California Pacific Currents 2004
Centers for Research in Clinical Excellence (CRCLE): The Wheel Keeps on Turning
The acronym CRCLE suggests a system whose components are interrelated and interdependent. Within the Centers for Research in Clinical Excellence (CRCLE) at California Pacific, the acronym stands for a program in which researchers and clinicians work together to search for clues in patients’ medical histories, diagnostic studies and responses to treatment that can be used to improve care.
Physician-investigators chosen for the CRCLE program apply rigorous research methods and data collection techniques to their studies. Each CRCLE project studies a cohort of patients, who have agreed to participate and are cared for at the Medical Center. They receive intensive diagnostic work-ups, treatment and follow-up care. Patient outcomes such as hospitalization, metastasis of a tumor, complications of treatment or death are assessed at predetermined intervals. Biological specimens, such as blood or tissue, are collected and stored for potential future analyses.
In the past year, the CRCLE program has funded three projects. Here is an update on those studies.
The Breast Health Study
During the course of a year, about 30,000 women have screening mammograms at California Pacific’s Breast Health Center, which is directed by Fred Margolin, MD. Researchers conducting the CRCLE Breast Health study want to have at least half of these women participate in the research.
“Our goal is to discover a combination of measurements, such as a hormone level, breast density and other new measurements to give a woman an accurate assessment of her risk of developing breast cancer. We hope that eventually ‘risk of breast cancer’ will become part of the report about mammogram results,” says Steven Cummings, MD, FACP, an internationally recognized expert in women’s health, breast cancer prevention and screening, the epidemiology of osteoporosis and fractures, and aging. Dr. Cummings oversees the entire CRCLE program.
The study protocol involves obtaining a blood sample from women who have screening mammograms. Mammography units have been outfitted with a new device for assessing breast density.
Treatments will be available soon to decrease a woman’s risk for developing breast cancer. Identifying the women who will benefit from these interventions, however, is not yet a reality. Researchers want to expand the list of known breast cancer risk factors, such as having a family history of breast cancer. “We have shown that postmenopausal women who have higher levels of estrogen or testosterone also have a higher risk of developing breast cancer. There may be other ways to test women to determine if they have an increased risk of breast cancer. The first step is to include measuring the ‘density’ of the breast on a routine mammogram. Along with our initiative, other tests will continue to be designed and developed to help assess risk,” concludes Dr. Cummings.
“As a participant in the San Francisco Mammography Registry, the Breast Health Center already collects some risk factor data for breast cancer from our patients,” says Nadine Radovich, CRT, a specialist in mammography and manager of the center. “The Breast Health Study, however, will be the first cohort that includes measurements of breast density and certain identified blood serum and DNA markers.” The DNA specimens will help in the search for new genes that increase the risk of breast cancer.
The Role of Host Genetics in Treatment Outcomes: The BHIVE Study
“Our study is part of the burgeoning field of pharmacogenomics,” says Stephen Becker, MD, an HIV clinician and researcher at California Pacific. Pharmacogenomics studies how genetic factors influence the response to medications. This is not a new area of investigation for Dr. Becker, who has published on the effects of a patient’s metabolism, the action of membrane drug transporter elements, and activation of certain receptor sites in altering the activity and efficacy of antiviral drugs used to treat AIDS patients. Identifying how each of these factors affects clinical outcomes is a major objective of the Biobank for HIV Evaluations (BHIVE) study group.
Dr. Becker explains: “Early work in other therapeutic areas has demonstrated that host genetics are a significant determinant of treatment out-comes, affecting both effectiveness and toxicity of a given pharmaceutical regimen. It is likely that genetic factors will similarly affect HIV outcomes.” The BHIVE project will concentrate on two fundamental factors of HIV pharmacology: drug transport and metabolism. The eventual outcomes of this and other work is hoped to provide the basis for the individualization of anti-HIV therapy.
The BHIVE study integrates clinical data with tissue samples from HIV patients. Analyses of these samples—including peripheral blood cells, adipocytes (fat cells) and hepatocytes (liver cells) from selected patients—will determine whether or not genetic factors ultimately affect the efficacy and toxicity of HIV pharmacotherapy.
Data collection began in March 2004, and by early 2005 the research group plans to have 500 patients enrolled, with an additional 500 to follow by the beginning of 2006. The BHIVE cohort of patients will include men and women from several racial and ethnic groups at differing stages of HIV disease. Researchers will explore how these differences affect the safety and efficacy of treatment. The heterogeneity of the cohort will make the study closely representative of the general population of HIV patients.
Treatment complications will be noted, including the effects of body composition disorders, hyper or dyslipidemia, glucose disorders, alcohol and tobacco use, and hepatoxicity. Changes in weight will also be measured.
Evaluation of Patients with Nausea and Vomiting Associated with Delayed Gastric Emptying
Delayed gastric emptying, known clinically as gastroparesis, is a condition in which the stomach’s ability to empty its contents is impaired, even though there is no physical obstruction. The cause of gastroparesis is unknown, but disruption of nerve stimulation to the intestine may be responsible. Risk factors for gastroparesis include diabetes; systemic sclerosis, a connective tissue disease; previous digestive tract surgeries; damage or destruction of nerves in the abdominal or thoracic cavities; and use of medications for the treatment of irritable bowel syndrome. Some patients do not have any identifiable cause for the disorder.
Dietary management and available medications provide little long-term benefit. Besides the obvious discomfort of the condition and its effects on quality of life, gastroparesis can cause electrolyte imbalances, dehydration, and malnutrition due to persistent nausea and vomiting. Persons with diabetes may develop additional, serious complications related to poor blood glucose control.
Establishing Evidence-Based Guidelines
“The first step of this project, which began in late 2003, was to identify California Pacific patients who have symptoms of nausea, vomiting, and abdominal pain and distention associated with delayed gastric emptying as measured by a nuclear scan. Studying this cohort will enable our team of investigators to establish evidence-based guidelines for the evaluation and treatment of patients afflicted with nausea and vomiting due to gastroparesis,” says William J. Snape, Jr, MD, Director Gastro-intestinal Motility Services at California Pacific Medical Center.
Researchers, led by Dr. Snape, principal investigator, will collect prospective quality-of-life measurements, gastrointestinal peptide levels, DNA for classification of genetic polymorphism, and gastrointestinal motility measurements in more than 300 patients with delayed gastric emptying. These studies will allow determination of the different causes of symptomatic gastroparesis in the ethnically diverse0.
population of San Francisco.
Currently, there are no guidelines for the evaluation of these patients that incorporate the use of newer testing modalities such as antroduodenal motility (which measures the pressures in the stomach and intestines and how quickly food moves through the digestive system), electrogastrogram (similar to the electrocardiogram for the heart), gastric ultrasound, and barostat (a computer-controlled pump) testing of gastric tone. “Establishing evidence-based guidelines will enable us to more clearly define the role of certain tests in the diagnosis and treatment of this patient group. Understanding the causes of gastroparesis ultimately will lead to improved therapy,” says Dr. Snape.
Keeping Up the Momentum
New projects will be added soon to the roster, but the competition is keen for a place in the program. “Of the many deserving applications, only a few can be supported” says Alice LaRocca, Associate Director of CRCLE.
In addition to assistance with funding, CRCLE provides methodological and technical expertise. However, the expectation is that after an initial “launch,” programs will become largely self-supporting. By providing some initial momentum, CRCLE will be able to ensure that new and potentially breakthrough projects get off to the best possible start.