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ABSTRACT: Medial temporal atrophy is a well-established marker for Alzheimer’s disease (AD). However, due to normal variation in the
size of medial temporal structures and variability in how radiologists interpret images, the use of clinical reads in establishing
the presence of pathological atrophy is imprecise. A limitation of studies of magnetic resonance imaging (MRI) measures in
AD is diagnostic uncertainty as it can be unknown if pre- or early-symptomatic subjects go on to develop AD and most subjects
do not undergo autopsy verification of the diagnosis. In persons with or at-risk for AD due to fully-penetrant autosomal dominant
mutations in the PSEN1 and APP genes, the diagnosis or future development of AD can be predicted with essentially 100% accuracy. We used this predictability
to assess the ability of radiologists to detect hippocampal atrophy (HA) in persons destined to develop AD. Coronal T1-weighted
MRI scans of 39 persons demented from (n=4) or at-risk for inheriting (n=35) PSEN1 or APP mutations were independently assessed by two radiologists and the presence or absence of HA determined. Of the 39 subjects,
26 were FAD mutation carriers. Fifteen of 28 asymptomatic at-risk persons were FAD mutation carriers and four of these were
rated as having atrophy for a sensitivity of 27% and a specificity of 85%. Among seven mildly affected yet non-demented subjects,
atrophy was detected in three and in the four demented subjects HA was identified in two. Our results suggest that radiologists’
ability to detect HA in persons in whom the diagnosis of incipient AD is certain is sub-optimal and quantitative MRI techniques
or other biological markers of the disease are needed.
KeywordsAlzheimer’s disease-Familial Alzheimer’s disease-Magnetic resonance imaging-Hippocampus-Medial temporal lobe-Presenilin-1-Amyloid precursor protein
Journal of Neurology 04/2012; 257(5):839-842. · 3.47 Impact Factor
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[show abstract]
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ABSTRACT: Medial temporal atrophy is a well-established marker for Alzheimer's disease (AD). However, due to normal variation in the size of medial temporal structures and variability in how radiologists interpret images, the use of clinical reads in establishing the presence of pathological atrophy is imprecise. A limitation of studies of magnetic resonance imaging (MRI) measures in AD is diagnostic uncertainty as it can be unknown if pre- or early-symptomatic subjects go on to develop AD and most subjects do not undergo autopsy verification of the diagnosis. In persons with or at-risk for AD due to fully-penetrant autosomal dominant mutations in the PSEN1 and APP genes, the diagnosis or future development of AD can be predicted with essentially 100% accuracy. We used this predictability to assess the ability of radiologists to detect hippocampal atrophy (HA) in persons destined to develop AD. Coronal T1-weighted MRI scans of 39 persons demented from (n = 4) or at-risk for inheriting (n = 35) PSEN1 or APP mutations were independently assessed by two radiologists and the presence or absence of HA determined. Of the 39 subjects, 26 were FAD mutation carriers. Fifteen of 28 asymptomatic at-risk persons were FAD mutation carriers and four of these were rated as having atrophy for a sensitivity of 27% and a specificity of 85%. Among seven mildly affected yet non-demented subjects, atrophy was detected in three and in the four demented subjects HA was identified in two. Our results suggest that radiologists' ability to detect HA in persons in whom the diagnosis of incipient AD is certain is sub-optimal and quantitative MRI techniques or other biological markers of the disease are needed.
Journal of Neurology 05/2010; 257(5):839-42. · 3.47 Impact Factor
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ABSTRACT: Glioblastoma is the most common primary brain tumor with a relatively poor prognosis. This article reviews the current standard therapy and discusses new developments in treatment of this disease. Surgical resection followed by radiation and chemotherapy has proven to be the most effective initial therapy. Recent advancement in molecular targeted therapies has led to the Food and Drug Administration (FDA) approval of bevacizumab in the setting of recurrent glioblastoma. The molecular pathways of glioblastoma growth are highlighted in this review. While numerous molecular targets are currently being intensely investigated, vascular endothelial growth factor (VEGF) receptor targeted therapy has been the only one to have shown clinical effect. The role of bevacizumab in this context provides a dynamic breakthrough in cancer therapy. Clinical trials have demonstrated significantly increased overall survival and six month progression free survival (PFS) in recurrent glioblastoma treated with bevacizumab alone or in combination with irinotecan. The use of this agent has also dramatically changed the imaging characteristics of glioblastoma. The anti-angiogenesis effects of bevacizumab have complicated the criterion for determining tumor growth. This may lead to redefinition of progressive disease based on non-invasive monitoring.
Pharmacogenomics and Personalized Medicine 01/2010; 3:79-85.
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Melanie Kappadakunnel,
Ascia Eskin,
Jun Dong,
Stanley F Nelson,
Paul S Mischel,
Linda M Liau,
Phioanh Ngheimphu,
Albert Lai,
Timothy F Cloughesy,
Jonathan Goldin, Whitney B Pope
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ABSTRACT: Current therapies for glioblastoma (GBM) target bulk tumor through measures such as resection and radiotherapy. However, recent evidence suggests that targeting a subset of tumor cells, so-called cancer stem cells, may be critical for inhibiting tumor growth and relapse. The subventricular zone (SVZ), which lines the ventricles of the brain, is thought to be the origin for the majority of neural stem cells and potentially cancer stem cells. Therefore, we assessed the relationship between tumor contact with the SVZ as determined by MRI, cancer stem cell gene expression and survival in 47 patients with GBM. Using DNA microarrays, we found that genes associated with cancer stem cells were not over-expressed in tumors contacting the SVZ. Contact with the SVZ trended with shorter survival (median 358 versus 644, P = 0.066). Over-expression of CD133 (prominin-1) and maternal embryonic leucine zipper kinase (MELK) was associated with shorter survival, whereas mitogen activated protein kinase 8 (MAPK8) was associated with longer survival (P values 0.008, 0.005 and 0.002 respectively). Thus we found no evidence of a stem-cell derived genetic signature specific for GBM in contact with the SVZ, but there was a relationship between stem cell gene expression and survival. More research is required to clarify the relationship between the SVZ, cancer stem cells and survival.
Journal of Neuro-Oncology 09/2009; 96(3):359-67. · 3.21 Impact Factor
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Albert Lai,
Emese Filka,
Bruce McGibbon,
Phioanh Leia Nghiemphu,
Carrie Graham,
William H Yong,
Paul Mischel,
Linda M Liau,
Marvin Bergsneider, Whitney Pope,
Michael Selch,
Tim Cloughesy
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ABSTRACT: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma.
All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m(2) for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m(2) for 5 days every 4 weeks and continuation of BV every 2 weeks.
For these 10 patients, toxicities were compiled until study discontinuation or up to approximately 40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed.
The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.
International Journal of Radiation OncologyBiologyPhysics 09/2008; 71(5):1372-80. · 4.11 Impact Factor
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ABSTRACT: (18)F-FDOPA PET demonstrates higher sensitivity and specificity for gliomas than traditional [(18)F] FDG PET imaging. However, PET provides limited anatomic localization. The purpose of this study was to determine whether (18)F-FDOPA PET/MRI fusion can provide precise anatomic localization of abnormal tracer uptake and how this activity corresponds to MR signal abnormality.
Two groups of patients were analyzed. Group I consisted of 21 patients who underwent (18)F-FDOPA PET and MRI followed by craniotomy for tumor resection. Group II consisted of 70 patients with a pathological diagnosis of glioma that had (18)F-FDOPA PET and MRI but lacked additional pathologic follow-up. Fused (18)F-FDOPA PET and MRI images were analyzed for concordance and correlated with histopathologic data.
Fusion technology facilitated precise anatomical localization of (18)F-FDOPA activity. In group I, all 21 cases showed pathology-confirmed tumor. Of these, (18)F-FDOPA scans were positive in 9/10 (90%) previously unresected tumors, and 11/11 (100%) of recurrent tumors. Of the 70 patients in group II, concordance between MRI and (18)F-FDOPA was found in 49/54 (90.1%) of patients with sufficient follow-up; in the remaining 16 patients concordance could not be determined due to lack of follow-up. (18)F-FDOPA labeling was comparable in both high- and low-grade gliomas and identified both enhancing and non-enhancing tumor equally well. In some cases, (18)F-FDOPA activity preceded tumor detection on MRI.
(18)F-FDOPA PET/MRI fusion provides precise anatomic localization of tracer uptake and labels enhancing and non-enhancing tumor well. In a small minority of cases, (18)F-FDOPA activity may identify tumor not visible on MRI.
European journal of radiology 06/2008; 71(2):242-8. · 2.65 Impact Factor
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ABSTRACT: Careful examination of the medical record of brain-tumor patients can be an overwhelming task for the neuroradiologist. The number of clinical documents alone may approach 100 for a patient that has a 3-year-old brain tumor. The neuroradiologist's evaluation of a patient's brain tumor involves examining the current imaging exam and checking for previous imaging exams that may occur pre- or post-treatment. The goal of this research is to develop an effective method to review all of the pertinent patient information from the medical record. We have designed and developed a medical system that incorporates Hospital Information Systems, Radiology Information Systems, and Picture Archiving and Communications Systems information. Our research improves clinical review of patient's data by organizing image display, removing unnecessary documents, and mining for key clinical scenarios that are important in the assessment and care of brain-tumor patients.
Informatics for Health and Social Care 04/2008; 33(1):55-68. · 0.87 Impact Factor
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ABSTRACT: The purpose of this study was to prospectively evaluate a high-spatial-resolution contrast-enhanced 3-T MR angiography protocol for detection and characterization of intracranial aneurysms and to compare the results with those of MDCT angiography.
Forty-one patients with suspected intracranial aneurysm underwent high-spatial-resolution 3D contrast-enhanced MR angiography and CT angiography (CTA). With a generalized autocalibrating partially parallel acquisition algorithm with an acceleration factor of 4 at 3 T, contrast-enhanced MR angiographic images were acquired over 20 seconds with a spatial-resolution of 0.7 x 0.7 x 0.8 mm. CTA images were acquired with a spatial resolution of 0.35 x 0.35 x 0.8 mm on a 16-MDCT scanner in 17 seconds. The images from the two studies were evaluated independently by two neuroradiologists for image quality, presence of aneurysm, and characterization of aneurysm. The dimensions of the aneurysm were measured independently with both techniques.
A total of 25 aneurysms were identified with both contrast-enhanced MR angiography and CTA. A comparative analysis of detection and depiction of aneurysms showed excellent interobserver agreement for both contrast-enhanced MR angiography (kappa = 0.81) and CTA (kappa = 0.91) images. There was significant correlation between the techniques for both qualitative assessment of aneurysm depiction (rho = 0.92; 95% CI, 0.88-0.95) and quantitative dimensional measurement of aneurysm size (r = 0.94; 95% CI, 0.92-0.97).
Contrast-enhanced MR angiography at 3 T is reliable for evaluation and characterization of intracranial aneurysms. The results are comparable with those of MDCTA.
American Journal of Roentgenology 03/2008; 190(2):389-95. · 2.78 Impact Factor
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Wei Chen,
Sibylle Delaloye,
Daniel H S Silverman,
Cheri Geist,
Johannes Czernin,
James Sayre,
Nagichettiar Satyamurthy, Whitney Pope,
Albert Lai,
Michael E Phelps,
Timothy Cloughesy
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ABSTRACT: Evaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan.
Patients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival.
Twenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P = .003), and tended to have a prolonged progression-free survival (P = .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P = .006; 6 weeks, P = .002), compared with the MRI responses (P = .060 for both 6-week and best responses).
FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
Journal of Clinical Oncology 11/2007; 25(30):4714-21. · 18.37 Impact Factor
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ABSTRACT: We evaluated the amino acid and glucose metabolism of brain tumors by using PET with 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine ((18)F-FDOPA) and (18)F-FDG.
Eighty-one patients undergoing evaluation for brain tumors were studied. Initially, 30 patients underwent PET with (18)F-FDOPA and (18)F-FDG within the same week. Tracer kinetics in normal brain and tumor tissues were estimated. PET uptake was quantified by use of standardized uptake values and the ratio of tumor uptake to normal hemispheric tissue uptake (T/N). In addition, PET uptake with (18)F-FDOPA was quantified by use of ratios of tumor uptake to striatum uptake (T/S) and of tumor uptake to white matter uptake. The accuracies of (18)F-FDOPA and (18)F-FDG PET were determined by comparing imaging data with histologic findings and findings of clinical follow-up of up to 31 mo (mean, 20 mo). To further validate the accuracy of (18)F-FDOPA PET, (18)F-FDOPA PET was performed with an additional 51 patients undergoing brain tumor evaluation.
Tracer uptake in tumors on (18)F-FDOPA scans was rapid, peaking at approximately 15 min after intravenous injection. Tumor uptake could be distinguished from that of the striatum by the difference in peak times. Both high-grade and low-grade tumors were well visualized with (18)F-FDOPA. The sensitivity for identifying tumors was substantially higher with (18)F-FDOPA PET than with (18)F-FDG PET at comparable specificities, as determined by simple visual inspection, especially for the assessment of low-grade tumors. Using receiver-operating-characteristic curve analysis, we found the optimal threshold for (18)F-FDOPA to be a T/S of greater than 1.0 (sensitivity, 96%; specificity, 100%) or a T/N of greater than 1.3 (sensitivity, 96%; specificity, 86%). The high diagnostic accuracy of (18)F-FDOPA PET at these thresholds was confirmed with the additional 51 patients (a total of 81 patients: sensitivity, 98%; specificity, 86%; positive predictive value, 95%; negative predictive value, 95%). No significant difference in tumor uptake on (18)F-FDOPA scans was seen between low-grade and high-grade tumors (P = 0.40) or between contrast-enhancing and nonenhancing tumors (P = 0.97). Radiation necrosis was generally distinguishable from tumors on (18)F-FDOPA scans (P < 0.00001).
(18)F-FDOPA PET was more accurate than (18)F-FDG PET for imaging of low-grade tumors and evaluating recurrent tumors. (18)F-FDOPA PET may prove especially useful for imaging of recurrent low-grade tumors and for distinguishing tumor recurrence from radiation necrosis.
Journal of Nuclear Medicine 07/2006; 47(6):904-11. · 6.38 Impact Factor
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ABSTRACT: We sought to evaluate and compare the image quality and vessel delineation of the carotid arteries with high spatial-resolution contrast-enhanced MRA (CE-MRA) at 3.0 T using integrated parallel acquisition (iPAT) with acceleration factors of 2 and 4.
Using an 8-channel neurovascular array coil, we performed prospective high-spatial resolution CE-MRA at 3.0 T of the head and neck on 24 patients (11 men, 13 women, ages 37-89) with suspected arterio-occlusive disease who were assigned randomly to 2 groups. Twelve patients (group A) were examined with a 3D-GRE sequence using iPAT with acceleration factor of 2. For the next 12 patients (group B) a near-identical sequence with an acceleration factor of 4 was applied. Higher iPAT factors were used to increase the spatial-resolution while keeping scan time unchanged. Two volunteers were scanned by both protocols. Phantom measurements were performed to assess the signal-to-noise ratio (SNR). The presence of artifact, noise, image quality of the arterial segments, and the presence and degree of arterial stenosis were evaluated independently by 2 radiologists. Statistical analysis of data was performed by using Wilcoxon rank sum test and 2-sample Student t test (P < 0.05 was indicative a statistically significant difference). The interobserver variability was tested by kappa coefficient.
SNR values were significantly lower when iPAT with acceleration factor of 4 was used (P < 0.001). There was no significant difference between 2 groups in regards to image noise (P = 0.67) and artifact (P = 0.8). Both readers visualized the majority of carotid circulation with good image quality in both groups. For smaller intracranial arteries, such as the second-division of anterior and middle cerebral artery, anterior communicating artery, and superior cerebellar artery, the image quality and vessel delineation was significantly better at an iPAT factor of 4 (P < 0.01). The overall interobserver agreement for both the vessel depiction, and detection of arterial stenoses was higher in group B compared with group A.
Use of parallel acquisition techniques with a high acceleration factor (iPAT-4) results in superior depiction of small intracranial arterial segments. Imaging at higher magnetic field strength, in addition to the use of an optimized 8-channel array coil, provides sufficient SNR to support faster parallel acquisition protocols, leading to improved spatial-resolution. More extensive clinical studies are warranted to establish the range of applications and confirm the accuracy of the technique.
Investigative Radiology 04/2006; 41(4):391-9. · 4.59 Impact Factor
