University Times

American Society of Clinical Oncology annual meeting

Melanoma vaccine shows promising results

Results from the largest multi-site study to date evaluating a peptide-derived therapeutic vaccine for melanoma have demonstrated a correlation between tumor growth (progression free survival) and immune response for patients with advanced disease who received the vaccination.

The findings provide promising evidence that researchers can activate a patient’s own immune system to fight advanced melanoma, according to investigators from the Eastern Cooperative Oncology Group (ECOG).

“This is the first time we have evaluated peptide-derived melanoma vaccine results from a multi-center cooperative group trial,” said John Kirkwood, principal investigator of the study, professor of medicine at Pitt and director of UPCI’s Melanoma Center. “While these results are preliminary, we have found evidence that the vaccine stimulates an immune response.”

The phase II study evaluated a multiepitope CD8 T-cell vaccine comprised of three peptides derived from tumor-associated antigens of melanoma. The vaccine was evaluated alone, in combination with granulocyte macrophage-colony stimulating factor (GM-CSF), in combination with interferon and in combination with both GM-CSF and interferon.

Malignant melanoma is one of the deadliest forms of skin cancer. An estimated 54,200 new cases of melanoma are expected in 2003 and 7,600 deaths are expected to occur.

The study includes more than 30 institutions and is funded by the National Institutes of Health and the Schering Plough and Immunex Corporations.

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Combination therapy benefits older patients with advanced lung cancer

According to researchers at the University of Pittsburgh Cancer Institute (UPCI), lung cancer patients aged 70 and older can benefit from a combination treatment for advanced non-small cell lung cancer (NSCLC) when compared to younger patients.

The results indicate that older patients with NSCLC responded to and tolerated the combination therapy similar to younger patients.

The study, presented by Chandra P. Belani, lead investigator and a Pitt professor of medicine, demonstrated that weekly paclitaxel in combination with full doses of carboplatin offer a safe and effective treatment option for elderly patients with advanced NSCLC.

“Aggressive chemotherapy regimens are often avoided in older patients with advanced lung cancer due to concerns about toxic effects associated with the treatment,” said Belani, who also co-directs the Lung Cancer Program at UPCI. “Old age should not be a deterrent to prescribing the most appropriate and effective treatment for advanced lung cancer as demonstrated clearly in this study.”

A difficult cancer to treat due to its advanced stage at diagnosis, lung cancer will be newly diagnosed in over 170,000 people in the United States in 2003. Incidence of lung cancer increases as people age and is highest in individuals over the age of 70.

Co-investigator of the study was Sakkaraiappan Ramalingam of Pitt. Support was provided by Bristol-Myers Squibb.

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New strategy improves lung cancer survival

Other results presented by Pitt professor Chandra P. Belani, co-director of UPCI’s Lung Cancer Program, demonstrate that a new therapeutic radiation strategy for non-small cell lung cancer (NSCLC) — the most common form of the disease — leads to improved survival for lung-cancer patients with locally advanced disease. 

In the study, hyperfractionated accelerated radiotherapy (HART) was compared to standard thoracic radiotherapy following chemotherapy. HART is a strategy in which radiation is administered frequently over a shorter period of time for two and a half weeks compared to seven weeks.  

“We found that chemotherapy followed by HART was an effective treatment strategy that was well tolerated by patients enrolled in the trial,” said Belani, lead investigator of the study.

Non-small cell lung cancer is the most common type of lung cancer, accounting for almost 80 percent of lung cancers.

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Society of Academic Emergency Medicine annual meeting

Body cooling promotes survival, brain recovery after cardiac arrest

Cooling body temperature to levels consistent with hypothermia improves survival when induced after cardiac arrest and also promotes growth factors important for the brain’s recovery, suggests a study performed by researchers in the Department of Emergency Medicine at Pitt’s School of Medicine.

Although the study involved animals, the findings already have had an influence on the management of cardiac arrest patients being treated at UPMC, where the lead researcher is also a practicing emergency medicine physician. 

Cardiac arrest is the sudden, abrupt loss of heart function. Death usually occurs within minutes unless cardiopulmonary resuscitation (CPR) and rapid defibrillation is available. As cardiac arrest progresses, blood flow to the brain ceases. If a patient survives long enough to make it to the hospital, the patient often will be in a coma and at risk of permanent brain injury. In fact, less than 10 percent of patients make it through the chain-of-survival (early access to care, early CPR, early defibrillation and early advanced care). Pitt researchers sought to find out if hypothermia treatment played a role in survival from cardiac arrest and brain recovery.

The researchers found that when the animals were cooled to 33 degrees Celsius (91.4 degrees Fahrenheit) beginning one hour after cardiac arrest, there was 100 percent survival, whereas only 75 percent of the animals left at normal temperature of 37 degrees C (98.6 degrees F) survived.

Furthermore, microscopic brain injury was reduced by half, and some animals showed functional improvement in as little as 12 hours after cardiac arrest. Conversely, the animals left at normal temperature after cardiac arrest showed little or no functional improvement.

Previous studies from the researchers detected increased levels of growth factors derived from brain cells when hypothermia was induced after cardiac arrest. In the current study, researchers also found that levels of growth factors derived from glia-cells in the brain that support nerve cells are increased by hypothermia as well. These growth factors may play an important role in brain recovery after cardiac arrest.

“Although it is known from clinical studies that cooling the brain offers therapeutic benefits to patients, further studies need to be done to determine how much the brain should be cooled and for how long,” said Clifton Callaway, a Pitt assistant professor of emergency medicine. “By understanding the molecular mechanisms of brain recovery in cardiac arrest, we can prescribe a more effective treatment.”

Based on this and other studies, Callaway and colleagues are already beginning the routine cooling of cardiac arrest patients brought to the emergency department at UPMC Presbyterian.

Co-investigators of this study include Katherine M. Schmidt, Brian J. D’Cruz and Donald B. DeFranco, all of Pitt’s medical school.

This research was funded in part by the National Emergency Medicine Foundation, the Pittsburgh Emergency Medicine Foundation and the National Institutes of Health.

New guidelines could save health care industry billions

New decision guidelines for identifying patients with low-risk heart failure may prevent unnecessary hospitalizations and could significantly reduce health care-related expenses, which according to the National Heart Lung and Blood Institute, cost the industry an estimated $21 billion per year.

These guidelines come from a Pitt study.

Heart failure is the primary reason for hospital admissions of 1 million patients each year in the United States. Most of these patients are 65 years of age and older, an age segment expected to expand over the next several decades, putting even more strain on the health care system. Approximately 70 percent are first treated in the emergency department, making it an ideal setting for a heart failure clinical decision guideline to help physicians identify low-risk patients who could be treated at home, a much less costly alternative.

Pitt researchers sought to build a clinical decision guideline based on data collected from the emergency department to identify patients with heart failure who are at low risk of inpatient death or serious medical complications. Based on more than 33,000 cases, they developed a guideline that identified nearly 16 percent as low risk.

“Treatments for heart failure can improve the quality of life for people with this condition but cannot stop the progression. The number of patients seeking treatment in the emergency department for this disease will likely spiral upward as the elderly population continues to grow,” said Thomas E. Auble, research assistant professor in the emergency medicine department and one of the study investigators.

“Variable hospital admission rates and inaccurate physician estimates of prognosis for patients with heart failure suggest that a clinical prediction rule is needed to assist providers with risk assessment and hospitalization decisions,” said Donald M. Yealy, professor and vice chairman of emergency medicine and study investigator. Yealy also is president of the Society of Academic Emergency Medicine.

The researchers teamed with Michael J. Fine, associate professor of medicine at Pitt, and members of the University of Pittsburgh Pneumonia Patient Outcomes Research Team that had used a similar approach to develop a clinical decision guideline for the admission of patients with community-acquired pneumonia. A recently completed study that implemented the guideline in emergency departments in Connecticut and Pennsylvania showed that physicians used it safely to reduce the admission of low-risk patients.

“Similar success is anticipated with the new heart failure guidelines,” Yealy said.    

Co-investigators of this study include Margaret Hsieh and Julie B. McCausland of the emergency medicine department; William Gardner and Gregory F. Cooper of the medicine department, and Roslyn Stone of the Graduate School of Public Health’s biostatistics department.

This research was funded by the Agency for HealthCare Research and Quality.

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American Transplant Congress

Bone marrow injections improve outcomes for children getting heart transplants

One to five years after heart transplantation, children who had received injections of their donor’s bone marrow into their thymus during the surgery had significantly fewer “late” rejection episodes than children who received heart transplants without the addition of the bone marrow containing donor immune system cells, according to a study performed by researchers from Pitt’s School of Medicine and Children’s Hospital of Pittsburgh.

The children receiving the injections also required fewer anti-rejection drugs.

“Our main objective for this pilot study was to prove intrathymic injection during heart transplantation to be both safe and feasible,” said Steven A. Webber, a Pitt associate professor of pediatrics and medical director of heart and heart-lung transplantation at Children’s Hospital of Pittsburgh. “But at follow-up, our findings also suggest that this approach is of benefit to patients as well. The much lower rate of acute cellular rejection occurring later than six months after transplantation is clearly a positive outcome. While it is too soon to know, the lower incidence could make the children who received intrathymic injections less likely to develop chronic rejection down the road.”

Chronic rejection, which is characterized by scarring and narrowing of the heart’s vessels, is a major limitation to long-term survival for heart transplant patients.

The thymus is located behind the breastbone — accessible in children during heart transplant surgery — where T cells from bone marrow are educated to distinguish cells of self from those that are foreign. It is most active during infancy and childhood; after puberty it begins to shrink in size.

The idea behind infusing donor bone marrow into the thymus, as opposed to other sites within the body, is to fool the recipient’s T cells that are being educated in the thymus into thinking that the donor bone marrow is “self” as well. Those T cells that would see the donor tissue as foreign would either die in the thymus or become weakened. Without these active cells in circulation, an immune system attack against the donor organ might be avoided.

New organ preservation solution easier to use, more cost-effective

A new organ preservation solution offers comparable results to a solution currently in use but is more cost-effective and has logistical advantages that makes it more practical for keeping donated livers viable before transplantation, according to UPMC researchers.

The researchers compared Histidine-Tryptophan-Ketogluterate (HTK) solution to the University of Wisconsin (UW) solution.

Preservation solutions are used to extend the period that an organ remains viable. With current technology, hearts and lungs can be preserved safely for 4-6 hours, livers for about 12-18 hours, kidneys about 24 hours.

According to Bijan Eghtesad, associate professor of surgery at Pitt’s Thomas E. Starzl Transplantation Institute, outcome measures looking at initial organ function, the incidence of primary non-function and other clinical measures were similar between the two solutions.

However, HTK’s much lower viscosity and its biochemical makeup offer certain advantages that make it more practical and easier to use. For instance, surgeons found it to penetrate the liver’s vessels and bile duct structures better.

“While further study is needed, we believe that this lower viscosity makes it a better solution to use for livers recovered from non-heart-beating donors because of its ability to flush out any residual blood left behind in vessels by the sudden stoppage of the heart,” explained Eghtesad.

Because HTK contains much less potassium, high levels of which can cause cardiac arrest, surgeons had fewer concerns about traces of the solution presenting such risk.

HTK does not need to be stored or transported in cold storage as does UW solution, and no additional products are required when using it. In addition, the Pittsburgh study found there to be less waste due to the solution’s packaging.

A cost-analysis done by the Center for Organ Recovery and Education indicated that HTK also is more cost effective than UW. Based on 160 cases, the projected annual savings is between $73,000 and $137,000, Eghtesad reported.

Since February 2002, HTK has been the solution routinely used at UPMC for all liver, kidney and pancreas transplants.

HTK was developed by German company Dr. Franz Kohler Chemie GmbH, located in Alsbach-Hahnlein, and is marketed in the United States as Custodiolñ HTK Solution. The U.S. Food and Drug Administration has approved its use for preservation of donor kidneys.

Physicians abandon use of PTLD drug

Following the largest clinical trial of its kind involving pediatric liver transplant patients, physicians say they have abandoned any notion of using the drug they thought might prevent Post-Transplant Lymphoproliferative Disease (PTLD), a complication more common in children whereby certain immune cells proliferate to form tumors, in favor of vigilant screening and a more conservative approach.

PTLD is a complication associated with the Epstein-Barr Virus (EBV), to which about 90 percent of the world’s population eventually will be exposed.

But many children and young adults have not yet been exposed to EBV, making children who receive transplants particularly vulnerable because the drugs they take that suppress the immune system to prevent organ rejection also impair the immune system’s ability to fight this infection. About two-thirds of pediatric transplant recipients will develop a primary EBV infection within six months of transplantation. The course of this infection ranges from an infection with no outward symptoms to a far more serious outcome, with progression of the virus to PTLD or lymphoma.

Researchers from Pitt’s School of Medicine and Children’s Hospital of Pittsburgh initiated the trial in 1995 to study the effectiveness of the drug CytoGam for the prevention of PTLD in pediatric liver transplant recipients. In 1999, four other centers joined the study, which eventually enrolled nearly 90 children into the double-blind randomized trial.

But the drug proved somewhat disappointing, according to results presented by Michael Green, a Pitt professor of pediatrics and surgery and the study’s principal investigator.

While the incidence of PTLD two years after transplantation was 8 percent in the children who received the active drug versus 16 percent in the group that received a placebo drug, the researchers say the difference was not statistically significant.

Besides the relatively small sample size, another potential explanation for the failure to achieve a statistically significant difference might have been a shift in clinical practice that occurred with the availability of EBV viral load monitoring methods, potentially confounding the study’s results. Although physicians were encouraged not to obtain surveillance EBV viral loads on patients participating in this study, methods became readily available in 1998 and viral loads were increasingly obtained in response to even the most subtle clinical symptoms thought to be suggestive of an early EBV infection.

If an elevated EBV viral load was detected, physicians caring for the children frequently reduced the patient’s immunosuppression by lowering the doses of anti-rejection drugs, a move that has previously been shown to reduce the risk of progression to PTLD.

“This strategy may have diminished the risk of PTLD in patients regardless of whether they received CytoGam or placebo and thus impacted on the study’s power to identify a statistical difference,” reported Green.

The other centers in the trial were Mount Sinai Medical School, Northwestern University School of Medicine, the University of North Carolina at Chapel Hill and the University of Chicago.

Liver transplant patients off anti-rejection drugs have altered cellular profile, studies suggest

Liver transplant patients who are off all immunosuppression and those who are undergoing withdrawal of their anti-rejection drugs have higher concentrations of a special immune system cell than those patients who have failed attempts at weaning or who have a history of organ rejection, reported Pitt researchers.

Those off drugs have the same cellular profile as normal, healthy volunteers.

Results of the study were published in the June issue of the American Journal of Transplantation and presented at the ATC meeting.

Researchers hope the findings will bring them one step closer to developing a simple blood test predictive of transplant tolerance and of which patients can be successfully weaned off all drugs.

Lead author George Mazariegos, associate professor of surgery at the Thomas E. Starzl Transplantation Institute and Pitt’s School of Medicine, said: “Our finding a higher incidence of a subtype of a certain dendritic cell in our weaned and nearly weaned patients is a positive step toward this goal.”

Looking for the presence of different kinds of dendritic cells, researchers found that patients off all anti-rejection drugs and those in the process of drug withdrawal had significantly more of a beneficial kind of dendritic cell and fewer numbers of the more harmful dendritic cells, a cellular profile that was similar to normal, healthy non-transplant patients who served as a control group. Compared to those who required daily doses of anti-rejection drugs — those who failed at being weaned or who had a history of rejection episodes — the patients off drugs or nearing that target also had a much higher ratio of the good cells to bad cells.

These so-called beneficial dendritic cells are immature or precursor dendritic cells that derive from plasmacytoid T cells (pDC2). While dendritic cells, a rare type of white blood cell that is present in all tissues, are usually known for their ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen, not until recently did researchers identify subtypes like the pDC2 that have the opposite effect. These appear to regulate the immune response and determine that a frontline attack against the organ by T cells is unwarranted.

Angus Thomson, professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute and Pitt’s School of Medicine, is senior author of the study.

This study was performed as a project of the ITN, a seven-year clinical research project headquartered at the University of California, San Francisco and supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation.

New protocol could change care for lung transplant patients

UPMC surgeons have instituted a new clinical protocol that has the potential to redefine the standard of care for lung transplant patients.

Bucking conventional thought that successful lung transplantation can only be achieved with a three-punch assault on the immune system, the new protocol is a departure from the triple-drug therapy in place at nearly every other transplant center.

Instead, UPMC surgeons favor a regimen involving fewer pills that are given less often over time. The protocol is an important achievement for lung transplant patients, in whom studies that seek to reduce or eliminate anti-rejection drugs are rarely performed out of fear that the lungs, already the most vulnerable organ to rejection, would succumb to an irreversible immune system attack, placing patients at risk for death.

Ironically, lung recipients have the greatest incidence

of immunosuppression-related complications, such as infection and chronic kidney dysfunction, providing incentive to search for alternative immunosuppression approaches.

According to Kenneth R. McCurry, director of lung and heart-lung transplantation at UPMC, 18 of 20 patients are doing well taking lower-than-normal doses of one mainstay anti-rejection drug, tacrolimus, as opposed to the usual three-drug combination that is given twice a day.

Two patients died, one of a common complication associated with nonfunction of the organ, and the other from causes that have yet to be determined. While eight of the 18 currently remain on a twice-a-day regimen of the single drug, five are taking tacrolimus once a day and five just four times a week. In addition, all 18 patients are on a daily 5-milligram dose of prednisone, a negligible dose compared to the more typical 20 milligram dose that is usually given.  

“The reason the lung transplant patients are taking low-dose prednisone, unlike the other organ recipients at UPMC, is because the majority were taking steroids prior to their transplants and abrupt discontinuance would likely lead to adrenal insufficiency,” explained McCurry, who also is assistant professor of surgery at Pitt’s School of Medicine.  

The clinical protocol, developed by Thomas E. Starzl and the Pittsburgh team, is based on two principles: pre-treatment of the recipient and the administration of as little immunosuppression as possible.

Comparing outcomes of the 20 patients to 15 patients who were treated using conventional triple-drug therapy before the new protocol was introduced, acute rejection rates were comparable. But, suppressing acute rejection was never meant to be a goal of the protocol, says the transplant team. The surgeons believe that some level of immune activation is needed for long-term organ acceptance and fault conventional approaches that “over-immunosuppress” patients for inhibiting this activation process.

While it is too soon to gauge whether chronic rejection rates will be less in these patients, that certainly is the hope, said McCurry. Chronic rejection is the most common cause of death for lung recipients beyond two to three years of transplantation.

“At this point, many of our patients are doing extremely well on low levels of immunosuppression and we have strong evidence that this approach may be very beneficial to patients,” McCurry said. “Even reducing the steroids in these patients is a somewhat remarkable feat, since so-called steroid sparing has only been successful in kidney and liver recipients.”

Since July 2001, more than 550 transplant patients receiving kidney, liver, pancreas, small intestine or lung transplants at UPMC have been treated under the new protocol.

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Triple-drug therapy does not seem to raise cholesterol in men with HIV

Treatment with highly active antiretroviral therapy (HAART), commonly known as triple-drug therapy, does not appear to raise cholesterol levels in men with human immunodeficiency virus (HIV), according to Pitt researchers.

These findings, published in the June 11 issue of the Journal of the American Medical Association, help to clarify a controversial issue that has been debated since the advent of HAART seven years ago.

“Increases in blood lipid levels have been widely reported in HIV patients treated with HAART, but until now there were no studies that included patients’ lipid levels taken before they were infected with HIV,” said study author Sharon A. Riddler, assistant professor in the Pitt Department of Medicine’s infectious diseases division. “With access to such unique data, we were able to look at lipid levels across a broader spectrum in time and determine that after three years of HAART, the average total cholesterol and LDL cholesterol levels appear to be about where they were before HIV infection.”

The researchers used data from the Multicenter AIDS Cohort Study (MACS), an ongoing 19-year-old National Institutes of Health-funded study of homosexual and bisexual men that has enrolled 5,622 participants, both HIV-positive and HIV-negative, in Pittsburgh, Baltimore, Chicago and Los Angeles. Participants visit the study clinics every six months for an interview, physical examination and collection of blood samples.

For this study, researchers analyzed lipid levels of 50 MACS participants from whom blood samples were available from each of the following points in time: before HIV infection (preseroconversion), after infection but before initiation of HAART, at two points during HAART between 1997 and 1999 and at two points during HAART between 2000 and 2002.

“The results confirmed that yes, total cholesterol does increase with HAART,” Riddler said, “but in most cases it increases back to or near the pre-infection level, and in that sense it represents a return to normal.” Riddler cautioned that it is possible the study results were affected by the timing of the analyses, and that additional studies are needed to determine whether a longer duration of HAART could result in further increases in cholesterol levels.

Another concern is the observation that while total and LDL lipid levels were relatively unchanged over three years on HAART, at the end of the study the participants’ average triglyceride levels were higher (225 mg/dL) and HDL levels were lower (42 mg/dL) than those in similar-aged men in the general population. In other studies, some HIV drugs have been associated with changes in glucose metabolism and the development of insulin resistance.

“The fact that average triglyceride and HDL levels were at unhealthy levels at the completion of this study raises a red flag,” said Riddler. “Until more is known, the current standard guidelines for treating high cholesterol should be followed. With the ongoing collection of data through MACS, we will be able to look further into the effects of long-term triple-drug therapy and continue to refine treatments for patients with HIV.”

This study was funded by the National Institutes of Health.