Researchers find better prostate cancer indicators

Identifying alterations in DNA methylation may also be useful in determining cancer progression

Researchers at Mayo Clinic have narrowed the search for effective prostate cancer biomarkers (genetic variations that point to a specific disease or condition), identifying changes in the expression of genes of the whole genome closely correlated to prostate cancer development and progression. They also showed that DNA hypermethylation (DNA modification without changing sequence) plays a significant role in these processes. Results of their study were published in the Feb. 15 issue of Clinical Cancer Research.

"This is good news in an area where our ability to diagnose and predict has previously been less than stellar," said Krishna Donkena, Ph.D., Mayo Clinic urologic researcher. "Our only tool is the PSA test, which has little predictive value. These findings move us much closer to a more accurate test."

The search to identify biomarkers that can be translated into affordable and effective medical tests can be complicated. Prostate cancer causes differential expression of hundreds of different genes, each potentially an indicator of whether a man may get the disease, or already has it. They also may be used to provide information on the development of the cancer, without the need for a painful tumor biopsy.

When seeking to narrow their search to a manageable level, the researchers analyzed 32 cancerous and eight benign patient-tissue samples using genome microarrays representing 33,000 human genes. The information they gleaned from this analysis allowed them to identify 624 differentially-expressed genes between cancerous and benign tissue. They validated these findings in the original 40 tissue samples as well as in 32 additional samples (20 cancerous, 12 benign). The results showed eight genes with significant under-expression and three with significant over-expression, strongly implicating them in prostate cancer development and progression.

Over the years, research has shown that DNA methylation is commonly linked to the development and progression of cancers. This epi-genetic alteration results in silencing or seriously inhibiting gene expression, which in turn lessens the body's ability to defend against cancer. Current research has not done enough to discover ways to convert this information into a useful medical test, in large part due to the limited number of genes that have been thoroughly studied, and their insufficient sensitivity and specificity (probability of getting a true positive or true negative) for prostate cancer detection.

Dr. Donkena's team looked at 62 cancerous and 36 benign tissue samples to assess the degree of methylation in the three previously identified under-expressed genes, comparing two known methylated genes. They determined that one gene, PDLIM4, had hypermethylation that could serve as an effective sensitivity marker, accurately detecting prostate cancer 95 percent of the time. The researchers further determined that the combined measurement of a previously known gene, GSTP1, and PDLIM4 improved the detection rate to 98 percent.

Prostate cancer is the second leading cause of cancer death for men in the United States, exceeded only by lung cancer. The sooner a cancer can be diagnosed, the better treatment outcomes will be, so Dr. Donkena and her colleagues are constantly looking for ways to predict who will get prostate cancer, as well as to find better ways to diagnose early or even prevent this disabling and often fatal disease. "We hope that in addition to being a valuable diagnostic and prognostic tool, our discoveries about these genes will help us develop new treatments for prostate cancer," she said.

Other Mayo researchers involved in this study include Karla Ballman, Ph.D.; Bruce Morlan; John Cheville, M.D.; Roxann Neumann; Michael Lieber, M.D.; Donald Tindall, Ph.D.; and Charles Young, Ph.D.

This research was funded by grants from the National Institutes of Health and is the result of ongoing studies conducted under the auspices of a National Cancer Institute (NCI) SPORE grant -- Specialized Programs of Research Excellence. Mayo Clinic currently is working on projects under six SPORE grants: breast, brain, lymphoma, myeloma, pancreas and prostate cancer.

Gene-Diet Link May Shield Some Men From Prostate Cancer

Men with a common gene variation may be able to reduce their prostate cancer risk simply by altering their diet to include more antioxidants, a new study suggests.

The study of more than 1,000 men found that about 25 percent of them carried the AA gene variant of a specific gene called MnSOD.

"Specifically, we found that men carrying the AA genotype are more susceptible to prostate cancer if their antioxidant levels are low," study leader Dr. Haojie Li, of Brigham and Women`s Hospital in Boston, said in a prepared statement.

"The good news is that if these men get adequate antioxidants from food and possibly from supplements, they seem to be even more likely to benefit from the nutrients` cancer fighting properties than other men," Li said.

In men with the AA gene variant, increased levels of selenium, vitamin E and the tomato pigment lycopene greatly reduced prostate cancer risk, the researchers report in the current issue of Cancer Research.

The effect was weak in men who carried other variants (VV or VA) of the MnSOD gene, however.

Previous research in breast cancer has linked similar interactions between variations in the MnSOD gene and dietary antioxidant.

"Our findings suggest that certain individuals are more sensitive to antioxidant status," Li said.

Going with the flow

Prostate vaporization is:

A. the subject of a lost "Star Trek" episode featuring an ill-fated Scotty

B. in some countries, the punishment for leaving the toilet seat up

C. a legitimate medical procedure - you hope

Yes, despite the sinister-sounding name, prostate vaporization is an actual procedure. In fact, if you're a man who's having a little trouble "going with the flow," it might be right up your alley.

Used by urologists to treat enlarged prostates, the vaporization technique is accomplished with a system known as GreenLight PVP, which uses a laser to zap prostate tissue that is blocking urine flow. This clears a path for a normal stream and provides fast relief of symptoms and little postoperative bleeding.

Enlargement of the prostate - a condition known in the medical community as benign prostatic hyperplasia, or BPH - is pretty common and occurs naturally with the aging process. The result of all this growth in some men is a constriction of the urethra - a tube that transports urine out of the body and passes through the prostate and into the bladder.

According to the Mayo Clinic, half of men in their 60s have BPH symptoms; in those over the age of 80, it's about 90 percent. Symptoms of the condition include dribbling after urination, frequent urination (especially at night), a hesitant or weak urine stream, a sudden or urgent need to urinate and the feeling of having a not-quite-empty bladder.

If BPH is left untreated, it could lead to frequent urinary tract infections, a weakened bladder or chronic kidney infections.

Not exactly a pleasant list.

So it's no surprise that Mid-Hudson Urological Associates in Newburgh sees a fair share of enlarged prostates come through the door.

Out of the multitude of surgical treatment options out there for BPH, the minimally invasive GreenLight has become one of the favorites, says Dr. Conrado Tojino Jr. of Mid-Hudson Urological. He's been using the device since last year, and so far, patients have been very pleased with the results. "They have a strong stream, and it's like they're 20-year-olds again," he says.

The gold standard for treating enlarged prostates has been to carve out meddlesome enlarged prostate tissue with a special cutting instrument (during a procedure known as TURP, or transurethral resection of the prostate). Patients can expect to spend a few recovery days in the hospital with a catheter. Despite the improved urine flow and long-lasting results, the invasive surgery can be bloody and involve a six- to eight-week healing period, Tojino says. There is also the risk of side effects such as impotence and incontinence.

The GreenLight, which has been on the market for five years, has proven to be just as effective, delivering high-powered green laser light to literally vaporize prostate tissue. Depending on the size of the prostate - normally the size of a walnut but in many cases enlarged to the size of a plum - the procedure can take from as little as 30 minutes to an hour and a half. The device also cauterizes as it goes along, so there is little to no blood loss during surgery.

The patient has an overnight hospital stay with a catheter and then is on his way, "peeing up a storm," Tojino says.

Besides the benefit of a shorter hospital stay, the procedure doesn't carry the same risk for impotence or incontinence because the laser's energy is more targeted - meaning no risk of injuring the nearby nerve that aids erections or the muscle that helps prevent urine leakage.

Possible side effects following the procedure include burning urination for a couple of weeks and a condition known as retrograde ejaculation - when semen pushes back into the bladder instead of going out through the urethra.

There is also the possibility that in 10-15 years the prostate tissue may grow back. The area can always be retreated, Tojino says.

Unlike the hush-hush world of women's urinary problems, Tojino says most of his patients are pretty open with their issues. "Men at this age are OK with saying, 'Doc, I can't pee. I need some help,'" he says.

Hot chilli peppers a remedy for prostate cancer a study claims

The ingredient in jalapeno peppers, which makes them hot also destroys prostate cancer cells, according to a study.

Tests showed that capsaicin in the peppers triggered 80% of the cells to start to die.

The US research in the journal Cancer Research also found tumours treated with capsaicin diminished and capsaicin was also found to reduce the amount of prostate-specific antigen (PSA), a protein produced by cancer cells.

UK prostate experts agreed that capsaicin could be the basis for a future drug but they cautioned against eating too many hot peppers because of a link with stomach cancer.

In the study at Cedars-Sinai Medical Centre mice genetically modified to have human prostate cancer cells were investigated.

The animals were given a dose of pepper extract that would be equal a man of 200 pounds (90.7kg) taking 400 milligrams of capsaicin three times weekly.

This would be the equivalent of having between three and eight fresh habanera peppers, which are the highest rated peppers for capsicum content.

Dr Soren Lehmann, who led the research, said: "Capsaicin had a profound anti-proliferative effect on human prostate cancer cells in culture.

"It also dramatically slowed the development of prostate tumours."

Chris Hiley, head of policy and research at The Prostate Cancer Charity, said: "This is interesting laboratory-based work on cells but we don't yet know how, if at all, it might help men with prostate cancer.

"Eventually, it may be possible to extract the capsaicin and make it available as a drug treatment," he added.

PSA Velocity and Prostate Cancer Detection: The Absence of Evidence is not the Evidence of Absence

Paul Perrin
Centre Hospitalier Lyon Sud, France

The article by Schröder et al. [1] touches on an important topic and shows evidence that adds to the current confusion about the role of prostatespecific antigen velocity (PSAV) in prostate cancer early detection and screening: in a prescreened population for prostate cancer (second round) once the serum (total) PSA has reached the cut-off value of 4 ng/ml, the PSAV adds no new information about the presence of a cancer. This is disappointing, considering the urgent need to improve the discriminative power of serum total PSA to separate subjects with prostate cancer from those without.

When evaluating this study, its design needs to be kept in mind, since it deals with men who went from a PSA below 4 to a PSA above 4 during the four-year interval between screens in the programme. The conclusion of this article relates ‘‘only’’ to the use of PSAV as an addition to serum total PSA retrospectively once the PSA is above 4 and cannot be generalized to an a priori utilisation of PSAV in a second-round screening.

This article complements a previous report by the same group that highlights the lack of value of PSAV on prescreened men with a PSA below 4 ng/ml [2]. Again the design of the study suffers the same limitations described earlier: selection of the men who had a serum PSA below 4 and remained below 4 during the time of the study and excluding those where PSA rose above 4. A global analysis of the entire population (including men with PSA below and above 4 ng/ml) may give a better view of the place of PSAV in a prescreened population.

There is an increasing body of evidence in favour of the use of PSAV to predict prostate cancer either in symptomatic patients or in the context of screening programmes. Carter et al. [3] were the first to advocate the use of PSAV to distinguish prostate cancer from benign lesions. The use of a PSAV cut-off of 0.1 ng/ml/yr is associated with an OR of 6.53 for men with a PSA between 2 and 4 ng/ml [4]. Berger et al. [5] in a screened population clearly demonstrated that the PSAV differs between cancer and no cancer (0.409 ng/ml versus 0.03 ng/ml). Nadler et al. [6] in men with PSA of 2.6–4 ng/ml noted a significantly greater PSAV in men with cancer (as opposed to those without (0.47 ng/ml versus 0.05 ng/l). Eggener et al. [7], in a study of men with a previous negative biopsy, showed that PSAV is a significant risk factors among others, albeit weak. In a nomogram for predicting a positive repeat biopsy in prostate with previous negative biopsy, Lopez-Corona et al. [8] stressed the impact of PSA slope as a significant risk predictor.

Only the series from Lynn et al. [9] showed that the short-term PSAV alone had the same diagnostic accuracy as the serum PSA level. The absence of evidence is not the evidence of absence [10].

None of these studies prove the diagnostic value of PSAV, but a significant difference of PSAV between prostate cancer and no cancer is a sufficient indication to deserve a study on a population that is representative of the question: Is PSAV better at predicting prostate cancer than a fixed serum total PSA cut-off in early detection or primary or secondary screening?

The amount of benign prostatic hyperplasia in the prostate gland may account for the lack of specificity of total PSA. It is one important reason why the evaluation of PSAV carries so much hope [6]. Even the Schro ¨der group, when analyzing the secondround screening population with the whole range of PSA values included, was able to demonstrate a clear difference in PSAV between prostate cancer and prostate without cancer (0.62 ng/ml/yr versus 0.42 ng/ml/yr) and a modest diagnostic benefit over a PSA cut-off of 3 ng/ml (at a cut-off of 0.02 ng/ml/yr, PSAV will save 12.5% of unnecessary biopsies with a sensitivity of 95%) [11]. Noteworthy is the PSAV of the noncancer population that is among the highest reported in the literature.

To explain the lack of diagnostic value of PSAV in their prescreened population, the authors have postulated that the interval between the two rounds may not allow a difference in PSAV to appear in a screened population that has already been cleared from some prostate cancer with PSA above 4 ng/ml in round one. The graph from Berger [5] shows that the slopes take four years to diverge between population with cancer versus the population without cancer. This fact is already mentioned by Carter et al. [3] and Fang et al. [4].

The relationship between the aggressiveness of prostate cancer and PSAV is an important working track at present, especially since D’Amico et al. pointed out an increase risk of death for patients, treated by surgery [12] or radiation [13], with a PSA greater than 2 ng/ml/yr. In addition to its potential better specificity, PSAV may allow earlier detection of men at risk of prostate cancer [14].

In conclusion, the clinical utility of PSAV has not yet been demonstrated. But there is an accumulation of good data that indicates its usefulness. Given the importance of the stakes: improved specificity of the diagnostic test, earlier detection of cancer, definition of aggressive cancer, we can only encourage the pursuit of the quest for evidence.

References
[1] Schröder FH, et al. Does PSA velocity predict prostate cancer in pre-screened populations? Eur Urol 2006;49: 460–5.
[2] Roobol MJ, et al. Prostate-specific antigen velocity at low prostate-specific antigen levels as screening tool for prostate cancer: results of second screening round of ERSPC (ROTTERDAM). Urology 2004;63(2):309–13, discussion 313–5.
[3] Carter HB, et al. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA 1997;277(18):1456–60.
[4] Fang J, et al. PSA velocity for assessing prostate cancer risk in men with PSA levels between 2.0 and 4.0 ng/ml. Urology 2002;59(6):889–93, discussion 893–4.
[5] Berger AP, et al. Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk. Prostate 2005;64(3):240–5.
[6] Nadler RB, et al. Use of 2.6 ng/ml prostate specific antigen prompt for biopsy in men older than 60 years. J Urol 2005;174(6):2154–7, discussion 2157.
[7] Eggener SE, Roehl KA, Catalona WJ. Predictors of subsequent prostate cancer in men with a prostate specific antigen of 2.6 to 4.0 ng/ml and an initially negative biopsy. J Urol 2005;174(2):500–4.
[8] Lopez-Corona E, et al. A nomogram for predicting a positive repeat prostate biopsy in patients with a previous negative biopsy session. J Urol 2003;170(4 Pt 1):1184–8, discussion 1188.
[9] Lynn NN, Collins GN, O’Reilly PH. The short-term prostate-specific antigen velocity before biopsy can be used to predict prostatic histology. BJU Int 2000;85(7): 847–50.
[10] Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995;311(7003):485.
[11] Raaijmakers R, et al. Prostate-specific antigen change in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. Urology 2004;63(2): 316–20.
[12] D’Amico AV, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351(2):125–35.
[13] D’Amico AV, et al. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005;294(4):440–7.
[14] Riffenburgh RH, Amling CL. Use of early PSA velocity to predict eventual abnormal PSA values in men at risk for prostate cancer. Prostate Cancer Prostatic Dis 2003;6(1): 39–44.

Source: European Urology March 2006

Awards for Cardiff prostate cancer team

Cancer researchers at Cardiff University have been recognised for their ground-breaking work into the spread of prostate cancer by the American Society of Clinical Oncology (ASCO) the world's largest oncology society.

The Metastasis and Angiogenesis Research Group, concerned with how and why cancer spreads, in the School of Medicine has received four Investigators Merit Awards at the ASCO Foundation conference on prostate cancer in San Francisco, a unique situation where all four awards came to members of the same research group.

Although this is world class recognition, the awards are tinged by sadness due to the unexpected death of one of the winners, Dr Gaynor Davies, who had developed a hugely respected reputation in the field of prostate cancer research.

The other winners included Mr Azad Howizy, Mr Jo Lewis-Russel and Dr Lin Ye.

Professor Wen G Jiang, of the School's Department of Surgery, who oversaw the research said, "We are delighted with this well deserved success for some very eminent young researchers but the loss of Gaynor has taken some of the sheen off the awards. Our thoughts are very much with Gaynor's family at this time."

Cancer Research Wales, which has a keen interest in prostate cancer, provided the funding for this work.