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Biomedical subjects

A N Freedman

Publications and source records attributed to A N Freedman.

At least 19 recordsLinked to original sources
PubMed2005

The relation between projected breast cancer risk, perceived cancer risk, and mammography use. Results from the National Health Interview Survey.

BACKGROUND: Although the use of mammography on at regular intervals can save lives, not all women obtain the repeat mammography recommended in guidelines. OBJECTIVE: To assess the associations between routine mammography use, perceived cancer risk, and actual projected cancer risk. METHODS: We include women who were 45 to 75 years of age and who had responded to the 2000 National Health Interview Survey. Women who reported that they believed their risk of getting cancer in the future was "medium" or "high" were considered jointly as "medium/high-risk perception.""Routine mammography use" was defined as having > or =3 mammograms in the previous 6 years. We used logistic regression to determine the independent relation between cancer risk perception, projected breast cancer risk, and routine mammography use. RESULTS: Of the 6,002 women who met our inclusion criteria, 63.1% reported routine mammography use. About 76% of women in the highest quartile of projected breast cancer risk reported routine mammography use, compared with only 68%, 64%, and 51% in the third, second, and first quartiles, respectively (P<.001 chi-square test for trend). After adjusting for indicators of access to care, sociodemographic and behavioral factors, and perceived cancer risk, women in the highest quartiles of projected cancer risk were significantly more likely to report routine mammogram use than women in the lowest quartile (odds ratio [OR] of women in third and fourth quartiles were 1.57 [1.24 to 1.99], and 2.23 [1.73 to 2.87] vs the lowest quartile, respectively). Women with a higher perceived cancer risk were significantly more likely to undergo routine mammography (adjusted OR: 1.29 [1.12 to 1.48] P=.001). Cancer risk perceptions tended to be higher among women who were younger age, obese, smokers, depressed, or reported one of the following breast cancer risk factors: family breast cancer history, prior abnormal mammogram, and early age at menarche. CONCLUSION: Actual and perceived risk were independent predictors of routine mammography use, suggesting that efforts to incorporate risk profiles into clinical decision making may need to involve more than just relaying information about projected risks to patients, but also to explore how risk perceptions can be affected by this information.

Aged↗
PubMed2005

Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians.

BACKGROUND: Clinically relevant genetics knowledge is essential for appropriate assessment and management of inherited cancer risk, and for effective communication with patients. This national physician survey assessed knowledge regarding basic cancer genetics concepts early in the process of introduction of predictive genetic testing for breast/ovarian and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. METHODS: A stratified random sample was selected from the American Medical Association Masterfile of all licensed physicians. In total, 1251 physicians (820 in primary care, 431 in selected subspecialties) responded to a 15 minute questionnaire (response rate 71%) in 1999-2000. Multivariate logistic regression analyses were conducted to identify demographic and practice characteristics associated with accurate response to three knowledge questions. RESULTS: Of the study population, 37.5% was aware of paternal inheritance of BRCA1/2 mutations, and 33.8% recognised that these mutations occur in <10% of breast cancer patients. Only 13.1% accurately identified HNPCC gene penetrance as >or=50%. Obstetrics/gynaecology physicians, oncologists, and general surgeons were significantly more likely than general and family practitioners to respond accurately to the breast/ovarian questions, as were gastroenterologists to the HNPCC question. CONCLUSIONS: These nationally representative data indicate limited physician knowledge about key cancer genetics concepts in 1999-2000, particularly among general primary care physicians. Specialists were more knowledgeable about syndromes they might treat or refer elsewhere. Recent dissemination of practice guidelines and continued expansion of relevant clinical literature may enhance knowledge over time. In addition to educational efforts to assist physicians with the growing knowledge base, more research is needed to characterise the organisational changes required within the healthcare system to provide effective cancer genetics services.

Adult↗
PubMed2003

US physicians' attitudes toward genetic testing for cancer susceptibility.

Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes toward these tests. To assess US physicians' opinions on unresolved issues surrounding genetic testing, a 15-min survey was administered to a stratified random sample of 1,251 physicians from 8 specialties, selected from a file of all licensed physicians in the US (response rate = 71.0%). Dependent measures included physicians' attitudes toward genetic counseling and testing qualifications, availability of guidelines, patient confidentiality and insurance discrimination issues, and clinical utility of genetic tests. More than 89% of physicians reported a need for physician guidelines, 81% thought that patients with positive genetic test results are at risk for insurance discrimination, and more than 53% thought that it was difficult to ensure the confidentiality of test results. Almost 25% indicated that genetic tests for cancer susceptibility have too many inaccurate or ambiguous results; nearly 75% thought that clear guidelines are not available for managing patients with positive test results. Only 29% of physicians reported feeling qualified to provide genetic counseling to their patients. More than 84% of oncologists considered themselves qualified to recommend genetic testing to their patients compared with 40% of primary care physicians (PCPs), and 57% of tertiary care physicians (TCPs). US physicians expressed great uncertainty about issues surrounding genetic testing for cancer susceptibility. Results of this national survey underscore the need to provide physicians with clear guidelines on the use of genetic cancer susceptibility tests and effective medical training on their appropriate implementation.

Attitude of Health Personnel↗
PubMed1999

Incidence of colorectal carcinoma in the U.S.: an update of trends by gender, race, age, subsite, and stage, 1975-1994.

BACKGROUND: Colon carcinoma incidence rates have risen sharply over the second half of this century, particularly among males and blacks. In the late 1970s, incidence rates among whites began to decline for distant disease. Approximately 10 years later regional disease rates began to fall. The decline in incidence rates among whites largely has been attributed to more widespread colorectal carcinoma screening. However, similar trends by stage in blacks have not been observed. METHODS: The incidence of colorectal carcinoma was evaluated by race, gender, age, and stage of disease for each subsite using data from > 220,000 cases diagnosed between 1975 and 1994 in the U. S. Surveillance, Epidemiology, and End Results program. RESULTS: Recent data have continued to show a decrease in incidence rates of total colorectal carcinoma in whites since the mid-1980s, particularly for the distal colon and rectum. Overall, proximal colon carcinoma rates were higher than distal colon or rectal carcinoma rates throughout the study period. Proximal colon carcinoma rates in blacks were considerably higher than in whites and continued to increase, whereas rates in whites showed signs of declining. The age-specific and stage-specific trends for proximal colon carcinoma in blacks were not consistent with the possibility of earlier disease detection through screening. CONCLUSIONS: Etiologic studies are necessary to understand the large increases in the incidence of proximal colon carcinoma among blacks.

Adult↗
PubMed1999

Prognostic significance of p53 and p21(waf1/cip1) immunoreactivity in epithelial cancers of the ovary.

OBJECTIVES: Theprognostic value of p53 expression in epithelial ovarian cancer remains unresolved. We hypothesized that prognosis may relate more to expression of p21(waf1/cip1), the major downstream effector of p53, which can also be induced through p53-independent mechanisms. We therefore studied the relationship of p53 and p21(waf1/cip1) expression in epithelial ovarian cancers to clinicopathological variables and prognosis. METHODS: Fixed, embedded tumors from 85 patients with untreated, primary epithelial ovarian cancer were immunostained with antibodies to p53 and p21(waf1/cip1). Expression was correlated with clinicopathological features and prognosis. Survival curves were calculated by the Kaplan-Meier method and compared using the log-rank test for p53, p21(waf1/cip1), and all combinations of expression of the two markers. RESULTS: Sixty-two percent of tumors expressed p53, and 42% expressed p21(waf1/cip1). There was no correlation between p53 and p21(waf1/cip1) expression. Advanced stage, grade, age >/=50, and p53 expression were associated with worse disease-free survival. Patients whose tumors were p53(+)/waf1(-), however, had a particularly strong association with poorer disease-free survival when compared with other combinations of p53 and p21(waf1/cip1) expression (P = 0.003). Neither p53, nor p21(waf1/cip1), nor combinations of expression were independently related to survival when histology, age, stage, and differentiation were considered. CONCLUSIONS: p53 expression in the absence of p21(waf1/cip1) expression is a better marker of poor prognosis than either p53 or p21(waf1/cip1) expression status alone in univariate analysis. Absence of independent prognostic significance may be related to the paucity of early stage cases in the current study.

Cyclin-Dependent Kinase Inhibitor p21↗
PubMed1999

Prevalence of pedigrees suggestive of hereditary nonpolyposis colorectal cancer among a community sample of women eligible for screening mammography.

OBJECTIVE: To determine from a large cohort of women eligible for screening mammography, the number who would meet criteria for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: Detailed personal and family cancer histories, obtained from 6,682 women aged 50-80 years randomly selected from communities in Washington State, were matched to the Amsterdam criteria, Bethesda guidelines, and Japanese criteria for HNPCC. RESULTS: One (0.015%) respondent met the Amsterdam criteria, 2 (0.035%) met the Japanese criteria and 5 (0.075%) met the Bethesda guidelines. CONCLUSION: Using the time of presentation for initial mammography as an opportunity to screen for HNPCC would detect very few families at high risk for this condition.

Journal Article↗
PubMed1999

Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival.

Most ovarian carcinomas present at advanced stage, principally as the result of dissemination to peritoneal sites. Standard CD44 (CD44S) is the principal receptor for hyaluronic acid, and in vitro and animal studies have suggested that the attachment of ovarian carcinoma cells to the peritoneal mesothelium involves the interaction between CD44S on ovarian carcinoma cells and hyaluronic acid on mesothelial surfaces. We, therefore, analyzed a series of ovarian carcinomas for the expression of CD44S by immunohistochemistry to see whether expression of this receptor by tumor cells correlated with clinicopathological factors and measures of patient outcome. Fifty-six fixed, paraffin-embedded primary epithelial ovarian tumors were immunostained with antibody to CD44S. Membrane staining was considered positive, and results were correlated with stage, grade, age, histology, and survival. Twenty-two (39%) tumors were positive for CD44S. There was no correlation between CD44 expression and histological type, grade, age, or stage. However, CD44 expression was significantly associated with survival in both univariate (P = 0.003) and multivariate (P = 0.006) analyses. These results support a role for CD44S expression in the spread of ovarian epithelial cancer and suggest that expression of this molecule is a significant independent predictor of survival in women with this disease.

Age Factors↗
PubMed1999

Prognostic significance of p53, PCNA, and c-erbB-2 in endometrial enocarcinoma.

Previous studies of oncogenes, tumor suppressor genes, and proliferation markers in endometrial adenocarcinoma have obtained conflicting results regarding the usefulness of these markers in predicting prognosis. This study examined p53, PCNA, and c-erbB-2 immunohistochemically to clarify the relationship of these markers to each other and to FIGO stage, myometrial invasion, and survival. We studied 64 cases of endometrial carcinoma, treated between 1988 and 1995, for overexpression of p53, percentage of PCNA expression (PCNA index), and c-erbB-2 cytoplasmic membrane staining. Thirty-two percent of tumors expressed p53, 39% displayed a PCNA index of > = 25%, and 69% expressed c-erbB-2. p53 overexpression was significantly associated with stage (p=0.027), PCNA index > = 25% (p=0.005), c-erbB-2 expression (p=0.018), and vital status (p=0.04). PCNA index > = 25% was associated with stage (p=0.008), myometrial invasion (p=0.008), and c-erbB-2 expression (p=0.05), and weakly associated with vital status (p=0.07). No associations were observed for c-erbB-2 with stage, invasion, or vital status. There was some suggestion of a decreased survival in patients whose tumors overexpressed p53 (Log Rank; p=0.09) or had a PCNA index > = 25% (Log Rank; p=0.13). Additional, larger studies are needed to evaluate the prognostic value of PCNA and p53 expression in endometrial adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Somatic alterations and metabolic polymorphisms.

Cancer is a multistep process in which multiple genetic alterations occur, causing a cumulative adverse effect on the control of cell differentiation, cell division and growth control. Somatic alterations acquired at the level of the cell become fixed in the developing cancer as chromosomal translocations, deletions, inversions, amplifications or point mutations. Since the ultimate unit of susceptibility to carcinogens is at the level of the cell, somatic gene alterations play an important role in carcinogenesis, as all neoplastic tumours exhibit somatic alterations. The incorporation of somatic alterations, such as oncogenes and tumour-suppressor genes, into epidemiological research provides an opportunity to clarify the role of exposure, other genetic changes and prognosis in cancer pathogenesis. The manner in which environmental factors act to initiate, accelerate or retard neoplastic progression Is currently being investigated using somatic gene mutational spectra to identify specific etiological carcinogens. Exploring the relationships between germline and somatic alterations may help to identify the timing of genetic events, important etiological exposures and gene-gene epistatic phenomena. Examining somatic alterations within the context of carcinogen-metabolizing enzymes may elucidate specific carcinogenic mechanisms. The use of somatic alterations to predict prognoses for patients with various malignancies may also help to enhance our ability to define subgroups of patients with different disease courses and treatment responses.

Cell Differentiation↗
PubMed1998

Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.

Acid Anhydride Hydrolases↗
PubMed1998

Bcl-2 immunohistochemistry in a surgical series of non-small cell lung cancer patients.

The bcl-2 gene is implicated in oncogenesis by its ability to prolong cell survival through the inhibition of apoptosis, without increasing cell proliferation. An association between immunohistochemical staining for bcl-2 protein and the histological type and prognosis of non-small cell carcinoma was hypothesized by Pezzella et al. (N Engl J Med 329:690-694, 1993). In a case series, we stained formalin-fixed, paraffin-embedded tumor tissue from 106 surgical non-small cell lung cancer patients with an antibody to bcl-2 protein (DAKO clone 124, Carpinteria, CA). The resulting bcl-2 staining data were evaluated for associations with demographic, histological, immunohistochemical, and genetic features, including p53 mutations. Bcl-2 staining was observed in tumors from 29 of 106 (27%) of subjects, but was significantly less frequent in subjects' adenocarcinoma histology (8 of 55, 14.6%) (P = .007). This finding persisted after adjustment for age, gender, stage, grade, smoking history, and disease-free survival. In univariate analyses, no association was seen with age, weight, body mass index, gender, or pack-years smoking; tumor grade, stage, or patient performance status; p53 or c-erbB2 immunohistochemical staining, or p53 mutations. These data agree with earlier reports that bcl-2 staining is less common in adenocarcinomas; however, our data do not support the hypothesis that bcl-2 staining confers a better prognosis overall, in squamous cell carcinoma, or in an older patient population.

Adenocarcinoma↗
PubMed1998

Aspirin use and p53 expression in colorectal cancer.

p53 protein overexpression indicates loss of tumor suppressor activity and is the most common genetic alteration in colorectal neoplasms. Epidemiologic and experimental studies suggest that regular use of aspirin may reduce colorectal cancer risk. We set out to determine whether p53 overexpression of the colorectum was associated with a patient's history of aspirin use. Self-administered questionnaires, including information on aspirin use, were obtained from 163 patients with nonfamilial colorectal cancer and from 326 healthy controls. Nuclear p53 protein overexpression using anti-p53 CM-1 polyclonal antibody was observed in 44.8% (73/163) of patients' tumors. A nonsignificant inverse association was observed between use of aspirin and colorectal cancer. Compared with that for nonusers, the odds ratio (OR) for individuals who took aspirin at least twice weekly was 0.68 (95% confidence interval [95% CI]: 0.39-1.18). The odds ratio for those individuals who used aspirin for less than 5 years was 0.54 (95% CI: 0.24-1.23), and 0.80 (95% CI: 0.42-1.51) for those who used aspirin for 5 years or more, when compared with nonusers. An inverse association of regular aspirin use (two times per week or more) was found both for cases with p53 overexpression (OR: 0.79; 95% CI: 0.39-1.59), and for cases without p53 overexpression (OR: 0.56; 95% CI: 0.25-1.22). There was little evidence of a difference in the effect of aspirin use on cancer risk between cases with and without p53 overexpression, even after adjustment for potential confounders.

Adenocarcinoma↗
PubMed1998

p21waf1/cip1 and transforming growth factor beta 1 protein expression correlate with survival in non-small cell lung cancer.

p21waf1/cip1 encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways. Because p21waf1/cip1, p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21waf1/cip1 and TGF-beta 1 and identified four patient groups with distinct survival outcomes. Concordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and high TGF-beta 1 expression or low p21waf1/cip1 and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and low TGF-beta 1 expression or low p21waf1/cip1 and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21waf1/cip1 protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21waf1/cip1 protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21waf1/cip1 protein. These findings indicate that p21waf1/cip1 immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

Oral contraceptives, reproductive factors and p53 gene expression in colorectal cancer.

Protective effects of oral contraceptives and high parity on the development of colorectal cancer have been hypothesized. However, the epidemiological data are inconsistent. This inconsistency may be due in part to the biological heterogeneity of colorectal tumors. A recent investigation of hepatocellular carcinoma demonstrated an association between lack of p53 expression and oral contraceptive use. We investigated the relationship between oral contraceptive use and other reproductive factors with p53 over-expression in 64 post-menopausal women, 45-86 years of age, with non-familial colorectal adenocarcinoma. Fifty per cent (32/64) of colorectal tumors displayed nuclear over-expression of p53 protein. Women with a history of oral contraceptive use were significantly less likely to have p53 positive (+) tumors than women who never used oral contraceptives (P = 0.02). In contrast, tumors from women who had never been pregnant were more likely to be p53 + compared to tumors from parous women (P = 0.10). These data suggest that oral contraceptive use and pregnancy are associated with a p53 independent pathway in the development of colorectal cancer.

Aged↗
PubMed1997

Methodological issues in the use of tumour markers in cancer epidemiology.

In this chapter, we review major methodological and practical issues associated with the use of tumour markers. At this stage of development, studies with a combination of tumour, susceptibility and exposure markers are needed to illustrate the link between exposure and biological response and to assess the interactive effects of tumour susceptibility markers in this process. Several practical issues related to the application of tumour markers are discussed, including banking of tumour tissue, setting a laboratory strategy and performing etiological heterogeneity analysis.

Biomarkers, Tumor↗
PubMed1996

Gravid health status, medication use, and risk of neuroblastoma.

The epidemiology of neuroblastoma suggests that prenatal exposures may be important etiologic factors in this disease. The authors describe the role of maternal health status and prenatal medication usage and risk of neuroblastoma. This retrospective study was based on completed interviews with 183 histologically confirmed neuroblastoma cases aged 0-14 years diagnosed among residents of New York State (excluding New York City) between 1976 and 1987. Controls were matched to cases on year of birth and race and were drawn from the New York State live birth certificate registry. Interviews were satisfactorily completed with 85% of the cases and 87% of controls. Significantly elevated odds ratios were noted for vaginal infections during pregnancy (odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.2-4.0), medical treatments for vaginal infection during pregnancy (OR = 2.4, 95% CI 1.2-4.9), and any reported use of sex hormones during pregnancy (OR = 3.0, 95% CI 1.3-6.9). Point estimates for any hormone use suggested elevated risk among male offspring (OR = 4.4, 95% CI 1.5-13.3). Among the individual exposures comprising any hormone use, only hormone use related to infertility was observed to be significant (OR = 10.4, 95% CI 1.2-89.9). A protective effect was noted for self-reported vitamin use (OR = 0.28, 95% CI 0.03-0.69). Although it is not possible to presume a specific role for prenatal hormone exposure as initiator or promoter, these findings lend support to an association between prenatal hormone exposure and risk of neuroblastoma.

Adolescent↗
PubMed1996

The relationship between smoking exposure and p53 overexpression in colorectal cancer.

Although epidemiological studies of the relationship between cigarette smoking and colorectal cancer risk have been equivocal, a positive association is consistently found for colorectal adenoma development. We performed an epidemiological study to determine whether p53 protein overexpression, in tumours obtained at the time of resection, is associated with cigarette exposure in colorectal cancer. A total of 163 colorectal cancer cases and 326 healthy controls responded to a standardised questionnaire on colorectal cancer risk factors including detailed information on their history of cigarette smoking. All patients' tumours were analysed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Comparison of colorectal cases with controls revealed an elevated risk for ex-smokers (OR = 1.34, 95% CI 0.85-2.12) and current smokers (OR = 1.13, 95% CI 0.63-2.02) when compared with non-smokers. No dose-response relationship was found for total pack-years of smoking (trend test: P = 0.19). However, a trend for total pack-years of smoking was found when p53-positive cases were compared with p53-negative cases suggesting aetiological, heterogeneity (trend test: P = 0.06). Estimating the individual relative risk of developing a p53-positive tumour relative to controls showed no associations for smoking status or total pack-years of smoking. However, when p53-negative cases were compared with controls, an elevated risk was found for ex-smokers (OR = 1.84, 95% CI 1.00-3.37) and current years of smoking (trend test: P = 0.03). Colorectal tumours developing through p53-positive dependent pathways were not associated with smoking exposure. A significant increase in risk was observed for the p53-negative independent pathway with smoking. p53 overexpression appears to be associated with smoking exposure in colorectal cancer.

Adult↗