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In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent's ability to restore immunological function in the context of intended use.

Background and Importance: Spinal cord oligodendrogliomas are rare tumors, with a reported incidence varying between 0.8% and 4.7% of all spinal cord tumors and just over 50 cases reported in the literature. Of these, only 9 cases are histologically defined as anaplastic oligodendrogliomas, with few having complete molecular characterization. The diffuse tumor spread that can occur along the subarachnoid space with secondary invasion of the leptomeninges is called oligodendrogliomatosis and is associated with poor outcome., Clinical Presentation: A 68-year-old man with a history of lumbar stenosis status after lumbar decompression presented with new-onset right lower-extremity weakness. Magnetic resonance imaging demonstrated an intramedullary lesion from T9 to T12. During an attempted diagnostic biopsy, numerous intradural intramedullary lesions not present on magnetic resonance imaging were observed. Tissue biopsy demonstrated a 1p/19q-codeleted anaplastic oligodendroglioma with diffuse oligodendrogliomatosis. Postoperative treatment included 39.2-Gy radiation over 22 fractions from T1 to the bottom of the thecal sac with a boost to the T9-T12 area, the primary site of disease, to a total dose of 43.2 Gy in 24 fractions, followed by adjuvant temozolomide at a dose of 200 mg/m on days 1 to 5 in a 28-day cycle. At the 1-year follow-up, the patient demonstrated moderate neurological improvement., Conclusion: Management, prognosis, and use of molecular data in the decision-making algorithm for these patients are discussed, together with a review of all cases of primary intradural intramedullary spinal anaplastic oligodendrogliomas reported to date. Our study indicates that the combination of sequential treatment with radiation and temozolomide might provide a favorable outcome in the case of 1p/19q-codeleted spinal anaplastic oligodendrogliomas and that molecular analysis can be beneficial in guiding treatment strategies, although the impact of IDH mutations on these tumors is still unclear.

Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b + cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

Introduction: Juvenile xanthogranuloma (JXG) is a histiocytic condition in the spectrum of non-Langerhans histiocytosis that preferentially affects children. Rarely this condition can involve the central nervous system (CNS) with devastating consequences., Methods: The authors report the unique case of an 11-year-old child who initially presented with a sellar lesion without evidence of the cutaneous stigmata typical of JXG. She was later discovered to have JXG following initial diagnosis of granulomatous hypophysitis, with development of widespread intracranial disease and subsequent neurological deterioration. She underwent subtotal resection of her sellar lesion followed by whole brain radiation and systemic chemotherapy; however, she succumbed to her disseminated disease within 1 month of the JXG diagnosis., Conclusions: This is a rare case of fatal disseminated intracranial JXG without cutaneous manifestations. Additionally, the initial presentation as a sellar lesion is particularly unusual and seldom described in the literature.

Parotid masses remain challenging secondary to the great diversity of primary tumors that may arise in the salivary glands and propensity for regional and even distant metastases to occur in this region. Meningioma must also be considered in the differential diagnosis of parotid masses, whether from direct extension, metastases, or as an extracranial primary. We herein report 4 cases of aggressive meningioma involving the parotid gland and the pathologic considerations in evaluating these tumors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Angiocentric glioma (AG) has been formally codified in the revised 2007 WHO Classification of Tumours of the Central Nervous System. AGs characteristically exhibit mixed features of ependymal and diffuse astrocytic differentiation and low proliferation rates, with Ki-67 labeling indices ranging from less than 1 to 5%. A single case with anaplastic recurrence and a labeling index of 10% has been reported. In the present study, we report a series of three AGs (Case 1: 4-year-old girl at right frontal lobe; Case 2: 4-year-old boy at left frontal lobe; Case 3: 9-year-old boy at right temporal lobe). Case 1 with elevated proliferation index (~10%) and increased mitotic activity (six mitoses per 10 high-power fields) on phospho-histone H3 (pHH3) immunostain at presentation, nonetheless, has shown protracted recurrence-free survival after 6 years of follow-up. So far, this is the first report for evaluating the mitotic activity in AGs using pHH3 immunostain.

Malignant gliomas are aggressive malignancies which inevitably recur despite multimodality treatment. In a subset of patients who are longer term survivors of this disease, progressive radiologic worsening can also occur from late effects of radiation rather than recurrent tumor, a differential diagnosis that is commonly considered in this setting. However, other causes for radiologic progression are not as well recognized and could potentially confound management leading to incorrect treatment decisions. Progressive multifocal leukoencephalopathy (PML) is a rare infectious demyelinating disease of the central nervous system seen primarily in immunocompromised patients, the early diagnosis and treatment of which remains a challenge. Here, we report a case of a long term survivor with glioblastoma whose diagnostic and therapeutic management was confounded by the development of PML. We review the radiological features and clinical course of this patient to highlight the dramatic neurological course in the setting of a highly malignant tumor, and emphasize the unusual changes in diffusion weighted images, and the need for clinical suspicion for early diagnosis of PML.

An atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal tumor most often occurring in the posterior fossa in children younger than 3 years of age. Adult cases of AT/RT are very rare, and 27 cases with a diagnosis of either AT/RT or (malignant) rhabdoid tumor have been reported to date. The authors report an adult case of an AT/RT occurring in the pineal region with molecular cytogenetic and immunohistochemical confirmation. A 33-year-old woman presented with a 2-month history of headache and blurred vision progressing to diplopia, and was admitted emergently due to deteriorating mental status. An MR image showed a heterogeneously enhancing mass involving the posterior third ventricle and pineal region with mild hydrocephalus. She underwent a subtotal resection of the tumor and was then treated with chemoradiation. Thirteen months after surgery, she was still alive with radiological evidence of recurrence/residual lesions. Histological sections showed epithelioid cellular sheets of rhabdoid tumor cells with scattered mitotic figures. Immunohistochemically, the tumor cells were diffusely and strongly positive for epithelial membrane antigen and vimentin, and showed focal expression of glial fibrillary acidic protein, pancytokeratin, and neurofilament protein. Loss of nuclear immunoreactivity for INI1 protein was observed. Fluorescence in situ hybridization analysis showed monosomy 22. Histologically, this tumor consisted exclusively of epithelioid tumor cells with rhabdoid features. The differential diagnoses include rhabdoid glioblastoma, metastatic carcinoma, and rhabdoid meningioma. Molecular testing to identify monosomy 22 or deletions of the chromosome 22q11 containing the INI1/hSNF5 gene and/or immunohistochemical staining with INI1 antibody is of great importance for the diagnosis of this tumor.

Objective: The pineal region is a rare intracranial site for metastasis. We report three patients initially considered to have metastatic papillary adenocarcinoma to the pineal region. On review, these papillary, keratin-positive neoplasms meet the criteria for papillary tumor of the pineal region (PTPR)., Clinical Presentation: These neoplasms occurred in three women (age range, 37-55 yr). Imaging studies demonstrated well-circumscribed lesions in the pineal region. All patients presented with obstructive hydrocephalus and symptoms attributable to hydrocephalus and tectal compression., Intervention: All three patients underwent near total microsurgical resection of the pineal region neoplasm, followed by adjuvant radiotherapy. The two patients with long-term follow-up (56-60 mo) have remained clinically stable without evidence of local or distant recurrence. The first two patients were initially diagnosed as having papillary metastatic carcinoma of unknown origin. The third patient was treated after the recent description of PTPR and met the histopathological diagnostic criteria. Retrospective pathological review of the previous two patients resulted in designation as PTPR., Conclusion: The morphological features of the tumors in our series, along with the clinical presentations, are similar to those in the original description of the PTPR. Our findings agree with the original hypothesis that the cells composing the PTPR are similar to ependymal cells of the subcommissural organ, thus furthering the hypothesis that the PTPR derives from a specialized ependymocyte associated with the subcommissural organ. The two patients with long-term follow-up (56-60 mo) have remained clinically stable without evidence of local or distant recurrence.

Context: Resorbable substances used to achieve hemostasis during neurosurgical procedures comprise 3 principal classes based on chemical composition: (1) gelatin sponge, (2) oxidized cellulose, and (3) microfibrillar collagen. Nonresorbable hemostatic aides include various forms of cotton and rayon-based hemostats (cottonoids and kites). Resorbable and nonresorbable hemostatic agents have been reported to cause symptomatic mass lesions, most commonly following intra-abdominal surgery. Histologic examination typically shows a core of degenerating hemostatic agent surrounded by an inflammatory reaction. Each agent exhibits distinctive morphologic features that often permit specific identification. Hemostat-associated mass lesions have been variously referred to as textilomas, gossypibomas, gauzomas, or muslinomas., Objectives: The aims of this study were to (1) identify cases of histologically proven cases of textiloma in neurosurgical operations, (2) characterize the specific hemostatic agent associated with textiloma formation, and (3) characterize the preoperative magnetic resonance imaging appearance of textiloma., Design: Cases in which a textiloma constituted the sole finding on repeat surgery for recurrent brain tumor, or was a clinically significant component of a radiologically identified mass lesion together with residual tumor, constituted the study set., Results: Five textilomas were identified and evaluated. The primary neoplasm was different in each case and included pituitary adenoma, tanycytic ependymoma, anaplastic astrocytoma, gliosarcoma, and oligodendroglioma. In all cases, preoperative magnetic resonance imaging suggested recurrent tumor. Textilomas included all categories of resorbable hemostatic agent. Other foreign bodies were present in some cases; the origin of these foreign bodies was traced to fibers shed from nonresorbable hemostatic material placed temporarily during surgery and removed before closure (cottonoids and kites). Inflammatory reactions included giant cells, granulomas, and fibroblastic proliferation. Microfibrillar collagen (Avitene) textilomas were associated with a striking eosinophil infiltration that was not seen with any other hemostatic agent., Conclusions: Hemostatic agents may produce clinically symptomatic, radiologically apparent mass lesions. When considering a mass lesion arising after intracranial surgery, the differential diagnosis should include textiloma along with recurrent tumor and radiation necrosis.

Cerebellar liponeurocytoma is a rare, benign neuroepithelial tumor that occurs exclusively in the cerebellum of adults. Its salient histological features include advanced neuronal/neurocytic differentiation, focal vacuolated cells resembling mature adipose cells, low mitotic activity, and lack of endothelial proliferation and/or necrosis. The morphological appearance of this neoplasm can be confused with that of oligodendroglioma, neurocytoma, ependymoma, medulloblastoma, hemangioblastoma, metastatic renal cell carcinoma, and other clear cell carcinomas. Its full biological potential and histological features, however, have not been fully exploited due to the rarity of this tumor. The authors describe a case with clinical, imaging, histological, immunohistochemical, and ultrastructural features.

Objects: Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive neoplasms that afflict infants and young children. The objective of this retrospective study was to determine the association between DNA content (DNA ploidy, cell cycle analysis), tumor suppressor gene (p53, pRb, p16, and MMAC/PTEN) expression and the biologic aggressiveness of these tumors., Methods: Eight tumors from 7 patients (1 girl, 6 boys; median age 4+/-6.7 months) were studied. Two patients had DNA aneuploidy and 5 patients manifested diploid DNA content at diagnosis. The proliferative index of the tumors ranged from 10% to 28% (median, 12+/-6.4%). The single tumor with a low proliferative index (i.e., <10%) was aneuploid. Immunohistochemical evaluation of p53, pRb, p16, and MMAC/PTEN expression patterns showed that most of the tumors contained more cells with abnormal pRb and p16 expression than cells with abnormal p53 and MMAC/PTEN expression. Expression of tumor suppressor genes, however, was inhomogeneous., Conclusion: Our findings led us to conclude that AT/RT of childhood is characterized by a high proliferative index and DNA aneuploidy. The high expression of abnormal pRb and p16 and the low expression of abnormal p53 and MMAC/PTEN indicate alteration of the G1-to-S phase step in the cell cycle, which could be an explanation for the aggressive nature of these tumors.

Cell spheroids have been proposed as models of early tumor growth from which a better understanding of tumor cell heterogeneity and its effects on treatment response might be gained. Results of experiments performed to understand the underlying dynamics of cell growth within a spheroid formed by SNB19, a high-grade glioblastoma cell line, are presented. We discuss the spatiotemporal distribution of the cells and their cell cycle status based on physical measurements, immunohistochemistry, and flow cytometry analysis. The size of the spheroids and their growth rates were dependent on the initial cell number, the proliferation was mostly limited to the outermost region as the spheroids grew in size, and the number of dead cells increased with age and size as well. Interestingly, though the population of the proliferating cells became localized to the outer rim as spheroids grew, the fraction of proliferating cells did not change drastically. Also, our data reveal that the calculated density varied with respect to age of the spheroid as well as position within the spheroid. We show that a simple exponential model is not adequate for modelling the growth characteristics that have been seen by these experiments. In contradiction to available studies, we report that an acellular (necrotic) center appeared and then disappeared during the period of investigation. Furthermore, after the acellular region disappeared, a few proliferative cells appeared in the center area, raising many questions about the growth-related dynamics of the spheroids formed by this particular cell type.

The right cerebral hemisphere of 24 rhesus monkeys scheduled for necropsy at the completion of another project were studied histopathologically 1-30 days after a single dose of 60Co-irradiation. Histopathologically, inflammation and gliosis consistently occurred at specific time points but varied in severity between individuals. Multifocal hemorrhage, edema, and an acute neutrophilic inflammatory response were observed initially whereas perivascular accumulations of lymphocytes were observed in specimens at the end of the study. Microglia/macrophages were most prominent during the first week after irradiation, whereas astrocytes were reactive throughout the observation period. The early clinical manifestations of the central nervous system (CNS), because of brain irradiation in humans, correspond temporally with acute vascular responses, acute and subacute inflammatory cell responses, and subacute demyelination and reactive astrocytic and microglial responses observed in the rhesus monkey. Initial responses of the CNS to gamma-irradiation may have potential implications for the development of radiation-induced late injury of the CNS.

MMAC/PTEN, a tumor suppressor gene located on chromosome 10q, has recently been shown to act as a phosphatidylinositol 3,4,5-triphosphate phosphatase and to modulate cell growth and apoptosis. Somatic mutations of MMAC/PTEN have been reported in a number of human cancers, especially in glioblastoma multiforme (GBM), although the number of identified mutations (approximately 10-35%) is significantly lower than the frequency of LOH affecting the MMAC/PTEN locus in the specimens (approximately 75-95%). To further investigate the possible alterations that may affect MMAC/PTEN, we examined the expression of the gene by reverse transcription-PCR in a series of gliomas. A significant difference (P < 0.001) was observed between the expression of MMAC/PTEN in GBMs versus lower grades of gliomas, thus mimicking the difference in allelic deletion associated with the locus in these tumors. Furthermore, Kaplan-Meier survival plots, adjusted for age and tumor grade, showed a significantly better prognosis for patients whose tumors expressed high levels of MMAC/PTEN. Additionally, immunostaining of GBMs revealed little or no MMAC/PTEN expression in about two-thirds of the tumors, whereas the other approximately one-third of tumors had significantly higher levels of expression. However, in about two-thirds of the high-expressing specimens, a heterogeneous pattern of expression was observed, indicating that certain cells within the tumor failed to express MMAC/PTEN. The combination of these results suggest that, in addition to molecular alterations affecting the gene, altered expression of MMAC/PTEN may play a significant role in the progression of GBM and patient outcome.

Extensive genomic deletions involving chromosome 10 are the most common genetic alteration in glioblastoma multiforme (GBM). To localize and examine the potential roles of two chromosome arm 10q tumor suppressor regions, we used two independent strategies: mapping of allelic deletions, and functional analysis of phenotypic suppression after transfer of chromosome 10 fragments. By allelic deletion analysis, the region of 10q surrounding the MMAC/PTEN locus was shown to be frequently lost in GBMs but maintained in most low-grade astrocytic tumors. An additional region at 10q25 containing the DMBT1 locus was lost in all grades of gliomas examined. The potential biological significance of these two regions was further assessed by examining microcell hybrids that contained various fragments of 10q. Somatic cell hybrid clones that retained the MMAC/PTEN locus have a less transformed phenotype with clones exhibiting an inability to grow in soft agarose. However, presence or absence of DMBT1 did not correlate with any in vitro phenotype assessed in our model system. These results support a model of molecular progression in gliomas in which the frequent deletion of 10q25-26 is an early event and is followed by the deletion of the MMAC/PTEN during the progression to high-grade GBMs.

The biologic behavior of ependymomas is highly variable, and its correlation with histologic features is at best imprecise. This retrospective study attempted to correlate the malignant histologic characteristics of ependymomas with MIB-1 proliferation index and survival. Biopsy and resection specimens taken from 34 patients who received treatment 1972 to 1996 were histologically examined. The patients' ages range was 1 to 59 years. The histologic specimens were assessed for anaplastic features (necrosis, mitosis, vascular proliferation, cellular pleomorphism, and overlapping of nuclei) and an MIB-1 (Ki-67 antigen) proliferation index was also determined. The overall median MIB-1 proliferation index was 7.8% (range 0.1 - 62.5%). An MIB-1 of 20% was significant for a decrease in survival (RR = 5.7) (p = 0.0013). The median MIB-1 for patients < 20 years old was 20.6% with range (0.1, 43%), while that for patients > 20 years was 5.1% (range 0.2, 9.4%) (KW p = 0.055). Three of 5 histological features evaluated were significantly associated with outcome: > 5 mitotic figures per high-power field, necrosis, and vascular proliferation, but not nuclear overlap or pleomorphism. All pathologic factors except pleomorphism were significantly related to the MIB-1 proliferation index. In brief, our data support the association of poor prognoses in ependymomas with young age, the presence of three to four anaplastic histologic features, and an MIB-1 proliferation index > 20%.

The frequency of loss of heterozygosity (LOH) around MMAC/PTEN and DMBT1 loci and survival analyses based on the LOH status were assessed in 110 patients with different histological groups of gliomas. Twenty-six of the patients had anaplastic oligodendrogliomas, 31 had anaplastic astrocytomas, and 53 had glioblastomas multiforme (GM). At the DMBT1 locus, LOH was observed very frequently in all three histological groups, with no significant difference in the frequency of LOH among the three histological groups. At the MMAC/PTEN locus, patients with GM exhibited a significantly increased frequency of LOH (72%) compared with patients with anaplastic astrocytomas (29%) or anaplastic oligodendrogliomas (31%) (P < 0.0001). Kaplan-Meier survival plots showed that patients with LOH at the MMAC/PTEN locus had a significantly worse prognosis than did patients without LOH at the MMAC/PTEN locus [hazard ratio (LOH versus non-LOH), 2.65; 95% confidence interval (CI), 1.69-4.46; P < 0.0001]. Cox proportional hazards regression analysis, adjusted for age at surgery and histological grades (GM and non-GM), showed that LOH at the MMAC/PTEN locus was a significant predictor of shorter survival [hazard ratio (LOH versus non-LOH), 2.01; 95% CI, 1.1-3.5; P = 0.018). Our analysis failed to indicate a similar association between the frequency of LOH at the DMBT1 locus and patient survival [hazard ratio (LOH versus non-LOH), 2; 95% CI, 0.37-3.13; P = 0.2]. These results suggest that the DMBT1 gene may be involved early in the oncogenesis of gliomas, whereas alterations in the MMAC/PTEN gene may be a late event in the oncogenesis related to progression of gliomas and provide a significant prognostic marker for patient survival.

ATP-sensitive K+ (KATP) channels modulated by sulfonylurea compounds have been previously identified in the anterior pituitary of the rat and have been demonstrated to influence GH release. Recently, a sulfonylurea receptor (SUR) has been cloned from an islet cell tumor and identified as a member of the ATP binding cassette superfamily capable to coupling with inwardly rectifying potassium channels. To determine if the same receptor is expressed in pituitary tumors, SUR mRNA levels were measured in 28 human macroadenoma specimens using an RNase protection assay. All immunonegative, corticotrophin (ACTH), growth hormone (GH), and GH/prolactin (GH/Prl) immunostaining tumors expressed detectable amounts of SUR message. Among these tumors, only the GH and GH/ Prl adenomas were functional. Of the tumors immunostaining for luteinizing hormone (LH), follicle-stimulating hormone (FSH), or both, SUR mRNA was present in small amounts in 5/11. Only 1/3 Prl immunostaining tumors contained SUR mRNA. In summary, we have demonstrated that SUR mRNA expression is common in several types of silent pituitary adenomas and in functional tumors that secrete GH. Lower levels are seen in some gonadotrophin immunostaining tumors.

A candidate tumor suppressor gene, MMAC1/PTEN, located in human chromosome band 10q23, was recently identified based on sequence alterations observed in several glioma, breast, prostate, and kidney tumor specimens or cell lines. To further investigate the mutational profile of this gene in human cancers, we examined a large set of human tumor specimens and cancer cell lines of many types for 10q23 allelic losses and MMAC1 sequence alterations. Loss of heterozygosity (LOH) at the MMAC1 locus was observed in approximately one-half of the samples examined, consistent with the high frequency of 10q allelic loss reported for many cancers. Of 124 tumor specimens exhibiting LOH that have been screened for MMAC1 alterations to date, we have detected variants in 13 (approximately 10%) of these primary tumors; the highest frequency of variants was found in glioblastoma specimens (approximately 23%). Novel alterations identified in this gene include a missense variant in a melanoma sample and a splicing variant and a nonsense mutation in pediatric glioblastomas. Of 76 tumor cell lines prescreened for probable LOH, microsequence alterations of MMAC1 were detected in 12 (approximately 16%) of the lines, including those derived from astrocytoma, leukemia, and melanoma tumors, as well as bladder, breast, lung, prostate, submaxillary gland, and testis carcinomas. In addition, in this set of tumor cell lines, we detected 11 (approximately 14%) homozygous deletions that eliminated coding portions of MMAC1, a class of abnormality not detected by our methods in primary tumors. These data support the occurrence of inactivating MMAC1 alterations in multiple human cancer types. In addition, we report the discovery of a putative pseudogene of MMAC1 localized on chromosome 9.

Telomerase, the enzyme that stabilizes telomere length, is reactivated with almost all cancer types, and it may be necessary for unlimited cell proliferation. Assessment of malignancy in ordinary meningiomas is inconclusive because no clear-cut correlation exists between aggressive clinical behavior and histological features or karyotypic abnormalities. We analyzed telomerase activity in 52 cases of meningioma by using the highly sensitive telomeric repeat amplification protocol and then compared clinical behavior in telomerase-positive and -negative ordinary meningiomas. Twenty-six of the 52 tumors (50%) had detectable telomerase activity. Twenty-one of the 22 neoplasms classified as malignant or atypical (95%) had detectable telomerase activity, and these tumors generally had a poor outcome. Interestingly, 5 of 30 ordinary (morphologically benign) meningiomas (17%) also showed detectable telomerase activity. Of the 5 patients with telomerase-positive ordinary meningiomas, 3 had rapid regrowth of the tumor despite gross total resection. The remaining 2 patients also had other primary malignancies. We observed a highly significant correlation in ordinary meningiomas between the presence of telomerase activity and a poor prognosis for the patient (P = .0002). Telomerase activity in benign meningiomas is clinically relevant because the presence of the enzyme suggests that these benign-appearing tumors may contain a population of immortal cells. The detection of telomerase activity may help to identify benign meningiomas that would be more likely to continue to grow and to recur clinically if surgical resection were incomplete.

Deletions involving regions of chromosome 10 occur in the vast majority (> 90%) of human glioblastoma multiformes. A region at chromosome 10q23-24 was implicated to contain a tumour suppressor gene and the identification of homozygous deletions in four glioma cell lines further refined the location. We have identified a gene, designated MMAC1, that spans these deletions and encodes a widely expressed 5.5-kb mRNA. The predicted MMAC1 protein contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins, tensin and auxilin. MMAC1 coding-region mutations were observed in a number of glioma, prostate, kidney and breast carcinoma cell lines or tumour specimens. Our results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.

The pleomorphic xanthoastrocytoma (PXA) is a unique astrocytic neoplasm with an unexpectedly favorable prognosis despite striking pleomorphism of the cellular constituents. Although a majority of patients experience extended survival, these tumors may recur and some cases progress to high-grade astrocytoma. Recurrence inevitably involves the anatomic vicinity of the primary tumor. In this report, we describe a malignant brain stem astrocytoma that occurred 15 years after surgery and radiation treatment of a 16-year-old patient who had a temporal lobe PXA. To our knowledge, this is the first reported case of a malignant astrocytoma arising outside the primary anatomic site of a previously treated PXA and likely represents a radiation-induced secondary neoplasm.

Tanycytic ependymoma is an uncommon fibrillar variant of ependymoma characterized by streams of piloid, or hair-like, cells having "ependymal" nuclei. True ependymal rosettes are absent, and perivascular rosettes are inconspicuous. Misinterpretation as schwannoma or astrocytoma is a diagnostic problem and well-documented cases are scarce. The purpose of this report is to document the ependymal features of the neoplasm and to increase awareness of the entity's existence. Biopsy tissues from three patients with tanycytic ependymoma were examined. All tumors consisted of sheets of spindle cells that were positive for glial fibrillary acidic and S-100 proteins. Ultrastructural examination showed characteristic ependymal features, including intracytoplasmic intermediate filaments, prominent intercellular junctions, numerous slender surface microvilli, and microvilli-lined lumina. Accurate recognition of the ependymal nature of this spindle neoplasm requires a high index of suspicion. Because the spindle cells are immunoreactive with antibodies to both glial fibrillary acidic and S-100 proteins, ultrastructural confirmation of ependymal features is necessary.

Background: During the course of their neuropathology practice, the authors received cases to review in consultation. In some cases, the patients came to the authors' hospital for therapy; in others, the primary pathologists requested a consultation. Because changes in diagnosis might significantly alter patient management, protocol entry, care costs, or the potential for physician liability, the authors determined the frequency and degrees of their disagreements with the original diagnoses submitted to them., Methods: The authors reviewed the first 500 brain or spinal cord biopsy cases that were submitted to their neuropathology consultation service for a second opinion in 1995. Disagreements were coded into 10 categories, but were grouped for this analysis as follows: serious (having immediate significance for therapy or intervention), less serious but potentially substantial (calling for a change in type or grade of glioma), minor (adding or deleting information), and those in which the authors made the first diagnosis themselves., Results: There was some degree of disagreement between the original and review diagnoses in 214 (42.8%) of the 500 cases. Disagreements were counted as serious in 44 cases (8.8%), less serious but substantial in 96 cases (19.2%), and minor in 50 cases (10.0%); the authors made the first diagnosis in 24 cases (4.8%)., Conclusions: Clinically important diagnostic errors that can affect immediate patient care decisions occur in a substantial number of brain and spinal cord biopsy cases. Thus, seeking expert neuropathology consultation is prudent and cost-effective for pathologists who are less experienced with these types of cases. Cost savings in case management might result from confirmation of diagnosis before definitive therapy is administered to the patients. The rates of discrepancy between original diagnoses and second opinions in other subspecialties of pathology should be examined.

Ganglioglioma is an uncommon brain tumor with glial and neuronal cellular components and a somewhat benign course. We are presenting an unusual case of ganglioglioma with malignant transformation in both cellular components associated with an aggressive clinical course. An almost complete resolution of the recurrent progressing tumor was achieved after treatment with cis-retinoic acid (cRA) as a single agent. A possible differential effect of cRA on the neuronal component of the tumor is suggested.

Because meningiomas arise from arachnoid cells present in the meninges, they can occur in any location where meninges or ectopic meninges exist, such as the nasal cavity, the paranasal sinuses, the middle ear, and even the mediastinum. Although the tumors may range in appearance from epithelial to mesenchymal, they are characterized by a uniform distribution of cells with shapes ranging from polygonal epithelial-like to spindled and fusiform. Historically, classification of meningiomas has been based upon cell shapes, cell patterns, cell products, or stroma, implying clinicopathologic differences among the types. Numerous observations have shown that certain conditions may indicate a predisposition for developing meningiomas, prompting extensive studies of meningiomas using cytogenetic techniques. Meningiomas are common neoplasms arising from the central nervous system meninges. They are important because of the morbidity they produce. Their critical intracranial and intraspinal locations make diagnosis and surgical removal difficult.

Meningiomas from 40 adult patients were labeled immunohistochemically with monoclonal antibodies to bromodeoxyuridine (BUdR) and the Ki-67 antigen, MIB-1. The meningiomas were classified as classical, or benign (n = 31); atypical (n = 4); or malignant (n = 5). Meningeal sarcomas and hemangiopericytomas were excluded. The patient population consisted of 26 women and 14 men, ranging in age from 26 to 75 years. BUdR proliferation indices ranged from 0% to 5.8%, measurements that were expectedly lower than those for MIB-1, which ranged from 1.5% to 19.3%. MIB-1 proliferation indices were not significantly affected regarding steroid pretreatment or age. These results show a good correlation between the BUdR and MIB-1 proliferation markers (rs = 0.72; P < .0001), which supports the use of anti-MIB-1 as an alternative labeling tool to BUdR for the determination of the proliferation index in meningiomas, thus avoiding the administration of a potentially mutagenic drug.

An adult female rhesus monkey that had received 44.0 Gy of cobalt 60 radiation to 8 cm of the cervical and upper thoracic spinal cord approximately 2.8 years postirradiation developed a sudden onset of self-mutilation and loss of function of the right arm followed progressively by loss of function of the left arm and terminally bilateral paresis of the legs. Histopathologic examination of the cervical spinal cord revealed a glioblastoma multiforme that extended from the cervical medullary junction to the sixth cervical vertebrae. Because of the infrequent occurrence of spontaneous neoplasia in rhesus monkeys and the location in the radiation field, the glioblastoma is believed to be radiation induced.

Diagnostic dilemmas of biopsy specimens in the central nervous system (CNS) tumors are often the result of multiple factors, including fixation artifact, biopsy size, lack of immunohistochemical techniques to distinguish cell types, and unawareness of rare entities. Correct diagnosis and confirmation of diagnosis of primary CNS neoplasms is imperative and may require electron microscopic examination. In some instances, use of electron microscopy may be the only approach for accurate recognition of an entity. Although diagnostic electron microscopy is expensive and cost cutting is encouraged in today's practice of medicine, cost must be weighed against the consequences of even 1 patient developing CNS treatment-related necrosis or a radiation-induced neoplasm secondary to misdiagnosis of a benign entity. This study reviews the ultrastructural differences of three groups of diagnostically difficult CNS lesions: clear cell neoplasms (ependymoma, oligodendroglioma, central neurocytoma), rare entities containing astrocytes invested by a basal lamina (pleomorphic xanthoastrocytoma, the desmoplastic neuroepithelial tumors of infancy), and benign entities characterized by transitional cell forms (subependymoma, subependymal giant cell astrocytoma).

The cdk inhibitor p21WAF1/Cip1 (p21), which can be transcriptionally activated by p53, functions to block cell cycle progression. In this study, we analysed the expression of p21 in normal and reactive brain and in gliomas of various malignancy grades. Southern blotting showed no p21 gene deletion. Western blotting and immunohistochemical assay showed that the levels of p21 protein in normal and reactive brain tissue were very low; however, p21 was elevated in a majority of gliomas tested, regardless of their malignancy grades. In glioblastoma multiforme, marked elevation of p21 was observed in samples harboring either wild-type or mutant p53. But, in anaplastic astrocytomas, the level of p21 was not elevated in samples harboring mutant-type p53. Immunohistochemical staining of paraffin-embedded astrocytomas and glioblastomas showed that tumor cells and not contaminating normal cells were positive for p21. Therefore, overexpression of p21 appears to be an early event in the development of glial neoplasms and p53-dependent p21 expression appears to be tumor grade specific.

Malignant gliomas are invasive into surrounding brain and are refractory to therapy. Telomerase stabilises telomere length and may immortalise cells to allow unlimited proliferation. Our analysis of telomerase activity in 90 human gliomas showed that 19 of 19 oligodendrogliomas and 38 of 51 glioblastoma multiformes have detectable telomerase activity. The absence of telomerase activity in anaplastic astrocytomas (2/20 positive) and in one-quarter (13/51) of the glioblastomas suggests that these tumours follow different pathways of neoplastic progression. Thus we have found that a distinct subgroup of brain tumour consists of transformed yet pre-immortal cells.

The WAF1/Cip1 protein is an important regulator at the G1 checkpoint in the cell cycle. The WAF1/Cip1 protein binds to the cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. We investigated the expression of WAF1/Cip1 protein in 14 glioblastoma cell lines and found that WAF1/Cip1 expression was detectable in many of the cell lines, even when mutant p53 was present. We also showed that WAF1/Cip1 protein level was very low in LN-Z308 cells that do not express endogenous p53. Transfection of the wild-type p53 into this cell line activated WAF1/Cip1 expression and inhibited cell growth. In contrast, transfection of the p53 mutant 248Trp failed to activate WAF1/Cip1 expression. Transfection of WAF1/Cip1 alone also inhibited LN-Z308 cell proliferation. However, cotransfection of the p53 mutant 248Trp with WAF1/Cip1 attenuated the growth-suppression effect of WAF1/Cip1. Our analysis with Western blot showed that the levels of cyclin E increased in cells transfected with p53 mutants. We conclude that p53 mutants may counter the negative regulators, such as WAF1/Cip1, by the elevation of positive cell cycle regulators, and the presence of WAF1/Cip1 in tumor cells is not sufficient for growth inhibition.

A 37-year-old female physician was admitted to the hospital with severe headache, facial and hand paresthesias, dysarthria, and ataxia. Neurologic examination disclosed signs of brain stem dysfunction. There was rapid neurologic deterioration, and she died in 28 hours. Postmortem studies showed the characteristic features of acute hemorrhagic leukoencephalitis.

This case study documents a demyelinating process associated with atypical glial intranuclear inclusions. The patient, a 38-year-old woman, presented with acute onset of headaches and weakness. Magnetic resonance imaging revealed two discrete intrahemispheric lesions. Light microscopic examination showed small, homogeneous, eosinophilic inclusions chiefly in astroglial nuclei. By electron microscopy these inclusions were shown to be clusters of filamentous structures. Attempts to identify the particles with an antibody to measles virus and in situ hybridization to JC virus were negative. The morphologic appearance of the inclusions in this case is similar to that described in neuronal intranuclear inclusion disease.

Recent publications emphasized the correlation between molecular events in brain tumors and clinical outcome. Alterations in tumor-suppressor genes, growth factors, and enzyme systems have been previously described in gliomas; the relationships between these various changes and tumor grade, growth rate, and response to therapy are subjects of current investigations. Loss of genetic heterozygosity on chromosomes 10 and 17p, amplification and rearrangement of the epidermal growth factor receptor gene, express ion of its protein product, and changes in chromosomes 9, 19, and the enzyme system protein kinase C are the specific molecular events that were compared. Changes in chromosome 22 were correlated with histologic features of meningioma. Various methods of measuring tumor cell proliferation (proliferating cell nuclear antigen, bromodeoxyuridine, Ki-67, nucleolar organizer regions, and DNA flow cytometry) are being compared with each other and correlated with clinical outcome in an attempt to validate these methods and to discover the most relevant one. More recently described tumor types continue to be characterized using standard techniques and some of these newer methods. Neurocytoma has been morphologically and immunochemically defined as a neuronal neoplasm, but determination of the full compass of its clinical behavior and position in the continuum of cerebral neuronal tumors awaits additional studies.

The purpose of this study is to determine the effects of ischemia in the spinal cord when a calcium channel blocker, nimodipine, is administered intravenously before, during, and after crossclamping of the thoracic aorta. In this series of experiments, 18 pigs underwent thoracotomies and had 17.5 to 18.0 cm of the thoracic aorta clamped for 30 minutes. By random selection, nine animals received intravenous nimodipine (2 micrograms/kg per minute) and nine control animals received only a carrier solution. Of the nine animals that received nimodipine, eight walked after the operation. In contrast, in the control group only two of nine animals walked. The ninth nimodipine-treated animals walked but had a severe delayed deterioration response. All animals, except one control animal, had a negative central spinal perfusion pressure. Morphologic examination of serial sections of spinal cords from control animals showed diffuse neuronal necrosis. In comparison, cords from the nimodipine group had swollen neurons accompanied by an inflammatory infiltrate and only occasional necrotic neurons. With this data, we conclude that certain calcium channel blockers, when administered in sufficient doses, can lend a protective effect to the spinal cord during ischemic events even when cord perfusion pressure has dropped to dangerously low levels.

Magnetic resonance imaging (MRI) provides a noninvasive method of monitoring the pathologic response to spinal cord injury. Specific MR signal intensity patterns appear to correlate with degrees of improvement in the neurologic status in spinal cord injury patients. Histologic correlation of two types of MR signal intensity patterns are confirmed in the current study using a rat animal model. Adult male Sprague-Dawley rats underwent spinal cord trauma at the midthoracic level using a weight-dropping technique. After laminectomy, 5- and 10-gm brass weights were dropped from designated heights onto a 0.1-gm impounder placed on the exposed dura. Animals allowed to regain consciousness demonstrated variable recovery of hind limb paraplegia. Magnetic resonance images were obtained from 2 hours to 1 week after injury using a 2-tesla MRI/spectrometer. Sacrifice under anesthesia was performed by perfusive fixation; spinal columns were excised en bloc, embedded, sectioned, and observed with the compound light microscope. Magnetic resonance axial images obtained during the time sequence after injury demonstrate a distinct correlation between MR signal intensity patterns and the histologic appearance of the spinal cord. Magnetic resonance imaging delineates the pathologic processes resulting from acute spinal cord injury and can be used to differentiate the type of injury and prognosis.

This is a report of extensive intracranial papillary endothelial hyperplasia in a 12-day-old twin. The infant presented with progressive macrocephaly, anemia and hydrocephalus. An MR image showed a large (6 x 5 cm) mass in the right middle cranial fossa. Histologic examination of the resected mass revealed multifocal hemorrhage, organizing in a floridly papillary pattern, in proximity to numerous fibrous bands containing reactive fibroblasts, scattered chronic inflammatory cells and foci of extramedullary hematopoiesis. Although the pattern was complex, neither the papillary regions nor the other areas in the lesion displayed solid proliferations of endothelial cells to support a diagnosis of angiosarcoma. Subsequent to the resection, the infant continued to have hemostatic abnormalities and increasing hydrocephalus. Repeat scans showed a recurrent mass (4 x 4 cm). The child was placed on a protocol for chemotherapy treatment. We hypothesize that the hemorrhage and subsequent organization could have been superimposed upon a preexistent vascular malformation or hemangioma even though Masson's trichrome stain does not unequivocally demonstrate this feature. Most importantly, we would like to emphasize the dilemmas involved in diagnosis and management of this benign disorder.

This series of experiments is designed to follow the fate of implanted Schwann cells by first labeling them with a recombinant retrovirus encoding the bacterial beta-galactosidase gene, then injecting them into the spinal cord after a demyelinating lesion has been produced. The label provides a means of distinguishing the exogenous Schwann cells from endogenous ones and of determining their travel pattern and myelinating or ensheathing behavior in the central nervous system (CNS). Neonatal rat primary Schwann cells were stimulated to divide by administering glial growth factor and forskolin. Fresh virus-containing supernatant from Psi2 cells producing retrovirus LZ1 was placed in cell culture to label the cells. The capacity of infected Schwann cells to form myelin was verified by coculturing in vitro with neurons from embryonic dorsal root ganglia. Infected cells were injected into the right side of adult syngenic rat spinal cords after a lysolecithin-induced demyelinating lesion had been produced 1 cm caudal on the left side. After 3 weeks the animals were killed, perfused for electron microscopy, and spinal cord sections histochemically stained for beta-galactosidase activity using the chromogenic substrate 5-bromo-4-chloro-3-indoyl-beta-D-galactosidase (X-Gal) which forms a blue precipitate in infected cells. The labeled cells, easily recognized macro- and microscopically, were clustered at the cell injection site, in the dorsal meninges and, at the area of demyelination, bilaterally in the superficial aspect of the dorsal funiculi. Labeled cells were not evident in the neuropil midway between the injection and demyelination sites.(ABSTRACT TRUNCATED AT 250 WORDS)

The goal of this study is to determine the average numbers of afferent axons and postganglionic autonomic (sympathetic) efferent axons supplying the cat knee joint through the medial and posterior articular nerves. Interestingly, both nerves are composed primarily of unmyelinated axons. Only 20% of the axons in the medial articular nerve are myelinated, with the overwhelming majority, 80%, being unmyelinated. The posterior articular nerve has 78% unmyelinated and 22% myelinated axons. Neither nerve contains ventral root efferent axons. The sympathetic chain, in both nerves, contributes no myelinated and only 50% of the unmyelinated axons. The medial and posterior articular nerves are therefore predominantly afferent, since all myelinated and the remaining 50% of the unmyelinated axons arise from the dorsal root ganglion cell. The ratio of afferent unmyelinated to myelinated axons is 2:1. The roles of these afferent unmyelinated axons must now be considered in regard to joint kinesthetics and pain.

The present study suggests a mixture of buffered osmic acid and 1.5% potassium ferricyanide as a post-fixation to improve the fixation of neural tissue. This procedure results in an improved preservation of membranes as well as cytoplasm and cytoplasmic organelles. It is to be emphasized that the quality of the initial perfusion is the primary determinant of quality of the fixation, but the addition of 1.5% potassium ferricyanide to post-fixation fluid makes good fixation better and allows data to be gathered from otherwise unusable material.