Core Director: Dennis M. Jensen, M.D., Professor of Medicine, UCLA

Co-Directors: Lin Chang, M.D., Brennan Spiegel, M.D., MSHS

Core Associate Director: Thomas O.G. Kovacs, M.D.

OBJECTIVES

The mission of the Human Studies Core is to provide shared resources, personnel, services, education, and consultation to CURE investigators, trainees, and their collaborators for the study of patients with selected digestive diseases. The primary goal of this Core is to facilitate collaboration, education about, and performance of GI clinical trials, human physiological studies, and health services studies in digestive diseases. The traditional focus of the Human Studies Core has been the investigation of peptic diseases and upper GI physiology including secretion, motility, and hormonal regulation. This focus has been broadened to include the study of other important gastrointestinal illnesses such as complicated ulcer disease, gastroesophageal reflux disease (GERD), Barrett's epithelium, GI hemorrhage, non-ulcer dyspepsia, Helicobacter pylori infection, pre-cancer conditions (gastritis, polyposis, and ulcerative colitis), and inflammatory bowel disease. An overriding theme is the study of the physiology of visceral pain which may be associated with all of these disorders. The importance of this area in GI diseases is highlighted by the impact of GI symptoms on quality of life and demand for health care services. With this in mind, the Core has greatly expanded the study of neuroenteric diseases such as IBS, non-ulcer dyspepsia, and non-cardiac chest pain.

The specific purposes of this Core are to provide CURE investigators, trainees, and their collaborators with access to: (1) a quality clinical research unit for performance of GI clinical research at a low cost, (2) utilization of fully equipped endoscopy units for GI clinical and physiologic research studies, (3) laboratory services for GI secretory tests, GI motility and pH testing, and H. pylori assessments (ELISA, C13 breath testing, and histopathology), (4) teaching of clinical research techniques and consultation about study design, data management, statistical analysis, and routine outcomes, (5) tissue and clinical data banks of patients with selected GI diseases (the largest data bases are for GI hemorrhage and functional GI disease), (6) consultation about conducting health services research including design of studies, cost assessments, quality of life instruments, effectiveness studies, and modeling cost-effectiveness studies, (7) specialized equipment for GI studies (such as equipment for ablating Barrett's epithelium or endoscopic ultrasound instruments), (8) psychophysiology and GI motility laboratories for the study of neuroenteric diseases, and (9) utilization of a brain imaging unit for the study of neuroenteric diseases. The instruments and personnel required for these services and functions are expensive, so that sharing them among various investigators in a core is cost effective and promotes collaboration.

CORE SERVICES

A. SECRETORY TESTS

Basal and stimulated (by pentagastrin or food) acid secretion is performed in the CURE CRC Human Studies Unit. Secretin stimulation for diagnosis of Zollinger-Ellison syndrome is performed by core personnel and is available to center investigators in collaboration with Drs. J. Pisegna, G. Ohning, or T. Kovacs.

B. MOTILITY AND pH TESTS

Tests offered at the CURE CRC Human Studies Unit and supervised by T. Kovacs are 24 and 48 hour pH probe tests. Twenty-four hour ambulatory gastroduodenal manometry, anorectal manometry, and biofeedback, and colonic manometry are performed in the Neurovisceral Disease Unit and are supervised by Dr. Chang.

C. HELICOBACTER PYLORI TESTS

The tests offered include ELISA study for detection of IgG, C13 urea breath tests, and endoscopic biopsy (for rapid urease or histology-Giemsa staining). These tests are offered to all Center members, coordinated by Ms. Altman, and performed by Drs. Kovacs, Dulai, or Ohning in the CURE CRC Human Studies Unit.

D. VIDEOENDOSCOPY, BIOPSY AND HISTOLOGY

Videoendoscopy is offered with mavigraph pictures or video documentation. This can be combined with biopsies (for example for fresh tissue for translational or collaborative investigators; or specific studies such as modified Giemsa stain for H. pylori, histopathology for grading gastritis or dysplasia of Barrett’s epithelium, or immunohistopathology) fluid collection, endoscopic brushing or cytology. These tests are performed within the CURE CRC Human Studies Unit. Research technicians offer these tests to all Core investigators and collaborators. These are coordinated by Ms. Altman and Dr. Kovacs, and G. Dulai.

E. SPECIALIZED ENDOSCOPIC RESEARCH PROCEDURES

Specialized endoscopic procedures include reflectance spectroscopy (as an index of mucosal blood flow), endoscopic ultrasound with fine needle aspiration, endoscopic echoprobe studies, endoscopic ablation of Barrett's epithelium with multipolar probe or argon plasma coagulator, Doppler ultrasound probe for blood flow studies, optical coherence tomography, and capsule endoscopy (for small intestinal morphology and motility studies). Mr. Hirabayashi and Drs. Jensen, Kovacs, and Dulai or other CURE: DDRCC Core personnel offer these specialized procedures to Core investigators and collaborators. Scheduling of these procedures is coordinated by J. Pham.

F. DATA MANAGEMENT

Core personnel are available for consultation and training in data management of patient-oriented trials, pilot and feasibility studies, or collaborative studies (Drs. Gornbein, Lousuebsakul and Jensen), in neurovisceral disorders (Drs. Bolus and Chang), and in outcomes studies (Drs. Dulai and Gralnek).

G. OUTCOMES ASSESSMENTS AND BIOSTATISTICAL CONSULTATION

Consultation is available on outcome assessments of patient-oriented research in Barrett’s epithelium, peptic diseases, multicenter randomized prospective trials (Drs. Gornbein, Jensen, and Kovacs); or in neurovisceral diseases or women’s health (Drs. Bolus, Chang and Dr. Mayer); and biostatistical consultation for patient-oriented studies (Dr. Jeffrey Gornbein); and health outcomes research studies in peptic disease or multicenter randomized prospective trials (Drs. Gralnek, Dulai, and Jensen).

H. CURE CRC CLINIC AND RN SUPPORT

Research coordination and (nursing) support are available for patient-oriented research studies (Ms. Altman, St. Amand). Assistance in study design, preparation of human studies protocols, forms design (Drs Jensen, Kovacs, and Lousuebsakul) and in patient recruitment and liaison with the IRB’s at UCLA and VA (Ms. Altman and St. Amand) is readily available. Dr. Kovacs and Ms. Altman schedule clinic staff and endoscopy visits, and Ms. Pham schedules for Core utilization of rooms or services on a first-come-first serve basis, prioritized as described below.

I. CORE TISSUE BANKS (with associated data bases of patient demographics, treatments, and outcomes)

I-1. Dr. Jensen and the CURE Hemostasis Research Group have a tissue bank of paraffin-embedded endoscopic gastric biopsies from more than 250 patients with H. pylori infection or NSAID ulcers from their multicenter trials of patients with ulcer hemorrhage. Serial specimens are available on patients with recent hemorrhage from gastric or duodenal ulcers from NSAID ulcers and from other patients before and after H. pylori eradication. Corresponding databases (of coded patient demographics, treatments, and outcomes) are also available for collaborative studies. This tissue bank was developed to facilitate collaborative studies with patient-oriented and laboratory researchers. Collaboration is coordinated by Mr. Hirabayashi and Dr. Jensen.

I-2. Dr. Weinstein has paraffin embedded tissue blocks from endoscopic biopsies of 200 patients with GERD and Barrett's epithelium. Approximately 20% of these have dysplasia (low or high grade). He is studying tissue markers of differentiation, proliferation and dysplasia. Approximately 100 patients have serial sets of biopsies at six-month intervals for two years while on sustained hypochlorhydria (omeprazole treated) or lesser acid suppression (ranitidine treated). Databases of relevant coded patient information on computer files and these tissues are available for collaborative studies. Dr. Weinstein also has tissue blocks from endoscopic biopsies of approximately 100 other patients with erosions and gastropathy related to NSAIDs and other etiologies. These and the relevant patient information on computer databases are also available for collaborative studies. The Barrett's epithelium tissue bank will continue to grow because of ongoing NIH K23 (from Dr. Gareth Dulai) and K24 (from Dr. Jensen) grants that include collaborative studies of GERD and Barrett's epithelium. Dr. Weinstein coordinates requests for collaboration and utilization of this tissue bank.

I-3. Drs. J. Randolph Hecht and James Farrell maintain a tissue bank that contains approximately 250 frozen malignancies (colon, pancreas, esophageal, and gastric cancers) maintained at -70OC. These are available for collaborative studies and are from surgical resection, endoscopic biopsies and FNA specimens of documented human GI malignances. They also have a comprehensive clinical database for the patients. Using molecular biology techniques, they are studying the diagnosis (e.g., pancreatic cancer with K-ras gene mutations) and possible carcinogenesis (e.g., colorectal cancer with cyclooxygenase regulation) of GI cancers. Frozen ERCP biopsies, brushings, and FNA’s from approximately 40 patients with proven and suspected pancreatic or bile duct cancers also contribute to this GI tumor bank and are available for collaborative studies. Drs. Hecht and Farrell coordinate requests for collaboration.

I-4. Dr. Peter Anton maintains a bank of colonic tissues from approximately 75 patients with inflammatory bowel disease (IBD), other healthy patients (controls), and AIDS patients for collaborative studies. Dr. Anton and his collaborators are studying the pathophysiology of mucosal inflammation in AIDS patients and patients with Crohn's Disease (CD) or ulcerative colitis (UC). Frozen and paraffin embedded endoscopic biopsies from patients with mucosal inflammation (active UC or CD), and without macroscopic mucosal inflammation (AIDS syndrome and inactive UC or CD), and normal subjects are available for collaborative study. Databases of coded patient demographics, treatments, and outcomes data on computer files are also available for these patients for ongoing and new collaborative research. Dr. Anton coordinates the collaboration for this tissue bank. AIDS samples are part of the UCLA NIH-funded AIDS Center GI Tissue Core directed by Dr. Anton (AI-28697). Dr. Anton also offers consultation to other CURE investigators about how to obtain IRB approval for development of tissue or sera banks through UCLA, how to establish such banks, and the details of maintaining and utilizing such a resource for collaborative research.

Users of the tissue banks listed in Exhibit IV-A are chiefly those involved in funded clinical research projects that involve endoscopic biopsies of esophagus, stomach or colon. However, Dr. Weinstein also has an extensive archive of mucosal tissue specimens from esophagus, stomach, duodenum, jejunum, and colon that will be available for exploratory research projects leading to new grant applications in the areas of Barrett’s esophagus, acute and chronic gastritis, duodenal ulcer, inflammatory bowel disease, production of antibacterial peptides by mucosal tissues, and carcinogenesis. For example, these tissues can be used to determine normal distribution of receptors and gastrointestinal peptides, including ghrelin, which is being studied by Drs. Tache, Sachs, and Ohning, and novel taste receptors expressed in the stomach and duodenum which are being studied by Dr. Rozengurt and his colleagues. Also tissues are available for translational research by CURE: DDRCC scientists studying pathophysiology of inflammatory diseases, including, but not limited to, Maria Abreu, Peter Anton, Jonathan Braun, Ian McGowen, and George Sachs, and pre-neoplastic or neoplastic diseases, including, but not limited to, C. Randolph Hecht, Enrique Rozengurt, Lee Slice, James Sul, Wilfred Weinstein, James Farrell, Gareth Dulai, and Dennis Jensen. In addition, it is anticipated that several other CURE: DDRCC Investigators and their trainees will take advantage of the tissue banks for translational research to perform preliminary studies that can lead to Pilot and Feasibility proposals and to full NIH or VA grant proposals.

J. SERUM BANK OF PATIENTS WITH ULCER HEMORRHAGE

Dr. Jensen and the CURE Hemostasis Research Group have a serum bank from multicenter trials of patients with ulcer hemorrhage either related to H. pylori infection (200 patients) or non-steroidal anti-inflammatory drugs (NSAIDs - 50 patients). Serial samples before H. pylori eradication (or at baseline for NSAID patients), one to three months after eradication (or after baseline for NSAID ulcers), six months after eradication (or after baseline for NSAID ulcers), and annually thereafter are available and linked with prospectively collected clinical and breath test data on patients in a data base. Currently, there are more than 350 sera in the serum bank. The serum bank is maintained by the research technician, Mr. Hirabayashi and, with the assistance of the data manager, Dr. Lousuebsakul, is linked with the databases of coded patient demographics, treatments, and outcomes. This serum bank is being utilized for collaborative studies. Mr. Hirabayashi and Dr. Jensen coordinate requests for collaboration of the serum bank.

K. DATA BASES OF PATIENTS WITH GI HEMORRHAGE

The data manager, data entry clerk, and Drs. Gornbein and Jensen maintain a data base of more than 3,000 patients with GI hemorrhage who have been enrolled in CURE prospective studies. The data are detailed for coded patient demographics, laboratory and endoscopy findings, treatments, and outcomes during acute and long-term follow-up. These include approximately 1,500 patients with peptic ulcer hemorrhage, 400 patients with esophageal or gastric varix hemorrhage, 250 cirrhotic patients prior to first variceal hemorrhage, 250 patients with GI angiomata, 200 patients with small bowel hemorrhage, 400 patients with severe colonic hemorrhage, and approximately 200 patients from other non-variceal UGI hemorrhage. Data are from randomized prospective hemostasis trials and other prospective CURE studies of GI hemorrhage. These databases are being utilized for collaborative research in epidemiologic, routine outcomes, health outcomes and cost-assessment studies. The databases and the patients who are being followed are available for other new collaborative studies, including new diagnostic and therapeutic trials and health outcomes studies. Ms. Pham and Dr. Jensen are responsible for coordinating new requests for collaborative research with these databases or patients. As one recent example of a database study, Dr. Jensen and Gornbein applied for NIH funding (NIDDK) for an R12 (secondary data analysis) grant to explore the feasibility of developing a scoring system to stratify patients with lower gastrointestinal hemorrhage.

L. VISCERAL SENSITIVITY AND AUTONOMIC FUNCTION TESTS

Visceral sensitivity studies including a quantitative Bernstein test and barostat testing of the esophagus, stomach and colon for visceral sensitivity are offered by the Core. These are supervised by Dr. Naliboff. Motility technicians perform these tests that are available to CURE: DDRCC investigators. The technicians are directed by Dr. Chang. Autonomic function tests supervised by Dr. Naliboff include skin conductance measurements and heart rate variability measurements (vagal tone). Neuroendocrine response measurements are performed and analyzed by Dr. Chang in her role as Co-Director of the Core.

M. DATA BASE OF PATIENTS WITH NEUROENTERIC DISEASES

Drs. Roger Bolus, Lin Chang, Bruce Naliboff, and Emeran Mayer, and a data manager maintain a database of more than 3,500 patients with functional GI disorders. Once each patient is studied in the CNS/WH Clinical Studies Program, there are detailed coded data stored on the medical history, laboratory findings, psychological testing, and quality of life (QOL) measures. Included are over 550 patients with dyspepsia and 1,500 with other irritable bowel syndromes (IBS). Within the IBS data base are patients with constipation predominant IBS (12%), patients with diarrhea predominant IBS (20%), patients with alternating constipation and diarrhea (8%), patients with non-specified IBS (46%), and patients with IBS plus some with other functional disorders (such as fibromyalgia, GERD, or dyspepsia, 14%). In addition, 140 normal subjects (controls) and 220 patients with inflammatory bowel disease (IBD) have coded medical, psychological, and QOL data in this database. This database and the patients who are being followed are available for collaborative research in neurovisceral disorders, including new health outcomes, diagnostic instruments or therapeutic trials. Drs. Bolus and Chang are responsible for evaluating new requests for collaborative research with these patients or the database. The database has also served as an excellent source for training fellows in issues faced in conducting secondary data analyses research. Within the past year, the database was used to support research by fellows on subclassification of functional bowel diseases using Traditional Chinese Medicine algorithms (D. S. Tan), the clinical and psychological correlates of IBS patients’ quality of life (Dr. B. Spiegal), and the characteristics of IBS patients classified as Alternaters under classic ROME II designations (Dr. K. Tillisch). To date a number of fellows and other trainees have published high quality papers using this database along with consultation from the CNS/WH faculty.

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