Journal of Neuro-Oncology

Treatment for anaplastic astrocytoma (AA) is controversial. To assess three primary treatment approaches, patients from a single institution were retrospectively evaluated. To represent modern treatment selection, patients diagnosed with AA from December 2003 to December 2009 were selected. Those with insufficient data, incomplete pathology, and transformation or reclassification to glioblastoma in fewer than 6 months were excluded. A total of 163 patients were included in the final analyses. Median follow-up time was 4.2 years (range 0.5–7.8 years). Median age and Karnofsky performance status at diagnosis were 39.2 years and 90, respectively. 23.6 % of patients underwent biopsy, and 72.2 % underwent resection. Approximately 31 % received concurrent chemoradiation (CRT), 26.1 % had radiation therapy alone (RT), 38.2 % had radiation therapy followed by chemotherapy (RT-C), and 3 % were treated only with chemotherapy. Temozolomide was used almost exclusively during CRT (94.2 %) and adjuvantly. A median of 9.5 cycles of adjuvant chemotherapy was given. The combination of radiation and chemotherapy, either concurrent or sequential trended toward a higher rate of radiation necrosis. Median progression free survival (PFS) favored RT (not reached) over CRT (1.5 years) and RT-C (3.6 years) adjusted for pairwise comparison (p = 0.033, p = 0.050). Median overall survival (OS) was 5.7 years, and did not differ significantly by treatment group. OS for patients with AA did not vary by initial treatment selection. Although the longer PFS in those receiving RT versus CRT may be confounded by pseudoprogression, the equivalent OS among groups supports RT.

Episodic cerebro or retinovascular ischemic events without apparent cause occur in patients with cancer. We report a patient in remission from lymphoma whose multiple episodes of presumed ocular ischemia occurred in the setting of a circulating lupus anticoagulant. Symptoms resolved following therapy with Warfarin.

Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age ≥18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75–100 mg/m2 day 1–21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.

What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? Adult patients with imaging suggestive of a low-grade glioma. Stereotactic biopsy is recommended when definitive surgical resection is limited by lesions that are deep-seated, not resectable, and/or located within eloquent cortex, or in patients unable to undergo craniotomy due to medical co-morbidities to obtain the critical tissue diagnosis needed for targeted treatment planning for patients with low-grade gliomas. What is the best technique for brain biopsy? Adult patients with imaging suggestive of a low-grade glioma. Frameless and frame-based stereotactic brain biopsy for low-grade gliomas are recommended based on clinical circumstances as they provide similar diagnostic yield, diagnostic accuracy, morbidity, and mortality. It is recommended the surgeon consider advanced imaging techniques (e.g., perfusion, spectroscopy, metabolic studies) to target specific regions of interest to potentially improve diagnostic accuracy.

The differences in the clinical course and histopathology of sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) were investigated retrospectively. The collective comprised 38 NF1 patients and 14 sporadic patients. NF1 patients were significantly younger at diagnosis (p < 0.001) and had a significantly shorter survival time than sporadic patients (median survival 17 months vs. 42 months, Breslow p < 0.05). The time interval to local recurrence and metastatic spread was also significantly shorter in NF1 patients (9.4 months vs. 30.0 months, p < 0.01; 9.1 months vs. 33.2 months, p < 0.001, respectively). In patients with the original histopathological data available (22 NF1 patients, 14 sporadic cases), NF1-associated MPNST showed a significantly higher cellularity compared to sporadic tumors (p < 0.001) whereas sporadic MPNST featured a significantly higher pleomorphism (p< 0.01). Most importantly, while histopathological variables correlated with French Fédération Nationale des Centres de Lutte Contre le Cancer grading in sporadic MPNST, this was not the case for NF1-associated tumors. The differences between NF1-associated and sporadic MPNST in regard to the clinical course and histopathology may reflect some fundamental differences in biology and pathomechanism of the two tumor groups. Our findings indicate the necessity for a separate grading scheme which takes into account the genetic background in NF1 patients.

This issue of the Journal of Neuro-Oncology is devoted to recent investigations of low-grade gliomas. The purpose of this issue is not to debate the relative merits and liabilities of different management strategies for low-grade gliomas, but to present new data concerning novel and innovative approaches to evaluating these lesions. The common theme of many of these reports represents a departure from grading systems that primarily depend on a morphology-based analysis from light microscopy to classify these tumors. The purpose of this review is to present the reasoning behind the selection of authors for this issue of the Journal of Neuro-Oncology and to provide a format for presentation of new ideas concerning these interesting tumors. It is clear that standard classification systems that address only the morphological characteristics of tumor cells can not adequately represent the wide variation in biological activity that is found with these lesions. It is hoped that these articles will stimulate further interest and research into low-grade gliomas that will one day lead to more effective therapy.

Only a few Methyl-[11C]-l-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 ± 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 ± 0.46) and low grade tumors (mean MET-uptake = 1.84 ± 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone.

Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan–Meier analyses with log-rank p-values and cox proportional hazards regression were performed. The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71–15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4–107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50–53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.