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R Millikan

Publications and source records attributed to R Millikan.

At least 19 recordsLinked to original sources
PubMed2005

Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies.

The associations between haplotypes and disease phenotypes offer valuable clues about the genetic determinants of complex diseases. It is highly challenging to make statistical inferences about these associations because of the unknown gametic phase in genotype data. We describe a general likelihood-based approach to inferring haplotype-disease associations in studies of unrelated individuals. We consider all possible phenotypes (including disease indicator, quantitative trait, and potentially censored age at onset of disease) and all commonly used study designs (including cross-sectional, case-control, cohort, nested case-control, and case-cohort). The effects of haplotypes on phenotype are characterized by appropriate regression models, which allow various genetic mechanisms and gene-environment interactions. We present the likelihood functions for all study designs and disease phenotypes under Hardy-Weinberg disequilibrium. The corresponding maximum likelihood estimators are approximately unbiased, normally distributed, and statistically efficient. We provide simple and efficient numerical algorithms to calculate the maximum likelihood estimators and their variances, and implement these algorithms in a freely available computer program. Extensive simulation studies demonstrate that the proposed methods perform well in realistic situations. An application to the Carolina Breast Cancer Study reveals significant haplotype effects and haplotype-smoking interactions in the development of breast cancer.

Algorithms↗
PubMed2001

Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC.

PURPOSE: We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging. PATIENTS AND METHODS: A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy. RESULTS: There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured. CONCLUSION: These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.

Adult↗
PubMed2001

Genetic testing for colorectal carcinoma susceptibility: focus group responses of individuals with colorectal carcinoma and first-degree relatives.

BACKGROUND: Colorectal carcinoma (CRC) may be the most frequent form of hereditary cancer. Genetic counseling and testing for heritable CRC is a promising approach for reducing the high incidence and mortality rates associated with the disease. Patients with CRC or those with at least one family member with the disease are the most likely persons to request or be offered genetic testing in the clinical or research setting. Currently, however, little is known about the behavioral, psychosocial, ethical, legal, and economic outcomes of CRC genetic counseling and testing. METHODS: Eight focus group interviews, four for CRC patients (n = 28) and four for first-degree relatives (n = 33), were conducted to obtain insights into attitudes, beliefs, and informational needs about genetic testing for hereditary CRC. RESULTS: Focus group interviews revealed a general lack of knowledge about cancer genetics and genetic testing; worry about confidentiality issues; strong concern for family members, particularly children; and a need for primary care providers to be informed about these issues. Major perceived advantages of genetic testing included improving health-related decisions, guiding physicians in making recommendations for surveillance, and informing relatives about risk potential. Disadvantages included potential discrimination, adverse psychologic effects, and financial costs associated with testing. CONCLUSIONS: As knowledge and media coverage of genetics continue to expand, it becomes increasingly important to continue efforts on behalf of, and in partnership with, those individuals most affected by genetic testing for hereditary cancer syndromes. These findings provide data needed to develop and implement informational, educational, counseling, and research-oriented programs that are sensitive to individuals' concerns and preferences.

Adult↗
PubMed2001

Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer.

Eighty-nine patients with progressive prostate cancer despite suppression of testosterone and withdrawal of anti-androgens were studied. This was a relatively advanced population, with 63 of 89 having either osseous metastases (mets) beyond the axial skeleton or visceral mets. Patients were randomly assigned to receive either ketoconazole alone, or ketoconazole with weekly doxorubicin. All patients received replacement hydrocortisone. The primary endpoints were response and survival. Based on PSA reduction criteria (>/= 80% maintained for at least 8 weeks), 14 of 45 patients (31%) in the single-agent ketoconazole arm responded. Sixteen of 44 patients (36%) in the combination ketoconazole/doxorubicin arm responded. There were no important differences between the two treatments in any outcome measure. The median overall survival for all patients was 12.5 months; median time to progression was 3.3 months. Toxicity was significant with both regimens, and more severe in the doxorubicin arm. Fully 20% of patients in each arm discontinued therapy due to intolerable side effects.Each of these regimens is toxic, and produced responses in fewer than half of treated patients. Although the observed median survival does compare favorably with reports from similar cohorts treated in the community, the potential benefit is only modest. In our view, neither of these regimens is sufficiently promising to justify phase 3 evaluation.

Journal Article↗
PubMed2001

Tumor characteristics in African American and white women.

BACKGROUND: Previous studies provide evidence that breast cancers occurring in different age and ethnic groups are not evenly distributed with regard to their biologic, pathologic and clinical characteristics. We evaluated the distributions of 11 pathological and biological variables between African-American (AA) and white patients and between three different age groups (20-39, 40-59 and 60-74 years). We examined whether racial differences existed across levels of age. METHODS: Data were obtained from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study of breast cancer in North Carolina. Eighty hundred and sixty one women with a first diagnosis of invasive breast cancer participated in Phase I of the CBCS. Diagnostic paraffin blocks were obtained from 807 cases. One representative block was scored for histologic type and grade (architectural, nuclear, mitotic and overall). Medical chart review yielded tumor size, lymph node status, distant metastases, stage, hormone receptor status (ER/PR) and DNA ploidy. RESULTS: Pathologically advanced tumors (large size, high grade, high stage, ER/PR negative) were significantly more common in young and AA women. Racial differences varied by age. Among younger, AAs and whites differed only with respect to ER/PR status, while among older women AAs and whites differed only with respect to stage at diagnosis. CONCLUSIONS: The results of this study confirm the presence of poorer prognosis breast cancer among AA and younger women. They also highlight the need for age and race to be considered together when evaluating pathologic and biologic characteristics of disease and when making inferences regarding tumor aggressiveness.

Adult↗
PubMed2001

Development and implementation of a science training course for breast cancer activists: Project LEAD (leadership, education and advocacy development).

OBJECTIVE: To develop and implement Project LEAD (leadership, education, and advocacy development), a science course for breast cancer activists. POPULATION: Students were breast cancer activists and other consumers, mainly affiliated with advocacy organizations in the United States of America. SETTING: Project LEAD is offered by the National Breast Cancer Coalition; the course takes place over 5 days and is offered 4 times a year, in various cities in the United States of America. RESULTS: The Project LEAD curriculum has developed over 5 years to include lectures, problem-based study groups, case studies, interactive critical appraisal sessions, a seminar by an 'expert' scientist, role play, and homework components. A core faculty has been valuable for evaluating and revising the course and has proved necessary to provide consistent high quality teaching. Course evaluations indicated that students gained critical appraisal skills, enhanced their knowledge and developed confidence in selected areas of basic science and epidemiology. CONCLUSIONS: Project LEAD comprises a unique curriculum for training breast cancer activists in science and critical appraisal. Course evaluations indicate that students gain confidence and skills from the course.

Adult↗
PubMed2001

Area-level characteristics and smoking in women.

OBJECTIVES: This study examined whether area-level characteristics are associated with individual smoking behavior among women. METHODS: Analyses included 648 women enrolled as control patients in the Carolina Breast Cancer Study (1993-1996). Smoking and covariate information was obtained from interviews. Area-level characteristics included census block-group education level, poverty, unemployment, car-home ownership, crowding, and, for 431 women, city-level crime rates. RESULTS: In multivariate logistic regression models, no area characteristics were clearly associated with a history of smoking. Among those who had ever smoked, continued smoking was associated with living in low-education areas (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.0, 2.9), high-unemployment areas (OR = 1.7, 95% CI = 1.0, 2.8), and high-crime areas (OR = 1.6, 95% CI = 0.8, 3.2). CONCLUSIONS: The present findings are consistent with a growing literature suggesting that area-level social and economic disadvantage influences individual smoking behavior.

Adult↗
PubMed2001

Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder.

Tumor invasion and metastasis are regulated by the expression of genes such as E-cadherin, which regulates cell adhesion, and matrix metalloproteinase-9 (MMP-9), which alters the integrity of the extracellular matrix. Both up-regulation of MMP-9 and down-regulation of E-cadherin correlate with bladder cancer metastasis. The purpose of this study was first to determine whether an imbalance between MMP-9 and E-cadherin expression correlates with metastasis from human transitional cell carcinoma (TCC) of the bladder after therapy with neoadjuvant chemotherapy and radical cystectomy and then to determine whether treatment of human TCC xenografts growing in nude mice with interferon (IFN)-alpha would restore this balance, thereby limiting tumor invasion and metastasis. We used in situ hybridization to evaluate the expression of several metastasis-related genes, including MMP-9 and E-cadherin, in paraffin-embedded biopsy specimens from 55 patients with muscle-invasive TCC treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy and radical cystectomy. By multivariate analysis, an MMP-9:E-cadherin ratio of >1.8 was an independent prognostic factor for disease progression. In vitro incubation of an IFN-resistant, highly metastatic human TCC cell line, 253J B-V(R) with noncytostatic concentrations of IFN-alpha down-regulated the activity of MMP-9, up-regulated E-cadherin, and inhibited in vitro invasion. 253J B-V(R) cells were implanted into the bladders of athymic nude mice. Systemic therapy with IFN-alpha (10,000 units s.c. daily) decreased the expression of MMP-9, increased expression of E-cadherin, reduced tumor volume, and inhibited metastasis. The MMP-9:E-cadherin ratio was 4.5 in untreated controls and 1.1 after IFN-alpha treatment. Moreover, systemic low-dose daily IFN-alpha potentiated the efficacy of paclitaxel. These studies indicate that in addition to its antiproliferative and antiangiogenic effects, IFN-alpha limits tumor invasion by restoring the normal balance between MMP-9 and E-cadherin and enhances the activity of systemic chemotherapy.

Adult↗
PubMed2000

A Phase II trial of bryostatin-1 for patients with metastatic renal cell carcinoma.

BACKGROUND: Patients with metastatic renal cell carcinoma have a poor prognosis and no standard therapy is available. The authors performed a Phase II trial of the novel agent bryostatin-1 in this patient population. METHODS: In all, 30 patients with measurable, previously untreated metastatic renal cell carcinoma were studied. Patients had excellent physiologic reserve and preserved performance status. Bryostatin-1 (25 microg/m(2)) was given in the PET (polyethyleneglycol, ethanol, and Tween 80) formulation as a 30-minute intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. In general, treatment was continued until disease progression. RESULTS: Two patients had significant objective responses, although methodologic problems made interpretation difficult. The median time to progression for all patients was 2.1 months; the median overall survival was 13.1 months. The treatment was generally well tolerated. Myalgia was the most common adverse event. One patient died while on study. This was a sudden death for a patient receiving a 15th cycle of therapy. Aside from this patient (for whom the correlation of study drug to death was not clear), no Grade 4 nonhematologic toxicity was encountered in more than 150 treatment courses delivered. CONCLUSIONS: There is minimal, if any, clinically relevant single-agent activity of bryostatin-1 at this dose and schedule for patients with metastatic renal cell carcinoma.

Adult↗
PubMed2000

Cyclophosphamide and carboplatin and selective consolidation in advanced seminoma.

This prospective Phase II study assesses the clinical efficacy and complications of a treatment regimen of combination chemotherapy with cyclophosphamide and carboplatin and selective consolidation in advanced seminoma. Of 46 patients who entered the study between December 1992 and October 1998, 46 were evaluable. Thirty-two achieved a complete remission (70%; 95% confidence interval, 56-83%) after chemotherapy alone. Fourteen achieved a complete remission (30%; 95% confidence interval, 18-46%) after chemotherapy plus consolidation. Forty-three of the 46 patients (93%; 95% confidence interval, 82-97%) remained in remission after a median follow-up period of 27.4 months. No patient experienced nephrotoxic, neurotoxic, or ototoxic effects or hemorrhagic cystitis. No patient had neutropenic fever requiring hospitalization. Thirteen % required platelet transfusions, and 9% required transfusions of packed RBCs. For patients with advanced seminoma, treatment with cyclophosphamide and carboplatin and selective consolidation is safe and effective.

Adolescent↗
PubMed2000

Country of birth and prevalence of gallbladder disease in Mexican Americans.

OBJECTIVES: This research sought to describe the association between country of birth and gallbladder disease (GBD) in Mexican Americans, identify subgroups at especially high risk, and identify risk factors that may mediate a birthplace-GBD association. DESIGN: Cross-sectional. METHODS: Our study population included 4157 Mexican Americans aged 20-74 who participated in the 1988-94 third National Health and Nutrition Examination Survey. GBD was diagnosed by ultrasound. Information on country of birth, education, income, and selected GBD risk factors was obtained from interviews. Prevalence odds ratios (POR) for GBD in Mexico- vs. US-born Mexican Americans were estimated by unconditional logistic regression, along with 95% confidence intervals (CI). To evaluate the extent to which GBD risk factors mediated the birthplace-GBD association, PORs for country of birth were compared in models with and without additional covariates. RESULTS: Age-adjusted GBD prevalence was lower in Mexico- than in US-born Mexican-American women (POR = 0.70, 95% CI 0.50, 0.98) and men (POR = 0.63, 95% CI 0.40, 0.97). The difference was especially pronounced among subjects of lower socioeconomic status. Despite substantial differences in GBD risk factor distributions by birthplace, none could completely explain the prevalence difference. CONCLUSIONS: The observation that GBD prevalence is higher among US-born Mexican Americans is consistent with research showing poorer health in this group. Further research is needed to identify strategies for reducing morbidity from GBD in Mexican Americans.

Adult↗
PubMed2000

Glutathione S-transferases M1, T1, and P1 and breast cancer.

We examined associations for glutathione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) genotypes and breast cancer in the Carolina Breast Cancer Study, a population-based, case-control study in North Carolina. Odds ratios were close to the null value for each GST locus among African-American women (278 cases and 271 controls) and white women (410 cases and 392 controls), as well as pre- and postmenopausal women. For women with a history of breast cancer in one or more first-degree relatives, odds ratios were 2.1 (95% confidence interval, 1.0-4.2) for GSTM1 null and 1.9 (0.8-4.6) for GSTT1 null genotypes. Among women with a family history, age at diagnosis was significantly earlier for those with the GSTM1 null genotype. We did not observe strong evidence for modification of odds ratios for smoking according to GST genotypes. There was no evidence for combined effects of GSTM1, GSTT1, and GSTP1 genotypes, and there were no combined effects for GST genotypes and the catechol O-methyltransferase genotype. We conclude that GSTM1, GSTT1, and GSTP1 genotypes do not play a strong role in susceptibility to breast cancer. However, the role of GST genotypes in age at onset and risk of breast cancer among women with a family history merits further investigation.

Adult↗
PubMed2000

Dichlorodiphenyldichloroethene, polychlorinated biphenyls, and breast cancer among African-American and white women in North Carolina.

We examined plasma dichlorodiphenyldichloroethene (DDE) and total polychlorinated biphenyl (PCB) levels in relation to breast cancer in a population-based, case-control study of African-American women (292 cases and 270 controls) and white women (456 cases and 389 controls) in North Carolina. Adjusted odds ratios (ORs) for breast cancer comparing the highest to lowest third of DDE were 1.41 [95% confidence interval (CI), 0.87-2.29] in African-American women and 0.98 (95% CI, 0.67-1.43) in white women. ORs comparing the highest to lowest third of total PCBs were 1.74 (95% CI, 1.00-3.01) in African-American women and 1.03 (95% CI, 0.68-1.56) in white women. Among African-Americans, the OR for total PCBs was highest for obese women (body mass index 234.2; OR, 4.92; 95% CI, 1.63-14.83). In contrast, the OR for DDE was highest for the leanest African-American women (body mass index, <25; OR, 3.84; 95% CI, 0.98-15.08). ORs for DDE were not elevated among women who lived or worked on farms or elevated among farming women who reported exposure to pesticides. Our results suggest absence of a strong effect for DDE or total PCBs in breast cancer but lend support for associations among subgroups of women. In our study, factors such as income, parity, breastfeeding, race/ethnicity, and body mass index influenced the relationship of organochlorines and breast cancer. Differing distributions of such factors may explain some of the inconsistencies across previous studies.

Adult↗
PubMed2000

The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy.

To determine the prognostic value of angiogenesis factor expression for patients with muscle-invasive transitional cell carcinoma (TCC) of the bladder treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy and radical cystectomy, we evaluated the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8) by in situ hybridization, and we determined microvessel density (MVD) by immunohistochemistry. These factors were evaluated in 55 biopsy specimens prior to therapy and in the cystectomy specimens of 51 patients after completion of therapy. By univariate analysis, VEGF expression and MVD in the biopsy specimens were significant predictors of disease recurrence. By multivariate analysis, only VEGF expression was an independent prognostic factor. Pathological stage, bFGF expression, and MVD in the cystectomy specimens after therapy were all independent prognostic factors for disease recurrence. The results of this exploratory study indicate that the expression levels of VEGF and bFGF as indicated by in situ hybridization and MVD as indicated by immunohistochemistry identify patients with muscle-invasive TCC who are at high risk of developing metastasis after aggressive therapy with systemic M-VAC chemotherapy and radical cystectomy.

Adult↗
PubMed1999

Lactation and breast cancer risk.

BACKGROUND: Data from the Carolina Breast Cancer Study, a population-based, case-control study of breast cancer in African-American and white women residents of North Carolina, were evaluated to determine whether specific aspects of lactation are associated with a reduction in the risk of breast cancer. METHODS: Analyses included 751 parous cases and 742 parous controls frequency-matched on age and race. Information on lactation, reproductive history, lifestyle characteristics and family history were obtained through a personal interview. RESULTS: When women who breastfed were compared to those who never breastfed, odds ratios and 95% confidence intervals of 0.8 (0.5-1.1) and 0.7 (0.5-0.9) were found for women 20-49 years and 50-74 years, respectively. Similar inverse associations were observed for each of three categories of lifetime duration (1-3, 4-12, 13+ months). The inverse associations persisted and did not vary when number of children breastfed, ages at first and last lactation and lactational amenorrhoea were examined. CONCLUSIONS: Our findings suggest that any lactation, regardless of duration or timing, is associated with a slight reduction in the risk of breast cancer among younger and older parous women.

Adult↗
PubMed1997

Correlations among human blood levels of specific PCB congeners and implications for epidemiologic studies.

Specific congeners of PCBs may differ with respect to their human health risks. For epidemiologic studies, however, measuring levels of specific congeners--as compared with estimating the concentration of total PCBs present, may be of limited value if levels of specific congeners are highly correlated. We examined the correlations among levels of specific congeners in three groups: controls from a case-control study of breast cancer in North Carolina and two groups from Wisconsin with exposure to fish from contaminated waters. Levels of specific congeners were, in general, highly correlated (Pearson r > 0.80). However, the level of congener 180, a heptachlorobiphenyl, tended to be less correlated with levels of lower-chlorinated biphenyls. Among the implications of these findings are that measurement of a select group of congeners may yield essentially the same information as measurement of a large panel, and may be more cost efficient.

Adult↗