University Times

Study finds CyberKnife radiosurgery safe, effective treatment for benign tumors

Treating benign tumors outside the brain with CyberKnife Frameless Radiosurgery resulted in significant improvement in symptoms and minimal toxicity, according to a study by Pitt’s School of Medicine researchers presented recently at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology in Atlanta.

CyberKnife is a non-invasive robotic radiosurgical device that can remove tumors and other lesions without open surgery, using a robotic arm, controlled by a computer that sends multiple beams of high-dose radiation directly to the tumor site.

“While stereotactic radiosurgery for the treatment of benign brain tumors has become widely accepted, our knowledge about the use of this technology for benign tumors outside the brain has been limited,” said Steve Burton, study co-author and assistant professor, department of radiation oncology in Pitt’s School of Medicine. “The results of our study indicate that treating these tumors with CyberKnife is safe and effective and can successfully control their growth and progression.”

The study evaluated the feasibility, toxicity and local control of patients with symptomatic benign tumors treated with CyberKnife, Seventy-eight percent of patients treated with CyberKnife experienced an improvement in their pre-treatment symptoms, which included pain and weakness. The local control rate – the rate at which the tumor’s growth was controlled locally – was 96 percent for the 26 patients who underwent follow-up imaging from one to 25 months after the treatment was administered.

Our findings demonstrate that CyberKnife may offer a promising treatment option for patients with benign tumors who are not candidates for surgery or whose tumors are not amenable to surgery,” Burton said. “The potential benefits are significant and include short-term treatment time in an outpatient setting with rapid recovery and symptomatic response.”

He added that follow-up studies will seek to assess the long-term tumor control rates as well as any future effects.

“This study represents the largest to date on the use of frameless radiosurgery to treat benign extra-cranial lesions, and the results thus far are very encouraging. Of noteworthy interest, CyberKnife was able to control aggressive benign tumors that had progressed despite surgery and/or conventional radiation,” said Ajar Bhatnagar, resident, department of radiation oncology, Pitt’s School of Medicine.

Other Pitt researchers involved include: Peter Gerszten and W.C. Welch, department of neurological surgery, and Anurag Agarwal, C.W. Ozhasoglu and William Vogel, department of radiation oncology. Also participating was Shalom Kalnicki, now of the department of radiation oncology, Montefiore Medical Center, New York.

Researchers study use of stem cells found in fat

While questions still remain about the nature and function of stem cells found in fat, a group of researchers and clinicians convened today in Pittsburgh at the Second Annual Meeting of the International Fat Applied Technology Society (IFATS) agreed that research should move forward with the ultimate goal of performing human clinical trials to test the cells’ therapeutic potential for specific indications.

The scientific sessions explored how fat can be an abundant source of stem cells that could be used for tissue engineering and regenerative medicine. An important outcome of the meeting was the development of a consensus defining key scientific questions for future study and determining the field’s most promising clinical applications.

More than 300,000 liposuction procedures are performed in the United States each year, producing about 150,000 gallons of fat that is normally discarded. In 2001, researchers first reported that such tissue contained stem cells, and since then, additional studies have suggested they can be coaxed into other cell types, such as nerve, bone, muscle and blood vessels; or it may be that they have properties of these cells. Some research has progressed more rapidly, with animal studies indicating potential for the development of treatments for heart attack or bone injury, for example, while results looking at other uses are still quite preliminary.

There are currently no human trials in the United States evaluating the potential of stem cells derived from fat, but in reaching consensus on the most promising clinical applications, those attending the IFATS meeting believe the first clinical attempts in patients should be for repairing or healing bone defects, promoting growth of blood vessels in tissues not receiving sufficient blood supply, and for treating acute or chronic cardiac and peripheral vascular diseases.

Moreover, the group felt the best use of the technology should be to develop therapies using patients’ own cells, as opposed to cells that might be donated by other individuals. Because adipose is both abundantly available and easily accessible, it offers a practical source of stem cells.

A key question the group answered was simply what to call the cells, with the decision in favor of the term adipose-derived stem cells, even though it also was agreed that these cells are most likely comprised of multiple cell populations – some that are capable of proliferation and differentiation and other groups consisting of mature cells. The society aims to develop common scientific methods in order to best compare results between studies, and believes that much of the research effort should be directed toward identifying the protein markers for adipose stem cells in order to better understand how they differentiate into other cell types and what factors they secrete.

In developing its consensus, the society focused on three main areas, with separate sessions addressing each. Leading discussions that addressed the biology of the cells was Patricia Zuk, research director, Regenerative Bioengineering and Repair Lab, at the David Geffen School of Medicine, University of California, Los Angeles. Jeffrey Gimble, professor at the Pennington Biomedical Research Center at Louisiana State University, led the session focusing on scientific methods. Discussions on clinical applications and opportunities were moderated by Keith March, director of the Indiana Center for Vascular Biology and Medicine and professor of medicine at the Indiana University School of Medicine.

IFATS, the only interdisciplinary fat tissue society, is dedicated to facilitating the development of new technology derived from and directed toward adipose tissue. The society’s current scientific areas of interest include facilitating the development of treatments for excess body fat, generation of new fat tissue for reconstruction after cancer or birth-related defects and the use of adipose tissue as a source of stem cells that have the potential to regenerate and repair different tissues in the body.

J. Peter Rubin, assistant professor of plastic and reconstructive surgery at Pitt’s School of Medicine, co-director of the Aesthetic Surgery Center and director of the Life After Weight Loss Program at UPMC, is the society’s current president.

Exposure to indoor smoky coal emissions may hike risk of lung cancer

According to a study directed by a Pitt researcher, individuals in Xuan Wei County, China, who are exposed to smoky coal emissions from cooking and heating their homes, may carry genetic mutations that greatly increase their risk of developing lung cancer. The study was presented recently at the 35th annual meeting of the Environmental Mutagen Society in Pittsburgh.

“Lung cancer mortality rates in Xuan Wei are among the highest in China in both nonsmoking women and men who smoke, and are associated with exposure to indoor emissions from the burning of smoky coal,” said Phouthone Keohavong, study author and associate professor, department of environmental and occupational health, Pitt’s Graduate School of Public Health (GSPH). “In order to account for the high rates of disease within this region, we tested for mutations generally associated with lung cancer in people who had no evidence of disease. We found that a good number of these individuals had mutations that indicated they were at higher risk for developing lung cancer in the future.”

“Tobacco smoking is rare in women from Xuan Wei, yet the female population has an abnormally high lung cancer death rate,” Keohavong said. “Women in this region traditionally start the fires and cook, spending more time inside homes that lack ventilation. As a result, they are more likely to be exposed to potentially dangerous emissions.”

The lung cancer mortality rate in some communities in Xuan Wei County is among the highest in China, and more than 20 times that country’s national average. The levels of polycyclic aromatic hydrocarbons generated during cooking with smoky coal are comparable to exposure levels experienced by coke oven workers.

Co-authors of the study include Qing Lan, division of cancer epidemiology and genetics, National Cancer Institute; Wei-Min Gaol, department of internal medicine, University of Michigan, Ann Arbor; Kui-Cheng Zheng, department of environmental and occupational health, Pitt’s GSPH; Hussam H. Mady, and Mona F. Melhem, department of pathology, Pitt’s School of Medicine, and Judy L. Mumford, National Health and Environmental Effects Laboratory, U.S. Environmental Protection Agency. The study was funded by a grant from the American Cancer Society.

Profession more than gender affects ethical decision making

A study conducted by a Pitt researcher has concluded that a person’s profession, more than gender, may influence whether an individual would make ethical decisions based on a scenario where a father was forced to steal medication to save his daughter’s life from cancer.

In the Summer issue of the Journal of Clinical Ethics, Susan Zickmund, assistant professor of internal medicine and communication at the Pitt’s School of Medicine and a member of the Center for Health Equity Research and Promotion at UPMC, presented the scenario to 98 people – half men and half women – and asked them how they would handle it.

Zickmund’s study concluded that those in the legal professions were statistically more likely to consider it acceptable under the circumstances to steal the medication, while those in the medical professions were more likely to consider it unethical.

She presented a modified version of the classic “Heinz dilemma” in which a father was forced to steal an expensive drug to save his daughter from cancer. This dilemma was presented to professionals – lawyers, staff physicians, nurses, medical residents and academic administrators. The participants read the dilemma in private and then provided their judgments and reasoning using a hand-held tape recorder.

In the final analysis, 50 individuals (25 females and 25 males) considered taking the medicine to be wrong, while 29 individuals (15 females, and 14 males) considered it correct under the circumstances. Fourteen individuals (8 women and 6 men) said it was a crime but understandable under the circumstances, while five were undecided.

Zickmund explained: “While there were no differences in decision-making based on gender, professional differences were statistically significant. Fourteen of the nurses and 10 of the staff physicians considered it morally wrong to steal medication. Only one lawyer agreed. Conversely, 13 lawyers considered it acceptable under the circumstances to take the medication, while only three staff physicians and four nurses agreed.”

The main arguments against taking the medication were that “stealing is always wrong” and “it violates religious rules of conduct,” according to Zickmund. Physicians also added that the father should not be dispensing medicine without medical advice. The main arguments for taking the medication were that “life is more precious than property” and that “life-saving medicines should, in a just society, be free,” he said.

The lawyers frequently quoted Victor Hugo’s novel Les Miserables to highlight the injustice of punishing a father for trying to save the life of his daughter.

“The results call for a balance of professional groups on ethics committees and on ethics consult services so that a diversity of viewpoints can be presented,” Zickmund said.

New techniques yield higher volume of kidney/pancreas transplants 

Due to refined surgical techniques and advances in anti-rejection therapy, transplant surgeons at the Pitt’s Thomas E. Starzl Transplantation Institute (STI) are able to successfully perform a higher volume of kidney-pancreas transplants – more than 22 kidney-pancreas transplants in the past three months – which yields a shorter wait time on the transplant list and a better graft survival and quicker recovery.

People need to be more aware of our services, in particular, diabetic patients with end-stage renal disease,” said Ngoc Thai, assistant professor of surgery and director of pancreas transplantation at STI.

Another advance in the field of kidney-pancreas transplantation is the use of the drug campath – a powerful immunosuppressant that depletes T and B cells – the cells that may cause rejection of the new organ. Only one dose is given before the transplant surgery. Because of its potency, a single dose of campath can be given to treat active rejection as well. There is little risk above and beyond the usual side effects of immunosuppression. The advantage is that patients only need to take the anti-rejection medication FK after surgery, as opposed to a combination of FK, MMF and steroids. Currently, researchers at STI are one of a few transplant centers in the United States participating in a clinical trial to study the advantages of campath therapy for kidney-pancreas transplant recipients.

The pancreas is a five-inch organ that is located behind the stomach. One function of the pancreas is to produce enzymes that aid in the digestion of food. It also produces insulin, which is essential for life because it regulates the use of blood sugar throughout the body.

In patients with diabetes, the pancreas stops producing insulin and the organ may shut down, eventually requiring a transplant. This stress also can affect the kidneys, so often a patient in need of a pancreas often will need a new kidney as well.

The three procedures used in these patients include a kidney from either a living or cadaveric donor and eventually a cadaveric pancreas at a later date; a simultaneous kidney-pancreas transplant; or a pancreas transplant alone.

According to the United Network for Organ Sharing (UNOS) there are currently 2,420 people in the United States waiting for a kidney-pancreas transplant and 1,645 people waiting for a pancreas transplant alone. Currently at UPMC, there are roughly 20 people waiting for a combined kidney-pancreas transplant and approximately 20 people waiting for a pancreas transplant alone.

UPMC transplant programs comprise the world’s largest and busiest, where surgeons perform more types of organ transplants than at any other institution. On average, a transplant is performed every 12 hours at UPMC Montefiore or Children’s Hospital of Pittsburgh. Since 1981, more than 12,000 transplants have been performed including the liver, kidney, pancreas, small bowel, liver/small bowel, heart, heart/lung, double-lung, single-lung and multiple-organ transplants.

Cigarette smoke causes breaks in DNA, defects to a cell’s chromosomes

The amount of smoke in just one or two puffs of a cigarette can cause breaks in DNA and defects to a cell’s chromosomes, leading to irreversible changes in genetic information being passed to a newly divided cell, according to Pitt researchers. Their findings, reported recently at the 35th annual meeting of the Environmental Mutagen Society, are the first to show that cigarette smoke causes chromosome instability.

The meeting, “Genes, Mutations and Disease: The Environmental Connection,” was held from Oct. 2 to 6 in Pittsburgh.

While most research has focused on the changes in DNA sequence caused by cigarette smoke, little attention has been given to how smoke affects genomic stability of cells. In laboratory studies using human fibroblasts, common cells found in connective tissue, William S. Saunders and colleagues discovered that exposure to even a small amount of cigarette smoke condensate – equal to about 1/25 of a cigarette – caused breaks to both strands of DNA and compromised the integrity of the cell’s chromosomes.

Cigarette smoke contains some 5,000 organic compounds, including chemicals known to cause cancers. While the researchers did not expose cells to actual puffs of smoke, the cigarette smoke condensate they used was derived from burning real cigarettes and obtained from the R.J. Reynolds Tobacco Company. Containing mostly particulates, the extracted smoke was liquefied as part of a solvent mixture before it was exposed to the cells.

“Double-stranded breaks are considered the most mutagenic type of DNA damage because the broken ends can fuse to other chromosomes in the cell. Chromosome fusion is detrimental to normal chromosome segregation, which in turn leads to genetic imbalances,” explained Saunders, associate professor of biological sciences, Pitt’s School of Arts and Sciences, and a researcher with the Oral Cancer Center of Discovery at Pitt’s Cancer Institute.

Before a cell undergoes division, its DNA is replicated and compressed into identical copies of each chromosome inside the cell nucleus. The chromosomes are then segregated during cell division, so that each daughter nucleus receives a complete copy of the genetic material. The stage when chromosomes are segregated and become separated is called anaphase. Normally, each set of chromosomes is pulled with equal force in opposite directions so that each daughter cell receives the same number of chromosomes.

But when the researchers exposed cells in culture to cigarette smoke, they found that the fused chromosomes were being pulled simultaneously from both directions much like a piece of taffy, forming so-called anaphase bridges between its two ends. Eventually, these chromosomes either tear apart, leaving two broken pieces, or if they don’t break apart, the abnormal, elongated chromosomes may persist after anaphase is completed. Either way, a major change in the structure of the chromosomes is the end result.

“Others have found the presence of anaphase bridges is correlated with chromosome instability in cancer cells. Because cigarette smoking is linked to oral, larynx, lung, bladder and esophageal cancers, our results showing that cigarette smoke can produce anaphase bridges and destabilize a cell’s chromosomes have added significance,” Saunders said.

“The failure of the cell to accurately repair the cigarette smoke condensate-induced double-stranded breaks probably leads to anaphase bridge formation and chromosomal instability,” added Li Z. Luo, a graduate student in Pitt’s Department of Biological Sciences, who presented the findings.

According to their results, which also are detailed in an upcoming article in the journal Mutation Research, the development of anaphase bridges and chromosome instability is most likely due to reactive oxygen species that form as the cell is exposed to the various chemicals in smoke.

Treating the smoke-exposed cells with different antioxidants, agents that block formation of reactive oxygen species, prevented most occurrences of anaphase bridge formation and significantly reduced genomic imbalances.

“Unfortunately, no amount of scientific evidence arguing against smoking will get everyone to stop or not begin to smoke in the first place. So, perhaps one long-term goal should be to develop cigarettes that somehow prevent what we’ve seen happen to the cells in our lab,” remarked Saunders.

In addition to Luo and Saunders, other authors of the abstract and paper are Kristen M. Werner, a former undergraduate student in the Pitt’s Department of Biological Sciences; and Susanne M. Gollin, professor of human genetics at Pitt’s Graduate School of Public Health and co-investigator at the Oral Cancer Center of Discovery at Pitt’s Cancer Institute.

Intensity modulated radiation therapy reduces radiation dose to healthy breast tissue

Results from a Pitt study evaluating intensity modulated radiation therapy (IMRT) for breast cancer indicate that IMRT results in a lower dose of radiation to healthy breast tissue when compared to standard radiation. The findings were presented recently at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO) in Atlanta.

“More than 70 percent of breast cancer patients receive ionizing radiation therapy to treat their disease,” said Dwight E. Heron, study co-author and assistant professor of radiation oncology, Pitt School of Medicine and vice chairman of radiation oncology, UPMC. “While these high-energy beams are targeted to the tumor site as precisely as possible, they often inadvertently injure healthy breast tissue that surrounds the tumor site, limiting the doses of radiation that can be used to effectively destroy cancer cells,” he said. “With this study, we sought to discover whether tightly focused radiation beams, such as those provided by IMRT, would make a difference in the amount of radiation received by the side of the breast opposite from the tumor site.”

The results from the study are encouraging evidence that breast cancer patients can benefit from IMRT,” Heron said. “With more homogenous and conformal treatment, breast cancer patients may be spared side effects from standard radiotherapy that can include skin irritation and breakdown and scarring of the lungs. The risk of treatment-related heart complications, though rare, also may be further reduced with IMRT.”

During radiation therapy, high-energy beams are aimed at cancer cells to destroy them by permanently damaging their underlying genetic material. Unlike standard radiation therapy, IMRT administers a radiation field that consists of several hundred small beams of varying intensities that pass through normal tissue without doing significant damage, but converge to give a precise dose of radiation at the tumor site. IMRT can potentially limit the adverse side effects from radiation while increasing the intensity of doses that can be given to effectively destroy cancer cells.

IMRT is combined with a process called inverse treatment planning to determine the best way to treat a patient. It relies on CT (computed tomography) data from patients that is processed and analyzed by a complex computer system to produce the ideal radiation dose distribution for that patient.

Co-authors of the study include Deborah Sonnick, Ajay Bhatnagar, Edward Brandner, Kristina Gerszten and Melvin Deutsch, all of the Department of Radiation Oncology at the Pitt’s School of Medicine.