Chronic dosing of oltipraz in people at increased risk for colorectal cancer.

The dithiolethione oltipraz is being developed as a chemopreventive agent for many malignancies, including colorectal cancer, on the basis of its in vivo protective activity against chemically induced tumors in a variety of animal models. This protection has been associated with an enhanced capacity to detoxify reactive carcinogens and, more recently, with increased DNA repair. In a previous single-dose study, elevated detoxification gene expression was observed in the days after oltipraz dosing. Now, in this clinical study, we evaluated the effects of oltipraz when given over a 3-month period. Fourteen individuals with increased risk for colorectal cancer were randomly assigned to one of two oral doses (125 or 250 mg/m2) of oltipraz twice weekly for 12 weeks. Two of seven subjects at the 250 mg/m2 dosage required dose reductions, owing to significant fatigue. The 125 mg/m2 dose level was well tolerated by all patients. Blood or colon tissue (or both) for evaluation of glutathione, glutathione S-transferase, DT-diaphorase activity, and DT-diaphorase mRNA expression were obtained prior to treatment and at weeks 6, 12, and 16. No significant modulation of phase II detoxification enzymes was seen at either dose studied during this period. Phase II trials evaluating a tolerable regimen of oltipraz (as demonstrated in this study) and other possible mechanisms that may be responsible for the protective activity of oltipraz should be pursued.

Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population.

A clear benefit of increased hospital procedure volume or teaching hospital status on outcomes of rectal cancer surgery has yet to be shown. Few have examined treatment differences that may lead to varying outcomes. This study assessed the impact of hospital procedure volume and teaching status on both treatment and outcome measures of rectal cancer surgery in a large general population. Data were obtained for 1072 incident cases of rectal adenocarcinoma diagnosed in 1990 from Ontario, Canada, and treated with a major resection. Hospitals were classified by teaching status and procedure volume. Pathology reports were examined for 418 procedures. Abdominoperineal resections accounted for 31.0% of all procedures. There were no clinically significant differences in treatment measures, operative mortality, and long-term survival among the hospital groups according to both univariate and multivariate analyses. In conclusion, the absence of a hospital volume or teaching status effect on treatment and outcome measures suggests that for rectal cancer surgery in Ontario, centralization of procedures into high-volume or teaching centers is unlikely to improve surgical quality.

Exploring family relationships in cancer risk counseling using the genogram.

OBJECTIVES: The genogram is a tool that has facilitated counseling in family therapy and social work for many years. It is hypothesized that genograms may also be useful in genetic counseling, because they help the counselor to acquire more objective and consistent information from the client, as well as to incorporate family dynamics and psychosocial issues into the counseling approach. MATERIALS AND METHODS: A pilot study of genograms used as an adjunct to genetic counseling was performed at Fox Chase Cancer Center's Family Risk Assessment Program. A questionnaire was developed to elicit genograms from 38 women at risk for familial breast and/or ovarian cancer. After standard pedigree expansion, a series of questions was asked about the consultand's relationship with other family members, communication patterns within the family, attitudes toward genetic testing, family reactions to cancer, roles individuals play in the family, and significant historical or anniversary events. Relationships were defined by the consultand as close, very close, conflictual, fused and conflictual, distant, or estranged. RESULTS: The majority of relationship types reported by 38 individuals was "very close" or "close." Eighty-one % reported having close/very close relationships with their spouses, 83% reported close/very close relationships with their mothers, and 70% reported close/very close relationships with their fathers. The degree of familial cohesion as depicted by the genogram correlates positively with scores obtained on the standardized Social Adjustment Scale Self-Report (P = 0.01). CONCLUSIONS: Given the family-wide implications of genetic testing, the genogram may offer important guidance in family-targeted interventions.

Prostate cancer risk assessment program. A model for the early detection of prostate cancer.

Prostate cancer is the most common form of cancer (except skin cancer) in men. Several factors have been associated with an increased risk for prostate cancer, including age, ethnicity, family history, lifestyle, and environmental exposures. Recognition of the importance of the interaction of these factors in prostate cancer has led to an interest in their evaluation as a model both for studying genetic susceptibility patterns and for studying and providing educational tools and preventive interventions. One such model has been developed at Fox Chase Cancer Center. Critical to the implementation of the model has been the establishment of the Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP). Together, they serve as a unique resource for investigating the interaction between environmental factors and genetic susceptibility patterns; exploring the early, premalignant biological markers of prostate cancer; and prospectively assessing the quality of life (QOL) of men at risk. In addition, PRAP facilitates the evaluation of models for prostate cancer risk counseling and screening in the community. This paper describes this model for early detection and risk reduction, along with preliminary data from its first two study aims. The program is particularly relevant in view of the wealth of genetic information emerging from the Human Genome Project.

Clinical relevance of chromosome abnormalities in non-small cell lung cancer.

The relationship between clonal chromosome alterations and various clinical parameters was evaluated in 70 patients with non-small cell lung cancer (NSCLC) for whom detailed karyotypic assessment was possible. Included in the analysis are karyotypes of 63 previously published cases and seven new NSCLCs. Clinical features investigated were diagnosis, tumor stage and grade, gender, smoking history measured in pack years, and survival. Certain chromosome abnormalities were significantly associated with histologic subtype, tumor grade, stage, and prognosis. Rearrangements involving chromosome arms 2p and 3q were more common in squamous cell carcinoma (SCC) than in adenocarcinoma (ADC). Loss of 3p was observed more often in SCC. Gain of 7p was more frequent in ADC. Rearrangement of 17p was associated with a lower tumor grade. Rearrangement of Xp and loss of chromosome 12 or 22 were each associated with higher tumor stage. Rearrangement of 3p or 6q was correlated with a better survival outlook. In contrast, loss of chromosomes 4 or 22 portended a poor prognosis. Finally, an increased number of marker chromosomes was observed in patients having a higher number of pack years. These data indicate that chromosome abnormalities can have clinical and pathologic significance in NSCLC.

Implications of fine-needle aspiration in patients with resectable pancreatic cancer.

A 9-year experience with fine-needle aspiration (FNA) in patients with resectable pancreatic adenocarcinoma was reviewed to determine whether this procedure is associated with positive peritoneal cytology, peritoneal recurrences, or decreased survival in patients who had pancreatic resection with curative intent. Forty-one patients underwent pancreatic resection for primary pancreatic adenocarcinoma from July 1987 to February 1996. Nine patients had open biopsies prior to definitive resection and were excluded from this study. Of the remaining 32 patients, 21 (66%) had preoperative computed tomography-guided or fluoroscopically guided FNA biopsy of the pancreas for diagnosis. FNA confirmed the diagnosis of adenocarcinoma in 17 of 21 patients (80%). Fifteen of 21 FNA biopsies were performed in patients who went on to receive neoadjuvant chemoradiation. Twenty-eight of 32 patients (87%) had peritoneal washings at the time of laparotomy. Five patients had suspicious or positive washings (18%), and 23 patients had negative washings (82%). Three of 18 patients (16.7%) who had both FNA and peritoneal washings and 2 of 10 patients (20%) who had no FNA but had peritoneal washings had positive or suspicious peritoneal cytology. Eight of 32 patients ultimately failed in the peritoneum. Six of 21 patients (28%) who had prior FNA and 2 of 11 (18%) who had no prior FNA failed in the peritoneum. Although the number of patients is small, none of these differences proved to be statistically significant. No difference in median survival was observed between the FNA and no FNA groups. We conclude that FNA is a safe and useful tool to confirm the diagnosis of pancreatic cancer when patients are to be treated with neoadjuvant chemoradiation.

Employee response to a company-sponsored program of colorectal and prostate cancer screening.

Studies done in the mid-1970s documented increased risk for respiratory cancer and leukemia among employees in a chemical company manufacturing plant where chloromethyl ethers were used in production from 1948 to 1971. In the late 1980s, the company informed current and former employees about the results of follow-up studies which showed a moderation of risk of respiratory cancer and leukemia. New data showing elevated rates of mortality from colorectal, prostate, bladder, and pancreatic cancer in the population were also reported. Via mailed correspondence, the company made a no-cost program of colorectal and prostate cancer screening available to employees upon request; and information about bladder and pancreatic cancer was made available. Thirteen percent of employees in the population indicated interest in colorectal and prostate cancer screening (response). Thirty-one percent of these responders were screened (adherence). Multivariate analyses showed that education and length of employment in the plant were positively associated with response. Being white was positively associated with response for younger workers; while among older workers being male was positively associated with response. In terms of adherence, we found that older, more highly educated workers were more likely to have a screening examination. Findings indicate that employee participation in workplace-sponsored colorectal and prostate cancer screening can vary according to worker sociodemographic factors and length of employment in areas of potential exposure.

Preclinical and clinical evaluation of broccoli supplements as inducers of glutathione S-transferase activity.

Previous studies suggest that cruciferous vegetables may provide protection against carcinogen exposure by inducing detoxification enzymes. ICR(Ha) mice were gavaged with broccoli tablets (1 g/kg), and colon tissues were collected after treatment. Glutathione S-transferase (GST) activity was assayed and peaked on days 1 and 2 after treatment, respectively (P = 0.03). Elevations in GST activity were attributed to the increased expression of mu and pi. These data supported a clinical assessment of broccoli supplements. Twenty-nine subjects at increased risk for colorectal cancer were randomized to group 1 (no cruciferous vegetables) or group 2 (broccoli supplements, 3 g/day) for 14 days. Blood samples and colon biopsies were obtained pre- and postintervention. No significant difference was observed between the GST activities of the control and broccoli supplementation groups posttreatment. Mean lymphocyte GST activity was 107% of baseline in the broccoli supplementation group (range, 79-158%) and 102% of baseline in the control group (range, 75-158 percent;). Correlation of the GST activities of blood lymphocytes and colon mucosa taken simultaneously suggested that the GST activity of blood lymphocytes may be used as a biomarker of the responsiveness of colon tissue to chemopreventive regimens. Future clinical studies evaluating cruciferous vegetables should consider using concentrated dietary supplements in subjects with a previous history of colorectal cancer.

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.

Results of an office-based training program in clinical breast examination for primary care physicians.

BACKGROUND: This study hypothesized that an office-based training program in clinical breast examination (CBE) would improve the lump-detection skills of primary care physicians. METHODS: A one-group pretest-posttest design was utilized, without outcome measurements taken prior to instruction, immediately afterwards, and six months later. Fifty physicians from 117 practices that had been randomly selected and met program eligibility criteria elected to participate. The intervention was a one-hour office-based CBE training program based on the MammaCare method, a standardized approach to teaching the detection of breast lumps using silicone breast models. RESULTS: There were five lumps in the silicone model. The mean number of correct lump detections increased significantly, from 0.66 before to 3.2 after instruction, and this gain was maintained at six-month follow-up. The mean number of false positives decreased from 2.9 before to 1.16 after instruction, increasing slightly to 1.6 at six-month follow-up. Ninety-six percent of the physicians reported that they had modified their methods of CBE as a result of the training. CONCLUSIONS: This office-based instruction using an academic detailing model improved the participating physicians' abilities to correctly detect lumps in a silicone breast model and was received favorably.

Mammography interventions for 65- to 74-year-old HMO women. Program effectiveness and predictors of use.

This study evaluated the impact of two interventions designed to encourage mammography use among HMO women aged 65-74 who had not had a mammogram within the past year and had not used their referral for a free mammogram. Ninety days after the referral mailing, women were randomized to receive (a) a survey, (b) a survey in addition to telephone mammography counseling, or (c) a survey, telephone counseling, and a letter. Follow-up data indicated that only 13% of control group women compared to 27% who received phone counseling and 32% who received counseling and a letter obtained a mammogram within 120 days following the baseline survey and/or intervention. Results of the logistic regression analysis indicated that having received either of the interventions, mammography history, access ease, breast cancer/mammography beliefs, and having a friend or family member with breast cancer were independently and significantly related to mammography use.

Interest in genetic testing among first-degree relatives of breast cancer patients.

The recent cloning of a breast-ovarian cancer susceptibility gene (BRCA1), and determination of the locus of a related gene (BRCA2), offers potential for clinical genetic testing for breast cancer susceptibility. This study examined interest in and expectations about an impending genetic test among first-degree relatives (FDRs) of breast cancer patients. One hundred five females completed two structured telephone interviews to assess demographics, breast cancer risk factors, psychological factors, and attitudes about genetic testing for breast cancer susceptibility. Overall, 91% of FDRs said that they would want to be tested, 4% said they would not, and 5% were uncertain. The most commonly cited reasons for wanting genetic testing were to learn about one's children's risk, to increase use of cancer screening tests, and to take better care of oneself. Women with less formal education were motivated by childbearing decisions and future planning to a greater degree than were women with education beyond high school. Most women anticipated a negative psychological impact of positive test results, involving increased anxiety (83%), depression (80%), and impaired quality of life (46%). In addition, 72% of women indicated that they would still worry if they tested negative. In multivariate regression analysis, level of baseline depression was the strongest predictor of an anticipated negative impact of genetic testing (Beta = .15; P, .0001). These results suggest that the demand for genetic testing for breast cancer susceptibility may be great, even among women who are not likely to have predisposing mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutathione S-transferase activity and glutathione S-transferase mu expression in subjects with risk for colorectal cancer.

The glutathione S-transferases (alpha, mu, and pi), a family of Phase II detoxication enzymes, play a critical role in protecting the colon mucosa by catalyzing the conjugation of dietary carcinogens with glutathione. We investigated the efficacy of using the glutathione S-transferase (GST) activity of blood lymphocytes and GST-mu expression as biomarkers of risk for colorectal cancer. GST activity was measured in the blood lymphocytes of control individuals (n = 67) and in the blood lymphocytes (n = 60) and colon tissue (n = 34) of individuals at increased risk for colon cancer. Total GST activity was determined spectrophotometrically with the use of 1-chloro-2,4-dinitrobenzene as a substrate. The ability to express the um subclass of GST was determined with the use of an ELISA. Although interindividual variability in the GST activity of blood lymphocytes was greater than 8-fold (range, 16.7-146.8 nmol/min/mg), the GST activity of blood lymphocytes and colon tissue within an individual was constant over time and was unrelated to sex, age, or race. The GST activity of blood lymphocytes from high-risk individuals was significantly lower than that of blood lymphocytes from control individuals (P < or = 0.004). No association was observed between the frequency of GST-mu phenotype and risk for colorectal cancer. Blood lymphocytes from high-risk individuals unable to express GST-mu had lower levels of GST activity than did those from control subjects with the GST-mu null phenotype; however, this difference was significant in male subjects only (P < or = 0.006). Analysis of paired samples of blood lymphocytes and colon tissue indicated a strong correlation between the GST activity of the two tissue types (Spearman's rank correlation, r = 0.87; P < or = 0.0001). The GST activity of blood lymphocytes may be used to identify high-risk individuals with decreased protection from this Phase II detoxication enzyme who may benefit from clinical trials evaluating GST modulators as chemopreventive agents for colorectal cancer. The GST activity of blood lymphocytes may also be used in colorectal cancer chemoprevention trials to monitor the responsiveness of colon tissue to regimens that modify Phase II detoxication enzymes.

Effects of individualized breast cancer risk counseling: a randomized trial.

BACKGROUND: Studies have shown that a majority of women with a family history of breast cancer have exaggerated perceptions of their own risk of this disease and experience excessive anxiety. In response to the need to communicate more accurate risk information to these women, specialized programs for breast cancer risk counseling have been initiated in medical centers across the United States. PURPOSE: Our purpose was 1) to evaluate the impact of a standardized protocol for individualized breast cancer risk counseling on comprehension of personal risk among first-degree relatives of index breast cancer patients and 2) to identify women most and least likely to benefit from such counseling. METHODS: This study is a prospective randomized trial comparing individualized breast cancer risk counseling to general health counseling (control). We studied 200 women aged 35 years and older who had a family history of breast cancer in a first-degree relative. Women with a personal history of cancer were excluded. Risk comprehension was assessed as the concordance between perceived "subjective" lifetime breast cancer risk and estimated "objective" lifetime risk. RESULTS: The results of logistic regression analysis showed that women who received risk counseling were significantly more likely to improve their risk comprehension, compared with women in the control condition (odds ratio [OR] = 3.5; 95% confidence interval [CI] = 1.3-9.5; P = .01). However, in both groups, about two thirds of women continued to overestimate their lifetime risks substantially following counseling. Examination of subjects by treatment interaction effects indicated that risk counseling did not produce improved comprehension among the large proportion of women who had high levels of anxious preoccupation with breast cancer at base line (P = .02). In addition, white women were less likely to benefit than African-American women (OR = 0.34; 95% CI = 0.11-0.99; P = .05). CONCLUSION: Efforts to counsel women about their breast cancer risks are not likely to be effective unless their breast cancer anxieties are also addressed. IMPLICATIONS: Attention to the psychological aspects of breast cancer risk will be critical in the development of risk-counseling programs that incorporate testing for the recently cloned breast cancer susceptibility gene, BRCA1 (and BRCA2 when that gene has also been cloned).

Receptivity of African-American men to prostate cancer screening.

OBJECTIVE: The lifetime risk of prostate cancer among African-American men is two times higher than that of white men. Mortality from the disease is almost three times greater in African-Americans than in whites. This study assesses the receptivity of older (fifty to seventy-four years of age) African-American men (n = 86) in Chicago to periodic (annual and semiannual) prostate cancer screening. METHODS: A telephone survey conducted in January and February 1993, was used to collect data on subject sociodemographic background and medical history and to gather information on knowledge, attitudes, and beliefs about prostate cancer and screening. Univariate and multivariate analyses were carried out to identify factors associated with subject receptivity to annual and semiannual screening. RESULTS: Logistic regression analyses revealed that receptivity to annual and semiannual (every six months) examination is strongly associated with the degree to which screening is perceived as a salient and coherent (i.e., important, effective, and convenient) preventive health behavior. An additional factor independently associated with willingness to go through semiannual screening was subjects' awareness that African-American men are at increased risk for prostate cancer compared to white men. CONCLUSIONS: Findings from this study suggest that African-American men are willing to undergo prostate screening and are more receptive to annual than semiannual screening. Participation in screening may be facilitated by the provision of health education messages that emphasize the salience and coherence of early detection and elevated population risk.

Attitudes about genetic testing for breast-ovarian cancer susceptibility.

PURPOSE: In anticipation of the availability of genetic testing for a breast-ovarian cancer susceptibility gene (BRCA1), this study examined interest in and expectations about the impact of a potential genetic test. PATIENTS AND METHODS: The subjects were 121 first-degree relatives (FDRs) of ovarian cancer patients. The design was cross-sectional. Subjects completed a structured telephone interview of attitudes about cancer and genetic testing, and self-report psychologic questionnaires to assess coping style and mood disturbance. RESULTS: Overall, 75% of FDRs said that they would definitely want to be tested for BRCA1 and 20% said they probably would. In bivariate analyses, interest was associated positively with education, perceived likelihood of being a gene carrier, perceived risk of ovarian cancer, ovarian cancer worries, and mood disturbance. In logistic regression analysis, perceived likelihood of being a gene carrier was associated strongly with interest (odds ratio, 3.7; P = .006). Results of stepwise linear regression modeling indicated that an anticipated negative impact of genetic testing was associated with being younger (beta = -.66, P = .009), having more mood disturbance (beta = .015, P = .01), and having an information-seeking coping style (beta = .19, P = .002). CONCLUSION: These results suggest that the demand for genetic testing for BRCA1 among FDRs of cancer patients may be great. Moreover, those who elect to participate may represent a more psychologically vulnerable subgroup of high-risk women.

Recruiting high risk women into a breast cancer health promotion trial.

This study sought to identify factors that facilitate or hinder participation in a breast cancer health promotion trial among high-risk women. The subjects were 271 women ages 35 years and older who had a family history of breast cancer in at least one first-degree relative. All subjects were eligible for participation in a randomized trial which compares breast cancer risk counseling with general health counseling. Structured telephone interviews evaluated demographic characteristics, risk factors, risk perceptions, breast cancer concerns, and past screening practices. The results showed that education level was a key determinant of the importance of these factors in participation. Logistic regression modeling indicated that women with a high school education or less were most likely to participate if: (a) their relatives' diagnoses had greatly increased their perceptions of their personal risks [OR (OR) = 4.1], particularly if they perceived that risk to be very high (OR for interaction = 6.4); and (b) if they were ages 40-49 years versus 35-39 or 50 + years (OR = 2.6). By contrast, among women with education beyond high school, participation was predicted by (a) marital status (OR = 2.6), (b) employment (OR = 0.03 for employed), (c) number of affected relatives (OR = 0.07 for 1 versus 2 first-degree relatives), and (d) previous biopsy (OR = 0.42). These findings suggest that recruitment strategies that tailor messages to women's educational levels might be most effective.

Modeling adherence to colorectal cancer screening.

BACKGROUND: An explanatory framework referred to as the Preventive Health Model was used to identify factors associated with prospective adherence to colorectal cancer screening. METHODS: Data on sociodemographic, psychosocial, social influence, and program factors were collected via telephone survey for 501 older adult members of an independent practice association-type health maintenance organization. Subjects were later mailed fecal occult blood tests for completion and return. Adherence was defined as the return of the tests within 90 days. RESULTS: Structural analysis shows that for men (N = 145), perceived self-efficacy (OR = 1.4), salience and coherence of testing (OR = 2.3 for a 5-point increment on a 30-point scale), and exposure to health education interventions (OR = 6.8) were significant independent predictors of intention to adhere and of adherence. Among women (N = 185), predictors were age (OR = 1.8) and salience and coherence of testing (OR = 1.8 for a 5-point increment on a 30-point scale). CONCLUSIONS: These findings indicate that for both men and women, adherence is influenced strongly by the extent to which the behavior is judged to make sense in everyday life. It also appears that additional education and encouragement may persuade men and younger women to participate in screening.

Promoting mammography use through progressive interventions: is it effective?

This study evaluated interventions implemented with women in a health maintenance organization who had not utilized their annual free mammogram referral 45 days (step 2) and 95 days (step 3) after its mailing. The step 2 evaluation compared mammography utilization for women randomly assigned to receive a brief reminder letter or no reminder: 42% of the reminder group vs 28% of the control group obtained mammograms. The step 3 evaluation compared utilization for women randomly assigned to receive a second reminder, a letter suggesting a preventive office visit, or telephone counseling: 29% of those who received telephone counseling, 14% of those who received a letter, and 12% of those who received a second reminder obtained mammograms.