Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

Exceptional and Sustained Response to Belzutifan in Von Hippel-Lindau Disease-Associated Central Nervous System Hemangioblastoma.

Von Hippiel-Lindau (VHL) disease is a rare genetic disorder characterized by a variety of benign and malignant neoplastic growths arising in multiple different organ systems. About 60%-84% of patients develop hemangioblastomas, benign tumors comprised of newly formed blood vessels that often occur in the central nervous system (CNS) and retinas. Treatment options for this disease were limited before the Food and Drug Administration (FDA) approval of belzutifan, a HIF2α inhibitor. We present a case of a 25-year-old woman with VHL who underwent treatment with belzutifan over 18 months. It was noted that her CNS lesions decreased significantly in size over the course of her treatment, and she had minimal adverse effects. Her excellent and sustained therapeutic response to the treatment highlights the real-world clinical benefit of belzutifan and the possibility that this could play a crucial role in treating VHL by postponing or completely avoiding repeated surgical and radiotherapeutic intervention and their associated comorbidities.

Progressive Multifocal Leukoencephalopathy Presenting as Primary CNS Malignancy in an Immunocompetent Patient.

Progressive multifocal leukoencephalopathy (PML) is an infection caused by the John Cunningham virus (JCV), usually in an immunocompromised host. We present the case of a 74-year-old male who presented with a six-week history of progressive memory loss, episodic confusion, and aphasia. Cranial nerve, motor, sensory, and coordination testing were unremarkable. Magnetic resonance imaging (MRI) of the brain and spectroscopy were concerning for primary CNS lymphoma vs. diffuse glioma. Microscopic examination after the patient underwent left frontal stereotactic brain biopsy was suggestive of a viral infection, and further testing with JCV DNA in-situ hybridization (ISH) confirmed the diagnosis of PML. The patient's condition started resolving without treatment. This case demonstrates, to our knowledge, the first known case of primary PML masquerading as CNS lymphoma in modern literature.

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

BACKGROUND: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab. METHODS: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors. RESULTS: Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1). CONCLUSIONS: Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Glioblastoma: background, standard treatment paradigms, and supportive care considerations.

Glioblastoma is a brain tumor condition marked by rapid neurological and clinical demise, resulting in disproportionate disability for those affected. Caring for this group of patients is complex, intense, multidisciplinary in nature, and fraught with the need for expensive treatments, surveillance imaging, physician follow-up, and rehabilitative, psychological, and social support interventions. Few of these patients return to the workforce for any meaningful time frame, and because of the enormity of the financial burden that patients, their caregivers, and society face, utilization reviews become the focus of ethical scrutiny.

Cerebral amyloidoma mimicking intracranial tumor: a case report.

INTRODUCTION: Cerebral amyloidoma is an infrequently recognized condition that can be confused with a more malignant etiology. Few cases have been reported. We present a case report and a review of the literature. CASE PRESENTATION: Our patient was a 64-year-old Caucasian man who was incidentally discovered to have a brain mass. He was found to have a cerebral amyloidoma. CONCLUSION: After discovery of the true etiology of his brain abnormality, it was determined that our patient had a more benign disease than was initially feared. Cases such as this demonstrate why consideration of this disorder is important.

Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide.

Antiepileptic drugs (AEDs) are frequently used to treat seizures in glioma patients. AEDs may have an unrecognized impact in modulating O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that has an important role in tumor cell resistance to alkylating agents. We report that levetiracetam (LEV) is the most potent MGMT inhibitor among several AEDs with diverse MGMT regulatory actions. In vitro, when used at concentrations within the human therapeutic range for seizure prophylaxis, LEV decreases MGMT protein and mRNA expression levels. Chromatin immunoprecipitation analysis reveals that LEV enhances p53 binding on the MGMT promoter by recruiting the mSin3A/histone deacetylase 1 (HDAC1) corepressor complex. However, LEV does not exert any MGMT inhibitory activity when the expression of either p53, mSin3A, or HDAC1 is abrogated. LEV inhibits malignant glioma cell proliferation and increases glioma cell sensitivity to the monofunctional alkylating agent temozolomide. In 4 newly diagnosed patients who had 2 craniotomies 7-14 days apart, prior to the initiation of any tumor-specific treatment, samples obtained before and after LEV treatment showed the inhibition of MGMT expression. Our results suggest that the choice of AED in patients with malignant gliomas may have an unrecognized impact in clinical practice and research trial design.

Phase II trial of temozolomide in patients with progressive low-grade glioma.

PURPOSE: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma. PATIENTS AND METHODS: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m(2)/d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity. RESULTS: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to infinity months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced > or = grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death. CONCLUSION: Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted.

Treatment of spinal cord impact injury in the rat with transforming growth factor-beta.

To investigate the contribution of cytokines, proinflammatory TNF-alpha and inhibitory TGF-beta, to spinal cord injury (SCI) in a rat model, two studies were performed using adult Sprague-Dawley rats which were injured at T9/T10. In the first study, rats were sacrificed at 1, 6, 24, 96 and 168 h after SCI for immunocytochemistry of coronal sections for the presence of mononuclear phagocytes, astrocytes, TNF-alpha and TGF-beta, among other markers. From intervening frozen sections, RNA was extracted for semiquantitative polymerase chain reaction (RT-PCR) analysis of TNF-alpha and TGF-beta. In the second experiment, rats were treated with intravenous TGF-beta 30 min after injury and sacrificed at 6 and 48 h after injury. Spinal cord sections were immunocytochemically stained and RNA extracted for semiquantitative PCR as mentioned above, as well as quantitation of lesion volume. There were increases in mononuclear phagocytes and astrocytes, as early as 1 h after SCI, with steady progression over 168 h after injury. TNF-alpha and TGF-beta was produced locally by mononuclear phagocytes and astrocytes. There was an 18-h delay in peak mRNA production of TGF-beta compared to TNF-alpha. The treatment of SCI rats with TGF-beta reduced lesion volume by 50% at 48 h and this was associated with decreased accumulation of mononuclear phagocytes in and around the injury site. This reduction of mononuclear phagocyte numbers around the site of trauma would reduce their contribution to secondary injury.