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Biomedical subjects

R L Davis

Publications and source records attributed to R L Davis.

At least 289 records · Page 16Linked to original sources

Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas.

To determine the percentage of patients who developed multiple central nervous system (CNS) gliomas during postoperative radiation therapy and chemotherapy, the authors reviewed the records of 1047 patients treated between December 2, 1976, and August 16, 1985, who had an original diagnosis of supratentorial glioblastoma multiforme or other anaplastic glioma. The occurrence of multiple lesions was verified by neurodiagnostic studies (computerized tomography or myelography) or by findings at operation or autopsy. Twelve patients (1.1%) who presented with multiple lesions were excluded from this analysis. There were 405 patients with glioblastoma multiforme; their median age was 46.5 years (range 22 to 70 years). Eighteen (5%) of these patients had multiple CNS lesions, five of which were in the spinal cord. The median time from diagnosis to detection of the second lesion in this group was 59.5 weeks (range 10 to 182 weeks). There were 630 patients with anaplastic glioma (which included mixed malignant glioma and highly anaplastic, gemistocytic, moderately anaplastic, and anaplastic astrocytomas); their median age was 30 years (range 2 to 62 years). Fifty-four (8.6%) of these patients had multiple lesions, 10 of which were in the spinal cord; only one case of extraneural metastasis was found. The median time from diagnosis to detection of the second lesion in this group was 101 weeks (range 14 to 459 weeks). These results show that more than 90% of CNS gliomas recur at the site of the original tumor. Considering the high frequency of intellectual dysfunction after whole-brain radiation therapy, the use of focal radiation fields appears to be the most judicious approach to the treatment of patients with gliomas.

Adult↗

Northern California Oncology Group protocol 6G91: response to treatment with radiation therapy and seven-drug chemotherapy in patients with glioblastoma multiforme.

The Northern California Oncology Group (NCOG) conducted a nonrandomized phase II study to evaluate the benefit of a seven-drug chemotherapy protocol (NCOG 6G91) in patients with glioblastoma multiforme (GM). Time to tumor progression was the primary end point of the study. The treatment consisted of 5-FU and lomustine administered after surgery and before radiation therapy, hydroxyurea and misonidazole during radiation therapy, and procarbazine and vincristine alternated with carmustine and 5-FU after radiation therapy. Ninety patients entered the study; data from the 64 patients with GM who completed radiation therapy and at least started the postradiation chemotherapy regimen and returned for follow-up examination are analyzed in this report. The median time to tumor progression in the 64 adequately treated patients was 42 weeks; the 25th percentile value was 60 weeks. A Cox multivariate analysis showed that age and extent of surgical resection were important prognostic variables in patients with GM. The results of this treatment regimen were similar to those of a previous NCOG protocol (6G61), which consisted of hydroxyurea during radiation therapy followed by chemotherapy with carmustine or a combination of lomustine, procarbazine, and vincristine.

Adult↗

Establishment and characterization of a cell line from a human gliosarcoma.

A human gliosarcoma culture was characterized from the time of inception to the time of establishment of the cell line (SF-539 BT). Immunohistochemical analysis of the original tumor showed 2 distinct regions of cells. The gliomatous regions were identified by immunostains for glial fibrillary acidic protein and the sarcomatous regions by immunostains for laminin, collagen type IV, procollagen type III, and fibronectin. In early-passage culture, both types of cells maintained their characteristic immunohistochemical profiles; however, after the fourth subcultivation in monolayer culture, no cells expressing glial fibrillary acidic protein could be identified. All cells had become morphologically uniform and expressed laminin, collagen type IV, procollagen type III, and fibronectin only. The immunostaining profile of clones grown in soft agar was similar to that of cells in monolayer culture. At establishment, SF-539 BT has a saturation density of 1.3 X 10(6) cells/25 sq cm, a doubling time of 32 h, and a plating efficiency of 22% in monolayer culture. The tumor cell line is resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, has an abnormal karyotype, grows anchorage independently, and forms a tumor that most closely resembles a spindle cell sarcoma in athymic mice. Its ultrastructure in monolayer culture consists of large cells with an expanded rough endoplasmic reticulum and abundant multivesicular bodies; in athymic mice, extracellular collagen fiber formation is prominent. DEAE-cellulose chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cultures labeled with [3H] proline demonstrated interstitial collagen formation. We conclude that the cell line at establishment is a collagen-producing spindle cell sarcoma that resembles the sarcomatous regions of the original mixed tumor. Further cell separation and characterization studies are needed to determine the pathogenesis of mixed tumors such as gliosarcoma.

Animals↗

Phase II study of combined carmustine, 5-fluorouracil, hydroxyurea, and 6-mercaptopurine (BFHM) for the treatment of malignant gliomas.

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Adolescent↗

Pneumonia caused by a relatively resistant strain of Streptococcus pneumoniae.

A patient with pneumonia caused by a relatively resistant strain of Streptococcus pneumoniae that did not respond to prolonged therapy with intravenous ampicillin is described, and general principles of treatment for such cases are reviewed. The patient was a 16-month-old, 10-kg girl who was admitted to a hospital for treatment of severe smoke inhalation and burns. The patient was intubated immediately, but her respiratory status remained unstable. Chest roentgenograms showed numerous episodes of pneumonia; the organism was later identified as Strep. pneumoniae. Despite empiric therapy with ampicillin and tobramycin followed by a prolonged course of ampicillin and subsequent treatment with cefazolin, the patient's respiratory status did not improve, and she continued to have elevated temperatures. Strep. pneumoniae isolated from her blood was identified as relatively resistant to penicillin but sensitive to chloramphenicol. After a seven-day course of chloramphenicol, the patient recovered and was later discharged. Relatively resistant Strep. pneumoniae (RRSP) infections often occur at sites where high antibiotic concentrations are not achieved, such as in the CNS. Prior antibiotic therapy may increase or have no effect on the incidence of RRSP. The mechanism for RRSP is unknown, and these infections often are not detected until a patient has failed to respond to conventional therapy. Also, the incidence of RRSP has not been determined because many hospitals do not perform susceptibility tests for pneumococcal isolates routinely. Vancomycin or chloramphenicol may be alternates to penicillin for the treatment of RRSP, but antibiotic sensitivities should be determined for each isolate to ensure susceptibility.

Ampicillin↗

Tumor markers and cytologic features of cerebrospinal fluid.

Tumor markers are useful in establishing the diagnosis of certain central nervous system tumors, especially germinal tumors of the pineal region. They are not sufficiently specific to be able to replace biopsy for exact diagnosis. They may also be useful for monitoring of therapy, as an indicator of recurrence of the tumor. Cerebrospinal fluid cytology is not generally useful in establishing a specific histologic diagnosis, especially in children, but can help to monitor therapy and predict tumor recurrence. More extensive studies are needed in both areas to define more precisely the role of markers and cytologic studies.

Brain Neoplasms↗

Revision of the World Health Organization classification of brain tumors for childhood brain tumors.

A classification for childhood brain tumors based upon revision of nomenclature of all brain tumors published by the World Health Organization (WHO) in 1979 is proposed. Applicability of the WHO classification scheme was tested in a combined study of the clinical and pathologic features of approximately 3300 brain tumors in children. It was found to be adequate for many of the neoplasms but unsuitable for a significant proportion, including a number of complex cerebral tumors for which there was no appropriate name. Nomenclature of poorly differentiated or densely cellular neuroepithelial tumors was simplified to reflect the current state of knowledge of neuroembryology and neuro-oncology, although the Committee members recognized that such a proposal would likely perpetuate the long-standing and continuing controversy relative to the nature and origin of these neoplasms.

Brain Neoplasms↗

Herpes simplex virus type 2 encephalitis in two homosexual men with persistent lymphadenopathy.

Within a 5-month period, 2 homosexual men with persistent lymphadenopathy developed clinical findings consistent with herpes simplex virus (HSV) encephalitis. These signs included abrupt change in mental status, seizures, cerebrospinal fluid pleocytosis, and localized electroencephalographic abnormalities showing temporal lobe involvement. Initial computed tomographic scans were unremarkable. Treatment with adenine arabinoside was instituted and temporal lobe biopsies were performed. Although virus-specific antigens were detectable in only 1 patient, cultures of biopsy tissue from both patients yielded HSV type 2 organisms. Spiking fevers persisted and the patients failed to improve, prompting administration of acyclovir. Both patients recovered gradually after their second course of antiviral therapy and survived with severe neurological deficits. These patients should raise concerns about an increased incidence of type 2 encephalitic illness among homosexual men with persistent lymphadenopathy or acquired immune deficiency syndrome. In addition, the importance of using HSV type 2 antibody in the immunofluorescence test of brain biopsy tissue for rapid diagnosis of the disease is emphasized.

Adult↗

Cytomegalovirus and herpes simplex virus ascending myelitis in a patient with acquired immune deficiency syndrome.

Progressive ascending myelitis was the presenting feature of the acquired immune deficiency syndrome (AIDS) in a homosexual man who also had Kaposi's sarcoma, Pneumocystis pneumonia, and disseminated cytomegalovirus (CMV) infection. Neuropathological studies showed profuse cytomegalic cells throughout the brain and spinal cord, but no inflammatory response. At postmortem examination, CMV and herpes simplex virus, type 2 (HSV-2), were recovered from multiple sites throughout the central nervous system (CNS). HSV-2 was isolated from the anus, but from no other extraneural site; in contrast, pathology typical of CMV was also seen in the liver, gastrointestinal tract, adrenals, and lungs. Although histopathological evidence suggesting prior CMV infection has been seen in the brains of AIDS patients, the virus has never been cultured from the CNS in these immunosuppressed hosts, nor has it been known to infect the spinal cord. The absence of an inflammatory response suggests that the pathogenesis of CNS viral infections is altered in AIDS patients. Evidence for CMV infection of the CNS in AIDS patients is no longer circumstantial.

Acquired Immunodeficiency Syndrome↗

Selecting and recruiting health programs for the School Health Education Evaluation.

The School Health Curriculum Project (SHCP) and three promising health education approaches, Project Prevention, 3 Rs and High Blood Pressure (HBP), and Health Education Curriculum Guide, were the curricula used in the School Health Education Evaluation (SHEE) project. This paper contains program descriptions of each, and a brief description of the process that led to their selection. Inclusion of the School Health Curriculum Project (SHCP) was mandated by the use of government funds to support the SHEE. The three alternative curricula, Project Prevention, 3 Rs and High Blood Pressure, and Health Education Curriculum Guide, were selected on the basis of a protocol devised jointly by contractors, government project officers, and the project advisory panel.

Attitude to Health↗

Comprehensive school health education: a practical definition.

This article identifies 10 essential elements of comprehensiveness related to school health education that have been agreed upon by key personnel long involved in one or more of the four school health curriculum programs studied in the School Health Education Evaluation (SHEE) study. Each element is briefly described and followed with one or two examples of practical applications selected from the four curricula. The authors further concur with the concept that a Consumer Reports type of reporting of school health curriculum models might be useful in further SHEE data analysis and that the "elements of comprehensiveness" concept might be a valuable adjunct to such reporting.

Adolescent↗

Pharmacokinetics of three oral formulations of ciprofloxacin.

We compared the absorption of three formulations of ciprofloxacin after oral administration in 18 normal adult male volunteers. Each subject received 500 mg of ciprofloxacin as two 250-mg tablets, one 500-mg tablet, or a solution in a randomized crossover sequence. Pharmacokinetic parameters were determined by model independent methods. Because a solution is considered to be the ideal oral dosage form, the results determined for the tablets were compared to those for the solution. Mean values for the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, and the elimination half-life were 3.23 micrograms/ml, 1.00 h, and 5.04 h, respectively, for the solution. The mean renal clearance of ciprofloxacin was 372 ml/min and accounted for at least 50% of the total clearance. We recovered 44.4, 48.6, and 55.8% of the administered ciprofloxacin from the urine as unchanged drug within 24 h after dosing with the 250-mg tablets, 500-mg tablets, or solution, respectively. The 500-mg tablets were found to be bioequivalent to the solution with regard to all pharmacokinetic parameters. The 250-mg tablet was not bioequivalent to either of the other formulations; the relative bioavailability values were 78.7 and 74.1%, respectively, for the 500-mg tablet and the solution. The clinical significance of this difference in bioavailability is yet to be determined.

Administration, Oral↗

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

The v-abl protein of Abelson murine leukemia virus is a tyrosine-specific kinase. Its normal cellular homolog, murine c-abl, does not possess detectable tyrosine kinase activity in vitro. Previously, we have detected tyrosine kinase activity in vitro for an altered c-abl gene product (c-abl P210) in the K562 human chronic myelogenous leukemia cell line. The expression of this variant c-abl gene product correlates with chromosomal translocation and amplification of the c-abl gene in K562 cells. Like v-abl, c-abl P210 is a fusion protein containing non-abl sequences near the amino terminus of c-abl. We compared the in vitro tyrosine kinase activity of c-abl P210 with that of wild-type murine v-abl. The remarkable similarities of these two proteins with respect to cis-acting autophosphorylation, trans-acting phosphorylation of exogenous substrates, and kinase inhibition, using site-directed abl-specific antisera, suggested that c-abl P210 could function similarly to v-abl in vivo. In addition, c-abl P210 possessed an associated serine kinase activity in immunoprecipitates. The serine kinase activity was not inhibited by site-directed, abl-specific antisera that inhibit the tyrosine kinase activity, suggesting that the serine kinase activity is not an intrinsic property of c-abl P210. Thus, the activation of the c-abl gene in a human leukemia cell line may have functional consequences analogous to activation of the c-abl gene in Abelson murine leukemia virus.

Abelson murine leukemia virus↗

Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis sputum.

We studied sputum tobramycin concentrations after intravenous administration in 10 cystic fibrosis patients. Tobramycin concentrations were determined by a bioassay and a radioenzymatic assay (REA). The bacterial density of Pseudomonas aeruginosa in sputum was examined serially during therapy. Bioactivity of tobramycin in the sputum was low and increased little during treatment. In contrast, tobramycin content (as assayed by REA) showed a progressive accumulation of the drug to high concentrations: a mean of 82 micrograms/g sputum after 3 wk of therapy in 4 patients. Pseudomonas aeruginosa was eradicated from the sputum in 3 of 4 patients receiving antibiotic therapy for 3 wk. Eradication correlated with tobramycin sputum concentrations measured by REA, which were 20-fold greater than the apparent tobramycin inhibitory concentration. A bactericidal effect of aminoglycosides in the presence of sputum in vitro could only be reliably produced with concentrations 25-fold the MIC. We conclude that tobramycin penetrates cystic fibrosis (CF) sputum and accumulates over time. Although CF sputum antagonized the bioactivity of aminoglycosides, 3 wk of intravenous therapy combined with an antipseudomonal beta-lactam antibiotic may be effective in eradication of P. aeruginosa from sputum of certain CF patients.

Adolescent↗

Postirradiation cerebellar glioma. Case report.

A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

Adolescent↗

Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas.

The authors report the results of a randomized study conducted to evaluate the relative benefit of treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine (PCV) administered after radiation therapy with hydroxyurea to 76 evaluable patients with glioblastoma multiforme and 72 patients with other anaplastic gliomas. The primary end-point of the study was time to tumor progression. For better-risk patients with Karnofsky performance scores of 70 to 100, results suggest that PCV was of greater benefit than BCNU (p = 0.15 for glioblastoma multiforme; p = 0.13 for other anaplastic gliomas). Median times to tumor progression were 31 and 32 weeks for patients with glioblastoma multiforme; 25th percentile times to progression were 70 and 40 weeks for patients treated with PCV and BCNU, respectively. For patients with other anaplastic gliomas treated with PCV and BCNU, median times to progression were 123 and 77 weeks, respectively. Multivariate analysis showed that the prognostic variables of age and Karnofsky scores were important for patients with glioblastoma multiforme and other anaplastic gliomas, and that the extent of surgical resection was important for those with other anaplastic gliomas.

Adult↗

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricularly administered bleomycin in beagles.

The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [3H]inulin was used as a reference compound. Both [3H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a "minimally toxic" dose of bleomycin (approximately 0.1 mg/week) produces a CSF C X t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.

Animals↗