Primary Prevention and Screening Strategies for Colorectal Cancer: Which Strategy Should Take?

Objective: To explore and define the utility of different strategies for primary prevention (ASA, diet, physical activity) and strategies of screening test (FOBT, sigmoidoscopy, colonoscopy, etc.) for colorectal cancer. Data source: Databases consulted were MEDLINE (1966 to 2006), DARE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration’s Registry of Clinical Trials, Cochrane Database of Systematic Reviews and LILACS. Study selection: Studies such clinical trial, cohort and case-control studies of the effectiveness of tests for screening and primary prevention adenoma and colorectal cancer were identified by two reviewers. Data Extraction: The extraction of data and its evaluation is done in most of the process so paired. Limitations: Not strictly complies with the methodology of a systematic review and therefore reproducibility is questionable, the conclusions of this study should be extrapolated with caution. Conclusions: The major strategy of screening on the effectiveness of early detection of premalignant lesions or cancer is colonoscopy every 5 years, however it is necessary to evaluate this measure cost-effectiveness studies. For primary prevention, aspirin and cyclooxygenase-2 inhibitors reduce the incidence of colorectal adenomas. Aspirin can reduce colorectal cancer incidence. However, these medications may be associated with a significant risk of cardiovascular events and gastrointestinal bleeding. The balance between risks and benefits must be evaluated in future studies.

Older Breast Cancer Survivors: Factors Associated with Self-reported Symptoms of Persistent Lymphedema Over 7 years of Follow-up

Lymphedema of the arm is a common complication of breast cancer with symptoms that can persist over long periods of time. For older women (over 50% of breast cancer cases) it means living with the potential for long-term complications of persistent lymphedema in conjunction with the common diseases and disabilities of aging over survivorship. We identified women > or =65 years diagnosed with primary stage I-IIIA breast cancer. Data were collected over 7 years of follow-up from consenting patients' medical records and telephone interviews. Data collected included self-reported symptoms of persistent lymphedema, breast cancer characteristics, and selected sociodemographic and health-related characteristics. The overall prevalence of symptoms of persistent lymphedema was 36% over 7 years of follow-up. Having stage II or III (OR = 1.77, 95% CI: 1.07-2.93) breast cancer and having a BMI >30 (OR = 3.04, 95% CI: 1.69-5.45) were statistically significantly predictive of symptoms of persistent lymphedema. Women > or =80 years were less likely to report symptoms of persistent lymphedema when compared to younger women (OR = 0.44, 95% CI: 0.18-0.95). Women with symptoms of persistent lymphedema consistently reported worse general mental health and physical function. Symptoms of persistent lymphedema were common in this population of older breast cancer survivors and had a noticeable effect on both physical function and general mental health. Our findings provide evidence of the impact of symptoms of persistent lymphedema on the quality of survivorship of older women. Clinical and research efforts focused on risk factors for symptoms of persistent lymphedema in older breast cancer survivors may lead to preventative and therapeutic measures that help maintain their health and well-being over increasing periods of survivorship.

Factors Associated with Early Versus Late Development of Breast and Ovarian Cancer in BRCA1 and BRCA2 Positive Women

Hereditary breast and ovarian cancer (HBOC) is caused by a mutation in the BRCA1 or BRCA2 genes. Women with a BRCA1/2 mutation are at increased risks for breast and ovarian cancer and often develop cancer at an earlier age than the general population. However, some women with a BRCA1/2 mutation do not develop breast or ovarian cancer under the age of 50 years. There have been no specific studies on BRCA positive women with no cancer prior to age 50, therefore this study sought to investigate factors within these women with no cancer under age 50 with respect to reproductive risk factors, BMI, tumor pathology, screening history, risk-reducing surgeries, and family history. 241 women were diagnosed with cancer prior to age 50, 92 with cancer at age 50 or older, and 20 women were over age 50 with no cancer. Data were stratified based on BRCA1 and BRCA2 mutation status. Within the cohorts we investigated differences between women who developed cancer prior to age 50 and those who developed cancer at age 50 or older. We also investigated the differences between women who developed cancer at age 50 or older and those who were age 50 or older with no cancer. Of the 92 women with a BRCA1/2 mutation who developed cancer at age 50 or older, 46 developed ovarian cancer first, 45 developed breast cancer, and one had breast and ovarian cancer diagnosed synchronously. BRCA2 carriers diagnosed age 50 or older were more likely to have ER/PR negative breast tumors when compared to BRCA2 carriers who were diagnosed before age 50. This is consistent with one other study that has been performed. Ashkenazi Jewish women with a BRCA1 mutation were more likely to be diagnosed age 50 or older than other ethnicities. Hispanic women with a BRCA2 mutation were more likely to be diagnosed prior to age 50 when compared to other ethnicities. No differences in reproductive factors or BMI were observed. Further characterization of BRCA positive women with no cancer prior to age 50 may aid in finding factors important in the development of breast or ovarian cancer.

Hazardous air pollutants and childhood lymphohematopoietic cancer in Southeast Texas, 1995--2004

Southeast Texas, including Houston, has a large presence of industrial facilities and has been documented to have poorer air quality and significantly higher cancer rates than the remainder of Texas. Given citizens’ concerns in this 4th largest city in the U.S., Mayor Bill White recently partnered with the UT School of Public Health to determine methods to evaluate the health risks of hazardous air pollutants (HAPs). Sexton et al. (2007) published a report that strongly encouraged analytic studies linking these pollutants with health outcomes. In response, we set out to complete the following aims: 1. determine the optimal exposure assessment strategy to assess the association between childhood cancer rates and increased ambient levels of benzene and 1,3-butadiene (in an ecologic setting) and 2. evaluate whether census tracts with the highest levels of benzene or 1,3-butadiene have higher incidence of childhood lymphohematopoietic cancer compared with census tracts with the lowest levels of benzene or 1,3-butadiene, using Poisson regression. The first aim was achieved by evaluating the usefulness of four data sources: geographic information systems (GIS) to identify proximity to point sources of industrial air pollution, industrial emission data from the U.S. EPA’s Toxic Release Inventory (TRI), routine monitoring data from the U.S. EPA Air Quality System (AQS) from 1999-2000 and modeled ambient air levels from the U.S. EPA’s 1999 National Air Toxic Assessment Project (NATA) ASPEN model. Further, once these four data sources were evaluated, we narrowed them down to two: the routine monitoring data from the AQS for the years 1998-2000 and the 1999 U.S. EPA NATA ASPEN modeled data. We applied kriging (spatial interpolation) methodology to the monitoring data and compared the kriged values to the ASPEN modeled data. Our results indicated poor agreement between the two methods. Relative to the U.S. EPA ASPEN modeled estimates, relying on kriging to classify census tracts into exposure groups would have caused a great deal of misclassification. To address the second aim, we additionally obtained childhood lymphohematopoietic cancer data for 1995-2004 from the Texas Cancer Registry. The U.S. EPA ASPEN modeled data were used to estimate ambient levels of benzene and 1,3-butadiene in separate Poisson regression analyses. All data were analyzed at the census tract level. We found that census tracts with the highest benzene levels had elevated rates of all leukemia (rate ratio (RR) = 1.37; 95% confidence interval (CI), 1.05-1.78). Among census tracts with the highest 1,3-butadiene levels, we observed RRs of 1.40 (95% CI, 1.07-1.81) for all leukemia. We detected no associations between benzene or 1,3-butadiene levels and childhood lymphoma incidence. This study is the first to examine this association in Harris and surrounding counties in Texas and is among the first to correlate monitored levels of HAPs with childhood lymphohematopoietic cancer incidence, evaluating several analytic methods in an effort to determine the most appropriate approach to test this association. Despite recognized weakness of ecologic analyses, our analysis suggests an association between childhood leukemia and hazardous air pollution.^

DIETARY RELATIONSHIPS TO FATAL BREAST CANCER AMONG SEVENTH-DAY ADVENTISTS

Laboratory experiments in animals, correlational and migrant studies in humans suggest a role for diet in the etiology of breast cancer. Data gathered from individuals via case-control studies are less consistent. Seventh-day Adventist women experience lower mortality from breast cancer than comparable U.S. populations and this decrease is thought to be, at least in part, related to dietary practices (half are vegetarian). In 1960, 25,000 California Seventh-day Adventists completed a questionnaire which included a 21 item food frequency section. Cancer mortality in this population was monitored between 1960 and 1980 and the relationship of high fat food intake and fatal breast cancer was evaluated. Although established risk factors for breast cancer were observed in this population (e.g. age at menarche, age at first pregnancy, age at menopause and obesity) consumption of high fat foods were not observed to exert a strong influence on fatal breast cancer risk. Odds ratios (O.R.) for fatal breast cancer among non-vegetarians was 1.2. Increasing meat consumption bore little relation to risk; O.R. = 1.0, 1.2, 1.1 for consumption categories of none/occasional, 1-3 days/week and 4+ days/week respectively. Nor did the consumption of other high fat foods of animal origin (e.g. butter, cheese, milk, eggs) show any relationship to risk. These results remained unchanged after simultaneously controlling for the effect of other, potentially confounding variables (menstrual characteristics, obesity) via logistic regression analysis. ^

Bayesian and survival model for tumor relapse status and disease-specific survival, with applications to breast cancer

Breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women in the United States. Studies on ipsilateral breast tumor relapse (IBTR) status and disease-specific survival will help guide clinic treatment and predict patient prognosis.^ After breast conservation therapy, patients with breast cancer may experience breast tumor relapse. This relapse is classified into two distinct types: true local recurrence (TR) and new ipsilateral primary tumor (NP). However, the methods used to classify the relapse types are imperfect and are prone to misclassification. In addition, some observed survival data (e.g., time to relapse and time from relapse to death)are strongly correlated with relapse types. The first part of this dissertation presents a Bayesian approach to (1) modeling the potentially misclassified relapse status and the correlated survival information, (2) estimating the sensitivity and specificity of the diagnostic methods, and (3) quantify the covariate effects on event probabilities. A shared frailty was used to account for the within-subject correlation between survival times. The inference was conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in softwareWinBUGS. Simulation was used to validate the Bayesian method and assess its frequentist properties. The new model has two important innovations: (1) it utilizes the additional survival times correlated with the relapse status to improve the parameter estimation, and (2) it provides tools to address the correlation between the two diagnostic methods conditional to the true relapse types.^ Prediction of patients at highest risk for IBTR after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The goals of the second part of this dissertation were to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center, to determine the risk of IBTR in patients with DCIS treated with local excision, and to determine whether there is a subset of patients at low risk of IBTR. Patients who had undergone local excision from 1990 through 2007 at MD Anderson Cancer Center with a final diagnosis of DCIS (n=794) were included in this part. Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients with complete data. Nomogram for prediction of 5- and 10-year IBTR probabilities were found to demonstrate imperfect calibration and discrimination, with an area under the receiver operating characteristic curve of .63 and a concordance index of .63. In conclusion, predictive models for IBTR in DCIS patients treated with local excision are imperfect. Our current ability to accurately predict recurrence based on clinical parameters is limited.^ The American Joint Committee on Cancer (AJCC) staging of breast cancer is widely used to determine prognosis, yet survival within each AJCC stage shows wide variation and remains unpredictable. For the third part of this dissertation, biologic markers were hypothesized to be responsible for some of this variation, and the addition of biologic markers to current AJCC staging were examined for possibly provide improved prognostication. The initial cohort included patients treated with surgery as first intervention at MDACC from 1997 to 2006. Cox proportional hazards models were used to create prognostic scoring systems. AJCC pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort to validate the scoring systems. Binary indicators for pathologic stage (PS), estrogen receptor status (E), and tumor grade (G) were summed to create PS+EG scoring systems devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups than the current AJCC staging system. The ability of the PS+EG score to stratify outcomes was confirmed in both internal and external validation cohorts. The current study proposes and validates a new staging system by incorporating tumor grade and ER status into current AJCC staging. We recommend that biologic markers be incorporating into revised versions of the AJCC staging system for patients receiving surgery as the first intervention.^ Chapter 1 focuses on developing a Bayesian method to solve misclassified relapse status and application to breast cancer data. Chapter 2 focuses on evaluation of a breast cancer nomogram for predicting risk of IBTR in patients with DCIS after local excision gives the statement of the problem in the clinical research. Chapter 3 focuses on validation of a novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention. ^

EVIDENCE OF HUMAN ENDOGENOUS RETROVIRUS K INVOLVEMENT IN HUMAN CANCER

Many lines of clinical and experimental evidence indicate a viral role in carcinogenesis (1-6). Our access to patient plasma, serum, and tissue samples from invasive breast cancer (N=19), ductal carcinoma in situ (N=13), malignant ovarian cancer (N=12), and benign ovarian tumors (N=9), via IRB-approved and informed consent protocols through M.D. Anderson Cancer Center, as well as normal donor plasmas purchased from Gulf Coast Regional Blood Center (N=6), has allowed us to survey primary patient blood and tissue samples, healthy donor blood from the general population, as well as commercially available human cell lines for the presence of human endogenous retrovirus K (HERV-K) Env viral RNA (vRNA), protein, and viral particles. We hypothesize that HERV-K proteins are tumor-associated antigens and as such can be profiled and targeted in patients for diagnostic and therapeutic purposes. To test this hypothesis, we employed isopycnic ultracentrifugation, a microplate-based reverse transcriptase enzyme activity assay, reverse transcription – polymerase chain reaction (RT-PCR), cDNA sequencing, SDS-PAGE and western blotting, immunofluorescent staining, confocal microscopy, and transmission electron microscopy to evaluate v HERV-K activation in cancer. Data from large numbers of patients tested by reverse transcriptase activity assay were analyzed statistically by t-test to determine the potential use of this assay as a diagnostic tool for cancer. Significant reverse transcriptase enzyme activity was detected in 75% of ovarian cancer patients, 53.8% of ductal carcinoma in situ patient, and 42.1% of invasive breast cancer patient samples. Only 11.1% of benign ovarian patient and 16.7% of normal donor samples tested positive. HERV-K Env vRNA, or Env SU were detected in the majority of cancer types screened, as demonstrated by the results shown herein, and were largely absent in normal controls. These findings support our hypothesis that the presence of HERV-K in patient blood circulation is an indicator of cancer or pre-malignancy in vivo, that the presence of HERV-K Env on tumor cell surfaces is indicative of malignant phenotype, and that HERV-K Env is a tumor-associated antigen useful not only as a diagnostic screening tool to predict patient disease status, but also as an exploitable therapeutic target for various novel antibody-based immunotherapies.

Shifting the focus: Addressing breast cancer disparities at the health care organization level

The purpose of this study was to understand the scope of breast cancer disparities within the Texas Medical Center. The goal was to increase the awareness of breast cancer disparities at the health care organization level, and to foster the development of organizational interventions to reduce breast cancer disparities. The study seeks to answer the following questions: 1. Are hospitals in the Texas Medical Center implementing interventions to reduce breast cancer disparities? 2. What are their interventions for reducing the effects of non clinical factors on breast cancer treatment disparities? 3. What are their measures for monitoring, continuously improving, and evaluating the success of their interventions? ^ This research project was designed as a mixed methods case study. Quantitative breast cancer data for the years 2000-2009 was obtained from the Texas Cancer Registry (TCR). Qualitative data collection and analysis was done by conducting a total of 20 semi-structured interviews of administrators, physicians and nurses at five hospitals (A, B, C, D and E) in the Texas Medical Center (TMC). For quantitative analysis, the study was limited to early stage breast cancer patients: local and regional. The dependent variable was receipt of standard treatment: Surgery (Yes/No), BCS vs Mastectomy, Chemotherapy (Yes/No) and Radiation after BCS (Yes/No). The main independent variable was race: non-Hispanic White (NHW) , non-Hispanic Black (NHB), and Hispanic. Other covariates included age at diagnosis, diagnosis date, percent poverty, grade, stage, and regional nodes. Multivariate logistic regression was used to test the adjusted association between receipt of standard care and race. Qualitative data was analyzed with the Atlas.ti7 software (ATLAS.ti GmbH, Berlin). ^ Though there were significant differences by race for all dependent variables when the data was analyzed as a single group of all hospitals; at the level of the individual hospitals the results were not consistent by race/ethnicity across all dependent variables for hospitals A, B, and E. There were no racial differences in adjusted analysis for receipt of chemotherapy for the individual hospitals of interest in this study. For hospitals C and D, no racial disparities in treatment was observed in adjusted multivariable analysis. All organizations in this study were aware of the body of research which shows that there are disparities in breast cancer outcomes for patient population groups. However, qualitative data analysis found that there were differences in interest among hospitals in addressing breast cancer disparities in their patient population groups. Some organizations were actively implementing directed measures to reduce the breast cancer disparity gap in outcomes for patients, and others were not. Despite the differences in levels of interest, quantitative data analysis showed that organizations in the Texas Medical Center were making progress in reducing the burden of breast cancer disparities in the patient populations being served.^

Normalized Gaussian Networks with Mixed Feature Data

With mixed feature data, problems are induced in modeling the gating network of normalized Gaussian (NG) networks as the assumption of multivariate Gaussian becomes invalid. In this paper, we propose an independence model to handle mixed feature data within the framework of NG networks. The method is illustrated using a real example of breast cancer data.

On the simultaneous use of clinical and microarray expression data in the cluster analysis of tissue samples

This paper considers a model-based approach to the clustering of tissue samples of a very large number of genes from microarray experiments. It is a nonstandard problem in parametric cluster analysis because the dimension of the feature space (the number of genes) is typically much greater than the number of tissues. Frequently in practice, there are also clinical data available on those cases on which the tissue samples have been obtained. Here we investigate how to use the clinical data in conjunction with the microarray gene expression data to cluster the tissue samples. We propose two mixture model-based approaches in which the number of components in the mixture model corresponds to the number of clusters to be imposed on the tissue samples. One approach specifies the components of the mixture model to be the conditional distributions of the microarray data given the clinical data with the mixing proportions also conditioned on the latter data. Another takes the components of the mixture model to represent the joint distributions of the clinical and microarray data. The approaches are demonstrated on some breast cancer data, as studied recently in van't Veer et al. (2002).

Fractal Analysis for Cancer Research: Case Study and Simulation of Fractals

2010 Mathematics Subject Classification: 65D18.

Statistical analysis and meta-analysis of microarray data

The microarray technology provides a high-throughput technique to study gene expression. Microarrays can help us diagnose different types of cancers, understand biological processes, assess host responses to drugs and pathogens, find markers for specific diseases, and much more. Microarray experiments generate large amounts of data. Thus, effective data processing and analysis are critical for making reliable inferences from the data. ^ The first part of dissertation addresses the problem of finding an optimal set of genes (biomarkers) to classify a set of samples as diseased or normal. Three statistical gene selection methods (GS, GS-NR, and GS-PCA) were developed to identify a set of genes that best differentiate between samples. A comparative study on different classification tools was performed and the best combinations of gene selection and classifiers for multi-class cancer classification were identified. For most of the benchmarking cancer data sets, the gene selection method proposed in this dissertation, GS, outperformed other gene selection methods. The classifiers based on Random Forests, neural network ensembles, and K-nearest neighbor (KNN) showed consistently god performance. A striking commonality among these classifiers is that they all use a committee-based approach, suggesting that ensemble classification methods are superior. ^ The same biological problem may be studied at different research labs and/or performed using different lab protocols or samples. In such situations, it is important to combine results from these efforts. The second part of the dissertation addresses the problem of pooling the results from different independent experiments to obtain improved results. Four statistical pooling techniques (Fisher inverse chi-square method, Logit method. Stouffer's Z transform method, and Liptak-Stouffer weighted Z-method) were investigated in this dissertation. These pooling techniques were applied to the problem of identifying cell cycle-regulated genes in two different yeast species. As a result, improved sets of cell cycle-regulated genes were identified. The last part of dissertation explores the effectiveness of wavelet data transforms for the task of clustering. Discrete wavelet transforms, with an appropriate choice of wavelet bases, were shown to be effective in producing clusters that were biologically more meaningful. ^

The effects of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and relationship with the partner on the quality of life of men with prostate cancer

Prostate cancer, the leading cause of cancer in men, has positive survival rates and constitutes a challenge to men with its side effects. Studies have addressed the bivaritate relationships between prostate cancer treatment side effects masculinity, partner relationship, and quality of life (QOL). However, few studies have highlighted the relationships among prostate cancer treatment side effects (i.e., sexual dysfunction, urinary incontinence), masculinity, and relationship with the partner together on QOL in men. Most studies were conducted with predominately Caucasian sample of men. Miami is a unique multiethnic setting that hosts Cuban, Columbian, Venezuelan, Haitian, other Latin American and Caribbean communities that were not represented in previous literature. The purpose of this study was to examine relative contributions of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and perception of the relationship with the partner on the quality of life in men diagnosed with prostate cancer. Data were collected using self administered questionnaires measuring demographic variables, sexual and urinary functioning (UCLA PCI), masculinity (CMNI), partner relationship (DAS), and QOL (SF-36). A total of 117 partnered heterosexual men diagnosed with prostate cancer were recruited from four urology clinics in Miami, Florida. Men were 67.47 (SD = 8.42) years old and identified themselves to be of Hispanic origin (54.3 %, n = 63). Findings demonstrated that there was a significant moderate negative relationship between urinary and sexual functioning of men. There was a significant strong negative association between men's perceived relationship with partner and masculinity. There was a weak negative relationship between the partner relationship and QOL. Hierarchal multiple regression showed that the partner relationship (β = -.25, t (91) = -2.28, p = .03) significantly contributed overall to QOL. These findings highlight the importance of the relationship satisfaction in the QOL of men with prostate cancer. Nursing interventions to enhance QOL for these men should consider strengthening the relationship and involving the female partner as an active participant.^

Functional characterisation of putative Cis-Regulatory Risk Loci for breast cancer

Dissertação de Mestrado, Qualidade em Análises - Erasmus Mundus, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015

The Effects of Age, Ethnicity, Sexual Dysfunction, Urinary Incontinence, Masculinity, and Relationship with the Partner on the Quality of Life of Men with Prostate Cancer

Prostate cancer, the leading cause of cancer in men, has positive survival rates and constitutes a challenge to men with its side effects. Studies have addressed the bivaritate relationships between prostate cancer treatment side effects masculinity, partner relationship, and quality of life (QOL). However, few studies have highlighted the relationships among prostate cancer treatment side effects (i.e., sexual dysfunction, urinary incontinence), masculinity, and relationship with the partner together on QOL in men. Most studies were conducted with predominately Caucasian sample of men. Miami is a unique multiethnic setting that hosts Cuban, Columbian, Venezuelan, Haitian, other Latin American and Caribbean communities that were not represented in previous literature. The purpose of this study was to examine relative contributions of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and perception of the relationship with the partner on the quality of life in men diagnosed with prostate cancer. Data were collected using self administered questionnaires measuring demographic variables, sexual and urinary functioning (UCLA PCI), masculinity (CMNI), partner relationship (DAS), and QOL (SF-36). A total of 117 partnered heterosexual men diagnosed with prostate cancer were recruited from four urology clinics in Miami, Florida. Men were 67.47 (SD = 8.42) years old and identified themselves to be of Hispanic origin (54.3 %, n = 63). Findings demonstrated that there was a significant moderate negative relationship between urinary and sexual functioning of men. There was a significant strong negative association between men’s perceived relationship with partner and masculinity. There was a weak negative relationship between the partner relationship and QOL. Hierarchal multiple regression showed that the partner relationship (β = -.25, t (91) = -2.28, p = .03) significantly contributed overall to QOL. These findings highlight the importance of the relationship satisfaction in the QOL of men with prostate cancer. Nursing interventions to enhance QOL for these men should consider strengthening the relationship and involving the female partner as an active participant.