Results from many large clinical trials are never published

Contact: Tom Hughes tahughes@unch.unc.edu 919-966-6047 University of North Carolina Health Care

Non-publication is more common among industry-funded trials, study finds

CHAPEL HILL, N.C. – A new analysis of 585 large, randomized clinical trials registered with ClinicalTrials.gov finds that 29 percent have not been published in scientific journals. In addition, nearly 78 percent of the unpublished trials had no results available on the website, either.

As a result, nearly 300,000 people who were enrolled in the 171 unpublished trials “were exposed to the risks of trial participation without the societal benefits which accompany the dissemination of trial results,” said Christopher W. Jones, MD, a former resident physician at University of North Carolina School of Medicine who is now an attending physician at Cooper Medical School of Rowan University in Camden, N.J. and lead author of the study published in the Oct. 29, 2013 issue of the British Medical Journal.

Continue reading “Results from many large clinical trials are never published”

Cancerous cells from donor kidney linked to recipient skin cancer

 

Patients that receive kidney transplants have an increased risk of an invasive form of skin cancer. It is unclear if donor tissue contributes to cancer formation. In this issue of the Journal of Clinical Investigation, Philippe Ratajczak and colleagues at INSERM demonstrate that donor tissue can lead to caner formation in transplant recipients. They examined tumor cells and transplant tissues from a small sample of kidney transplant patients that had subsequently developed skin squamous cell carcinoma (SCC). In one patient they identified the presence of skin tumor cells that were the same genotype as the donated kidney and contained a mutation in a known cancer-causing gene. Furthermore, cells with this mutation were present in kidney biopsy samples taken at the time of transplant. As Cai-Bin Cui and David Gerber from the University of North Carolina discuss in their accompanying commentary, this case study has important implications for cancer research and clinical care of transplant recipients.

TITLE: Human skin carcinoma arising from kidney transplant–derived tumor cells

AUTHOR CONTACT: Philippe Ratajczak Inserm, Paris, , FRA bPhone: +33 1 42 38 54 28; E-mail: philippe.ratajczak@paris7.jussieu.fr

View this article at: http://www.jci.org/articles/view/66721?key=6f8e69f0c56dc67b17ec

ACCOMPANYING COMMENTARY

TITLE: Donor-associated malignancy in kidney transplant patients

AUTHOR CONTACT: David Gerber UNC School of Medicine, Chapel Hill, NC, USA Phone: 919-966-8008; Fax: 919-966-6308; E-mail: david_gerber@med.unc.edu

View this article at: http://www.jci.org/articles/view/70438?key=7a4b5b9cbc0b295d0073

Sublingual immunotherapy shows promise as treatment for peanut allergy

 EEV:  Do not attempt without medical supervision

Contact: Tom Hughes tahughes@unch.unc.edu 919-966-6047 University of North Carolina Health Care

CHAPEL HILL, N.C. – Peanuts are one of the most common triggers of severe food-induced allergic reactions, which can be fatal, and the prevalence of peanut allergy is increasing. However, there is currently no clinical treatment available for peanut allergy other than strict dietary elimination and, in cases of accidental ingestion, injections of epinephrine.

But a new multicenter clinical trial shows promise for sublingual immunotherapy (SLIT), a treatment in which patients are given daily doses, in gradually increasing amounts, of a liquid containing peanut powder. The patients first hold the liquid under the tongue for 2 minutes and then swallow it.

The two lead authors of the study, published in the January 2013 issue of the Journal of Allergy and Clinical Immunology, are David M. Fleischer, MD, of National Jewish Health in Denver, Colo., and Wesley Burks, MD, Curnen Distinguished Professor and Chair of the Department of Pediatrics in the University of North Carolina School of Medicine.

“These results are encouraging,” Burks said. “The immune response was stronger than we thought it might be, and the side effects of this treatment were relatively small. However, the magnitude of the therapeutic effect was somewhat less than we had anticipated. That’s an issue we plan to address in future studies.”

In the study, 40 people with peanut allergy, ages 12 to 37 years, were randomized to receive daily peanut or placebo SLIT. All were given a baseline oral food challenge of up to 2 grams of peanut powder to test how much peanut powder they could consume without symptoms.

After 44 weeks, all were given a second oral food challenge. Those who were able to consume either 5 grams, or at least 10-fold more peanut powder than their baseline amount, were considered to be responders (i.e., desensitized to peanut). At 44 weeks, 70 percent of those who received peanut SLIT were responders, compared to 15 percent of those receiving placebo. Among the peanut-SLIT responders, the median amount of peanut powder they could successfully consume increased from 3.5 to 496 milligrams. After 68 weeks, that amount increased significantly, to 996 milligrams.

Of 10,855 peanut doses given through week 44 of the study, 63.1 percent were symptom-free. When oral/pharyngeal symptoms were excluded from the analysis, 95.2 percent of doses were symptom-free.

The study concluded that peanut SLIT safely induced desensitization in a majority of participants compared to placebo, and that longer duration of therapy led to significant increases in the amount of peanut powder people could safely consume.

However, Burks cautions, this is not a treatment that people should try on their own. For now it’s a treatment that should only be given by medical professionals in a carefully monitored clinical trial, he said.

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Study participants were recruited from five U.S. sites:  New York, N.Y.; Baltimore, Md.; Little Rock, Ark.; Denver, Colo.; and Durham, N.C. Study co-authors include researchers from the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Johns Hopkins University School of Medicine, Mount Sinai School of Medicine, the EMMES Corp. in Rockville, Md., and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).

The study was funded by grants from the NIAID and the NIH’s National Center for Research Resources.

Most heart attack patients’ cholesterol levels did not indicate cardiac risk: half of the patients with a history of heart disease had LDL cholesterol levels lower than 100 mg/dL

Contact: Rachel Champeau
rchampeau@mednet.ucla.edu
310-794-2270
University of California – Los Angeles

A new national study has shown that nearly 75 percent of patients hospitalized for a heart attack had cholesterol levels that would indicate they were not at high risk for a cardiovascular event, according to current national cholesterol guidelines.

Specifically, these patients had low-density lipoprotein (LDL) cholesterol levels that met current guidelines, and close to half had LDL levels classified in guidelines as optimal (less than 100 mg/dL).

“Almost 75 percent of heart attack patients fell within recommended targets for LDL cholesterol, demonstrating that the current guidelines may not be low enough to cut heart attack risk in most who could benefit,” said Dr. Gregg C. Fonarow, Eliot Corday Professor of Cardiovascular Medicine and Science at the David Geffen School of Medicine at UCLA and the study’s principal investigator.

While the risk of cardiovascular events increases substantially with LDL levels above 40󈞨 mg/dL, current national cholesterol guidelines consider LDL levels less than 100� mg/dL acceptable for many individuals. The guidelines are thus not effectively identifying the majority of individuals who will develop fatal and non-fatal cardiovascular events, according to the study’s authors.

Researchers also found that more than half of patients hospitalized for a heart attack had poor high-density lipoprotein (HDL) cholesterol levels, according to national guidelines.

Published in the January issue of the American Heart Journal, the study suggests that lowering guideline targets for LDL cholesterol for those at risk for cardiovascular disease, as well as developing better treatments to raise HDL cholesterol, may help reduce the number of patients hospitalized for heart attack in the future.

“The study gives us new insight and intervention ideas to help reduce the number of heart attacks,” said Fonarow, who is also director of the Ahmanson–UCLA Cardiomyopathy Center.

“This is one of the first studies to address lipid levels in patients hospitalized for a heart attack at hospitals across the entire country.”

The research team used a national database sponsored by the American Heart Association’s Get with the Guidelines program. The database includes information on patients hospitalized for cardiovascular disease at 541 hospitals across the country.

Researchers analyzed data from 136,905 patients hospitalized for a heart attack nationwide between 2000 and 2006 whose lipid levels upon hospital admission were documented. This accounted for 59 percent of total hospital admissions for heart attack at participating hospitals during the study period.

Among individuals without any prior cardiovascular disease or diabetes, 72.1 percent had admission LDL levels less than 130 mg/dL, which is the current LDL cholesterol target for this population. Thus, the vast majority of individuals having their first heart attack would not have been targeted for effective preventative treatments based on the criteria used in the current guidelines.

The team also found that half of the patients with a history of heart disease had LDL cholesterol levels lower than 100 mg/dL, and 17.6 percent of patients had LDL levels below 70 mg/dL, which are guideline targets for LDL cholesterol in those at fair risk and at high risk for cardiovascular disease, respectively.

The study also showed that HDL cholesterol, or “good cholesterol,” levels have dropped in patients hospitalized for heart attack over the past few years, possibly due to increasing rates of obesity, insulin resistance and diabetes.

Researchers found that 54.6 percent of patients had HDL levels below 40 mg/dL. Developing more effective treatments to boost HDL levels may help reduce the number of patients hospitalized for heart attacks, according to the authors.

“We found that less than 2 percent of heart attack patients had both ideal LDL and HDL cholesterol levels, so there is room for improvement,” said Fonarow.

Fonarow said that only 59 percent of patients in the database had their lipid levels checked upon admission, which should be increased, since these early measurements can often help guide treatment decisions.

He also noted that only 21 percent of patients in the study were taking lipid-lowering medications before admission, despite almost half having a prior history of cardiovascular events, which would prompt treatment.

 

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The national cholesterol guidelines are set by the National Cholesterol Education Program, part of the National Heart, Lung and Blood Institute of the National Institutes of Health.

The study was sponsored by the Get with the Guidelines program, which is supported by the American Heart Association in part through an unrestricted education grant from the Merck Schering Plough Partnership.

Fonarow has conducted research for GlaxoSmithKline and Pfizer and serves a consultant and has received honorarium from Abbott, AstraZeneca, GlaxoSmithKline, Merck, Pfizer and Schering Plough companies. He is also chair of the Get with the Guidelines steering committee.

Other authors include: Dr. Amit Sachdeva, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; Dr. Christopher P. Cannon, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA; Dr. Prakash C. Deedwania, Department of Cardiology, VA Medical Center/UCSF School of Medicine, San Francisco, CA; Dr. Kenneth A. LaBresh, Masspro, Waltham, MA; Dr. Sidney C. Smith, Jr., University of North Carolina School of Medicine, Chapel Hill, NC; David Dai, MS and Dr. Adrian Hernandez, Duke Clinical Research Institute, Durham, NC.

Older overweight children consume fewer calories than their healthy weight peers

Contact: Tom Hughes tahughes@unch.unc.edu 919-966-6047 University of North Carolina Health Care

A study by UNC pediatrics researchers finds there is no such thing as a ‘1 size fits all’ explanation for childhood obesity

IMAGE:Asheley Cockrell Skinner, Ph.D., assistant professor in the Department of Pediatrics in the UNC School of Medicine, is lead author of the study.

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CHAPEL HILL, N.C. – A new study by University of North Carolina School of Medicine pediatrics researchers finds a surprising difference in the eating habits of overweight children between ages 9 and 17 years compared to those younger than 9.

Younger children who are overweight or obese consume more calories per day than their healthy weight peers. But among older overweight children the pattern is reversed:  They actually consume fewer calories per day than their healthy weight peers.

How to explain such a seemingly counterintuitive finding?

“Children who are overweight tend to remain overweight,” said Asheley Cockrell Skinner, PhD, assistant professor of pediatrics at UNC and lead author of the study published online Sept. 10, 2012 by the journal Pediatrics.

“So, for many children, obesity may begin by eating more in early childhood. Then as they get older, they continue to be obese without eating any more than their healthy weight peers,” Skinner said. “One reason this makes sense is because we know overweight children are less active than healthy weight kids. Additionally, this is in line with other research that obesity is not a simple matter of overweight people eating more — the body is complex in how it reacts to amount of food eaten and amount of activity.”

These results also suggest that different strategies may be needed to help children in both age groups reach a healthy weight. “It makes sense for early childhood interventions to focus specifically on caloric intake, while for those in later childhood or adolescence the focus should instead be on increasing physical activity, since overweight children tend to be less active,” Skinner said. “Even though reducing calories would likely result in weight loss for children, it’s not a matter of wanting them to eat more like healthy weight kids — they would actually have to eat much less than their peers, which can be a very difficult prospect for children and, especially, adolescents.”

These findings “have significant implications for interventions aimed at preventing and treating childhood obesity,” Skinner said.

In the study, Skinner and co-authors Eliana Perrin, MD, MPH, and Michael Steiner, MD, examined dietary reports from 19,125 children ages 1-17 years old that were collected from 2001 to 2008 as part of the National Health and Nutrition Examination Survey (NHANES). They categorized the weight status based on weight-for-length percentile in children less than 2 years old, or body mass index (BMI) percentile for children between 2 and 17, and performed statistical analyses to examine the interactions of age and weight category on calorie intake.

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All three study authors are faculty members in the UNC Department of Pediatrics.

Heavy drinking rewires brain, increasing susceptibility to anxiety problems

Contact: Tom Hughes tahughes@unch.unc.edu 919-966-6047 University of North Carolina Health Care

IMAGE:Thomas Kash, Ph.D., assistant professor of pharmacology at the Bowles Center for Alcohol Studies in the University of North Carolina School of Medicine, is one of the study’s authors….

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CHAPEL HILL, N.C. – Doctors have long recognized a link between alcoholism and anxiety disorders such as post-traumatic stress disorder (PTSD). Those who drink heavily are at increased risk for traumatic events like car accidents and domestic violence, but that only partially explains the connection. New research using mice reveals heavy alcohol use actually rewires brain circuitry, making it harder for alcoholics to recover psychologically following a traumatic experience.

“There’s a whole spectrum to how people react to a traumatic event,” said study author Thomas Kash, PhD, assistant professor of pharmacology at the University of North Carolina School of Medicine. “It’s the recovery that we’re looking at — the ability to say ‘this is not dangerous anymore.’ Basically, our research shows that chronic exposure to alcohol can cause a deficit with regard to how our cognitive brain centers control our emotional brain centers.”

The study, which was published online on Sept. 2, 2012 by the journal Nature Neuroscience, was conducted by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and UNC’s Bowles Center for Alcohol Studies.

“A history of heavy alcohol abuse could impair a critical mechanism for recovering from a trauma, and in doing so put people at greater risk for PTSD,” said NIAAA scientist Andrew Holmes, PhD, the study’s senior author. “The next step will be to test whether our preclinical findings translate to patients currently suffering from comorbid PTSD and alcohol abuse. If it does, then this could lead to new thinking about how we can better treat these serious medical conditions.”

Over the course of a month, the researchers gave one group of mice doses of alcohol equivalent to double the legal driving limit in humans. A second group of mice was given no alcohol. The team then used mild electric shocks to train all the mice to fear the sound of a brief tone.

When the tone was repeatedly played without the accompanying electric shock, the mice with no alcohol exposure gradually stopped fearing it. The mice with chronic alcohol exposure, on the other hand, froze in place each time the tone was played, even long after the electric shocks had stopped.

The pattern is similar to what is seen in patients with PTSD, who have trouble overcoming fear even when they are no longer in a dangerous situation.

The researchers traced the effect to differences in the neural circuitry of the alcohol-exposed mice. Comparing the brains of the mice, researchers noticed nerve cells in the prefrontal cortex of the alcohol-exposed mice actually had a different shape than those of the other mice. In addition, the activity of a key receptor, NMDA, was suppressed in the mice given heavy doses of alcohol.

Holmes said the findings are valuable because they pinpoint exactly where alcohol causes damage that leads to problems overcoming fear. “We’re not only seeing that alcohol has detrimental effects on a clinically important emotional process, but we’re able to offer some insight into how alcohol might do so by disrupting the functioning of some very specific brain circuits,” said Holmes.

Understanding the relationship between alcohol and anxiety at the molecular level could offer new possibilities for developing drugs to help patients with anxiety disorders who also have a history of heavy alcohol use. “This study is exciting because it gives us a specific molecule to look at in a specific brain region, thus opening the door to discovering new methods to treat these disorders,” said Kash.

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Study co-authors include Kristen Pleil, Chia Li and Catherine Marcinkiewcz of UNC and Paul Fitzgerald, Kathryn MacPherson, Lauren DeBrouse, Giovanni Colacicco, Shaun Flynn, Sophie Masneuf, Ozge Gunduz-Cinar and Marguerite Camp of NIAAA