RESEARCH HIGHLIGHTS

522 NATURE CLINICAL PRACTICE UROLOGY NOVEMBER 2005 VOL 2 NO 11

www.nature.com/clinicalpractice/uro

are at a substantially elevated risk for several cancers, and clinical suspicion for these tumors should be high in this population.

Carol Lovegrove

Original article Swerdlow AJ et al. (2005) Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst 97: 1204–1210

Powerful new markers for invasive bladder cancer

Researchers in the US have demonstrated that bladder cancer patients with inactivated SFRP genes and altered TP53 tumor-suppressor pro-teins are over 30 times more likely to develop the deadly invasive form of the disease.

The SFRP genes encode antagonists of the WNT PATHWAY. Disruption of the WNT and TP53 pathways is thought to be important in the development of an invasive phenotype.

Marsit and colleagues used tumor samples from their population-based bladder cancer case series (n = 355) to investigate the useful-ness of epigenetic silencing of SFRP genes as a diagnostic marker. Methylation-induced gene silencing was evaluated using METHYLATION- SPECIFIC POLYMERASE CHAIN REACTION.

The results showed that SFRP gene methyla-tion was significantly associated with advanced bladder cancer, and that the risk of invasive dis-ease increased with the number of SFRP genes methylated. This group has previously shown, using immunohistochemical staining, that alterations in TP53 protein are also significantly associated with an invasive phenotype. Here, using stratified multivariate logistic analysis, they showed that these effects occur indepen-dently of each other. They also found that SFRP gene methylation was significantly associated with reduced overall patient survival.

The authors conclude that SFRP gene meth-ylation status and TP53 immunohistochemistry could be used together to identify tumors likely to progress to invasive disease.

With the growing interest in DNA-based diagnostic tools for bladder cancer, fur-ther investigation into this promising area is warranted.

Tamsin Osborne

Original article Marsit CJ et al. (2005) Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 65: 7081–7085

A role for death receptors in BCG therapy for bladder cancer?

Intravesical instillation with bacillus Calmette-Guérin (BCG) is an established treatment for superficial bladder cancer and is the most effective prophylaxis for recurrent carcinoma following transurethral resection. Despite this clinical success, the mechanisms behind the antitumor effects of BCG remain unknown.

Death receptors belonging to the tumor necrosis factor superfamily, such as Fas ligand (FasL) and tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) have recently been reported to be involved in tumor apoptosis. In addition, the Fas/FasL pathway has also been shown to be critical for the anti-tumor effects of interleukin 12. Using immuno-fluorescent staining, Mehmut and colleagues examined the expression of FasL and TRAIL in infiltrating leukocytes in bladder cancer, and Fas expression levels in bladder carcinoma cells, before and after BCG treatment.

The number of infiltrating leukocytes increased significantly after BCG instillation compared with pretreatment samples. Within this infil-trate there was a significant increase in CD4+ T cells and macrophages that express FasL and TRAIL, and in FasL-expressing CD8+ T and nat-ural killer cells. In addition, Fas expression was up regulated, and the number of Fas-expressing tumor cells increased after BCG instillation.

These results imply that the enhanced infil-tration of leukocytes that express FasL and/or TRAIL, and the induction of Fas on tumor cells, might play an important role in the therapeutic effect of BCG instillation in the treatment of bladder cancer.

Carol Lovegrove

Original article Mehmut M et al. (2005) Fas ligand and TNF-related apoptosis-inducing ligand induction on infiltrating lymphocytes in bladder carcinoma by bacillus Calmette-Guérin treatment. Urol Int 75: 80–87

Risk of contralateral testicular cancer: to biopsy or not to biopsy?

A large, population-based, cohort study of American testicular cancer patients has recently shown that the risk of developing cancer in the contralateral testis is low and long-term survival

GLOSSARYWNT PATHWAYA signaling pathway of highly conserved WNT proteins that regulate cell-to-cell interactions in embryogenesis and are implicated in cancer

METHYLATION-SPECIFIC POLYMERASE CHAIN REACTIONA technique used to detect CpG methylation in genomic DNA, using sodium-bisulphate-modified DNA as a template, and primers for specific methylated promoters

Nature Publishing Group© 2005

RESEARCH HIGHLIGHTS

NOVEMBER 2005 VOL 2 NO 11 NATURE CLINICAL PRACTICE UROLOGY 523

www.nature.com/clinicalpractice/uro

high, supporting the current US practice of not performing a biopsy on the contralateral testis.

Fosså and colleagues evaluated the risk of developing a METACHRONOUS contralateral tumor in 29,515 testicular cancer patients reported to the National Cancer Institute’s Surveillance, Epidemiology and End Results Program between 1973 and 2001. They found that men with unilateral testicular cancer had a 12.4-fold increased risk of developing a contralateral tumor, compared to the general population. This risk decreased with time from diagnosis of the first tumor, indicating that the increase is not due to radiotherapy. Men with seminoma and those aged under 30 had a significantly higher risk than those with non-seminoma tumors and those aged over 30. The 10-year overall survival rate was 93% for patients with metachronous and 85% for patients with SYNCHRONOUS contra-lateral testicular cancer. Interestingly, develop-ment of a metachronous contralateral tumor did not decrease overall survival.

The authors point to indirect evidence that cisplatin-based chemotherapy might reduce the risk of developing a contralateral tumor, and call for further studies; meanwhile, they reiterate that all men should perform regular self-examination. Testicular ultrasonography or, sometimes, biopsy might be warranted for men at higher risk of developing contralateral tumors, as early detection might allow testis-sparing surgery.

Tamsin Osborne

Original article Fosså SD et al. (2005) Risk of contralateral testicular cancer: a population-based study of 29,515 US men. J Natl Cancer Inst 97: 1056–1066

Vardenafil compared with papaverine in penile Doppler ultrasonography

Penile color Doppler ultrasound is currently considered the ‘gold standard’ for the evalu-ation of erectile dysfunction; however, the technique requires intracavernous injection of vasoactive drugs, such as papaverine, which are associated with adverse effects includ-ing prolonged erection and priapism. Anxiety and pain associated with the injection can also interfere with the sensitivity and specificity of the test. This study aimed to determine whether the oral phosphodiesterase type 5 inhibitor

vardenafil, which has few adverse effects, could be used instead of papaverine.

This study enrolled 24 men with erectile dysfunction aged between 28 and 62 years. Penile color Doppler ultrasound evaluation of cavernous arterial flow parameters was per-formed before and after administration of either papaverine or vardenafil, with genital and audio-visual sexual stimulation, at two separate ses-sions at least 5 days apart. Peak flow velocity had increased significantly by 30 min after oral vardenafil had been taken, reaching a maximum value by 60 min. There was no significant dif-ference in mean peak flow velocity between papaverine injection after 1, 5, 10 and 20 min, compared with oral vardenafil after 30, 45, 60, 75 and 90 min. Whereas 12.5% of patients who received papaverine suffered from prolonged erection requiring pharmacologic interven-tion, no such effects were seen with vardenafil. Around 83% of patients reported injection-related pain, and around 21% reported this to be severe. The most common side effect reported for vardenafil was headache (12.5%).

The authors conclude that penile color Doppler ultrasound with oral vardenafil has promise as a potential noninvasive technique for evaluating erectile dysfunction.

Carol Lovegrove

Original article Ardicoglu A et al. (2005) Effectiveness of vardenafil versus papaverine in penile Doppler ultrasonography. Urol Int 75: 75–79

Randomized controlled trial suggests healthy living could slow progression of prostate cancer

Questions over the wisdom of aggressive treatment for early prostate cancer have led to growing interest in the benefits of diet and exer-cise; however, randomized, controlled trials are lacking. Ornish and colleagues have examined the effects of intensive lifestyle changes on the progression of early prostate cancer by mea-suring serum prostate-specific antigen (PSA), serum-stimulated growth of LNCaP prostate cancer cells, and treatment trends.

They enrolled 93 men with biopsy-proven prostate cancer of Gleason score <7 and serum PSA of 4–10 ng/ml, none of whom had undergone conventional treatment for

GLOSSARYMETACHRONOUSOriginating on separate occasions

SYNCHRONOUSOriginating simultaneously

LNCaPA human prostate cancer cell line used to study the mechanisms and benefits of therapeutic interventions

Nature Publishing Group© 2005