Medicine Man

A simple blood test screening for a panel of biomarkers can accurately predict whether a patient who has had prostate cancer surgery will have a recurrence or spread of the disease.

Calling their findings a major step forward in prostate cancer care, Texas researchers report in the June 15 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, that the presence of seven of these biomarkers can predict prostate cancer risk with 86.6 percent reliability. This is at least 15 percentage points higher than standard clinical measures currently in use, the researchers say.

"We have been looking at these biomarkers for the past 10 to 15 years in the laboratory, but now we can translate these findings into progress for the individual patient," said Shahrokh F. Shariat, M.D., chief resident in urology at the University of Texas Southwestern Medical Center.

Clinicians need this information to decide whether to take a "watchful waiting" approach with their prostate cancer patients or to move to more aggressive additional therapy such as hormone therapy, chemotherapy or radiation, Shariat says. Urologists currently use a risk predictor that includes variables like stage, Gleason score and serum levels of prostate-specific antigen. "However, this method is only accurate about 70 percent of the time, which is not optimal," Shariat said.

Shariat and colleagues enrolled 423 patients who were surgically treated for prostate cancer with either radical prostatectomy or bilateral lymphadenectomy.

Using commonly available blood tests, they measured levels of the following seven biomarkers: transforming growth factor-â1, interleukin-6, interleukin-6 soluble receptor, vascular endothelial growth factor, vascular cell adhesion molecule-1, endoglin, urokinase plasminogen activator.

"We reviewed background literature over 60 separate biomarkers and determined that these were the optimal seven that would have predictive value," Shariat said.

Patients were followed for approximately four years, and researchers noted cancer recurrence in 17.7 percent of patients. Elevated levels of the seven biomarkers were associated with increased risk of relapse. For example, the presence of urokinase plasminogen inhibitor-1 increased risk by 37 percent, while the presence of vascular endothelial growth factor increased risk by 47 percent.

The combination of all seven biomarker variables accurately predicted risk 86.6 percent of the time in this study.

"This is a large and unique improvement for patient care. Neither preoperative MRI nor any of the clinical features we have used before even comes close to this level of accuracy," Shariat said.

http://www.aacr.org/

New research from Harvard University neuroscientists has pinpointed exactly how neural activity boosts blood flow to the brain. The finding has important implications for our understanding of common brain imaging techniques such as fMRI, which uses blood flow in the brain as a proxy for neural activity.

The research is described in the June 26 issue of the journal Neuron.

"When you see a brain image from fMRI studies, you are actually looking at changes in blood flow and oxygenation," says Venkatesh N. Murthy, professor of molecular and cellular biology in Harvard's Faculty of Arts and Sciences. "But because of the tight coupling between neural activity and blood flow, we are able to use the blood flow changes as a surrogate for brain activity. A better understanding of exactly how brain activity boosts blood flow should help us better read this process in reverse, which is what we do when interpreting fMRI images."

While it represents only about 5 percent of the human body's mass, the brain consumes 20 percent of the oxygen carried in its blood. Unlike muscle and other types of tissue, the brain has no internal energy stores, so all its metabolic needs must be met through the continuous flow of blood.

Murthy and colleagues studied mice and found that neurovascular coupling occurs through intermediary cells called astrocytes. By manipulating calcium levels, astrocytes can dilate or constrict blood vessels, depending on whether or not the cells are bound by neurotransmitters.

When a region of the brain becomes active, neurotransmitters begin to trickle out of that area's neural circuitry. The most common of these neurotransmitters in the mammalian brain, glutamate, is widely released at synapses and binds to astrocytes as well as to postsynaptic receptors. Murthy's group found that after binding glutamate, astrocytes elevate their intracellular calcium levels, dilating blood vessels and increasing blood flow to that region of the nervous system.

Murthy and colleagues studied this process in the olfactory bulb, which processes odors.

"When a mouse encounters a scent, discrete loci in its olfactory bulb are activated, which in turn increases blood flow in those spots," Murthy says. "We measured all this using sophisticated optical microscopy, actually counting the number and rate of red blood cells passing through capillaries in the area. In addition to showing directly that astrocytes are involved in neurovascular coupling, we discovered that there are multiple molecular signaling pathways involved."

The new research by Murthy and colleagues lays the groundwork for further study of how this exquisite neurovascular coupling may go awry in neurodegenerative diseases, such as Alzheimer's disease, as well as in the normally aging brain. A growing body of evidence suggests that as people age -- and especially with the onset of neurodegenerative disease -- neurovascular coupling can be impaired. It's still unknown whether this impairment can add to the cognitive defects associated with both healthy and diseased aging.

http://www.harvard.edu/

People who have never smoked but whose cells cannot efficiently repair environmental insults to DNA are at higher risk of developing lung cancer than those with effective genomic repair capability, according to researchers from the Department of Epidemiology at The University of Texas M. D. Anderson Cancer Center.

"About 15 percent of lung cancers occur in lifetime never smokers. Risk factors for lung cancer in people who have never smoked are poorly understood, but this study demonstrates that poor DNA repair capacity is an important predictor of lung cancer risk in never smokers," said the study's lead author, Olga Gorlova, Ph.D., an assistant professor in the Department of Epidemiology.

In the June issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research, the researchers say that, overall, nonsmokers with suboptimal DNA repair capacity (DRC) are almost twice as likely to develop lung cancer, compared with nonsmokers with normal DRC. Study participants with the lowest ability to repair their DNA had a more than a threefold increased risk, compared with individuals with efficient DRC.

Secondhand smoke exposure is another established risk factor; in participants with inefficient DRC who also reported such exposure, the risk of lung cancer was almost fourfold.

Although the research team has not pinpointed the gene or genes that cause suboptimal DRC, their data suggest that the trait is heritable to some degree. Notably they found that first-degree relatives of those with lowest DRC were 2.5 times more likely to develop lung cancer than were first-degree relatives of people with efficient DRC.

"Our findings demonstrate that suboptimal DNA repair capacity together with secondhand smoke exposure are strong lung cancer risk factors in lifetime never smokers," Gorlova said.

This is the first study that has looked at functional DNA repair capacity as a risk factor for lung cancer in nonsmokers. Researchers drew white blood cells from 219 lung cancer patients and 309 matched control participants, all of whom had never smoked. They used the cells to conduct a host-cell reactivation assay, a complicated test that introduced a specific carcinogen, benzo[a]pyrene diol epoxide (BPDE) into the cells. BPDE is a hydrocarbon found in smoke of all kinds (tobacco, wood, etc.) that is highly carcinogenic and mutagenic, capable of changing the composition of DNA.

The study is a continuation of research underway at M. D. Anderson that is looking for genetic and epigenetic components to lung cancer risk. The research group has previously shown that DNA repair capacity as measured by the host cell reactivation assay was significantly lower in lung cancer patients who were current or former smokers than in matched controls.

"Many people think they aren't at risk for lung cancer because they don't smoke, but anyone who has non-smoking relatives with lung cancer should avoid not just tobacco smoke, but all the other carcinogens and mutagens that are products of combustion," Gorlova said.

http://www.aacr.org/

Morbidly obese patients who undergo a particular type of gastric bypass surgery called Roux-en-Y gastric bypass (RYGB) are at an increased risk of developing kidney stones - small, pebble-like deposits that can result in severe pain and require an operation to remove them - earlier than previously thought. These stones develop in patients within only a few months following the procedure rather than several months to years, according to research published in the June issue of the Journal of the American College of Surgeons.

"Our data suggests that RYGB is associated with an increased risk of forming kidney stones as early as three months post-operation," according to the study's lead investigator, Manoj Monga, MD, FACS, Professor of Urologic Surgery, University of Minnesota, Minneapolis. "We hope our findings and subsequent research will eventually allow clinicians to more accurately counsel patients on their individual risk of kidney stones and develop strategies for the prevention of this sometimes painful condition, such as dietary modification and medical therapy."

RYGB is the most commonly performed surgical intervention for morbid obesity. During the procedure, a small pouch is created by stapling part of the stomach together or by banding the stomach, limiting the amount of food a patient can eat. Next, a Y-shaped section of the small intestine is attached to the pouch to allow food to bypass the first part of the intestines. This process causes reduced calorie and nutrient absorption. Although RYGB is a safe and effective treatment for morbid obesity, nephrolithiasis (the formation of kidney stones) has recently raised concerns among patients undergoing RYGB.

"Although this study demonstrates that there is a higher risk for developing kidney stones, it is important to weigh the risk against the many benefits that RYGB has for the morbidly obese patient, including decreasing cardiac morbidity and improving diabetes," Dr. Monga added.

Surgeons conducted a prospective, longitudinal study of 24 morbidly obese adults (9 men and 15 women) from a university-based bariatric surgery clinic scheduled to undergo RYGB between December 2005 and April 2007. Five patients had a history of nephrolithiasis. Patients provided 24-hour urine collections for analysis seven days before and 90 days after operation. The primary endpoints were change in the amount of the compound oxalate in the urine and the relative supersaturation of calcium oxalate (that is, whether the urine contained more calcium oxalate than could normally be dissolved, potentially leading to crystallization) from baseline to three months post-RYGB. Both of these factors have been demonstrated by earlier studies to be major risk factors for the development of kidney stones.

Significant increases were noted in urinary oxalate excretion (31 ? 10 mg/d versus 41 ? 18 mg/d; p=0.026) and relative supersaturation of calcium oxalate (1.73 ? 0.81 versus 3.47 ? 2.59; p=0.030) at only three months post-RYGB. Six patients (25%) developed de novo hyperoxaluria, with oxalate excretion increasing from 26? 12 mg/d to 63 ? 12 mg/d (p =0.0046) There were no preoperative patient characteristics predictive of increased risk of kidney stone formation.

The reason for increased likelihood of the development of kidney stones following this type of gastric bypass surgery is not entirely understood. A possibility is that the anatomic rearrangement caused by the operation establishes a mildly malabsorptive state, which may be responsible for the increase in the excretion of urinary electrolytes. Kidney stones could also result from an alteration in the gut microflora (normal bacteria) caused by the procedure.

http://www.facs.org

The pressures from an ageing population on the rising costs of healthcare in Australia will be the subject of the third annual Menzies Oration to be held at The Australian National University tonight.

Mr Gary Banks AO, Chairman of the Productivity Commission, will discuss the escalating budgetary pressures governments face from the increase in healthcare demand and costs at the public lecture to be held in the Finkel Lecture theatre at 5pm.

Mr Banks will suggest there is potential to raise productivity and reduce costs through policy initiatives in a number of areas of healthcare. A more cost-effective health system, rather than merely cost containment, must be the objective, he will argue.

The annual Menzies Oration aims to encourage open public debate on key health policy issues in Australia. It is presented by The Menzies Centre for Health Policy and Practice, a collaborative undertaking between The Australian National University and the University of Sydney.

The Centre was established in 2006 by a grant from the Sir Robert Menzies Memorial Foundation and aims to provide Australians with a better understanding of their health system and what it provides.

"Our aim is to bring independent, informed and balanced debate into Australia's health policy," says Co-Director of the Centre and Executive Director of ANU College of Medicine and Health Sciences Mr Robert Wells.

"We provide information to Australians about how they can influence health policy to ensure that it is consistent with their values and priorities and is able to deliver safe, high quality health care that is sustainable in the long term," he said.

http://www.anu.edu.au