UPMC Physician Resources

Pitt Researchers to Monitor Resistance to HIV Drugs in Africa

PITTSBURGH, Aug. 3, 2015 – Infectious diseases researchers from the University of Pittsburgh School of Medicine are leading a five-year, $5 million initiative to monitor drug resistance during the rollout of HIV prevention drugs in sub-Saharan Africa.

A cooperative agreement awarded by the U.S. Agency for International Development (USAID), will allow experts in the Infectious Diseases Division of the School of Medicine at Pitt to conduct laboratory research and develop evidence-based policy guidance for monitoring drug resistance during the large-scale rollout of drugs and microbicides that prevent HIV infection.

“HIV/AIDS is an epidemic in sub-Saharan Africa and, until now, we’ve been really focused on treating people who already have the disease. But to stem the epidemic, we also need to prevent new infections,” said Urvi Parikh, Ph.D., assistant professor of medicine at Pitt and senior project advisor. “It is truly amazing to turn years of research in HIV prevention into action helping people in the real world.”

Roughly 25 million people have HIV in sub-Saharan Africa, accounting for nearly 70 percent of the global total.

Pre-exposure prophylaxis (PrEP) and antiretroviral (ARV)-based microbicides help prevent new HIV infections through a regimen of daily pills, a monthly vaginal ring that slowly releases medication or a medicated gel used before and after sex.

A concern with widespread use of PrEP and ARV-based microbicides is that if a person becomes infected while on PrEP or microbicides, a strain of HIV could arise that resists drugs needed for treatment in the future. The resistant strain could then be spread to others.

The Pitt-led team is starting the project by analyzing laboratory data and previous research to create computer models and simulations that will balance the cost and inconvenience of testing with the risk of resistance to provide optimal testing recommendations, whether once a month, once every few months or once a year.

These findings will be presented to stakeholders in Africa, including the community leaders, doctors and health policy professionals who will be involved in implementing the prophylactic treatment effort.

In the third year, the team will provide finalized recommendations for HIV testing and then work with USAID and other groups, including the World Health Organization (WHO) and the United Nations Programme on HIV/AIDS, to implement recommendations in regions where PrEP and microbicides are distributed.

Finally, the team will train local clinics in using low-cost tests to detect drug resistance so data can continue to be collected and guide future HIV prevention initiatives.

“Through this carefully crafted, step-by-step process, we’ll be able to provide critical data to develop cost-effective and appropriate HIV diagnostic and resistance testing and monitoring plans. As a result, we should be able to stay on top of any drug resistance that arises from antiretrovirals implemented for HIV prevention,” said John W. Mellors, M.D., chief of Pitt’s Division of Infectious Diseases and project director.

In addition to Drs. Mellors and Parikh, other key members of the team include project administrator April Churilla, B.A., of Pitt; monitoring and evaluation advisor Ward Cates, M.D., of the nonprofit human development organization FHI 360; senior technical advisor Carole Wallis, Ph.D., of Lancet Laboratories in South Africa; external evaluator Ann Wessling, M.P.I.A., an independent consultant in Senegal. Other project contributors come from the Statistical Center for HIV/AIDS Research & Prevention in Seattle and the HIV Modeling Consortium in the United Kingdom.

This project is funded by the U.S. President’s Emergency Plan for AIDS Relief through USAID (award AID-OAA-A-15-00031), which administers the U.S. foreign assistance program providing economic and humanitarian assistance in more than 80 countries worldwide.

Ancient Proteins Involved in DNA Repair Could Shed Light on Tumor Development, Says Pitt Study

PITTSBURGH, July 28, 2015 – By studying the yeast used in beer- and bread-making, researchers at the University of Pittsburgh School of Medicine have uncovered the mechanism by which ancient proteins repair DNA damage and how their dysfunction could lead to the development of tumors. The findings, published online today in Nature Communications, could lead to new ways to tailor cancer therapies.

In humans, protein mutations called RAD51 paralogues have been associated with breast and ovarian tumors, said senior investigator Kara Bernstein, Ph.D., assistant professor of microbiology and molecular genetics at Pitt School of Medicine and the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter.

“These are proteins that have been present throughout evolution in many species, but very little has been known about what they do,” she said. “Our study shows for the first time the mechanism of how they are involved in the repair of damaged DNA.”

Because RAD51 paralogues are too difficult to work with in animal cells, the research team instead explored their function in yeast. They found the proteins interact with other proteins called the Shu complex to repair breaks in DNA strands, which can be caused by environmental toxins, radiation and other naturally occurring exposures.

Shu complex works synergistically with additional RAD51 paralogues to search for homologous, or complementary, DNA regions with double-strand breaks, in which both poles of the twisting DNA ladder have been broken, the researchers found. Pieces of the genetic code can be lost in such areas; the paralogues and complex repair the damage by filling in the missing pieces in a process called homologous recombination.

“Now that we understand what the proteins do, we can perhaps tailor therapies for patients who have cancer and mutations in these repair genes,” Dr. Bernstein said.

The team included Stephen K. Godin, Faiz F. Kabbinavar, and Andrew P. Van Demark, Ph.D., of Pitt; and William A. Gaines, Ph.D., Timsi Rao, Ph.D., and Patrick Sung, Ph.D., of Yale University. The project was funded by National Institutes of Health grants ES015252, ES007061, CA168635, GM088413 and GM101808.

UPCI Called ‘Outstanding’ as Comprehensive Cancer Center Grant Renewed by National Cancer Institute for $25.6M

PITTSBURGH, July 27, 2015 – The University of Pittsburgh Cancer Institute (UPCI) has been rated “outstanding” and renewed as a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, an award that recognizes the world-class research that sets the center among an elite group nationwide. The five-year grant is for $25.6 million and comes as UPCI celebrates its 30th year as a leader in working to reduce the burden of cancer.

UPCI is one of just 44 NCI-designated Comprehensive Cancer Centers in the U.S.

“The NCI renewal is an incredible accomplishment that comes after an extensive application and review process. The award recognizes our strength in basic, clinical and population research, education and community outreach and reflects the dedication of everyone here who is working toward a future without cancer,” said Nancy E. Davidson, M.D., director of UPCI and UPMC CancerCenter, Hillman Professor of Oncology and Distinguished  Professor of Medicine at Pitt, and president-elect of the American Association of Cancer Research.

With 320 faculty members from 42 Pitt departments, UPCI received $68 million in annual funding from NCI in 2015 to support cancer research activities.  Since the last renewal award, UPCI program members have published nearly 5,000 articles in peer-reviewed journals and received prestigious awards, including renewal of Specialized Programs of Research Excellence (SPOREs) grants in lung cancer, head and neck cancer, and melanoma and skin cancer and a new SPORE with another center in ovarian cancer.

Among other notable accomplishments, UPCI was also selected by the NCI as a National Clinical Trials Network Lead Academic Participating Site and as an Experimental Therapeutics-Clinical Trials Network Lead Academic Organization, both of which aim to streamline research trials.  In addition, UPCI is playing a key role in an international study examining how environmental and lifestyle exposures and genetics have affected the incidence, mortality and age-related outcomes of cancer in more than 81,000 Chinese men and women, an effort funded by the NCI.

“Our faculty members are among the most sought- after cancer experts in the country, and we’re proud of the work that sets UPCI apart from other cancer research centers,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine.

Known colloquially as the “core grant,” NCI’s Cancer Center Support Grant is awarded every five years. Established in 1985, UPCI first received its status as an NCI-designated Comprehensive Cancer Center in 1990 and has retained this distinction since then.

Menopause Associated with More Fat Around Heart, Raising Risk for Heart Disease

PITTSBURGH, July 22, 2015 – Late- and post-menopausal women have significantly greater volumes of fat around their hearts – a risk factor for heart disease – than their pre-menopausal counterparts, a University of Pittsburgh Graduate School of Public Health study has shown for the first time.

The finding, published online and scheduled for the Sept. 1 issue of The Journal of Clinical Endocrinology & Metabolism, likely can be attributed to changing hormone levels and could guide potentially life-saving interventions. The work was funded by the National Institutes of Health (NIH) and American Heart Association (AHA).

“Cardiovascular disease is the leading cause of death in women, and it increases after age 50 – the average age when a woman is going through menopause,” said lead author Samar R. El Khoudary, Ph.D., M.P.H., assistant professor in Pitt Public Health’s Department of Epidemiology. “By showing that menopause appears to be associated with a shift in fat deposits that leads to more fat around the heart, we’ve uncovered a new potential contributor to increased risk of cardiovascular disease in women.”

Weight gain in women during and after menopause has long been attributed to aging, rather than menopause itself. However, recent research identified changes in body fat composition and distribution due to menopause-related hormonal fluctuations.

No previous study had evaluated whether those changes in fat distribution during menopause affect cardiovascular fat. Increased and excess fat around the heart and vasculature can be more detrimental than abdominal fat, causing local inflammation and leading to heart disease. Doubling certain types of cardiovascular fat can lead to a more than 50 percent increase in coronary events.

Dr. El Khoudary and her team evaluated clinical data, including blood samples and heart CT scans, on 456 women from Pittsburgh and Chicago enrolled in the Study of Women’s Health Across the Nation (SWAN). The women averaged about 51 years of age and were not on hormone replacement therapy.

As concentrations of the sex hormone estradiol – the most potent estrogen – declined during menopause, greater volumes of cardiovascular fat were found. The finding held even after the team took into account the effects of age, race, obesity, physical activity, smoking, alcohol consumption, medication use and chronic diseases.

“Developing prevention strategies to reduce cardiovascular fat in women at midlife may reduce their heart disease risk, especially knowing that the menopausal transition puts women at risk for excess fat around their hearts,” said Dr. El Khoudary. “Previous studies suggest that reducing heart fat is feasible through weight loss or weight management, but these studies only looked at small numbers of people and there have been no clinical trials linking cardiovascular outcomes with heart fat changes due to weight management interventions. Clearly there is a need for larger scale studies to determine the best intervention strategies to help post-menopausal women reduce fat near the heart.”

Dr. El Khoudary and her research team are working on seeking more funds to evaluate whether cardiovascular fat volumes progress over time in midlife women, and, if so, whether this progression will be associated with greater evolution in atherosclerosis and more cardiovascular events in post-menopausal women.

Additional authors on this study are senior author Karen A. Matthews, Ph.D., of Pitt; and co-authors Kelly J. Shields, Ph.D., of Allegheny Health Network; Imke Janssen, Ph.D., and Lynda H. Powell, Ph.D., both of Rush University Medical Center; Carrie Hanely and Emma Barinas-Mitchell, Ph.D., both of Pitt; Matthew Budoff, M.D., of the Los Angeles Biomedical Research Institute; and Susan A. Everson-Rose, Ph.D., of the University of Minnesota Medical School.

This research was supported by NIH grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554 and HL065591; and AHA grant 12CRP11900031.

Pitt Gets $20 Million for Research from Institute for Transfusion Medicine’s Blood Science Foundation

PITTSBURGH, July 20, 2015 – University of Pittsburgh officials announced today that its Vascular Medicine Institute has received a new commitment of $15 million over the next 10 years from the Institute for Transfusion Medicine’s (ITxM) Blood Science Foundation, as well as an additional $5 million to establish the Institute for Transfusion Medicine Research Endowment. Funding from ITxM’s Blood Science Foundation and Hemophilia Center of Western Pennsylvania now totals $50 million since 2008.

“We are proud to celebrate this remarkable partnership and grateful that these organizations – working together – have enabled the University to take some bold steps in the past years to advance our research in vascular medicine and bring a new level of care to the people of our region and beyond,” said Pitt Chancellor Patrick Gallagher. “This is an extraordinary gift that will be a springboard to draw in other funding from the National Institutes of Health and other national organizations.”

“The tools and knowledge at our disposal have never been greater or more powerful, and their availability converges with a time of great need in this country,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine. “This generous support will help us seize the moment to seek solutions and provide answers.”

Such support has allowed the recruitment and support of outstanding investigators who are experts in vascular biology, red cell and platelet biology, and hemostasis and thrombosis research, all focused on understanding human vascular and blood diseases and developing new targeted therapies, noted VMI Director and Distinguished Professor Mark Gladwin, M.D., who also is the Dr. Jack D. Myers Professor of Internal Medicine and chair of the Department of Medicine, Pitt School of Medicine.

“This assistance also has supported the training of young investigators focused on blood and cardiovascular diseases,” he added. “We anticipate that the study of vascular biology will enable the development of new therapies and interventions for a multitude of vascular conditions, such as sickle cell disease, diabetes, coronary artery disease and hemophilia.”

“Research is one of the key pillars of our strategic plan and I cannot think of a more appropriate way for ITxM to execute on both our mission and strategy. It is an honor for us to be able to provide ongoing support for the Vascular Medicine Institute at the University of Pittsburgh, partnering to develop innovative therapies to improve the quality of life for people with blood related disorders,” said James P. Covert, ITxM president and chief executive officer.

In celebration of the gift, as well as a $5 million match from the University of Pittsburgh Physicians group for the ITxM Research Endowment, a private dinner will be held on Monday, July 20, at Alumni Hall in Oakland.

Cholesterol Metabolism in Immune Cells Linked to HIV Progression, May Lead to New Therapy

PITTSBURGH, July 17, 2015 – Enhanced cholesterol metabolism in certain immune cells may help some people infected with HIV naturally control disease progression, according to new research from the University of Pittsburgh Graduate School of Public Health.

The findings – funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH) and presented today at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment & Prevention in Vancouver – provides a basis for potential development of new approaches to control HIV infection by regulating cellular cholesterol metabolism.

“We’ve known for two decades that some people don’t have the dramatic loss in their T cells and progression to AIDS that you’d expect without drug therapy,” said lead author Giovanna Rappocciolo, Ph.D., an assistant professor in Pitt Public Health’s Department of Infectious Diseases and Microbiology. “Instead, the disease progresses more slowly, and we believe altered cholesterol metabolism in certain immune cells may be a reason.”

Immune cells known as antigen-presenting cells (APCs) can deliver HIV to its primary target – T cells – through a process known as trans infection. HIV then uses T cells as its main site of replication. It is through this mechanism that levels of HIV increase and overwhelm the immune system, leading to AIDs.

However, some HIV-infected people do not progress to AIDS for many years, even without antiretroviral therapy, because their APCs do not effectively trans infect T cells. These people are known as “nonprogressors.” A closer look revealed that this defect in trans infection is likely due to altered cholesterol metabolism within the APCs, which appears to be an inherited trait.

This discovery was made possible by using 30 years of data and biologic specimens collected through the NIH-funded Multicenter AIDS Cohort Study (MACS), a confidential research study of the natural history of untreated and treated HIV/AIDS in men who have sex with men. The Pittsburgh arm of the study is the Pitt Men’s Study.

Dr. Rappocciolo and her colleagues searched for patterns in gene expression, or the degree to which specific genes are turned on or off, in APCs from eight HIV nonprogressors and eight progressors enrolled in MACS.

“Compared to APCs from progressors, cells from nonprogressors expressed higher levels of several cholesterol-related genes associated with defective trans infection,” Dr. Rappocciolo said. “These results improve understanding of how nonprogressors control HIV without drug therapy and potentially may contribute to new approaches to manage HIV infection.”

Additional researchers on this work are Charles Rinaldo, Ph.D., Jeremy Martinson, D. Phil., Diana Campbell, B.S., and Maureen McGowan, B.S., all of Pitt Public Health.

This research was supported by NIH grants R01-AI118403-01, U01-AI35041 and R37-AI41870.

Older Age at Onset of Type 1 Diabetes Associated with Lower Brain Connectivity Later in Life

PITTSBURGH, July 14, 2015 – People diagnosed with type 1 diabetes in later childhood have weaker brain connectivity in midlife compared to those who were diagnosed at earlier ages according to a University of Pittsburgh Schools of the Health Sciences study.

The findings are reported in a special issue of Psychosomatic Medicine that is focused on diabetes, obesity and the brain. Sixty-six middle-aged adults (ages 32 to 58) who were diagnosed with type 1 diabetes as children participated in the study.

“Other studies have shown an association between earlier onset type 1 diabetes and cognitive difficulties, so we expected to find that people with earlier age of onset would have weaker connections between brain regions,” said John Ryan, Ph.D., assistant professor of psychiatry at Pitt. “But instead, we found that those who were diagnosed later in childhood had the weaker brain connections as they aged.”

All of the study participants had onset of type 1 diabetes before age 18 and were enrolled in the Pittsburgh Epidemiology of Diabetes Complications Study, which is an ongoing investigation led by Caterina Rosano, M.D., M.P.H., at Pitt’s Graduate School of Public Health  documenting long-term complications of type 1 diabetes among patients at Children’s Hospital of Pittsburgh of UPMC between 1950 and 1980.

The participant group is one of the few in the country in which people with childhood onset type 1 diabetes have been followed throughout their lifespan. “Due to advances in treatments, people with type 1 diabetes are living longer. But we don’t yet understand how diabetes and aging interact in the brain,” Dr. Ryan noted.

“The mechanisms underlying these associations are not yet clear,” he said.  “However, the relationships between age of diagnosis and connectivity was stronger in older participants, supporting a model of diabetes as accelerated aging.”

Additional researchers on this project include Howard J. Aizenstein, M.D., Ph.D., Trevor J. Orchard, M.B.B.Ch., M.Med.Sci., F.A.H.A., F.A.C.E., Christopher M. Ryan, Ph.D., Judith A. Saxton, Ph.D., David F. Fine, B.S., and Karen A. Nunley, Ph.D., all of Pitt Public Health.

Kids May Need More Vitamin D, Pitt/Children’s Study Finds

PITTSBURGH, July 9, 2015 – Currently recommended daily dietary allowances of vitamin D may be insufficient to prevent deficiency in children, according to researchers at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. In a report recently published in the Journal of Clinical Endocrinology and Metabolism, they noted that children with suboptimal vitamin D blood levels did not reach optimal levels after taking nearly twice the recommended amount of the nutrient daily for six months.

Vitamin D is important for calcium metabolism and bone health, said lead investigator and Children’s Hospital pediatrician Kumaravel Rajakumar, M.D., M.S., who also is an associate professor of pediatrics at Pitt’s School of Medicine. It is present in a few foods, milk is usually fortified with it and with enough exposure to sunlight the body naturally produces it.

“Vitamin D deficiency is common in the northeastern U.S., especially in black children whose darker skin complexions have higher amounts of melanin, preventing absorption of the ultraviolet light that’s needed to trigger vitamin D synthesis,” he explained.

Guidelines differ on adequate blood levels of vitamin D for bone health, highlighting the need for further research. Blood level of 25-hydroxyvitamin D is the best measure of vitamin D status. For example, a blood level of 20 or more nanograms per milliliter (ng/mL) of the vitamin is considered adequate for bone health by the Institute of Medicine, while the Endocrine Society recommends a level of 30 ng/mL for optimal bone health.

Between October and March of 2008 through 2011, the researchers randomly assigned 84 black and 73 white 8- to 14-year-old children from Pittsburgh and Kittanning, Pa., to take for six months either a daily pill of 1,000 international units (IU) of vitamin D3 or a placebo. They also performed periodic blood tests to assess their 25-hydroxyvitamin D levels and other markers of bone health.

The average vitamin D level at the initial assessment of all children, and particularly black children, was suboptimal (less than 20 ng/mL), and supplementation raised their average level to above 20 ng/mL but not as high as 30 ng/mL. After six months of vitamin D supplementation in children with initial vitamin D levels less than 20 ng/mL, 39 percent remained below 20 ng/mL and only 14 percent rose above 30 ng/mL. Biomarkers of bone turnover remained unchanged.

“Our findings suggest that currently recommended daily dietary allowances of vitamin D of 600 IU may be inadequate for preventing vitamin D deficiency in children,” Dr. Rajakumar said. “It may be important to revisit these recommendations, especially since the higher dose of vitamin D used in this study was safe and did not appear to lead to any side effects.”

The team included Charity G. Moore, Ph.D., M.S.P.H., Jonathan Yabes, Ph.D., Flora Olabopo, B.S., Mary Ann Haralam, M.S.N., Diane Comer, B.A., Susan Sereika, Ph.D., Jacqueline Dunbar-Jacob, Ph.D., and Susan L Greenspan, M.D., all of Pitt; Jaimee Bogusz, B.S., and Michael F. Holick, M.D., Ph.D., both of Boston University School of Medicine; and Anita Nucci, Ph.D., M.P.H., R.D., L.D., of Georgia State University.

The project was funded by National Institutes of Health grants HD052550, DK062895, AG024827, HL112985 and RR024153; and Children’s Hospital of Pittsburgh of UPMC.

Early HIV Treatment Improves Survival in Some Patients with Newly Diagnosed TB

PITTSBURGH, July 9, 2015 – Starting anti-HIV treatment within two weeks of the diagnosis of tuberculosis, or TB, improved survival among patients with both infections who had very low immune-cell counts, according to an analysis by researchers at the University of Pittsburgh Graduate School of Public Health. Those with strong immune systems, however, might benefit from waiting until after the end of the six-month TB treatment before initiating anti-HIV therapy, they found.

In a study published in the current issue of Annals of Internal Medicine, the team recommended updating physician guidelines to take the findings into account.

Infection with HIV can promote progression and re-infection to active TB after initial exposure to Mycobacterium tuberculosis, the organism that causes TB, explained senior author Jean B. Nachega, M.D., Ph.D., M.P.H., associate professor of infectious diseases and microbiology and of epidemiology, Pitt Public Health. Treating HIV and TB simultaneously is challenging for many reasons, including the requirement for patients to take multiple pills several times daily for each infection, drug-drug interactions and overlapping side effects.

“Current World Health Organization guidelines recommend starting TB treatment first, followed by HIV treatment as soon as possible within two to eight weeks for patients who have moderately to severely compromised immune systems, but there was not conclusive evidence to guide treatment in other levels of immune suppression,” Dr. Nachega said. “We aimed to investigate the optimal timing of HIV initiation in light of recent published randomized clinical trials on this topic.”

The team systematically reviewed data from more than 4,500 people participating in eight randomized clinical trials of early initiation of HIV anti-retroviral therapy (ART) conducted in Asia, Africa and the United States. They found that survival rates were better among patients who started ART within two weeks of the initiation of TB treatment and who also had very low CD4 T-cell counts of less than 0.050 x 109cells/liter, as measured by a blood test which reflects severe immune system suppression due to HIV infection. Of note, early initiation also was associated with a two-fold increase in the frequency of a complication called TB-Immune Reconstitution Inflammatory Syndrome, which can be fatal in rare occasions. There was no evidence to support or refute a survival benefit for patients with CD4 counts between 0.050 and 0.220 x 109cells/liter.

“Our findings support guidelines recommending early initiation of ART in patients with a high degree of immune system compromise,” Dr. Nachega said. “But delaying ART might be possible until the end of TB treatment with patients with CD4 counts greater than 0.220 x 109cells/liter, which could reduce the burden of taking two complex drug regimens at the same time.”

However, Dr. Nachega noted that there is other emerging evidence showing the clinical and public health benefits associated with early initiation of HIV treatment, other than survival. Indeed, early treatment may be beneficial by decreasing comorbidities due to ongoing inflammation caused by HIV and decreasing HIV sexual transmission.

“Clinicians will need to weigh these benefits against the burden of co-administration of TB and HIV treatment on a case-by-case basis, but the overarching goal is likely to be a move toward treating all HIV-positive people as early as possible,” said Dr. Nachega.

The team included researchers from the University of Pittsburgh; Warwick Medical School, United Kingdom; Liverpool School of Tropical Medicine, United Kingdom; Stellenbosch University, South Africa; South African Medical Research Council; University Medical Center Utrecht, The Netherlands; Johns Hopkins Bloomberg School of Public Health; and University College London, United Kingdom.

The research team was supported with funding from the Swedish Council for Working Life and Social Research; the National Institute for Allergy and Infectious Disease of the National Institutes of Health; the AIDS Clinical Trial Group; and Stellenbosch University Clinical Trial Unit; the Medical Education Partnership Initiative through the U.S. President Emergency Plan for AIDS Relief; the European Developing Countries Clinical Trial Partnership Senior Fellowship Award; the Wellcome Trust Southern Africa Consortium for Research Excellence; the European Commission Seventh Framework Programme (Rapid Identification of Respiratory Tract Infections Project); and the South African Medical Research Council.

Pitt Scientists Lead Consensus Guidelines for Thyroid Cancer Molecular Tests

PITTSBURGH, July 6, 2015 University of Pittsburgh Cancer Institute (UPCI) scientists recently led a panel of experts in revising national guidelines for thyroid cancer testing to reflect newly available tests that better incorporate personalized medicine into diagnosing the condition.

Their clinical explanation for when to use and how to interpret thyroid cancer tests is published in the July issue of the scientific journal Thyroid. The American Thyroid Association is revising its 2015 Guidelines for Thyroid Nodule and Thyroid Cancer Management to direct doctors to the scientific publication.

“Minimally invasive molecular testing for thyroid cancer has improved by leaps and bounds in the last several years,” said co-author Robert L. Ferris, M.D., Ph.D., professor and chief of the Division of Head and Neck Surgery in Pitt’s School of Medicine. “But different tests perform differently and, therefore, need to be interpreted carefully to make the best decisions regarding extent of surgery for patients with thyroid nodules. Our goal with this analysis is to give clinicians a clear understanding of what each type of test can tell them and when to use them to determine the best course of treatment.”

Cancer in the thyroid, which is located just below the “Adam’s apple” area of the neck, is the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.

UPCI, partner with UPMC CancerCenter, has been a national leader in developing personalized genetic tests for thyroid cancer that have spared patients repeat or unnecessary surgeries. A low-cost test called ThyroSeq, developed by a team led by Yuri Nikiforov, M.D., Ph.D., director of Pitt’s Division of Molecular and Genomic Pathology, allows pathologists to simultaneously test for multiple genetic markers of thyroid cancer using just a few cells collected from the nodule.

This allows doctors to “rule-in” a specific cancer diagnosis with a high degree of certainty, without a biopsy to remove a large portion of the thyroid, which would then have to be followed with a second surgery if cancer is detected to remove the entire gland. As Dr. Nikiforov’s group added more genetic sequences to the ThyroSeq test to create a larger and more sensitive version of the test, it is now also performing as a “rule-out” test that can tell doctors with a high degree of certainty that a patient does not have cancer.

Other available tests use different technology to serve as accurate “rule-out” tools, but do not have the high sensitivity needed to also reliably “rule-in” cancer. And, in some cases, the accuracy of the “rule out” tests depends on the prevalence of cancer in the patients seen by each individual cancer institute. This is critical because clinicians must know this rate at their institution to correctly calculate the accuracy of “rule-out” test results for each patient.

In addition to Dr. Ferris and co-author Sally E. Carty, M.D., who is professor and chief of the Division of Endocrine Surgery in Pitt’s School of Medicine and co-director of the UPMC/UPCI Multidisciplinary Thyroid Center, the panel reviewing the tests was a multidisciplinary group from a dozen institutions in the U.S. and Canada.

“This was a very innovative and collegial initiative,” said Dr. Carty.  “Through an objective review of the existing tests and the scientific literature characterizing their performance, we are seeking to help clinicians make the best decisions for their patients.”

Dr. Ferris agrees, noting that “this is an exciting time in personalized medicine, and these tests give us the ability to not only better diagnose and treat thyroid cancer, but also significantly reduce surgeries for people who don’t have cancer.”

Additional authors on this publication are Zubair Baloch, M.D., Ph.D., University of Pennsylvania Medical Center; Victor Bernet, M.D., Mayo Clinic; Amy Chen, M.D., Emory University; Thomas J. Fahey III, M.D., New York Presbyterian Hospital; Ian Ganly, M.D., Ph.D., and Ashok Shaha, M.D., both of Memorial Sloan-Kettering Cancer Center; Steven P. Hodak, M.D., and Kepal N. Patel, M.D., both of New York University Medical Center; Electron Kebebew, M.D., National Cancer Institute; David L. Steward, M.D., University of Cincinnati Medical Center; Ralph P. Tufano, M.D., Johns Hopkins University; and Sam M. Wiseman, M.D., St. Paul’s Hospital & University of British Columbia.

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