Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine.

BACKGROUND AND PURPOSE: Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. MATERIALS AND METHODS: A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. RESULTS: Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. CONCLUSIONS: This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.

Mechanisms of post-radiation injury: cerebral microinfarction not a significant factor.

Post-radiation leukoencephalopathy is characterized by cognitive impairment and white matter alternations on imaging. Cerebral small vessel disease (SVD) is one of several suggested etiologies. Cerebral microinfarction (CMI) is a recently described marker of SVD. We sought to examine the rate of CMI as a biomarker of ongoing ischemia among patients who underwent brain radiotherapy (RT). 110 patients treated with RT for primary or metastatic brain tumors were enrolled. A total of 685 brain MRI tests performed 1-108 months post-radiation were examined. The annual incidence of CMI was calculated. Only 2 definite CMI were found (2/685, 0.3 %). The calculated annual incidence of CMI was 0.11. This incidence is similar to the normal population, and lower than the reported incidence in patients with intracerebral hemorrhage or cognitive impairment. CMI incidence in patients treated with brain RT is similar to the general population. This finding suggests that post-radiation leukoencephalopathy and cognitive impairment are not due to active SVD solely but rather secondary to other causes such as inflammation, metabolic or direct cell damage.

Early Biomarkers from Conventional and Delayed-Contrast MRI to Predict the Response to Bevacizumab in Recurrent High-Grade Gliomas.

BACKGROUND AND PURPOSE: The interpretation of the radiologic response of bevacizumab-treated patients with recurrent high-grade gliomas represents a unique challenge. Delayed-contrast MR imaging was recently introduced for calculating treatment-response-assessment maps in patients with brain tumors, providing clear separation between active tumor and treatment effects. We studied the application of standard and delayed-contrast MR imaging for assessing and predicting the response to bevacizumab. MATERIALS AND METHODS: Twenty-four patients with recurrent high-grade gliomas were scanned before and during bevacizumab treatment by standard and delayed-contrast MR imaging. The mean change in lesion volumes of responders (overall survival, ≥1 year) and nonresponders (overall survival, <1 year) was studied. The lesion volumes at baseline and the changes in lesion volumes 1 month after treatment initiation, calculated from standard and delayed-contrast MRIs, were studied as possible predictors of outcome. In scans acquired at progression, the average change in lesion volume from previous follow-up in standard and delayed-contrast MRIs was compared. RESULTS: Response and progression patterns were identified from the mean change in lesion volumes, depicted from conventional T1WI, delayed contrast-enhanced MR imaging, and DSC MR imaging. Thresholds for early prediction of response were calculated by using these sequences. For each predictor, sensitivity, specificity, positive predictive values, and negative predictive values were calculated, reaching 85.7%, 87.5%, 75%, and 93.3% for conventional T1WI; 100%, 87.5%, 77.8%, and 100% for delayed-contrast MR imaging; and 75%, 78.6%, 50%, and 91.7% for DSC MR imaging. The benefit of delayed-contrast MR imaging in separating responders and nonresponders was further confirmed by using log-rank tests (conventional T1WI, P = .0022; delayed-contrast MR imaging, P < .0001; DSC MR imaging, P = .0232) and receiver operating characteristic analyses. At progression, the increase in lesion volumes in delayed-contrast MR imaging was 37.5% higher than the increase in conventional T1WI (P < .01); these findings suggest that progression may be depicted more effectively in treatment-response-assessment maps. CONCLUSIONS: The benefit of contrast-enhanced MR imaging for assessing and predicting the response to bevacizumab was demonstrated. The increased sensitivity of the treatment-response-assessment maps reflects their potential contribution to the management of bevacizumab-treated patients with recurrent high-grade glioma.

The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter?

The FDA-approved schedule and dose of bevacizumab (BVZ) for recurrent glioblastoma (rGB) (10 mg/kg q 2 weeks) were adopted from systemic cancer protocols. No dose-defining studies have been performed for glioblastoma. We began using BVZ for the treatment of rGB in 2005 at the dose of 5 mg/kg every 2 weeks combined with irinotecan, and later as single agent. Our previous report of 20 patients treated with BVZ 5 mg/kg every 2 weeks showed similar response rates and overall survival (OS) compared to other BVZ treatment protocols, with less adverse effects. In this study we retrospectively reviewed our 7 year experience with BVZ in 162 rGB patients. Treatment outcomes were analyzed from 87 patients who received BVZ at 5 mg/kg and 75 patients at 10 mg/kg. While median age was similar in both groups, the median KPS was significantly higher in the group treated with 10 mg/kg BVZ (85 versus 60). There was no significant difference in OS or progression free survival (PFS) between the groups treated with BVZ 5 versus 10 mg/kg. Overall survival was significantly improved in the subgroup treated with cytotoxic therapy in addition to BVZ 10 mg/kg. There were more adverse events seen with BVZ 10 mg/kg. There is no significant difference in OS for rGB treated with BVZ 5 mg/kg versus 10 mg/kg when given as monotherapy. The smaller dose was slightly less toxic. Addition of cytotoxic therapy resulted in prolongation of OS in a small subgroup of BVZ 10 mg/kg.

The value of ventriculo-peritoneal shunting in patients with glioblastoma multiforme and ventriculomegaly.

BACKGROUND: Patients with an advanced-stage glioblastoma multiforme (GBM) often show general motor, gait, and cognitive deterioration. Some have radiological evidence of ventriculomegaly, but the relevance of this to their symptoms may be unclear. Distinction between tumour patients who have dilated fluid spaces as a consequence of tissue loss from surgery or treatment, and those who have a symptomatic hydrocephalic process, one who may gain benefit from insertion of a ventriculo-peritoneal shunt, is an important clinical challenge. METHODS: From a series of 530 GBM patients treated by a single surgeon (ZR), we retrospectively reviewed 16 patients with advanced-stage GBM who had presented with non-obstructive ventriculomegaly and clinical deterioration not explained by progressive disease. Each had been treated by insertion of a ventriculo- peritoneal shunt (VPS). Assessments included clinical features, Karnofsky Performance Scale, motor and cognitive findings, complications and survival. FINDINGS: Ten patients benefited from insertion of the shunt, with moderate to significant cognitive improvement. Of seven patients who presented with motor symptoms, such as gait instability, general weakness, and slowness, four patients showed significant motor improvement in addition to major cognitive improvement. Early infectious complication occurred in five patients; a late shunt infection in one; one patient had symptoms related to overdrainage; and in another a mechanical shunt malfunction occurred. Three patients died from shunt-related complications. CONCLUSIONS: Insertion of a ventriculo-peritoneal shunt can improve cognitive and motor function in a small subset of patients with advanced-stage glioblastoma multiforme and ventriculomegaly. Infection is a major risk in this patient population.

Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis.

A 67-year-old man sequentially developed anti-Ma2-associated paraneoplastic encephalitis (PNE) and contralateral herpes simplex encephalitis (HSE). Brain biopsy 1 month before HSE revealed extensive infiltrates of T cells, B cells, and plasma cells. Most T cells expressed the cytotoxic granule-associated protein TIA-1 and the membranolytic protein granzyme-B. Although recovery was thought to be unlikely, treatment of the PNE with corticosteroids and resection of the associated lung cancer resulted in dramatic improvement for 21 months.

Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM.

Primary glioblastoma multiforme (GBM) commonly overexpresses the epidermal growth factor receptor (EGFR) gene and its ligand-independent mutant, EGFRvIII. Amplification of the EGFR gene has been implicated in the pathogenesis of primary GBM, in particular the small cell phenotype, and this finding may contribute to its aggressive clinical behavior. Anti-EGFR clinical trials for GBM are being conducted, and it would be useful to identify a rapid technique to determine whether EGFR expression and the small cell phenotype are associated with a response to therapy. In the present study we examined 56 cases of GBM using chromogenic in situ hybridization (CISH). CISH analysis and morphology identified 22 small cell (SCGBM) and 22 non-small cell glioblastoma (NSCGBM), and 12 cases of a mixed phenotype. Fourteen cases of SCGBM (14/22) showed EGFR amplification, while only 5 NSCGBM (5/22) cases showed amplification. We have therefore used CISH as an efficient, economic and reliable means for routinely assessing EGFR amplification in GBM, including the small cell variant.

Primary intracranial neoplasms in patients with HIV.

OBJECTIVE: To report a series of HIV-infected patients with intracranial tumors not known to be associated with immunodeficiency. BACKGROUND: The spectrum of HIV-associated diseases is changing with improved treatments and prolonged patient survival. Although primary central nervous system lymphoma (PCNSL) and toxoplasmosis continue to be the most common intracranial lesions in HIV-infected patients, the recognition of other pathologic entities is increasingly important. METHODS: The clinical characteristics and outcome of eight HIV-infected patients with nine intracranial neoplasms other than PCNSL are reported. In addition, all available pathologic specimens were tested for evidence of either HIV or Epstein-Barr virus (EBV) infection. An additional 28 patients reported in the literature are summarized. RESULTS: Five of eight patients had a glioblastoma multiforme; other tumors included an anaplastic ependymoma, a low-grade glioma, a subependymoma, and a leiomyosarcoma. More than half of the patients developed their tumor > or =6 years after the diagnosis of HIV infection. Patient prognosis and survival was best predicted by tumor histology. Treatment response and outcome did not appear to be influenced by HIV infection. Only the leiomyosarcoma demonstrated evidence of latent EBV infection. CONCLUSIONS: HIV-infected patients are at risk for intracranial neoplasms other than PCNSL, and benefit from aggressive tumor-specific therapy. It is possible that gliomas are occurring at a higher rate than in the general population. There was no evidence of HIV or EBV infection in any glial tumor.

Aging and primary central nervous system neoplasms.

The number of primary brain tumors in the aging population has increased over the past few decades. Although overall survival rates for many patients with primary central nervous system neoplasms have not changed drastically, patients with particular tumor types are benefitting from new treatments. Many factors must be considered when treating primary brain tumors in the elderly, including overall medical condition, tumor biology, and social issues.

Myoclonus epilepsy with ragged red fibers and multiple mtDNA deletions.

In a patient with clinical features of myoclonus epilepsy with ragged red fibers (MERRF), molecular genetic analysis of mitochondrial DNA did not show either of the two point mutations typically associated with MERRF but did show multiple deletions by Southern blot. This case further illustrates the heterogeneity observed with mtDNA mutations.

Carotid artery occlusion following a karate punch to the neck.

A 43-year-old corrections officer developed right neck and posterior head pain following a karate punch to the right side of the neck during self-defense training. One week later, he developed an acute left hemiparesis. Magnetic resonance imaging demonstrated a right hemisphere cerebral infarction and absence of signal flow void in the right internal carotid artery. Carotid ultrasound demonstrated complete occlusion of the right internal carotid artery without evidence of atherosclerotic disease. Carotid occlusion with cerebrovascular infarction is a possible complication of martial arts training involving forceful blows to the neck.