Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas.

The ability of the 10-23 DNAzyme to specifically cleave RNA with high efficiency has fuelled expectation that this agent may have useful applications for targeted therapy. Here, we, for the first time, investigated the antitumor and radiosensitizing effects of a DNAzyme (DZ1) targeted to the Epstein-Barr virus (EBV)-LMP1 mRNA of nasopharyngeal carcinoma (NPC) in patients. Preclinical studies indicated that the DNAzyme was safe and well tolerated. A randomized and double-blind clinical study was conducted in 40 NPC patients who received DZ1 or saline intratumorally, in conjunction with radiation therapy. Tumor regression, patient survival, EBV DNA copy number and tumor microvascular permeability were assessed in a 3-month follow-up. The mean tumor regression rate at week 12 was significantly higher in DZ1 treated group than in the saline control group. Molecular imaging analysis showed that DZ1 impacted on tumor microvascular permeability as evidenced by a faster decline of the K(trans) in DZ1-treated patients. The percentage of the samples with undetectable level of EBV DNA copy in the DZ1 group was significantly higher than that in the control group. No adverse events that could be attributed to the DZ1 injection were observed in patients.

Correlation of volume transfer coefficient Ktrans with histopathologic grades of gliomas.

PURPOSE: To evaluate the roles of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and optimum tracer kinetic parameters in the noninvasive grading of the glial brain tumors with histopathological grades (I-IV). MATERIALS AND METHODS: Twenty-eight patients with histopathologically graded gliomas were imaged. Images with five flip angles were acquired before injection of gadolinium-DTPA and were processed to calculate the T(1) value of each region of interest (ROI). All the DCE-MRI data acquired during the injection were processed based on the MRI signal and pharmacokinetic models to establish concentration-time curves in the ROIs drawn within the tumors, contralateral normal areas, and area of the individual artery input functions (iAIF) of each patient. A nonlinear least-square-fitting method was used to obtain tracer kinetic parameters. Kruskal-Wallis H-test and Mann-Whitney U-test were applied to these parameters in different histopathological grade groups for statistical differences (P < 0.05). RESULTS: Volume transfer coefficient (K(trans) ) and extravascular extracellular space volume fraction (V(e) ) calculated using iAIFs can be used not only to distinguish the low (ie, I and II) from the high (ie, III and IV) grade gliomas (P( Ktrans) < 0.001 and P(Ve) < 0.001), but also grade II from III (P( Ktrans) = 0.016 and P(Ve) = 0.033). CONCLUSION: K(trans) is the most sensitive and specific parameter in noninvasive grading, distinguishing the high (III and IV) from the low (I and II) grade and high grade III from low grade II gliomas.

CT perfusion imaging pitfall related to fetal posterior cerebral artery.

OBJECTIVE: The purpose of this article is to discuss how a unilateral fetal posterior cerebral artery (PCA) causes perfusion map asymmetry due to anteroposterior bolus arrival discrepancy. We performed region of interest analysis of asymmetric perfusion maps before and after delay correction was performed. CONCLUSION: Perfusion asymmetry becomes unapparent using a delay correction algorithm, indicating bolus arrival delay on the side opposite the fetal PCA. Delay correction algorithms can eliminate deconvolution errors related to bolus arrival delay.

Cerebral sparganosis in children: epidemiological, clinical and MR imaging characteristics.

BACKGROUND: Cerebral sparganosis in children is an extremely rare disease of central nervous system, and caused by a tapeworm larva from the genus of Spirometra. In this study, we discussed and summarized epidemiological, clinical and MR imaging characteristics of eighteen children with cerebral sparganosis for a better diagnosis and treatment of the disease. METHODS: Eighteen children with cerebral sparganosis verified by pathology, serological tests and MR presentations were retrospectively investigated, and the epidemiologic and clinical characteristics of the disease were studied. RESULTS: Twenty-seven lesions were found in the eighteen children. Twelve lesions in twelve patients were solitary while the lesions in the rest six patients were multiple and asymmetrical. The positions of the lesions were: seven in frontal, eleven in parietal, four in temporal and two in occipital lobes, one in basal ganglia, one in cerebella hemisphere and one in pons. The lesions were presented as slight hypointensity on T1-weighted images but moderate hyperintensity on T2-weighted images with perilesional brain parenchyma edema. Enhanced MR scans by using Gadopentetic Acid Dimeglumine Salt were performed in the patients, and the images demonstrated abnormal enhancements with the patterns of a peripheral ring, or a tortuous beaded, or a serpiginous tubular shape. Follow-up MR scans were preformed for eight patients, and three out of the eight cases exposed migrations and changes in shapes of the lesion areas. CONCLUSIONS: The MR presentations in our study in general were similar to those in previous studies. However serpiginous tubular and comma-shaped enhancements of lesions have not been previously reported. The enhanced MR imaging and follow-up MR scans with the positive results from serological tests are the most important methods for the clinical diagnosis of cerebral sparganosis in children.

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.

MRI and MRS of human brain tumors.

The purpose of this chapter is to provide an introduction to magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of human brain tumors, including the primary applications and basic terminology involved. Readers who wish to know more about this broad subject should seek out the referenced books (1. Tofts (2003) Quantitative MRI of the brain. Measuring changes caused by disease. Wiley; Bradley and Stark (1999) 2. Magnetic resonance imaging, 3rd Edition. Mosby Inc; Brown and Semelka (2003) 3. MRI basic principles and applications, 3rd Edition. Wiley-Liss) or reviews (4. Top Magn Reson Imaging 17:127-36, 2006; 5. JMRI 24:709-724, 2006; 6. Am J Neuroradiol 27:1404-1411, 2006).MRI is the most popular means of diagnosing human brain tumors. The inherent difference in the magnetic resonance (MR) properties of water between normal tissues and tumors results in contrast differences on the image that provide the basis for distinguishing tumors from normal tissues. In contrast to MRI, which provides spatial maps or images using water signals of the tissues, proton MRS detects signals of tissue metabolites. MRS can complement MRI because the observed MRS peaks can be linked to inherent differences in biochemical profiles between normal tissues and tumors.The goal of MRI and MRS is to characterize brain tumors, including tumor core, edge, edema, volume, types, and grade. The commonly used brain tumor MRI protocol includes T2-weighted images and T1-weighted images taken both before and after the injection of a contrast agent (typically gadolinium: Gd). The commonly used MRS technique is either point-resolved spectroscopy (PRESS) or stimulated echo acquisition mode (STEAM).

The role of the Supplementary Motor Area (SMA) in the execution of primary motor activities in brain tumor patients: functional MRI detection of time-resolved differences in the hemodynamic response.

BACKGROUND: Interpreting volume of activation maps of brain tumor patients remains difficult using blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) methods. A time-resolved fMRI may offer an informative strategy for investigating the possibility of functional reorganization by elucidating temporal variations in the activation of cortical structures . The aim of this study is to use time-resolved fMRI to investigate potential alterations in the spatially-varying and time-dependent hemodynamic response function within the supplementary motor area (SMA) and primary motor cortex (PMC) in the presence of an adjacent brain tumor, relative to normal control subjects. MATERIAL/METHODS: Fifteen patients and eight healthy volunteers were recruited. By utilizing a brief motor paradigm that exerts a differential effect on the activation of these structures, latency differences in the hemodynamic responses of such areas may be sensitively investigated. The present study determines the utility of this approach in brain tumor patients by examining the time to peak of the BOLD hemodynamic response within the SMA and PMC. RESULTS: In patients with glial tumors involving the PMC, the activation of the SMA was delayed and approached that of the PMC with time-to-peak difference between the PMC and SMA averaging 0.2 s. This delay in SMA activation was seen in all patients with glial tumors involving the PMC. CONCLUSIONS: The results suggest that in patients with high-grade brain tumors invading the PMC , the SMA may assume a greater role in the execution of primary motor activities, in addition to its role in executive motor planning.

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.

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

BACKGROUND: Clinical 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. METHODS: In 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. RESULTS: Unilateral 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. CONCLUSION: Acupuncture at LI-2 was associated with neuronal activations absent during sham acupuncture stimulation. Neuroimaging signal changes appear correlated to saliva production.

Magnetic Resonance Imaging Parameters and Their Impact on Survival of Patients with Glioblastoma: Tumor Perfusion Predicts Survival.

BACKGROUND: Many prognostic factors influence overall survival (OS) of patients with glioblastoma. Despite gross total resection and Stupp protocol adherence, many patients have poor survival. Perfusion magnetic resonance imaging may assist in diagnosis, treatment monitoring, and prognostication. METHODS: This retrospective study of 36 patients with glioblastoma assessed influence of preoperative magnetic resonance imaging parameters reflecting tumor cell density and vascularity and patient age on OS. RESULTS: The area under curve based on optimal receiver operating characteristic curves for the perfusion parameters normalized relative tumor blood volume (n_rTBV) and normalized relative tumor blood flow (n_rTBF) were 0.92 and 0.89, respectively, and the highest among all imaging parameters and age. OS showed strongly negative correlations with corrected n_rTBV (R = -0.70; P < 0.001) and n_rTBF (R = -0.67; P < 0.001). The Cox model, which included age and imaging parameters, demonstrated that n_rTBV and n_rTBF were most predictive of OS, with hazard ratios of 5.97 (P = 0.0001) and 8.76 (P = 0.0001), respectively, compared with 1.63 (P = 0.19) for age. Eighteen patients with corrected n_rTBV ≤2.5 (best cutoff value) had a median OS of 15.1 months (95% confidence interval (CI), 11.34-21.25) compared with 2.8 months (95% CI, 1.48-4.03; P < 0.001) for 18 patients with corrected n_rTBV >2.5. Twenty-four patients with n_rTBF ≤2.79 had a median OS of 12 months (95% CI, 10.46-17.9) compared with 2.8 months for 12 patients with n_rTBF >2.79 (95% CI, 1.31-4.2; P < 0.001). CONCLUSIONS: The dominant predictors of OS are normalized perfusion parameters n_rTBV and n_rTBF. Preoperative perfusion imaging may be used as a surrogate to predict glioblastoma aggressiveness and survival independent of treatment.

Reorganization of the cortical control of movement due to radiation necrosis. Case report.

The authors report a case of reorganization of the cortical control of movement caused by radiation necrosis based on an analysis of functional magnetic resonance (fMR) imaging data acquired during a finger-tapping paradigm. Radiation necrosis in this patient extended from the parietal lobe anteriorly to the primary motor cortex (PMC), and fMR imaging demonstrated an increase in activation in the ipsilateral supplementary motor area. This is similar to the consequences of invasion by glial tumors into the PMC.

Quantitative comparisons on hand motor functional areas determined by resting state and task BOLD fMRI and anatomical MRI for pre-surgical planning of patients with brain tumors.

For pre-surgical planning we present quantitative comparison of the location of the hand motor functional area determined by right hand finger tapping BOLD fMRI, resting state BOLD fMRI, and anatomically using high resolution T1 weighted images. Data were obtained on 10 healthy subjects and 25 patients with left sided brain tumors. Our results show that there are important differences in the locations (i.e., > 20 mm) of the determined hand motor voxels by these three MR imaging methods. This can have significant effect on the pre-surgical planning of these patients depending on the modality used. In 13 of the 25 cases (i.e., 52%) the distances between the task-determined and the rs-fMRI determined hand areas were more than 20 mm; in 13 of 25 cases (i.e., 52%) the distances between the task-determined and anatomically determined hand areas were > 20 mm; and in 16 of 25 cases (i.e., 64%) the distances between the rs-fMRI determined and anatomically determined hand areas were more than 20 mm. In just three cases, the distances determined by all three modalities were within 20 mm of each other. The differences in the location or fingerprint of the hand motor areas, as determined by these three MR methods result from the different underlying mechanisms of these three modalities and possibly the effects of tumors on these modalities.

The effect of prior surgery on blood oxygen level-dependent functional MR imaging in the preoperative assessment of brain tumors.

BACKGROUND AND PURPOSE: Blood oxygen level-dependent functional MR imaging (BOLD fMRI) is a clinically useful technique for preoperative mapping of eloquent cortices in patients with brain tumors. The purpose of this study was to determine the effect on BOLD fMRI accuracy of susceptibility artifacts caused by prior surgery by comparing volumes of activation in the primary motor cortex (PMC) of patients with and without prior brain surgery. METHODS: The volumes of fMRI activation of the PMC were measured for the tumor and nontumor sides in patients with (n = 13) and without (n = 30) prior neurosurgery. Statistical comparisons of the volumes were performed by using paired t tests and linear regression analysis. The location and degree of susceptibility artifact were subjectively assessed. RESULTS: No significant difference was found between the mean tumor and nontumor volumes of fMRI activations in patients without prior surgery (P = .51). In patients who had prior surgery, the volume of activation was significantly smaller on the side of the prior operation when compared with the contralateral side (P = .001). The volume of activation on the side of the tumor was also significantly smaller in the patients with prior surgery compared with those without prior surgery (P < .001). Nevertheless, the PMC was identified in all cases, and its location was confirmed intraoperatively. CONCLUSION: Prior surgery is associated with a decrease in the volume of fMRI activation in patients with prior surgery; however, by examining the T2 images, an astute radiologist can recognize this phenomenon, draw the appropriate conclusions, and correctly identify the PMC.

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.

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

OBJECTIVE: Functional 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. METHODS: Twenty-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 Broca's area regions of interest (ROIs). Hemisphere dominance, as established by laterality measurements, was compared with that determined by intraoperative electrocorticography and behavioral assessments. RESULTS: Localization 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 Broca's 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 Broca's 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. CONCLUSION: fMRI 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.

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.

Studying neonatal bilirubin encephalopathy with conventional MRI, MRS, and DWI.

INTRODUCTION: The purpose of this study was to evaluate the diagnostic value of conventional magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy ((1)H-MRS), and diffusion-weighted imaging (DWI) for neonatal bilirubin encephalopathy. METHODS: We collected conventional MRI in 24 neonates with neonatal bilirubin encephalopathy. We performed (1)H-MRS and DWI sequences to nine of the 24 patients and seven age-matched healthy control subjects. Multiple-voxel (1)H-MRS data were acquired using PRESS pulse sequence with TE = 135 ms and TR = 1500 ms. The spectroscopic regions of interest were the bilateral basal ganglia and thalamus with a 1.0 mL spatial resolution. The data from DWI were collected by using a single shot-spin echo-echo planar imaging sequence with TR/TE: 2900/98, and imaging regions were also focused on the bilateral basal ganglia and thalamus. RESULTS: Nineteen of the 24 patients had abnormal T(1)-weighted image hyperintensity in the globus pallidus, but these lesions appeared as normal T(2)-weighted image intensity in the same region. Ten of the 24 patients had T(1)-weighted image high signal intensity in the subthalamic nucleus and appeared as normal intensity in the region for the T(2)-weighted images. The peak area ratios of NAA/Cho and NAA/Cr were significantly decreased (t-test, P < 0.05) in the patients compared to the controls in the basal ganglia. CONCLUSION: Conventional MR imaging and (1)H-MRS are important complementary tools in the diagnosis of neonatal bilirubin encephalopathy. The study provides important information for applying these MR modalities to evaluate neonates with bilirubin encephalopathy.

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.