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Biomedical subjects

V A Levin

Publications and source records attributed to V A Levin.

At least 73 records · Page 4Linked to original sources
PubMed1995

The treatment of brain stem and thalamic gliomas with 78 Gy of hyperfractionated radiation therapy.

PURPOSE: To see whether increasing the dose of hyperfractionated radiation therapy from 72 to 78 Gy would increase survival time in patients with gliomas, particularly those with brain stem or thalamic tumors. METHODS: Seventy-eight patients with a clinical and radiographic diagnosis of a brain stem or thalamic glioma were enrolled in a trial to receive 78 Gy (1.0 Gy twice a day). Six patients with disease in other sites were also treated. The initial response to therapy was determined by comparing pretreatment magnetic resonance images and neurological examinations with those obtained within 2 weeks of completing therapy; subsequent responses were determined from bimonthly follow-up images. Time-to-tumor progression was measured from the date radiation therapy began until the date of documented radiographic or clinical progression. Survival time was measured from the date radiation therapy began until the date of death. Cox proportional hazards analysis was used to estimate the effects of specific variables on survival. RESULTS: Of 81 evaluable patients, 68 received > or = 76 Gy, 10 received between 70 and 75 Gy, and 3 received between 60 and 68 Gy. The overall response or stabilization rate was 70.4%. Tumor size decreased in 30.8% of patients; 39.5% had stable disease, and 29.6% had immediate progression. The median survival time was 12.7 months (16.1 months for adults and 10.8 months for children). The median time to tumor progression was 9.0 months (11.4 months for adults and 8.4 months for children). A duration of symptoms < or = 2 months and a diffuse lesion were each associated with shorter survival and progression times. CONCLUSIONS: For patients with brain stem or thalamic gliomas, increasing the dose of radiation therapy from 72 to 78 Gy did not significantly improve survival. Different treatment strategies are clearly needed.

Adolescent↗
PubMed1995

The Functional Assessment of Cancer Therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors.

BACKGROUND: This report describes the development and validation of a brain subscale for the Functional Assessment of Cancer Therapy (FACT) scale, and the revalidation of the subscales of the general version (FACT-G), which measure physical, social, family, emotional, and functional well-being and the quality of the relationship with the physician. METHODS: 101 patients with primary brain tumors, after giving informed consent, participated in the last two phases of a four-phase validation process: item generation, item reduction, validation, and reliability testing. In the validation phase, FACT-G subscale and total scores as well as the brain subscale scores were correlated with other tests of mood, response, bias, and quality of life (QOL). Test-retest reliability testing was performed with 46 patients who had primary brain tumors. RESULTS: Validity and reliability coefficients were high for the FACT-G and brain subscale, except for the comparison with a second QOL measure (FP-QLI) and the Karnofsky Performance Status (KPS). The lower scores were the result of inherent differences in the two QOL instruments and the relatively high performance status of the brain tumor patients, which restricted the KPS score range. CONCLUSION: The FACT-G has good psychometric properties supporting its broad generalizability and the brain subscale tests substantially different QOL issues than the core instrument. Use of this scale with the addition of the brain subscale provides a well rounded view of the various aspects of QOL from the patient's perspective. With modifications and further psychometric testing, the brain subscale may have broader applicability to subpopulations of patients with other brain disorders.

Adult↗
PubMed1995

MR of toxic effects of accelerated fractionation radiation therapy and carboplatin chemotherapy for malignant gliomas.

PURPOSE: To present MR findings of parenchymal brain injury after accelerated fractionation radiation therapy combined with carboplatin chemotherapy in the treatment of malignant brain gliomas. METHODS: Eighty-one evaluable subjects in an ongoing treatment protocol for malignant gliomas form the patient base for this report. After surgical resection of tumors, patients underwent a course of accelerated fractionation radiation therapy to a total dose of 60 Gy. Carboplatin was infused intravenously before each radiation treatment. Precontrast and postcontrast MR scans were obtained before treatment and at 4-week intervals afterward and were analyzed retrospectively. RESULTS: Posttreatment MR imaging in 20 of the 81 patients showed development of unusual parenchymal lesions or enlarging masses needing debulking, and these patients underwent second operations. Two groups emerged: those with tumor and necrotic brain (n = 11) and those with necrosis and reactive gliosis but no definitive tumor (n = 9). Enhancing lesions in the tumor-negative group appeared later than those in the tumor-positive group, were often multiple, and were usually located several centimeters away from the tumor resection site or even contralaterally. Common locations were the corpus callosum and corticomedullary junctions. Lesions in the tumor-positive group were more often solitary and located immediately adjacent to the surgical site. Positive and negative results of positron emission tomography with fludeoxyglucose F 18 were obtained in both groups. The incidence of brain necrosis without associated tumor was 11%. CONCLUSIONS: A pattern of unusual enhancing parenchymal brain lesions was seen on MR imaging after accelerated fractionation radiation therapy and concomitant carboplatin chemotherapy. The abnormalities seem more extensive than focal necrotic lesions on enhanced CT or MR imaging after conventional radiation therapy, and they may mimic recurrent tumor.

Brain↗
PubMed1995

Inhibition of human glioblastoma cell growth by WAF1/Cip1 can be attenuated by mutant p53.

The WAF1/Cip1 protein is an important regulator at the G1 checkpoint in the cell cycle. The WAF1/Cip1 protein binds to the cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. We investigated the expression of WAF1/Cip1 protein in 14 glioblastoma cell lines and found that WAF1/Cip1 expression was detectable in many of the cell lines, even when mutant p53 was present. We also showed that WAF1/Cip1 protein level was very low in LN-Z308 cells that do not express endogenous p53. Transfection of the wild-type p53 into this cell line activated WAF1/Cip1 expression and inhibited cell growth. In contrast, transfection of the p53 mutant 248Trp failed to activate WAF1/Cip1 expression. Transfection of WAF1/Cip1 alone also inhibited LN-Z308 cell proliferation. However, cotransfection of the p53 mutant 248Trp with WAF1/Cip1 attenuated the growth-suppression effect of WAF1/Cip1. Our analysis with Western blot showed that the levels of cyclin E increased in cells transfected with p53 mutants. We conclude that p53 mutants may counter the negative regulators, such as WAF1/Cip1, by the elevation of positive cell cycle regulators, and the presence of WAF1/Cip1 in tumor cells is not sufficient for growth inhibition.

Brain Neoplasms↗
PubMed1995

Prognostic significance of p53 immunoreactivity in patients with glioma.

Abnormal p53 as revealed by immunostaining has been shown to be a predictor of poor outcome in a variety of malignant tumors. This study examines the relationship of p53 immunostaining and survival in 182 adult patients with gliomas. Tumor tissues obtained from patients with glioma within 4 months of initial diagnosis were investigated by immunohistochemical analysis for detection of p53 protein abnormalities using the monoclonal antibody PAb 1801. There were 122 patients with glioblastoma multiforme, 48 patients with anaplastic glioma, and 12 patients with low-grade glioma. Among these patients, 73 of those with glioblastoma multiforme, 35 with anaplastic glioma, and 6 with low-grade glioma had positive p53 immunoreactivity. Kaplan-Meier survival plots (log rank test) showed that the patients with anaplastic astrocytoma or low-grade glioma and p53-positive tumors had longer survival times compared to the patients with p53-negative tumors. No differences in survival were detected among the glioblastoma patients. Cox proportional hazards regression analysis, adjusted for age at diagnosis, showed that the p53 positivity was a significant predictor of longer survival (relative risk = 0.56; 95% confidence intervals = 0.35, 0.90; P = 0. 015) in anaplastic astrocytoma patients, but not in glioblastoma patients (relative risk = 1.03; 95% confidence intervals = 0.82, 1. 29; P = 0.80). These results suggest that anaplastic glioma patients with p53 protein alterations may have a better response to chemoradiation, possibly because the malignant cells cannot arrest in G1 to correct lethal damage induced by chemotherapy or radiotherapy.

Adult↗
PubMed1994

Pattern of recurrence of medulloblastoma after low-dose craniospinal radiotherapy.

PURPOSE: We retrospectively evaluated relapse of medulloblastoma after low- or high-dose craniospinal radiotherapy, and after conventional or hyperfractionated posterior fossa irradiation. METHODS AND MATERIALS: Ninety-two pediatric patients were treated postoperatively since 1970 at the University of California, San Francisco. Until 1989, we employed conventional fractionation with low (< or = 30 Gy) or high-dose craniospinal fields and low-dose (< or = 56 Gy) posterior fossa boosts. Recently, hyperfractionation delivered low- or high-dose to the craniospinal axis and high-dose to the posterior fossa. Most patients treated after 1979 received chemotherapy. RESULTS: Median follow-up was 70 months. Five-year disease-free survival was 36% (22% for poor-risk vs. 59% for good-risk patients). Five-year overall survival was 52% (43% for poor vs. 68% for good-risk). Neither the dose to the posterior fossa nor the craniospinal axis was statistically related to recurrence. Failure in the posterior fossa occurred despite boosts greater than 56 Gy. Females, over the age of 6 years, had significantly better relapse-free survival than males of the same age. Six of the 54 patients who relapsed were long-term survivors. CONCLUSIONS: Low-dose craniospinal radiotherapy, where the majority of patients received chemotherapy, was not associated with increased failure. High-dose posterior fossa hyperfractionation did not improve control. Long-term survival was noted in a number of patients after relapse. We recommend 60 Gy or greater with conventional fractions to the primary area, and continued study of low-dose craniospinal irradiation with adjuvant chemotherapy.

Adolescent↗
PubMed1994

Germline p53 gene mutations in subsets of glioma patients.

BACKGROUND: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma. We recently reported that multifocal gliomas are frequently associated with other primary malignancies, and we hypothesized that genetic alterations may account for this phenomenon. PURPOSE: We examined the frequency of germline p53 gene mutations in patients with glioma and either multifocality of lesions, history of an additional primary (different) malignancy, or a family history of cancer. METHODS: Lymphocytes from 51 glioma patients were analyzed for germline p53 gene mutations using RNA-polymerase chain reaction analysis, single-strand conformation polymorphism, and gene sequencing techniques. RESULTS: Germline p53 gene mutations were detected in six of 19 patients with multifocal glioma, including two with family history of cancer, one with another primary malignancy, and two with all three risk factors; one of four patients with unifocal glioma, another primary malignancy, and a family history of cancer; and two of 15 patients with unifocal glioma and a family history of cancer but no second malignancies. No mutations were detected in the patient with unifocal glioma and another malignancy or in the 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients having mutations were younger than other patients in the same group. CONCLUSIONS: Germline p53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. IMPLICATIONS: Relatives at high risk can be identified for genetic counseling, early cancer detection, and possible enrollment in chemoprevention trials.

Adult↗
PubMed1994

Neurochemical basis of interleukin 2-modified discrimination behaviour.

We trained one group of rats to discriminate 0.8 mg/kg intraperitoneal (i.p.) d-amphetamine from 1 ml/kg saline and the other to discriminate 0.3 mg/kg i.p. (+/-)-ethylketocyclazocine (EKC) from saline. Recombinant human interleukin 2 (rIL-2), 2 x 10(6) U/kg (or 8.2 nmol/kg) given i.p. 1 h prior to tests, potentiated responses elicited by 0.4 mg/kg d-amphetamine. This potentiation of d-amphetamine responses was suppressed by the opioid receptor antagonist naloxone (1 mg/kg) when administered i.p. together with IL-2. IL-2 (4 x 10(6) U/kg) alone produced EKC-like responses in the EKC-trained animals. The cytokine also potentiated 0.1 mg/kg EKC responses at 2 x 10(6) U/kg, an action that was suppressed by 1 mg/kg naloxone. Data from the present study show that IL-2 exerts the same neurochemical action as that previously observed with IFN-alpha for both d-amphetamine and EKC discrimination in rats.

Animals↗
PubMed1994

The opioid mechanism of interferon-alpha action.

Rats were trained to discriminate the opioid receptor agonist ethylketocyclazocine (EKC) (0.3 mg/kg body weight, intraperitoneally) from saline. Interferon-alpha (IFN-alpha), when substituted for EKC, elicited a dose-related increase in EKC-like responses. This generalization of EKC responses was blocked by the opioid antagonist naloxone (1 mg/kg). Potentiation of responses to a low dose (0.1 mg/kg) of EKC by IFN-alpha (1 x 10(6) U/kg or 0.22 nmol/kg) was also observed. Data thus indicate the involvement of opioid neurons on the action of IFN-alpha. d-Amphetamine (0.8 mg/kg) was shown to potentiate both EKC (0.1 mg/kg) and IFN-alpha (1 x 10(6) U/kg). The present study confirms our previously proposed opioid-mediated dopaminergic mechanism of IFN-alpha.

Animals↗
PubMed1994

Prognostic significance of bromodeoxyuridine labeling in primary and recurrent glioblastoma multiforme.

To evaluate the prognostic significance of bromodeoxyuridine (BUdR) labeling index (LI) and to estimate tumor proliferative potential, BUdR LI was examined in 98 patients having a primary diagnosis of glioblastoma multiforme (GBM); 55 underwent infusion of 200 mg/m2 of BUdR at the time of the primary resection and 49 underwent infusion at the time of the second resection. The tumors of six patients were labeled at both operations. The tumor specimens were stained with hematoxylin and eosin for histopathology and by immunohistochemical methods to determine the ratio of labeled to unlabeled cells, i.e., BUdR LI. The median BUdR LIs for the primary and recurrent GBM were significantly different at 6.8 and 2.6%, respectively (P < 0.0001). However, there was no significant association between BUdR LI at the first or second operation and survival (log rank, P = 0.12; Cox regression analysis, P = 0.91; log rank, P = 0.55; Cox regression analysis, P = 0.17, respectively). Patients who underwent a second operation within 10 months of the first operation had a lower BUdR LI than did patients with a longer interval between procedures (P = 0.078; Spearman rank correlation, 0.26). The aggressive biological behavior of GBM is dependent on complex cellular kinetics, not simply on the number of cells within the S phase of the cell cycle. Caution should be used when determining prognosis with BUdR LI in GBM.

Adult↗
PubMed1994

Activity of pp60c-src in 60 different cell lines derived from human tumors.

The activity of the protein tyrosine kinase pp60c-src was determined for each of the 60 human cell lines in the panel used by the National Cancer Institute for the random screening of potential anticancer drugs. The leukemia, lymphoma, melanoma, and small-cell lung cancer derived cell lines had low pp60c-src activity. Surprisingly, non-small-cell lung and ovarian cell lines had a median pp60c-src activity which was greater than that of the panel of cells representing colon cancer, which is most often associated with elevated pp60c-src activity. This data defines homologous cell lines which contain low and high pp60c-src activity which will aid attempts to understand the role of this enzyme in human cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Detection of cellular proteins that interact with the NF2 tumor suppressor gene product.

The neurofibromatosis type 2 (NF2) gene was recently cloned, and the protein it encodes (merlin) was revealed to belong to a family of proteins that link cytoskeletal components with proteins in the cell membrane. To elucidate the biological function of merlin, we produced a bacterial fusion protein consisting of glutathione S-transferase and merlin and used it to detect five merlin-binding cellular proteins, designated p165, p145, p125, p85 and p70, by a protein-binding assay. p165 and merlin were phosphorylated on serine/threonine residues, and immunoprecipitation showed that p85 bound the native form of merlin. Although the entire merlin-ezrin-radixin-moesin (MERM) homology domain of merlin was found to be essential for binding to all five proteins, the MERM homology domains of ezrin and moesin did not bind to any of the five proteins. Since most reported NF2 mutations are in the region we determined was necessary for binding, the mutations probably impair binding. Therefore, the formation of the protein complex is probably crucial for tumor suppression.

Base Sequence↗
PubMed1993

Bacterial expression of an active tyrosine kinase from a protein A/truncated c-src fusion protein.

The carboxy-terminal half of the c-src protein fused to the protein A moiety was expressed in bacteria. The protein A/truncated c-src fusion protein, which does not have SH2 and SH3 domains, is found in the periplasmic space allowing for a simple one-step purification and demonstrated high efficiency in autophosphorylation and exogeneous substrate phosphorylation. The missense mutation at codon 294 (Ile-->Thr), which is located in the ATP-binding domain of the c-src, resulted in dramatic reduction of tyrosine kinase activity of the fusion protein. Using the fusion protein, we also revealed that staurosporin, a well-known kinase inhibitor, directly affects autophosphorylation of the C-terminal half of the c-src protein. This truncated c-src expression system provides a good source of enzyme for diverse experiments and is an ideal model for understanding the implication of structural alterations in the catalytic activity of the c-src kinase by site-directed mutagenesis experiments.

Alkaloids↗
PubMed1993

Detection of p53 alterations in human astrocytomas using frozen tissue sections for the polymerase chain reaction.

The polymorphism of amino acid residue 72 on the human p53 tumor-suppressor gene is a useful marker for detecting intragenic loss of heterozygosity (LOH). We examined the LOH of the p53 gene in human malignant astrocytomas by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis using DNA extracted from frozen tissue sections under histologic examination. Eleven of 16 informative cases (69%) of the malignant astrocytomas were found to have LOH in the p53 gene. Sequential frozen sections were analyzed by immunohistochemistry using anti-p53 antibody PAb1801 to detect overexpression of the p53 protein, which is presumably altered if it is detectable. Ten of the 11 cases that had LOH of the p53 gene overexpressed the p53 protein. Moreover, 4 of the 11 patients with LOH of the p53 gene developed a second neoplasm in addition to an astrocytoma, possibly indicating genetic instability in these patients. These data suggest that alterations of the p53 gene may play an important role in the genesis of malignant astrocytoma. The combination of the PCR-RFLP method and immunohistochemical analysis using frozen tissue sections is a practical diagnostic tool for examination of human malignancies, including astrocytomas. astrocytomas.

Astrocytoma↗
PubMed1993

Lipid peroxidation does not appear to be a factor in late radiation injury of the cervical spinal cord of rats.

PURPOSE: We tested the role of lipid peroxidation in the demyelination and white matter necrosis associated with radiation injury of the central nervous system. METHODS AND MATERIALS: We irradiated the cervical spinal cords of female F344 rats (23 Gy) and assayed for the accumulation of the peroxidation byproducts malondialdehyde and hydroxyeicosatetraenoic acids, and for the consumption of the endogenous free radical scavengers vitamins E and C. We further tested the role of lipid peroxidation in radiation injury of the central nervous system by determining the sensitivity of the cervical spinal cord to radiation in rats on diets containing deficient, normal, and supplemental levels of the antioxidant vitamin E. Rats were placed on these diets at 4 weeks of age and irradiated (18.5-21.5 Gy) 16 weeks later. RESULTS: During the 5 months between irradiation and the onset of paralysis, no accumulation of peroxidation byproducts or consumption of endogenous scavengers was seen in the cervical spinal cords of the irradiated rats. The cervical spinal cords of some of the rats placed on the diets with deficient, normal, and supplemental levels of vitamin E were analyzed at the time of irradiation and contained 197 +/- 57, 501 +/- 19, and 717 +/- 35 pmol vitamin E/mg protein, respectively. Despite the statistical differences in these levels, the radiation sensitivity of the cervical spinal cord (ED50 for white matter necrosis) in rats receiving the three diets was not different (20.4, 20.7, and 20.6 Gy). CONCLUSION: These data do not support a role for free radical-induced lipid peroxidation in the white matter damage seen in radiation injury of the central nervous system.

Animals↗