Friday, November 9, 2012

Colon Cancer Patients Who Consume Too Much Starchy, High Carbohydrate Food At Greater Risk For Cancer Recurrence

Colon cancer survivors whose diet is heavy in complex sugars and carbohydrate-rich foods are far more likely to have a recurrence of the disease than are patients who eat a better balance of foods, a new study by Dana-Farber Cancer Institute researchers indicates.

The connection is especially strong in patients who are overweight or obese, the authors write. More than 1,000 patients with advanced (stage III) colon cancer participated in the study, one of the first to examine how diet can affect the chances that the disease will recur. The findings are published online by the Journal of the National Cancer Institute and will appear later in the journal's print edition.

Although the results point to a potential hazard, for colon cancer patients, of a high-carbohydrate diet, the take-home message is not a conclusive "Eat less sugar," said lead author Jeffrey Meyerhardt, MD, MPH. "Our study certainly supports the idea that diet can impact the progression of colon cancer, and that patients and their doctors should consider this when making post-treatment plans. But further research is needed to confirm our findings."

Recent studies have shown that colorectal cancer survivors whose diet and activity patterns lead to excess amounts of insulin in the blood have a higher risk of cancer recurrence and death from the disease. High insulin levels can be produced by eating too many starchy and sugar-laden foods. In a previous study of advanced-stage colon cancer patients, Meyerhardt and his colleagues found that those with a typical "Western" diet -- marked by high intakes of meat, fat, refined grains, and sugar desserts -- were three times more likely to have a cancer recurrence than those whose diets were least Western. The new study was conducted to explore which component of the Western diet is most responsible for the increased risk of recurrence.

The study involved 1,011 stage III colon cancer patients who had undergone surgery and participated in a National Cancer Institute-sponsored Cancer and Leukemia Group B clinical trial of follow-up chemotherapy for their disease. Participants reported their dietary intake during and six months after the trial.

Researchers tracked the patients' total carbohydrates, as well as their glycemic index (a measure of how quickly blood sugar levels rise after eating a particular food), and glycemic load (which takes into account the amount of a carbohydrate actually consumed), and looked for a statistical connection between these measures and the recurrence of colon cancer.

They found that participants with the highest dietary levels of glycemic load and carbohydrate intake had an 80 percent increased risk of colon cancer recurrence or death compared with those who had the lowest levels. Among patients who were overweight or obese (had a body mass index above 25 kg/m2), the increase was even greater.

"In light of our and other's research, we theorize that factors including a high glycemic load may stimulate the body's production of insulin," Meyerhardt said. "That, in turn, may increase the proliferation of cells and prevent the natural cell-death process in cancer cells that have metastasized from their original site."

Meyerhardt added that while the study doesn't prove that diets high in glycemic load and carbohydrate intake cause recurrence of colon cancer, the results strongly suggest that such dietary factors play a role. "Our findings may offer useful guidance for patients and physicians in ways of improving patient survival after treatment."
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In Xenograft Model, Spread Of Human Melanoma Cells Correlates With Clinical Outcomes In Patients

UT Southwestern Medical Center scientists led by Dr. Sean Morrison, director of the Children's Medical Center Research Institute at UT Southwestern, have developed an innovative model for predicting the progression of skin cancer in patients.

In a new study published in Science Translational Medicine, Stage III human melanoma cells from 20 patients were implanted into specially selected mice with compromised immune systems. Using this xenograft model, in which tissue is transplanted from one species to another, the institute's team observed reproducible differences in the rate at which the cancer spread in the mice, or metastasized, that correlated with clinical outcomes in patients.

Dr. Morrison said human melanomas that metastasized efficiently in the mice eventually progressed to advanced, Stage IV disease in patients - spreading to distant organs, such as the brain, liver, or lungs. When the melanoma did not metastasize efficiently in the mice, it also did not form distant metastases in patients.

This xenograft model will make it possible to study the mechanisms that regulate disease progression and distant metastasis of melanomas in patients. The researchers said they hope that their system will lead to new prognostic markers that identify patients at highest risk of disease progression as well as new therapies.

"We believe this is the only time in cancer biology that anyone has developed a xenograft model in which disease progression correlates with what happens in the patient," said Dr. Morrison, senior author of the investigation and a Howard Hughes Medical Institute investigator at UT Southwestern. "The highly immune-compromised state of the mice makes it possible to observe the metastasis of human melanomas, and to study intrinsic differences among melanomas in their metastatic potential."

Previous studies of cancer metastasis were limited by a lack of workable models in which scientists could study the progression of a patient's cancer cells in laboratory animals in a way that correlated with clinical outcomes, he said.

But such correlation was clear in this study by the research institute, an innovative collaboration that melds the leading clinical resources of Children's Medical Center with the outstanding research resources of UT Southwestern. Melanomas that spread slowly and could not be detected in the blood of mice did not form distant tumors within 22 months in patients. Melanomas that spread rapidly in mice did form distant tumors in patients within the same time frame, giving rise to circulating melanoma cells in the blood of the mice. This finding suggests that entry of melanoma cells into the blood is a step that limits the rate of distant metastasis.

"Ultimately we want to identify new drug targets," Dr. Morrison said. "There are promising ideas coming out of this work that we hope will lead to clinical trials in melanoma."

The research arose from the Morrison laboratory's innovative techniques for studying neural crest stem cells - work that was recognized in 2004 with a Presidential Early Career Award for Scientists and Engineers. Neural crest stem cells make melanocytes, a type of cell that can mutate into melanoma if exposed, for example, to excessive sunlight.

The Children's Research Institute focuses on the interface of stem cell biology, cancer, and metabolism and will eventually include approximately 150 scientists in 15 laboratories. The work of Dr. Morrison, who also leads the Hamon Laboratory for Stem Cell and Cancer Biology, focuses on adult stem cell biology and cancers of the blood, nervous system, and skin.

"We're trying to do transformational science that not only changes scientific fields, but also creates new strategies for treating diseases," Dr. Morrison said. "The goal is for our work to have a direct impact on the patient."

Other UTSW researchers involved in the study were Drs. Elena Piskounova and Ugur Eskiocak, both postdoctoral researchers in the Children's Research Institute. This work originated with lead author Dr. Elsa Quintana and Dr. Mark Shackleton in Dr. Morrison's former lab at the University of Michigan. Other key collaborators from the University of Michigan were Dr. Douglas R. Fullen, director of dermatopathology, and Dr. Timothy Johnson, director of the Multidisciplinary Melanoma Clinic.

"This animal model offers unprecedented opportunities for discovery efforts that could be translated into patient care," Dr. Johnson said. "Dr. Morrison and I share a core mission to effectively treat melanoma, and that shared belief is the basis of the past, present, and future collaboration between UT Southwestern and the University of Michigan."
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Measures Developed To Prevent Health Problems Associated With Biogenic Amines In Wine

Biogenic amines may be one of the factors responsible for symptoms such as headaches, gastro-intestinal disorders, shortness of breath, fall in blood pressure, and even unconsciousness and cardiac arrhythmia in severe cases. Histamine, one of the best known members of this group, can cause serious physical problems. Biogenic amines can be produced in the body by natural metabolic activities but are also ingested in larger quantities with food. They play a special role in microbiologically produced food such as wine, beer, cheese, and sauerkraut. In a joint project Johannes Gutenberg University Mainz (JGU) and the Dienstleistungszentrum Landlicher Raum Rheinpfalz (DLR) have developed measures to identify and reduce biogenic amines in wine, where they can be of particular risk to human well-being.

The goal of these investigations was to avoid high concentrations of biogenic amines in wine. The corresponding investigations were performed in the Institute of Microbiology and Wine Research at Mainz University and the Dienstleistungszentrum Ländlicher Raum Pheinpfalz in Neustadt in a joint project sponsored by the Research Association of the German Food Industry (FEI). "It is important to make efforts in order to reduce biogenic amines in wine, since this problem shall increase in future," predicts Professor Dr. Helmut König of the JGU Institute of Microbiology and Wine Research (IMW). Compared to other microbiologically processed food such as cheese the concentration of biogenic amines in wine may be low. However, their effect on sensitive human beings may be strongly increased during simultaneous ingestion of wine and other problematic food since alcohol significantly impairs the body's ability to metabolize biogenic amines.

Therefore, Helmut König's team and the enologists of the working group of Ulrich Fischer in Neustadt have developed "Practicable Milestones" in order to enable wine-makers to lower the risk of the production of biogenic amines. There currently is no regulatory requirement regarding the upper limits for biogenic amines in wine. However, in view of the health risks and the need to prevent the development of off-flavors that can be caused by some bacteria, wine-makers shall take measures in respect to cellar and wine producing techniques now. The addressed problems may increase in future as a result of climate change, because higher temperatures will promote the growth of undesirable bacteria on the grapes. It has been shown that the production of biogenic amines will be enhanced due to elevated pH values. An earliness of the ripening period of the grapes may lead to an increase of the pH value of the grape juice.

Preventative and curative measures include the use of tested starter cultures, the early detection of the presence of biogenic amine-forming bacteria by molecular methods and procedures to prevent their growth, for example the application of flash pasteurization or the removal of biogenic amines with the help of bentonite or yeast cell walls. The most economic preventive measure is to lower the pH value by adding tartaric acid. This is already permitted in the warmer climate zones of the EU and in non-European countries, but German wine-makers are currently prohibited to apply this measure. However, in the last years an exemption to this regulation was granted.
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High Blood Pressure Ages The Brain

New research led by the University of California (UC) Davis found accelerated brain aging among young middle-aged people with high blood pressure, and even among those whose blood pressure would not be considered high enough to warrant clinical intervention. The researchers say their findings emphasize the need for "early and optimum control of blood pressure".

Reporting in The Lancet's 2 November online issue, senior author Charles DeCarli, professor of neurology and director of the Alzheimer's Disease Center at UC Davis, and colleagues, describe how they found evidence of structural damage in white matter and volume of gray matter in the brains of hypertensive and prehypertensive people in their 30s and 40s that suggests vascular brain injury "develops insidiously over the lifetime with discernible effects".

The study is thought to be the first to show structural damage to the brains of people in young middle age as a result of high blood pressure. Such damage has been linked with cognitive decline in older people.

DeCarli says in a statement:

"The message here is really clear: people can influence their late-life brain health by knowing and treating their blood pressure at a young age, when you wouldn't necessarily be thinking about it."

"The people in our study were cognitively normal, so a lack of symptoms doesn't mean anything."

High Blood Pressure and Cognitive Decline

Normal blood pressure is up to 120/80 ("one twenty over eighty": the first number being the systolic pressure, when the heart is contracting, and the second being the diastolic pressure, when the heart is resting). Prehypertension lies in the range 120-139/80-89, while blood pressures above 140/90 are classed as high (hypertension).

High blood pressure is linked to a 62% higher risk of cerebrovascular disease such as ischemic stroke, and a 49% higher risk of cardiovascular disease. It is the single greatest risk factor for premature death in the US, where it affects some 50 million people.

Previous studies have shown links between high blood pressure and a raised chance of brain injury and wasting away (atrophy), which in turn leads to reduced ability in thinking and memory, and a greater risk of developing dementia. High blood pressure is therefore indirectly an important risk factor for cognitive decline later in life, but it is a modifiable one because it can be treated.

The researchers say there is evidence that treating high blood pressure in middle age can prevent cognitive decline and dementia later.

The Study

For their study, DeCarli and colleagues analyzed data on 579 people taking part in the Framingham Heart Study, a longitudinal investigation that started following the cardiovascular health of people living in Framingham, Massachusetss, over 60 years ago. The study is now in its third generation of participants.

The participants were mostly in their late 30s when they were joined this part of the study, in 2009.

They had their blood pressure taken on entry, and were at that time assigned to one of three groups: normal blood pressure, prehypertensive, or high blood pressure. The researchers also noted their smoking status and if they were taking any medication for blood pressure.

After that, the participants underwent magnetic resonance imaging (MRI) brain scans that took extensive measurements of any white matter injury and gray matter.

Detailed Scans of White Matter

Some of the MRI scans were of a type known as "diffusion tensor imaging" that examines in microscopic detail the architecture of the brain's white matter.

The white matter of the brain comprises the axons, the long filaments that carry electrical signals from one area of the brain to another. Diffusion tensor imaging yields a measure known as "fractional anisotropy", which can sense whether axons are damaged or intact. It can be regarded as a measure of connectivity in the brain.

There is also another type of MRI scan that shows damaged white matter as areas of intense whiteness, or "white-matter hyperintensities".

When combined, the various imaging studies of white and gray matter produced a global measure that allowed comparison of of brain health among the different blood pressure groups.

The Results

When they analyzed the results, the researchers found that the brains of the people in the high blood pressure were significantly less healthy than those of the normal blood pressure group: in fact they looked like they had aged more.

For example, the brain of a typical 33-year-old member of the high blood pressure group, looked similar on the scans to the brain of a typical 40-year-old in the normal blood pressure group.

The more detailed measures showed that the brains of the people in the high blood pressure group had an average 6.5% reduction of fractional anisotropy in the frontal lobes. They also, on average, had 9% less gray matter, in the frontal and temporal lobes, compared to the normal blood pressure group.


The researchers did not propose a mechanism for how high blood pressure might cause the brain to age more quickly. But they did mention that high blood pressure leads to stiffer arteries, which in turn impedes blood flow, so the axons receive less oxygen and essential nutrients.

Lead author Pauline Maillard, a postdoctoral fellow in the UC Davis Department of Neurology, says the findings suggest the microscopic white matter damage that has been linked to high blood pressure in the elderly in other studies may be detectable earlier in life.

This supports the idea that "vascular brain injury may develop insidiously over several decades", says Maillard, and that there is a need for "early and optimum control of blood pressure, which is neither routinely achieved nor subject to testing in randomized controlled clinical trials".

Written by Catharine Paddock PhD
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"Rebooting" MS Drug Succeeds In Trials

Two phase 3 trials of a drug for treating multiple sclerosis (MS) that "reboots" the immune system showed it to be effective in patients who had not responded to first-line therapy: it reduced risk of disability and brain shrinkage. Reporting in the 1 November issue of The Lancet, the researchers describe how alemtuzumab (known commercially as Lemtrada), previously used to treat a type of leukaemia, was able to help people with early MS who relapsed on previous treatments as well as patients who had not yet received any treatment.

Alastair Compston, a professor from the University of Cambridge was principal investigator on both trials and also chaired the Steering Committee that supervised them and an earlier trial. He said in a statement from the University:

"Our research shows the transformative effect that alemtuzumab can have for people with MS."

The findings mark the conclusion of a unique development program for an MS drug that started in Cambridge in 1991. The statement from the University says:

"Never before has an MS drug been tested in clinical outcomes against such a high hurdle, an active first-line drug, in both one phase II trial and two phase III trials; and no drug for MS has been shown to be more effective, in both reducing the risk of disability and reducing the rate of brain atrophy, when compared to another active treatment."

MS is an autoimmune disease where the patient's immune system destroys nerve fibers and their protective insulation, the myelin sheath. The resulting damage stops nerves communicating with each other, leading eventually to loss of the nerve fiber, and progressive physical and cognitive disability.

The disease affects millions of people worldwide, including almost 100,000 in the UK, and 400,000 in the US.

The two randomized, controlled phase 3 trials, reported in two separate papers, are called CARE MS I and CARE MS II. They were both funded by Genzyme (Sanofi) and Bayer Schering Pharma.

The developers expect decisions on drug licences for alemtuzumab by the European and US regulatory authorities to be made in 2013.

In another study reported this week, scientists describe how it may be possible to repair the nerve fiber damage caused by MS.

CARE MS I: Alemtuzumab Versus Interferon beta-1a as First Treatment in RRMS Patients

This three-year trial involved 334 patients with active, early relapsing remitting MS (RRMS) who had not received any treatment for the disease (drug-naïve patients). It tested the performance of alemtuzumab against the first-line drug interferon beta-1a (commercially known as Rebif).

The patients were randomly assigned to one of three groups. One group received interferon beta-1a injections three times a week, and the other two groups each received a different daily intravenous dose of alemtuzumab.

The results showed that alemtuzumab reduced the number of attacks by 55% over and above that achieved by the other first-line drug.

Over a 2-year period, 78% of the patients taking alemtuzumab remained relapse free, compared with 59% in the interferon group.

The percentage of patients whose disability got worse during the trial was slightly lower in the alemtuzumab patients than in the interferon patients, but the result was not statistically significant.

The researchers conclude:

"Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis."

CARE MS II: Alemtuzumab After Failed First-Line Treatment in RRMS Patients

For this 2-year trial, researchers recruited 840 patients agd 18 to 55 with RRMS (from which data from 628 participants was used in the principal analysis), who had received first-line treatment but had recently relapsed during their therapy.

As with the MS I trial, the participants were randomly assigned to received either alemtuzumab or interferon beta-1a. Each patient had their disability assessed every three months by a researcher who did not know which drug they were receiving. They also underwent annual scans to assess lesions and brain shrinkage due to MS.

The results showed that new relapses were reduced by 49% more in the alemtuzumab than the interferon patients.

Over the 2-year period, 65% of patients on alemtuzumab remained relapse free compared with 47% of interferon patients.

Alemtuzumab reduced the risk of acquiring disability by 42% compared to interferon: disability worsened in 20% of interferon patients and 13% of alemtuzumab patients.

Plus, at the end of the study, on average, the patients taking alemtuzumab had less disability than when they started the trial whereas the patients taking interferon had more disability.

The brain scans showed that alemtuzumab not only reduced the number of new lesions, compared to interferon beta-1a, but also reduced the rate of brain shrinkage from the tissue damage caused by MS.

The researchers conclude:

"For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity."


Compston says:

"Patients who continue to show disease activity while on their initial therapy are especially difficult to treat. Now, we have shown that alemtuzumab works where first-line drugs have already failed."

The drug "not only reduces the chances of disability associated with MS", but it "may even result in long-term clinical improvements," he adds.

In both trials the main side effect from alemtuzumab was the development of other autoimmune diseases.

Additional work by some of the Cambridge researchers on these trials is looking into how to identify people who are susceptible to this side effect, and they are currently recruiting for a trial that is testing alemtuzumab with a new drug aimed at reducing the adverse reaction.

Written by Catharine Paddock PhD
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Longer Use Of Hormonal Contraception During Midlife Predicts Better Cognitive Function Later

Premenopausal use of hormonal contraceptives may improve the cognitive abilities of women in midlife and for years afterward. This finding may have implications for prevention of declining cognitive function that occurs with advancing age and in diseases such as Alzheimer's. The beneficial effects of hormones increase the longer a woman uses them, as described in a study published in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Women's Health website.*

Kelly Egan, University of Wisconsin School of Medicine and Public Health, and Carey Gleason, PhD, William S. Middleton Memorial Veterans Hospital, Madison, WI, present the results of cognitive performance tests administered to women enrolled in the Wisconsin Registry for Alzheimer's Prevention in the article "Longer Duration of Hormonal Contraceptive Use Predicts Better Cognitive Outcomes Later in Life."

"This study provides preliminary evidence that hormonal contraceptives may have a protective cognitive effect, even years after use is discontinued," says Editor-in-Chief Susan G. Kornstein, MD, Editor-in-Chief of Journal of Women's Health, Executive Director of the Virginia Commonwealth University Institute for Women's Health, Richmond, VA, and President of the Academy of Women's Health.
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