Knowledge, Attitudes, and Utilization of BRCA Testing Among Obstetricians and Gynecologists

Hereditary breast and ovarian cancer (HBOC) is an inherited cancer syndrome that is associated with mutations in the BRCA1 and BRCA2 genes. Carriers of BRCA mutations, both men and women, are at an increased risk for developing certain cancers. Carriers are most notably at an increased risk to develop breast and ovarian cancers; however an increased risk for prostate cancer, melanoma, and pancreatic cancers has also been associated with these mutations. In 2009 the American Congress of Obstetricians and Gynecologists (ACOG) released a practice bulletin stating that evaluating a patient’s risk for HBOC should be a routine part of obstetric and gynecologic practice. A survey was created and completed by 83 obstetricians and gynecologists in the greater Houston, TX area. The survey consisted of four sections designed to capture demographic information, attitudes towards HBOC and BRCA testing, utilization of BRCA testing, and the overall knowledge of respondents with regards to HBOC and BRCA testing. This study found that the majority of participants indicated that they felt that obstetricians and gynecologists should have the primary responsibility of identifying patients who may be at increased risk of carrying a BRCA mutation. Moreover, this study found that the majority of participants indicated that they felt comfortable or very comfortable in identifying patients at an increased risk of carrying a BRCA mutation. However, only about a quarter of participants indicated that they order BRCA genetic testing one to two times per month or more. Lastly, this study demonstrates that the overall knowledge of HBOC and BRCA testing among this population of obstetricians and gynecologists is poor. The results of this study stress the need for more education regarding HBOC, genetic testing, and strategies for identifying patients that may be at risk for having a mutation in a BRCA gene. Furthermore, it reiterates the importance of raising awareness to current practice guidelines and recommendations that can assist obstetricians and gynecologist to better identify and manage patients that may be at an increased risk of having HBOC.

Computer simulation of glioma growth and morphology.

Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion.

Computer simulation of glioma growth and morphology.

Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion.

TP53 as a Biomarker in Head and Neck Squamous Cell Carcinoma

Currently, there are no molecular biomarkers that guide treatment decisions for patients with head and neck squamous cell carcinoma (HNSCC). Several retrospective studies have evaluated TP53 in HNSCC, and results have suggested that specific mutations are associated with poor outcome. However, there exists heterogeneity among these studies in the site and stage of disease of the patients reviewed, the treatments rendered, and methods of evaluating TP53 mutation. Thus, it remains unclear as to which patients and in which clinical settings TP53 mutation is most useful in predicting treatment failure. In the current study, we reviewed the records of a cohort of patients with advanced, resectable HNSCC who received surgery and post-operative radiation (PORT) and had DNA isolated from fresh tumor tissue obtained at the time of surgery. TP53 mutations were identified using Sanger sequencing of exons 2-11 and the associated splice regions of the TP53 gene. We have found that the group of patients with either non-disruptive or disruptive TP53 mutations had decreased overall survival, disease-free survival, and an increased rate of distant metastasis. When examined as an independent factor, disruptive mutation was strongly associated with the development of distant metastasis. As a second aim of this project, we performed a pilot study examining the utility of the AmpliChip® p53 test as a practical method for TP53 sequencing in the clinical setting. AmpliChip® testing and Sanger sequencing was performed on a separate cohort of patients with HNSCC. Our study demonstrated the ablity of the AmpliChip® to call TP53 mutation from a single formalin-fixed paraffin-embedded slide. The results from AmpliChip® testing were identical with the Sanger method in 11 of 19 cases, with a higher rate of mutation calls using the AmpliChip® test. TP53 mutation is a potential prognostic biomarker among patients with advanced, resectable HNSCC treated with surgery and PORT. Whether this subgroup of patients could benefit from the addition of concurrent or induction chemotherapy remains to be evaluated in prospective clinical trials. Our pilot study of the p53 AmpliChip® suggests this could be a practical and reliable method of TP53 analysis in the clinical setting.

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS Michael Stephen Silosky, B.S. Supervisory Professor: S. Cheenu Kappadath, Ph.D. Evaluation of count rate performance (CRP) is an integral component of gamma camera quality assurance and measurement of system dead time (τ) is important for quantitative SPECT. The CRP of three modern gamma cameras was characterized using established methods (Decay and Dual Source) under a variety of experimental conditions. For the Decay method, input count rate was plotted against observed count rate and fit to the paralyzable detector model (PDM) to estimate τ (Rates method). A novel expression for observed counts as a function of measurement time interval was derived and the observed counts were fit to this expression to estimate τ (Counts method). Correlation and Bland-Altman analysis were performed to assess agreement in estimates of τ between methods. The dependencies of τ on energy window definition and incident energy spectrum were characterized. The Dual Source method was also used to estimate τ and its agreement with the Decay method under identical conditions and the effects of total activity and the ratio of source activities were investigated. Additionally, the effects of count rate on several performance metrics were evaluated. The CRP curves for each system agreed with the PDM at low count rates but deviated substantially at high count rates. Estimates of τ for the paralyzable portion of the CRP curves using the Rates and Counts methods were highly correlated (r=0.999) but with a small (~6%) difference. No significant difference was observed between the highly correlated estimates of τ using the Decay or Dual Source methods under identical experimental conditions (r=0.996). Estimates of τ increased as a power-law function with decreasing ratio of counts in the photopeak to the total counts and linearly with decreasing spectral effective energy. Dual Source method estimates of τ varied as a quadratic with the ratio of the single source to combined source activities and linearly with total activity used across a large range. Image uniformity, spatial resolution, and energy resolution degraded linearly with count rate and image distorting effects were observed. Guidelines for CRP testing and a possible method for the correction of count rate losses for clinical images have been proposed.

Mistreatment and self-neglect in community dwelling older adults: Studies of construct validity, measurement invariance and latent classes

Mistreatment and self-neglect significantly increase the risk of dying in older adults. It is estimated that 1 to 2 million older adults experience elder mistreatment and self-neglect every year in the United States. Currently, there are no elder mistreatment and self-neglect assessment tools with construct validity and measurement invariance testing and no studies have sought to identify underlying latent classes of elder self-neglect that may have differential mortality rates. Using data from 11,280 adults with Texas APS substantiated elder mistreatment and self-neglect 3 studies were conducted to: (1) test the construct validity and (2) the measurement invariance across gender and ethnicity of the Texas Adult Protective Services (APS) Client Assessment and Risk Evaluation (CARE) tool and (3) identify latent classes associated with elder self-neglect. Study 1 confirmed the construct validity of the CARE tool following adjustments to the initial hypothesized CARE tool. This resulted in the deletion of 14 assessment items and a final assessment with 5 original factors and 43 items. Cross-validation for this model was achieved. Study 2 provided empirical evidence for factor loading and item-threshold invariance of the CARE tool across gender and between African-Americans and Caucasians. The financial status domain of the CARE tool did not function properly for Hispanics and thus, had to be deleted. Subsequent analyses showed factor loading and item-threshold invariance across all 3 ethnic groups with the exception of some residual errors. Study 3 identified 4-latent classes associated with elder self-neglect behaviors which included individuals with evidence of problems in the areas of (1) their environment, (2) physical and medical status, (3) multiple domains and (4) finances. Overall, these studies provide evidence supporting the use of APS CARE tool for providing unbiased and valid investigations of mistreatment and neglect in older adults with different demographic characteristics. Furthermore, the findings support the underlying notion that elder self-neglect may not only occur along a continuum, but that differential types may exist. All of which, have very important potential implications for social and health services distributed to vulnerable mistreated and neglected older adults.^

Patenting genes and gene sequences: Analysis of public health implications and the law

At issue is whether or not isolated DNA is patent eligible under the U.S. Patent Law and the implications of that determination on public health. The U.S. Patent and Trademark Office has issued patents on DNA since the 1980s, and scientists and researchers have proceeded under that milieu since that time. Today, genetic research and testing related to the human breast cancer genes BRCA1 and BRCA2 is conducted within the framework of seven patents that were issued to Myriad Genetics and the University of Utah Research Foundation between 1997 and 2000. In 2009, suit was filed on behalf of multiple researchers, professional associations and others to invalidate fifteen of the claims underlying those patents. The Court of Appeals for the Federal Circuit, which hears patent cases, has invalidated claims for analyzing and comparing isolated DNA but has upheld claims to isolated DNA. The specific issue of whether isolated DNA is patent eligible is now before the Supreme Court, which is expected to decide the case by year's end. In this work, a systematic review was performed to determine the effects of DNA patents on various stakeholders and, ultimately, on public health; and to provide a legal analysis of the patent eligibility of isolated DNA and the likely outcome of the Supreme Court's decision. ^ A literature review was conducted to: first, identify principle stakeholders with an interest in patent eligibility of the isolated DNA sequences BRCA1 and BRCA2; and second, determine the effect of the case on those stakeholders. Published reports that addressed gene patents, the Myriad litigation, and implications of gene patents on stakeholders were included. Next, an in-depth legal analysis of the patent eligibility of isolated DNA and methods for analyzing it was performed pursuant to accepted methods of legal research and analysis based on legal briefs, federal law and jurisprudence, scholarly works and standard practice legal analysis. ^ Biotechnology, biomedical and clinical research, access to health care, and personalized medicine were identified as the principle stakeholders and interests herein. Many experts believe that the patent eligibility of isolated DNA will not greatly affect the biotechnology industry insofar as genetic testing is concerned; unlike for therapeutics, genetic testing does not require tremendous resources or lead time. The actual impact on biomedical researchers is uncertain, with greater impact expected for researchers whose work is intended for commercial purposes (versus basic science). The impact on access to health care has been surprisingly difficult to assess; while invalidating gene patents might be expected to decrease the cost of genetic testing and improve access to more laboratories and physicians' offices that provide the test, a 2010 study on the actual impact was inconclusive. As for personalized medicine, many experts believe that the availability of personalized medicine is ultimately a public policy issue for Congress, not the courts. ^ Based on the legal analysis performed in this work, this writer believes the Supreme Court is likely to invalidate patents on isolated DNA whose sequences are found in nature, because these gene sequences are a basic tool of scientific and technologic work and patents on isolated DNA would unduly inhibit their future use. Patents on complementary DNA (cDNA) are expected to stand, however, based on the human intervention required to craft cDNA and the product's distinction from the DNA found in nature. ^ In the end, the solution as to how to address gene patents may lie not in jurisprudence but in a fundamental change in business practices to provide expanded licenses to better address the interests of the several stakeholders. ^