PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
May 28, 2004

In this month's edition:

1. Colon Cancer from Prevention to Treatment: A Live Discussion on the Web at Thomas Jefferson University Hospital
2. Research at Fox Chase Targeting Tumor Cell Invasion; Focus Is on Biological Target Directly Connected to Cancer Progression
3. Innovative Research Methods at Children's Hospital, Drexel Discovered Gene for Cornelia de Lange Syndrome, Disabling Genetic Disease
4. Heart Failure and Transplant Program at the Hospital of the University of Pennsylvania Evaluates Heart Failure Treatments for Landmark Nationwide Study

Editors Note: Research and innovation at Philadelphia International Medicine® hospitals are leading to unique ways to diagnose and treat disease. Below are just four significant examples.

Colon Cancer from Prevention to Treatment: A Live Discussion on the Web at Thomas Jefferson University Hospital

Philadelphia - People who log on to the Web on Wednesday, June 9, at 4:30 pm Eastern Daylight Time will be able to watch, from the comfort of their home or office, a first for the Philadelphia area. Physicians, representing five specialties at Thomas Jefferson University Hospital, will discuss colon cancer - the second leading cause of cancer-related deaths in the United States.

"Screening for colon cancer enables us to find and remove polyps at an early stage," explains Richard Wender, MD, chair, Department of Family Medicine at Thomas Jefferson University Hospital and Jefferson Medical College of Thomas Jefferson University, who will serve as Webcast moderator. "Finding polyps early is important because polyps can become cancerous if they are not removed."

A panel of physicians from Thomas Jefferson University Hospital--representing the specialties that deal with colon and rectal cancer screening and treatment--will participate in the Webcast discussion. In addition, they will answer questions asked by the live audience and sent in by the e-mail audience. Patients who have undergone various colorectal screenings will also discuss their experiences.

"Colorectal cancer has a high cure rate when caught early," says Anthony J. DiMarino Jr., MD, director, Division of Gastroenterology and Hepatology at Thomas Jefferson University Hospital. "This is a disease that could be practically eliminated if everyone over age 50, or with a strong family history, was screened.

"There are numerous screening tools that help us to identify problems," Dr. DiMarino, who is also William Rorer Professor of Medicine and Director, division of Gastroenterology and Hepatology at Jefferson Medical College, said. "They include the gold standard--the colonoscopy--as well as the flexible sigmoidoscopy and fecal occult blood test (FOBT), which are often used together. In addition, patients at Jefferson who are unable to undergo a traditional colonoscopy may be eligible for the newer, virtual colonoscopy."

Among the topics scheduled for discussion are:

The Genetic Component: According to Bruce Boman, MD, PhD, one in approximately every 400 people has a genetic mutation that predisposes them to develop colorectal cancer. The key is to identify these individuals before they develop cancer in order to prevent cancer from occurring.

"It often begins with a patient who is diagnosed with colorectal cancer," Dr. Boman, director, Division of Genetic and Preventive Medicine at Thomas Jefferson University Hospital, says. "If the patient has one of two factors-a family history of colorectal cancer or is younger than age 60 when diagnosed with colorectal cancer-it is recommended that the patient go for genetic counseling.

"Once we identify someone with a genetic mutation for colorectal cancer risk, we can then screen the rest of their family to see if they carry the mutation. Once we confirm the mutation, we can institute measures such as aggressive screening with colonoscopy to remove pre-malignant polyps before they develop into cancer-an approach that will save many lives," says Dr. Boman, who is also professor of Medicine at Jefferson Medical College of Thomas Jefferson University.

Traditional and Virtual Colonoscopy: Anthony Infantolino, MD, director, Endoscopic Ultrasound and Photodynamic Therapy, Division of Gastroenterology and Hepatology at Thomas Jefferson University Hospital, and clinical professor of Medicine at Jefferson Medical College, will demonstrate the traditional colonoscopy and discuss which patients may not be candidates for this screening tool. Anna Lev-Toaff, MD, Department of Radiology, Thomas Jefferson University Hospital, and professor of Radiology at Jefferson Medical College of Thomas Jefferson University, will demonstrate the new virtual colonoscopy.

Colorectal Surgery: "Although this is the stage no one wants to get to," says Scott Goldstein, MD, director, Division of Colorectal Surgery at Thomas Jefferson University Hospital, "the surgeons at Thomas Jefferson University Hospital offer surgical options resulting in excellent cure rates while preserving normal gastrointestinal function." Dr. Goldstein also points out that if all persons were screened for colorectal cancers, it would no longer be the killer disease we know. Dr. Goldstein is assistant professor of Surgery at Jefferson Medical College of Thomas Jefferson University.

For information on how to join the Webcast, please contact Lucia Rosenberg, director, Philadelphia International Medicine Institute of Education, at lrosenberg@philadelphiamedicine.com. 

Research at Fox Chase Targeting Tumor Cell Invasion; Focus Is on Biological Target Directly Connected to Cancer Progression

Wilex AG, Munich, Germany, and Fox Chase Cancer Center have started a clinical trial with a novel compound, WX-UK1, targeting tumor cell invasion and metastasis. This Phase I trial marks the start of an innovative collaboration between the U.S. government, an academic research center (Fox Chase) and a biotech firm (Wilex) to rapidly move a laboratory discovery to the clinic for use in patients.

This is the first of two clinical trials with Wilex's compound WX-UK1 at Fox Chase funded by a $3.9 million grant from the U.S. Department of Defense (DoD) Breast Cancer Research Program to study the potential of this agent as a breast cancer therapeutic in the USA.

WX-UK1 is a non-cytotoxic small molecule that belongs to a new class of drugs. In animal models, WX-UK1 blocks tumor cell invasion, metastasis and primary tumor growth by inhibiting the urokinase Plasminogen Activator (uPA) system.

"The pre-clinical research with WX-UK1 provided strong data warranting a clinical trial to pursue the possible benefit this drug may have in the treatment of breast cancer," said Lori J. Goldstein, MD, principal investigator of this study and director of Fox Chase's Breast Evaluation Center and leader of the Breast Cancer Research Program at Fox Chase. "The DOD-Wilex-Fox Chase collaboration is an example of how government, private industry, and academia can work together to bring promising research from the laboratory to the clinic quicker than traditional avenues."

"Unlike conventional chemotherapeutic agents, WX-UK1 is focused on a biological target directly connected to cancer progression, and, therefore offers an entirely new mechanism of action," said Prof. Olaf G. Wilhelm, MD, Chief Executive Officer of Wilex. "It is our goal to develop WX-UK1 for use in combination with chemotherapy. With Fox Chase Cancer Center, we have a highly experienced and capable partner for the clinical development of WX-UK1 in the USA".

The open label dose escalation Phase I study will evaluate the safety and biological activity of WX-UK1 in combination with the oral chemotherapeutic agent capecitabine (Xeloda®) in up to 54 patients with advanced solid tumors. The maximum tolerated dose (MTD) of WX-UK1 in combination with capecitabine (Xeloda®) will be determined. In addition, pharmacokinetics and pharmacodynamics of the treatment regimen will be investigated.

Xeloda® is a registered trademark of F. Hofmann la Roche.

Innovative Research Methods at Children's Hospital, Drexel Discovered Gene for Cornelia de Lange Syndrome, Disabling Genetic Disease

An international team of researchers has discovered the gene for Cornelia de Lange syndrome, a disabling, multisystem genetic disease that affects an estimated one in 10,000 children. The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease.

Geneticists from The Children's Hospital of Philadelphia and Drexel University College of Medicine in Philadelphia led the study. In pinpointing the gene, they used an innovative research approach that may lend itself to investigations of other genetic conditions, particularly "orphan diseases:" rare, poorly understood disorders.

The lead researchers, Ian D. Krantz, MD, of Children's Hospital, and Laird G. Jackson, MD, of Drexel University College of Medicine, together maintain the world's largest database of patients with Cornelia de Lange syndrome (CdLS), drawing on clinical records and genetic samples first gathered 30 years ago.

Named for a Dutch physician who first described it in 1933, the syndrome often includes mental retardation, impaired growth, heart defects, gastroesophageal reflux and feeding problems, impaired vision, hearing loss, and upper limb abnormalities, including missing fingers or hands. There are typically distinctive facial features, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair. In the past, CdLS was often fatal in infancy; now, most children with the condition live into adulthood.

Although CdLS has been known for decades, the disease is a challenge to scientists. "This syndrome has been confusing for a long time, because it's been difficult to trace one source for its multiple effects on many organs," said Dr. Krantz, the lead author and principal investigator of the study. The disease is also variable - some patients have much milder forms of CdLS. In addition, because few individuals with CdLS had children, it is rare to find parents and children who both have the disease.

In the current study, the researchers analyzed the genomes (the entire genetic makeup in an individual's DNA) of 12 families having more than one member with CdLS. Through a process of elimination, they were able to identify four candidate regions for the CdLS gene. Further analysis narrowed the search to a region of chromosome 5. They combined this knowledge with cytogenetic data - the details of chromosomal rearrangements in a child with CdLS.
The team identified a large gene on chromosome 5, which they named NIPBL. Mutations giving rise to Cornelia de Lange syndrome occur at different locations within that gene.

NIPBL stands for Nipped B-like, because the human gene produces proteins similar to those produced by the Nipped-B gene in fruit flies. "The insect gene was called 'Nipped' because a mutation in that gene produces an abnormal fly wing that looks like it had a small bite taken out of it," said Dr. Jackson. Both the fruit fly gene and the human gene regulate biological signals that have wide-ranging effects during development, on a variety of organ systems.

When a genetic test for CdLS is developed, said Dr. Krantz, physicians will be able to provide a definitive diagnosis to confirm or rule out a clinical diagnosis. The test will also assist genetic counselors. "Fortunately," says Dr. Krantz, "the disease has a low recurrence risk. Families having one child affected by CdLS have only a one percent chance that a subsequent child will be affected. When a prenatal test is developed, we will determine before birth whether the fetus is among that one percent."

At Children's Hospital, Dr. Krantz directs a full-service clinic for children with CdLS, the only program in the world offering comprehensive services for children with the condition. At this clinic, which attracts patients from around the globe, specialists from a variety of medical disciplines treat each child's specific constellation of symptoms. Treatments may include heart medications, tube feeding and hand surgery.

The long-term goal of the gene discovery, of course, is to improve clinical treatments for the syndrome. "One cannot predict the exact path science takes from a basic discovery to a practical therapy," said Dr. Jackson. "However, better understanding of the specific biological pathways by which a gene mutation affects health and development may lead to new therapies to intervene at different points along the path."

The National Institute of Child Health and Human Development, part of the National Institutes of Health, funded the study. Drs. Krantz and Jackson are both long-standing members of the Cornelia de Lange Syndrome Foundation Clinical Advisory Board. Dr. Jackson was the first medical director of the Foundation.

Heart Failure and Transplant Program at the Hospital of the University of Pennsylvania Evaluates Heart Failure Treatments for Landmark Nationwide Study

"Heart failure is a leading cause of death and nearly 5 million people in the United States suffer from it," says Mariell Jessup, MD, Professor of Medicine and Medical Director of the Heart Failure and Transplantation Program at the Hospital of the University of Pennsylvania (HUP).

Jessup, along with David Callans, MD, Professor of Medicine and Director of the Electrophysiology Laboratory, served as co-principle investigators for HUP's component of the largest heart-failure device trial ever undertaken to investigate whether an implantable pacemaker-type device will reduce death and hospitalization for advanced heart failure patients.

Results from the three-year, multi-center Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure Study, or COMPANION, trial appeared in the May 20th issue of The New England Journal of Medicine. A total of 16 HUP patients were enrolled in the trial. The COMPANION trial took place at 128 other sites with about 1,500 participants total.

"For years, we have struggled with a critical dilemma in the management of heart failure -- how to effectively treat the patients' problems, provide them with improved quality of life and prolong their longevity," Jessup said. "This study is important because it helps us further clarify which patients will benefit most from which therapies."

Results indicate that cardiac resynchronization therapy (CRT) and optimized pharmacologic therapy (OPT) used in concert significantly improve participants' quality and length of life. CRT devices use electrical stimulation to synchronize contractions of the right and left ventricles. When compared with OPT alone, the COMPANION study showed a 19 percent reduction in combined overall mortality or hospitalization for heart-failure patients implanted with Guidant CRT pacemakers, as well as a similar reduction (20 percent) for patients implanted with Guidant CRT defibrillators. There was a 36 percent reduction in all-cause mortality for heart-failure patients who were implanted with Guidant's CRT defibrillators.

Although not a specific disease, heart failure describes an irreversible condition in which the heart muscle chambers "fail" to pump an adequate flow of oxygen and nutrient-rich blood throughout the body. As a result, many patients describe their debilitating symptoms-- exhaustion, breathlessness, and fluid accumulation-- as living while slowly dying.

There are several causes of heart failure: the heart can become weakened by many disorders, such as chronic high blood pressure, coronary heart disease, a large heart attack, or diabetes; or can be brought on because the patient was born with structural defects in his or her heart. Usually medications are unable to completely reverse the damage done to the heart and the only so-called cure is to undergo a heart transplant.

According to Jessup, heart failure is the cause for "at least 20 percent of all hospital admissions among persons older than 65 and over the past decade; the rate of hospitalization for heart failure has increased by 159 percent." (This data appeared in the May 15, 2003 review article in The New England Journal of Medicine that Jessup co-authored with Susan Brozena, MD, Associate Professor of Medicine.)

HUP's Heart Failure and Transplant Program is uniquely qualified to provide treatment to heart failure patients. It provides an integrated environment specializing in the care of patients with heart failure or heart transplants. The team includes six full-time heart-failure physicians; six full-time heart-failure nurses; three full-time research coordinators to handle the multiple pharmacology, NIH-funded and Penn-based studies of heart failure; and six full-time transplant coordinators. They work in close association with a team of 11 full-time cardiac electrophysiologists who focus on the rhythm disorders that are frequently found in patients with various forms of heart failure. In addition, their efforts are supported by a team of cardiac surgeons who are able to complement medical and electrical treatments with transplant or other pioneering surgical techniques.

Guidant Corporation was the sole sponsor of the COMPANION clinical trial.

Philadelphia International Medicine is an organization that provides medical and patient support services to international patients. It also provides continuing medical education and health care training and education to international physicians, administrators and other practitioners. As the international department of several Philadelphia-area hospitals, international patients gain access to physicians and hospitals rated among the best in the world through one telephone call to PIM. You can reach PIM by calling 1-215-735-3575; fax, 1-215-790-1267; or e-mail, physicians@philadelphiamedicine.com . You can find out more about PIM through its Website at www.philadelphiamedicine.com .