Bob L. Hou

Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

PURPOSE Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas. METHODS AND MATERIALS After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab. RESULTS Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%. DISCUSSION Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

Effect of brain tumor neovasculature defined by rCBV on BOLD fMRI activation volume in the primary motor cortex.

We utilized blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) and MR perfusion imaging methods to study the influence of brain tumor neovascularity on the BOLD fMRI activation volume in the primary motor cortex (PMC). The results from 57 brain tumor cases demonstrated that, for grade IV gliomas only, decreases in the BOLD fMRI activation volumes within the ipsilateral PMC, when compared with that observed in the contralateral PMC, correlated with increases in the relative regional cerebral blood volume (rCBV) in the PMC. In addition, relative increases in the activation volumes, corresponding to decreases in the rCBV, exhibited a linear dependence on the distance between the grade IV glioma and PMC. These findings lend support to the hypothesis that decreases in the fMRI activation volumes adjacent to a GBM may, in part, be due to the increased contribution of aberrant tumor neovascularity, with the resultant de-coupling of blood flow from neuronal activity. The nature of the relationship between the resulting activation volumes and adjacent tumor characteristics is complex, but is found to be dependent on the tumor grade and type, as well as the distance of the tumor to the PMC.

Functional magnetic resonance imaging (fMRI) changes and saliva production associated with acupuncture at LI-2 acupuncture point: a randomized controlled study

BackgroundClinical studies suggest that acupuncture can stimulate saliva production and reduce xerostomia (dry mouth). We were interested in exploring the neuronal substrates involved in such responses.MethodsIn a randomized, sham acupuncture controlled, subject blinded trial, twenty healthy volunteers received true and sham acupuncture in random order. Cortical regions that were activated or deactivated during the interventions were evaluated by functional magnetic resonance imaging (fMRI). Saliva production was also measured.ResultsUnilateral manual acupuncture stimulation at LI-2, a point commonly used in clinical practice to treat xerostomia, was associated with bilateral activation of the insula and adjacent operculum. Sham acupuncture at an adjacent site induced neither activation nor deactivation. True acupuncture induced more saliva production than sham acupuncture.ConclusionAcupuncture at LI-2 was associated with neuronal activations absent during sham acupuncture stimulation. Neuroimaging signal changes appear correlated to saliva production.

Assessment of the Language Laterality Index in Patients with Brain Tumor Using Functional MR Imaging: Effects of Thresholding, Task Selection, and Prior Surgery

BACKGROUND AND PURPOSE: Functional MR imaging (fMRI) is used to determine preoperatively the laterality of cortical language representation along with the relationship of language areas to adjacent brain tumors. The purpose of this study was to determine whether changing the statistical threshold for different language tasks influences the language laterality index (LI) for a group of controls, patients with tumor without prior surgery, and patients with tumor and prior surgery. MATERIALS AND METHODS: Seven controls, 9 patients with tumor without prior surgery, and 4 patients with tumor and prior surgery performed verb-generation, phonemic fluency, and semantic fluency language tasks during fMRI. Interhemispheric activation differences between the left and right Broca regions of interest were determined by calculating language LIs. LIs were compared within each group, between groups, and between language tasks. Intraoperative electrocortical mapping or the presence of aphasia during postoperative neurology examinations or both were used as ground truth. RESULTS: The language LI varied as a result of statistical thresholding, presence of tumor, prior surgery, and language task. Although patients and controls followed a similar shape in the LI curve, there was no optimal P value for determining the LI. Three patients demonstrated a shift in the LI between hemispheres as a function of statistical threshold. Verb generation was the least variable task both between tasks and across groups. CONCLUSION: For preoperative patients with tumor, the LI should be examined across a spectrum of P values and a range of tasks to ensure reliability. Our data suggest that the LI may be threshold- and task-dependent, particularly in the presence of adjacent tumor.

Functional MRI in the brain tumor patient.

Functional magnetic resonance imaging (fMRI) has been adopted almost universally by disciplines that endeavor to understand how the brain works. As basic scientists tune the technique, clinicians are increasingly able to apply brain mapping with fMRI to their clinical practice. We present here a guide to using fMRI in a clinical setting. We discuss the basic considerations of functional brain mapping in patients with brain tumors including: patient screening and training, paradigm design, data analysis and interpretation of the fMRI scans.

Effect of Age and Tumor Grade on BOLD Functional MR Imaging in Preoperative Assessment of Patients with Glioma

PURPOSE To retrospectively determine if there was a combined effect of advanced age and increased tumor grade on blood oxygen level-dependent (BOLD) functional magnetic resonance (MR) imaging signal intensity (SI) in patients with gliomas. MATERIALS AND METHODS The institutional review board approved this HIPAA-compliant study, and the informed consent requirement was waived. Data from 39 patients (27 men, 12 women; age range, 19-78 years) who had histopathologically confirmed gliomas and who underwent surgery after preoperative functional MR imaging were analyzed. Fourteen patients had grade II or grade III gliomas, and 25 patients had grade IV gliomas. A change in BOLD SI was measured in motor cortices of tumor-containing and non-tumor-containing hemispheres. The effect of age and tumor grade, both individually and together, on BOLD functional MR SI was assessed with t tests and regression analysis. RESULTS In patients with grade IV gliomas, SI change was lower in the tumor-containing hemisphere than in the non-tumor-containing hemisphere (P = .012). SI change decreased with increased age in the tumor-containing hemisphere in patients with grade II or III gliomas (P = .032) and in the non-tumor-containing hemisphere in patients with grade IV gliomas (P = .026). While advanced age and increased glioma grade reduced SI change, the combined effect of these factors was not additive. In patients with grade IV gliomas, tumor presence reduced SI change, but the level of reduction was uniform across all ages and did not correlate with age (P = .541). CONCLUSION In older patients with grade IV gliomas, BOLD SI is equivalent to that measured in younger patients with grade IV gliomas. Advanced age and tumor grade do not have a combined effect for reduction of BOLD SI. Rather, in patients with grade IV gliomas, tumor grade played a dominant role in reduction of SI change, whereas in patients with grade II and III gliomas, reduction of SI change correlated with only advanced age.

Presurgical evaluation of language using functional magnetic resonance imaging in brain tumor patients with previous surgery.

OBJECTIVEFunctional magnetic resonance imaging (fMRI) is used to assess language laterality in preoperative brain tumor patients. In postsurgical patients, susceptibility artifacts can potentially alter ipsilateral fMRI activation volumes and the assessment of language laterality. The purpose of this study was to investigate the ability of fMRI to correctly measure language dominance in brain tumor patients with previous surgery because this patient cohort is vulnerable to type II statistical errors and subsequent misjudgment of laterality. METHODSTwenty-six right-handed patients with left-hemisphere gliomas (16 with and 10 without previous surgery) underwent preoperative language fMRI. Language laterality was measured using hemispheric and Brocas area regions of interest (ROIs). Hemisphere dominance, as established by laterality measurements, was compared with that determined by intraoperative electrocorticography and behavioral assessments. RESULTSLocalization of primary language cortices was achieved in 24 of 26 patients studied. The hemisphere dominance evaluated by fMRI was verified by intraoperative corticography in only 14 patients (10 with and 4 without previous surgery), and only 12 of them had complete neuropsychological testing. Complete concordance of the laterality with intraoperative electrocorticography and behavioral assessments was found in patients without previous surgery. In patients with previous surgery, concordance was 75% using Brocas area ROI and 88% using hemispheric ROI, notwithstanding susceptibility artifacts. Differences in laterality between pre- and postsurgical patients, based on either hemispheric (P = 0.81) or Brocas area (P = 0.19) ROI measurements were not statistically significant. However, hemispheric ROI analyses were found to be less affected by postsurgical artifacts and may be more suitable for establishing hemisphere dominance. CONCLUSIONfMRI mapping of eloquent language cortices in brain tumor patients after surgery is feasible and can serve as a useful baseline evaluation for preoperative neurosurgical planning. However, findings should be interpreted with caution in the presence of postsurgical artifacts.

FEASIBILITY STUDY OF INTENSITY-MODULATED RADIOTHERAPY (IMRT) TREATMENT PLANNING USING BRAIN FUNCTIONAL MRI

The purpose of this work was to study the feasibility of incorporating functional magnetic resonance imaging (fMRI) information for intensity modulated radiotherapy (IMRT) treatment planning of brain tumors. Three glioma patients were retrospectively replanned for radiotherapy (RT) with additional fMRI information. The fMRI of each patient was acquired using a bilateral finger-tapping paradigm with a gradient echo EPI (Echo Planer Imaging) sequence. The fMRI data were processed using the Analysis of Functional Neuroimaging (AFNI) software package for determining activation volumes, and the volumes were fused with the simulation computed tomography (CT) scan. The actived pixels in left and right primary motor cortexes (PMCs) were contoured as critical structures for IMRT planning. The goal of replanning was to minimize the RT dose to the activation volumes in the PMC regions, while maintaining a similar coverage to the planning target volume (PTV) and keeping critical structures within accepted dose tolerance. Dose-volume histograms of the treatment plans with and without considering the fMRI information were compared. Beam angles adjustment or additional beams were needed for 2 cases to meet the planning criteria. Mean dose to the contralateral and ipsilateral PMC was significantly reduced by 66% and 55%, respectively, for 1 patient. For the other 2 patients, mean dose to contralateral PMC region was lowered by 73% and 69%. In general, IMRT optimization can reduce the RT dose to the PMC regions without compromising the PTV coverage or sparing of other critical organs. In conclusion, it is feasible to incorporate the fMRI information into the RT treatment planning. IMRT planning allows a significant reduction in RT dose to the PMC regions, especially if the region does not lie within the PTV.

Functional MRI in the Presurgical Evaluation of Patients with Brain Tumors: Characterization of the Statistical Threshold

We investigated whether an optimal statistical threshold could be obtained in healthy controls and patients with brain tumors undergoing presurgical functional MRI assessment. The volumes of activation of the primary motor cortex (PMC) and the lateral prefrontal cortex (PFC) were measured for the tumor and nontumor sides in 24 patients and 8 controls using four parameters; p values ranged between 10–2 and 10–31. The mean r value for first activation in the PMC was higher in controls than for both the tumor and nontumor sides in patients. The mean r value for ‘first activation in the noise area’ and ‘PMC and PFC ratio’ in controls was significantly different from the mean r value for the tumor and nontumor sides in patients (p < 0.05). The magnitude of the range of r values for the nontumor side was closer to the tumor side data than to the control data. It is imperative to evaluate functional MRI data with a wide range of statistical parameters, especially in the assessment of tumor patients.

Vascular Reactivity Maps in Patients with Gliomas Using Breath-Holding BOLD fMRI

To evaluate whether breath‐holding (BH) blood oxygenation level‐dependent (BOLD) fMRI can quantify differences in vascular reactivity (VR), as there is a need for improved contrast mechanisms in gliomas.