours experience substantial psychological distress while caring for someone with a progressive, life-limiting neurological illness. However, there are few interventions aimed at addressing the psychosocial needs of this population. We developed and are testing a population-specific, evidence-based, telehealth intervention (NeuroCARE) to reduce anxiety symptoms and improve psychosocial functioning in this caregiver population. METHODS AND ANALYSIS: This study is a non-blinded, randomised controlled trial of a psychological intervention for caregivers of patients with primary malignant brain tumours receiving care at the Massachusetts General Hospital Cancer Center or Dana-Farber Cancer Institute. We will enrol 120 caregivers who screen positive for heightened anxiety. Participants will be randomised 1:1 to the NeuroCARE intervention or a usual care control condition. Caregivers assigned to NeuroCARE will complete six individual telehealth sessions with a trained behavioural health specialist over 12 weeks. Caregivers randomised to the control condition will receive usual care, including possible referral to social work or other appropriate resources. Participants will complete self-report questionnaires at baseline and 11 weeks and 16 weeks postrandomisation. The primary outcome is anxiety symptoms at 11 weeks among NeuroCARE participants, compared with usual care. Secondary outcomes include caregiver-reported depressive symptoms, quality of life, caregiver burden, caregiving self-efficacy, perceived coping skills and post-traumatic stress disorder symptoms. We also will explore potential mediators of the NeuroCARE effect on caregiver anxiety symptoms. ETHICS AND DISSEMINATION: The study is funded by a Career Development Award from Conquer Cancer, the American Society of Clinical Oncology Foundation (award number 2019CDA-7743456038) and approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (Protocol #19-250 V.10.1). The study will be reported in accordance with the Consolidated Standards of Reporting Trials statement for non-pharmacological trials. Results will be presented at scientific meetings and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04109209.

Palliative Care in Neuro-oncology: an Update.

PURPOSE OF REVIEW: While the benefits of palliative care for patients with cancer are well established, palliative care in neuro-oncology is still in its early stages. However, in recent years, there has been increasing attention drawn to the need for better palliative care for patients with brain tumors. RECENT FINDINGS: There is a growing body of literature demonstrating the high symptom burden and significant supportive care and information needs of these patients and their caregivers. In the area of caregiver needs, the last 3 years has seen a more rapid growth in recognizing and characterizing these needs. However, there remains a knowledge gap regarding the optimal means of addressing these needs. In this article, we outline important recent advances in the literature on palliative care for patients with brain tumors and highlight areas in need of greater attention and investigation.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. METHODS: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. RESULTS: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ±â€…4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CONCLUSIONS: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients.

PURPOSE: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS: The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.

Characterizing Distress and Identifying Modifiable Intervention Targets for Family Caregivers of Patients with Malignant Gliomas.

Background: Individuals caring for patients with malignant gliomas experience high rates of anxiety; however, an in-depth understanding of their distress and evidence-based interventions to target their needs are lacking. Objective: We conducted semistructured interviews with caregivers with elevated anxiety to characterize their drivers of anxiety, identify modifiable intervention targets, and capture their preferences for a psychosocial intervention. Design: From 9/2017 to 3/2019, we conducted semistructured interviews with 21 caregivers of patients with malignant gliomas, at time points following the patient's diagnosis or within one to three months after the patient's death. Setting/Subjects: Eligible caregivers in the United States had clinically significant anxiety as measured by a Hospital Anxiety and Depression Scale-Anxiety score >7. Measurements: Three independent coders employed thematic content analysis to analyze the qualitative data with NVivo 12, achieving high intercoder agreement (Kappa = 0.98). Results: On average, caregivers were 54.81 years old (SD = 10.85) with elevated anxiety (M = 10.90, SD = 3.25). We identified six themes in which caregivers described (1) coping through reassurance seeking or avoidance, (2) changes in their relationship with the patient, (3) challenges with social support, (4) vacillation between certainty and uncertainty regarding the future, (5) devaluation of self-care for the patients' needs, and (6) challenges communicating with the health care team. Caregivers were interested in an intervention soon after the patient's diagnosis, yet expressed concern about finding the time to participate. Conclusions: Emergent themes characterized the distress experienced by caregivers of patients with malignant gliomas and provided insight into their psychosocial intervention preferences. We identified evidence-based intervention components based on the modifiable factors arising from these themes.

Palliative care and end-of-life care in adults with malignant brain tumors.

BACKGROUND: This systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for palliative care in adults with malignant brain tumors. It provides an overview of palliative care options, including during the end-of-life phase for patients with malignant brain tumors. METHODS: A systematic literature search was conducted from 2016 to 2021 focusing on four main topics: (1) symptom management, (2) caregiver needs, (3) early palliative care, and (4) care in the end-of-life phase. An international panel of palliative care experts in neuro-oncology synthesized the literature and reported the most relevant updates. A total of 140 articles were included. RESULTS: New insights include that: Hippocampal avoidance and stereotactic radiosurgery results in a lower risk of neurocognitive decline in patients with brain metastases; levetiracetam is more efficacious in reducing seizures than valproic acid as first-line monotherapy antiseizure drug (ASD) in glioma patients; lacosamide and perampanel seem well-tolerated and efficacious add-on ASDs; and a comprehensive framework of palliative and supportive care for high-grade glioma patients and their caregivers was proposed. No pharmacological agents have been shown in randomized controlled trials to significantly improve fatigue or neurocognition. CONCLUSIONS: Since the 2017 EANO palliative care guidelines, new insights have been reported regarding symptom management and end-of-life care, however, most recommendations remain unchanged. Early palliative care interventions are essential to define goals of care and minimize symptom burden in a timely fashion. Interventional studies that address pain, fatigue, and psychiatric symptoms as well as (the timing of) early palliative care are urgently needed.

Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience.

BACKGROUND: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. METHODS: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). CONCLUSIONS: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

Factors associated with psychological distress in caregivers of patients with malignant gliomas.

PURPOSE: Caregivers of patients with malignant gliomas are at risk for psychological distress. However, factors associated with distress in this population have not been well described. We conducted a prospective study evaluating psychological distress in patients with malignant gliomas and their caregivers and exploring factors associated with caregiver distress. METHODS: We enrolled patients with newly diagnosed malignant gliomas (N = 77) and their caregivers (N = 61). At baseline and 3, 6, and 9 months after diagnosis, we administered the Hospital Anxiety and Depression Scale to assess psychological distress and the Caregiver Reaction Assessment to evaluate caregiver burden. We performed multivariable regression analyses to investigate caregiver-related, patient-related, and tumor-related factors associated with caregivers' distress. RESULTS: At baseline, 48.3% (29/60) and 26.2% (16/61) of caregivers reported clinically significant anxiety and depression symptoms, respectively. Anxiety and depression symptoms persisted over time. Greater caregiver depression was associated with male gender (B = 1.48, 95% CI 0.16-2.81, p = 0.03), higher caregiver burden (B = 0.08, 95% CI 0.01-0.15, p = 0.02), caregiver anxiety (B = 0.53, 95% CI 0.38-0.68, p < 0.0001), patient depression (B = 0.34, 95% CI 0.13-0.55, p = 0.002), and caring for a younger patient (B = -0.07, 95% CI -0.15 to 0.00, p = 0.049). Factors associated with greater caregiver anxiety symptoms were caregiver depression (B = 0.91, 95% CI 0.71-1.12, p < 0.0001) and younger patient age (B = -0.15, 95% CI -0.24 to -0.05, p = 0.003). CONCLUSION: Male gender, higher caregiver burden, greater patient depression symptoms, and younger patient age are associated with increased distress among caregivers of patients with malignant gliomas, underscoring the need for tailored supportive care interventions targeting caregivers at highest risk for psychological distress.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial.

CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

A practical guide to neuro-oncology fellowship.

Neuro-oncology is a growing, interdisciplinary field at the intersection of neurology and oncology, devoted to the care of patients with central nervous system tumors and neurologic complications of cancer, and collaboratively interfacing with neurosurgery, neuropathology, medical oncology and radiation oncology. There is increasing trainee interest in the field of neuro-oncology and an increasing number of fellowship training programs, attracting applicants with backgrounds in neurology, neurosurgery and medical oncology. The present guide aims to provide some general recommendations for residents and fellows to help them make the most out of their neuro-oncology fellowship and enable them to start their careers as a neuro-oncologists on firm footing.

Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma.

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

Characterization and prognosis of temozolomide-induced aplastic anemia in patients with central nervous system malignancies.

BACKGROUND: Temozolomide-induced aplastic anemia (TIAA) is a rare but highly challenging complication of temozolomide (TMZ) therapy. Evidence describing prognosis, clinical characteristics, and treatment of this entity is very limited. METHODS: We performed a multicenter, 22-year observational cohort study of patients with central nervous system (CNS) malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery. RESULTS: Of 3821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA. Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle. 23 patients (67.6%) ultimately achieved a hematologic recovery. Patients without recovery were more likely to develop febrile neutropenia (72.7% vs. 30.4%, P = .03), infectious complications (45.5% vs. 8.7%, P = .02), require hospitalization (81.8% vs. 43.5%, P = .04), and die (100.0% vs. 60.9%, P = .02). Median overall survival from TIAA diagnosis was 752 days in patients achieving a partial hematologic recovery versus 28 days in those who did not (P < .0001). 29 patients (85.3%) received one or more hematopoietic growth factors; hematologic recovery rates were higher in patients receiving thrombopoietin receptor agonists (81.8% vs. 60.9%) but were not higher in patients receiving granulocyte colony-stimulating factors. CONCLUSIONS: TIAA occurs in <1% of patients receiving TMZ for CNS malignancies, but is highly morbid when it occurs and frequently fatal in the one-third of patients not achieving hematologic recovery. Thrombopoietin receptor agonists may improve the likelihood of a hematologic recovery.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

MR spectroscopic imaging predicts early response to anti-angiogenic therapy in recurrent glioblastoma.

BACKGROUND: Determining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS). METHODS: We performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies. RESULTS: After stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival. CONCLUSIONS: Changes in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes.

Mosaicism for Receptor Tyrosine Kinase Activation in a Glioblastoma Involving Both PDGFRA Amplification and NTRK2 Fusion.

Rearrangements involving the neurotrophic receptor tyrosine kinase (NTRK) gene family have been reported in diverse tumor types, and NTRK-targeted therapies have recently been approved. In this article, we report a case of a 26-year-old man with an NTRK2-rearranged isocitrate dehydrogenase-wild-type glioblastoma who showed a robust but temporary response to the NTRK inhibitor larotrectinib. Rebiopsy after disease progression showed elimination of the NTRK2-rearranged tumor cell clones, with secondary emergence of a PDGFRA-amplified subclone. Retrospective examination of the initial biopsy material confirmed rare cells harboring PDGFRA amplification. Although mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma has been previously described, mosaicism involving a fusion gene driver event has not. This case highlights the potential efficacy of NTRK-targeted treatment in glioblastoma and the implications of molecular heterogeneity in the setting of targeted therapy. KEY POINTS: This case highlights the efficacy of the NTRK inhibitor larotrectinib in treating NTRK-rearranged glioblastoma. This is the first case to demonstrate mosaicism in glioblastoma involving both a fusion gene and amplification for receptor tyrosine kinases. Intratumoral heterogeneity in glioblastoma has significant implications for tumor resistance to targeted therapies.