Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth.

BACKGROUND: Toxic neuropathies induced by cisplatin and other chemotherapeutic agents are important clinical problems because of their high incidence, their lack of effective treatment, and the fact that neuropathy represents a dose-limiting factor for these therapies. The pathogenic basis for toxic neuropathies induced by chemotherapeutic agents has not been completely elucidated. METHODS AND RESULTS: We investigated the hypothesis that experimental toxic neuropathy results from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum, and accordingly that the neuropathy could be prevented or reversed by locally administered VEGF gene transfer without augmenting tumor growth. In an animal model of cisplatin-induced neuropathy, nerve blood flow was markedly attenuated, and there was a profound reduction in the number of vasa nervorum associated with marked endothelial cell apoptosis, resulting in a severe peripheral neuropathy with focal axonal degeneration characteristic of ischemic neuropathy. After intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 in animals with an established neuropathy, vascularity and blood flow returned to levels similar to those of control rats, peripheral nerve function was restored, and histological nerve architecture was normalized. Gene therapy administered in parallel with cisplatin chemotherapy completely attenuated endothelial cell apoptosis and inhibited destruction of nerve vasculature, deterioration of nerve function, and axonal degeneration. In a rat tumor model, VEGF gene transfer administered locally did not alter tumor growth or vascularity. CONCLUSIONS: These findings implicate microvascular damage as the basis for toxic neuropathy induced by cisplatin and suggest that local angiogenic gene therapy may constitute a novel prevention or treatment for this disorder without augmenting tumor growth or vascularization.

Pituitary apoplexy precipitating diabetes insipidus.

OBJECTIVE: To describe a case of pituitary apoplexy complicated by diabetes insipidus and to review management of patients with pituitary apoplexy and water excretion disturbances associated with transsphenoidal surgery. METHODS: We describe clinical, laboratory, and radiologic findings in a patient with pituitary apoplexy and central diabetes insipidus. RESULTS: A 74-year-old woman presented with severe headache and sudden loss of vision for 12 hours, accompanied by thirst and frequent urination. Visual field examination demonstrated bitemporal hemianopsia. Her laboratory findings were significant for a serum sodium level of 152 mEq/L and urine specific gravity of <1.005. A magnetic resonance imaging scan of her pituitary gland identified a 3.5-cm suprasellar mass compressing the optic chiasm. She subsequently underwent transsphenoidal pituitary surgery with subtotal resection of this mass. Microscopic evaluation of tumor tissue revealed a pituitary adenoma with evidence of recent infarct and hemorrhage. Her clinical and biochemical course was consistent with the triphasic response that may occur after pituitary surgery related to damage to the hypothalamus and supraopticohypophyseal tract. CONCLUSION: Pituitary apoplexy may be rarely associated with diabetes insipidus.

Prognostic limitations of the Daumas-Duport grading scheme in infratentorial neuroglial tumors in children.

The Daumas-Duport grading scheme (DDGS) utilizes four histologic features in an additive method (grade 1 if none present, grade 2 if only one is present, etc.). Its efficacy in achieving prognostically homogeneous groups of childhood infratentorial neuroglial tumors and its concordance with World Health Organization (WHO) diagnoses has not been evaluated. We investigated these questions using the Childhood Brain Tumor Consortium (CBTC) database of 1241 neuroglial tumors limited to the infratentorial compartment. We calculated survival function estimates for various DDGS grades as well as the histologic features within each grade. The feature of endothelial prominence improved survival expectation, whereas the remaining three features of nuclear atypia, mitoses, and necrosis were associated with worsened survival. Survival estimates for tumors with DDGS grades 2 and 3 did not differ. Some grades contained feature subsets with significantly different survival distributions. The survival distributions of DDGS grade 1, DDGS grade 2 with only endothelial prominence, and DDGS grade 3 with nuclear atypia and endothelial prominence were not significantly different. DDGS grade within WHO diagnoses had no significant effect on survival expectation. We conclude that grading by summation of only four histologic features, as in the DDGS, is inappropriate for assessment of childhood neuroglial tumors. A classification scheme considering the complete histologic content is more likely to provide clinically useful diagnoses. Such a scheme, based on the CBTC database is available. This scheme uses 26 histologic features identified as reliable in read-reread studies.

Vasculitis of the spinal cord.

BACKGROUND: Vasculitis of the central nervous system is rare but well described. It affects the cerebral hemispheres predominantly and only exceptionally involves the spinal cord. OBJECTIVE: To describe a case of spinal cord vasculitis with unusual pathologic changes. DESIGN: Case report with clinicopathologic correlation. Case Description A young man developed leg weakness and sensory symptoms over several weeks. He had an asymmetric paraparesis with impaired vibration sense in the feet and a Romberg sign but no sensory level. The cerebrospinal fluid contained 123 white blood cells x103/ micro L, mostly lymphocytes, and a protein concentration of 52 mg/dL; oligoclonal bands were not detected, but the illness simulated multiple sclerosis. Magnetic resonance imaging scans of the spinal cord and brain were normal. His condition improved on several occasions with intravenous infusions of corticosteroid agents, but his neurologic signs gradually worsened over several months, and he acquired a thoracic sensory level and sphincteric abnormalities. An explosive preterminal illness occurred with paraplegia, nystagmus, and coma. The findings of a pathologic examination showed numerous ischemic areas in the spinal cord, some cavitated, and a vasculitis of the leptomeningeal branches of the anterior spinal artery and of subpial vessels. The vessel walls were not necrotic, but many of their lumens were occluded by fibrinous material. There were similar findings in regions of cerebral hemorrhagic infarction. CONCLUSIONS: A destructive and vasculitic process should be considered in cases of subacute myelopathy with persistent cellular reaction in the cerebrospinal fluid and clinical responsiveness to corticosteroid therapy. The magnetic resonance imaging scan of the spinal cord may be normal.

Histopathologically proven poliomyelitis with quadriplegia and loss of brainstem function due to West Nile virus infection.

Recent electrophysiological and histopathological reports point to motor neurons in the anterior horn of the spinal cord and the brainstem as targets of severe West Nile virus (WNV) infection. We report histopathological confirmation of this poliomyelitis-like syndrome in a patient with WNV infection in Massachusetts.

Clinical and survival covariates of eight classes of childhood supratentorial neuroglial tumors.

BACKGROUND: In the current study, the authors investigated clinical, surgical, and histologic characteristics (covariates) and their interactions in eight previously identified classes of childhood supratentorial neuroglial tumors. The classes resulted from 5 factor score profiles on 703 supratentorial neuroglial tumors in the Childhood Brain Tumor Consortium database. METHODS: The Cox proportional models were used to identify class survival covariates. RESULTS: Age was found to be a survival covariate only in Class 1, in which older age increased the 5-year survival rate 73% from the first year (0.49) to the tenth year (0.85). A greater amount of tumor removed improved survival in Classes 2 and 4 only. Rosenthal fibers improved survival in Class 2 and overrode the negative effects of high Proliferative factor scores and pleomorphic nuclei. Survival for Class 3 children with high Proliferative factor scores improved from 0.60 to 0.95 as the Spongy factor scores increased. Survival in Class 4 increased from 0.17 to 0.39 with total tumor removal. Irregular nuclei and glomeruloid capillaries improved survival in Class 5 patients. Class 6 survival improved with low cell density. Macrocysts in tumors in Classes 1 and 5 were found to improve survival. CONCLUSIONS: As a result of the current study, the authors conclude that survival covariates differ with tumor class and may modify prognosis considerably.