[From CASE Reports, Vol. 11, No. 4, 1996]


WEST HAVEN VA SITE OF
MAJOR RESEARCH INITIATIVES

A Connecticut VA Center Integrates Medical Research with
Patient Care to Benefit Region's Veterans

Perched high above Interstate 95, overlooking Long Island Sound and the office towers of New Haven, is one of the nation's most active Veterans Administration (VA) medical research facilities.

At the West Haven Campus of the VA Connecticut Healthcare System, formerly known as the West Haven VA Medical Center, 90 investigators are currently carrying out more than 300 basic science and clinical research projects. According to Fred S. Wright, Associate Chief of Staff for research, the West Haven Campus ranks first nationwide in the VA system in terms of VA medical research funds granted to its investigators in 1995, and it is within the top five VA centers in terms of other criteria, such as the number of investigators on staff and total research dollars spent.

Currently, the Congressional appropriation for VA research is $252 million, $7.1 million of which is being spent in West Haven. Another $8.1 million come to West Haven from non-VA sources, such as the National Institutes of Health, Eastern Paralyzed Veterans of America, and others. About 70% of VA funds nationally and at West Haven are granted to physician researchers, while 30% goes to scientists with PhD degrees.

As a result, VA research has "a different texture," says Dr. Wright, from research primarily funded by the National Institutes of Health or other sources. "The impetus for a project tends to come from the researcher's clinical practice, so VA research is rather more clinically based."

Research focuses on issues and problems of concern to veterans in the specialties of psychiatry, medicine, surgery, neurology, and related basic sciences. Currently, at West Haven over 100 projects involve human subjects, another 100 use animal models, and the balance are carried out with cells, computers, and chemicals.

The West Haven Campus is affiliated with the Yale University School of Medicine, and all VA medical staff hold appointments at Yale. The research activity is integral to both the medical training that takes place at West Haven with Yale residents and the facility's medical services to its veteran population. It is also a valuable factor in recruiting Yale faculty, who must carry out research as part of their professional development.

During the most recent review of applications for research awards from the VA, seven West Haven investigators received new or renewed funding. This represents a 44% acceptance rate for proposals, more than double the national average of 21% for VA funding. These 1996 awards cover research in the following fields:

The funding of these seven projects will bring almost $2.5 million in additional research funds to West Haven over the next 5 years.

CASE Reports recently visited the West Haven Campus, which is larger than many Connecticut towns, to talk first-hand with just a few of the principal investigators about the details of their research. A report of this sampling follows.

A Cancer Program Begins

With the completion of a new cancer center and the arrival of its new director, Edward Chu, cancer research at West Haven moves into high gear.

The cancer center, which is the only VA hospital in the United States to receive accreditation as a Comprehensive Cancer Center, offers the facilities, staff, and patients to carry out clinical studies, especially pilot studies, to examine new cancer drug therapies. At the same time, Dr. Chu and his colleagues are developing a strong laboratory-based research program to carry out basic molecular and cellular biology studies.

"In academic centers, researchers want to be able to translate the most exciting and promising findings from the laboratory bench to the patient's bedside," says Dr. Chu. "We want to take this one step further and take findings from the clinical bedside back to the laboratory to determine how our therapies can be improved or changed."

Thus, studies will focus not only on whether a particular clinical protocol works, but also on whether changes or improvements can be made to enhance our therapy of cancer. This is a research approach used at the National Cancer Institute, where Dr. Chu was previously on staff as a Senior Investigator, and at leading cancer centers such as Johns Hopkins and the University of Chicago.

The first clinical trial being proposed for the new research program is a pilot study examining the combination chemotherapy of 5-fluorouracil (5-FU) and benzylacyclouridine (BAU). Previous studies, both here at the Yale Cancer Center and at Brown University, have shown BAU to enhance the anticancer effects of

5-FU. The West Haven study will examine closely the pathways being targeted by the combination of 5-FU and BAU with a parallel study taking place at the Yale Cancer Center. If results are promising within the 12- to 16-month first phase, Dr. Chu hopes to expand the patient population through the Yale network of community-based oncologists.

The West Haven center is closely integrated with the Yale Cancer Center, where Dr. Chu is co-director of the Experimental Therapeutics Program. The VA has a tremendous resource of patients, and the Yale Cancer Center is especially strong in the area of drug development and clinical pharmacology.

As with other departments, the oncologists' work with patients helps to drive the laboratory research work. According to Dr. Chu, "The main focus of our laboratory studies arose from clinical observations about drug resistance. Specifically, we will examine, at the molecular level, how cancer cells become resistant to the antimetabolite class of cancer drugs.

"The long-term strategy of our program," Dr. Chu adds, "is to use these very detailed molecular studies as the foundation for the rational design and development of new therapeutic approaches that could be applied to the VA clinic."

Exploring Fungal Metabolism

In a building near the center of the campus are the laboratory facilities for Brian Wong, Chief of Infectious Diseases, and four other Principal Investigators. Their work, also involving both basic and clinically oriented studies, focuses on fungi that cause significant infections in humans.

Of about 50,000 fungal species identified to date, only about a dozen are known to cause human infections. These infections are becoming increasingly important, however. Candida albicans, for example, is the fourth leading cause of hospital-acquired bloodstream infections in the United States and, according to the Centers for Disease Control and Prevention, its frequency has increased 11 fold in the past 10 years.

Candida is a normal resident of the human gastrointestinal tract. In individuals with compromised immune systems, such as patients undergoing gastrointestinal or transplant surgery or people with AIDS or cancer, this otherwise harmless organism can suddenly become virulent and attack any organ. Current diagnostic testing is technically difficult, laborious, and inaccurate.

Dr. Wong's research focuses on several sugars produced by these fungi and present in elevated levels in individuals with fungal infections. Earlier basic research led to the identification of an enzyme that could be used with an autoanalyzer to detect small levels of the sugar D-arabinitol, produced by Candida albicans. The team is currently collaborating with Sheldon Campbell, of the VA's Department of Laboratory Medicine and Pathology, to establish a reference laboratory testing facility at West Haven. Once sufficient reagent has been developed and procedures standardized, the laboratory will offer Candida testing services to hospitals nationwide.

"We are now trying to extend this general scientific approach to other difficult-to-diagnose fungal diseases," says Dr. Wong. "Although we are not as far along as we are with Candida, we have identified a microbial enzyme that may be useful for diagnosing infections caused by the fungus Aspergillus."

Dr. Wong's basic research also focuses on carbohydrates produced by fungi. Studies are ongoing to answer questions about the sugars' function, the effects of genetic mutations that decrease sugar production, and identification of the metabolic pathways involved in the production.

"Ideally, we believe that if we are able to understand these pathways," says Dr. Wong, "we'll be able to manipulate them and lessen the harmful effects of these fungi on humans."

The researchers are applying classic genetic processes, for example, to create a mutant form of Cryptococcus that produces less mannitol than its wild-type parent. When compared with the wild-type, these mutants were found to be less tolerant of heat and other stresses; they were significantly more susceptible to killing by mammalian phagocytes; and when injected into mice, they were much less virulent.

"Our findings indicate that mannitol is probably needed by Cryptococcus for full virulence," says Dr. Wong. "If confirmed, these findings could lead to a treatment based on interfering with the virulence pathway."

Combating the Complications of Liver Disease

Another Yale/VA scientist committed to bridging the gap between basic and clinical science is Roberto Groszmann, Chief of the Digestive Disease Section of the medicine service.

Specifically, Dr. Groszmann and his team are focusing their efforts on portal hypertension, a major complication of chronic liver diseases such as cirrhosis and schistosomiasis. Cirrhosis is the fourth leading cause of death in Americans under age 65. It has several causes, including alcoholism and, increasingly in the VA patient population, chronic hepatitis C infection. Almost all patients with cirrhosis develop portal hypertension as a result of increased pressure within and around damaged hepatic blood vessels. Eventually gastroesophageal varices (thin-walled blood vessels) form and, in at least one quarter of patients, hemorrhage within one year of variceal diagnosis. Nearly half of patients experiencing hemorrhaging die, and the risk of recurrent hemorrhage in the survivors approaches 70%.

Previous studies at the West Haven VA and elsewhere have demonstrated that nonselective beta-adrenergic blockers, such as propranolol, can prevent hemorrhage in patients with varices. Recently, Dr. Groszmann's laboratory found that when beta-blockers are administered early in the portal-hypertension process in mice, the development of varices was prevented and progressive increases in portal pressure were ameliorated.

Building on these animal studies, Dr. Groszmann is currently coordinating an international multicenter clinical trial, funded with $2.5 million from the National Institutes of Health, to show if the beta-blocker timolol can prevent varice formation and/or hemorrhage. The study, designed to end in the year 2000, involves 212 patients in Boston, London, and Barcelona, as well as Yale and the West Haven VA Campus. It marks the first time patients who have not yet developed varices are taking part in a beta-blocker study.

From the same study, the researchers also hope to determine if sequential measurements of portal pressure can predict the development of varices. If so, this could be used to manage patients with cirrhosis and portal hypertension.

"Ultimately, the solution to the problems of chronic liver disease will be prevention," says Dr. Groszmann. "We must identify better ways to prevent hepatitis, better agents to prevent complications."

Prevention is the aim of another major clinical trial for Dr. Groszmann's team. West Haven is one of 17 VA centers taking part in a VA-funded cooperative trial to determine if large doses of lecithin can ameliorate complications in chronic alcoholics who have liver damage but have not yet developed cirrhosis.

VA Cooperative Studies Coordinating Center

VA cooperative studies such as the lecithin trial are an important element of VA-sponsored research. In fact, the West Haven Campus is the site of one of four national Cooperative Studies Coordinating Centers. These centers have doctoral-level statisticians and other specialists on staff and high-powered mainframe computers. Responsibilities include study design; organizing financing; and data collection, monitoring, and synthesis. The center currently is coordinating about 10 multicenter trials. As an additional benefit, this specialized facility is also available to assist individual West Haven researchers design and set up new research projects.

The West Haven Campus of the VA Connecticut Healthcare System demonstrates the potential of a close relationship between research and high-quality medical care. The work of its clinician-researchers is known internationally-they published 213 articles in 1995 alone in German, Spanish, British, and American publications-and their Connecticut veteran patients are the first beneficiaries.--J. Lynne Dodson, freelance medical writer.


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