Prognostic implications of p53 nuclear overexpression and high proliferation index of Ki-67 in adult soft-tissue sarcomas.

BACKGROUND: Morphologically similar soft-tissue sarcomas may behave in very different fashions, making it difficult to predict clinical outcomes and to properly design therapeutic interventions. In a preliminary study, we observed that TP53 mutations and nuclear overexpression of p53 protein were frequent events in soft-tissue sarcoma, and we noticed an association between p53-positive phenotype and poor clinical outcome. PURPOSE: We examined the potential clinical relevance of p53 overexpression in adults with soft-tissue sarcomas. We also studied the clinical implications of a high proliferation index. METHODS: A cohort of 174 adults with soft-tissue sarcomas were analyzed using anti-p53 and anti-Ki-67 antibodies and immunohistochemical assays on consecutive fresh frozen tissue samples. RESULTS: We observed a significant association between p53 nuclear overexpression and tumor grade (P = .001) and tumor size (P = .01). Patients displaying a p53-positive phenotype had significantly reduced survival (P = .02). Similarly, a significant difference was observed between high proliferation index and tumor grade (P < .001) and reduced patient survival (P = .03). A high Ki-67 proliferation index was detected in association with p53 nuclear overexpression. CONCLUSIONS: Overexpression of p53 protein and a high proliferation index strongly correlate with poor clinical outcome and reduced survival in patients having soft-tissue sarcomas.

Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas.

Genetic alterations in the p53 and mdm2 genes have been reported to occur in soft tissue sarcomas. This study was designed to determine the prevalence and potential clinical value of detected molecular abnormalities and altered patterns of expression of mdm2 and p53 genes in adult soft tissue sarcomas. A cohort of 211 soft tissue sarcomas from adults that were both clinically and pathologically well characterized was analyzed. Monoclonal antibodies directed against mdm2 and p53 proteins were used to measure overexpression of these proteins in the nuclei of cells from sections of these tumors. Seventy-six of 207 tumors had abnormally high levels of mdm2 proteins and 56 of 211 tumors overexpressed p53 protein. Twenty-two cases had abnormally high levels of both mdm2 and p53 proteins based upon immunoreactivity with these antibodies. There was a striking statistically significant correlation between the overexpression of p53 and mdm2 proteins in the same tumor and poor survival (P < 0.05) of the patients. A group of 73 soft tissue sarcomas was chosen for analysis using Southern blots, single strand conformation polymorphisms, and direct DNA sequencing to confirm mdm2 gene amplifications and p53 mutations and correlate these with the results of the immunoreactivities. The overexpression of p53 and mdm2 proteins in the nuclei of tumor cells did not always correlate well with gene amplification at the mdm2 locus or mutation at the p53 gene. The possible reasons for these discrepancies are discussed.

Validity of the MMPI with native Americans.

A study was conducted to determine the validity of the MMPI for 142 American Indian patients from Pacific Northwest tribes. All the MMPI profiles were similar and had significant elevations in the Sc, Pd, and Pa scales. There was no significant difference between diagnostic groups on many clinical scales. Nonpsychotic, depressed Indian patients could not be distinguished from schizophrenic patients on any clinical scale, and there were no significant differences between antisocial-alcoholic patients and those with situational reactions. There were minimal differences between the Northwest Coast, Plateau, and Plains cultural groups. The authors believe that the similarity of all subgroup profiles demonstrates a significant cultural influence on the results of the MMPI in this population of American Indians.

Tobacco smoking, occupation, and p53 nuclear overexpression in early stage bladder cancer.

Epidemiological studies show an increased risk of bladder cancer associated with tobacco smoking and occupational exposures. Certain carcinogens in tobacco and occupational exposures cause DNA damage and may produce specific mutations. TP53 is considered a common target for carcinogenic agents, and mutations of this gene are reported to be the most frequent nuclear abnormalities in human cancer. In order to investigate the relationship between tobacco smoking, occupations, and altered patterns of p53 expression, we have analyzed a group of 109 incident patients with superficial transitional cell carcinoma of the bladder. We assessed p53 nuclear overexpression by the use of anti-p53 antibody PAb1801 and immunohistochemistry, and identified 45 of 109 patients (41%) displaying p53-positive phenotype. We observed a significant association between the number of cigarettes smoked per day and p53 nuclear overexpression (p = 0.02). The odds ratios were 2.3 for those smoking 1-2 packs per day and 8.4 for smoking more than 2 packs per day. Similar estimates were obtained after controlling for age, sex, and race. Elevated odds ratios were also observed for dye-/ink-related (odds ratio = 2.0; 95% CI, 0.4-9.4) and cooking-related occupations (1.8, 0.6-5.0), although those were not statistically significant. These data support the hypothesis that certain carcinogens derived from cigarette smoking and occupations may induce TP53 mutations, which in turn are involved in early steps of bladder carcinogenesis.

Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.

Reliability of smoking history in medical charts in relation to interview data.

We previously reported on a series of studies exploring relationships between cigarette smoking and mutations of tumor suppressor genes; the studies relying on medical charts for data on smoking. To assess the accuracy of these data we compared them with data obtained using a conventional epidemiologic interview. As part of an ongoing case-control study of tobacco-related cancers, a trained interviewer questioned 144 patients about their smoking habits using a structured interview instrument; the medical charts were then reviewed. Using the Spearman test to compare the data obtained from the two sources, the correlation coefficient was 0.85 for cigarettes per day; 0.88 for years of smoking and 0.95 for pack-years, suggesting that the data in the charts were reliable. The kappa coefficient was 0.96 for current smoking status, indicating a very strong agreement between the two sources of data. The sensitivity and specificity for chart review were 96.3% and 100% respectively, compared with the 'gold standard' of a structured interview. These results show that when patients cannot be interviewed, for example when performing retrospective studies using existing collections of archived tumors or other biologic materials, then data on smoking abstracted from medical charts may be a reliable substitute.

Factors associated with p53 nuclear accumulation in prostatic adenocarcinoma.

Prostatic adenocarcinoma is an age-related cancer. The extremely high proportion of this disease with advanced age merits the study of age-dependent carcinogenesis. TP53 is considered a common target for carcinogenic agents including exogenous carcinogens as well as endogenous mutagens. Mutations of this gene are reported to be the most frequent nuclear abnormalities in human cancer. In order to investigate the relationship between age and altered patterns of p53 expression, we have analyzed a group of 48 patients with primary prostatic adenocarcinoma. We assessed p53 nuclear accumulation immunohistochemically by the anti-p53 antibodies PAb1801 and CM-1, and identified 9 out of 48 patients (19%) displaying p53-positive phenotype. We observed a significant association between advanced age and p53 nuclear accumulation. The data suggest that p53 nuclear accumulation may be related to the aging process in prostatic adenocarcinoma.

Menstrual cycle and social behavior in vervet monkeys.

We assessed the relationship between social behavior and the menstrual cycle in 11 adult female vervet monkeys (Cercopithecus aethiops sabaeus) living in an established, stable social group. The findings indicated that fluctuations in ovarian steroids are accompanied by behavioral changes in vervet monkeys. A significant increase in aggressive action, avoidance of social overtures, and retreats from threat occurred during the late luteal phase. However, the social environment can greatly affect behavior independent of the phase of the menstrual cycle. The 10 nondominant (or subordinate) individuals not only exhibited behavioral changes across their own menstrual cycles, but also were responsive to the dominant female's cycle. During the dominant female's late luteal phase, subordinate females significantly increased aggression and decreased social activity. Some of behavioral patterns in female vervet monkeys are therefore relatively independent of direct hormonal modulation and support the contention of the dominant female as the driving force for behavioral changes related to aggression and social interaction. The differential effect of hormones and social status and other environmental factors on behavior has not been critically evaluated in human studies of the premenstrual syndrome. The present study suggests that it is important to assess which behavioral patterns in women are hormonally mediated and which are dependent on the environment.

Factors associated with six-month mortality in recipients of community-based long-term care.

OBJECTIVES: To determine factors associated with short-term mortality in recipients of community-based long-term care (CBLTC). DESIGN: A cohort study. SETTING: A Medicaid home- and community-based waiver and state-funded homecare program. PARTICIPANTS: All persons age 65 and older newly admitted to the program from January 1, 1988, to March 31, 1991. MEASUREMENTS: Demographics, functional, cognitive, and health status, depression, and social support were obtained in an admission assessment. Six-month mortality data were obtained by linking assessment data to a state mortality registry. RESULTS: There were 718 deaths among 6784 CBLTC clients. Male sex (AOR 1.8, 95% CI 1.5-2.1), the presence of cancer (AOR 3.2, CI 2.6-3.9), heart disease (AOR 1.3, CI 1.1-1.5), chronic obstructive pulmonary disease (AOR 1.8, CI 1.4-2.2), or nutritional problems (AOR 1.7, CI 1.4-2.0), functional impairment (AOR for lowest compared to highest quartile 2.9, CI 2.0-4.1), severe cognitive impairment (AOR 1.6, CI 1.3-2.1), self-assessment of health as poor (AOR 1.5, CI 1.1-2.0), feeling depressed (AOR 1.2, CI 1.1-1.3), and hospitalization (AOR 2.7, CI 2.2-3.2) were independently associated with 6-month mortality in bivariate and multivariate analyses. CONCLUSIONS: Clinical data obtained during routine assessment of CBLTC clients can be used to assess short-term mortality. Six-month mortality is associated with poor functional and cognitive status, the presence of cancer, heart disease, COPD, and nutritional problems, depression, perception of poor health, and hospitalization.

Who dies at home? Determinants of site of death for community-based long-term care patients.

OBJECTIVE: To determine characteristics associated with site of death in a cohort of long-term homecare patients. DESIGN: Cohort study. SETTING: Community-based long-term care program. SUBJECTS: All patients 65 years of age or older who died within 1 year of admission during 1989 and 1990. MAIN OUTCOME MEASURE: Site of death. RESULTS: Of 620 subjects, site of death was hospital for 302 (49%), home for 132 (21%), nursing home for 124 (20%), and inpatient hospice for 45 (7%). Among patients living at home before death, factors associated with dying at home rather than in a hospital or inpatient hospice included female gender (relative risk (RR) 1.40, 95% confidence interval (CI) 1.00, 1.90); severely dependent functional status (RR 2.38, CI 1.39, 4.17) and cognitive status (RR 1.51, CI 1.10, 2.06); and dying of cancer (RR 1.68, CI 1.11, 2.55), chronic lung disease (AOR 1.75, CI 1.04, 2.95), or coronary artery disease (RR 1.93, CI 1.21, 3.09). Living with a child (RR 1.45, CI .99, 2.11) showed a trend toward association with dying at home. CONCLUSIONS: Even among a subgroup of older persons receiving community-based long-term care, the frequency of home death is low. The finding of an association between functional, social, and disease status and site of death suggests that the relationship between these factors and patients' preferences and care needs must be examined in order to understand how to optimize the site of terminal care.

A critique and case study of nodular sclerosing Hodgkin's disease.

This paper presents a critique of the present concepts of the pathology of nodular sclerosing Hodgkin's disease and particularly of the criteria required for diagnosis for the condition and its separation from other types of Hodgkin's disease. In addition, the natural history and histopathology of the condition have been studied among 104 cases of Hodgkin's disease presenting at The London Hospital, and the significance of the appearance is discussed.

Application of positron emission tomography to determine cerebral glucose utilization in conscious infant monkeys.

Cerebral glucose metabolism has been used as a marker of cerebral maturation and neuroplasticity. In studies addressing these issues in young non-human primates, investigators have used positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) to calculate local cerebral metabolic rates of glucose (1CMRG1c). Unfortunately, these values were influenced by anesthesia. In order to avoid this confounding factor, we have established a method that permits reliable measurements in young conscious vervet monkeys using FDG-PET. Immature animals remained in a conscious, resting state during the initial 42 min of FDG uptake as they were allowed to cling to their anesthetized mothers. After FDG uptake, animals were anesthetized and placed in the PET scanner with data acquisition beginning at 60 min post-FDG injection. FDG image sets consisted of 30 planes separated by 1.69 mm, parameters sufficient to image the entire monkey brain. Our method of region-of-interest (ROI) analysis was assessed within and between raters and demonstrated high reliability (P < 0.001). To illustrate that our method was sensitive to developmental changes in cerebral glucose metabolism, quantitative studies of young conscious monkeys revealed that infant monkeys 6-8 months of age exhibited significantly higher 1CMRG1c values (P < 0.05) in all regions examined, except sensorimotor cortex and thalamus, compared to monkeys younger than 4 months of age. This method provided high resolution images and 1CMRG1c values that were reliable within age group. These results support the application of FDG-PET to investigate questions related to cerebral glucose metabolism in young conscious non-human primates.

Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys.

In a counter-balanced, cross-over study, we examined the contributions of serotonergic systems to the acquisition of social dominance in adult male vervet monkeys. Subjects were members of 12 social groups, each containing 3 adult males, at least 3 adult females, and their offspring. Animals were observed in 5 intervals including a first baseline, a first experimental, a second baseline, a second experimental, and a third baseline period. At the end of the first baseline period, the dominant male was removed from each group. In each group, one of the two remaining subordinate males was selected at random for treatment and during the first experimental period, 6 of the 12 treated males received drugs that enhanced serotonergic activity (3 were given tryptophan 40 mg/kg/day and 3 fluoxetine 2 mg/kg/day). The other 6 treated males received drugs that reduced serotonergic function (3 were given fenfluramine 2 mg/kg/day and 3 cyproheptadine 60 micrograms/kg/day). At the end of the first experimental period, the original dominant male was returned to his group and the second baseline period began. In all instances, the originally dominant male regained his dominant position. The second experimental period began with the dominant male again being removed and, the 12 treated males were given the treatment they had not received in the first experimental period. At the start of the third 12-week baseline period, the original dominant male was returned to his group and resumed his dominant status. When the 12 treated subjects received tryptophan or fluoxetine, they became dominant in all instances. When they received fenfluramine or cyproheptadine, their vehicle-treated cage mates became dominant. The sequence of the behavioral changes shown by the treated males as they acquired dominance status paralleled those seen in naturalistic conditions. These observations support the distinction between dominance and aggression and strongly suggest that when hierarchical relationships are uncertain, serotonergic mechanisms may mediate the behaviors which permit a male to attain high dominance status.

Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during the first year of life as measured by positron emission tomography.

Recently, advances in spatial resolution have provided the opportunity to utilize positron emission tomography (PET) to examine local cerebral metabolic rates for glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated lCMR(glc) measurements in the same animal. Previous studies have attempted to describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of sedation during the tracer uptake period may influence lCMR(glc). This study was conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross-sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern suggested an increase in lCMR(glc) values between 2 and 8 months of age with decreased metabolism observed at 10-12 months of age in all regions. Peak lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen at the youngest age examined quantitatively (2-3 months). The regions of greatest and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres (90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals supported this developmental pattern, demonstrating the ability to detect changes in cerebral glucose metabolism within animals and the potential for FDG-PET in nonhuman primate models of brain maturation. By determining the normative profile of lCMR(glc) during development in monkeys, future application of FDG-PET will provide the opportunity to longitudinally assess the effects of environmental or pharmacological intervention on the immature brain.

Plasma catecholamines and social behavior in male vervet monkeys (Cercopithecus aethiops sabaeus).

Many investigations in humans indicate that epinephrine, norepinephrine and their ratio may correlate with such traits as social competence, academic achievement, and aggression. However, the socioeconomic, dietary, and environmental confounds accompanying most human studies complicate their interpretation. Social status, aggression, and other social behaviors can be reliably assessed in nonhuman primates under conditions controlling for crucial environmental factors. If interpretation of human studies is correct, dominant and subordinate male vervet monkeys should exhibit distinctive patterns of catecholamine secretion. To test this possibility, seventeen adult male monkeys living in six stable social groups were observed for 6 months. Based on their success in agonistic events, subjects were categorized as dominant or subordinate. Alpha scores were calculated from empirically derived factors to provide a noncategorical measure of dominant behavioral style. Plasma epinephrine and norepinephrine samples obtained from anesthetized subjects did not differ between dominant and subordinate males. Alpha scores, however, distinguished high from low norepinephrine/epinephrine ratio groups. These findings are consistent with studies in humans linking high epinephrine, low norepinephrine, and social competence.

Population-based guidelines for performance measurement: a preliminary report.

This paper describes the development of--and early efforts to validate--guidelines that indicate average amounts of service expected to be used by a population of patients with a given disorder who are served by a comprehensive mental health system. These guidelines address expected service use by individuals in 55 diagnostic groups. The purpose of these guidelines is to provide a gauge for evaluating the amounts of service being delivered by managed care organizations. Three population-based guidelines (for attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia) are compared to actual amounts of service delivered to enrollees in large behavioral health care systems.

Repair of abdominal wall defects: Gore-Tex vs. Marlex graft.

The purpose of this study was to provide experimental evidence for the role of Gore-Tex polytetraflourethylene as an abdominal wall prosthesis. This was achieved by evaluating tissue reaction in animals to the plastic and comparing it to that of Marlex mesh. Ten Wistar rats received especially prepared Gore-Tex implants, and another ten received Marlex. The materials were inserted in a fashion that yielded results both intraperitoneally and extraperitoneally. Gross and microscopic data were recorded at the time of sacrifice, which ranged from two to ten weeks postoperatively. Grossly, both plastics were found to be similar in intraperitoneal tissue reaction. Microscopically, all of the Gore-Tex grafts retained their original shape and demonstrated focal adherence to the muscle. In contrast, strands of Marlex showed disorganization in the host in 90 per cent of the specimens and no focal adherence to muscle. Instead, it was seen walled off in fibrous tissues. It was concluded that specifically formulated Gore-Tex may provide the more suitable abdominal wall prosthesis and that further research is necessary.

A three-decade perspective on community and public psychiatry training in Oregon.

The public psychiatry training program at Oregon Health Sciences University, established in 1973, educates psychiatric residents to work in community mental health centers and state hospitals. The authors present a brief history of this program, which spans three decades, and describe recent developments in its operation, with special attention to financing, administrative structure, and educational elements. Several program graduates have chosen careers in public-sector work. The program is founded on the principle that just as dollars should follow patients in health care systems, so should residents in training follow patients. Administrative and fiscal arrangements must be flexible to support this mobility.

The credibility of nonprofit boards: a view from the 1990s and beyond.

The wrongdoings of nonprofit organizations have become grist for the media mill. The authors explore five of the more recently publicized cases of nonprofits gone wrong: the United Way of America, National Association for the Advancement of Colored People, Foundation for New Era Philanthropy, Jewish Community Center of Greater Washington, and Upsala College, and their significance in regard to the role and functioning of the board. Discussion focuses on the implications of these cases in regard to nonprofits' credibility and strategic options for enhancing accountability. Unless governing boards address some of their deficiencies, tighter government regulations, increased donor skepticism, and greater demands and expectations upon them will result.