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

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.

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

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.

Spinal intradural teratomas: developmental programs gone awry?

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.

Comparison of Surgical Outcomes and Recurrence Rates of Cystic and Solid Vestibular Schwannomas.

Objective Cystic vestibular schwannomas (CVSs) are anecdotally believed to have worse clinical and tumor-control outcomes than solid vestibular schwannomas (SVSs); however, no data have been reported to support this belief. In this study, we characterize the clinical outcomes of patients with CVSs versus those with SVSs. Design This is a retrospective review of prospectively collected data. Setting This study is set at single high-volume neurosurgical institute. Participants We queried a database for details on all patients diagnosed with vestibular schwannomas between January 2009 and January 2014. Main Outcome Measures Records were retrospectively reviewed and analyzed using univariate and multivariate analyses to study the differences in clinical outcomes and tumor progression or recurrence. Results Of a total of 112 tumors, 24% ( n = 27) were CVSs and 76% ( n = 85) were SVSs. Univariate analysis identified the extent of resection, Koos grade, and tumor diameter as significant predictors of recurrence ( p ≤ 0.005). However, tumor diameter was the only significant predictor of recurrence in the multivariate analysis ( p = 0.007). Cystic change was not a predictor of recurrence in the univariate or multivariate analysis ( p ≥ 0.40). Postoperative facial nerve and hearing outcomes were similar for both CVSs and SVSs ( p ≥ 0.47). Conclusion Postoperative facial nerve outcome, hearing, tumor progression, and recurrence are similar for patients with CVSs and SVSs. As CVS growth patterns and responses to radiation are unpredictable, we favor microsurgical resection over radiosurgery as the initial treatment. Our data do not support the commonly held belief that cystic tumors behave more aggressively than solid tumors or are associated with increased postoperative facial nerve deficits.

Using ex vivo proton magnetic resonance spectroscopy to reveal associations between biochemical and biological features of meningiomas.

OBJECT: The goal in this study was to determine if proton ((1)H) MR spectroscopy can differentiate meningioma grade and is associated with interpretations of biological behavior; the study was performed using ex vivo high-resolution spectra indicating metabolic characteristics. METHODS: Sixty-eight resected tissue samples of meningiomas were examined using ex vivo (1)H MR spectroscopy. Of these meningiomas, 46 were WHO Grade I, 14 were WHO Grade II, and 8 were WHO Grade III. Fifty-nine were primary meningiomas and 9 were recurrences. Invasion of adjacent tissue (dura mater, bone, venous sinus, brain) was found in 32 cases. Thirty-nine meningiomas did not rapidly recur (as defined by expansion on MR imaging within a 5-year follow-up period), whereas rapid recurrence was confirmed in 24 meningiomas, and follow-up status was unknown in 5 cases. RESULTS: The absolute concentrations of total alanine and creatine were decreased in high-grade compared with low-grade meningiomas, as was the ratio of glycine to alanine (all p < 0.05). Additionally, alanine and the glycine/alanine ratio distinguished between primary and recurrent meningiomas (all p < 0.05). Finally, the absolute concentrations of alanine and creatine, and the glycine/alanine and choline/glutamate ratios were associated with rapid recurrence (p < 0.05). CONCLUSIONS: These data indicate that meningioma tissue can be characterized by metabolic parameters that are not typically identified by histopathological analysis alone. Creatine, glycine, and alanine may be used as markers of meningioma grade, recurrence, and the likelihood of rapid recurrence. These data validate a previous study of a separate group of Grade I meningiomas.

Endogenous stem cell proliferation induced by intravenous hedgehog agonist administration after contusion in the adult rat spinal cord.

OBJECT: Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration. METHODS: The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted. RESULTS: Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means +/- SDs, 46.9 +/- 12.9 vs 20.9 +/- 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups. CONCLUSIONS: An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.

Prospective trial of gross-total resection with Gliadel wafers followed by early postoperative Gamma Knife radiosurgery and conformal fractionated radiotherapy as the initial treatment for patients with radiographically suspected, newly diagnosed glioblastoma multiforme.

OBJECT: The purpose of this study was to determine whether increased local control and improved survival can be achieved in patients with glioblastoma multiformes (GBMs) who undergo aggressive resection, Gliadel wafer implantation, Gamma Knife radiosurgery (GKS), and fractionated radiotherapy (RT) as the initial treatment. METHODS: Thirty patients with radiographically suspected GBMs were screened for enrollment in a Phase I/II prospective clinical trial. Twenty-seven patients were eligible and underwent gross-total resection and Gliadel wafer implantation. Gamma Knife radiosurgery (12 Gy at 50%) was administered to the resection cavity within 2 weeks of surgery. Patients then received standard fractionated RT (total dose 60 Gy over 6 weeks). Temozolomide was prescribed for patients at the time of recurrence. Surveillance MR imaging, neurological examination, and quality-of-life evaluations were performed at 2-month intervals. To estimate the potential effects on the DNA repair mechanism, tumor tissue was analyzed with methylation-specific polymerase chain reaction analysis and immunohistochemical assays for MGMT gene promoter methylation and protein expression. RESULTS: The median survival for all patients was 50 weeks and the 2-year survival rate was 22%. When stratified into standard and high-risk patient groups, the median survivals were 76 and 33 weeks, respectively. Two patients remain alive at the time of this report with no clinical or radiographic evidence of disease at > 189 and 239 weeks posttreatment and excellent performance status. Local tumor control was achieved in 53% of patients, and local failure occurred in 47%. No acute early toxicity was noted; however, delayed symptomatic radionecrosis occurred in 47% of patients, which required repeated operations 9-24 months after the initial treatment. Delayed hydrocephalus requiring ventriculoperitoneal shunt placement occurred in 47% of patients. There was a significant difference in survival between patients whose tumors contained the methylated and unmethylated MGMT promoter, 103 versus 45 weeks, respectively (p = 0.0009, log-rank test). CONCLUSIONS: The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone. Delayed focal radionecrosis was increased to 47% in this series and was managed with steroids and repeated resection. Aggressive local tumor control with these multimodal therapies should be approached judiciously for a select group of high performance patients and the probability of developing symptomatic radionecrosis requiring surgery should be anticipated and fully disclosed to patients who undergo this treatment.

Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial.

OBJECT: In 1998, the Radiation Therapy Oncology Group initiated a Phase II study of observation for adults < 40 years old with cerebral low-grade glioma who underwent a neurosurgeon-determined gross-total resection (GTR). METHODS: Patient eligibility criteria included the presence of a World Health Organization Grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma confirmed histologically; age 18-39 years; Karnofsky Performance Scale score > or = 60; Neurologic Function Scale score < or = 3; supratentorial tumor location; neurosurgeon-determined GTR; and pre- and postoperative MR imaging with contrast enhancement available for central review by the principal investigator. Patients were observed following GTR and underwent MR imaging every 6 months. Prognostic factors analyzed for their contribution to patient overall survival, progression-free survival (PFS), and tumor recurrence included age, sex, Karnofsky Performance Scale score, Neurologic Function Scale score, histological type, contrast enhancement on preoperative MR imaging, preoperative tumor diameter, residual disease based on postoperative MR imaging, and baseline Mini-Mental State Examination score. RESULTS: Between 1998 and 2002, 111 eligible patients were entered into the study. In these 111 patients, the overall survival rates at 2 and 5 years were 99 and 93%, respectively. The PFS rates in these 111 patients at 2 and 5 years were 82 and 48%, respectively. Three prognostic factors predicted significantly poorer PFS in univariate and multivariate analyses: 1) preoperative tumor diameter > or = 4 cm; 2) astrocytoma/oligoastrocytoma histological type; and 3) residual tumor > or = 1 cm according to MR imaging. Review of the postoperative MR imaging results revealed that 59% of patients had < 1 cm residual disease (with a subsequent 26% recurrence rate), 32% had 1-2 cm residual disease (with a subsequent 68% recurrence rate), and 9% had > 2 cm residual disease (with a subsequent 89% recurrence rate). CONCLUSIONS: These data suggest that young adult patients with low-grade glioma who undergo a neurosurgeon-determined GTR have a > 50% risk of tumor progression 5-years postoperatively, warranting close follow-up and consideration for adjuvant treatment.

Surgical treatment for intramedullary spinal cord melanocytomas.

Spinal meningeal melanocytomas are rare lesions that are histologically benign and can behave aggressively, with local infiltration. The authors present their experience with intramedullary spinal cord melanocytomas consisting of 3 cases, which represents the second largest series in the literature. A retrospective chart review was performed following identification of all spinal melanocytomas treated at the author's institution, based on information obtained from a neuropathology database. The charts were reviewed for patient demographics, surgical procedure, clinical outcome, and long-term tumor progression. Three patients were identified in whom spinal melanocytoma had been diagnosed between 1989 and 2006. The patients' ages were 37, 37, and 48 years, and the location of their tumor was C1-3, T9-10, and T-12, respectively. All 3 had complete resection with no adjuvant radiotherapy during follow-up periods of 16, 38, and 185 months, respectively. One patient demonstrated a recurrence 29 months after resection and the other 2 patients have demonstrated asymptomatic recurrences on imaging studies obtained at 16 and 38 months following resection. With these cases added to the available literature, the evidence strongly suggests that complete resection is the treatment of choice for spinal melanocytomas. Even with complete resection, recurrences are common and close follow-up is needed for the long term in these patients. Radiation therapy should be reserved for those cases in which complete resection is not possible or in which there is recurrence.

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

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.

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

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.

The histopathology of hypothalamic hamartomas: study of 57 cases.

Hypothalamic hamartomas (HHs) are rare developmental tumors that cause seizures or pituitary axis dysfunction, usually beginning in childhood. We analyzed HH tissue from 57 patients whose tumors were resected through recently developed transcallosal interforniceal and transventricular endoscopic surgical approaches. All cases were composed of abnormally distributed but cytologically normal neurons and glia, including fibrillary astrocytes and oligodendrocytes. Neuronal elements predominated in most cases, but a relative increase in astrocytic elements was seen with increasing age. All had various sized nodular foci of neurons as well as areas of diffusely distributed neurons with interspersed glial cells. Smaller neurons predominated, and most cases had only a few interspersed large ganglion cells. Immunohistochemistry demonstrated extensive production of synapse-associated proteins. Immunohistochemistry for phosphorylated and nonphosphorylated neurofilament and alpha-internexin demonstrated staining patterns consistent with mature neurons. In contrast to cortical dysplasia, atypical large ganglion-like balloon cells were almost never seen. In summary, although their number and distribution vary, mature smaller neurons were the most prominent and most consistent histologic feature of HH. Nodules of these small neurons were a universal feature of the microarchitecture of HH lesions associated with epilepsy. Characterization of these neurons may aid in understanding the mechanism of seizure development in HH.

Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis.

The hypothalamic hamartoma (HH) is a rare developmental malformation commonly associated with gelastic seizures that are notoriously refractory to medical therapy. Recent evidence supports the intrinsic seizure propensity of HH. Despite increasing clinical recognition of this condition, the mechanisms of seizure genesis in HH tissue remain unclear. This review summarizes the histochemical and electrophysiological properties of HH neurons, and relates these findings to those characteristics identified in other types of epileptic tissue. Initial studies have revealed two distinct populations of neurons in surgically resected HH tissue. One group consisted of small gamma-aminobutyric acid (GABA)-expressing neurons that occurred principally in clusters and displayed spontaneous rhythmic firing. The second group was composed of large, quiescent, pyramidal-like neurons with more extensive dendritic and axonal arborization. We propose that the small, spontaneously firing GABAergic neurons send inhibitory projections to and drive the synchrony of large output neurons. These observations constitute the basis for future investigations aimed at elucidating the mechanisms of subcortical epileptogenesis.

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

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.

Cytokeratin CK20 is a sensitive marker for Crooke's cells and the early cytoskeletal changes associated with hypercortisolism within pituitary corticotrophs.

Crooke's cells are nonneoplastic corticotroph cells found in the adenohypophysis of patients who have an endogenous or exogenous excess of glucocorticoids. Classic Crooke's cells have a prominent hyaline cytoplasmic ring that displaces the basophilic granules of the normal cell. This characteristic appearance is produced by a perinuclear accumulation of cytokeratin filaments. Immunohistochemistry for cytokeratins is a sensitive way to identify Crooke's cells, but a keratin antibody specific for Crooke's hyaline change has not been reported. Normal pituitary epithelial cells are variably reactive for many keratin antibodies but are negative for cytokeratin 20 (CK20) expression. We evaluated the use of CK20 immunohistochemistry as a marker for Crooke's cells. We examined sections from 25 pituitary glands resected from 15 patients who had undergone exogenous glucocorticoid administration and from 10 patients with an endogenous source of hypercortisolism; sections from 10 normal pituitary glands obtained at autopsy were used as controls. CK20 immunoreactivity was observed only in corticotrophs. A staining pattern consistent with classic Crooke's cells was seen in pituitary gland sections from 15 of the cases. Cells with less intense CK20 positivity were present in sections from all 25 cases. We found CK20 to be a sensitive and specific marker for Crooke's cells and also for the previously unrecognized, subtle, cytoskeletal changes that occur in corticotrophs in response to hypercortisolism.

Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets.

The invasive phenotype of glioblastoma multiforme (GBM) is a hallmark of malignant process, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. Gene expression profiles of human glioma cells were assessed from laser capture-microdissected GBM cells collected from paired patient tumor cores and white matter-invading cell populations. Changes in gene expression in invading GBM cells were validated by quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemistry in an independent sample set. QRT-PCR confirmed the differential expression in 19 of 21 genes tested. Immunohistochemical analyses of autotaxin (ATX), ephrin B3, B-cell lymphoma-w (BCLW), and protein tyrosine kinase 2 beta showed them to be expressed in invasive glioma cells. The known GBM markers, insulin-like growth factor binding protein 2 and vimentin, were robustly expressed in the tumor core. A glioma invasion tissue microarray confirmed the expression of ATX and BCLW in invasive cells of tumors of various grades. GBM phenotypic and genotypic heterogeneity is well documented. In this study, we show an additional layer of complexity: transcriptional differences between cells of tumor core and invasive cells located in the brain parenchyma. Gene products supporting invasion may be novel targets for manipulation of brain tumor behavior with consequences on treatment outcome.

Sinonasal leiomyosarcoma: review of literature and case report.

OBJECTIVES/HYPOTHESIS: To determine prognosis of primary sinonasal leiomyosarcomas after treatment. STUDY DESIGN: Literature review and case report. METHODS: Review of English literature from MEDLINE and independent sources with the addition of our case. RESULTS: Including our case, 63 cases have been reported. Primary treatment includes resection with or without radiation. Chemotherapy has not been reported to be effective. In our case, however, chemotherapy, consisting of etoposide and high-dose ifosfamide, caused the tumor to shrink significantly. On the basis of a review of all reported cases, the overall survival rate at a mean follow-up of 38.24 month is 66%. The minimal overall survival rates at 5 and 10 years are 20% and 6%, respectively. CONCLUSION: The prognosis for primary sinonasal leiomyosarcomas is poor. However, a 10-year survival has been reported in a few patients. Chemotherapy may be a useful adjunct when managing extensive lesions unamenable to curative resection.

Cytokeratin CK 7 and CK 20 expression in pituitary adenomas.

The pattern of immunohistochemical expression of cytokeratins 7 (CK 7) and 20 (CK 20) is commonly used to assess possible primary sites of metastatic carcinomas. Because pituitary tumors are almost always benign, there has been little interest in their cytokeratin profile. However, we recently reported the use of CK 7/20 expression to document malignant progression and metastasis of a pituitary tumor, indicating the potential diagnostic usefulness of the CK 7/20 profile of pituitary adenomas. We analyzed CK 7/20 expression in 97 pituitary adenomas subclassified by immunohistochemical hormone expression. In about 90% of all subtypes, CK 7 was either negative or reactive in only a few scattered cells. Corticotrophs and sparsely granulated growth hormone-positive adenomas were consistently CK 20 positive (and CK 7 negative) whereas all other subtypes were almost always CK 20 negative. This CK 20-positive, CK 7-negative profile is previously described consistently only in colonic adenocarcinomas. This study documents that subtypes of pituitary adenomas have different CK 7/20 profiles. Whereas this pattern is likely to have diagnostic usefulness in only rare adenomas, the presence of a unique CK signature in corticotrophs and sparsely granulated growth hormone-positive adenomas, subtypes particularly noted for invasive and aggressive behavior, merits further investigation.

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

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.

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

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.