Meningiomas occur more commonly in females. The coincidence between meningioma and breast cancer and case reports of tumor growth during pregnancy support a hormonal hypothesis. A case control study was conducted to investigate this. Female subjects treated between 1987 and 1992 were identified from 3 hospitals in the Chicago area. Female spouses of male back pain patients were recruited as controls. A self-administered mail questionnaire focused on exogenous, endogenous and other hormonal factors, personal and family medical history as well as radiation exposures. Odds ratios and 95% confidence intervals were estimated using crude, stratified and multivariable logistic models including 219 cases and 260 controls. Participation rates were 86% among cases and 75% among controls. An increased odds ratio (OR) was observed comparing African Americans to Caucasians [OR 5 2.4, 95% confidence interval (CI) 5 1.0-6.1]. A protective effect was observed for pregnancy, which increased with number and age at first pregnancy. The odds ratio for 3 or more pregnancies compared to none was 0.3 (95% CI 5 0.2-0.6). Age at menarche or total period of hormonal activity was not protective. Ever smokers showed a decreased odds ratio for meningioma (OR 5 0.6, 95% CI 5 0.4-0.9). The increased odds ratios with African Americans was retained in post-menopausal women, while the protective odds ratios for pregnancy, smoking and oral contraceptives (OCs) became stronger in pre-menopausal women. The pattern by duration and timing of use does not suggest an etiologic role for OCs or hormone replacement therapy. These data add to the evidence that factors known to influence endogenous hormones (pregnancy and indirectly smoking) may have protective effects for meningiomas primarily in premenopausal women. ' 2006 Wiley-Liss, Inc.Key words: case-control; meningioma; hormonal; reproductive The hypothesis of a hormonal influence on the occurrence of meningiomas was initially put forth because of the female preponderance in rates, the coincidence between meningioma and breast cancer 1 and case reports of tumor growth during pregnancy. 2 These indirect observations, stimulated studies of sex steroid receptors and a number of receptors and growth factors have been identified in tumor tissue. 3 Progesterone receptors predominate, although estrogen receptors may be present. 4 Although the role of these biologic markers in tumor development has not been established, it appears that the evidence for a role in tumor progression is stronger for progesterone receptors than for estrogen receptors. 5-7 A progesterone antagonist, mifepristone (RU-486), has been used therapeutically in an attempt to slow the growth of unresectable meningiomas, 8 but it has slowed the proliferation of meningioma tumor cells in vitro. 9 The role of hormone replacement therapy (HRT) in symptomatic postmenopausal women with previously treated disease or dormant tumors remains controversial. 6 A few small epidemiological studies suggested a potential role for both endogenous and exo...

The completion of the Human Genome Project combined with the development of microarray technology and recent advances in mathematical biology have set the stage for the genome-wide discovery of differential gene expression between any biological samples from any living system. The term discovery implies the extrapolation of data without the confound of pre-existing biases. This laboratory has developed a mathematical solution for discovering highly specific states of genetic expression between genetic samples (up-or down-regulated). The false discovery rate of the algorithm for microarrays that contain 19,200 CDNAs is Ͻ 0.001%. 1 To explore the idea that genomic expression discovery predicts pathways and functions behind the biological phenotypes of living systems, we compare a tumor to its normal host organ. The expression data accurately predict activation of signaling pathways and propose that unbalanced opposing genetic functions create "aberrant" phenotypes. In addition, known molecular interactions reveal a rich network of stimulatory and inhibitory genetic interconnections.We use microarrays containing 19,200 cDNAs to profile gene expression in 10 meningiomas versus normal brain. Meningiomas are compared with normal brain, its host organ, because both tissue types contain non-tumor cells such as blood vessels and cells of lymphocytic lineage. Meningiomas comprise 15-20% of all primary intracranial tumors. They are abundantly vascular, tend to bleed during surgery, and often show ectopic calcification on computed tomagraphic (CT) scanning. Multiple meningiomas occur in association with a mutated neurofibromatosis type II tumor suppressor gene, known as merlin or schwannomin. Merlin protein appears to stabilize F-actin (2-4). Normal brain RNA was pooled from the occipital lobes of four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. EXPERIMENTAL PROCEDURESReagents-Information on the antibodies used may be obtained from the corresponding web sites: anti-␤-catenin, www.upstatebiotech.com; anti-glyceraldehydes-3-phosphate dehydrogenase (G3PDH), www. trevigen.com.; anti-Akt, 2 anti-phospho-Akt (Ser-473), anti-p44/42 MAP kinase (ERK), and anti-phospho-p44/p42 Map kinase (Thr-202/Tyr-204, ERK-P), www.cellsignal.com.Tumors-Patients signed informed consents, and the study is approved by the Institutional Review Boards of Rush University and Cook County Hospital. Tumor samples are frozen in liquid nitrogen in the operating room. The quality of RNA is assayed by gel electrophoresis; only high quality reference and sample RNAs are processed.Microarray Experiments-All total RNA samples are analyzed in reference to a single standard obtained by pooling RNA from human occipital lobes. The latter are harvested and pooled from four individuals with no known neurological disease whose brains were frozen less than 3 h postmortem. Total RNA (5-10 g) is reverse-transcribed and the cDNA products labeled by the amino-allyl method with switching of probes between sample and refere...

Aqueductal CSF flow is strongly correlated with ventricular morphology, especially with the total ventricular volume and the third ventricle width, but not with the tested hydrodynamic parameters. In addition, ASV is linearly correlated with aqueductal lumen area, suggesting that the aqueductal CSF flow characteristics can be explained by oscillating pressure differences on the order of less than 0.01 mmHg. These findings may explain why a standalone ASV is a poor diagnostic marker and an insensitive indicator of shunt outcome in idiopathic normal pressure hydrocephalus.

A novel approach toward the treatment of glioma was developed in a murine model. The genes for both interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were first transfected into a mouse fibroblast cell line that expresses defined major histocompatibility complex (MHC) determinants (H-2k). The double cytokine-secreting cells were then cotransplanted intracerebrally with the Gl261 murine glioma cell line into syngeneic C57BL/6 mice (H-2b) whose cells differed at the MHC from the cellular immunogen. The results indicate that the survival of mice with glioma injected with the cytokine-secreting allogeneic cells was significantly prolonged, relative to the survival of mice receiving equivalent numbers of glioma cells alone. Using a standard 51Cr-release assay, the specific release of isotope from labeled Gl261 cells coincubated with spleen cells from mice injected intracerebrally with the glioma cells and the cytokine-secreting fibroblasts was significantly higher than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. The cellular antiglioma response was mediated by natural killer/lymphokine-activated killer and Lyt-2.2+ (CD8+) cells. The increased survival of mice with glioma and the specific immunocytotoxic responses after immunization with fibroblasts modified to secrete both IL-2 and IFN-gamma indicate the potential of an immunotherapeutic approach to gliomas with cytokine-secreting cells.

We have measured insulin and insulin-like growth factor I (IGF-I) binding in human gliomas, meningiomas, and normal brain and studied the effect of insulin on the morphology, proliferation, and differentiation of central nervous system tumor and normal fetal cells in culture. Specific 125I-insulin and 125I-IGF-I binding was demonstrated by competition-inhibition binding assays. Insulin binding was measured in plasma membrane preparations from 9 freshly isolated human meningiomas, 4 glioblastomas multiforme (GBMs), a low-grade glioma, a normal adult brain, and a fetal brain. IGF-I binding was measured in similar preparations from 5 meningiomas, 4 GBMs, a low-grade glioma, and a normal adult brain. Incubations were carried out at 4 degrees C for 18 to 20 hours. Meningiomas showed higher specific insulin binding per 0.25 mg of protein than GBMs (19% versus 3%, P less than 0.005), and this difference was not related to small differences observed in insulin degradation. By contrast, IGF-I binding was significantly higher in gliomas than in meningiomas (27% versus 12%, P less than 0.05). Also, IGF-I binding was significantly higher than insulin binding in GBMs (27% versus 3%, P less than 0.03); binding of both IGF and insulin was high in meningiomas. In normal adult brain IGF-I and insulin binding was 7 to 10%. The ability of insulin to support and enhance the growth of central nervous system tumor cells in culture was investigated. Cell cultures were derived from a freshly isolated glioblastoma, a low-grade glioma, and 3 meningiomas.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors have previously reported the presence of insulin-like growth factor (IGF) receptors in central nervous system (CNS) tumors and the production of IGF's and their binding proteins by CNS tumors in situ. This study was designed to investigate whether CNS tumor cells are capable of autocrine secretion of IGF-I and IGF-II in vitro. Production of IGF's was studied by specific radioimmunoassay of tumor-cell-conditioned serum-free media from 34 CNS tumors: 12 gliomas, 12 meningiomas, and 10 miscellaneous tumors. Normal human serum and cerebrospinal fluid served as controls. Insulin-like growth factor I was detected in five of 12 meningiomas but in none of the gliomas studied. In contrast, IGF-II was detected in four of 12 gliomas and in six of 11 meningiomas studied. Four miscellaneous tumors produced IGF-I and/or IGF-II. These results suggest that CNS tumors differentially produce IGF-I and IGF-II in vitro. Preferential production of IGF's may be an important marker of the tumor-cell differentiation or malignancy and may be useful as a clinical diagnostic tool. These results add further support to the concept that IGF's may play a role in the regulation of the behavior of CNS tumors.

Direct IC administration of fibroblasts genetically engineered to secrete IL-2 was more effective in prolonging survival than peripheral subcutaneous administration in the treatment of mice with IC glioma or melanoma.

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