Publications by authors named "Stephen W Coons"

53 Publications

Immediate Label-Free Ex Vivo Evaluation of Human Brain Tumor Biopsies With Confocal Reflectance Microscopy.

J Neuropathol Exp Neurol 2017 Dec;76(12):1008-1022

Department of Neuropathology and Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; Department of Neurosurgery, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania; School of Life Sciences, Arizona State University, Tempe, Arizona; Irkutsk State Medical University, Irkutsk, Russia; Department of Neurobiology, Barrow Brain Tumor Research Center and The Biobank Core, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Division of Neurogenomics, Translational Genomics Institute, Phoenix, Arizona.

Confocal microscopy utilizing fluorescent dyes is widely gaining use in the clinical setting as a diagnostic tool. Reflectance confocal microscopy is a method of visualizing tissue specimens without fluorescent dyes while relying on the natural refractile properties of cellular and subcellular structures. We prospectively evaluated 76 CNS lesions with confocal reflectance microscopy (CRM) to determine cellularity, architecture, and morphological characteristics. A neuropathologist found that all cases showed similar histopathological features when compared to matched hematoxylin and eosin-stained sections. RNA isolated from 7 tissues following CRM imaging retained high RNA integrity, suggesting that CRM does not alter tissue properties for molecular studies. A neuropathologist and surgical pathologist masked to the imaging results independently evaluated a subset of CRM images. In these evaluations, 100% of images reviewed by the neuropathologist and 95.7% of images reviewed by the surgical pathologist were correctly diagnosed as lesional or nonlesional. Furthermore, 97.9% and 91.5% of cases were correctly diagnosed as tumor or not tumor by the neuropathologist and surgical pathologist, respectively, while 95.8% and 85.1% were identified with the correct diagnosis. Our data indicate that CRM is a useful tool for rapidly screening patient biopsies for diagnostic adequacy, molecular studies, and biobanking.
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http://dx.doi.org/10.1093/jnen/nlx089DOI Listing
December 2017

An extent of resection threshold for seizure freedom in patients with low-grade gliomas.

J Neurosurg 2018 04 26;128(4):1084-1090. Epub 2017 May 26.

1Department of Neurosurgical Oncology, Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix.

OBJECTIVE Seizures are the most common presenting symptom of newly diagnosed WHO Grade II gliomas (low-grade glioma [LGG]) and significantly impair quality of life. Although gross-total resection of LGG is associated with better seizure control, it remains unclear whether an extent of resection (EOR) "threshold" exists for long-term seizure control. Specifically, what proportion of FLAIR-positive tissue in patients with newly diagnosed LGG must be removed to achieve Engel Class I seizure freedom? To clarify the EOR threshold for long-term seizure control, the authors analyzed data from a consecutive series of patients with newly diagnosed LGG who presented with seizures and subsequently underwent microsurgical resection. METHODS The authors identified consecutive patients with newly diagnosed LGG who presented with seizures and were treated at the Barrow Neurological Institute between 2002 and 2012. Patients were dichotomized into those who were seizure free postoperatively and those who were not. The EOR was calculated by quantitative comparison of pre- and postoperative MRI. Univariate analysis of these 2 groups included the chi-square test and the Mann-Whitney U-test, and a multivariate logistic regression was constructed to predict the impact of multiple independent variables on the likelihood of postoperative seizure freedom. To determine a threshold of EOR that optimizes seizure freedom, a receiver operating characteristic curve was plotted and the optimal point of discrimination was determined. RESULTS Data from 128 patients were analyzed (male/female ratio 1.37:1; mean age 40.8 years). All 128 patients presented with seizures, usually generalized (n = 57, 44.5%) or simple partial (n = 57, 44.5%). The median EOR was 90.0%. Of 128 patients, 46 (35.9%) had 100% volumetric tumor resection, 64 (50.0%) had 90%-99% volumetric tumor resection, and 11 (8.6%) had 80%-89% volumetric tumor resection. Postoperatively, 105 (82%) patients were seizure free (Engel Class I); 23 (18%) were not (Engel Classes II-IV). The proportion of seizure-free patients increased in proportion to the EOR. Predictive variables included in the regression model were preoperative Karnofsky Performance Scale score, seizure type, time from diagnosis to surgery, preoperative number of antiepileptic drugs, and EOR. Only EOR significantly affected the likelihood of postoperative Engel Class I status (OR 11.5, 95% CI 2.4-55.6; p = 0.002). The receiver operating characteristic curve generated based on Engel Class I status showed a sensitivity of 0.65 and 1 - specificity of 0.175, corresponding to an EOR of 80%. CONCLUSIONS For adult patients with LGG who suffer seizures, the results suggest that seizure freedom can be attained when EOR > 80% is achieved. Improvements in both the proportion of seizure-free patients and the durability of seizure freedom were observed beyond this 80% threshold. Interestingly, this putative EOR seizure-freedom threshold closely approximates that reported for the overall survival benefit in newly diagnosed hemispheric LGGs, suggesting that a minimum level of residual tumor burden is necessary for both disease and symptomatic progression.
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http://dx.doi.org/10.3171/2016.12.JNS161682DOI Listing
April 2018

Immediate ex-vivo diagnosis of pituitary adenomas using confocal reflectance microscopy: a proof-of-principle study.

J Neurosurg 2018 04 26;128(4):1072-1075. Epub 2017 May 26.

2Neuropathology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.

OBJECTIVE The objective of this study was to evaluate the feasibility of using confocal reflectance microscopy (CRM) ex vivo to differentiate adenoma from normal pituitary gland in surgical biopsy specimens. CRM allows for rapid, label-free evaluation of biopsy specimens with cellular resolution while avoiding some limitations of frozen section analysis. METHODS Biopsy specimens from 11 patients with suspected pituitary adenomas were transported directly to the pathology department. Samples were immediately positioned and visualized with CRM using a confocal microscope located in the same area of the pathology department where frozen sections are prepared. An H & E-stained slide was subsequently prepared from imaged tissue. A neuropathologist compared the histopathological characteristics of the H & E-stained slide and the matched CRM images. A second neuropathologist reviewed images in a blinded fashion and assigned diagnoses of adenoma or normal gland. RESULTS For all specimens, CRM contrasted cellularity, tissue architecture, nuclear pleomorphism, vascularity, and stroma. Pituitary adenomas demonstrated sheets and large lobules of cells, similar to the matched H & E-stained slides. CRM images of normal tissue showed scattered small lobules of pituitary epithelial cells, consistent with matched H & E-stained images of normal gland. Blinded review by a neuropathologist confirmed the diagnosis in 15 (94%) of 16 images of adenoma versus normal gland. CONCLUSIONS CRM is a simple, reliable approach for rapidly evaluating pituitary adenoma specimens ex vivo. This technique can be used to accurately differentiate between pituitary adenoma and normal gland while preserving biopsy tissue for future permanent analysis, immunohistochemical studies, and molecular studies.
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http://dx.doi.org/10.3171/2016.11.JNS161651DOI Listing
April 2018

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

Mol Genet Genomic Med 2015 Jul 8;3(4):283-301. Epub 2015 Apr 8.

Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.

Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.
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http://dx.doi.org/10.1002/mgg3.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521965PMC
July 2015

Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424.

Int J Radiat Oncol Biol Phys 2015 Mar 30;91(3):497-504. Epub 2015 Jan 30.

University of Maryland Medical Systems, Baltimore, Maryland.

Purpose: Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power.

Methods And Materials: Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ.

Results: From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P<.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis.

Conclusions: The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%.
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http://dx.doi.org/10.1016/j.ijrobp.2014.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329190PMC
March 2015

Long-term follow-up of surgical resection of microcystic meningiomas.

J Clin Neurosci 2015 Apr 9;22(4):713-7. Epub 2015 Feb 9.

The University of Arizona, College of Medicine - Phoenix, Phoenix, AZ, USA; Division of Neurosurgery, Maricopa Medical Center, Phoenix, AZ, USA. Electronic address:

Microcystic meningioma is a rare tumor with myxoid and microcystic features. Our objective was to evaluate the efficacy of surgical resection of microcystic meningioma. Between December 1985 and October 2000 we treated 25 microcystic meningioma patients with surgical resection. We retrospectively analyzed the results including the long-term follow-up of this patient population. We identified 15 women and 10 men with a mean age of 53.8 years (24-76 years) who had microcystic meningiomas treated with surgery. Based on the Simpson grade, we found four Grade I (16%), 16 Grade II (64%), three Grade III (12%) and two Grade IV (8%) resections. The mean preoperative Karnofsky Performance Scale (KPS) score was 80.3 (range 60-100). The mean postoperative KPS score was 90.4 (range 60-100). At a mean follow-up of 101.7 months (range 16-221) the KPS score improved to a mean of 93.8. The recurrence/progression free survival (RFS/PFS) rates at 3 and 5 years were 96% and 88%, respectively. The 3 and 5 year RFS/PFS rates based on the Simpson grade were evaluated. The 3 year RFS/PFS rates for Grade I, II, III and IV were 100%, 100%, 66.6% and 100%, respectively. The 5 year RFS/PFS rates were 66.6%, 90%, 66.6% and 100%, respectively. Microcystic meningioma is a rare tumor, which is characterized by extracellular microcystic spaces filled by edematous fluid and peritumoral edema. Following surgical resection these tumors have a positive prognosis with a benign course. The surgical outcomes seem to be associated with the risks related to the surgical procedure.
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http://dx.doi.org/10.1016/j.jocn.2014.12.004DOI Listing
April 2015

A post-mortem stereological study of striatal cell number in human obesity.

Obesity (Silver Spring) 2015 Jan 19;23(1):100-4. Epub 2014 Sep 19.

Obesity and Diabetes Clinical Research Section, NIDDK-NIH, DHHS, Phoenix, Arizona, USA; Department of Neurology, University of Leipzig, Leipzig, Germany.

Objective: Neuroimaging studies have revealed abnormalities in brain structure, including the striatum, in obese people. In this study, the cellular and parenchymal basis for these findings in post-mortem brain tissue was investigated.

Methods: Design-based (unbiased) stereology combined with histochemical and immunocytochemical staining was used to quantify total number of neurons and astrocytes in post-mortem striatal brain samples from nine obese (BMI 40.2 ± 6.1 kg/m(2) ) and eight lean (BMI 24.4 ± 1.0 kg/m(2) ) donors. Total numbers of Nissl-stained neurons and glial fibrillary acidic protein-immunopositive astrocytes were counted in 10 systematic-random sections starting from the frontal pole of the striatum.

Results: There were no differences in mean total numbers of neurons (obese: 7.60 E+06; SD 2.50 E+06; lean: 7.85 E+06; SD 8.26 E+05; P < 0.78) or astrocytes (obese: 7.42 E+06; SD 2.27 E+06; lean: 7.43 E+06; SD 2.50 E+06; P < 0.99). A higher variance was found for number of neurons (P < 0.007) but not astrocytes (P < 0.72) in the obese group. Neuron/glia ratios were similar in both groups (obese: 1.07, SD 0.39; lean: 1.15, SD 0.37; P < 0.70) with an overall striatal neuron/glia ratio of 1.11 (SD 0.37) across the entire study population (n = 17).

Conclusions: No difference was found in the average numbers of neurons and astrocytes in the anterior striatum between lean and obese people. The morphological basis for structural brain changes in obesity requires further investigation.
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http://dx.doi.org/10.1002/oby.20897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276484PMC
January 2015

Association of amyloid burden, brain atrophy and memory deficits in aged apolipoprotein ε4 mice.

Curr Alzheimer Res 2014 Mar;11(3):283-90

Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, 500 W Thomas Road, Suite 300, Phoenix AZ 85013, USA.

Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer's disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice. Male ApoE4 transgenic mice and age-matched control mice at age 12 months and 24 months were tested in the Morris Water Maze (MWM). Brain volume changes (including whole brain, hippocampus, cortex, total ventricles and caudate putamen) were assessed by using small animal 7T-MRI. Aβ level was assessed by immunohistochemistry (IHC) and immunoprecipitation/western blot. In MWM, escape latency was longer and time spent in the target quadrant was shorter in aged ApoE4 mice (12- and 24-month-old), suggesting age- and ApoE4-dependent visuospatial deficits. Atrophy on MRI was prominent in the hippocampus (p=0.039) and cortex (p=0.013) of ApoE4 mice (24-month-old) as compared to age-matched control mice. IHC revealed elevated Aβ deposition in the hippocampus. Consistently, both soluble and insoluble Aβ aggregates were increased in aged ApoE4 mice. This increase was correlated inversely with hippocampal atrophy and cognitive deficits. These data give further evidence that ApoE4 plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition.
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http://dx.doi.org/10.2174/156720501103140329220007DOI Listing
March 2014

Predictors of functional recovery in adults with posterior fossa ependymomas.

J Neurosurg 2014 May 28;120(5):1063-8. Epub 2014 Feb 28.

Division of Neurological Surgery.

Object: After complete resection and radiation therapy, the 10-year overall survival rates for adult patients with posterior fossa ependymomas approach 85%. This favorable outcome profile emphasizes the critical importance of functional preservation to this patient population. Here, the authors identify predictors of functional outcome following microsurgical resection of adult posterior fossa ependymomas.

Methods: The authors identified adult patients with newly diagnosed WHO Grade II posterior fossa ependymomas who underwent microsurgical resection at the Barrow Neurological Institute from 1990 to 2011. Clinical and radiographic variables were collected, including volumetric extent of resection, foramen of Luschka extension, cystic changes, peritumoral T2 signal changes, Karnofsky Performance Scale (KPS) score, National Institutes of Health Stroke Scale (NIHSS) score, progression-free survival (PFS), and overall survival (OS).

Results: Forty-five patients were identified, with a median clinical follow-up of 103 months. The median PFS and OS were 6.8 and 8.6 years, respectively. Extent of resection and adjuvant radiotherapy were predictive of improved PFS (p = 0.005) and were nonsignificantly associated with improved OS. Univariate analysis revealed that tumor size (p < 0.001), cystic changes (p < 0.01), postoperative T2 signal (p < 0.01), and CSF diversion (p = 0.048) predicted functional and neurological recovery rates, based on KPS and NIHSS scores, respectively. Multivariate regression analysis identified tumor size (p < 0.001), cystic changes (p = 0.01), and CSF diversion (p = 0.02) as independent predictors of slower functional recovery, while only tumor size (p = 0.007) was an independent predictor of neurological recovery. Specifically, by 6 weeks postoperatively, baseline KPS score was recovered by only 43.8% of patients with tumors larger than 30 cm(3) (vs 72.4% patients with tumors < 30 cm(3)), 35.3% of patients with cystic tumors (vs 78.6% of patients with noncystic tumors), and 46.7% of patients requiring CSF diversion (vs 70% of patients not requiring CSF diversion).

Conclusions: Greater extent of resection and adjuvant radiotherapy significantly improve PFS in adult patients with posterior fossa ependymomas. Tumor size, cystic changes, and the need for CSF diversion were independent predictors of the rate of functional recovery in this patient population. Taken together, these functional outcome predictors may guide preoperative estimations of recovery following microsurgical resection.
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http://dx.doi.org/10.3171/2014.1.JNS131590DOI Listing
May 2014

In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor-labeled TRP-2 antibodies.

Neurosurg Focus 2014 Feb;36(2):E12

Neuro-Oncology Research.

Object: For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies.

Methods: GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope.

Results: Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes.

Conclusions: Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors.
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http://dx.doi.org/10.3171/2013.12.FOCUS13488DOI Listing
February 2014

An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity.

J Neurosurg 2014 Apr 31;120(4):846-53. Epub 2014 Jan 31.

Division of Neurological Surgery.

Object: Despite improvements in the medical and surgical management of patients with glioblastoma, tumor recurrence remains inevitable. For recurrent glioblastoma, however, the clinical value of a second resection remains uncertain. Specifically, what proportion of contrast-enhancing recurrent glioblastoma tissue must be removed to improve overall survival and what is the neurological cost of incremental resection beyond this threshold?

Methods: The authors identified 170 consecutive patients with recurrent supratentorial glioblastomas treated at the Barrow Neurological Institute from 2001 to 2011. All patients previously had a de novo glioblastoma and following their initial resection received standard temozolomide and fractionated radiotherapy.

Results: The mean clinical follow-up was 22.6 months and no patient was lost to follow-up. At the time of recurrence, the median preoperative tumor volume was 26.1 cm(3). Following re-resection, median postoperative tumor volume was 3.1 cm(3), equating to an 87.4% extent of resection (EOR). The median overall survival was 19.0 months, with a median progression-free survival following re-resection of 5.2 months. Using Cox proportional hazards analysis, the variables of age, Karnofsky Performance Scale (KPS) score, and EOR were predictive of survival following repeat resection (p = 0.0001). Interestingly, a significant survival advantage was noted with as little as 80% EOR. Recursive partitioning analysis validated these findings and provided additional risk stratification at the highest levels of EOR. Overall, at 7 days after surgery, a deterioration in the NIH stroke scale score by 1 point or more was observed in 39.1% of patients with EOR ≥ 80% as compared with 16.7% for those with EOR < 80% (p = 0.0049). This disparity in neurological morbidity, however, did not endure beyond 30 days postoperatively (p = 0.1279).

Conclusions: For recurrent glioblastomas, an improvement in overall survival can be attained beyond an 80% EOR. This survival benefit must be balanced against the risk of neurological morbidity, which does increase with more aggressive cytoreduction, but only in the early postoperative period. Interestingly, this putative EOR threshold closely approximates that reported for newly diagnosed glioblastomas, suggesting that for a subset of patients, the survival benefit of microsurgical resection does not diminish despite biological progression.
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http://dx.doi.org/10.3171/2013.12.JNS13184DOI Listing
April 2014

The impact of extent of resection on malignant transformation of pure oligodendrogliomas.

J Neurosurg 2014 Feb 6;120(2):309-14. Epub 2013 Dec 6.

Divisions of Neurological Surgery and.

Object: Recent evidence suggests that a greater extent of resection (EOR) extends malignant progression-free survival among patients with low-grade gliomas (LGGs). These studies, however, rely on the combined analysis of oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas-3 histological subtypes with distinct genetic and molecular compositions. To assess the value of EOR in a homogeneous LGG patient population and delineate its impact on LGG transformation, the authors examined its effect on newly diagnosed supratentorial oligodendrogliomas.

Methods: The authors identified 93 newly diagnosed adult patients with WHO Grade II oligodendrogliomas treated with microsurgical resection at Barrow Neurological Institute. Clinical, laboratory, and radiographic data were collected retrospectively, including 1p/19q codeletion status and volumetric analysis based on T2-weighted MRI.

Results: The median preoperative and postoperative tumor volumes and EOR were 29.0 cm(3) (range 1.3-222.7 cm(3)), 5.2 cm(3) (range 0-156.1 cm(3)), and 85% (range 6%-100%), respectively. Median follow-up was 75.4 months, and there were 14 deaths (15%). Progression and malignant progression were identified in 31 (33%) and 20 (22%) cases, respectively. A greater EOR was associated with longer overall survival (p = 0.005) and progression-free survival (p = 0.004); however, a greater EOR did not prolong the interval to malignant progression, even when controlling for 1p/19q codeletion.

Conclusions: A greater EOR is associated with an improved survival profile for patients with WHO Grade II oligodendrogliomas. However, for this particular LGG patient population, the interval to tumor transformation is not influenced by cytoreduction. These data raise the possibility that the capacity for microsurgical resection to modulate malignant progression is mediated through biological mechanisms specific to nonoligodendroglioma LGG histologies.
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http://dx.doi.org/10.3171/2013.10.JNS13368DOI Listing
February 2014

Primary histiocytic sarcoma of the brain mimicking cerebral abscess.

J Neurosurg Pediatr 2013 Sep 26;12(3):251-7. Epub 2013 Jul 26.

Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.

Histiocytic sarcoma is a rare malignancy with only 10 reports confirmed primarily involving the CNS. The diagnosis is dependent on the finding of malignant cells with histiocytic morphology and immunophenotype. The authors report a case of pathologically proven HS of the CNS. A 16-year-old boy presented with headaches, emesis, and altered sensorium. Noncontrast head CT scanning demonstrated a left parietal mass consistent with a tumor. Surgery was undertaken. Intraoperative findings revealed green-yellow exudates consistent with an abscess. Cultures were obtained and broad-spectrum antibiotics were started. The patient subsequently underwent multiple surgical procedures, including drainage and debulking of abscesses and hemicraniectomy. Two months after initial presentation, the patient's diagnosis of histiocytic sarcoma was confirmed. Pathological examination demonstrated necrotizing inflammation with preponderant neutrophil infiltration, variably atypical mononuclear and multinucleate histiocytes, and numerous mitoses. Additional immunohistochemistry studies confirmed immunoreactivity for CD68, CD45, CD45RO, and CD15 and were negative for CD3, CD20, melanoma cocktail, CD30, CD1a, CD34, HMB-45, and melan-A. Once the diagnosis of histiocytic sarcoma was confirmed, antibiotics were stopped and radiation therapy was undertaken. Despite treatment, the patient's neurological status continued to decline and the patient died 126 days after initial presentation. This case represents a rare confirmed example of CNS histiocytic sarcoma. A profound inflammatory infiltrate seen on pathology and green exudates seen intraoperatively make the condition difficult to distinguish from an abscess. Immunohistochemistry showing a histiocytic origin and negative for myeloid, dendritic, or other lymphoid markers is essential for the diagnosis. Further research is needed to establish consensus on treatment.
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http://dx.doi.org/10.3171/2013.6.PEDS12533DOI Listing
September 2013

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor.

Neuroreport 2013 Jun;24(9):469-75

Departments of Neurology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, Arizona, USA.

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ∼75% in vitro and ∼60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis.
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http://dx.doi.org/10.1097/WNR.0b013e3283619fc8DOI Listing
June 2013

Hypothalamic hamartomas: neuropathological features with and without prior gamma knife radiosurgery.

Stereotact Funct Neurosurg 2013 29;91(1):45-55. Epub 2012 Nov 29.

Hypothalamic Hamartoma Program, Phoenix Children's Hospital, Phoenix, AZ 85013, USA. neuropub @ chw.edu

Background: The neuropathological consequences of Gamma Knife radiosurgery (GK) on hypothalamic hamartoma (HH) are unknown.

Objective: In a cohort of patients undergoing surgery for treatment-resistant epilepsy, we compared surgically resected HH tissue from patients without (group I; n = 19) and with (group II; n = 10) a history of GK (median dose 16 Gy to the 50% isodose margin).

Methods: Techniques included thick-section stereology for total nucleated and total neuron cell counts, and thin-section immunohistochemistry. Normal human hypothalamus derived from age-matched autopsy material was used as control tissue for CD68 immunohistochemistry. Qualitative scoring of tissue sections was performed by a neuropathologist who was blind to the GK treatment history.

Results: GK is associated with decreased total cell density (p < 0.02). A dose-dependent association of GK with decreased total neuron density approached significance (p = 0.06). Group II HH tissue had significantly more (1) reactive gliosis, (2) thickened capillary endothelium and (3) microglial activation. Degenerative features, including karyorrhexis and pyknotic nuclei, were infrequent in group II and absent in group I HH tissue.

Conclusions: Nonnecrotizing doses of GK radiosurgery decrease cell density in human HH tissue. Cell loss resulting from GK may contribute to decreased excitation in the neuronal networks responsible for seizure onset in HH tissue.
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http://dx.doi.org/10.1159/000341076DOI Listing
July 2013

Spinal intradural teratomas: developmental programs gone awry?

Neurosurg Focus 2012 Oct;33(4):E1

Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ, USA.

Intradural spinal teratomas are rare tumors of the spinal cord that are infrequently encountered in children. Although the mechanistic basis for the formation of these tumors is unclear, several lines of evidence suggest that a dysembryogenic process in the embryo results in their formation. The authors present a case of spinal intradural teratoma in an 18-year-old, previously healthy man and review the literature linking the development of these tumors to defects in neurulation and embryogenesis.
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http://dx.doi.org/10.3171/2012.8.FOCUS12230DOI Listing
October 2012

Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802.

J Clin Oncol 2012 Sep 30;30(25):3065-70. Epub 2012 Jul 30.

Department of Radiation Oncology, Wake Forest University School of Medicine, 2000 W. First St, Winston-Salem, NC 27104, USA.

Purpose: A prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG).

Patients And Methods: Eligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests.

Results: In all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02).

Conclusion: PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.
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http://dx.doi.org/10.1200/JCO.2011.35.8598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732006PMC
September 2012

Immunosignaturing can detect products from molecular markers in brain cancer.

PLoS One 2012 16;7(7):e40201. Epub 2012 Jul 16.

Biodesign Institute, Center for Innovations in Medicine, Arizona State University, Tempe, Arizona, United States of America.

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer's disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O(6)-methyl-guanine-DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397978PMC
March 2013

Giant cell ependymoma-report of three cases and review of the literature.

Int J Clin Exp Pathol 2012 5;5(5):458-62. Epub 2012 May 5.

Department of Pathology and Lab. Medicine, North Shore and Long Island Jewish Health System, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY 11042, USA.

Ependymomas constitute the most common type of primary spinal cord tumors, and are subclassified as myxopapillary ependymoma, classic ependymoma, and anaplastic ependymoma. Ependymomas can be further subclassified based on morphologic phenotype: cellular, papillary, tanycytic, clear cell, pigmented and epithelioid. Giant cell ependymoma (GCE), a rare variant, has recently been described. Reported cases have exhibited a wide anatomic distribution, including spinal cord, cerebrum and cerebellum. We report here three cases of GCE, arising from cerebrum in a 5-year-old girl, spinal cord in a 34-year-old female and cerebellum in an 86-year-old female respectively. Histologically those cases showed prominent pleomorphic giant cells with focal perivascular pseudorosettes in all cases. Tumor cells were immunopositive for GFAP and EMA. Only the first case was qualified for anaplastic ependymoma. No recurrence was noted in these three cases after 57, 46 and 6 months of follow-up respectively. By reviewing the literature, GCEs arising from spinal cord and cerebellum tended to have low-grade morphology while supratentorially located GCEs tended to have anaplastic features. GCEs were preferentially located in extraventricular regions. Anaplastic GCEs in adult population seemed to pursue a more aggressive behavior. Gross total resection should still be the main treatment for GCEs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396061PMC
December 2012

Long-term radiosurgical control of subtotally resected adult pineocytomas.

J Neurosurg 2012 Aug 15;117(2):212-7. Epub 2012 Jun 15.

Division of Neurological Surgery, Barrow Neurological Institute, 310 North Third Avenue, Phoenix, Arizona 85013, USA.

Object: The optimal management of pineocytomas remains controversial. Although the value of complete microsurgical removal is well accepted, gross-total resection is not always feasible. Data regarding the role of postoperative adjuvant stereotactic radiosurgery (SRS) for residual disease is limited and conflicting. Here, the authors review the largest single-institution experience with multimodal pineocytoma management in an effort to quantify the utility of adjuvant radiosurgical treatment of residual disease.

Methods: The medical records and radiographic studies for all patients with histologically confirmed pineocytoma at the Barrow Neurological Institute between 1999 and 2011 were retrospectively reviewed. Clinical and radiographic data, including the volumetric extent of resection, were collected retrospectively, and Kaplan-Meier analysis was used to identify progression-free survival.

Results: Fourteen adults with newly diagnosed pineocytomas were surgically treated in the period from 1999 to 2011. The median clinical and radiographic follow-ups were 44 and 53 months, respectively. Twelve patients (86%) underwent microsurgical removal and 2 (14%) underwent endoscopic biopsy. Five patients (36%) had complete resections and 9 (64%) demonstrated residual disease. Three patients (21%) presented with radiographic recurrence at a median interval of 43 months after initial treatment (range 13-83 months). At the time of recurrence, the median preoperative tumor volume was 2.6 cm(3). Adjuvant SRS was used to treat 3 subtotally resected tumors (33%) following initial presentation and 2 (66%) at the time of recurrence. Among patients with subtotally resected tumors, progression-free survival was significantly longer (p < 0.05) for those who did as compared with those who did not undergo adjuvant radiosurgery. To date, no patient who underwent adjuvant radiosurgery has demonstrated radiographic or clinical evidence of disease progression.

Conclusions: Microsurgical removal remains the definitive treatment for pineocytomas, yet residual disease can be effectively controlled using adjuvant SRS.
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http://dx.doi.org/10.3171/2012.5.JNS1251DOI Listing
August 2012

Reevaluating the imaging definition of tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression, and radiation necrosis to predict survival.

Neuro Oncol 2012 Jul 3;14(7):919-30. Epub 2012 May 3.

Department of Radiology, Mayo Clinic in Arizona, Phoenix, AZ 85054, USA.

Introduction: Contrast-enhanced MRI (CE-MRI) represents the current mainstay for monitoring treatment response in glioblastoma multiforme (GBM), based on the premise that enlarging lesions reflect increasing tumor burden, treatment failure, and poor prognosis. Unfortunately, irradiating such tumors can induce changes in CE-MRI that mimic tumor recurrence, so called post treatment radiation effect (PTRE), and in fact, both PTRE and tumor re-growth can occur together. Because PTRE represents treatment success, the relative histologic fraction of tumor growth versus PTRE affects survival. Studies suggest that Perfusion MRI (pMRI)-based measures of relative cerebral blood volume (rCBV) can noninvasively estimate histologic tumor fraction to predict clinical outcome. There are several proposed pMRI-based analytic methods, although none have been correlated with overall survival (OS). This study compares how well histologic tumor fraction and OS correlate with several pMRI-based metrics.

Methods: We recruited previously treated patients with GBM undergoing surgical re-resection for suspected tumor recurrence and calculated preoperative pMRI-based metrics within CE-MRI enhancing lesions: rCBV mean, mode, maximum, width, and a new thresholding metric called pMRI-fractional tumor burden (pMRI-FTB). We correlated all pMRI-based metrics with histologic tumor fraction and OS.

Results: Among 25 recurrent patients with GBM, histologic tumor fraction correlated most strongly with pMRI-FTB (r = 0.82; P < .0001), which was the only imaging metric that correlated with OS (P<.02).

Conclusion: The pMRI-FTB metric reliably estimates histologic tumor fraction (i.e., tumor burden) and correlates with OS in the context of recurrent GBM. This technique may offer a promising biomarker of tumor progression and clinical outcome for future clinical trials.
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http://dx.doi.org/10.1093/neuonc/nos112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379799PMC
July 2012

In vivo intraoperative confocal microscopy for real-time histopathological imaging of brain tumors.

J Neurosurg 2012 Apr 27;116(4):854-60. Epub 2012 Jan 27.

St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Object: Frozen-section analysis is the current standard for the intraoperative diagnosis of brain tumors. Intraoperative confocal microscopy is an emerging technology with the potential to visualize tumor histopathological features and cell morphology in real time. The authors report their findings using this new intraoperative technology in vivo with sodium fluorescein contrast during the course of 50 microsurgical tumor resections.

Methods: Eighty-eight regions were visualized with confocal microscopy, and corresponding biopsy samples were examined with routine neuropathological analysis. The tumors studied included meningiomas, schwannomas, gliomas of various grades, and a hemangioblastoma. The confocal microscopic features of each tumor and of various artifacts inherent to the technology were documented. A pathologist working in a blinded fashion reviewed a subset of the images in a further evaluation of the usefulness of the device as a diagnostic tool.

Results: Overall, intraoperative confocal imaging correlated surprisingly well with corresponding traditional histological findings, including the identification of many pathognomonic cytoarchitectural features of various brain tumors. In the blinded study, 26 (92.9%) of 28 lesions were diagnosed correctly.

Conclusions: Further study will be necessary for better definition of the role of intraoperative confocal microscopy as a routine adjunct for intraoperative brain tumor diagnosis.
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http://dx.doi.org/10.3171/2011.12.JNS11696DOI Listing
April 2012

Catastrophic demyelinating encephalomyelitis after intrathecal and intravenous stem cell transplantation in a patient with multiple sclerosis.

J Child Neurol 2012 May 7;27(5):632-5. Epub 2011 Dec 7.

Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Stem cell transplantation is an investigational therapy for multiple sclerosis. The authors describe a case of catastrophic demyelinating encephalomyelitis following stem cell transplantation in a 17-year-old girl. Nine months after an initial diagnosis of multiple sclerosis, she underwent stem cell transplantation in Costa Rica. Subsequently, she deteriorated and was transported back to the United States with headache and vomiting progressing to quadriparesis, locked-in syndrome, and superimposed encephalopathy. Magnetic resonance imaging and brain biopsy were consistent with fulminant demyelinating encephalomyelitis with enhancing parenchyma and leptomeninges. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis and high protein. The protracted illness required tracheostomy and gastrostomy. After methyleprednisone, intravenous immunoglobulin, and cyclophosphamide, she improved during 2.5 months to an ambulatory, functionally independent state. Subsequently, typical less severe multiple sclerosis relapses occurred. This case demonstrates that stem cell transplantation may provoke life-threatening encephalomyelitis in patients with multiple sclerosis. This highlights the need to restrict transplantation to trials with appropriate safety controls.
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http://dx.doi.org/10.1177/0883073811422831DOI Listing
May 2012

Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas.

J Neurosurg 2011 Oct 15;115(4):740-8. Epub 2011 Jul 15.

Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, Arizona 85013, USA.

Object: Greater extent of resection (EOR) for patients with low-grade glioma (LGG) corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is a strategy that can improve EOR in gliomas, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a handheld probe that provides real-time fluorescent imaging at up to 1000× magnification. The authors report a combined approach in which intraoperative confocal microscopy is used to visualize 5-ALA tumor fluorescence in LGGs during the course of microsurgical resection.

Methods: Following 5-ALA administration, patients with newly diagnosed LGG underwent microsurgical resection. Intraoperative confocal microscopy was conducted at the following points: 1) initial encounter with the tumor; 2) the midpoint of tumor resection; and 3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence.

Results: Ten consecutive patients with WHO Grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses.

Conclusions: Intraoperative confocal microscopy can visualize cellular 5-ALA-induced tumor fluorescence within LGGs and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation, and for LGGs in combination with intraoperative confocal microscopy and neuronavigation, a Phase IIIa randomized placebo-controlled trial (BALANCE) is underway at the authors' institution.
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http://dx.doi.org/10.3171/2011.6.JNS11252DOI Listing
October 2011

Deficits in spatial learning and memory is associated with hippocampal volume loss in aged apolipoprotein E4 mice.

J Alzheimers Dis 2011 ;27(1):89-98

Department of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.

Apolipoprotein E ε4 (ApoE4) has been implicated as a potential genetic risk factor for dementia. In this study, we investigate the effect of ApoE4 on learning and memory, changes in brain volume and neuroinflammatory responses in brain of ApoE4 transgenic mice. Four groups of male mice with ApoE4 and age-matched wild type (WT) (6-, 12-, 18- and 24-month) were studied. Spatial learning and retaining of mice was examined in the Morris Water Maze (MWM). Changes in brain volume (including the whole brain, hippocampus, cortex, total ventricles, and caudate putamen) were assessed by using 7T small animal MRI. Neuroinflammatory responses were analyzed by measuring the levels of microglia (Iba-1), iNOS, TNFα, and IL-6 quantitatively. In the MWM, ApoE4 mice showed longer escape latency (p < 0.05) and swim distance (p < 0.05) at age 12 month and older, comparing with the WT mice. They also demonstrated poor memory retention in the probe test (p < 0.05). Brain atrophy was significant in ApoE4 mice than age-matched WT mice (18 months: 0.079 ± 0.004 versus 0.086 ± 0.003, p = 0.018; and 24 months: 0.074 ± 0.005 versus 0.084 ± 0.006, p = 0.008). The expression of Iba-1, iNOS, and TNFα in hippocampus and cortex were significantly higher in ApoE4 mice than in WT mice at 12 months and older. These data suggest that ApoE4 plays an important role in learning and memory impairment. These deficits are associated with neuroinflammatory responses that may in turn lead to atrophy in hippocampus and cortex.
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http://dx.doi.org/10.3233/JAD-2011-110479DOI Listing
February 2012

Intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans.

Neurosurgery 2011 Jun;68(2 Suppl Operative):282-90; discussion 290

Department of Neurological Surgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA.

Background: The ability to diagnose brain tumors intraoperatively and identify tumor margins during resection could maximize resection and minimize morbidity. Advances in optical imaging enabled production of a handheld intraoperative confocal microscope.

Objective: To present a feasibility analysis of the intraoperative confocal microscope for brain tumor resection.

Methods: Thirty-three patients with brain tumor treated at Barrow Neurological Institute were examined. All patients received an intravenous bolus of sodium fluorescein before confocal imaging with the Optiscan FIVE 1 system probe. Optical biopsies were obtained within each tumor and along the tumor-brain interfaces. Corresponding pathologic specimens were then excised and processed. These data was compared by a neuropathologist to identify the concordance for tumor histology, grade, and margins.

Results: Thirty-one of 33 lesions were tumors (93.9%) and 2 cases were identified as radiation necrosis (6.1%). Of the former, 25 (80.6%) were intra-axial and 6 (19.4%) were extra-axial. Intra-axial tumors were most commonly gliomas and metastases, while all extra-axial tumors were meningiomas. Among high-grade gliomas, vascular neoproliferation, as well as tumor margins, were identifiable using confocal imaging. Meningothelial and fibrous meningiomas were distinct on confocal microscopy--the latter featured spindle-shaped cells distinguishable from adjacent parenchyma. Other tumor histologies correlated well with standard neuropathology tissue preparations.

Conclusion: Intraoperative confocal microscopy is a practicable technology for the resection of human brain tumors. Preliminary analysis demonstrates reliability for a variety of lesions in identifying tumor cells and the tumor-brain interface. Further refinement of this technology depends upon the approval of tumor-specific fluorescent contrast agents for human use.
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http://dx.doi.org/10.1227/NEU.0b013e318212464eDOI Listing
June 2011

Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays.

J Neuropathol Exp Neurol 2011 Jan;70(1):1-12

Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validation step, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-α protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multi-cohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.
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http://dx.doi.org/10.1097/NEN.0b013e3182018f1cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839953PMC
January 2011

Centrally administered pertussis toxin inhibits microglia migration to the spinal cord and prevents dissemination of disease in an EAE mouse model.

PLoS One 2010 Aug 25;5(8):e12400. Epub 2010 Aug 25.

Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, United States of America.

Background: Experimental autoimmune encephalomyelitis (EAE) models are important vehicles for studying the effect of infectious elements such as Pertussis toxin (PTx) on disease processes related to acute demyelinating encephalomyelitis (ADEM) or multiple sclerosis (MS). PTx has pleotropic effects on the immune system. This study was designed to investigate the effects of PTx administered intracerebroventricularly (icv) in preventing downstream immune cell infiltration and demyelination of the spinal cord.

Methods And Findings: EAE was induced in C57BL/6 mice with MOG(35-55). PTx icv at seven days post MOG immunization resulted in mitigation of clinical motor symptoms, minimal T cell infiltration, and the marked absence of axonal loss and demyelination of the spinal cord. Integrity of the blood brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact. PTx icv markedly increased microglia numbers in the brain preventing their migration to the spinal cord. An in vitro transwell study demonstrated that PTx inhibited migration of microglia.

Conclusion: Centrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928301PMC
August 2010

Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1.

Horm Res Paediatr 2010 14;73(5):312-9. Epub 2010 Apr 14.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Background/aims: Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor alpha (TGFalpha), and GRM1A, which encodes the type 1 metabotropic glutamate receptor alpha isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.

Methods: Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFalpha, KISS1, GPR54, and GRM1A.

Results: Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFalpha, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.

Conclusion: Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.
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http://dx.doi.org/10.1159/000308162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868525PMC
July 2010

Miniaturized handheld confocal microscopy for neurosurgery: results in an experimental glioblastoma model.

Neurosurgery 2010 Feb;66(2):410-7; discussion 417-8

Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.

Introduction: Recent developments in optical science and image processing have miniaturized the components required for confocal microscopy. Clinical confocal imaging applications have emerged, including assessment of colonic mucosal dysplasia during colonoscopy. We present our initial experience with handheld, miniaturized confocal imaging in a murine brain tumor model.

Methods: Twelve C57/BL6 mice were implanted intracranially with 10(5) GL261 glioblastoma cells. The brains of 6 anesthetized mice each at 14 and 21 days after implantation were exposed surgically, and the brain surface was imaged using a handheld confocal probe affixed to a stereotactic frame. The probe was moved systematically over regions of normal and tumor-containing tissue. Intravenous fluorescein and topical acriflavine contrast agents were used. Biopsies were obtained at each imaging site beneath the probe and assessed histologically. Mice were killed after imaging.

Results: Handheld confocal imaging produced exquisite images, well-correlated with corresponding histologic sections, of cellular shape and tissue architecture in murine brain infiltrated by glial neoplasm. Reproducible patterns of cortical vasculature, as well as normal gray and white matter, were identified. Imaging effectively distinguished between tumor and nontumor tissue, including infiltrative tumor margins. Margins were easily identified by observers without prior neuropathology training after minimum experience with the technology.

Conclusion: Miniaturized handheld confocal imaging may assist neurosurgeons in detecting infiltrative brain tumor margins during surgery. It may help to avoid sampling error during biopsy of heterogeneous glial neoplasms, with the potential to supplement conventional intraoperative frozen section pathology. Clinical trials are warranted on the basis of these promising initial results.
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http://dx.doi.org/10.1227/01.NEU.0000365772.66324.6FDOI Listing
February 2010