Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel.

Despite the progress in neurosurgery and radiotherapy, almost all patients treated with malignant gliomas develop recurrent tumors and die of their disease. Eighty-eight patients (median age 56 years) with recurrent glioblastoma (median tumor volume 32.7 cm3) were treated with noninvasive fractionated stereotactic radiosurgery and concurrent paclitaxel used as a sensitizer. The median interval between diagnosis of primary glioblastoma and salvage radiosurgery was 7.8 months. Four weekly treatments (median dose: 6.0 Gy) were delivered after the 3-hour paclitaxel infusion (median dose: 120 mg/m2). Survival was calculated by the Kaplan-Meier method from radiosurgery treatment. Overall median survival was 7.0 months, and the 1-year and 2-year actuarial survival rates were 17% and 3.4%, respectively. When grouped by performance status, there was no difference in survival between the patients with low and high Karnofsky score. Patients with tumor volume less than 30 cm3 survived significantly longer than those with tumor greater than 30 cm3 (9.4 vs. 5.7 months, p = 0.0001). Their 1-year survival rate was 40% and 8%, respectively. Eleven patients (11%) had reoperation because of expanding mass. Stable disease was seen in 40% of patients (n = 34), and increase in radiographically detected mass was observed in 41 patients (48.8%). Although the treatment of recurrent GBM is mostly palliative, the fractionated radiosurgery offers a chance for prolonged survival, especially in patients with a smaller tumor volume.

Fractionated stereotactic radiosurgery and concurrent taxol in recurrent glioblastoma multiforme: a preliminary report.

PURPOSE: Surgery and systemic chemotherapy offer modest benefit to patients with recurrent glioblastoma multiforme. These tumors are associated with rapid growth and progressive neurological deterioration. Radiosurgery offers a rational alternative treatment, delivering intensive local therapy. A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous (i.v.) Taxol as a radiation sensitizer. METHODS AND MATERIALS: The treatment outcome was analyzed in 14 patients with recurrent glioblastoma treated with fractionated stereotactic radiosurgery and concurrent Taxol. Median tumor volume was 15.7 cc and patients received a mean radiation dose of 6.2 Gy at 90% isodose line, 4 times weekly. The median dose of Taxol was 120 mg/m2. RESULTS: The median survival was 14.2 months, 1-year survival was 50%. CONCLUSIONS: Survival for this small group of patients was similar to or better than historical controls or patients treated with single-fraction radiosurgery alone. This data should stimulate the investigation of both fractionated radiosurgery and the development of radiation sensitizers to further enhance treatment.

Microencephaly in children congenitally infected with human immunodeficiency virus--a gross-anatomical morphometric study.

A quantitative technique involving serial sectioning and semiautomatic morphometric analysis was used to assess the severity of the reduction in size of the major brain structures in cerebral hemispheres of children congenitally infected with HIV-1. Cerebral hemispheres from 12 children (18-48 months of age) who died of AIDS were sectioned into 5-mm-thick serial slabs and photographed. The cross-sectional areas of grossly recognizable brain structures were digitized, and the volumes were calculated according to Cavalieri's principle. The results were compared with those of an identically processed group of control brains from non-AIDS children. Analysis of the brain weight showed that there was a significant reduction in supratentorial and infratentorial weight in the AIDS group. The results of the morphometric study revealed that the loss in brain mass was associated with a statistically significant reduction in the total volume of both hemispheres, the entire cortex, white matter, and basal ganglia. Detailed analysis of individual brain structures also showed a significant reduction in volume of all cortical regions and most of the subcortical gray matter (e.g., caudate nucleus, putamen, globus pallidus, claustrum, and thalamus). It appears that in the microencephaly observed as a frequent sequel in pediatric AIDS, the loss of brain tissue is global and includes an almost proportional loss of cortex, subcortical gray matter and white matter.

The degenerative diseases or syndromes in maturing central nervous system.

The diagnosis of degenerative diseases or syndromes in the nervous system in based on their morphological picture. The changes occur in selected CNS structures or systems being induced in the course of more or less known processes sometimes with known, more often unknown etiology. Degenerative syndromes may be classified according to the topography of changes. They appear often with aging, but also in even greater number in infants. We tried to analyze the problem and find out to what degree the structure and topography of CNS degenerative changes in infants depend on maturity of nervous tissue constituting the background of pathologic process. The cases with two syndromes representative for small infants: progressive poliodystrophy of Alpers type and a degenerative syndrome with cerebral calcifications and disseminated demyelination were examined from this point of view. Our observations revealed that the stage of CNS development stipulates the type and topography of degenerative changes.

Opportunistic infections of the central nervous system in children with HIV infection: report of 9 autopsy cases and review of literature.

Central nervous system (CNS) abnormalities attributed to direct effects of HIV infection are seen in most of children with acquired immunodeficiency syndrome (AIDS). Secondary CNS infections with opportunistic and common pathogens are infrequent in this age group. We report 9 cases of opportunistic infection of the CNS found among 65 autopsy cases of pediatric AIDS. These included 4 cases of cytomegalovirus (CMV) infection, 1 of which was associated with aspergillosis, and 2 cases of candidiasis, 1 of which coexisted with Mycobacterium avium intracellulare (MAI) infection. There were also 2 cases of leptomeningitis, 1 due to Mycobacterium tuberculosis (MTB) and the other to Cryptococcus neoformans. In 1 child progressive multifocal leukoencephalopathy (PML) coexisted with mycotic encephalitis caused by an Aspergillus sp.

Skeletal muscle metastasis in a patient with Wilms tumor and multiple late recurrences.

Stage III Wilms tumor was diagnosed in a 9-year-old girl. Four and a half years after the treatment, which consisted of an operation, radiation therapy, and chemotherapy, the patient had a solitary metastasis in the liver, which was successfully treated with chemotherapy and surgical resection. Five years later, right lung metastases were eradicated by chemotherapy, radiation, and surgical resection. Three and a half years later, she had a metastasis in the left calf, for which she underwent surgical resection and received chemotherapy. This patient has several interesting features: (1) multiple recurrences, two in the usual sites of metastasis and one in an extremely rare site, i.e., skeletal muscle; (2) long intervals between recurrences; and (3) unusual histopathologic features, i.e., gradual evolution from a triphasic Wilms tumor at the primary site, to a predominance of differentiated mucinous epithelium in the skeletal muscle metastasis.

Immune electron microscopic characterization of monoclonal antibodies to Alzheimer neurofibrillary tangles.

Characterization of eleven monoclonal antibodies (MAbs), raised to isolated sodium dodecyl sulfate (SDS)-treated Alzheimer's neurofibrillary tangles (ANT), has revealed the presence of at least two different epitopes. MAbs were tested for reactivity to ubiquitin and paired helical filaments (PHF) isolated by three different procedures. The effect of protease and/or alkaline phosphatase pretreatment on the reactivity of the MAbs with isolated PHF was also examined. All MAbs that had reacted strongly in the ELISA with sonicated SDS-treated ANT also immune decorated isolated PHF to varying degrees. Two MAbs exhibited a high reactivity to PHF: 3-39 and 5-25. MAb 3-39 was found to recognize a protease sensitive epitope. In contrast MAb 5-25 was found to consistently decorate isolated PHF in all preparations and exhibited a strong reactivity to ubiquitin, and the epitope in isolated PHF was not protease sensitive. Thus structural PHF after protease treatment and detergent treatment contain an antigenic site that is present in ubiquitin.

Amebic meningoencephalitis in a patient with AIDS caused by a newly recognized opportunistic pathogen. Leptomyxid ameba.

A fatal case of meningoencephalitis due to a leptomyxid ameba in a patient with the acquired immunodeficiency syndrome is presented. This opportunistic organism has not been previously recognized as a human pathogen. A 36-year-old male intravenous drug abuser died after an 18-day hospital course heralded by fever and headache and followed by nuchal rigidity and hemiparesis. Computed tomography of the head showed multiple hypodense lesions. Neuropathologic examination showed that in addition to human immunodeficiency virus encephalomyelitis, there was multifocal meningoencephalitis with trophozoites and cysts morphologically indistinguishable from those of Acanthamoeba. These organisms were also found in the kidneys and adrenal glands. By immunofluorescence, the parasites showed antigenic identity with a free-living leptomyxid ameba and failed to react with any of a spectrum of antiacanthamoeba antisera. This emphasizes the importance of immunofluorescence identification of morphologically indistinguishable ameba species.

Skeletal muscle pathology in AIDS: an autopsy study.

A survey of skeletal muscle pathology in 92 autopsied cases of AIDS revealed microscopic alterations in 64 cases. There were 40 cases of disuse atrophy, 8 of denervation atrophy, 2 of cryptococcal myositis, 1 of Mycobacterium avium intracellulare (MAI) infection and 2 of necrotizing myopathy associated with hyperkalemia. A second group of cases with changes of unknown etiology was found. These were tentatively ascribed to the direct or indirect action of HIV. This category includes 8 cases of inflammatory myopathy, 8 of necrotizing myopathy in absence of a known etiological factor, 3 of extreme atrophy and 4 of "regenerating" myopathy.

Pathogenesis of amyloid formation in Alzheimer's disease, Down's syndrome and scrapie.

Paired helical filaments (PHF) are abnormal fibrous structures found in human nerve cells and their processes. Ultrastructural studies of the proto-filaments that make up the PHF revealed that the individual proto-filaments have a different substructure from normal neurofilaments or any other known fibrous profiles. Studies using immunological and biochemical methods suggested that abnormally phosphorylated tau, ubiquitin and neurofilament peptides are part of the PHF. Deposits of amyloid fibres in Alzheimer's disease and senile dementia of the Alzheimer type (AD/SDAT) are found in meningeal and brain vessels, choroid plexus and neuritic plaques. In 1984 Glenner and Wong reported the sequence of a beta-protein isolated from cerebrovascular amyloid. We used the amino acid sequence of the cerebrovascular amyloid protein to synthesize oligonucleotide probes specific for the gene encoding this amyloid protein. Screening of a human brain cDNA library allowed us to isolate a clone which encodes the amyloid peptide. In situ hybridization studies and Southern blot analysis of a DNA sample isolated from a human-mouse hybrid cell line indicated that the corresponding genomic sequences of this cDNA clone are located on human chromosome 21. Using immunochemical and histochemical methods, we have identified the cells associated with the formation of the amyloid fibres. With immunochemical and biochemical methods we and others also showed that the protein constituting amyloid in AD/SDAT is different from amyloid in unconventional slow virus diseases.

The effect of zinc on vitamin D3-induced cardiac necrosis.

Multifocal heart muscle necrotic lesions in rats were induced with high oral doses of vitamin D3 (300,000 iu/rat in three daily doses 100 000 iu each). The calcium content increased over 100 fold in the hearts of rats receiving vitamin D3. Parenteral pre-treatment with zinc sulphate (50 or 200 mg/rat in ten daily doses) resulted either in a reduction or in the total prevention of myocardial lesions on macroscopic, light and electron microscopic examination. The effect of zinc was dose-dependent. The administration of various doses of zinc sulphate resulted in a gradual normalization of heart calcium content.

Ultrastructure of the lung alveoli as revealed by freeze-etching technique.

The alveolar wall and the morphological equivalents of pulmonary surfactant have been studied by freeze-etching. Linear ridges on the fracture faces of the lamellae of lamellar bodies may represent early stages of transformation of lamellar bodies into tubular myelin. Parallel rows of particles on the fracture faces of tubular myelin are well documented, but the nature of these particles is not known.