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March 7, 2002


Lung cancer protein linked to cancer of head & neck, researchers at UPCI discover

Researchers from the University of Pittsburgh Cancer Institute (UPCI) are the first to find that a protein appearing on lung cancer cells in people with extensive smoking histories also is present in head and neck cancers.

The results, published in the March 6 issue of the Journal of the National Cancer Institute, suggest that the protein gastrin-releasing peptide receptor (GRPR), known to be associated with lung cancer, is linked to the growth and proliferation of squamous cell carcinoma of the head and neck (SCCHN).

"Previous research from our group has indicated that when stimulated by its hormone, gastrin-releasing peptide, GRPR triggers lung cancer cells to grow," said Jennifer R. Grandis, associate professor in the Pitt School of Medicine's otolaryngology and pharmacology departments.

Since tobacco exposure is a well-known risk factor for both lung cancer and SCCHN, the investigators decided to examine the expression of GRPR in the cells of patients with head and neck cancer.

"We found that GRPR was expressed in the cells of patients with head and neck cancer and that increased GRPR expression occurs early on in the formation of SCCHN tumors," added Jill M. Siegfried, co-author of the study and co-leader of UPCI's lung cancer program.

In the study, Grandis and her colleagues compared that expression of GRPR in 25 people with SCCHN and six people without cancer. They found a fivefold increase in the level of GRPR in the tissues of people with cancer compared to those without cancer.

According to Grandis, who also leads the head and neck cancer program at UPCI, strategies that specifically target gastrin-releasing peptide to block GRPR may prove to be effective therapies for SCCHN.

"If we can create new receptor-directed therapies for head and neck cancer, this may result in very useful anti-cancer strategies for patients," she said. "This is especially important given that survival rates for head and neck cancer are among the lowest compared to other major cancers and that treatment studies over the past two decades have failed to demonstrate improved survival for patients with locally advanced SCCHN."

Nearly 45,000 cases of head and neck cancer are diagnosed annually in the United States, and 13,000 people die from causes related to this disease. Head and neck cancer occurs in the oral cavity, pharynx and larynx.

Early warning signs are:

* persistent mouth sores that do not heal;

* lumps on the lips, mouth, throat or neck;

* difficulty chewing or swallowing;

* chronic hoarseness or a change in the voice;

* red or white patches in the mouth;

* persistent earaches.

Support for the UPCI study was provided by a grant from the National Cancer Institute Early Detection Research Network.



Grant funds study of medication to treat those with autism

Researchers at Pitt's School of Medicine have received a grant to study a medication that may be useful in treating cognitive deficits in children with autism.

Autism Spectrum Disorders affect about one in 1,000 individuals and are characterized by deficits in social interaction, impaired communication and repetitive and stereotyped patterns of behavior, interests and activities.

The research team headed by Benjamin L. Handen, associate professor of psychiatry and pediatrics and program director of the John Merck Child Outpatient Program at Western Psychiatric Institute and Clinic, hopes to find out if the drug donepezil HCL will enhance cognitive functioning in children with Autism Spectrum Disorders.

The drug has been effective in treating other illnesses that cause cognitive problems, such as Alzheimer's disease and attention-deficit hyperactivity disorder.

A recent open-label study of the safety and effectiveness of donepezil HCL in 25 boys with Autism Spectrum Disorders found significantly increased speech production and a statistical trend toward improvement in core symptoms of the disorder.

Handen and his colleagues will recruit 40 children and adolescents with Autism Spectrum Disorders during the next three years to participate in a 10-week double blind, placebo-controlled study of donepezil HCL.

The study will help to determine if the drug is effective in providing enhanced cognitive functioning and also will examine side effects.



Immune response uniquely activated in pregnancy

Pitt scientists are zeroing in on cellular changes associated with normal pregnancy and what these changes may mean in relation to disorders of pregnancy.

What they are finding is that normal pregnancy results in a significant increase in certain key cells that make up the body's immune response. These cells prepare the mother to fight off infection, yet protect the growing fetus from being rejected as a foreign invader.

"We are the first ones to study immune system alterations during pregnancy in such great detail," said Patrizia Luppi, a research assistant professor of pediatrics at Pitt's School of Medicine. Luppi is principal investigator of the study, reported in the February issue of the American Journal of Reproductive Immunology.

"We think that by helping to define the changes that take place at the cellular level in normal pregnancy, we can learn more about some of the problems of pregnancy, such as preeclampsia, premature labor or miscarriage, also at the cellular level," Luppi added.

What Luppi and her colleagues found, specifically, was an increase in immune cells known as monocytes and neutrophils — white blood cells that destroy foreign particles such as bacteria and tissue debris. These immune cells were not only more numerous, they were also far more active than usual, releasing more of the specialized chemical markers that determine interactions among immune cells and between these cells and the walls of blood vessels. Such cellular interactions are vital to immune system defense against infection and disease.

Blood samples collected during the third trimester of pregnancy were compared from 36 women with normal pregnancies and 26 who were not pregnant, Luppi said.

While some immune system cells increased during pregnancy, others, such as lymphocytes, decreased, the study found. Also a form of white blood cell, lymphocytes produce antibodies. Luppi and her colleagues now are expanding their study of these alterations by measuring cytokines released by the activated immune cells. Cytokines are proteins produced by immune cells that promote inflammation.

"This is all considered to be part of a generalized inflammatory response," said Luppi. "A heightened immune response during pregnancy could conceivably protect the mother and baby during gestation, especially from an attack by foreign pathogens. This would explain why pregnant women usually don't die from infections."

Further studies are needed to track immune response and associated cytokine activity throughout pregnancy, but these novel findings are intriguing, according to Luppi.

"Defining the immunological profile that occurs during normal pregnancy is the first step," she said. "We can then compare the immunological changes that take place during a complicated pregnancy for diagnosis."

In addition to providing tools needed to identify women at risk, predict outcomes and formulate possible interventions, this work may provide useful insights into the causes of pregnancy complications, Luppi said.



New approach studied to help depressed people avoid excessive alcohol use

Pitt School of Medicine researchers have received funding from the National Institute on Alcohol Abuse and Alcoholism to study whether combining an antidepressant and a drug used to treat alcoholism is an effective way of helping depressed people avoid excessive alcohol use.

Alcohol use among people with psychiatric disorders such as depression is a major public health problem. Depressed patients who abuse alcohol often do not comply with treatment and do not do as well in psychotherapy. They also have a higher rate of suicide.

Pitt researchers led by Ihsan Salloum, associate professor of psychiatry, will examine the effectiveness of combining fluoxetine and naltrexone with counseling. Fluoxetine is a common antidepressant, while naltrexone is a drug used to treat alcoholism.

"This is a new approach to help people with depression and excessive alcohol use," Salloum said. "If successful, this treatment will relieve depressive symptoms and help patients have more alcohol-free days."

Both study medications are FDA-approved and study procedures are provided at no cost to study participants.

For more information, call 412/383-2740. All calls are confidential.



Pitt leads investigation into genetic, inflammatory markers of sepsis

In the first study of its kind, researchers will investigate risk factors for sepsis, the leading cause of death in non-coronary intensive care unit patients nationwide.

The Genetic and Inflammatory Markers of Sepsis (GenIMS) study, a multi-center trial funded by a $6 million National Institutes of Health grant, is coordinated by the department of critical care medicine at Pitt's School of Medicine.

Sepsis includes a variety of clinical conditions caused by the immune response to infection. Patients experience pain, fever and swelling as the result of the coagulation and inflammation characteristics of sepsis. In severe cases, sepsis leads to organ dysfunction and failure. Sepsis affects more than 750,000 Americans each year, with a mortality rate of 30 percent, making it the 10th leading cause of death in the United States. In addition, many patients who die of other diseases have their hospital courses complicated by sepsis.

John Kellum, associate professor of critical care medicine and co-principal investigator of the study, said: "Genetic and environmental variables play into how sick a person gets. People may be programmed to respond to infection in different ways. Some have aggressive immune systems that may be able to wipe out infection before it manifests itself in physical symptoms, while others may have less aggressive immune systems that allow them to get sick more often.

"However, when fighting the micro-organisms that cause infection, the body's cells take 'co-lateral' damage, leading to the theory that those with more aggressive immune systems might get infections less, but if they do, they may actually incur more injury," Kellum said. "This is the first population-level study to test this theory. Our results could dramatically change the way we treat patients in the future."

In GenIMS, researchers will try to determine markers indicating the risk for infection, the risk for severe sepsis and the risk for adverse outcomes in patients with community-acquired pneumonia, the most common cause of sepsis. According to researchers, current methods available to identify high risk patients are inadequate.

"We hope to find a pattern of proteins in the blood of patients that will identify those at risk for severe sepsis, multiple organ failure and death. This would give us a simple blood test that would allow us to test patients for risk much like how we now test patients for heart attacks and pancreatitis," said Derek C. Angus, associate professor of critical care medicine and medicine and principal investigator of GenIMS.

Identifying patients at high risk will permit better allocation of hospital resources and improving targeting of expensive new therapies currently being developed, he said.

The GenIMS study involves researchers from up to 30 centers in western Pennsylvania, Connecticut, Detroit and Memphis, Tenn., who will collect clinical data from 3,600 patients, followed by genetic analysis. They hope to identify whether certain changes in the DNA for key inflammatory molecules are associated with the risk of developing pneumonia and the risk of progression to severe sepsis, septic shock, organ dysfunction and death.

Researchers also will investigate the relationships among these genetic changes and their influence on patient outcome. The data also will be used to develop and evaluate clinical decision tools regarding the inflammatory response.



Region of gene found for inherited pancreatic cancer

Researchers at Pitt's School of Medicine, in collaboration with the Fred Hutchinson Cancer Research Center and the University of Washington (UW) School of Medicine, have mapped the location of a gene associated with inherited pancreatic cancer, which accounts for about 10 percent of all such malignancies.

Study co-directors David C. Whitcomb, director of the division of gastroenterology, hepatology and nutrition at Pitt; Leonid Kruglyak, a Fred Hutchinson statistical geneticist, and Teresa Brentnall, a UW gastroenterologist report their findings in an early electronic edition of the April issue of the American Journal of Human Genetics.

The discovery marks the identification of the first genetic defect that is directly linked to pancreatic cancer. By locating the region of the mutation, researchers now will be able to sequence the gene, which has the potential to yield promising new insights into pancreatic cancer.

"By understanding the genetics of pancreatic cancer, we can begin to understand the mechanism by which the disease develops, availing new methods of how to detect, prevent and treat this deadly cancer," said Whitcomb, who also is director of Pitt's Center for Genomic Sciences.

Of the 29,000 Americans who this year will learn they have pancreatic cancer, all but 100 will die within 12 months of diagnosis. Pancreatic cancer is one of the most difficult cancers to treat in that it is undetectable by a physical exam, asymptomatic and progresses quickly. These factors also limit the amount of data available for research, hindering significant advances in the understanding of the disease.While pancreatic cancer is the fifth leading cause of cancer death in the United States, it is one of the least well-funded areas of cancer research.

"Pancreatic cancer is a very aggressive cancer with extremely low survival rates," said Ronald B. Herberman, Pitt associate vice chancellor for research, Health Sciences, and director of the University of Pittsburgh Cancer Institute. "Until now, we have had very limited ability to identify people at high risk for this disease or to make the diagnosis of the disease before it has invaded the rest of the body. This discovery represents a significant finding that may permit identification of individuals at risk so that they can be monitored regularly, to detect the cancer when it can be treated while still in an early stage, which might substantially enhance the likelihood of survival."

Researchers were able to gather sufficient genetic data for this study through the cooperation of a large Northwestern family known in scientific communities as "Family X." Family X is the largest pancreatic cancer family ever studied. Twenty affected family members were studied. Nine have died of the disease, including five out of six brothers. Brentnall has been working with Family X for more than seven years.

Virtually every member of Family X with pancreatic cancer or its precursor was found to harbor a specific genetic marker on the long arm of chromosome 4, where the single-gene mutation responsible for pancreatic cancer is thought to exist. None of the unaffected family members inherited this marker, supporting the significance of the findings.

According to researchers, identifying these markers may lead to the discovery of a specific pancreatic cancer gene — a finding that will allow doctors to screen people for genetic risk for pancreatic cancer with a simple blood test.

Support for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Mental Health, the National Pancreas Foundation, the Lustgarten Foundation, Pitt's Center for Genomic Sciences and the Chiron Corp.

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