Publications (10)54.04 Total impact
-
Article: Sarcoidosis of the pineal gland: an unusual presentation of neurosarcoidosis.
[show abstract] [hide abstract]
ABSTRACT: Sarcoidosis is an inflammatory disease characterized by noncaseating granulomas that is rarely found as primary CNS pathology. We report an unusual case of sarcoidosis involving the pineal gland with radiographic, histopathology, and clinical data. A 45-year-old man without evidence of systemic sarcoidosis presented with a history of gradual onset of blurry vision and diplopia that progressed over 3 months. MR imaging demonstrated an enhancing mass in the pineal region. A suboccipital craniotomy was performed with resection of the mass through a supra-cerebellar infratentorial approach. Histopathologic analysis did not reveal a pineoblastoma but instead revealed noncaseating granulomas within the pineal gland. Extensive hematologic laboratory examinations, cerebral spinal fluid studies, and cultures for infection were all negative. This mass lesion was diagnosed as solitary neurosarcoidosis of the pineal gland, without dissemination. The patient was treated with steroids and at 4-year follow-up is asymptomatic with an unremarkable MRI scan. This is an unusual case of pineal sarcoidosis mimicking a tumor with associated MRI, CT and histopathologic findings reported together. Although rare, sarcoidosis of the pineal gland should not be excluded from a comprehensive differential diagnosis of an enhancing pineal region mass.Journal of Neuro-Oncology 09/2008; 91(1):113-6. · 3.21 Impact Factor -
Article: Correlation of magnetic resonance spectroscopic and growth characteristics within Grades II and III gliomas.
[show abstract] [hide abstract]
ABSTRACT: The accurate diagnosis of World Health Organization Grades II and III gliomas is crucial for the effective treatment of patients with such lesions. Increased cell density and mitotic activity are histological features that distinguish Grade III from Grade II gliomas. Because increased cellular proliferation and density both contribute to the in vivo magnetic resonance (MR) spectroscopic peak corresponding to choline-containing compounds (Cho), the authors hypothesized that multivoxel MR spectroscopy might help identify the tumor regions with the most aggressive growth characteristics, which would be optimal locations for biopsy. They investigated the ability to use one or more MR spectroscopic parameters to predict the MIB-1 cell proliferation index (PI), the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling cell death index (DI), the cell density, and the ratio of proliferation to cell death (PI/DI) within different regions of the same tumor. Patients with presumed Grades II or III glioma underwent 3D MR spectroscopic imaging prior to surgery, and two or three regions within the tumor were targeted for biopsy retrieval based on their spectroscopic features. Biopsy specimens were extracted from the tumor during image-guided resection, and the PI, DI, and cell density were assessed in the specimens using immunohistochemical methods. The authors found that the relative levels of Cho and N-acetylaspartate (NAA) correlated with the cell density, PI, and PI/DI ratio within different regions of the same tumor and that the association held for the subpopulation of nonenhancing tumors. The association was stronger in tumors with large ranges of Cho/NAA values, irrespective of the presence of contrast enhancement. The findings demonstrate the validity of using MR spectroscopy to identify regions of aggressive growth in presumed Grade II or III gliomas that would be suitable targets for retrieving diagnostic biopsy specimens.Journal of Neurosurgery 05/2007; 106(4):660-6. · 2.96 Impact Factor -
Article: Controlled cortical impact in swine: pathophysiology and biomechanics.
[show abstract] [hide abstract]
ABSTRACT: Investigations of the basic pathological, cellular, and molecular mechanisms of traumatic brain injury (TBI) over the past two decades have been carried out primarily in rodents. Unfortunately, these studies have not translated into improved outcome in patients with TBI. To better model human TBI, a swine model of controlled cortical impact (CCI) was developed. A CCI device was used to generate a focal lesion in 23 anesthetized male Yorkshire swine. In 10 swine, CCI parameters of velocity and dwell time were varied to achieve a consistent injury (3.5 m/sec, 400 msec, respectively). In 13 swine, depth of depression was varied from 9 to 12 mm. Physiological data, including heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP), were collected for 10 h after injury. Following injury, ICP and HR increased above baseline values in all swine, with a more pronounced elevation in animals impacted to a depth of depression of 12 mm. An 11-mm depth of depression was found to most closely mimic pathological features of human TBI with edema, infiltration of inflammatory cells, pericapillary hemorrhage, and petechial hemorrhages in the white matter. Injury to a depth of depression of 12 mm resulted in cortical laceration obscuring these features. Immunohistological staining with Neu-N, MAP-2, and Fluoro Jade B revealed evidence of degenerating neurons, axonal disruption, and impending cell death. These results indicate that the swine model of CCI results in a defined and reproducible injury with pathological features similar to human TBI. Physiological parameters after injury are readily monitored in a setting mimicking conditions of an intensive care unit, establishing a more clinically relevant experimental model for future investigations.Journal of Neurotrauma 03/2006; 23(2):128-39. · 3.65 Impact Factor -
Article: Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma
[show abstract] [hide abstract]
ABSTRACT: Abstract Background We previously identified brain type fatty acid-binding protein (FABP7) as a prognostic marker for patients with glioblastoma (GBM). Increased expression of FABP7 is associated with reduced survival. To investigate possible molecular mechanisms underlying this association, we compared the expression and subcellular localization of FABP7 in non-tumor brain tissues with different types of glioma, and examined the expression of FABP7 and epidermal growth factor receptor (EGFR) in GBM tumors. Methods Expression of FABP7 in non-tumor brain and glioma specimens was examined using immunohistochemistry, and its correlation to the clinical behavior of the tumors was analyzed. We also analyzed the association between FABP7 and EGFR expression in different sets of GBM specimens using published DNA microarray datasets and semi-quantitative immunohistochemistry. In vitro migration was examined using SF763 glioma cell line. Results FABP7 was present in a unique population of glia in normal human brain, and its expression was increased in a subset of reactive astrocytes. FABP7 immunoreactivity in grade I pilocytic astrocytoma was predominantly cytoplasmic, whereas nuclear FABP7 was detected in other types of infiltrative glioma. Nuclear, not cytoplasmic, FABP7 immunoreactivity was associated with EGFR overexpression in GBM (N = 61, p = 0.008). Expression of the FABP7 gene in GBM also correlated with the abundance of EGFR mRNA in our previous microarray analyses (N = 34, p = 0.016) and an independent public microarray dataset (N = 28, p = 0.03). Compared to those negative for both markers, nuclear FABP7-positive/EGFR-positive and nuclear FABP7-positive/EGFR-negative GBM tumors demonstrated shortest survival, whereas those only positive for EGFR had intermediate survival. EGFR activation increased nuclear FABP7 immunoreactivity in a glioma cell line in vitro , and inhibition of FABP7 expression suppressed EGF-induced glioma-cell migration. Our data suggested that in EGFR-positive GBM the presence of nuclear FABP7 immunoreactivity increases the risk of poor prognosis Conclusion In this study, we identified a possible mechanism as the basis of the association between nuclear FABP7 and poor prognosis of GBM. FABP7 expression can be found in all grades of astrocytoma, but neoplastic cells with nuclear FABP7 were only seen in infiltrative types of tumors. Nuclear FABP7 may be induced by EGFR activation to promote migration of GBM tumor cells. Positive nuclear FABP7 and EGFR overexpression correlated with short survival in EGFR-positive GBM patients. Therefore, nuclear FABP7 immunoreactivity could be used to monitor the progression of EGFR-overexpressed GBM.BMC Cancer. 01/2006; -
Article: Differentiation of low-grade oligodendrogliomas from low-grade astrocytomas by using quantitative blood-volume measurements derived from dynamic susceptibility contrast-enhanced MR imaging.
[show abstract] [hide abstract]
ABSTRACT: Histopathologic evaluation remains the reference standard for diagnosis of glioma and classification of histologic subtypes, but is challenged by subjective criteria, tissue sampling error, and lack of specific tumor markers. Anatomic imaging is essential for surgical planning of gliomas but is limited by its nonspecificity and its inability to depict beyond morphologic aberrations. The purpose of our study was to investigate dynamic susceptibility contrast-enhanced (DSC) MR imaging characteristics of the two most common subtypes of low-grade infiltrating glioma: astrocytoma and oligodendroglioma. We hypothesized that tumor blood-volume measurements, derived from DSC MR imaging, would help differentiate the two on the basis of differences in tumor vascularity. We studied 25 consecutive patients with treatment-naive, histopathologically confirmed World Health Organization grade II astrocytoma (n = 11) or oligodendroglioma (n = 14). All patients underwent anatomic and DSC MR imaging immediately before surgical resection. Histologic confirmation was obtained in all patients. Anatomic MR images were analyzed for morphologic features, and DSC MR data were processed to yield quantitative cerebral blood volume (CBV) measurements. The maximum relative CBV (rCBV(max)) in tumor ranged from 0.48 to 1.34 (0.92 +/- 0.27, median +/- SD) in astrocytomas and from 1.29 to 9.24 (3.68 +/- 2.39) in oligodendrogliomas. The difference in median rCBV(max) between the two tumor types was significant (P < .0001). The tumor rCBV(max) measurements derived from DSC MR imaging were significantly higher in low-grade oligodendrogliomas than in astrocytomas. Our findings suggest that tumor rCBV(max) derived from DSC MR imaging can be used to distinguish between the two low-grade gliomas.American Journal of Neuroradiology 03/2005; 26(2):266-73. · 2.93 Impact Factor -
Article: Expression of the aquaporin-1 water channel in human glial tumors.
[show abstract] [hide abstract]
ABSTRACT: Malignant glial tumors are associated with cerebral edema. The aquaporins (AQPs) are a family of membrane proteins that provide a major pathway for water transport in mammals. In the central nervous system, AQP1 is selectively expressed in the choroid plexus and thought to participate in cerebrospinal fluid production. Prior studies have suggested that AQP1 may be up-regulated in glial tumors, potentially contributing to tumor-associated edema. The objective of this study was to investigate the expression of AQP1 in a large series of human glial tumors. Thirty-six human glial tumors were obtained from the University of California, San Francisco Neurosurgery Tissue Bank. AQP1 expression was evaluated by reverse transcriptase polymerase chain reaction, complementary deoxyribonucleic acid gene array, Western blot analysis, and immunohistochemical analyses. AQP1, normally restricted to choroid epithelia, was highly expressed in glioblastomas. Complementary deoxyribonucleic acid array, Western blot analysis, and immunohistochemical analysis revealed intense up-regulation of AQP1 expression in all glioblastomas studied. The abnormal up-regulation of AQP1 in glial tumors suggests a potential pathological role for this membrane water channel and raises the possibility that selective AQP1 inhibition might offer a new therapeutic target for treatment of tumor-associated edema.Neurosurgery 03/2005; 56(2):375-81; discussion 375-81. · 2.79 Impact Factor -
Article: Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas
[show abstract] [hide abstract]
ABSTRACT: Abstract Background Oligodendroglioma (ODG) and oligoastrocytoma (OAC) are diffusely infiltrating primary brain tumors whose pathogenesis remains unclear. We previously identified a group of genes whose expression was inversely correlated with survival in a cohort of patients with glioblastoma (GBM), and some of these genes are also reportedly expressed in ODG and OAC. We examined the expression patterns and localization of these survival-associated genes in ODG and OAC in order to analyze their possible roles in the oncogenesis of these two tumor types. Methods We used UniGene libraries derived from GBM and ODG specimens to examine the expression levels of the transcripts for each of the 50 GBM survival-associated genes. We used immunohistochemistry and cDNA microarrays to examine expression of selected survival-associated genes and Id4, a gene believed to control the timing of oligodendrocyte development. The expression of FABP7 and Id4 and the survival of patients with ODG and OAC were also analyzed. Results Transcripts of most survival-associated genes as well as Id4 were present in both GBM and ODG tumors, whereas protein expression of Id4 and one of the survival-associated genes, brain-type fatty acid-binding protein (FABP7), was present in cells with astrocytic features, including reactive and neoplastic astrocytes, but not in neoplastic oligodendrocytes. Id4 was co-expressed with FABP7 in microgemistocytes in ODG and in neoplastic astrocytes in OAC. Id4 and FABP7 expression, however, did not correlate with the clinical outcome of patients with ODG or OAC tumors. Conclusion Expression of Id4 and some of our previously identified GBM survival-associated genes is present in developing or mature oligodendrocytes. However, protein expression of Id4 and FABP7 in GBM, ODG, and OAC suggests that this group of functionally important genes might demonstrate two patterns of expression in these glioma subtypes: one group is universally expressed in glioma cells, and the other group of genes is expressed primarily in neoplastic astrocytes but not in neoplastic oligodendrocytes. Differential protein expression of these two groups of genes in ODG and OAC may be related to the cellular origins and the histological features of the neoplastic cells.BMC Clinical Pathology. 01/2005; -
Article: Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.
[show abstract] [hide abstract]
ABSTRACT: Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.Nature Genetics 12/2002; 32(3):453-8. · 35.53 Impact Factor -
Article: Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis.
[show abstract] [hide abstract]
ABSTRACT: Chronic focal encephalitis (CFE) generally presents with seizures that increase in severity and frequency as the disease progresses. Malfunction of synaptic transmission through altered glutamate signaling has been proposed as a likely mechanism triggering CFE. In addition, profuse inflammation is commonly seen in histopathological examination of resected tissue. To further explore the roles of glutamatergic activity and inflammation in this disease, we examined the expression of 52 genes by real time RT-PCR (kinetic RT-PCR or kRT-PCR) in a brain specimen from a CFE patient with active seizures, eight control specimens from patients with several other neurologic disorders, and two from individuals with no recorded history of neurological abnormalities. The CFE specimen displayed a dramatic increase in the expression of several inflammation-related genes (i.e. IL1 beta, IgVH, and IL2R gamma among others) and a striking down-regulation of several GluRs, in particular mGluR4. This type of analysis may prove useful in describing the molecular events underlying intractable epilepsy.Journal of Neuroimmunology 08/2002; 128(1-2):9-15. · 2.96 Impact Factor -
Article: Chromosomal Abnormalities Subdivide Ependymal Tumors into Clinically Relevant Groups
[show abstract] [hide abstract]
ABSTRACT: Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.
