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May 30, 2002


Researchers present findings at ASCO meeting

Pitt researchers presented findings at the annual meeting of the American Society for Clinical Oncology (ASCO).

* Radioactive glass bead treatment reduces liver tumors, improves quality of life

A new treatment option for inoperable primary liver cancer called TheraSphere=AE appears to be safe and effective for liver cancer patients, according to results presented by a Pitt study. Brian Carr, professor and director of the liver tumor service at UPMC, evaluated the safety and effectiveness of the novel treatment. The treatment involves the emission of beta rays via microscopic glass beads delivered by catheter directly into the liver through the hepatic artery.

"Hepatocellular carcinoma, a type of cancer that arises from liver cells, can be a deadly disease when diagnosed at an advanced stage, leaving patients with limited treatment options," Carr explained. "TheraSphere allows physicians to deliver a much higher dose to the liver than is possible with standard radiotherapy and is fairly well tolerated even in patients whose livers are highly susceptible to radiation-induced damage."

Carr reported findings for 36 patients with advanced stage hepatocellular carcinoma (HCC) who had received a maximum of two treatments with TheraSphere to each liver lobe. Thirty-one of these patients were able to be evaluated for a response to the treatment.

Six patients had a partial response to the treatment, which resulted in a decrease in tumor size. Eighteen patients remained stable with no tumor progression. Disease progressed in seven patients.

Toxicities associated with the treatment were relatively minor. None of the 36 patients treated with TheraSphere exhibited radiation-induced toxicities outside of the liver, resulting in improved quality of life.

TheraSphere is an outpatient procedure that lasts 30-40 minutes. The glass beads are delivered by catheter into the femoral artery up through the hepatic artery and into the liver. Once the catheter reaches the liver, TheraSphere is released and blood carries the beads into the tumor where they remain with a half-life of 64.2 hours. The beads are prevented from being swept away from the tumor and into other parts of the body due to the large size of the beads which are unable to fit through the liver's capillary system.

HCC kills up to a half million people each year, primarily in Africa and Asia, due to the prevalence of hepatitis. In the United States, about 15,000 cases of HCC are diagnosed annually.

* Gemcitabine shows promise for patients with bladder cancer

Patients with bladder cancer could benefit from treatment with gemcitabine, a chemotherapeutic agent that has been used to treat pancreatic cancer and non-small cell lung cancer, according to a Pitt study.

Merrill J. Egorin, professor of medicine and pharmacology, University of Pittsburgh Cancer Institute (UPCI), demonstrated that little, if any, toxicity was associated with gemcitabine in patients who received it through a tube inserted in the urethra to treat early stage bladder cancer.

"Many patients with bladder cancer are at high risk for relapse," Egorin said. "In fact, 50 to 80 percent of bladder cancer patients suffer a recurrence of the disease within three years and current standard treatments often cause toxic side effects. There is a need for the development and application of new agents that destroy cancer cells in the bladder but do not cause serious adverse effects. Gemcitabine, as an antimetabolite that interferes with cancer cells by slowing their growth and spread through the body, shows early promise."

The study included 15 patients with superficial, or early stage, bladder cancer. The patients received gemcitabine in doses of 500, 1,000, 1,500 and 2,000 mg. The results demonstrated that either no or very low levels of gemcitabine were found in plasma samples from patients, indicating that only a small amount of gemcitabine was absorbed systemically into the blood. The results also demonstrated that in individual patients, doses absorbed correlated well with doses recovered in patients' urine. These results further defined the appropriate dose for a phase II trial of gemcitabine in superficial bladder cancer and such a trial is ongoing. A large phase III trial designed to fulfill FDA requirements for approval of gemcitabine as a treatment for superficial bladder cancer is planned.

A difficult cancer to treat due to high rates of recurrence, bladder cancer is newly diagnosed in 55,000 people in the United States each year and an estimated 12,500 deaths occur annually.

Co-investigators of the study include Eleanor G. Zuhowski, from UPCI.


Findings presented at AUA meeting

Pitt researchers presented findings at the annual meeting of the American Urological Association (AUA).

* Muscle derived cell transplants may be alternative to traditional incontinence therapies

Researchers from the School of Medicine have found that, in animal models, autologous skeletal muscle derived cell (MDC) transplants offer a safer, more effective and longer lasting treatment for urinary incontinence than existing methods. In the procedure, muscle cells are taken from the individual, purified and cloned, and then reinjected into the bladder.

"In patients who need more advanced treatments for incontinence, we currently have the options of treating them through surgery or through the injection of bulking agents like collagen. Although collagen injections give good short-term results and are less invasive than surgery, there is a possibility of the collagen being reabsorbed or causing allergic reactions," said Ryan J. Pruchnic of urology and orthopaedic surgery (DEPT CORRECT??) and lead author of the study. "In our study, MDCs have the potential to offer a longer-term solution without the risk of rejection."

Researchers obtained a mixed population of MDCs from a mouse skeletal muscle biopsy. The cells were purified to obtain a population that was purely myogenic, meaning that the cells were from muscle and capable of producing muscle. One cell from this population was genetically engineered and cloned to form a large population. These cells were then injected into the bladders of mice.

The bladders of the mice were evaluated at one, four and eight weeks and six months. Researchers noted the presence of myofibers, or differentiated muscle cells, throughout the smooth muscle layer, the number of which did not significantly decrease over time. Some of the myofibers expressed a-smooth muscle actin, suggesting differentiation of the cells into smooth muscle. Researchers also observed the presence of neuromuscular junctions, indicating that the muscle was supplied with nerves giving the muscle the ability to become functional tissue.

"These findings indicate that the use of MDCs may prove to be a very promising new therapy in the treatment of urinary incontinence. Essentially, we are giving the bladder muscles the ability to fix themselves by generating new muscle," said Michael Chancellor, professor of urology and gynecology.

Urinary incontinence affects 13 million Americans and is typified by the inability to control the flow of urine. Incontinence can be caused by a number of different anatomic, physiologic and pathologic factors and can be temporary or chronic.

* Researchers use Botox to treat overactive bladder

Botulinum toxin A (BTX) injections, commonly known as botox, show promise as a treatment for a variety of lower urinary tract dysfunctions, according to a Pitt study.

"Bladder dysfunction affects a staggering number of people worldwide. The use of botox injections can offer many of these patients a safe, but temporary, solution to this embarrassing problem," said Michael Chancellor, professor of urology and gynecology at the School of Medicine.

In the study, 50 patients were injected with BTX into the bladder or urethra. Patients suffered from a variety of voiding dysfunctions, including multiple sclerosis, spinal cord injury, stroke, overactive bladder and interstitial cystitis. Each experienced involuntary contractions of the bladder muscle, which caused incontinence typified by either uncontrolled voiding of urine or the inability to completely empty the bladder.

Forty-one of the 50 patients, or 82 percent, reported a decrease or absence of incontinence for approximately six months. None of the patients experienced long-term complications.

BTX binds to the nerve endings of muscles, blocking the release of the chemical that causes the muscle to contract. When injected into specific muscles, the muscle becomes paralyzed, but leaves surrounding muscles unaffected.

Common urologic conditions like neurogenic detrusor hyperreflexia and overactive bladder are caused by involuntary contractions of the detrusor muscle, which controls the bladder. This new therapy helps alleviate the contractions, restoring normal bladder function.

Over 17 million Americans suffer from overactive bladder. An estimated 80 percent of these patients do not seek help.


Grants awarded to researchers

The National Institute on Alcohol Abuse and Alcoholism has granted medicine and psychiatry professor John Donovan $731,378 for studies that concern the family and peer risk factors for preadolescent drinking.

Linda Jen-Jacobson of the biology department has received a $353,081 grant from the National Institute of General Medicine Sciences to use restriction endonucleases as models to understand the structural and energetic factors that determine specificity in site-specific DNA-protein interactions.

The computer science department's Rami Melhem has been awarded $401,547 from the Defense Advanced Research Projects Agency to investigate an integrated power-aware architecture that maximizes the reward of systems constrained by deadlines and limited power resources.

The National Heart, Lung, and Blood Institute has granted environmental and occupational health professor Barry Stripp $340,557 for studies on pulmonary stem cell populations and their contributions to airway repair.

Anna Vainchtein of mathematics has received a $346,428 grant from the National Science Foundation for studies concerned with physically motivated thermomechanical models of materials.

The medical school's Xiao Xiao has been awarded $275,880 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to study AAV vectors for muscular dystrophy gene therapy.

The Department of the Army-Robert Morris Acquisition Center has given chemistry professor John Yates $298,000 for research on the interaction between a hybrid thin-film system consisting of enzymes and antibodies and chemical and biological agents.


Enlarged prostates vary, research shows

Men with asymptomatic benign prostatic hyperplasia (BPH), symptomatic BPH, and BPH with prostate cancer express different genes, according to a Pitt study in the Proceedings of the National Academy of Sciences (PNAS). These findings are the first to investigate the molecular differences underlying BPH, commonly referred to as an enlarged prostate.

Robert Getzenberg, director of urological research, associate professor of urology and co-director of the prostate and urologic cancer program, said, "Now, we can look into targeting the different types of BPH and creating new therapies to alleviate the symptoms of the disease based upon their unique properties."

Researchers identified a set of 511 genes that were differentially expressed in tissue samples taken from four groups of patients: patients without BPH, BPH without symptoms, BPH with symptoms, and BPH with cancer. Analysis showed that each group was clearly distinguishable from the another. The prostates of men with symptomatic BPH were most similar to the BPH areas of the individuals with prostate cancer. This relationship may indicate the presence of a potential link between BPH and prostate cancer that has not been previously identified as well as support the concept of a genetic "field effect" in individuals with prostate cancer.

Further analysis showed that there were unique sets of genes that serve as a signature of each of the groups. Genes associated with cell proliferation were up regulated in the symptomatic BPH group. A series of genes including oncogenes were up regulated in the BPH cancer group. A cluster of genes with unknown function distinguished the asymptomatic BPH from the others.

"Studying patterns of gene expression is a powerful tool. Already it is providing important clues about the fundamental nature of disease which will allow us to more strategically target our therapies," said Joel B. Nelson, professor and chairman of urology and co-director of the Comprehensive Prostate and Urologic Cancer Program at UPCI, said "One of the most striking of these discoveries is the strong correlation between inflammation and symptomatic BPH. This is a key finding because now we may be able to stratify our treatments and diagnostics to better treat patients," Getzenberg said.

More than half of men over the age of 60, and 80 percent by age 80, will have enlarged prostates. Forty to 50 percent will develop symptoms of BPH.

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