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August 28, 2003

Research Notes

Physicians’ responses to patient deaths intensify with length of care

The longer a doctor spends caring for a patient, the more vulnerable that doctor is to feelings of loss when the patient dies — but doctors often suffer these emotions in silence.

Those findings from a study by Pitt researchers were published this month in a theme issue of The British Medical Journal entitled, “What Is a Good Death?”

Previous studies had shown that physicians, particularly younger and less experienced ones, often feel sad and even guilty over the death of a patient. Pitt researchers, working with investigators from Harvard Medical School, expanded on that information by looking at training levels as well as other variables related to physician response, and how these physicians deal with emotions that arise over the death of a patient.

“Physicians form bonds with their patients, and when a patient dies, the physician is going to have some emotions surface,” said investigator and senior author Robert M. Arnold, who is the Leo H. Criep Chair in Patient Care, professor of medicine and chief of the Section of Palliative Care and Medical Ethics at Pitt’s School of Medicine. “Today’s medical education system does not address this important issue. I worry that this may be partly responsible for the high rate of burnout among physicians.”

Researchers surveyed 188 interns, residents and primary attending physicians who were caring for 68 patients at the time of death at two U.S. teaching hospitals. They examined how training level, sex, marital status and duration of care predicted outcomes such as doctors’ experiences, emotional reactions and use of coping resources.

As is usually the case in a teaching hospital, most physicians (82 percent) had not known the patient before the final hospital admission. At the time of death, 36 percent knew the patient for three days or less, and 36 knew the patient for four to seven days. Only 28 percent of surveyed physicians cared for the patient longer than a week. As a result, 62 percent classified their relationship to the patient as “not close.” Providing care for a longer period of time was associated with stronger doctor-patient ties, with 11 percent of physicians describing their relationship as “very close.”

Thirty-one percent of doctors reported having a strong emotional reaction to a patient’s death; 23 percent found the death “disturbing,” and 6 percent reported feelings of grief.

“Surprisingly, a physician’s level of training was not the variable that pointed to a stronger emotional reaction to the patient’s death,” said first author Ellen Redinbaugh, a research instructor in Pitt’s Department of Psychiatry. “Instead, emotional reaction was determined primarily and consistently by the duration of the doctor-patient relationship.” The reactions also were stronger among female physicians than among males.

While most doctors surveyed reported requiring little emotional support from their colleagues, interns and residents required the most support, and females reported needing more than males. However, most residents and interns found the support they needed from one another or their families instead of from attending physicians, and attending physicians in need of support reported finding no one to help them.

“This study points to a major gap in the clinical education of interns and residents, with a culture of silence about emotions that are bound to surface in physicians many times during their careers,” said Arnold. “Educators must address this issue and know how to identify clinicians who may be at risk of higher levels of emotional distress, then provide guidance in dealing with these emotions.”

This study was funded by the Nathan Cummings Foundation. Co-authors included Pitt’s Ann M. Mitchell, Deborah Seltzer and Jennifer Wolford as well as researchers from Harvard Medical School.

Drug safe for patients with advanced colorectal cancer
Results from a large multi-site study led by University of Pittsburgh Cancer Institute (UPCI) researcher Ramesh Ramanathan demonstrate that the drug oxaliplatin is safe for patients with advanced colorectal cancer.

“Our results are encouraging because they affirm that oxaliplatin is safe for patients with advanced colorectal cancer,” said Ramanathan, lead investigator and associate professor in the division of hematology/oncology at Pitt’s School of Medicine. “We found a relatively low occurrence of toxicity from treatment regimens that included oxaliplatin, indicating that it may be a promising option for colorectal patients.”

Ramanthan, also director of UPCI’s gastrointestinal cancer center, added that these results are important given the dire need for therapies for patients with advanced colorectal cancer who have failed first-line treatment.

The current study included 5,176 patients with locally advanced or metastatic colorectal cancer who did not respond to at least one prior chemotherapy regimen containing fluorouracil (FU), the most common therapy administered to colorectal cancer patients.

Patients enrolled in the study received oxaliplatin as a single-agent or oxaliplatin in combination with FU, with or without leucovorin (LV). Results indicated that the incidence of high-grade gastrointestinal side effects was lowest (18 percent) in patients who received oxaliplatin in combination with FU and LV, compared to incidences of 28 to 33 percent in the other regimens. Patients who received oxaliplatin alone had the lowest incidence of hospitalization.

Overall, the results demonstrated a relatively low occurrence of blood toxicity (25 percent) and gastrointestinal toxicity (24 percent) and a less than 1 percent incidence of death from treatment-related adverse events. In addition, oxaliplatin dose-intensity was maintained at 80 percent to 94 percent in treatment regimens in the study, even in patients considered at high risk of treatment-related complications.

Oxaliplatin was approved by the Food and Drug Administration in August 2002 for patients with previously treated advanced colorectal cancer. Studies on the safety and efficacy of oxaliplatin in combination with other therapies for colorectal cancer are ongoing at UPCI.Study results were published in the Aug. 1 issue of the Journal of Clinical Oncology.

The study was funded by a grant from Sanofi-Synthelabo. Co-authors included researchers from the Dana Farber Harvard Cancer Center, the Memorial Sloan-Kettering Cancer Center, the USC Norris Comprehensive Cancer Center, the Cancer Center of the Carolinas, the University of Pennsylvania Cancer Center, Thomas Jefferson University and the Ochsner Clinic Foundation.

Cancer research grant awarded

The V Foundation for Cancer Research has awarded a $100,000, two-year grant to Lin Zhang, assistant professor of pharmacology and medicine, for research on anti-cancer agents in human cancer cells.

“Understanding how anti-cancer drugs kill cancer cells — and, more importantly, why they fail so often — is crucial for using them more efficiently and for developing improved drugs,” Zhang said. “Most anti-cancer drugs kill cancer cells by initiating a normal physiological process called programmed cells death, or apoptosis, which is a suicidal process to selectively remove cells that are no longer needed, damaged or dangerous. Apoptosis is fundamental to our health: Failure of cells to die leads to initiation and progression of cancer, and makes cancer cells resistant to anti-cancer drugs.”Recent studies have found that BAX, a key controller of apoptosis, plays an important role in influencing cancer cells’ response to anti-cancer drugs. Loss of BAX makes cancer cells resistant to a group of drugs widely used to prevent the development of colorectal cancer, suggesting that drug therapy aimed at preventing cancer might be improved by taking into consideration the ability of cancer cells to shut down normal cell death pathways.

“To further understand how apoptosis is uncontrolled in cancer cells, we have identified PUMA, a novel controller of apoptosis which acts through BAX,” said Zhang. “PUMA can be activated by commonly used anti-cancer drugs and is even more efficient in killing cancer cells than BAX. We propose to use a combination of genetic and biochemical approaches to study how BAX, PUMA and other molecules that control apoptosis adjust cancer cells’ response to anti-cancer drugs.”

The V Foundation for Cancer Research was created by the late North Carolina State basketball coach Jim Valvano and ESPN in 1993.

Best therapy found for lung cancer, researchers believe
weekly regimens of paclitaxel in combination with full doses of carboplatin are reasonably well tolerated by lung cancer patients and the efficacy results appear promising, according to findings published in the Aug. 1 issue of the Journal of Clinical Oncology.

The study, led by Chandra P. Belani, Pitt professor of medicine and co-director of the University of Pittsburgh Cancer Institute (UPCI)’s Lung Cancer Program, compared three regimens of weekly paclitaxel plus carboplatin in patients with advanced non-small cell lung cancer (NSCLC) and found that higher weekly doses of paclitaxel in combination therapy for lung cancer did not result in an added benefit for patients and caused a higher incidence of adverse side effects.

“Our study demonstrates that both agents can be administered with ease and without substantial toxicity when weekly paclitaxel is combined with full doses of carboplatin administered on day 1 of each cycle with few side effects,” said Belani. “Administration of a higher weekly dose of paclitaxel did not improve survival and was more likely to cause toxic effects from treatment. This is a major concern for lung cancer patients with advanced disease given that the primary goal of therapy is to improve survival, reduce symptoms and to improve the patient’s quality of life.”

The purpose of the study was to explore the efficacy and safety of three regimens of weekly paclitaxel plus carboplatin. The study included 401 patients with stage III and IV NSCLC from 47 community and academic sites in the United States.

The study results are encouraging and will lead to increasing use of this regimen in advanced NSCLC, according to Belani. A phase III randomized study is underway to compare this schedule with the standard three week regimen of paclitaxel and carboplatin.

Lung cancer will be newly diagnosed in over 170,000 people in the United States in 2003. Non-small cell lung cancer is the most common type of lung cancer, accounting for nearly 80 percent of lung cancers.

Research developing tissue engineered solutions for heart disease
The National Institutes of Health (NIH) has awarded a grant of nearly $5 million to Pitt’s McGowan Institute for Regenerative Medicine to fund research aimed at developing unique tissue-engineered solutions for heart disease.

Projects related to the grant will focus on the development of a tissue-engineered “cardiac patch” and tissue-engineered blood vessels for possible surgical use following heart attack or other cardiovascular events.

The grant, through the NIH’s National Heart, Lung and Blood Institute, goes to a multidisciplinary team assembled by project principal investigator William Wagner, associate professor of surgery and bioengineering at Pitt’s School of Medicine and associate professor of chemical and petroleum engineering at the School of Engineering.

“We are working on ways to grow tissues that will not just be similar to our own in terms of their make-up, but also that will be mechanically strong and functional,” said Wagner, who also is a deputy director of the McGowan Institute. “To do this, we will need to train the tissue as it develops for the role that it will ultimately assume.”

Such tissue development efforts aim to help the body regenerate its own components needed to repair damage caused by heart attack or underlying disease such as congestive heart failure (CHF), a loss of functional heart muscle. Nearly 5 million Americans are currently living with CHF, according to the American Heart Association. About 550,000 new cases are diagnosed annually. Of those, about 50 percent likely will die within five years.

Significantly, CHF also can substantially diminish quality of life. Because the heart pumps inefficiently, patients can feel breathless and weak after minor exertion. According to the Centers for Disease Control and Prevention, CHF is responsible for about 260,000 deaths a year. In 1995 alone, Medicare paid $3.4 billion for heart failure treatment.

Being able to provide tissue-engineered treatments to increase muscle strength and replace arteries blocked by heart disease could have significant positive impact on patient care.

To reach this goal, planned projects of the grant combine the expertise of University of Pittsburgh faculty in stem cell biology, tissue engineering and imaging in what is called a Bioengineering Research Partnership, Wagner added. “The great thing about Pitt is that we have these lines of communication already in place through the McGowan Institute.”

Both projects establish populations of stem cells from muscles or bone marrow within a polymer that is specially formulated for flexibility and permeability and that biodegrades at a stable rate into non-toxic components in the body. The plan is to use this polymer scaffold as a bridge to generate new, healthy, native tissue.

In one project, a team of surgeons and bioengineers is developing a myocardial patch, which aims to serve as replacement tissue for damaged or diseased heart muscle. The process involves seeding of stem cells onto a biodegradable polymer scaffold and training this tissue for the rhythmic contractions that it ultimately will need to perform.

For the second project, a team led by David Vorp, an associate professor in the departments of surgery and bioengineering at Pitt’s schools of medicine and engineering, respectively, is working to develop tissue-engineered blood vessels that are a biological and functional equivalent to the patient’s own blood vessels, such as those used for coronary artery bypass surgery. Mechanical stresses are being applied to these constructs in order to train them to grow and function similarly to natural blood vessels.

Related projects will track the development of these treatment options on a molecular level, measuring biological markers of stem cells to establish differentiation into appropriate cell lineages, including cardiomyocytes, smooth muscle cells and endothelial cells. These cells are among the main components of heart muscle and blood vessel construction. Cell components will be tagged with fluorescent proteins that can be targeted by imaging technologies to follow the development of the cells and tissues after they have been placed in the body. Project scope will encompass in vitro and preclinical studies of tissue-engineered products.

In addition, discoveries made in the course of this research could benefit tissue-engineering efforts aimed at disorders that involve other “mechanically active tissues,” such as the bladder and urethra, said Wagner, adding that researchers hope to be close to the brink of clinical trials in terms of refining techniques at the close of the five-year grant period.

UPB professor studies stress reduction for jurors
Gregory Page, an assistant professor of psychology at Pitt’s Bradford campus, presented the paper, “The Reduction of Juror Stress through a Brief Post-Trial Debriefing,” at an international conference in Scotland.

Page and Deb Hope from the University of Nebraska at Lincoln conducted research for more than a year to see if debriefing sessions with jurors, held after a civil or criminal trial to reduce stress, were effective. The debriefing sessions were used to help identify stress and aid in coping with any stress that jurors experienced due to hearing testimony, being a juror and having to deal with the disruption of their daily routines because of jury duty.

Results of debriefing 47 jurors from a variety of civil and criminal trials indicated that the jurors in the study did not initially report experiencing stress, but during the debriefing session they began to recognize several aspects of the trial that could produce stress.

Page and his colleagues helped the jurors alleviate stress by addressing three aspects associated with stress relief. Besides breathing deeply and adhering to a healthy lifestyle, jurors were introduced to a technique called “self-talk,” in which they asked themselves questions such as “What is the worst that can happen? How likely is that?”

During the debriefing, the jurors were asked to try to recognize when they were using negative self-talk and to challenge those ideas with the three questions.

Page has plans to develop a class in the spring semester that will focus on psychology and law. “This class will provide the perfect opportunity to integrate this research into my teaching,” Page said.

Research on infectious diseases presented
Clinical and basic science findings of several studies were presented by Pitt and Magee-Women’s Research Institute scientists at a meeting of the Infectious Diseases Society for Obstetrics and Gynecology, Aug. 7-9, at the Cape Codder Resort in Hyannis, Mass.

Findings included the following:

Parvovirus infection during pregnancy often has no symptoms

Potentially deadly parvovirus infection during pregnancy often has no symptoms, reported Hyagriv Simhan, assistant professor of obstetrics and gynecology at Pitt’s School of Medicine.

In healthy adults, parvovirus is more of a nuisance, and can cause flu-like symptoms that are similar to the common cold. In children, it is more likely to be characterized by a “slapped face” appearing rash on the cheeks. But for the developing fetus, parvovirus infection can be a contributing factor in heart failure and death. This is contrary to the little research previously published on the subject, which indicated that a majority of women have symptoms.

Simhan and his colleagues studied cases of 25 pregnant women found to be infected with parvovirus B19 between 1998 and 2001 at Magee-Womens Hospital. Of these, only 16 percent exhibited any symptoms themselves, said Simhan, who also is an assistant investigator at the Magee-Womens Research Institute. The vast majority of women were diagnosed because their older, school-age children showed signs of infection. In the study group, there were three cases (12 percent) of fetal heart failure and four cases (16 percent) of fetal death.

“So far this year, we have seen 15 cases of parvovirus infection in pregnant women,” Simhan said. “This is a more common problem than many people realize.”

Because there is no vaccine available, current practice involves counseling and close monitoring of high-risk patients, which includes anyone who has school-age children and those who work with children such as teachers and day-care providers.

Mild PID can impair fertility
Even mild pelvic inflammatory disease (PID) can impair fertility, reported a team led by Harold Wiesenfeld, associate professor of obstetrics, gynecology and reproductive sciences at Pitt’s School of Medicine.

In a study of 767 women at high risk for PID, Wiesenfeld and his colleagues found that those with subclinical (undetectable by clinical tests) PID were twice as likely to have infertility problems as those who did not have PID.

“Previous studies have shown that 25 percent of women who have chlamydia or gonorrhea, and 15 percent of women who have bacterial vaginosis, also have subclinical PID,” said Wiesenfeld, who also is an assistant investigator at the Magee-Womens Research Institute. “Given the vast number of women who have lower genital tract infections, our findings reveal that a substantial number of reproductive-aged women are at risk for infertility.”

Wheelchair enables users to operate on two wheels

The U.S. Food and Drug Administration (FDA) on Aug. 13 approved the sale of a new wheelchair that enables users to operate on two wheels, allowing them to better negotiate obstacles like stairs and uneven pavement.

Research conducted at Pitt’s School of Health and Rehabilitation Sciences (SHRS), in cooperation with Independence Technology, a Johnson & Johnson company, contributed to the FDA’s approval.

“This device has the potential to significantly improve mobility for the two million Americans who use wheelchairs,” said Rory Cooper, professor and chair of the Department of Rehabilitation Science and Technology in SHRS and co-principal investigator of the trial. “We at the University of Pittsburgh School of Health and Rehabilitation Sciences are proud that, through our research, we are able to play a part in the development of such revolutionary technology.”

Researchers at SHRS completed the second phase of a clinical trial that tested the investigational advanced mobility device known as the INDEPENDENCE IBOT. The IBOT is an advanced gyro-balanced system that is designed to operate on four wheels or two wheels, stabilizing the user by instantly and automatically adjusting and balancing itself.

In its two-wheel position, it allows a seated user to move about at standing eye-level. Its rotating four-wheel base allows the user to climb over street curbs and travel over uneven and hilly terrain, such as grass, sand and rocky pathways.

“The development and approval of this device marks a remarkable advancement for people with mobility impairments,” said Michael Boninger, director of the UPMC’s Center for Assistive Technology (CAT), and co-principal investigator of the trial. “For the first time, people who use wheelchairs will be able to do things they never thought possible.”

Phase II of the clinical trial consisted of 14 study subjects — 10 unimpaired non-wheelchair users and four expert wheelchair users, all of whom tested the device in their own homes and throughout their daily routines for three days and one week, respectively.

Powered by a rechargeable battery that can operate up to a full day on a single charge, the wheelchair uses an integrated system of electronic, sensor and software components to automatically adjust itself according to the seat’s movement and the user’s center of gravity. These components are accompanied by a backup system to assure the user’s safety.

It was invented by Dean Kamen, founder of DEKA Research and Development Corp. of Manchester, N.H. Johnson & Johnson has been partnering with Kamen over the past six years to develop the IBOT for FDA approval.

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