New Blood Test Greatly Reduces False-positives In Prostate Cancer Screening

ScienceDaily (May 28, 2009) — A new blood test used in combination with a conventional prostate-specific antigen (PSA) screening sharply increases the accuracy of prostate cancer diagnosis, and could eliminate tens of thousands of unneeded, painful, and costly prostate biopsies annually, according to a study led by researchers at Dana-Farber Cancer Institute.

At the annual meeting of the American Society of Clinical Oncology in Orlando, Fla., William K. Oh, M.D., and Robert W. Ross, M.D., will report that the six-gene molecular diagnostic test, when combined with a PSA test, accurately detected prostate cancer more than 90 percent of the time. Earlier studies suggest that the conventional PSA test is 60-70 percent accurate in detecting cancer. The findings will be discussed at a poster session on May 31.

Men who are found to have elevated levels of PSA in routine screening tests are often referred for a biopsy of the gland to check for tumors. Nearly two-thirds of biopsies performed -- a painful procedure with some risk of complications -- do not find any cancerous cells. This high rate of "false positive" PSA test results underscores the need for a more accurate method for detecting prostate cancer, said Oh, who is the clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The two-year study involved 484 participants. The group comprised 204 men with known prostate cancer, 110 men with benign prostatic hypertrophy (BPH), and 170 healthy men in a control group. (BPH can elevate PSA levels in the blood, which often leads to a biopsy to rule out prostate cancer.) These groups were split into age-matched training and validation sets.

The researchers sought to measure the accuracy of a six-gene whole blood RNA transcript-based diagnostic test developed by Source MDx in Boulder, Colo., both in terms of its sensitivity (the ability to detect prostate cancer) and specificity (the ability to identify people who don't have prostate cancer).

Source MDx researchers developed the test after initially working with a set of 174 candidate genes whose activity was compared in the different study groups. They narrowed the pool down to just six genes that, as a group, were highly sensitive in predicting which patients had prostate cancer and which were normal.

The study found that "the six-gene model was more accurate than PSA alone at predicting cancer if you had it and no cancer if you didn't," said Oh. The test's accuracy improved even more when PSA measurements were added. Combined, the two tests achieved a diagnostic accuracy of more than 90 percent in specificity and sensitivity and eliminated most of the false-positives yielded by the PSA test.

Based on these findings, the researchers are planning to conduct a larger, multicenter clinical trial involving approximately 1,000 men to determine if the findings remain valid.

"These findings are very encouraging and suggest that this new test could spare tens of thousands of men from undergoing an unnecessary biopsy," Oh said. "However, until we can verify our findings, it is important to recognize that the PSA test, despite its limitations, is still the best test available for diagnosing prostate cancer at this time."

The study was funded in part by Source MDx and a Prostate Cancer SPORE grant at Dana-Farber/Harvard Cancer Center.

Carbohydrate Restriction May Slow Prostate Tumor Growth

ScienceDaily (May 26, 2009) — Restricting carbohydrates, regardless of weight loss, appears to slow the growth of prostate tumors, according to an animal study being published this week by researchers in the Duke Prostate Center.

"Previous work here and elsewhere has shown that a diet light in carbohydrates could slow tumor growth, but the animals in those studies also lost weight, and because we know that weight loss can restrict the amount of energy feeding tumors, we weren't able to tell just how big an impact the pure carbohydrate restriction was having, until now," said Stephen Freedland, M.D., a urologist in the Duke Prostate Center and lead investigator on this study.

The researchers believe that insulin and insulin-like growth factor contribute to the growth and proliferation of prostate cancer, and that a diet devoid of carbohydrates lowers serum insulin levels in the bodies of the mice, thereby slowing tumor growth, Freedland said.

Animals in the study were fed one of three diets: a very high fat/ no carbohydrate diet; a low-fat/ high carbohydrate diet; and a high fat/ moderate-carbohydrate diet, which is most similar to the "Western" diet most Americans eat, Freedland said. They were then injected with prostate tumors at the same time.

"The mice that were fed a no-carbohydrate diet experienced a 40 to 50 percent prolonged survival over the other mice," Freedland said.

Mice on the no-carbohydrate diet consumed more calories in order to keep body weights consistent with mice on the other study arms.

"We found that carbohydrate restriction without energy restriction – or weight loss – does indeed result in tumor growth delay," he said.

The researchers plan to begin recruiting patients at two sites – Duke and the University of California – Los Angeles – for a clinical trial to determine if restricting carbohydrate intake in patients with prostate cancer can similarly slow tumor growth. The trial should begin within a few weeks.

"It's very exciting – this is a potential new mechanism to fight prostate cancer growth and help patients live longer with their disease," Freedland said.

The findings appear in the May 26, 2009 online edition of the journal Cancer Prevention Research. Funding was provided by the United States Department of Veterans Affairs, the Department of Defense Prostate Cancer Research Program; the American Urological Association/ Foundation Astellas Rising Star in Urology Award, and the Robert C. Atkins Foundation. The Atkins Foundation supported this study but had no additional input or influence on the results.

Other researchers involved in this study include John Mavropoulos, William Buschmeyer, Alok Tewari, Dmitriy Rohkfeld, Phillip Febbo, Gayathri Devi, Eric Westman, Bercedis Peterson and Salvatore Pizzo of Duke; Michael Pollak and Yunhua Zhao of McGill University; Pinchas Cohen and David Hwang of UCLA and Wendy Demark-Wahnefried of the University of Texas – M.D. Anderson Cancer Center.

Protein That Suppresses Androgen Receptors Could Improve Prostate Cancer Diagnosis, Treatment

ScienceDaily (May 20, 2009) — A protein that helps regulate expression of androgen receptors could prove a new focal point for staging and treating testosterone-fueled prostate cancer, Medical College of Georgia researchers say.

Levels of the protein, βarrestin2, are lower in some prostate cancer cells than in normal prostate cells while expression of testosterone-fed androgen receptors is higher, they recently reported in Proceedings of the National Academy of Sciences Online Early Edition.

"An increase in the number of androgen receptors is believed responsible for prostate cancer progression in men with advanced disease," says the study's corresponding author, Dr. Yehia Daaka, Distinguished Chair in Oncologic Pathology in the MCG School of Medicine.

With increased numbers of androgen receptors, prostate cancer can make use of the limited testosterone available after a diseased prostate gland is removed or after testosterone production is blocked by drug therapy. In fact, the increased number of androgen receptors may mutate so they can start feeding off other steroids or even growth factors, Dr. Daaka says.

These wily skills help explain why cancer returns despite initially promising treatment results.

"It is clear that signaling by the androgen receptor is paramount for not only the initiation but also the progression of the disease, including escape to a hormone-refractory disease," he says. Moves androgen receptors make to support cancer growth make it "unbeatable at this point," for some patients.

However increased levels of βarrestin2 appear to halt the potentially deadly increase in androgen receptor expression, the MCG research team has found.

Androgen receptors have co-factors that can activate or repress their activity. "You could make the leap and say perhaps prostate cancer initiation and progression may be regulated by expression or non-expression of these co-factors," says Dr. Daaka, a Georgia Cancer Coalition Distinguished Cancer Scholar.

Their studies in human tissue – both in culture and transplanted into mice – show this appears the case for βarrestin2. First the team identified βarrestin2 as cofactor for androgen receptors. Next they found a reciprocal relationship: androgen receptor expression is low when βarrestin2 expression increases. That's the scenario in healthy prostate cells while the exact opposite is true in some prostate cancer. When they forced increased expression of βarrestin2, androgen receptor expression and activity went down.

βarrestin2 locks up an androgen receptor by binding to it, then the pair bind to yet another protein, ubiquitin ligase, which tags the receptor as waste and the trio make their way to the cell's garbage dump. "The neat thing about it is βarrestin2 inhibits or blunts the androgen receptor by promoting its degradation. So it disappears," Dr. Daaka says.

His future studies include determining what happens when βarrestin2 expression is further decreased in the face of prostate cancer. These studies will also help determine how big a player βarrestin2 is in prostate cancer progression, says Dr. Daaka, noting that numerous other corepressors and activators of androgen receptors are known.

Since all the happenings occur inside prostate cells, the findings don't point toward a new blood or urine test for prostate cancer but could lead to new ways to stage prostate cancer from the first biopsy. In fact, Dr. Daaka and his team already are collecting samples from patients whose cancer has been staged to see if specific levels of βarrestin2 expression correlate with different stages of disease.

Another goal is to develop a small molecule that can get inside a patient's cell and mimic βarrestin2's ability to suppress androgen receptor expression and so restore healthy levels found in prostate cells.

Prostate cancer falls behind skin cancer as the second most common cancer in men and more than 192,000 new cases will be diagnosed this year in the United States, according to the American Cancer Society.

Collaborators include Dr. Vijayabaskar Lakshmikanthan, postdoctoral fellow; Dr. Lin Zou, former postdoctoral fellow; Jae Kim, graduate student; Dr. Nidia C. Messias, assistant professor; and Dr. Zhongzhen Nie, assistant professor; from the MCG Department of Pathology; and Drs. Allison Michal and Jeffrey L. Benovic from Thomas Jefferson University.

Quick Test For Prostate Cancer

ScienceDaily (May 18, 2009) — A new 3-minute test could help in diagnosing prostate cancer, the most common cancer in men in the UK, according to scientists.

Researchers have developed the test by using light energy to measure the level of citrate in fluid samples from the prostate gland. The technique could provide the basis of a rapid means of detecting prostate cancer in the future. Almost a quarter of male cancers in the UK are diagnosed as prostate cancer and more than 10,000 men die from the disease each year.

Scientists, led by Prof David Parker from Durham University's Chemistry Department, have worked with experts from the University of Maryland, USA to develop the technique that measures the wavelength of light as it is shone through diluted samples of body fluids.

The research team, funded by the North East Proof of Concept Fund and the EPSRC, believe that the technique which can measure, with speed and accuracy, how citrate levels fall in the prostate gland as cancer develops, could also find use for the diagnosis of other medical conditions, associated with poor kidney function.

Prof Parker said: "Citrate provides a significant biomarker for disease that may provide a reliable method for screening and detecting prostate cancer, and for the monitoring of people with the disease. This technique could form the basis of a simple screening procedure for prostate cancer that could be used in outpatient departments at local hospitals."

His team have shone light into over 100 different chemical structures to see how they function and respond to the presence of certain important bioactive species. They have looked particularly closely at how citrate and lactate bind to luminescent structures within fluids.

Citrate and lactate are vital for our bodies' metabolism for normal function. Citrate provides energy for cells and the amount found in the prostate varies considerably due to an enzyme called m-aconitase which transforms it. This enzyme is very sensitive to zinc and, in prostate cancer sufferers, zinc levels are depressed and the enzyme switches on again.

Prof Leslie Costello from the University of Maryland said: "Citrate is formed in cell metabolism processes which alter as cancers grow. The analysis of the citrate concentration of prostatic fluid can provide an accurate way to screen and diagnose prostate cancer.

Since citrate concentrations decrease markedly early in malignancy, this technique makes it possible to analyse what's happening quickly in the early and treatable stage of prostate cancer. It shows much promise as a clinical tool."

The new test requires only a microlitre of fluid and the sample can be easily measured in an optical instrument. Using samples from male volunteers, the researchers have developed a portable instrument that can give results in 3 minutes.

The team's challenge has been how to accurately measure changes in the amount of citrate or lactate in fluid samples using the technique. The early results are promising and the team intends to look at the analysis of other body fluids. A possible way forward is to examine the citrate levels in seminal fluid samples, which are made up of 50% prostate fluid.

The University has launched a spin-out company called FScan Ltd to develop the technique and to seek commercial backing. The team has looked at 20 samples so far and verified the analysis in every case. The next stage is to work with a local hospital and examine samples from 200 volunteers to see whether the first Durham results correlate.

Prof Parker says: "It's been a complex process to develop the technique but we're very optimistic about it. Ultimately, this could provide an accurate method of screening for prostate cancer in men that could be carried out in 3-minutes once a biopsy has been obtained from the patient at a hospital outpatient department."

The discovery follows the invention in 2006 by Durham University Professor Douglas Newton of a Urine Flow Meter. The UFlow Meter helps men to assess if they have a restricted rate of urine flow - one of the warning signs of prostate problems.

The establishment of FScan Ltd is part of the University's aim to enhance the exploitation of the Intellectual Property generated by high quality research activities.

Tim Hammond, Head of Technology Transfer at Durham University, said: '"We quickly realised the potential of this research and have worked closely with Professor Parker and his team to secure initial proof of concept funding through NorthStar Equity Investors and the North East Proof of Concept Fund and to establish FScan Limited as the vehicle to validate and commercialise the technology."


Process for testing:

• Sample of prostatic fluid taken from patient in hospital using local anaesthetic 200 fold dilution of 1 microlitre of sample with a buffer solution into pre-coated disposable cuvettes.
• Optical spectroscopy on the sample, using a versatile bench top instrument with easy to use software.
• Reading of results after 3 min measurement cycle directly reading out actual citrate concentration.
• The sample is taken from the prostate gland – this is part of the biopsy procedure during clinical analysis in urology.

Molecular Pathway Behind Invasive Prostate Cancers

ScienceDaily (May 18, 2009) — University of Cincinnati (UC) cancer and cell biologists have identified a new molecular pathway key to the development of invasive prostate cancers.

In a preclinical study led by Maria Diaz-Meco, PhD, the UC team found that simultaneous inactivation of two particular genes—known as PTEN and Par-4—caused the rapid development of invasive prostate cancer tumors in mice.

"We knew that independent mutations in either of these genes could result in benign tumors, but when those changes occur simultaneously it appears to have a synergistic effect that causes prostate cancer," explains Diaz-Meco, an associate professor of cancer and cell biology at UC and corresponding author of the paper. "This switch affects the cell's ability to both grow and survive, leading to more aggressive and invasive tumors."

"This is an important discovery because—until now—those signaling pathways were not clearly defined. Without a clear molecular target, it's impossible to develop effective drugs to treat this disease without causing harm to the patient," she adds.

Diaz-Meco and her team report their findings online ahead of print in Proceedings of National Academy of Sciences (PNAS) the week of May 18.

PTEN is a well-defined gene shown to be suppressed in prostate cancer tumors, as well as in other types of cancer. Its mutation has been shown to result in the formation of benign tumors. Par-4 gene is also mutated in prostate cancer, but this study is the first to report its relationship with PTEN mutations and aggressive prostate cancer tumor development.

The UC study was done in a laboratory mouse model over the course of two years. Data from the mouse model was correlated and compared to human prostate cancer tissue samples to determine if their findings were applicable in humans as well.

"Theoretically, this new knowledge could be used to better categorize a tumor's aggressiveness by measuring the levels of PTEN and Par-4 expressed in a tissue biopsy," adds Diaz-Meco. "That would help clinicians make tough decisions about how aggressively to treat a patient's prostate cancer and minimize unnecessary treatment."

Cancer and cell biologists are working on identifying the molecular targets involved in cancer progression to develop a better understand the mechanisms of action that lead to prostate cancer so that pharmaceutical companies and clinicians can develop better methods of diagnosing and treating the disease.

Funding for this study comes from the National Cancer Institute and National Institutes of Health. Coauthors of the study include UC's Shadi Abu-Baker, Jayashree Joshi, Anita Galvez, Elias Castilla, and Jorge Moscat, PhD. Spanish National Cancer Research Center's scientists Pablo Fernandez-Marcos, Marta Canamero, Manuel Collado, Gema Moreno-Bueno and Manuel Serrano and Carmen Saez of the Biotechnology Centre of Oslo in Norway also contributed to the study.

Men With Prostate Cancer Worry Less About Recurrence Than Their Spouses Do

Researchers at The Mount Sinai Medical Center in New York have found that, when it comes to worrying about the recurrence of prostate cancer, male patients worry less than their female spouses or partners. The study was presented at the 30th annual meeting of the Society of Behavioral Medicine in Montreal.

In a study of 96 men and their spouses or partners, Michael Diefenbach, Ph.D., Associate Professor of Urology and Oncological Sciences at Mount Sinai School of Medicine, found that, at the time of prostate cancer diagnosis, the male patients described themselves as "moderately worried" about the chance of their disease recurring, while their female spouses and partners described themselves as "very much" worried.

"We know that illness perception and worries about cancer recurrence influence the emotional well-being of patients. But our studies show that this worry is actually a greater stress on spouses and partners. This research can help us develop programs to address the emotional health of the entire family unit," said Dr. Diefenbach.

For both groups, the concern about recurrence decreased over the next 12 months, though it decreased more for the male patients than it did for their spouses and partners.

This led to an even greater disparity after one year than what was observed at the time of diagnosis, with the men describing themselves as "a little bit" worried and their spouses and partners saying they were "moderately worried."

The study also showed that men were less likely to worry about their cancer recurring if they believed that treatment options for their cancer would be effective, while their spouses' and partners' worries were generally unaffected by outside factors.

"For the male patients, the main driver of worry about cancer recurrence was whether they believed that effective treatment was available for their disease," said Dr. Diefenbach.

"But for their spouses and partners it was not possible to determine the main driver of worry, as their response was mainly an emotional one. The one factor we could really measure that affects the level of spouse and partner worry is age in general, the older the spouse or partner, the more concerned they were about cancer recurrence."

Dr. Diefenbach leads a federally funded research program that aims to improve treatment decision making, patient-physician communication and quality of life through innovative patient and family focused programs. He is also the developer of the Prostate Interactive Education System (PIES), a Web tool that helps prostate cancer patients weigh their treatment options.

Source: Mount Sinai Medical Center

Video: Da Vinci Prostatectomy

The following video provides an overview of the radical prostatectomy with the daVinci System from www.intuitivesurgical.com. Dr. J.H. Witt www.pznw.de St. Antonius Hospital Gronau, Germany.

Scientists Find New Way to Identify Deadly Forms of Prostate Cancer

Researchers have discovered a new method to help doctors identify the most aggressive forms of prostate cancer.

A struggle for medical professionals in identifying prostate cancer is determining which forms are very aggressive and will require surgery and which forms are dormant and can be left untreated without risk.

Reporting in the British Journal of Cancer Research, scientists noted that bubbles of fat passed through the urine could provide new clues to deciding how to treat individuals with prostate cancer.

With about 34,000 new cases being found each year, prostate cancer is the most common form of cancer among men in the UK.

Doctors have previously used prostate specific antigen testing to screen patients for prostate cancer.

PSA testing can produce faulty results. Researchers have discovered that fatty capsules, called exosomes, come directly from the tumor and contain genetic information about they cancer.

“We hope that this innovative approach to studying prostate cancer will reveal new biomarkers for aggressive tumors,” said Dr Jonas Nilsson, at the VU University Medical Centre in Amsterdam.

“Tumor-derived RNA is preserved in these capsules and gives us an insight into the genetics of an individual’s tumor.”

But Matthew Shuford, urologist at Baylor University Medical Center at Dallas, said that PSA testing is still effective, and it saves lives.

“Keep in mind that it is only curable when caught early; it can only be caught early by screening; and the screening is a simple blood test that is cheap and easy.”

Approximately 90 percent of all prostate cancers are currently diagnosed at an early stage, according to the National Cancer Institute.

“Early diagnosis greatly increases a man’s chances of successful treatment,” said Dr. Shuford.