Neuro-oncology: an overview

The direct, indirect, and treatment-related effects of cancer on the nervous system have received variable attention by neurologists over the past century. The diseases encompassed in the neuro-oncology field and our understanding of them have increased rapidly during the past 30 years. In part, progress has been driven by technological achievements in neuroimaging, in particular, computed tomography and magnetic resonance imaging. These advances have allowed unprecedented opportunities to view the anatomy and pathology of the central nervous system (CNS) and, to an extent, portions of the peripheral nervous system that could be affected by cancer or its treatment. Clear gains have occurred in diagnostic accuracy, neurosurgical safety, ease of tumor resection, and safer and more accurate radiotherapy. After carmustine chemotherapy was introduced in the late 1960s, neurosurgeons and a new breed of physician, the neuro-oncologist, investigated the clinical benefits of an increasing number of anticancer agents against gliomas, medulloblastomas, and metastatic tumors in the CNS. In parallel, another sector of neuro-oncology developed that was more closely allied with neurology. The focus of this activity was in correlative neurology and pain management issues.     

Effect of diltiazem and pinacidil on the response of the rabbit urinary bladder to repetitive stimulation and in vitro ischemia

The effect of repetitive stimulation, in the presence and absence of diltiazem or pinacidil, on the contractile responses of isolated strips of rabbit bladder detrusor to field stimulation and carbachol, after 2 hr of incubation in a medium that serves as an in vitro model of ischemia (oxygen and substrate depleted Tyrode's solution), was determined. Our results are summarized as follows: a) The magnitude of the contractile dysfunctions after in vitro ischemia was enhanced by repetitive stimulation. b) Pre-incubation of isolated strips of detrusor with diltiazem (50 microM) inhibited the contractile responses to field stimulation (FS) and carbachol by 43 and 50%, respectively. Pinacidil (100 microM) inhibited the contractile responses to FS and carbachol by 37 and 32%, respectively. c) Neither diltiazem nor pinacidil protected the bladder strips against the effects of 2 hr of incubation in in vitro ischemia medium. However, d) both pinacidil and diltiazem reduced the level of contractile dysfunctions induced by repetitive stimulation. In conclusion, the contractile response to FS was significantly more sensitive to in vitro ischemia and repetitive stimulation than was the contractile response to carbachol. Both diltiazem and pinacidil protected the contractile responses to FS and carbachol from the degenerative effects of repetitive stimulation, but not from the effects of in vitro ischemia.     

Pilocarpine toxicity in retinal ganglion cells

PURPOSE: Muscarinic agents reduce intraocular pressure by enhancing aqueous outflow, probably by stimulating ciliary muscle contraction. However, pilocarpine is a well characterized neurotoxin and is widely used to generate animal seizure models. It was therefore investigated whether pilocarpine was also toxic to retinal ganglion cells. METHODS: Dissociated whole retinal preparations were prepared from postnatal day 16 to 19 rats. Retinal ganglion cells had been previously back-labeled with a fluorescent tracer. Retinal cells were incubated with pilocarpine, lithium, and inositol derivatives, and viability of the retrogradely labeled retinal ganglion cells was assayed after 24 hours. RESULTS: Pilocarpine was toxic to retinal ganglion cells in a dose-dependent fashion. This toxicity was potentiated by lithium and blocked by epi- and myo-inositol. CONCLUSIONS: Pilocarpine is toxic to retinal ganglion cells in a mixed culture assay. This toxicity appears to depend on the inositol pathway and is similar to its mode of action in other neurons. However, 0.4 mM pilocarpine (the lowest concentration that did not affect ganglion cell survival) is roughly 1000-fold higher than the vitreal concentration and 20-fold higher than the scleral concentration that can be obtained with topical administration of 2% pilocarpine in the rabbit eye.     

Is neuroprotection a viable therapy for glaucoma?

Treatment of glaucoma continues to be directed at lowering intraocular pressure to decrease the likelihood of disease progression. In the future intraocular pressure reduction might be augmented by other therapeutic approaches. Interest has been increasing in preventing progression of glaucomatous optic neuropathy using approaches based on the premise that glaucoma is a neurodegenerative disease. Neuroprotection of the glaucomatous optic nerve therefore would be an adjuctive therapeutic paradigm for use with conventional intraocular pressure-lowering treatments or by itself.     

A new approach to the closure of cloacal exstrophy

Summary Cloacal exstrophy patients are often difficult to reconstruct. Urinary continence is usually achievable only with a catheterizable stoma of some type. Since cloacal exstrophy is usually associated with omphalocele or gastroschisis, one-stage closure of the abdominal wall defect is frequently impossible. We prefer to incorporate the exstrophic large bowel, which separates the hemibladders, into the closed bladder as a sort of natural augmentation to maximize its volume for use as a continent reservoir. If a silastic silo or synthetic mesh is required to close the abdominal wall, excessive scarring occurs and later creation of a continent stoma is usually difficult and time-consuming. In all but those with the smallest abdominal wall defects we recommend that the omphalocele and upper abdominal wall be repaired first, replacing the evicted gut into the peritoneal cavity. During nutritional stabilization a tissue expander is placed under the superficial musculature of the chest wall. The flap is enlarged by gradual inflation of the tissue expander until it fills the abdominal wall defect left by subsequent closure of the cloacal exstrophy. The flap is then rotated inferiorly with blood supply intact at the time of bladder closure to make good the remaining abdominal wall defect. This flap improves the appearance of the abdominal wall and reduces scarring. Thus, this approach has the possibility of making subsequent operations to provide continence shorter, simpler, and more successful in most infants with cloacal exstrophy.     

Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens

Summary Intracerebral murine glioma 26 was used as a model system for evaluating two-drug combinations of antitumor agents. BCNU was combined with either procarbazine, dianhydrogalactitol, or ellipticine. CCNU was combined with procarbazine. All combinations were more active than the individual drugs alone. The most potent combinations achieved 85–100% tumor cure at 120 days, with combined toxicity indices of 0.25 (CCNU-procarbazine) to 1.30 (BCNU-dianhydrogalactitol). The experimental data were compared to clinical studies with CCNU, procarbazine, and vincristine, and BCNU-procarbazine.American Cancer Society Faculty Research Award FRA-155This work was supported by NIH Center Grant CA-13525, and gifts from Phi Beta Psi Sorority and the Margaret M. Anton Memorial Fund Reprint requests should be addressed to:Editorial Office, 350 Parnassus Avenue, Suite 807, University of California, San Francisco, California, 94143, USA     

Heuristic modeling of drug delivery to malignant brain tumors

It is apparent that chemotherapy against malignant brain tumors is generally ineffective. While some agents are more effective than others, none appreciably alters the clinical course of and the poor prognosis for patients with brain tumors. Even though new and more effective agents are being or will be developed, chemotherapy depends as much on the delivery of drug as it does on the drug used. Therefore, we have defined factors that we believe are of primary importance in drug delivery to brain tumors, and, using computer simulation, we have modeled the effects of these factors. In this article we discuss (a) the extent of the breakdown in the blood-brain barrier (BBB) that accompanies the development of malignant tumors in the brain, (b) factors that influence drug transport from tumor capillaries to tumor cells at varying distances from the capillaries, (c) the problems inherent in drug delivery from a well-vascularized tumor outward to normal brain tissue that might harbor malignant cells but that does not have leaky vessels (i.e., normal BBB), and (d) the difficulties in drug delivery from a well-perfused, highly permeable outer tumor shell to a central, poorly perfused tumor core.This work was supported by American Cancer Society Grant CH-75 and NIH Program Project Grant CA-13525. V. A. L. is the recipient of an American Cancer Society Faculty Research Award (FRA-155).