PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
April 26, 2004

In this month's edition:

1. Fox Chase Cancer Center Research Reveals How COX-2 Causes Ovarian Cancer; Finding Helps Understand How COX-2 Inhibitors May Prevent This Lethal Disease 
2. MossRehab Offers First Neurological Physical Therapy Residency 
3. Temple Celebrates Two Decades of Leadership In Heart Care 
4. Penn ICUs to be Linked Through Smart Technology 
5. Increasing the Body's Good Cholesterol May be a Pill Away; Penn Study Pinpoints Protein Inhibitor that Raises HDL Levels

Editor's Note: This month's edition of the Philadelphia International Medicine® News Bureau presents samples of the outstanding medical research underway at our hospitals, as well as examples of use of the latest technology to help us provide the best possible care for our patients.

Fox Chase Cancer Center Research Reveals How COX-2 Causes Ovarian Cancer; Finding Helps Understand How COX-2 Inhibitors May Prevent This Lethal Disease

Philadelphia - Fox Chase Cancer Center scientists have identified how an enzyme called COX-2 may promote the development of ovarian tumors, adding further insight into the mechanism of COX-2 inhibitors and the prevention of this highly lethal disease. The data was presented at the 95th Annual Meeting of the American Association for Cancer Research.

"We have found that the over-expression of COX-2 correlates with the loss of the basement membrane in ovarian epithelium cells, thus promoting cancer," said Mike (Xiang-Xi) Xu, PhD, who heads the Fox Chase team in this research. "A COX-2 inhibitor may reduce the loss of basement membrane and thus decrease cancer risk."

Previous research had shown that COX-2 inhibitors such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) slow the growth of tumors, particularly of the breast and colon, but only now are researchers beginning to understand how COX-2 inhibitors work in thwarting cancer.

In the ovaries and other tissues, basement membrane provides a scaffold to which cells called epithelial cells adhere in an organized fashion, Xu explained. When there is no basement membrane, the epithelial cells become disorganized and unregulated and may undergo transformation from a normal to cancerous state. Xu added that basement membrane is also lost during ovulation, which may help explain the association between frequent ovulation and higher ovarian cancer risk.

Ovarian cancer claims the lives of over 14,000 women each year in the United States, making it the most lethal of all gynecologic malignancies. A strong family history of ovarian or breast cancer is evident in about 5 to 10 percent of ovarian cancer cases. While an average woman's risk of getting ovarian cancer is only about 1.4 percent over her lifetime, the risk increases to between 15 and 60 percent if two or more first-degree relatives (parents, siblings or children) have developed ovarian, breast or a certain type of bowel cancer.

The important role of inheritance has led many women with a family history of breast or ovarian cancer to have their breasts and ovaries removed as a means of preventing the development of cancer. Xu and his colleagues studied the tissues removed during prophylactic oophorectomy (removal of the ovaries) for clues about the precancerous changes that go on in the cells.

One of the cell proteins they analyzed was COX-2, a physiologically important enzyme that plays a role in ovulation as well as in antibacterial, immunologic and inflammatory processes. COX-2 has also been shown to stimulate tumor cell division and angiogenesis (new blood vessel formation) and to inhibit a type of programmed cell death called apoptosis, which helps control the growth of tumors. Xu's analysis of the ovarian tissue specimens showed that as the level of COX-2 increases, it appears to promote the loss of basement membrane.

Treatment with COX-2 inhibitors may prevent the development of cancer cells. In fact, the National Cancer Institute will launch a human clinical trial of COX-2 inhibitors. Mary B. Daly, MD, PhD, director of Fox Chase's Cancer Control Program, is heading the multi-center trial, which will include Fox Chase as one of its sites. Fox Chase has one of four Specialized Programs of Research Excellence (SPORE) in Ovarian Cancer, established by the NCI in 1999.

Understanding what happens in ovarian cells before they become cancerous is important not only because it may lead to preventive therapies but also because it may lead to the identification of markers of the disease that will be useful for diagnosis and for assessing treatment results. One of the reasons for the high death rate among women who develop ovarian cancer is that diagnosis often is delayed until late stages of the disease.

In addition to Xu and Daly, the Fox Chase research team includes Isabelle H. Roland, Wan-Lin Yang, PhD, Dong-Hua Yang, MD, PhD, Robert F. Ozols, MD, PhD, Thomas C. Hamilton, PhD, Henry T. Lynch, PhD, and Andrew K. Godwin, PhD. The Fox Chase SPORE grant and an additional NCI grant supported the research.

MossRehab Offers First Neurological Physical Therapy Residency

MossRehab, a member of Philadelphia International Medicine and a leading provider of physical medicine and rehabilitation services, has established the first accredited neurological physical therapy residency program in the country. The residency, designed to educate and train practicing physical therapists toward becoming board certified neurological clinical specialists and leaders in the treatment of individuals with neurologic impairments, recently received accreditation from the American Physical Therapy Association.

MossRehab physical therapist Robin Myers has been the driving force behind the efforts to gain accreditation for the program, which began with a grant several years ago from the Albert Einstein Society. "For therapists, this is an excellent opportunity to gain, in one years' time, the clinical expertise that would normally take five or six years of practical, hands-on experience to achieve," said Myers.

The unique 50-week curriculum, offered at no cost to the participant, includes more than 1,500 hours of combined classroom/lab instruction, mentored treatment sessions, clinical practice, and specialty practice observation. During the residency, participants are employed by MossRehab making them eligible for employee healthcare benefits and compensation for providing patient care on an as needed basis. Upon completion of the program, students are well prepared to sit for the Neurologic Physical Therapy Specialist Certification Examination.

"Because of the expectations of the residency and the encouragement provided by my mentors and peers, I have accomplished goals I never expected to achieve this early in my career," said Jasleen Birdi, PT. "I knew this was going to be the best 'physical therapy' experience of my career. And that is exactly what it has been."

The residency program is limited to two therapists each year. Candidates must submit a completed application, resume and registration fee for consideration.

Recognized as a national leader in medical rehabilitation, MossRehab provides high-quality, compassionate medical care for individuals with physical disabilities. MossRehab offers a wide range of specialized services, including comprehensive programs for brain and spinal cord injury, stroke, amputation and orthopaedic conditions.

Temple Celebrates Two Decades of Leadership In Heart Care

In April, the Temple Heart Transplant program celebrated the 20th anniversary of its founding as the region's first heart transplant program. Since the program was established in 1984, both medical and surgical treatment options for heart failure patients have expanded greatly. Left ventricular assist device (LVAD) therapy offers hope for patients who are not candidates for transplant. Small implantable heart monitors now easily collect valuable data directly from the heart's right ventricle. And new immunosuppressant agents are improving survival rates for transplant recipients.

While Temple has earned a reputation as a leader in heart transplantation, it is also recognized as one of the nation's most comprehensive centers for heart failure treatment and research. Temple cardiologists practice aggressive management of end-stage heart failure, combining unique expertise in ventricular assist devices with clinical trials involving less invasive procedures and new technologies.

"Our aggressive, hemodynamically-guided approach to the treatment of heart failure can improve the patient's clinical status to the point where transplantation may not be needed," says Gail Berman, MD, medical director of heart transplantation at Temple.

"We have a strong commitment to finding hearts for our patients, and we are particularly qualified to improve the patient's quality of life while they wait," adds Satoshi Furukawa, MD, section chief and surgical director of cardiopulmonary transplantation. Temple's program is among the best in categories measuring the percent of patients who survive the wait for a transplant. Temple physicians sustain 95 percent of their patients on the transplant list until a suitable heart becomes available, and the post-transplant survival rate is 85 percent.

LVAD Therapy Offers New Hope

Left ventricular assist devices are now a viable destination therapy for patients who are not candidates for transplant. In 2003, Temple doctors were the first in Philadelphia to implant an LVAD as a destination therapy.

"Our extensive LVAD experience has given us new insights into the ability of prolonged unloading with LVADs to reverse many of the pathophysiologic abnormalities of end-stage heart failure," says Berman. "The hope is that we are paving the way for future approaches which may allow the reversal of severe heart failure."

Innovative Monitoring Yields Valuable Data

The Chronicle® Heart monitor is a matchbook-sized device that is implanted into a patient's upper chest. A sensor attached to the Chronicle's monitor is threaded into the heart's right ventricle, where it measures heart rate, heart temperature and blood pressure. The patient passes a magnetic wand over his or her chest to transmit this critical data over a phone line to a physician's office.

Temple was one of the first hospitals in the nation to implant this monitor. Cardiologists have found that the monitor's ease and speed of use substantially benefit the patient's health and quality of life.

Preventing Transplant Rejection

A crucial way to improve survival rates for transplant recipients is by reducing the incidence and severity of acute rejection and cardiac allograft vasculopathy. Temple is involved in several immunosuppressant drug trials, investigating novel approaches to prevent and reverse cardiac transplant rejection and arteriopathy. Howard Eisen, M.D., director of Temple's Heart Failure Unit, recently released promising study findings on the new immunosuppressant everolimus in the New England Journal of Medicine.

The Temple Heart Failure and Transplant program provides a comprehensive approach to treating patients with cardiovascular diseases. For more information, or to refer a patient to the program, call 1-800-TEMPLE-MED.

Penn ICUs to be Linked Through Smart Technology

The University of Pennsylvania Health System (UPHS) will be one of the first health systems to offer its critical care patients the eICU technology. The eICU solution uses high fidelity telemedicine, Smart Alert® early warning software and electronic monitoring to connect and provide off-site critical care physicians and nurses with the information needed to proactively care for ICU patients. The around-the-clock advanced technology enables Leapfrog ICU patient safety compliance and provides fundamental changes in hospital ICU care. The eICU project includes initially connecting the eICU system to ICUs at the Hospital of the University of Pennsylvania and Pennsylvania Hospital before rolling the technology out to 121 ICU beds at all four UPHS hospitals. The new technology underscores the commitment of UPHS to continually improve patient safety by providing the highest quality of care to patients in its intensive-care units, or ICUs.

"The eICU solution is a sophisticated, proven technology that reinforces our commitment to superior patient care and service excellence while enabling the University of Pennsylvania Health System to continue to bring the future of medicine to residents of the Delaware Valley and beyond," said Ralph W. Muller, chief executive officer of UPHS.

"Penn physicians continue to lead the way in care advancements, including the eICU solution," added David E. Longnecker, MD, chief medical officer of UPHS. "This technology will enable us to provide the expertise of skilled intensivists across the entire health system around-the-clock, and it will strengthen both our clinical care programs and our resident education programs. The combination of outstanding clinicians and sophisticated technology offers the greatest potential for major leaps in the quality and safety of health care in the future."

Increasing the Body's Good Cholesterol May be a Pill Away; Penn Study Pinpoints Protein Inhibitor that Raises HDL Levels

An important clinical advance in the prevention of heart disease has been identified by researchers at the University of Pennsylvania School of Medicine, in collaboration with researchers at Tufts University and Pfizer. The study led by Daniel Rader, MD, associate professor of Medicine and director of Penn's Preventive Cardiovascular Medicine & Lipid Center, involved a novel pharmacologic approach - inhibition of the cholesteryl ester transfer protein (CETP) - and showed that this approach is highly effective in raising high-density lipoprotein (HDL) levels in patients with low levels. The study was published in the April 8 issue of The New England Journal of Medicine.

The drug torcetrapib, made by Pfizer, significantly increased levels of HDL in patients with low levels of this "good" cholesterol, whether or not they were also being treated with the cholesterol-lowering drug atorvastatin (Lipitor). The combination therapy used in the trial proved so effective that, among those patients who received the highest dosages of both drugs, HDL cholesterol levels were increased by more than 100 percent. "These results are striking because it is generally very difficult to raise HDL levels in people with already low-levels of good cholesterol," said Rader.

According to Rader, torcetrapib works by inhibiting the ability of the cholesteryl ester transfer protein to transfer cholesterol from HDL (the "good" cholesterol) into LDL (the "bad" cholesterol). And, although the drug's CETP-inhibitor properties proved effective when administered by itself, its effectiveness was maintained when given in combination with a statin -- which is the most common class of drugs used to lower LDL cholesterol levels.
The implications of this study - which took place at Penn and Tufts/New England Medical Center, Boston -- could have far-reaching effects when it comes to heart disease. A low level of HDL cholesterol is the most common lipid abnormality observed in patients with known coronary heart disease. Torcetrapib is still in clinical development but is designed as chronic long-term therapy to raise HDL levels and reduce heart disease risk, just as statins are used to lower LDL levels. Further studies are being done to determine whether it successfully reduces the risk of heart disease.

Researchers also contributing to this study include Margaret E. Brousseau, PhD, Ernst J. Schafer, MD (Lipid Research Laboratory, Division of Endocrinology, Metabolism, Diabetes, and Molecular Medicine, New England Medical Center and Tufts University), Megan L. Wolfe, BS, LeAnn T. Bloedon, MS, RD (the Department of Medicine and Center for Experimental Therapeutics, University of Pennsylvania School of Medicine), Andres G. Digenio, MD, PhD, Ronald W. Clark, MS, and James P. Mancuso, PhD from Pfizer.

This investigator-initiated study was funded in part by Pfizer, which is developing torcetrapib. The General Clinical Research Center at the Hospital of the University of Pennsylvania provided additional funding.

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