Desmoplastic myxoid tumor of pineal region, SMARCB1-mutant, in young adult.

We present a young adult woman who developed a myxoid tumor of the pineal region having a SMARCB1 mutation, which was phenotypically similar to the recently described desmoplastic myxoid, SMARCB1-mutant tumor of the pineal region (DMT-SMARCB1). The 24-year-old woman presented with headaches, nausea, and emesis. Neuroimaging identified a hypodense lesion in CT scans that was T1-hypointense, hyperintense in both T2-weighted and FLAIR MRI scans, and displayed gadolinium enhancement. The resected tumor had an abundant, Alcian-blue positive myxoid matrix with interspersed, non-neoplastic neuropil-glial-vascular elements. It immunoreacted with CD34 and individual cells for EMA. Immunohistochemistry revealed loss of nuclear INI1 expression by the myxoid component but its retention in the vascular elements. Molecular analyses identified a SMARCB1 deletion and DNA methylation studies showed that this tumor grouped together with the recently described DMT-SMARCB1. A cerebrospinal fluid cytologic preparation had several cells morphologically similar to those in routine and electron microscopy. We briefly discuss the correlation of the pathology with the radiology and how this tumor compares with other SMARCB1-mutant tumors of the nervous system.

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. INTERPRETATION: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. FUNDING: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Population based analysis ependymoma patients in Alberta from 1975 to 2007.

BACKGROUND: Ependymomas are rare tumors of the central nervous system whose management is controversial. This population-based study of adults and children with ependymoma aims to (1) identify clinical and treatment-related factors that impact survival and (2) determine if postoperative radiotherapy (RT) can improve survival of patients with subtotal resection (STR) to levels similar to patients who had gross total resection (GTR). METHODS: This retrospective population-based study evaluated 158 patients with ependymoma diagnosed between 1975-2007 in Alberta, Canada. RESULTS: Younger patients (<7 years of age) were more likely to be diagnosed with grade III tumors compared with adults in whom grade I tumors were more common (p=0.003). Adults were more likely to have spinally located tumors compared to young children whose tumors were typically found in the brain. Overall, young children with ependymoma were more likely to die than older children or adults (p=0.001). An equivalent number of patients underwent GTR as compared with STR (48% vs 45%, respectively). Overall, older age, spinal tumor location, lower grade, and GTR were associated with improved progression free survival but only GTR was associated with significant improvement in overall survival. Median survival after STR and RT was 82 months compared with 122 months in patients who had GTR (p=0.0022). CONCLUSIONS: This is the first Canadian population-based analysis of patients with ependymoma including adults and children. Extent of resection appears to be the most important factor determining overall survival. Importantly, the addition of RT to patients initially treated with STR does not improve survival to levels similar to patients receiving GTR.

Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide.

PURPOSE: To analyse patterns of failure in patients with glioblastoma multiforme treated with concurrent radiation and temozolomide. MATERIALS AND METHODS: A retrospective review of patients treated with concurrent radiation and temozolomide was performed. Twenty patients treated at the University of Alabama at Birmingham, with biopsy-proven disease, documented disease progression after treatment, and adequate radiation dosimetry and imaging records were included in the study. Patients generally received 46 Gy to the primary tumour and surrounding oedema plus 1 cm, and 60 Gy to the enhancing tumour plus 1 cm. MRIs documenting failure after therapy were fused to the original treatment plans. Contours of post-treatment tumour volumes were generated from MRIs showing tumour failure and were overlaid onto the original isodose curves. The recurrent tumours were classified as in-field, marginal or regional. Recurrences were also evaluated for distant failure. RESULTS: Of the 20 documented failures, all patients had some component of failure at the primary site. Eighteen patients (90%) failed in-field, 2 patients (10%) had marginal failures, and no regional failures occurred. Four patients (20%) had a component of distant failure in which an independent satellite lesion was located completely outside of the 95% isodose curve. CONCLUSIONS: Radiation concurrent with temozolomide appears to be associated with a moderate risk of distant brain failure in addition to the high rate of local failure. The risk of distant failure was consistent with that observed with radiation alone, suggesting that temozolomide does not act to reduce distant brain failure but to improve local control.

Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone.

PURPOSE: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF. METHODS AND MATERIALS: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility. The primary endpoint was DBF. Potential predictors included number of metastases, tumor volume, histologic characteristics, extracranial disease, and use of temozolomide. RESULTS: One-year actuarial risk of DBF was 61% for all patients. Significant predictors of DBF included more than three metastases (hazard ratio, 3.30; p = 0.004), stable or poorly controlled extracranial disease (hazard ratio, 2.16; p = 0.04), and melanoma histologic characteristics (hazard ratio, 2.14; p = 0.02). These were confirmed in multivariate analysis. Those with three or fewer metastases, no extracranial disease, and nonmelanoma histologic characteristics (N = 18) had a median time to DBF of 89 weeks vs. 33 weeks for all others. One-year actuarial freedom from DBF for this group was 83% vs. 26% for all others. CONCLUSIONS: Independent significant predictors of DBF in our series included number of metastases (more than three), present or uncontrolled extracranial disease, and melanoma histologic characteristics. These factors were combined to identify a lower risk subgroup with significantly longer time to DBF. These patients may be candidates for initial localized treatment, reserving whole-brain radiation therapy for salvage. Patients in the higher risk group may be candidates for initial whole-brain radiation therapy or should be considered for clinical trials.

Molecular targets in radiation-induced blood-brain barrier disruption.

Disruption of the blood-brain barrier (BBB) is a key feature of radiation injury to the central nervous system. Studies suggest that endothelial cell apoptosis, gene expression changes, and alteration of the microenvironment are important in initiation and progression of injury. Although substantial effort has been directed at understanding the impact of radiation on endothelial cells and oligodendrocytes, growing evidence suggests that other cell types, including astrocytes, are important in responses that include induced gene expression and microenvironmental changes. Endothelial apoptosis is important in early BBB disruption. Hypoxia and oxidative stress in the later period that precedes tissue damage might lead to astrocytic responses that impact cell survival and cell interactions. Cell death, gene expression changes, and a toxic microenvironment can be viewed as interacting elements in a model of radiation-induced disruption of the BBB. These processes implicate particular genes and proteins as targets in potential strategies for neuroprotection.

Intercellular adhesion molecule-1 and blood-spinal cord barrier disruption in central nervous system radiation injury.

Central nervous system (CNS) injury is a major dose-limiting toxicity that limits the effectiveness of radiation therapy. Blood-brain barrier (BBB) disruption and white matter necrosis are prominent features. Increased expression of intercellular adhesion molecule-1 (ICAM-1) accompanies and is believed to be important in BBB disruption in other CNS injuries. Our aim was to assess the expression of ICAM-1 and its relationship to regions of blood-spinal cord barrier (BSCB) disruption in the irradiated rat spinal cord. ICAM-1 protein was detected by immunohistochemistry and quantified by digital image analysis. Cells expressing ICAM-1 were identified. BSCB disruption was assessed by immunohistochemical detection of serum albumin. ICAM-1 expression localized predominantly to vascular endothelium and increased in white matter but not in grey matter at 24 hours and 17 to 20 weeks after 22 Gy. A dose response was observed from 16 to 20 Gy. ICAM-1 expression colocalized with regions of BSCB disruption. ICAM-1 expression was also observed in glia, a majority of which were astrocytes. The parallel dose response, time course, and spatial distribution of ICAM-1 expression and albumin leakage suggest a role for ICAM-1 in late BSCB disruption after radiation.

Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor.

PURPOSE: Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1alpha (HIF1alpha) induction, we studied the relationships of hypoxia, HIF1alpha expression, and expression of VEGF in this damage pathway. EXPERIMENTAL DESIGN: Expression of HIF1alpha, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1H-imidazole-L-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-A(hi/+)), reduced (VEGF-A(lo/+)), and wild-type VEGF activity to thoracolumbar irradiation. RESULTS: In rat spinal cord, the number of cells expressing HIF1alpha and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1alpha and VEGF. HIF1alpha and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-A(lo/+) mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-A(hi/+) mice. CONCLUSIONS: VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.