Roberta P. Glick

Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis.

OBJECTIVE Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient’s prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. METHODS On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. RESULTS One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. CONCLUSION A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.

Association of meningioma with reproductive factors.

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 = 2.4, 95% confidence interval (CI) = 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 = 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 = 0.6, 95% CI = 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.

Insulin and insulin-like growth factor I in brain tumors: binding and in vitro effects.

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)

Use of Halifax interlaminar clamps for posterior C1-C2 arthrodesis

Eight patients with atlantoaxial instability secondary to trauma or rheumatoid arthritis were treated with posterior C1-C2 arthrodesis using the Halifax interlaminar clamp and autogenous bone graft or methylmethacrylate. Thus far, with an average follow-up of 6 months, satisfactory stability has been achieved with no instrument failure.

Application of interleukin-2-secreting syngeneic/allogeneic fibroblasts in the treatment of primary and metastatic brain tumors.

We found previously that mice injected intracerebrally (i.c.) with a mixture of malignant cells and allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) survived longer than mice in various control groups. The primary goal of this study was to determine if an established i.c. glioma (Gl261) or breast carcinoma (SB-5b) could be treated by injection of IL-2–secreting allogeneic fibroblasts into the tumor region. As an additional objective, these results were compared with the effectiveness of injecting IL-2–secreting allogeneic fibroblasts prior to the introduction of the tumor cells as a means of preventing the development of an i.c. glioma or breast carcinoma. The results demonstrated that treatment of mice bearing an established i.c. glioma or breast carcinoma with IL-2–secreting allogeneic fibroblasts resulted in a prolonged survival. Furthermore, the results demonstrate a significant delay (P<.005) in the development of glioma in the animals treated with either allogeneic nonsecreting or IL-2–secreting fibroblasts prior to introduction of tumor cells. In addition, 50% of the animals pretreated with IL-2–secreting allogeneic fibroblasts injected subsequently with Gl261 glioma cells did not develop a tumor, whereas all of the animals injected with glioma cells alone and 92% of those treated with nonsecreting fibroblasts eventually died. Evidence also exists that long-term immunity was established in the treated animals because there was a significant prolongation of survival in comparison to naïve controls (P<.01) for those animals without evidence of glioma that previously had been immunized with treatment cells when challenged again with tumor cells. In a parallel experiment, 62% of the animals pretreated with nonsecreting allogeneic fibroblasts and 75% of the animals pretreated with allogeneic IL-2–secreting fibroblasts subsequently injected with SB-5b breast carcinoma cells did not develop tumors. The results indicate that IL-2–secreting allogeneic fibroblasts can be effective in the treatment of an established brain tumor. These data also suggest that i.c. injection of allogeneic IL-2–secreting fibroblasts is effective in prevention of the development of a brain tumor when the fibroblasts are introduced into the same site where the tumor is subsequently injected.

Insulin-like growth factors in central nervous system tumors

Insulin-like growth factors (IGFs) appear to play arole in the development of tumors in generaland brain tumors in particular. Specific receptors forIGFs have been identified in normal human andrat brain, and evidence suggests that components ofthe IGF signal transduction system may play arole in the transformation process. Secretion of IGFsby a variety of human brain tumors hasbeen confirmed, and these growth factors appear tohave an autocrine stimulatory effect on these tumors.IGFs circulate in the blood stream bound toat least six distinct binding proteins which maymodulate the effects of these growth factors ontarget tissues. Sex steroids may also regulate thebehavior of certain brain tumors such as meningiomasat least in part through their effects onthe expression of IGFs and their binding proteins.Recently, antisense gene technology against certain IGFs ortheir receptors have resulted in potent antitumor effectsin the case of several gliomas, although themechanism for this remains unclear.

Hormone Binding in Brain Tumors

Brain tumors from 64 patients were studied for the presence of hormone binding. Estradiol binding was detected in 34 patients: 13 of 21 meningiomas, 4 of 8 schwannomas, 1 oligodendroglioma, 1 of 5 benign gliomas, 4 of 5 malignant gliomas, 5 of 11 metastatic tumors, and 6 of 11 pediatric tumors: 1 medulloblastoma, 2 malignant ependymomas, 1 benign astrocytoma, 1 malignant sarcoma, and 1 malignant teratoma. Eleven patients were studied for progesterone binding, which was measurable in 7: 1 schwannoma, 3 meningiomas, 1 malignant sarcoma (pediatric group), 1 astrocytoma--gemistocytic (pediatric group), and 1 metastatic adenocarcinoma. There were 41 females and 23 males in the study. Fifteen females were premenopausal, 18 were postmenopausal, and 8 were in the pediatric group. Of the 34 tumors with measurable estradiol binding, 23 occurred in females. In the progesterone group, 4 of the 7 tumors with measurable binding activity were from female patients. In the pediatric group, estradiol binding was detected in 1 medulloblastoma, 2 malignant ependymomas, 1 malignant teratoma, 1 malignant sarcoma, and 1 astrocytoma. Five of the 6 pediatric tumors with estradiol binding were malignant, and both pediatric tumors with progesterone binding were also malignant. Of the 10 gliomas studied, 4 of the 5 malignant tumors had estradiol binding, whereas only 1 of the 5 benign tumors showed binding. Our studies with the pediatric tumors and the gliomas suggest that a relationship exists between the malignancy of the tumor and the presence of hormone binding. The ubiquitous nature of the presence of hormone binding is discussed, as is the possible correlation between age, sex, histological grade, and significance of hormone binding in brain tumors.

High does epsilon-aminocaproic acid prolongs the bleeding time and increases rebleeding and intraoperative hemorrhage in patients with subarachnoid hemorrhage

epsilon-Aminocaproic acid (EACA) has been used to prevent rebleeding in patients with intracranial aneurysms because it crosses the blood-brain barrier and is an inhibitor of fibrinolysis. Recommended doses have ranged from 24 to 48 g/day. We now describe an inhibitory effect on platelet function at the higher dose range. In vitro, a dose-dependent inhibition of adenosine diphosphate- and collagen-induced platelet aggregation was observed with concentrations of EACA beginning at 7.6 mM. In vivo, prolongation of the template bleeding time was observed in all eight patients receiving 48 g/day (greater than 20 minutes in four), in all five on 36 g/day (greater than 20 minutes in three), and in none of seven on smaller doses. More importantly, rebleeding and excessive intraoperative bleeding (requiring more than 1 litre of blood replacement) occurred predominantly in patients receiving the larger doses of EACA. Within 48 hours of the discontinuation of EACA, the bleeding times returned to normal values in all but one patient. We conclude that EACA exerts a dose-dependent inhibitory effect on platelet function and that patients receiving doses in excess of 24 g/day may be at risk of serious bleeding. Patients receiving EACA should be monitored with serial bleeding time tests.

Genomic Expression Discovery Predicts Pathways and Opposing Functions behind Phenotypes

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19,200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192,000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems.

Imprints, smears, and frozen sections of brain tumors.

In this study, we compared the suitability and accuracy of imprints, smears, and frozen sections of suspected brain and spinal cord tumors of 150 patients. Eighty-six percent of the imprints, 91% of the smears, and 99% of the frozen sections were suitable for interpretation. Among the suitable preparations, 82% of the imprints, 92% of the smears, and 99% of the frozen sections agreed with our diagnosis on paraffin sections. Although frozen sections were clearly more accurate than imprints and smears, the latter two provided diagnoses in patients with acquired immunodeficiency syndrome where frozen sections were not done to avoid contaminating our cryostat and in a patient with an epidermoid cyst of the middle fossa that could not be adequately frozen sectioned. Our study shows that imprints and smears complement frozen sections in the intraoperative diagnosis of tumors of the central nervous system.