Pre-operative MRI radiomics model non-invasively predicts key genomic markers and survival in glioblastoma patients.

PURPOSE: Although glioblastoma (GBM) is the most common primary brain malignancy, few tools exist to pre-operatively risk-stratify patients by overall survival (OS) or common genetic alterations. We developed an MRI-based radiomics model to identify patients with EGFR amplification, MGMT methylation, GBM subtype, and OS greater than 12 months. METHODS: We retrospectively identified 235 patients with pathologically confirmed GBMs from the Cancer Genome Atlas (88; TCGA) and MD Anderson Cancer Center (147; MDACC). After two neuroradiologists segmented MRI tumor volumes, we extracted first-order and second-order radiomic features (gray-level co-occurrence matrices). We used the Maximum Relevance Minimum Redundancy technique to identify the 100 most relevant features and validated models using leave-one-out-cross-validation and validation on external datasets (i.e., TCGA). Our results were reported as the area under the curve (AUC). RESULTS: The MDACC patient cohort had significantly higher OS (22 months) than the TCGA dataset (14 months). On both LOOCV and external validation, our radiomics models were able to identify EGFR amplification (all AUCs > 0.83), MGMT methylation (all AUCs > 0.85), GBM subtype (all AUCs > 0.92), and OS (AUC > 0.91 on LOOCV and 0.71 for TCGA validation). CONCLUSIONS: Our robust radiomics pipeline has the potential to pre-operatively discriminate common genetic alterations and identify patients with favorable survival.

A Coclinical Radiogenomic Validation Study: Conserved Magnetic Resonance Radiomic Appearance of Periostin-Expressing Glioblastoma in Patients and Xenograft Models.

PURPOSE: Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma. EXPERIMENTAL DESIGN: Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients (n = 93) and orthotopic xenografts (OX; n = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin (POSTN) expression levels. RNA and protein levels confirmed RNAi-mediated POSTN knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict POSTN expression status in patient, mouse, and interspecies. RESULTS: Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. POSTN expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted POSTN expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar POSTN expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; P = 02.021E-15). CONCLUSIONS: We determined causality between radiomic texture features and POSTN expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human-mouse matched coclinical trials.

Comparison of functional localization accuracy with different co-registration strategies in presurgical fMRI for brain tumor patients.

PURPOSE: Presurgical fMRI is an important tool for surgery navigation in achieving maximum resection of a brain tumor. However, the functional localization accuracy may be compromised by spatial transformation from echo-planar images to high-resolution structural images. We evaluated functional localization errors associated with the spatial transformation process using three algorithms commonly applied to the presurgical fMRI in the clinic. METHODS: MR images of 20 brain tumor patients for presurgical evaluation of eloquent areas near motor cortices were analyzed. All fMRI data were spatially transferred to 3D T1-weighted images using three algorithms: (a) coordinate matching (CM), (b) automated registration (AR), and (c) AR plus manual adjustment (ARadj ). Activation clusters overlaid on original echo-planar images were manually delineated on slice-matched 2D T1- weighted images and then transferred to the 3D T1-weighted image volume, and served as the reference localization. Functional localization errors were estimated by measuring the distance between the reference localization and the activation cluster after spatial transformation and then compared for the three algorithms. RESULTS: The 3D Euclidean distance for AR (10.2 ± 4.9 mm) was found to be significantly larger (P < 0.05) than those for CM (5.6 ± 2.6 mm) and ARadj (5.8 ± 3.0 mm) algorithms. The difference between the localization errors in CM and ARadj was not statistically significant. CONCLUSIONS: A procedure was proposed to evaluate functional localization errors associated with spatial transformation in presurgical fMRI. Our results highlighted the necessity of routine quality control for the AR processing in the clinic.

Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome.

INTRODUCTION: The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients. METHODS: We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups. RESULTS: Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037). CONCLUSION: Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.

Silent Sentence Completion Shows Superiority Localizing Wernicke's Area and Activation Patterns of Distinct Language Paradigms Correlate with Genomics: Prospective Study.

Preoperative mapping of language areas using fMRI greatly depends on the paradigms used, as different tasks harness distinct capabilities to activate speech processing areas. In this study, we compared the ability of 3 covert speech paradigms: Silent Sentence Completion (SSC), category naming (CAT) and verbal fluency (FAS), in localizing the Wernicke's area and studied the association between genomic markers and functional activation. Fifteen right-handed healthy volunteers and 35 mixed-handed patients were included. We focused on the anatomical areas of posterosuperior, middle temporal and angular gyri corresponding to Wernicke's area. Activity was deemed significant in a region of interest if P < 0.05. Association between fMRI activation and genomic mutation status was obtained. Results demonstrated SSC's superiority at localizing Wernicke's area. SSC demonstrated functional activity in 100% of cancer patients and healthy volunteers; which was significantly higher than those for FAS and CAT. Patients with 1p/19q non-co-deleted had higher extent of activation on SSC (P < 0.02). Those with IDH-1 wild-type were more likely to show no activity on CAT (P < 0.05). SSC is a robust paradigm for localizing Wernicke's area, making it an important clinical tool for function-preserving surgeries. We also found a correlation between tumor genomics and functional activation, which deserves more comprehensive study.

Image guidance based on MRI for spinal interstitial laser thermotherapy: technical aspects and accuracy.

OBJECTIVE Image guidance for spinal procedures is based on 3D-fluoroscopy or CT, which provide poor visualization of soft tissues, including the spinal cord. To overcome this limitation, the authors developed a method to register intraoperative MRI (iMRI) of the spine into a neuronavigation system, allowing excellent visualization of the spinal cord. This novel technique improved the accuracy in the deployment of laser interstitial thermal therapy probes for the treatment of metastatic spinal cord compression. METHODS Patients were positioned prone on the MRI table under general anesthesia. Fiducial markers were applied on the skin of the back, and a plastic cradle was used to support the MRI coil. T2-weighted MRI sequences of the region of interest were exported to a standard navigation system. A reference array was sutured to the skin, and surface matching of the fiducial markers was performed. A navigated Jamshidi needle was advanced until contact was made with the dorsal elements; its position was confirmed with intraoperative fluoroscopy prior to advancement into a target in the epidural space. A screenshot of its final position was saved, and then the Jamshidi needle was exchanged for an MRI-compatible access cannula. MRI of the exact axial plane of each access cannula was obtained and compared with the corresponding screenshot saved during positioning. The discrepancy in millimeters between the trajectories was measured to evaluate accuracy of the image guidance RESULTS Thirteen individuals underwent implantation of 47 laser probes. The median absolute value of the discrepancy between the location predicted by the navigation system and the actual position of the access cannulas was 0.7 mm (range 0-3.2 mm). No injury or adverse event occurred during the procedures. CONCLUSIONS This study demonstrates the feasibility of image guidance based on MRI to perform laser interstitial thermotherapy of spinal metastasis. The authors' method permits excellent visualization of the spinal cord, improving safety and workflow during laser ablations in the epidural space. The results can be extrapolated to other indications, including biopsies or drainage of fluid collections near the spinal cord.

Radiomic Texture Analysis Mapping Predicts Areas of True Functional MRI Activity.

Individual analysis of functional Magnetic Resonance Imaging (fMRI) scans requires user-adjustment of the statistical threshold in order to maximize true functional activity and eliminate false positives. In this study, we propose a novel technique that uses radiomic texture analysis (TA) features associated with heterogeneity to predict areas of true functional activity. Scans of 15 right-handed healthy volunteers were analyzed using SPM8. The resulting functional maps were thresholded to optimize visualization of language areas, resulting in 116 regions of interests (ROIs). A board-certified neuroradiologist classified different ROIs into Expected (E) and Non-Expected (NE) based on their anatomical locations. TA was performed using the mean Echo-Planner Imaging (EPI) volume, and 20 rotation-invariant texture features were obtained for each ROI. Using forward stepwise logistic regression, we built a predictive model that discriminated between E and NE areas of functional activity, with a cross-validation AUC and success rate of 79.84% and 80.19% respectively (specificity/sensitivity of 78.34%/82.61%). This study found that radiomic TA of fMRI scans may allow for determination of areas of true functional activity, and thus eliminate clinician bias.

Contrast-enhanced Reformatted MR Images for Preoperative Assessment of the Bridging Veins of the Skull Base.

Magnetic resonance (MR) venography and computed tomographic (CT) venography are suited for displaying the convexity veins that drain the medial and lateral surfaces of the brain hemispheres. However, such is not the case for the bridging veins of the skull base. Technical factors prevent contrast material-enhanced MR or CT images obtained in standard axial, coronal, and sagittal planes from fully displaying the curved pathways of these clinically important venous structures. This limitation can be overcome by using a reconstruction technique that depicts these venous structures and their interconnections. Curved and multiplanar reformatted images that distill the important venous features often require knowledgeable manipulation of source images by an operator who is familiar with numerous venous variants and their surgical implications. The normal anatomy of the draining veins is detailed-anatomy that radiologists must master before they can show the surgeon the important venous anatomy that is often missing at standard imaging; this information will foster better communication between radiologists and their surgical colleagues. As a practical matter, the skull base veins are arbitrarily subdivided into those that are at greatest risk with the pterional approach and the subtemporal approach, respectively. These approaches can be expanded to define connections between the superficial venous system and the other valveless venous networks that drain the deep portions of the cerebral hemisphere, the scalp, face, muscles of the neck, diploë of the skull, and meninges. As radiologists gain experience, their image interpretations should mature beyond simple analysis of the primary hemodynamic changes induced by intraoperative sacrifice or injury.

Prolonged survival of a patient with metastatic leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report.

BACKGROUND: Leptomeningeal metastasis of melanoma is a devastating complication with a grave prognosis, and there are no known effective standard treatments. Although selective BRAF inhibitors have demonstrated a significant clinical activity in patients with metastatic melanoma harboring a BRAF mutation, the clinical benefit of BRAF inhibitor-based therapy in leptomeningeal disease is not clear. CASE PRESENTATION: We present a case of prolonged survival of a patient with BRAF V600E-mutant leptomeningeal disease who was treated with vemurafenib followed by whole brain radiation and a combination of dabrafenib and trametinib. Both vemurafenib and the sequential treatment of radiation and dabrafenib/trametinib led to regression of the leptomeningeal disease, and the patient survived for 19 months after the diagnosis of the leptomeningeal disease. CONCLUSION: This case suggests a possible clinically meaningful benefit of BRAF inhibitor-based therapy and a need for close investigation of this therapeutic approach in patients with this devastating disease.

Glial tumors in brodmann area 6: spread pattern and relationships to motor areas.

The posterior frontal lobe of the brain houses Brodmann area 4, which is the primary motor cortex, and Brodmann area 6, which consists of the supplementary motor area on the medial portion of the hemisphere and the premotor cortex on the lateral portion. In this area, safe resection is dependent on accurate localization of the motor cortex and the central sulcus, which can usually be achieved by using thin-section imaging and confirmed by using other techniques. The most reliable anatomic landmarks are the "hand knob" area and the marginal ramus of the cingulate sulcus. Postoperatively, motor deficits can occur not only because of injury to primary motor cortex but also because of injury to the supplementary motor area. Unlike motor cortex injury, the supplementary motor area syndrome is transient, if it occurs at all. On the lateral hemisphere, motor and language deficits can also occur because of premotor cortex injury, but a dense motor deficit would indicate subcortical injury to the corticospinal tract. The close relationship of the subcortical motor fibers and premotor cortex is illustrated. In contrast to the more constant landmarks of the central sulcus and marginal ramus, which aid in preoperative localization, the variable interruptions in the precentral and cingulate sulci of the posterior frontal lobe seem to provide "cortical bridges" for spread of infiltrating gliomas.

Stereoscopic visualization of diffusion tensor imaging data: a comparative survey of visualization techniques.

Diffusion tensor imaging (DTI) data has traditionally been displayed as a grayscale functional anisotropy map (GSFM) or color coded orientation map (CCOM). These methods use black and white or color with intensity values to map the complex multidimensional DTI data to a two-dimensional image. Alternative visualization techniques, such as V max maps utilize enhanced graphical representation of the principal eigenvector by means of a headless arrow on regular nonstereoscopic (VM) or stereoscopic display (VMS). A survey of clinical utility of patients with intracranial neoplasms was carried out by 8 neuroradiologists using traditional and nontraditional methods of DTI display. Pairwise comparison studies of 5 intracranial neoplasms were performed with a structured questionnaire comparing GSFM, CCOM, VM, and VMS. Six of 8 neuroradiologists favored V max maps over traditional methods of display (GSFM and CCOM). When comparing the stereoscopic (VMS) and the non-stereoscopic (VM) modes, 4 favored VMS, 2 favored VM, and 2 had no preference. In conclusion, processing and visualizing DTI data stereoscopically is technically feasible. An initial survey of users indicated that V max based display methodology with or without stereoscopic visualization seems to be preferred over traditional methods to display DTI data.

Deformable anatomic templates improve analysis of gliomas with minimal mass effect in eloquent areas.

BACKGROUND: Despite improvements in advanced magnetic resonance imaging and intraoperative mapping, cases remain in which it is difficult to determine whether viable eloquent structures are involved by a glioma. A novel software program, deformable anatomic templates (DAT), rapidly embeds the normal location of eloquent cortex and functional tracts in the magnetic resonance images of glioma-bearing brain. OBJECTIVE: To investigate the feasibility of the DAT technique in patients with gliomas related to eloquent brain. METHODS: Forty cases of gliomas (grade II-IV) with minimal mass effect were referred for a prospective preoperative and postoperative DAT analysis. The DAT results were compared with the patient's functional magnetic resonance imaging, diffusion tensor imaging, operative stimulation, and new postoperative clinical deficits. RESULTS: Fifteen of the 40 glioma patients had overlap between tumor and eloquent structures. Immediate postoperative neurological deficits were seen in 9 cases in which the DAT showed the eloquent area both within the tumor and within or at the edge of the resection cavity. In 6 cases with no deficits, DAT placed the eloquent area in the tumor but outside the resection cavity. CONCLUSION: This is proof of concept that DAT can improve the analysis of diffuse gliomas of any grade by efficiently alerting the surgeon to the possibility of eloquent area invasion. The technique is especially helpful in diffuse glioma because these tumors tend to infiltrate rather than displace eloquent structures. DAT is limited by tract displacement in gliomas that produces moderate to severe mass effect.

Deformable anatomic templates embed knowledge into patient's brain images: Part 1. Construction and display.

OBJECTIVE: This paper describes the methods used to create annotated deformable anatomic templates (DATs) and display them in a patient's axial 2-dimensional and reformatted volume brain images. METHODS: A senior neuroradiologist annotated and manually segmented 1185 color-coded structures on axial magnetic resonance images of a normal template brain using domain knowledge from multiple medical specialties. Besides the visible structures, detailed pathways for vision, speech, cognition, and movement were charted. This was done by systematically joining visible anatomic anchor points and selecting the best fit based on comparisons with cadaver dissections and the constraints defined on the companion 2-dimensional images. RESULTS: The DAT is commercially available for use on a picture archiving and communication system or as a standalone workstation. CONCLUSIONS: The DAT can quickly embed extensive, clinically useful functional neuroanatomic knowledge into the patient's brain images. Besides labeling visible structures, DAT displays clinically important, previously uncharted subdivisions of the fiber tracts.

Deformable anatomic templates embed knowledge into brain images: part 2. Validation using functional magnetic resonance imaging of the motor hand.

OBJECTIVE: This study evaluated the concordance between the Deformable Anatomic Template (DAT)-identified origin of motor hand fibers and localization of the motor cortex of the hand by functional magnetic resonance imaging (fMRI). METHODS: Preoperative fMRI during hand motor tasks was performed on 36 hemispheres in 26 patients with gliomas in or near eloquent areas. Reformatted volume-rendered surface images were labeled with the DAT's hand motor fibers and fMRI data. Five reviewers assessed the data for concordance. RESULTS: Available fMRI data were diagnostically usable in 92% (33/36 analyzed hemispheres), with DAT anatomic accuracy in the remaining cases. The DAT prediction and fMRI findings were concordant in all 9 normal hemispheres and in 20 (83%) of 24 glioma-bearing hemispheres. The 4 discordant cases resulted from substantial mass effect by large frontal tumors. CONCLUSIONS: This study validated DAT's anatomic atlas and alignment process for the expected position of the motor cortex of the hand.

Imaging characteristics of hyperfunctioning parathyroid adenomas using multiphase multidectector computed tomography: a quantitative and qualitative approach.

OBJECTIVE: The objective of the study was to characterize the enhancement pattern of hyperfunctioning parathyroid adenomas on multiphase multidetector computed tomography (CT) or 4-dimensional CT. METHODS: We retrospectively studied the enhancement patterns of 48 pathologically confirmed parathyroid adenomas with 4-dimensional CT, compliant with institutional review and the Health Insurance Portability and Accountability Act. Region-of-interest analysis was done at baseline and at arterial (25 seconds), venous (55 seconds), and delayed (85 seconds) enhancement phases over the adenoma and adjacent normal thyroid tissue. Qualitative and quantitative analysis was done. Discriminant functions were calculated using a multivariate logistic regression model, and receiver operating characteristic curves were measured. RESULTS: Adenomas are lower than thyroid in density, demonstrate avid early contrast enhancement, and show rapid wash-out of contrast. Adenomas and thyroid had baseline Hounsfield unit attenuations of 35 ± 11 and 94 ± 21 and enhancement percentage change from baseline to arterial of 493% ± 328% and 132% ± 148%, respectively (P < 0.0001 both). Quantitative analysis showed that these 2 measures of baseline density and the percentage change from baseline to arterial were the most powerful discriminatory features, with contrast wash-out from arterial peak to venous phase being a less powerful discriminator. Several discriminant functions were derived, the best of which was: X = 13.74 - (0.207 × baseline Hounsfield unit) - (0.006 × percent density change from baseline to arterial). X > 0.2 classifies tissue as parathyroid with high certainty (area under the receiver operating characteristic curve = 0.98; specificity, 0.938; sensitivity, 0.999). CONCLUSIONS: Parathyroid adenomas have a characteristic enhancement pattern that can be distinguished from thyroid tissue: the key diagnostic discriminators are baseline density, percentage change in density from baseline to arterial enhancement, and percentage decrease in density from arterial to venous phases.

Comparison of gadolinium-enhanced fat-saturated T1-weighted FLAIR and fast spin-echo MRI of the spine at 3 T for evaluation of extradural lesions.

OBJECTIVE: Inversion recovery has been used to correct the loss of CSF and tissue contrast at 3 T versus 1.5 T but has not been formally investigated in the spine after IV administration of gadolinium-based contrast agent. The purpose of this study is to compare two sequences for gadolinium-enhanced spine imaging at 3 T--fat-saturated T1-weighted FLAIR and fat-saturated T1-weighted fast spin-echo (FSE)--for evaluation of extradural lesions and CSF-cord contrast. MATERIALS AND METHODS: After IV administration of gadolinium-based contrast agent, fat-saturated T1-weighted FSE and FLAIR sequences were obtained in 156 MRI scans of 143 patients at 3 T. Three experienced radiologists compared these sequences for conspicuity differences in bone lesions, disk lesions, other epidural lesions, and cord-CSF contrast. A 7-point visual rating scale was used, with lower numbers indicating increased conspicuity on gadolinium-enhanced fat-saturated T1-weighted FLAIR and higher numbers indicating increased conspicuity on gadolinium-enhanced fat-saturated T1-weighted FSE. RESULTS: A slight increase in the conspicuity of gadolinium-enhancing bone lesions (mean score, 3.6; p < 0.0001), disk lesions (mean score, 3.5; p < 0.0001), and epidural lesions (mean score, 3.4; p < 0.0001) was seen on fat-saturated T1-weighted FLAIR compared with fat-saturated T1-weighted FSE. A higher degree of contrast between the spinal cord and CSF was seen on fat-saturated T1-weighted FLAIR, by a large margin (mean score, 1.8; p < 0.0001). All enhancing lesions seen on fat-saturated T1-weighted FSE images were also seen on fat-saturated T1-weighted FLAIR images. CONCLUSION: Decreased CSF-cord contrast at 3 T, as seen on T1-weighted FSE, can be regained by using T1-weighted FLAIR. Fat-saturated T1-weighted FLAIR may increase conspicuity of gadolinium-enhancing extradural lesions compared with fat-saturated T1-weighted FSE.

Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system.

PURPOSE: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS: A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS: The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION: The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Magnetic resonance imaging features of pilocytic astrocytoma of the brain mimicking high-grade gliomas.

OBJECTIVE: The typical magnetic resonance/computed tomographic imaging appearance of pilocytic astrocytoma (PA) is that of a cyst with an intensely enhancing mural nodule. The purpose of this study was to illustrate the aggressive imaging features of PA. METHODS: One hundred patients referred to the cancer center with brain tumors histologically proven to be PA were retrospectively reviewed (95 by magnetic resonance imaging and 5 by computed tomographic imaging) and analyzed. RESULTS: The patient population includes 76 pediatric patients younger than 18 years and 24 adults ranging from 19 to 45 years old. Tumor locations consisted of the following: optic chiasm (22), lateral ventricle (3), thalamus (12), basal ganglia (1), cerebral hemisphere (10), corpus callosum (2), brain stem (26), fourth ventricle (1), and cerebellum (23). The imaging appearance of PA consisted of typical features in 71 cases and aggressive features in 29 cases. CONCLUSIONS: It is important to recognize the aggressive imaging appearance of PA (grade 1 astrocytoma) because it can be mistaken for high-grade gliomas and may thus lead to inappropriate therapy. Despite the aggressive imaging appearance of PA, there is no histopathologic evidence of anaplasia.

Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice.

Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had impressive reductions in MRI contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant improvements in progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have an uncharacteristic pattern of tumor progression, which can be observed radiographically as an increase in hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) MRI. To date, there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 illustrative cases of gliomas that demonstrated an apparent phenotypic shift to a predominantly infiltrative pattern of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas on MRI revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular "normalization," which was uncharacteristically adjacent to regions of necrosis. High levels of insulin-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In an attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angiogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice.

Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer.

This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40-82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3-4 drug-related toxicities included thrombocytopenia (n=3), anorexia (n=2), and dehydration (n=2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients.