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October 24, 2013

Research Notes

UPCI prof contributes to cancer testing checklist

A University of Pittsburgh Cancer Institute (UPCI) professor contributed to guidelines that will be used by the National Cancer Institute (NCI) to evaluate proposals for clinical trials that include biological assessments of individual cancer risk and treatment recommendations.

William L. Bigbee, previous leader of the Cancer Biomarkers Facility at UPCI and outgoing chair of the National Institutes of Health (NIH) cancer biomarkers study section, is co-author of an article in the Oct. 1 issue of Nature that includes a proposed, 30-point NCI checklist of criteria for the use of omics-based predictors in clinical trials.

Tests based on omics are those that use computational modeling to interpret molecular measurements of blood, tissue or other bodily samples in order to recommend a clinical course of action, such as cancer therapy or preventative surgery. Genomics, transcriptomics and proteomics are among the fields of study that are the basis of these tests.

Said Bigbee, pathology faculty member in the School of Medicine: “Omics-based tests are very powerful, emerging tools that are revolutionizing medicine, particularly in predicting and treating cancer. However, there are many variables and opportunities for error, including study design, patient selection, biological sample integrity and data analysis and management. The NCI checklist is intended to provide clear expectations and guidelines for the development and implementation of omics-based tests and will hopefully eliminate unintentional errors.”

The checklist is the result of a 2011 Institute of Medicine review of the omics field and the recommendations of a 2011 NCI workshop bringing together scientists and stakeholders in this research. The review and workshop arose following widely publicized cases of premature advancement of omics-based tests used to guide treatment decisions.

The checklist is divided into five sections: specimen issues; assay issues; model development, specification and preliminary performance evaluation; clinical trial design, and ethical, legal and regulatory issues.

Based on his research expertise in cancer biomarkers, Bigbee’s primary contributions to the checklist involved the specimen and assay issues sections.

“There’s a whole series of issues involving the biological specimens selected for omics-based testing on which research conclusions and clinical recommendations will be made,” said Bigbee. “From which patients will biological specimens be obtained? Are the selected patients representative of all relevant patients with a given malignancy? How are these specimens collected, processed and stored to ensure reproducible results?”

For example, if a research project seeks to use omics-based testing to determine the best course of treatment for an individual cancer patient, it is important that the predictor be developed and tested in specimens from patients with similar clinical characteristics, including stage of disease.

“The field is rife with promising results in patients with late-stage cancer that may or may not be relevant to patients with early-stage cancer,” said Bigbee. “We don’t want to give the wrong toxic drugs to patients or give them too much or too little. The goal of personalized medicine is to give the right therapy to the right patient at the right time.”

Additional co-authors were from NCI, the University of North Carolina, Massachusetts Institute of Technology, Harvard and the University of Michigan.


Night work increases diabetes risk

People who regularly work night shifts in their lifetimes are twice as likely to have diabetes, even if they have retired and returned to a normal, daytime schedule, according to a new study published in the Journal of Biological Rhythms.

The study complements previous international research that found night shift work is associated with a decrease in metabolic health, impaired glucose metabolism, increased body mass index (BMI) and impaired insulin resistance. In the U.S., a recent nurses’ health study showed a night shift work-related increase in BMI and diabetes risk in working female nurses.

Pitt’s study is the first to examine the increased risk of diabetes in a large, U.S. sample of retired men and women with varying pre-retirement occupations who are no longer subject to the stresses of night shift work.

Said Timothy H. Monk, the study’s lead author and psychiatry faculty member in the School of Medicine: “The results are worrisome, given the current epidemic of diabetes and obesity in the U.S. Increasingly, scientific study has confirmed the importance of regular sleep patterns and sufficient sleep in maintaining good health.”

For this study, researchers interviewed more than 1,000 retired night shift workers over 65 years old living in western Pennsylvania, and divided the respondents into five groups: those who worked night shifts for zero years, one-seven years, eight-14 years, 15-20 years and more than 20 years.

The results showed:

• Both BMI and diabetes rates were higher in retired former night shift workers than in retired former day workers.

• Night shift retirees were about twice as likely as retired former day workers to be diabetic if they had done night shift work and had a higher BMI.

• Even when BMI was excluded as a factor, diabetes risk still was higher in retired night shift workers (1.4 times greater risk as opposed to 2 times greater risk).

• Diabetes risk within the five shift-work-exposed groups did not differ, suggesting that any exposure to night shift work can be associated with increased risk.

“We ought to recognize that there is a health cost to society of exposing large numbers of people to night shift work,” said Monk. “Steps should be taken both to encourage day work as an alternative wherever possible, and also to provide education and support for employees who are in occupations that, by their very nature, require work at night.”

The authors also recommended that intensive educational campaigns be launched to encourage night shift workers to adopt behavioral strategies regarding diet, exercise and circadian adjustment because of their increased vulnerability to metabolic health problems.


Mobile-device drug info prevents nursing home mishaps

Nearly nine out of 10 nursing home physicians report that using their mobile devices to look up prescription drug information prevented at least one adverse drug event in the previous month, according to a School of Medicine Department of Biomedical Informatics study published in the Journal of the American Medical Directors Association.

As lead investigator Steven M. Handler, faculty member in biomedical informatics, geriatric medicine, and clinical and translational sciences in the School of Medicine, noted, adverse drug events are associated with an estimated 93,000 deaths and $4 billion in excess health care costs in nursing homes each year. Half of these events are thought to be preventable.

“Most U.S. nursing homes do not have electronic medical record systems and, as a result, physicians frequently do not have access to current medication information at the point of prescribing,” Handler said. “The lack of accurate and timely medication information can lead to adverse drug events and drug-drug interactions. Our hypothesis was that if physicians could look up drug information first, many of these mistakes could be avoided.”

He and his team surveyed more than 550 nursing home doctors attending the 2010 annual meeting of the American Medical Directors Association about their ownership and use patterns of mobile devices, the type of drug reference software on these devices and how frequently it was used, and the perceived impact of drug reference information obtained from the devices on adverse drug events and drug-drug interactions.

The researchers found that 42 percent of study participants said they used a mobile device to check drug information, and greater use was more common among those who had been in practice for fewer than 15 years. Of the device users, almost all (98 percent) said they used drug reference software daily in the previous four weeks, and three-quarters reported an average of three or more lookups daily.

Eighty-eight percent of the participants reported that using a mobile device to check drug information prevented one or more potential adverse drug events in the previous four weeks, leading to greater patient safety.

“To our knowledge, this is the first large study of the use of drug reference software on mobile devices in the nursing home setting,” Handler said. “Those who did look up medication information on their mobile devices clearly felt that this was helpful and improved medication safety. However, we found that fewer than half of the nursing home doctors were doing this, which suggests that there is a lot of potential to reduce adverse event rates further if more of them took advantage of these tools.”

Co-authors of the paper were medical school faculty Richard D. Boyce, Frank M. Ligons, Subashan Perera, David A. Nace and Harry Hochheiser.

The project was funded by the Agency for Healthcare Research and Quality, NIH, the National Institute of Aging, the National Library of Medicine and the U.S. Department of Veterans Affairs.


Plaques & hardening of arteries linked

Older adults with hardening of the arteries are more likely to have beta-amyloid plaques in their brain even if they have no signs of dementia, according to a University study published in Neurology.

While researchers still do not know whether amyloid plaques in the brain are the cause or a byproduct of dementia, their presence is associated with and considered the hallmark of Alzheimer’s disease. Arterial stiffness, also known as arteriosclerosis or hardening of the arteries, indicates how hard the heart has to work to pump blood through the body, and is associated with a higher risk of cardiovascular diseases such as stroke and hypertension. Arterial stiffness also affects cerebral blood flow, leading to increased and possibly damaging blood flow in areas of the brain while leaving other areas without enough.

Said study author Timothy M. Hughes, who conducted the research while at the Graduate School of Public Health (GSPH) and is now a senior postdoctoral fellow at Wake Forest School of Medicine: “This research shows more evidence that vascular health and brain health are closely connected. The findings show that measures of vascular disease, independent of blood pressure, are associated with amyloid deposition in the brain of dementia-free older adults.”

Researchers scanned the brains of 91 individuals aged 83-96 who did not have dementia to measure plaque levels in the brain. Two years later, researchers examined the amount of stiffness in the participants’ arteries.

Approximately half of the participants had beta-amyloid plaques in their brains, and were more likely to have high blood pressure and higher arterial stiffness. Furthermore, arterial stiffness was highest in people who had both types of brain lesions: amyloid plaques and white matter or cerebrovascular lesions.

Each unit of increase in arterial stiffness was associated with a two- to four-fold increase in the odds of having both amyloid plaques and a high amount of brain lesions. According to the authors, individuals with both conditions therefore may be at significantly greater risk of developing dementia. Amyloid imaging studies, using compounds like the Pittsburgh Compound B, also show beta-amyloid deposition is more common than expected in elderly adults.

Previous studies have demonstrated that arterial stiffness is associated with cerebrovascular disease, impaired cognitive function and dementia in the elderly. Recent studies suggest that elevated blood pressure is associated with amyloid deposits in the brain, and that arterial stiffness may be the driving factor. This study is the first to associate arterial stiffness and beta-amyloid deposits in the brain.

“We don’t yet know why amyloid occurs or what the risk factors are,” added Hughes. “This study adds to the growing research suggesting that arterial stiffness may be more important than current hypertension and both are important potential targets for the prevention of age-related amyloid deposition. Future research will have to tell us if successfully treating hypertension will reduce the beta-amyloid burden in the brains of older adults.”

Co-authors included Lewis H. Kuller, Emma J.M. Barinas-Mitchell, Rachel H. Mackey, Eric M. McDade, William E. Klunk, Howard J. Aizenstein, Ann D. Cohen, Beth E. Snitz, Chester A. Mathis and Oscar L. Lopez, all of Pitt, and a researcher from the University of Virginia.

The study was supported by NIH.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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