Dr. Born obtained his medical degree from the University of Virginia where he also completed a Ph.D. in Neuroscience. His next training occurred at the University of Washington as an Anatomic Pathology resident and Neuropathology fellow. He moved to Stanford in 2013 and as Clinical Professor of Pathology he sees a wide range of samples related to the field of neuropathology.
- Anatomic Pathology
- Ocular Pathology
Clinical Professor, Pathology
Neuropathology Fellowship CCC Chair, Pathology (2015 - Present)
Assistant Director Neuropathology Laboratory, Pathology (2013 - Present)
Residency: University of Washington Medicine Pathology (1993) WA
Medical Education: University of Virgina School of Medicine (1987) VA
Board Certification: American Board of Pathology, Anatomic Pathology (1995)
Board Certification: American Board of Pathology, Neuropathology (1995)
Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
This will be a multi-center, proof of concept phase 0 study to assess the suppression of p-AKT in Vestibular Schwannoma (VS) and meningiomas by AR-42 in adult patients undergoing tumor resection. AR-42 is a small molecule which crosses the blood brain barrier (BBB) in rodents, but the investigators are not certain yet if it will penetrate human VS. Meningiomas are outside the BBB, but seem to be unusually resistant to all current medical treatments. The primary endpoint of the bioactivity of suppression of p-AKT by AR-42 was selected as drug activity seems more informative than bioavailability. Our preclinical data and others have shown dose dependent suppression of p-AKT by AR-42 in both VS and meningiomas.
Stanford is currently not accepting patients for this trial.
Graduate and Fellowship Programs
Neuropathology (Fellowship Program)
DSC perfusion MRI-derived fractional tumor burden and relative CBV differentiate tumor progression and radiation necrosis in brain metastases treated with stereotactic radiosurgery.
American Journal of Neuroradiology
2022; 43 (5): 689-695
View details for DOI 10.3174/ajnr.A7501
- Intracranial Grade II Meningioma Oligometastatic to the Cervical Spine CUREUS 2021; 13 (1)
Correlative Microscopy to Localize and Characterize Iron Deposition in Alzheimer's Disease.
Journal of Alzheimer's disease reports
2020; 4 (1): 525–36
Background: Recent evidence suggests that the accumulation of iron, specifically ferrous Fe2+, may play a role in the development and progression of neurodegeneration in Alzheimer's disease (AD) through the production of oxidative stress.Objective: To localize and characterize iron deposition and oxidation state in AD, we analyzed human hippocampal autopsy samples from four subjects with advanced AD that have been previously characterized with correlative MRI-histology.Methods: We perform scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and electron energy loss spectroscopy (EELS) in the higher resolution transmission electron microscope on the surface and cross-sections of specific iron-rich regions of interest.Results: Specific previously analyzed regions were visualized using SEM and confirmed to be iron-rich deposits using EDS. Subsequent analysis using focused ion beam cross-sectioning and SEM characterized the iron deposition throughout the 3-D volumes, confirming the presence of iron throughout the deposits, and in two out of four specimens demonstrating colocalization with zinc. Analysis of traditional histology slides showed the analyzed deposits overlapped both with amyloid and tau deposition. Following higher resolution analysis of a single iron deposit using scanning transmission electron microscope (STEM), we demonstrated the potential of monochromated STEM-EELS to discern the relative oxidation state of iron within a deposit.Conclusion: These findings suggest that iron is present in the AD hippocampus and can be visualized and characterized using combined MRI and EM techniques. An altered relative oxidation state may suggest a direct link between iron and oxidative stress in AD. These methods thus could potentially measure an altered relative oxidation state that could suggest a direct link between iron and oxidative stress in AD. Furthermore, we have demonstrated the ability to analyze metal deposition alongside commonly used histological markers of AD pathology, paving the way for future insights into the molecular interactions between Abeta, tau, iron, and other putative metals, such as zinc.
View details for DOI 10.3233/ADR-200234
View details for PubMedID 33532700
- ALK-positive compound Spitz nevus with extensive perineural and intraneural neurotropism. Journal of cutaneous pathology 2020
Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.
Acta neuropathologica communications
2020; 8 (1): 151
The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
View details for DOI 10.1186/s40478-020-01027-z
View details for PubMedID 32859279
Incidence Rates of Benign and Malignant Eyelid Lesions at Stanford Healthcare from 2016-2019
OXFORD UNIV PRESS INC. 2020: 681–82
View details for Web of Science ID 000538796100116
Histologic Investigation of Graft-Versus-Host Disease in the Central Nervous System
OXFORD UNIV PRESS INC. 2020: 676
View details for Web of Science ID 000538796100094
Retrospective Analysis of Incidence Rates of Benign and Malignant Eyelid Lesions at a San Francisco Bay Area Tertiary Hospital
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554528304019
Expanding the spectrum of Kabuki syndrome with novel neuropathological, ocular and genetic findings in an autopsy case
OXFORD UNIV PRESS INC. 2020: 677
View details for Web of Science ID 000538796100099
- Tenosynovial giant cell tumor of the suboccipital region - A rare, benign neoplasm in this location. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2020
ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS
OXFORD UNIV PRESS INC. 2019: 151–52
View details for Web of Science ID 000509478703106
Rosette-Forming Glioneuronal Tumor is Defined by FGFR1 Activating Alterations with Frequent Accompanying PI3K and MAPK Pathway Mutations
OXFORD UNIV PRESS INC. 2019: 554
View details for Web of Science ID 000472806000141
Validation and Clinical Use of Whole Slide Digital Imaging at Stanford Neuropathology
OXFORD UNIV PRESS INC. 2019: 576
View details for Web of Science ID 000472806000230
Granular Cell Pituitary Tumor in a Patient with Multiple Endocrine Neoplasia-1.
2019; 11 (4): e4541
Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant disorder characterized by parathyroid, pancreatic islet, and pituitary tumors. Approximately 40% of MEN-1 patients harbor a pituitary adenoma. Separately, granular cell tumors (GCTs) of the sellar/parasellar region are an exceedingly rare clinical entity with less than 100 reported cases in the literature. These slow-growing, often asymptomatic lesions are difficult to diagnose and may mimic pituitary adenoma, Rathke cleft cyst, or other sellar/supra-sellar pathology. There is no known association with MEN-1 or any other familial syndrome. A 36-year-old neurologically normal woman with known MEN-1 underwent a screening magnetic resonance imaging (MRI) scan which revealed a 10 mm x 6 mm x 7 mm sellar/suprasellar lesion. She underwent endoscopic endonasal transsphenoidal resection. Subsequent neuropathological analysis was consistent with GCT of the pituitary gland. Here we describe the first report to our knowledge of a GCT of the pituitary gland occurring in a patient with MEN-1.
View details for DOI 10.7759/cureus.4541
View details for PubMedID 31275768
View details for PubMedCentralID PMC6592835
- Granular Cell Pituitary Tumor in a Patient with Multiple Endocrine Neoplasia-1 CUREUS 2019; 11 (4)
Clinical Utility of GlioSeq Next-Generation Sequencing Test in Pediatric and Young Adult Patients With Brain Tumors.
Journal of neuropathology and experimental neurology
Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.
View details for DOI 10.1093/jnen/nlz055
View details for PubMedID 31298284
Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals Rb1 signaling as a Novel Mediator and Biomarker.
Clinical cancer research : an official journal of the American Association for Cancer Research
Most WHO Grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.MS-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by western blot. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and western blot validation revealed regulation of AKT and Cell Cycle Checkpoint cascades. Rb1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.Rb1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
View details for DOI 10.1158/1078-0432.CCR-18-0641
View details for PubMedID 31615938
Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma.
Clinical cancer research : an official journal of the American Association for Cancer Research
Preclinical studies have demonstrated that post-irradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in newly diagnosed glioblastoma patients.We enrolled 9 patients to the phase I study and an additional 20 patients to phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via PICC line for four consecutive weeks beginning at day 35 of conventional treatment with concurrent chemo-radiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 µg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months (95% Confidence Interval (CI) 15.9, NA) with a progression-free survival of 14.5 months (95% CI 11.8, NA). MRI and histopathology support the mechanism of action to inhibit post-irradiation tumor revascularization.Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemo-irradiation in newly diagnosed GBM patients and improves local control of tumor recurrences.
View details for DOI 10.1158/1078-0432.CCR-19-1421
View details for PubMedID 31537527
Kinase Activity in Recurring Primary Skull Base Chordomas and Chondrosarcomas: Identification of Novel Pathways of Oncogenesis and Potential Drug Targets
2017; 107: 75–81
Chordomas and chondrosarcomas can occur in the skull base. Currently, 45% of chordomas and 56% of chondrosarcomas recur within 5 years of surgery. The role of adjuvant therapy is highly debated. No pharmacotherapies have been approved by the U.S. Food and Drug Administration for chordomas or chondrosarcomas. High propensity for recurrence and lack of definitive adjuvant therapy necessitate additional basic science research to identify molecular anomalies associated with recurrent disease.We pooled tumor lysates from patients based on clinical criteria into 4 groups: primary chordomas, primary chordomas that recurred, primary chondrosarcomas, and primary chondrosarcomas that recurred. We used a peptide labeling method, isobaric tags for relative and absolute quantitation, to uniquely identify each tumor group. Phosphorylated peptides were identified and quantified via mass spectroscopy to determine and predict active kinases.Six groups of phosphorylated peptides were associated with primary tumors that later recurred. Specific kinases associated with primary chordomas that recurred were FES and FER. Specific kinases associated with primary chondrosarcomas that recurred were FES, FER, SRC family kinases, PKC, ROCK, and mitogen-activated protein kinase signaling (JNK, ERK1, p38).These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors with a propensity to recur. Many of these kinases can be efficaciously inhibited by Food and Drug Administration-approved drugs that have not yet been used in clinical trials for treatment of skull base chordomas or chondrosarcomas. Validation of kinases identified in this study may advance treatment options for patients with these tumors.
View details for PubMedID 28647652
Anti-PD-1-associated inflammatory-demyelinating lesions in patients with brain metastases
OXFORD UNIV PRESS INC. 2017: 500–501
View details for Web of Science ID 000404906900045
Lymphoplasmacytic Lymphoma Presenting As Giant Cell Arteritis: A Novel Case Report
OXFORD UNIV PRESS INC. 2017: 545
View details for Web of Science ID 000404906900225
Why do inguinal hernia patients have pain? Histology points to compression neuropathy.
American journal of surgery
2017; 213 (5): 975-982
The purpose of this study is to describe the known soft tissue neuro-histology factors associated with compression neuropathy in relation to the incidence of preoperative pain in primary inguinal hernia. Enlargement of the ilioinguinal nerve occurs in 63% of patients with primary inguinal hernia; compression neuropathy has similar gross features.Patients completed pain questionnaires pertaining to preoperative pain and the quality of pain experienced. During routine inguinal hernia repair, nerve segments were sampled for histologic evaluation.Twenty-two thickened nerve segments (63% of total) with proximal and distal specimens were resected for examination and comparison. We quantified various histologic indicators including nerve diameter, fascicle count, myxoid content within the epineurium, perineurium and endoneurium. Increased preoperative patient pain scores correlate with increased nerve diameter, increased fascicle count and increased myxoid material both within the perineurium and endoneurium.These findings support the concept that preoperative hernia pain is associated with compression neuropathy.
View details for DOI 10.1016/j.amjsurg.2017.03.013
View details for PubMedID 28388973
Comparative Proteomic Profiling Using Two-Dimensional Gel Electrophoresis and Identification via LC-MS/MS Reveals Novel Protein Biomarkers to Identify Aggressive Subtypes of WHO Grade I Meningioma.
Journal of neurological surgery. Part B, Skull base
2017; 78 (5): 371–79
Background Meningomas represent the most common primary intracranial tumor. The majority are benign World Health Organization (WHO) Grade I lesions, but a subset of these behave in an aggressive manner. Protein biomarkers are needed to distinguish aggressive from benign Grade I lesions. Materials and Methods Pooled protein lysates were derived from five clinically aggressive Grade I and five typically benign WHO Grade I tumors snap frozen at the time of surgery. Proteins were separated in each group using two-dimensional gel electrophoresis (2DGE) and protein spots of interest were identified using liquid chromatography-mass spectrometry (LC-MS). Potential biomarker candidates were validated using western blot assays in individual tumor samples and by tissue microarray (TMA). Results Seven candidate biomarkers were obtained from the 2DGE and validated via western blot and TMA. Biomarker validation data allowed for the creation of predictive models using binary logistical regression that correctly identified 85.9% of aggressive tumors within the larger cohort of Grade I meningioma. Conclusion Simple protein separation by 2DGE and identification of candidate biomarkers by LC-MS allowed for the identification of seven candidate biomarkers that when used in predictive models accurately distinguish aggressive from benign behavior in WHO Grade I meningioma.
View details for PubMedID 28875114
View details for PubMedCentralID PMC5582960
Prognostic significance of relative 1p/19q codeletion in oligodendroglial tumors
JOURNAL OF NEURO-ONCOLOGY
2015; 125 (2): 249-251
1p/19q codeletion is a favorable prognostic marker for oligodendroglial tumors (OT). Compare outcome in OT with simple deletions of 1p or 19q to those with relative deletions defined as the presence of both increased copy number (polysomy) and 1p/19q codeletion. 525 cases were examined by fluorescence in situ hybridization (FISH) using dual color probes to determine the deletion status of chromosome arms 1p and 19q. Categories included simple deletions defined as a proportion of either 1p32 or 19q13 FISH signals compared to 1q42 or 19p13 signals less than 0.80 and relative deletions (1p or 19q) defined as the combination of a <0.80 proportion with >30 % of nuclei showing increased chromosome number (based on enumeration of 1q25 or 19p13). 464 (80 %) were WHO Grade II or III OT of which 209 (48 %) had both 1p and 19q deleted (codeletion). 72 (16 %) had relative deletions for either one or both 1p and 19q of which 28 (6 %) had relative deletions of 1p and 19q (relative codeletion). Overall survival in WHO Grade II OT was 13 + years when 1p/19q codeleted (n = 156); 5 + years in uni- or nondeleted (n = 86); 6 + years in relative deletion for either 1p or 19q (n = 41); and 6 + years in relative 1p/19q codeletion (n = 15). Similarly in WHO Grade III OT (n = 168) overall survival was 11 + years in 1p/19q codeleted (n = 54) OT; 2.5 years in uni- or nondeleted (n = 70); 3 years in relative deletion for one or both 1p or 19q (n = 31); and 4 + years in relative 1p/19q codeletion (n = 13). Survival for OT regardless of grade with relative codeletion of 1p/19q was approximately one half that of 1p/19q codeleted tumors. The presence of relative 1p/19q codeletion is of prognostic significance.
View details for DOI 10.1007/s11060-015-1906-y
View details for Web of Science ID 000363245300003
View details for PubMedID 26341371
Periostin is a novel therapeutic target that predicts and regulates glioma malignancy
2015; 17 (3): 372-382
Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical implications of periostin expression and function related to its therapeutic potential have not been fully explored.Periostin expression levels and patterns were examined in human glioma cells and tissues by quantitative real-time PCR and immunohistochemistry and correlated with glioma grade, type, recurrence, and survival. Functional assays determined the impact of altering periostin expression and function on cell invasion, migration, adhesion, and glioma stem cell activity and tumorigenicity. The prognostic and functional relevance of periostin and its associated genes were analyzed using the TCGA and REMBRANDT databases and paired recurrent glioma samples.Periostin expression levels correlated directly with tumor grade and recurrence, and inversely with survival, in all grades of adult human glioma. Stromal deposition of periostin was detected only in grade IV gliomas. Secreted periostin promoted glioma cell invasion and adhesion, and periostin knockdown markedly impaired survival of xenografted glioma stem cells. Interactions with αvβ3 and αvβ5 integrins promoted adhesion and migration, and periostin abrogated cytotoxicity of the αvβ3/β5 specific inhibitor cilengitide. Periostin-associated gene signatures, predominated by matrix and secreted proteins, corresponded to patient prognosis and functional motifs related to increased malignancy.Periostin is a robust marker of glioma malignancy and potential tumor recurrence. Abrogation of glioma stem cell tumorigenicity after periostin inhibition provides support for exploring the therapeutic impact of targeting periostin.
View details for DOI 10.1093/neuonc/nou161
View details for Web of Science ID 000352479700010
View details for PubMedID 25140038
View details for PubMedCentralID PMC4483094
Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients.
journal of clinical investigation
2014; 124 (9): 4082-4092
BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome. METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated. RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5-57+) months and OS of 20 (range 13-57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG. CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT. TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669. FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.
View details for DOI 10.1172/JCI76739
View details for PubMedID 25105369
View details for PubMedCentralID PMC4151207
A case of malignant peripheral nerve sheath tumor of the hypoglossal nerve after stereotactic radiosurgery treatment.
Journal of neurological surgery reports
2014; 75 (1): e42-6
Objectives Hypoglossal schwannomas are rare. Surgical resection has been the standard treatment modality. Radiosurgery has been increasingly used for treatment. Radiation-associated secondary malignancy/malignant transformation has not been documented in the literature for the treatment of nonvestibular schwannomas. Setting The patient was a 52-year-old man with an enlarging high cervical/skull base lesion 8.5 years after CyberKnife treatment of a presumed vagal schwannoma. A decision was made for surgical resection, and the tumor was found to originate from the hypoglossal nerve intraoperatively. Final pathology diagnosis was malignant peripheral nerve sheath tumor. Results Patient had a gross total resection. Three months after resection, he received fractionated radiation of 50 Gy in 25 fractions and a boost gamma knife radiosurgery of 10 Gy to the 50% isodose surface. He remained tumor free on repeat magnetic resonance imaging 9 months after the resection. Conclusion Although extremely rare, radiation treatment of nonvestibular schwannomas can potentially cause malignant transformation.
View details for DOI 10.1055/s-0033-1358797
View details for PubMedID 25083387
View details for PubMedCentralID PMC4110120
Invasion and proliferation kinetics in enhancing gliomas predict IDH1 mutation status.
2014; 16 (6): 779-786
Glioblastomas with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a better prognosis than gliomas with wild-type IDH1.Here we compare the IDH1 mutational status in 172 contrast-enhancing glioma patients with the invasion profile generated by a patient-specific mathematical model we developed based on MR imaging.We show that IDH1-mutated contrast-enhancing gliomas were relatively more invasive than wild-type IDH1 for all 172 contrast-enhancing gliomas as well as the subset of 158 histologically confirmed glioblastomas. The appearance of this relatively increased, model-predicted invasive profile appears to be determined more by a lower model-predicted net proliferation rate rather than an increased model-predicted dispersal rate of the glioma cells. Receiver operator curve analysis of the model-predicted MRI-based invasion profile revealed an area under the curve of 0.91, indicative of a predictive relationship. The robustness of this relationship was tested by cross-validation analysis of the invasion profile as a predictive metric for IDH1 status.The strong correlation between IDH1 mutation status and the MRI-based invasion profile suggests that use of our tumor growth model may lead to noninvasive clinical detection of IDH1 mutation status and thus lead to better treatment planning, particularly prior to surgical resection, for contrast-enhancing gliomas.
View details for DOI 10.1093/neuonc/nou027
View details for PubMedID 24832620
View details for PubMedCentralID PMC4022227
A Case of Bone-Only Extraneural Metastatic WHO Grade II Oligodendroglioma
LIPPINCOTT WILLIAMS & WILKINS. 2014: 632–33
View details for Web of Science ID 000336732100189
Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes
2014; 15 (12)
The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes to assay both point mutations and gene amplifications within spatially distinct regions of 14 glial tumors.We find evidence of regional mutational heterogeneity in multiple tumors, including mutations in TP53 and RB1 in an anaplastic oligodendroglioma and amplifications in PDGFRA and KIT in two glioblastomas (GBMs). Immunohistochemistry confirms heterogeneity of TP53 mutation and PDGFRA amplification. In all, 3 out of 14 glial tumors surveyed have evidence for heterogeneity for clinically relevant mutations.Our results underscore the need to sample multiple regions in GBM and other glial tumors when devising personalized treatments based on genomic information, and furthermore demonstrate the importance of measuring both point mutation and copy number alteration while investigating genetic heterogeneity within cancer samples.
View details for DOI 10.1186/s13059-014-0530-z
View details for Web of Science ID 000346609500010
View details for PubMedCentralID PMC4272528
Teaching NeuroImages: Sacral spine chloroma
2013; 81 (11): E87–E88
A 23-year-old man with recurrent acute myeloid leukemia (AML) underwent successful reinduction and was judged posttherapy to be in complete remission. Soon thereafter, he complained of pain in his left buttock radiating into his left posterior thigh. Neurologic examination was unremarkable. Radiographic evaluation demonstrated a left S2 lesion suggestive of a nerve sheath tumor (figure 1). An open biopsy was performed that revealed a chloroma pathologically (figure 2), sometimes referred to as a myeloid sarcoma.(1,2) Most chloromas are found in patients with recurrent AML and are overwhelmingly intracranial.(1) Infrequently, chloromas are paraspinal, and in this location present with epidural spinal cord compression.(2) Intraspinal invasion by a chloroma is rare. Systemic evaluation confirmed recurrent AML, for which he was successfully treated with reinduction and whole-body irradiation followed by an allogeneic transplant. He is currently disease-free and neurologically asymptomatic 1 year posttransplant.
View details for PubMedID 24019392
View details for PubMedCentralID PMC3888196
Two patients with primary sellar leiomyomas, a rare entity
JOURNAL OF CLINICAL NEUROSCIENCE
2013; 20 (6): 897-901
Leiomyomas are benign smooth muscle tumors commonly found in the genitourinary or gastrointestinal tracts. Rarely, they present as primary intracranial extra-axial brain tumors. Most of these lesions have been described in immunocompromised patients, but have been found very rarely in the immunocompetent patient. We present two patients with sporadic sellar leiomyomas. The first patient is a 25-year-old woman who presented with a 2-year history of amenorrhea and a heterogeneous lesion. The second is a 53-year-old man who presented with headaches and progressive panhypopituitarism, and a large cystic lesion expanding the sella. In both patients, transnasal transphenoidal surgery was performed for resection of the tumor. We review the intraoperative findings, neuropathology and immunohistochemistry and the clinical follow-up. A literature search, which revealed only two prior reported cases of sporadic sellar leiomyomas, and subsequent review led us to conclude that the natural history of sellar leiomyomas relates to the immune status of the patient and that these tumors may cause pituitary dysfunction through infiltration of the gland, mass effect and compression, or even potentially as a byproduct of prolactin secretion intrinsic to the tumor itself. Complete surgical resection of these infiltrating tumors may not be advisable when pituitary function is intact. Long-term endocrine follow-up in these patients is advised.
View details for DOI 10.1016/j.jocn.2012.07.001
View details for Web of Science ID 000320352800030
Contractility and kinetics of human fetal and human adult skeletal muscle
JOURNAL OF PHYSIOLOGY-LONDON
2013; 591 (12): 3049-3061
Little is known about the contraction and relaxation properties of fetal skeletal muscle, and measurements thus far have been made with non-human mammalian muscle. Data on human fetal skeletal muscle contraction are lacking, and there are no published reports on the kinetics of either fetal or adult human skeletal muscle myofibrils. Understanding the contractile properties of human fetal muscle would be valuable in understanding muscle development and a variety of muscle diseases that are associated with mutations in fetal muscle sarcomere proteins. Therefore, we characterised the contractile properties of developing human fetal skeletal muscle and compared them to adult human skeletal muscle and rabbit psoas muscle. Electron micrographs showed human fetal muscle sarcomeres are not fully formed but myofibril formation is visible. Isolated myofibril mechanical measurements revealed much lower specific force, and slower rates of isometric force development, slow phase relaxation, and fast phase relaxation in human fetal when compared to human adult skeletal muscle. The duration of slow phase relaxation was also significantly longer compared to both adult groups, but was similarly affected by elevated ADP. F-actin sliding on human fetal skeletal myosin coated surfaces in in vitro motility (IVM) assays was much slower compared with adult rabbit skeletal myosin, though the Km(app) (apparent (fitted) Michaelis-Menten constant) of F-actin speed with ATP titration suggests a greater affinity of human fetal myosin for nucleotide binding. Replacing ATP with 2 deoxy-ATP (dATP) increased F-actin speed for both groups by a similar amount. Titrations of ADP into IVM assays produced a similar inhibitory affect for both groups, suggesting ADP binding may be similar, at least under low load. Together, our results suggest slower but similar mechanisms of myosin chemomechanical transduction for human fetal muscle that may also be limited by immature myofilament structure.
View details for DOI 10.1113/jphysiol.2013.252650
View details for Web of Science ID 000320398000008
View details for PubMedID 23629510
View details for PubMedCentralID PMC3832119
Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies
2013; 136: 508-521
The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
View details for DOI 10.1093/brain/aws344
View details for Web of Science ID 000314995200020
View details for PubMedCentralID PMC3572924
Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy
2012; 11 (6): 1027-1035
Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3- and 18-month-old mice into 3- and 20-month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ≤ 0.0001) median survival in both 3-month (37.5 vs. 83 days) and 20-month (38 vs. 67 days) hosts, indicating that age-dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF-1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age-dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age-dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas.
View details for DOI 10.1111/acel.12004
View details for Web of Science ID 000311113500012
View details for PubMedID 22958206
View details for PubMedCentralID PMC3504614
INVASION AND PROLIFERATION KINETICS PREDICT IDH-1 MUTATION IN CONTRAST-ENHANCING GLIOMAS
17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO)
OXFORD UNIV PRESS INC. 2012: 131–131
View details for Web of Science ID 000310971300521
MODELING THE IMPACT OF CELL OF ORIGIN AND HOST AGING ON CLINICAL FEATURES OF GLIOMA MALIGNANCY
17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO)
OXFORD UNIV PRESS INC. 2012: 164–164
View details for Web of Science ID 000310971300647
Radiation Necrosis: Relevance with Respect to Treatment of Primary and Secondary Brain Tumors
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
2012; 12 (3): 276-285
Radiation injury to the central nervous system (CNS) manifests in multiple forms and is divided into three categories termed acute, early-delayed, and late-delayed injury patterns. Late-delayed radiation injury, primarily manifesting as leukoencephalopathy or radiation necrosis, is often progressive and may have a negative impact on quality of life. Radiation injury is believed to be a consequence of cell membrane and DNA injury with a pathological expression as vascular injury, depletion of oligodendroglial progenitor cells, and failure of cell-cell interactions that constitute the cellular network of the CNS. In addition, radiation injury results in activation of the inflammatory cascade with perturbation of cytokines, production of reactive oxygen species and vascular endothelial growth factor. Medical treatment of CNS radiation injury and in particular radiation necrosis remains problematic as there is a paucity of clinical trial data to inform treatment decisions, and aside from surgery and corticosteroids only bevacizumab appears to have a compelling therapeutic role.
View details for DOI 10.1007/s11910-012-0258-7
View details for Web of Science ID 000303515500007
View details for PubMedID 22350279
Clinicopathologic Assay of 15 Tumor Resections in a Family with Neurofibromatosis Type 2
JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE
2012; 73 (2): 90-103
The objective of this study is the management of multiple family members with multiple neurofibromatosis type 2 (NF2) related tumors of the skull base that can be challenging, on purely technical, decision-making, and ethical levels. These issues are addressed in this manuscript based on an experience treating an unique large family with NF2. A retrospective chart review was performed, reviewing clinical, radiological, surgical, and pathological data. A unique family of 17 siblings, whose father was the proband as a sporadic mutation is reported. Over a 4-month period, five of eight affected siblings underwent 12 procedures for resection of 15 different NF2-related tumors. This single family experience of NF2-related skull base tumors underscores the importance of preservation of function and quality of life as the major determinants of treatment success.
View details for DOI 10.1055/s-0032-1301394
View details for Web of Science ID 000321267800002
View details for PubMedID 23543817
View details for PubMedCentralID PMC3424622
Multiplex Immunoassays of Peptide Hormones Extracted from Formalin-Fixed, Paraffin-Embedded Tissue Accurately Subclassify Pituitary Adenomas
2012; 58 (2): 366-374
The current gold standard for diagnostic classification of many solid-tissue neoplasms is immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded (FFPE) tissue. Although IHC is commonly used, there remain important issues related to preanalytic variability, nonstandard methods, and operator bias that may contribute to clinically significant error. To increase the quantitative accuracy and reliability of FFPE tissue-based diagnosis, we sought to develop a clinical proteomic method to characterize protein expression in pathologic tissue samples rapidly and quantitatively.We subclassified FFPE tissue from 136 clinical pituitary adenoma samples according to hormone translation with IHC and then extracted tissue proteins and quantified pituitary hormones with multiplex bead-based immunoassays. Hormone concentrations were normalized and compared across diagnostic groups. We developed a quantitative classification scheme for pituitary adenomas on archived samples and validated it on prospectively collected clinical samples.The most abundant relative hormone concentrations differentiated sensitively and specifically between IHC-classified hormone-expressing adenoma types, correctly predicting IHC-positive diagnoses in 85% of cases overall, with discrepancies found only in cases of clinically nonfunctioning adenomas. Several adenomas with clinically relevant hormone-expressing phenotypes were identified with this assay yet called "null" by IHC, suggesting that multiplex immunoassays may be more sensitive than IHC for detecting clinically meaningful protein expression.Multiplex immunoassays performed on FFPE tissue extracts can provide diagnostically relevant information and may exceed the performance of IHC in classifying some pituitary neoplasms. This technique is simple, largely amenable to automation, and likely applicable to other diagnostic problems in molecular pathology.
View details for DOI 10.1373/clinchem.2011.170613
View details for Web of Science ID 000300303700009
View details for PubMedID 22205691
CYSTIC GLIOMAS ARE QUANTITATIVELY LESS BIOLOGICALLY AGGRESSIVE
16th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO)/AANS/CNS Section on Tumors
OXFORD UNIV PRESS INC. 2011: 65–65
View details for Web of Science ID 000297026600266
Pseudoprogression: Relevance With Respect to Treatment of High-Grade Gliomas
CURRENT TREATMENT OPTIONS IN ONCOLOGY
2011; 12 (3): 240-252
The post-treatment imaging assessment of high-grade gliomas remains challenging notwithstanding the increased utilization of advanced MRI and PET imaging. Several post-treatment imaging entities are recognized including: late-delayed radiation injury, including radionecrosis mimicking tumor progression; early-delayed (within 6 months of temozolomide-based chemoradiation) post-treatment radiographic changes, herein referred to as pseudoprogression (the subject of this review); early post-treatment changes following local glioma therapy (i.e. biodegradable BCNU wafer implantation or stereotactic radiotherapy); and pseudoresponse, seen following treatment with angiogenic inhibition based therapy such as bevacizumab. A literature review searched specifically for "pseudoprogression" within the last 5 years (2005-2010). Approximately 24 recent papers were identified and reviewed in detail. Eight small population-based studies demonstrate 26-58% (median 49%) of glioblastoma patients treated with chemoradiotherapy manifest early disease progression at first post-radiotherapy imaging. Patients with early radiographic disease progression continued on planned therapy, and a median of 38% (range 28-66%) showed radiographic improvement or stabilization and were defined retrospectively as manifesting pseudoprogression. In conclusion, pseudoprogression is a frequent early post-treatment imaging change that at present is not easily differentiated from tumor progression by anatomic or physiologic brain imaging. Consequently, an operational definition of pseudoprogression has been adopted by the Response Assessment in Neuro-Oncology Working Group wherein either the index (i.e. target) lesion stabilizes or diminishes in size on continued post-radiation (temozolomide) therapy as determined by follow-up radiologic imaging.
View details for DOI 10.1007/s11864-011-0157-1
View details for Web of Science ID 000293407200003
View details for PubMedID 21594589
HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells
2011; 71 (13): 4640-4652
Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions.
View details for DOI 10.1158/0008-5472.CAN-10-3320
View details for Web of Science ID 000292287300033
View details for PubMedID 21712410
View details for PubMedCentralID PMC3129496
Parahippocampal Corpora Amylacea: Case Report
2010; 66 (6): E1206-U340
Corpora amylacea (CA) normally accumulate within perivascular, subpial, and subependymal astrocytic processes. CA are associated with a number of conditions including normal aging, hippocampal sclerosis associated with temporal lobe epilepsy, multiple sclerosis, Lafora-type progressive myoclonic epilepsy, and adult polyglucosan body disease. Reports of massive localized accumulation of CA in the brain outside of these conditions are rare.A 49-year-old woman, with a long-standing history of migraine headaches, presented to her primary care provider for increased headache duration. Brain magnetic resonance imaging (MRI) revealed a left parahippocampal lesion, suggestive of low-grade glioma.Given the MRI suggestive of left parahippocampal glioma, left-sided frontotemporal craniotomy was performed for resection of the lesion. Specimens obtained during the operation revealed focal high-density accumulation of CA with no evidence of neoplasm, ischemia, or hypoxic injury.This case illustrates the possibility that localized high-density CA accumulation can present as an intrinsic lesion on brain MRI. CA should be included in the differential diagnosis for patients presenting with brain MRI suggestive of nonenhancing space-occupying lesions.
View details for DOI 10.1227/01.NEU.0000369196.94664.4E
View details for Web of Science ID 000278006200057
View details for PubMedID 20495392
A Case of High-Grade Undifferentiated Sarcoma after Surgical Resection and Stereotactic Radiosurgery of a Vestibular Schwannoma
SKULL BASE-AN INTERDISCIPLINARY APPROACH
2010; 20 (3): 179-183
Stereotactic radiosurgery has become a more frequently used treatment modality for vestibular schwannomas; a few reports of malignant transformation and/or radiation-associated tumors have surfaced. The majority of these reported cases were in patients with underlying neurofibromatosis. The authors report a case of a 74-year-old man with rapid progression of a cerebellar-pontine angle tumor 14 years after surgical resection of a vestibular schwannoma (VS) from the same site, and 6 years after stereotactic radiosurgery. A pathological study of the recent tumor showed a high-grade spindle cell neoplasm that bore no resemblance to the initial schwannoma. The patient had no diagnosis of neurofibromatosis. Secondary malignancy occurred in a non-neurofibromatosis patient 6 years after stereotactic radiosurgery. It is our belief that documentation of such cases will provide important evidence that helps evaluate the long-term effect of radiosurgery for VS. Such observations can influence clinical decisions regarding the choice of treatment modalities.
View details for DOI 10.1055/s-0029-1242195
View details for Web of Science ID 000276538500007
View details for PubMedID 21318035
View details for PubMedCentralID PMC3037102
Quantitative Proteomic Analysis of Oligodendrogliomas With and Without 1p/19q Deletion
JOURNAL OF PROTEOME RESEARCH
2010; 9 (5): 2610-2618
Approximately 50-80% of oligodendrogliomas demonstrate a combined loss of chromosome 1p and 19q. Chromosome 1p/19q deletion, appearing early in tumorigenesis, is associated with improved clinical outcomes, including response to chemotherapy and radiation. Although many hypotheses have been proposed, the molecular mechanisms underlying improved clinical outcomes with 1p/19q deletion in oligodendrogliomas have not been characterized fully. To investigate the molecular differences between oligodendrogliomas, we employed an unbiased proteomic approach using microcapillary liquid chromatography mass spectrometry, along with a quantitative technique called isotope-coded affinity tags, on patient samples of grade II oligodendrogliomas. Following conventional biochemical separation of pooled tumor tissue from five samples of undeleted and 1p/19q deleted grade II oligodendrogliomas into nuclei-, mitochondria-, and cytosol-enriched fractions, relative changes in protein abundance were quantified. Among the 442 total proteins identified, 163 nonredundant proteins displayed significant changes in relative abundance in at least one of the three fractions between oligodendroglioma with and without 1p/19q deletion. Bioinformatic analyses of differentially regulated proteins supported the potential importance of metabolism and invasion/migration to the codeleted phenotype. A subset of altered proteins, including the pro-invasive extracellular matrix protein BCAN, was further validated by Western blotting as candidate markers for the more aggressive undeleted phenotype. These studies demonstrate the utility of proteomic analysis to identify candidate biological motifs and molecular mechanisms that drive differential malignancy related to 1p19q phenotypes. Future analysis of larger patient samples are warranted to further refine biomarker panels to predict biological behavior and assist in the identification of deleted gene products that define the 1p/19q phenotype.
View details for DOI 10.1021/pr100054v
View details for Web of Science ID 000277353200049
View details for PubMedID 20337498
View details for PubMedCentralID PMC3119493
Histopathological changes in brain arteriovenous malformations after embolization using Onyx or N-butyl cyanoacrylate Laboratory investigation
JOURNAL OF NEUROSURGERY
2009; 111 (1): 105-113
The aim of this study was to analyze the histopathological changes in a consecutive series of 32 patients with brain arteriovenous malformations that were resected after undergoing endovascular embolization (22 using Onyx and 10 using N-butyl cyanoacrylate [NBCA]).Selections from fixed paraffin-embedded specimens were stained for histological examination with H & E and Verhoeff-van Gieson stain. Lipid dye Oil Red O was used to stain vessel specimens that were embolized using NBCA. Specimens were evaluated for the presence of embolic agent, inflammation, angionecrosis, and evidence of recanalization. These results were correlated with the time interval between the bleeding, embolization, and resection.The smallest vessel occluded by the embolic agent was 5 microm in the Onyx group and 20 microm in the NBCA group. There was evidence of vascular or perivascular inflammation in 20 (90.9%) of 22 and 9 (90%) of 10 specimens after Onyx and NBCA embolization, respectively. Chronic foreign-body giant cells were observed in 12 (54.5%) of 22 specimens after Onyx embolization, but were absent in specimens after NBCA embolization. Angionecrosis of the embolized vessel was observed in 13 (59.1%) of 22 specimens and in 4 (40%) of 10 specimens after Onyx and NBCA embolization, respectively. There was evidence of recanalization in Onyx embolized vessels in 4 (18.2%) of 22 specimens, and there was no evidence of recanalization after NBCA embolization.Onyx penetrates much smaller vessels than NBCA. Inflammation occurs with both embolic agents at equal frequency. Evidence of chronic foreign-body giant cells and recanalization after Onyx embolization shows a long-standing reaction to Onyx and raises questions about the permanence of occlusion after Onyx embolization.
View details for DOI 10.3171/2008.12.JNS08441
View details for Web of Science ID 000267383900023
View details for PubMedID 19326974
A patient with Huntington's disease and long-surviving fetal neural transplants that developed mass lesions
2009; 117 (3): 329-338
Transplantation of human fetal neural tissue into adult neostriatum is an experimental therapy for Huntington's disease (HD). Here we describe a patient with HD who received ten intrastriatal human fetal neural transplants and, at one site, an autologous sural nerve co-graft. Although initially clinically stable, she developed worsening asymmetric upper motor neuron symptoms in addition to progression of HD, and ultimately died 121 months post transplantation. Eight neural transplants, up to 2.9 cm, and three ependymal cysts, up to 2.0 cm, were identified. The autologous sural nerve co-graft was found adjacent to the largest mass lesion, which, along with the ependymal cyst, exhibited pronounced mass effect on the internal capsules bilaterally. Grafts were composed of neurons and glia embedded in disorganized neuropil; robust Y chromosome labeling was present in a subset of grafts and cysts. The graft-host border was discrete, and there was no evidence of graft rejection or HD pathologic changes within donor neurons. This report, for the first time, highlights the potential for graft overgrowth in a patient receiving fetal neural transplantation.
View details for DOI 10.1007/s00401-008-0465-0
View details for Web of Science ID 000263540500010
View details for PubMedID 19057918
View details for PubMedCentralID PMC2676786
The effects of binge alcohol exposure in the 2nd trimester on the estimated density of cerebral microvessels in near-term fetal sheep
2008; 1231: 75-80
Heavy fetal alcohol exposure is associated with a spectrum of neurological abnormalities, although the mechanism of injury is largely unknown. We previously reported attenuated cerebral blood flow response to hypoxia in fetal and newborn sheep which were exposed to alcohol earlier in pregnancy. One possible mechanism for this effect of alcohol on the developing cerebral vasculature is a decrease in cerebral microvessel density, similar to its effect on developing neurons. Therefore, we tested the hypothesis that prenatal alcohol exposure decreases cerebral microvessel density. Pregnant ewes received intravenous infusions of ethanol or saline during days 60-84 of gestation (term=150 days) and at 125 days of gestation we obtained the fetal brains for study. We immunohistochemically labeled vessels of the left cerebral forebrain hemispheres with antibody to endothelial nitric oxide synthase and then obtained unbiased stereological estimates of cerebral microvessel density using a modified optical fractionator method. We studied 20 fetal brains of which 9 were alcohol-exposed, 11 were saline-controls, and all were products of a twin gestation. Although brain and body weights were not different between groups, the alcohol-exposed group had significantly lower brain weight as a percentage of body weight. Estimates of cerebral microvessel density were not significantly different between alcohol-exposed and saline-control groups: 12.7+/-8.7 and 9.1+/-2.8 microvessels per mm(3), respectively (mean+/-SD, p=0.32). Since there is no change in estimated cerebral microvessel density after prenatal alcohol exposure, we conclude that decreased cerebral microvessel density is not a likely explanation for attenuated cerebral blood flow in response to hypoxia.
View details for DOI 10.1016/j.brainres.2008.06.125
View details for Web of Science ID 000259887800008
View details for PubMedID 18657528
View details for PubMedCentralID PMC2583365
Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with Onyx: Single-center experience and technical nuances
2008; 62 (6): 1213-1225
To report our experience with the treatment of brain arteriovenous malformations (AVM) with microsurgical resection after embolization with Onyx liquid embolic agent (eV3, Irvine, CA).Between August 2005 and December 2006, 28 patients were treated by the same surgical-endovascular team. Twenty-eight AVMs were embolized preoperatively in 55 sessions (71 pedicles) with Onyx. We analyzed the AVM size, volume, number of embolization sessions, degree of preoperative obliteration, time to embolization and resection after the bleed, intraprocedural complications, intraoperative blood loss, other complications, and postoperative outcome at 6 months. Technical nuances of the embolization and surgical resection of the embolized AVMs are illustrated in illustrative cases.The average size and volume of AVMs treated with Onyx were 3.56 cm (largest, 7.6 cm), and 13.03 ml, respectively. The average Spetzler-Martin grade was 2.75. The average preoperative volumetric obliteration was 74.1%. The average blood loss during resection of embolized AVMs was 348 ml. Complications related to embolization were stuck microcatheter (two patients), proximal vessel perforation (one patient), and anterior choroidal territory stroke (one patient). Surgical complications included wound infection (one patient), residual AVM nidus (one patient), normal pressure perfusion breakthrough with worsening of neurological deficit caused by embolization (one patient), and new-onset motor deficits in five patients. At the time of the 6-month follow-up examination, four patients with new-onset motor deficits had recovered completely or nearly completely, and one patient was disabled. One patient died, never recovering from the initial poor condition due to the bleed. Pathological examination of resected AVMs showed angionecrosis in 42.9%, foreign body giant cells in 39.3%, and evidence of recanalization of Onyx-embolized vessels in 14.3% of specimens.Multimodality treatment with microsurgery is safe and effective after embolization with Onyx. High occlusion rates and low complication rates were observed after Onyx embolization and were comparable to those in previous reports. Superselective intranidal or perinidal catheter positions and slow, controlled injections that protect the draining veins make the therapy safe even in complex AVMs and critical locations. We recommend resection of the AVM despite apparently complete embolization with Onyx. Team work and coordination between the surgeon and the interventional neuroradiologist are important to achieve a good outcome.
View details for Web of Science ID 000258226500011
View details for PubMedID 18824988
Graft overgrowth and ependymal cyst formation despite initial clinical improvement in a Huntington's patient who received fetal neural transplants
15th Annual Meeting of the American-Society-for-Neural-Therapy-and-Repair
COGNIZANT COMMUNICATION CORP. 2008: 469–69
View details for Web of Science ID 000255930500047
The effect of binge fetal alcohol exposure on the number of vasoactive intestinal peptide-producing neurons in fetal sheep brain
2008; 30 (4): 276-284
Previously we demonstrated that fetal alcohol exposure attenuates hypoxic cerebral vasodilation in fetal and neonatal sheep. One mechanism may be altered expression of brain vasoactive substances. We hypothesized that early fetal alcohol exposure alters the number of fetal neurons expressing vasoactive intestinal peptide (VIP), a potent cerebral vasodilator. Thirteen pregnant ewes received daily i.v. infusions of alcohol (1.5 g/kg) or saline on days 30-54 of gestation (term = 145 days). Fourteen fetal brains (6 alcohol-exposed, 8 saline control) were obtained on gestational day 126. Using unbiased stereology, we counted immunohistochemically-labeled VIP neurons in one half of each forebrain with an optical fractionator. The total NeuN-labeled neurons were similarly counted. Alcohol-exposed fetal sheep brains had fewer VIP-immunopositive neurons per hemisphere, 14.6 x 10(6), compared to saline controls, 19.8 x 10(6). The total neuron number was not different, 1.19 x 10(9) versus 1.23 x 10(9) respectively, indicating a selective decrease in VIP neurons as a result of alcohol exposure. In sheep, alcohol exposure early in gestation is associated with fewer VIP-producing neurons later in gestation compared to saline controls; therefore, alcohol-related changes in the number of VIP-expressing neurons may be responsible in part for the attenuated hypoxic cerebral vasodilation described in fetal and neonatal sheep exposed to alcohol earlier in gestation.
View details for DOI 10.1159/000110349
View details for Web of Science ID 000255586600007
View details for PubMedID 17960055
- Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity (vol 74, pg 6108, 2006) INFECTION AND IMMUNITY 2007; 75 (3): 1540-1540
Epidermal growth factor receptor and p53 expression in a large series of gliosarcomas: A tissue microarray study
96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology
NATURE PUBLISHING GROUP. 2007: 300A–300A
View details for Web of Science ID 000244922402214
Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity
INFECTION AND IMMUNITY
2006; 74 (11): 6108-6117
The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant. We find that zebrafish are exquisitely susceptible to M. marinum strain M. Intraperitoneal injection of five organisms produces persistent granulomatous tuberculosis, while the injection of approximately 9,000 organisms leads to acute, fulminant disease. Bacterial burden, extent of disease, pathology, and host mortality progress in a time- and dose-dependent fashion. Zebrafish tuberculous granulomas undergo caseous necrosis, similar to human tuberculous granulomas. In contrast to mammalian tuberculous granulomas, zebrafish lesions contain few lymphocytes, calling into question the role of adaptive immunity in fish tuberculosis. However, like rag1 mutant mice infected with M. tuberculosis, we find that rag1 mutant zebrafish are hypersusceptible to M. marinum infection, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity. We confirm the previous finding that M. marinum DeltaRD1 mutants are attenuated in adult zebrafish and extend this finding to show that DeltaRD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with DeltaRD1 attenuation in zebrafish embryos is ongoing during adult infection.
View details for DOI 10.1128/IAI.00887-06
View details for Web of Science ID 000241600500010
View details for PubMedID 17057088
View details for PubMedCentralID PMC1695491
Spinal intramedullary histoplasmosis as the initial presentation of human immunodeficiency virus infection: case report.
2006; 59 (5): E1146-?
Spinal intramedullary histoplasmosis is an extremely rare condition. We report a case of isolated intramedullary histoplasmosis as the initial manifestation of human immunodeficiency virus (HIV) infection.A 27-year-old man presented with a rapidly progressive paraparesis. Magnetic resonance imaging scans revealed an enhancing lesion at C7-T1 with edema extending as far as the cervicomedullary junction. He improved with steroid medications.The patient underwent laminectomy and biopsy of the lesion. The diagnosis of histoplasmosis was made by histology, culture, and polymerase chain reaction identification of fungal deoxyribonucleic acid. The patient did not have disseminated histoplasmosis. Subsequent to the biopsy, the patient was discovered to have HIV infection.The isolated spinal histoplasmosis lesion thus represented the initial presentation of HIV infection. Management of the case and diagnostic issues are discussed.
View details for PubMedID 17143208
Effects of first trimester binge alcohol exposure on developing white matter in fetal sheep
2006; 59 (4): 560-564
Heavy prenatal alcohol exposure is associated with neurodevelopmental abnormalities. Neuropathologic and neuroimaging studies have shown a wide range of structural problems, including abnormal neuronal migration and volume reduction in specific brain regions, including white matter. We identified foci of significant fetal white matter microglia-macrophage immunoreactivity in a "binge" model of early prenatal alcohol exposure in sheep. Ewes of alcohol-exposed fetuses received daily 90 min alcohol (1.5 gm/kg i.v.) infusions at 30-60 d gestation (term = 147 d). Ewes of control fetuses received same volume infusions of normal saline intravenously. Near-term (125 d gestation) fetal brains were labeled with microglia-macrophages using HAM56 antibody. We quantified dense immunoreactive cellular regions across sections and anatomical locations using computer-assisted microscopy and quantitative morphometry. The proportional HAM56-positive area in cortical white matter was greater in the alcohol-exposed fetuses (1.6%) compared with the saline controls (0.7%). The areas were localized to the frontal gyral white matter, temporal gyral white matter, optic radiation, and others (corpus callosum, septum pellucidum, fasciculus subcallosus, and external capsule), with a greater distribution in the gyral white matter. The greater area of macrophage-rich regions in near-term fetal sheep brain suggests a vulnerability of developing white matter that is enhanced by early alcohol exposure.
View details for DOI 10.1203/01.pdr.0000203102.01364.de
View details for Web of Science ID 000236359200013
View details for PubMedID 16549529
Clinical utility of somatiostatin receptor scintigraphic imaging (Octreoscan) in esthesioneuroblastoma: A case study and survey of somatostatin receptor subtype expression
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
2006; 28 (4): 305-312
For tumors that express somatostatin receptors (SSTR), radiolabeled somatostatin analogs, such as 111In-pentetreotide, can demonstrate the presence of tumor by radioligand uptake using somatostatin receptor scintigraphy (SRS). The use of 111In-pentetreotide for SRS depends on the specific high affinity of octreotide for SSTR subtypes 2, 3, and 5. Of these, SSTR2 has the greatest affinity for octreotide and the greatest relevance for tumor detection with Octreoscan imaging. Discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery is often difficult, but in a case of recurrent esthesioneuroblastoma (ENB) we found the use of Octreoscan imaging clinically useful. To better define the general relevance of this imaging technique in this setting, we analyzed SSTR subtype expression in a panel of ENB tumors.The case history and correlations between MRI and 111In-pentetreotide SRS of a patient with recurrent ENB were reviewed. The expression pattern of the SSTR subtypes in a panel of ENB tumors was then analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) to better define the potential of more general use of Octreoscan for imaging ENB. To correlate SSTR2 protein expression with 111In-pentetreotide uptake, immunohistochemistry to detect SSTR2 was performed on tumor samples from regions of increased uptake on Octreoscan.The SSTR2 message was expressed at high levels in all five ENB tumor samples, and either SSTR2 protein or histologic findings typical for ENB were found in all tumor tissue obtained from regions of increased 111In-pentetreotide uptake. Furthermore, Octreoscan imaging in this case proved useful in clinical decision making.The expression pattern of SSTR2 and the specificity of the Octreoscan for regions of active tumor growth support further investigation of the utility of Octreoscan imaging in the diagnosis and surveillance of ENB. Recent advances in novel therapies based on SSTR ligand binding also provide the rationale to consider such novel therapeutic approaches in patients with ENB.
View details for DOI 10.1002/hed.20356
View details for Web of Science ID 000236536300003
View details for PubMedID 16470879
NeuN expression correlates with reduced mitotic index of neoplastic cells in central neurocytomas
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
2005; 31 (4): 429-438
In the developing brain, neuronal differentiation is associated with permanent exit from the mitotic cycle. This raises the possibility that neuronal differentiation may suppress proliferative activity, even in neoplastic cells. As a first step towards understanding the relation between neuronal differentiation and mitotic cycling in brain tumours, we studied the expression of NeuN (a neuronal marker) and Ki-67 (a mitotic marker) by double-labelling immuno-fluorescence in 16 brain tumours with neuronal differentiation. The tumours included a series of 11 central neurocytomas, and five single cases of other tumour types. In the central neurocytomas, NeuN(+) cells had a 15-fold lower Ki-67 labelling index, on average, than did NeuN(-) cells (P < 0.01). In the other tumours (one extraventricular neurocytoma, one desmoplastic medulloblastoma, one olfactory neuroblastoma, one ganglioglioma and one anaplastic ganglioglioma), the Ki-67 labelling index was always at least fourfold lower in NeuN(+) cells than in NeuN(-) cells. These results indicate that neuronal differentiation is associated with a substantial decrease of proliferative activity in neoplastic cells of central neurocytomas, and suggest that the same may be true across diverse types of brain tumours. However, tumours with extensive neuronal differentiation may nevertheless have a high overall Ki-67 labelling index, if the mitotic activity of NeuN(-) cells is high. The correlation between NeuN expression and reduced mitotic activity in neurocytoma cells is consistent with the hypothesis that neuronal differentiation suppresses proliferation, but further studies will be necessary to determine causality and investigate underlying mechanisms.
View details for DOI 10.1111/j.1365-2990.2005.00665.x
View details for Web of Science ID 000231015400010
View details for PubMedID 16008827
Quantitative proteomic analysis of oligodendrogliomas with and without ip/19q deletion.
81st Annual Meeting of the American-Association-of-Neuropathologists
LIPPINCOTT WILLIAMS & WILKINS. 2005: 438–38
View details for Web of Science ID 000228945800040
Aberrant neuronal-glial differentiation in Taylor-type focal cortical dysplasia (type IIA/B)
2005; 109 (5): 519-533
Focal cortical dysplasia (FCD) type IIA/B (Taylor type) is a malformation of cortical development characterized by laminar disorganization and dysplastic neurons. FCD IIA and FCD IIB denote subtypes in which balloon cells are absent or present, respectively. The etiology of FCD IIA/B is unknown, but previous studies suggest that its pathogenesis may involve aberrant, mixed neuronal-glial differentiation. To investigate whether aberrant differentiation is a consistent phenotype in FCD IIA/B, we studied a panel of neuronal and glial marker antigens in a series of 15 FCD IIB cases, and 2 FCD IIA cases. Double-labeling immunofluorescence and confocal imaging revealed that different combinations of neuronal and glial antigens were co-expressed by individual cells in all cases of FCD IIA/B, but not in control cases of epilepsy due to other causes. Co-expression of neuronal and glial markers was most common in balloon cells, but was also observed in dysplastic neurons. The relative expression of neuronal and glial antigens varied over a broad range. Microtubule-associated protein 1B, an immature neuronal marker, was more frequently co-expressed with glial antigens than were mature neuronal markers, such as neuronal nuclear antigen. Our results indicate that aberrant neuronal-glial differentiation is a consistent and robust phenotype in FCD IIA/B, and support the hypothesis that developmental defects of neuronal and glial fate specification play an important role in its pathogenesis.
View details for DOI 10.1007/s00401-005-1005-9
View details for Web of Science ID 000229803200009
View details for PubMedID 15877232
Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat
2005; 128: 174-188
We recently described an in vivo model of post-traumatic epilepsy (PTE) in the rat where chronic spontaneous recurrent seizures appear following a single episode of fluid percussion injury (FPI). PTE, studied during the first 2 months post-injury, was focal and seizures originated predominantly from the frontal-parietal neocortex at or around the injury site. However, rarer bilateral seizures originating from a different and undefined focus were also observed. To shed light on the Posttraumatic Epileptogenic mechanisms and on the generation of bilateral seizures, we studied rats up to 7 months post-injury. In vivo paired epidural and depth-electrode recordings indicated that the anterior hippocampus evolves into an epileptic focus which initiates bilateral seizures. The rate of frontal-parietal seizures remained constant over time after 2 weeks post-injury, while the rate of hippocampal seizures greatly increased over time, suggesting that different mechanisms mediate neocortical and hippocampal post-traumatic epileptogenesis. Because of different temporal evolution of these foci, the epileptic syndrome was characterized by predominant frontal-parietal seizures early after injury, but by predominant mesio-temporal seizures at later time points. Pathological analysis demonstrated progressive hippocampal and temporal cortex pathology that paralleled the increase in frequency and duration of bilateral seizures. These results demonstrate that FPI-induced frontal-parietal epilepsy (FPE) progresses to mesial-temporal lobe epilepsy (MTLE) with dual pathology. These observations establish numerous similarities between FPI-induced and human PTE and further validate it as a clinically relevant model of PTE.
View details for DOI 10.1093/brain/awh337
View details for Web of Science ID 000226187800019
View details for PubMedID 15563512
View details for PubMedCentralID PMC2696356
Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat
22nd Annual National-Neurotrauma-Society Symposium
MARY ANN LIEBERT, INC. 2004: 1317–17
View details for Web of Science ID 000223962900221
Post-traumatic epilepsy following fluid percussion injury in the rat
2004; 127: 304-314
The lack of an adequate model of post-traumatic epilepsy (PTE), in which, similarly to the human condition, chronic spontaneous focal seizures follow a single episode of traumatic brain injury, has hampered the identification of clinically relevant epileptogenic mechanisms and the development of effective therapies. We studied the electrophysiological, behavioural and structural consequences of a clinically relevant model of closed head injury, the lateral fluid percussion injury (FPI), in the rat. We found that a single episode of severe FPI is sufficient to cause PTE. Chronic electrocorticography (ECoG) demonstrated spontaneous chronic seizures that were partial, originated from the neocortex at the site of injury, and progressively worsened and spread over time. The cases of epilepsy in the post-traumatic population increased over time following injury. Post-FPI epileptic rats exhibited pauses in their behaviour, facial automatisms and myoclonus at the time of epileptiform ECoG events. In vitro local field potential recordings demonstrated persistent hyperexcitability of the neocortex at and around the site of injury that was associated with intense glial reactivity. These results for the first time demonstrate persistent hyperexcitability of the injured neocortex and define a useful model for pathophysiological studies of basic mechanisms of spontaneous epileptogenesis and for preclinical screening of effective antiepileptogenic drugs.
View details for DOI 10.1093/brain/awh038
View details for Web of Science ID 000188389900007
View details for PubMedID 14607786
View details for PubMedCentralID PMC2680006
Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat
58th Annual Meeting of the American-Epilepsy-Society
WILEY-BLACKWELL. 2004: 358–358
View details for Web of Science ID 000224420101057
Posttraumatic epilepsy following fluid percussion injury in the rat.
21st Annual National-Neurotrauma-Society Symposium
MARY ANN LIEBERT INC. 2003: 1059–59
View details for Web of Science ID 000186072300039
Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis
2003; 44 (4): 565-568
To examine the subgroup of patients with medically intractable epilepsy receiving temporal lobectomies who have pathologically verified mesial temporal sclerosis (MTS) and to determine the relation of demographic and clinical factors, results of diagnostic testing, and details of the surgical procedure with prognosis for achieving control of seizures.All patients receiving surgical treatment for intractable epilepsy between 1991 and 1998 at the University of Washington were reviewed. There were 118 patients who met inclusion criteria of adequate pathological analysis showing MTS without a progressive process and a minimum of 1-year follow-up.Only personal history of status epilepticus demonstrated significant (p = 0.0276) prediction of outcome, increasing the risk of surgical failure. No other factors were significant predictors of outcome, including history of febrile seizures, possible etiologic factors, EEG, magnetic resonance imaging (MRI) or neuropsychological testing results, or extent of resection.Many factors that have been previously described to predict favorable outcome in the overall group of patients receiving temporal lobe resections for intractable epilepsy are, in fact, predictors of MTS and lose their predictive value when the subgroup of patients with confirmed MTS is examined. Neurosurgical treatment of MTS can be very effective even in the presence of significant etiologic factors, or of bilateral or extratemporal abnormalities on EEG or MRI.
View details for Web of Science ID 000182253100011
View details for PubMedID 12681006
Atypical speech is rare in individuals with normal developmental histories
2003; 60 (6): 1042-1044
The prevalence of atypical (right, bilateral) speech lateralization is unknown in normal populations. The authors investigated this by studying people with normal developmental histories but a later, specific adult neurologic event leading to intractable epilepsy. Fifty of 836 people receiving intracarotid amobarbital procedures (IAPs) met criteria of normal neurologic histories through age 15 years, with later head trauma or cerebral infection as probable cause of subsequent epilepsy. All 50 patients had left hemispheric speech on IAP. Atypical speech lateralization is rare unless there is also a positive neurologic history.
View details for Web of Science ID 000182948600035
View details for PubMedID 12654981
The effect of fetal alcohol exposure on the number of vasoactive intestinal peptide producing neurons in fetal sheep brain.
Western Regional Meeting of the American-Federation-for-Medical-Research
LIPPINCOTT WILLIAMS & WILKINS. 2003: S140–S140
View details for Web of Science ID 000180569600290
The application of direct immunofluorescence to intraoperative neurosurgical diagnosis
2000; 17 (1): 17-22
A diagnostic problem can occur at the time of intraoperative consultation of neurosurgical tumors as to whether the tumor is of neuroectodermal origin or whether it represents an epithelial metastasis from another site. Intraoperative diagnoses based on hematoxylin and eosin stained frozen sections are often later confirmed by immunocytochemical analysis of formalin-fixed, paraffin-embedded tissue sections that are not available at the time of surgery. The objective of the current study was to demonstrate that the application of direct immunofluorescence to the intraoperative diagnosis of neurosurgical tumors would provide unequivocal, and nearly immediate results. This report describes a new application of an existing technique for an optimized, rapid procedure utilizing direct immunocytochemistry with fluorescence-labeled primary antibodies to analyze surgical biopsies intraoperatively. The examination of five neurosurgical biopsies established a neuroectodermal origin of three tumors via immunolabeling for glial fibrillary acidic protein (GFAP) and lack of labeling with keratin markers, whereas several metastatic lung carcinomas were identified by immunostaining for keratin, but not GFAP, markers. The results of the direct immunolabeling method were unequivocal and required only minutes. The same diagnoses were confirmed by standard immunocytochemical labeling of formalin-fixed, paraffin-embedded sections, though it required several days to obtain the results. Direct immunofluorescence using fluorescently conjugated primary antibodies is a practical and rapid method for deciding whether a neurosurgical tumor is a primary glial or an epithelial metastatic tumor in origin. It is the first reported application of the technique for this aspect of rapid neurosurgical diagnosis.
View details for Web of Science ID 000089919900003
View details for PubMedID 11042473
Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI
SEIZURE-EUROPEAN JOURNAL OF EPILEPSY
2000; 9 (6): 407-411
Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.
View details for Web of Science ID 000089609300007
View details for PubMedID 10985997
Intraoperative hippocampal electrocorticography to predict the extent of hippocampal resection in temporal lobe epilepsy surgery
JOURNAL OF NEUROSURGERY
2000; 93 (1): 44-52
Among the variety of surgical procedures that are performed for the treatment of medically refractory mesial temporal lobe epilepsy (TLE), no consensus exists as to how much of the hippocampus should be removed. Whether all patients require a maximal hippocampal resection has not yet been determined.At the University of Washington, all TLE operations are performed in a tailored fashion, guided by electrocorticography (ECoG). The amount of hippocampal resection is determined intraoperatively by the extent of interictal epileptiform abnormalities on ECoG recorded from that structure, resulting in a hippocampal resection that is individualized for each patient. Using this approach, the authors prospectively observed 140 consecutive patients who underwent surgery for mesial TLE with pathological diagnoses of either mesial temporal sclerosis with neuronal loss (MTS group) or mild gliosis without neuronal loss (non-MTS group) to determine whether the extent of hippocampal resection correlates with outcome when a tailored approach is used. Additionally, the authors analyzed whether the presence of residual interictal epileptiform activity on ECoG following mesial temporal resection predicts poorer seizure control. With at least 18 months of clinical follow up, 67% of the 140 patients were seizure free or had only a single postoperative seizure. There was no correlation between the size of the hippocampal resection and seizure control in the group as a whole or when stratified by pathological subtype. Using an intraoperatively tailored strategy, individuals with a larger hippocampal resection (> 2.5 cm) were not more likely to have seizure-free outcomes than patients with smaller resections (p = 0.9). Additionally, both MTS and non-MTS patients, in whom postoperative ECoG detected residual epileptiform hippocampal (but not cortical or parahippocampal) interictal activity following surgical resection, had significantly worse seizure outcomes (p = 0.01 in the MTS group; p = 0.002 in the non-MTS group).Intraoperative hippocampal ECoG can predict how much hippocampus should be removed to maximize seizure-free outcome, allowing for sparing of possibly functionally important hippocampus.
View details for Web of Science ID 000087813100007
View details for PubMedID 10883904
Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus
ANNALS OF NEUROLOGY
2000; 47 (1): 113-117
The phenotype of severe congenital hydrocephalus secondary to neural cell adhesion molecule L1 (L1CAM) gene mutations includes the distinct finding of brainstem corticospinal tract hypoplasia. Using diffusion-weighted imaging (DWI), we failed to demonstrate anisotropy in the corticospinal tracts of the basis pontis in 4 affected boys with L1CAM mutations. The DWI findings correlated with the neuropathological findings in a fifth patient. DWI may be a useful technique to screen for boys with L1CAM mutations.
View details for Web of Science ID 000084636800018
View details for PubMedID 10632110
Morphological plasticity in an infant monkey model of temporal lobe epilepsy
5th Workshop on the Neurobiology of Epilepsy (WONOEP V)
WILEY-BLACKWELL. 2000: S70–S75
Seizures in early life are thought to contribute to the development of human temporal lobe epilepsy. To examine the consequences of early seizures, we elicited status epilepticus in immature, 5.5- to 7.0-month-old pigtailed macaques by unilateral microinfusion of bicuculline methiodide into the entorhinal cortex.This report focuses on neuropathological changes in the hippocampus. Bicuculline infusion consistently elicited limbic-like seizures with prolonged, relatively localized electrographic activity. Magnetic resonance imaging revealed enhanced signal intensity in the ipsilateral hippocampus after seizures; in some cases, there was also progressive hippocampal atrophy. Histological changes were variable; in two of five monkeys, there was significant hippocampal neuron loss, gliosis, granule cell dispersion, and mossy fiber reorganization.The histopathological findings and associated magnetic resonance imaging abnormalities after bicuculline-induced status epilepticus in infant monkeys mimic common aspects of human temporal lobe epilepsy.
View details for Web of Science ID 000089156500014
View details for PubMedID 10999523
- Brainstem diffusion-weighted MRI in boys with L1CAM mutations 43rd Annual Meeting of the Society-for-Research-into-Hydrocephalus-and-Spina-Bifida GEORG THIEME VERLAG KG. 1999: 41–42
Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients
ANNALS OF NEUROLOGY
1999; 46 (3): 343-358
Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.
View details for Web of Science ID 000082360000010
View details for PubMedID 10482265
Seizures induced in young primates as a model of temporal lobe epilepsy.
LIPPINCOTT WILLIAMS & WILKINS. 1999: 545–45
View details for Web of Science ID 000080201700156
Development of a model of status epilepticus in pigtailed macaque infant monkeys
1999; 21 (3-5): 352-364
Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline 'cocktail' was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans.
View details for Web of Science ID 000084057600022
View details for PubMedID 10575259
Chromogranin-A in the human hippocampus in normal development and in perinatal hypoxic/ischemic encephalopathy
WILEY-BLACKWELL. 1999: 201–201
View details for Web of Science ID 000082947600807
Hippocampal GAD 65 & 67 labeled cells and mRNA levels per cell in temporal lope epilepsy patients.
WILEY-BLACKWELL. 1999: 155–156
View details for Web of Science ID 000082947600626
Synaptophysin immunocytochemistry with thermal intensification: a marker of terminal axonal maturation in the human fetal nervous system
BRAIN & DEVELOPMENT
1999; 21 (1): 41-50
Synaptophysin is a protein of synaptic vesicles and may be demonstrated in tissue sections of human brain and spinal cord by immunocytochemistry using a monoclonal antibody. Synaptophysin immunoreactivity was studied in paraffin-embedded sections of the central nervous system (CNS) in 14 normal human fetuses and neonates ranging in age from 8 to 41 weeks gestation, and in three brains with heterotopic neurons or malformations. A progressive expression of synaptophysin is seen in axonal terminals within grey matter in various parts of the CNS, beginning in the ventral horns of the spinal cord and brainstem tegmentum at 12-14 weeks. In the cerebellum, the molecular layer shows a band of reactivity from 18 weeks; by term two parallel bands of synaptophysin are seen in the molecular layer and reactivity also is demonstrated in the Purkinje and internal granular layers. In the cerebral neocortex, the molecular zone has weak synaptophysin reactivity as early as 10 weeks, though reactivity is not detected in the deep layers of the cortical plate until 19 weeks and in layers 2-4 until 25 weeks gestation. Synaptophysin reactivity is strong at the surface of neurons but not detected in their somatic cytoplasm; coarsely beaded reactivity within the neuropil probably corresponds to synaptic vesicles in terminal axons. Similar granular synaptophysin reactivity is seen around heterotopic neurons in the subcortical white matter, in dysgenesis of the cerebellar cortex and in the residual anencephalic forebrain. Thermal intensification by heating the incubating solution in a microwave oven often enhances immunoreactivity because of more complete antigen retrieval and is recommended for tissue stored in formalin or in paraffin for long periods. Synaptophysin provides a useful tissue marker of synaptogenesis during normal development and in cerebral dysgeneses, and may provide useful correlations with functional imaging of the brain in living patients. Used in conjunction with other neuronal markers, the expression of synaptophysin in terminal axons of distant neurons, in temporal relation to the maturation of the neurons they innervate, may provide clues to the pathogenesis of epilepsy in early infancy.
View details for Web of Science ID 000078632800009
View details for PubMedID 10082252
The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus
42nd Annual Meeting of the Society-for-Research-into-Hydrocephalus-and-Spina-Bifida
GEORG THIEME VERLAG KG. 1998: 10–14
Neural cell adhesion molecules (CAM) play important roles in neural development, neurite outgrowth, axonal guidance, fasciculation and synapse formation. Neuropathological studies of X-linked hydrocephalus (XLH) associated with L1 CAM mutations emphasize marked hypoplasia of the pyramidal tract, agenesis of the corpus callosum and septum pellucidum, and a thin cerebral mantle with hypoplastic white matter, but there are no detailed studies of the cerebral cortex in the literature. We report clinical, neuroimaging, and neuropathological findings in three boys with XLH. All had severe congenital hydrocephalus with marked thinning of the cerebral mantle and severe development disabilities. The brain specimens from the three boys showed both pachygyria and polymicrogyria, hypoplasia of the medullary pyramids, hypoplasia of the corpus callosum, small anterior commissure, hypoplasia and poorly differentiated hippocampi. A small but patent aqueduct was present in all three brains. Despite the extensive cerebral malformations, the cortex in all three brains showed normal-appearing laminar cortical neuronal architecture and absence of gliosis. In XLH, it is likely that the poor developmental outcome of spasticity, contractures and severe mental retardation results from a disturbance of neuronal connectivity, fasciculation, and synapse formation rather than aqueductal stenosis, increased intracranial pressure, or abnormal neuroblast migration.
View details for Web of Science ID 000078237900004
View details for PubMedID 9926316
Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients
NEUROBIOLOGY OF DISEASE
1998; 5 (3): 151-176
This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.
View details for Web of Science ID 000076770000003
View details for PubMedID 9848088
Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in the early human fetal nervous system
XIIIth International Congress of Neuropathology
ELSEVIER SCIENCE BV. 1998: 88–94
Neuronal nuclear antigen (NeuN) immunocytochemistry was studied in 15 normal human fetal nervous systems of 8-24 weeks gestation and in four term neonates. Material was derived from products of conception or from autopsy. Antigen retrieval was enhanced for immunocytochemistry by microwave heating of formalin-fixed paraffin sections. NeuN appears highly specific as a marker of neuronal nuclei in human fetal brain. Only rare nuclei are recognized in the germinal matrix. Cerebellar external granule cells are more strongly immunoreactive than postmigratory internal granule cells until 24 weeks gestation; by term most internal and only a few external granule cells are recognized by NeuN antibody. In the cerebrum, some reactive nuclei are demonstrated along radial glial fibers, particularly near the cortical plate. Within the cortical plate, only deep neurons (future layers 4-6) are marked at 19-22 weeks, but by 24 weeks most neurons in the cortical plate exhibit immunoreactivity, though at term some in layer 2 are still non-reactive. Some neurons fail to be recognized by NeuN at all ages: Cajal-Retzius cells, Purkinje cells, inferior olivary and dentate nucleus neurons, and sympathetic ganglion cells are examples. Despite their common origin in the cerebellar tubercle, basal pontine neurons are strongly reactive even before midgestation, hence NeuN does not predict embryonic origin. Neurons of dorsal root and cranial nerve ganglia are reactive even at 8 weeks. This study of normal fetal central nervous system provides a basis for neuropathological evaluation and as a prelude to applications in cerebral dysgeneses.
View details for Web of Science ID 000072610300005
View details for PubMedID 9545178
Ultrastructral localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1997; 94 (23): 12676-12681
Zinc transporter-3 (ZnT-3), a member of a growing family of mammalian zinc transporters, is expressed in regions of the brain that are rich in histochemically reactive zinc (as revealed by the Timm's stain), including entorhinal cortex, amygdala, and hippocampus. ZnT-3 protein is most abundant in the zinc-enriched mossy fibers that project from the dentate granule cells to hilar and CA3 pyramidal neurons. We show here by electron microscopy that ZnT-3 decorates the membranes of all clear, small, round synaptic vesicles (SVs) in the mossy fiber boutons of both mouse and monkey. Furthermore, up to 60-80% of these SVs contain Timm's-stainable zinc. The coincidence of ZnT-3 on the membranes of SVs that accumulate zinc, and its homology with known zinc transporters, suggest that ZnT-3 is responsible for the transport of zinc into SVs, and hence for the ability of these neurons to release zinc upon excitation.
View details for Web of Science ID A1997YF39300078
View details for PubMedID 9356509
View details for PubMedCentralID PMC25081
NeuN: A marker of neuronal maturation in the human fetal CNS
WILEY-BLACKWELL PUBLISHING, INC. 1997: 1271–71
View details for Web of Science ID A1997XQ52700392
Markers of neuronal maturation
XIIIth International Congress of Neuropathology
WILEY-BLACKWELL PUBLISHING, INC. 1997: 1269–70
View details for Web of Science ID A1997XQ52700391
CORRELATION OF PATHOLOGICAL-CHANGES IN THE MESIAL TEMPORAL-LOBE AND SURGICAL OUTCOME
WILEY-BLACKWELL. 1995: 370–370
View details for Web of Science ID A1995TD34700295
UNILATERAL VESTIBULAR SCHWANNOMA IN A CHILD WITH PRIOR ORBITAL RHABDOMYOSARCOMA
1994; 42 (2): 125-129
In the absence of neurofibromatosis, vestibular schwannomas (acoustic neuromas) are rarely found in children. We report a case of a 13-year-old boy who presented with unilateral vestibular schwannoma 11 years after resection of an orbital rhabdomyosarcoma. The coincidence of these tumors has not been previously reported.
View details for Web of Science ID A1994PJ02200007
View details for PubMedID 8091288
Paragangliomas of the sellar region: report of two cases.
1993; 32 (5): 844-847
Two cases of paraganglioma arising from the parasellar region are presented. Both occurred in middle-aged women who sought treatment of headaches but who had no endocrinological dysfunction; one case was associated with ophthalmoplegia from cavernous sinus involvement. Diagnosis in both cases was confirmed by typical histological appearance and cytochemical demonstration of immunoreactive chromogranin in tumor cells. The pathological features and possible pathogenesis of parasellar paragangliomas are discussed.
View details for PubMedID 8492863
- PRENATAL SONOGRAPHIC DIAGNOSIS OF A PONTINE LIPOMA JOURNAL OF ULTRASOUND IN MEDICINE 1992; 11 (10): 559-561