Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer.

A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.

Exposure of treating physician to radiation during prostate brachytherapy using iodine-125 seeds: dose measurements on both hands with thermoluminescence dosimeters.

BACKGROUND AND PURPOSE: Only sparse reports have been made about radiation exposure of the treating physician during prostate seed implantation. Therefore, thermoluminescence dosimeter (TLD) measurements on the index fingers and the backs of both hands were conducted. MATERIAL AND METHODS: Stranded iodine-125 seeds with a mean apparent activity of 27.4 MBq per seed were used. During application, the treating physician manipulated the loaded needle with the index fingers, partially under fluoroscopic control. Four physicians with varying experience treated 24 patients. The radiation exposure was determined with TLD-100 chips attached to the index fingertips and the backs of hands. Radiation exposure was correlated with the physician's experience. RESULTS: The average brachytherapy duration by the most experienced physician was 19.2 min (standard deviation sigma = 1.2 min; novices: 34.8 min [sigma = 10.2 min]). The mean activity was 1,703 MBq (sigma = 123 MBq), applied with 16.3 needles (sigma = 2.5 needles; novices: 1,469 MBq [sigma = 229 MBq]; 16.8 needles [sigma = 2.3 needles]). The exposure of the finger of the "active hand" and the back of the hand amounted to 1.31 mSv (sigma = 0.54 mSv) and 0.61 mSv (sigma = 0.23 mSv), respectively (novices: 2.07 mSv [sigma = 0.86 mSv] and 1.05 mSv [sigma = 0.53 mSv]). CONCLUSION: If no other radiation exposure needs to be considered, an experienced physician can perform about 400 applications per year without exceeding the limit of 500 mSv/year; for novices, the corresponding figure is about 200.

Simulation of stress urinary incontinence for in-vitro studies.

A simulation system that generates dynamic bladder pressures for the use of testing and examining artificial urinary sphincters is designed, implemented, and compared to in-vivo measurements of Valsalva and coughing profiles. Cylinder and piston, which are integrated into the universal testing machine, simulating the bladder are connected with explanted sow urethras. The AMS 800 artificial urinary sphincter closes the urethra with well-defined external pressures. In order to select appropriate profiles for the bladder pressure, 34 Valsalva and coughing profiles of 6 patients were evaluated with respect to amplitude, pressure raise, dwell time, and half width.

Optimization of the artificial urinary sphincter: modelling and experimental validation.

The artificial urinary sphincter should be long enough to prevent strangulation effects of the urethral tissue and short enough to avoid the improper dissection of the surrounding tissue. To optimize the sphincter length, the empirical three-parameter urethra compression model is proposed based on the mechanical properties of the urethra: wall pressure, tissue response rim force and sphincter periphery length. In vitro studies using explanted animal or human urethras and different artificial sphincters demonstrate its applicability. The pressure of the sphincter to close the urethra is shown to be a linear function of the bladder pressure. The force to close the urethra depends on the sphincter length linearly. Human urethras display the same dependences as the urethras of pig, dog, sheep and calf. Quantitatively, however, sow urethras resemble best the human ones. For the human urethras, the mean wall pressure corresponds to (-12.6 +/- 0.9) cmH2O and (-8.7 +/- 1.1) cmH2O, the rim length to (3.0 +/- 0.3) mm and (5.1 +/- 0.3) mm and the rim force to (60 +/- 20) mN and (100 +/- 20) mN for urethra opening and closing, respectively. Assuming an intravesical pressure of 40 cmH2O, and an external pressure on the urethra of 60 cmH2O, the model leads to the optimized sphincter length of (17.3 +/- 3.8) mm.

Prostate biopsy in Switzerland: a representative survey on how Swiss urologists do it.

OBJECTIVE: The procedure of prostate biopsy is often performed but has not been standardized. Therefore, a survey of all urologists in Switzerland was carried out to investigate indications, patient preparation and technique with regard to transrectal prostate biopsy. MATERIAL AND METHODS: A questionnaire was mailed to all 178 urologists working in Switzerland, either as self-employed urologists (SEUs) or as employed urologists at a hospital (EUHs), i.e. a teaching centre. RESULTS: The questionnaire was returned by 133 urologists (75%). Eighty-seven of the respondents (65%) are SEUs and 46 (35%) work as EUHs. If digital rectal examination (DRE) raises suspicion of cancer, 129 urologists perform a biopsy. A serum prostate-specific antigen (PSA) level of 4 ng/ml is used as a cut-off value by 84% of respondents (SEUs 83%, EUHs 87%). A fluoroquinolone antibiotic is prescribed by 126 of the respondents. Fifty-nine percent of respondents (SEUs 52%, EUHs 72%) are offering periprostatic injection of a local anaesthetic drug. At the initial biopsy, 24% of respondents (SEUs 30%, EUHs 13%) obtain six cores, 45% (SEUs 37%, EUHs 61%) 8-10 and 17% (SEUs 18%, EUHs 15%) > or =12. The subsequent procedure performed after two negative biopsy sessions varies considerably. CONCLUSIONS: This survey provides an insight into the practice pattern of urologists in Switzerland concerning prostate biopsy. For almost all urologists, a positive DRE is an indication for prostate biopsy. The majority use a serum PSA level of 4 ng/ml as a cut-off value. A fluoroquinolone is the antibiotic of choice. Periprostatic nerve block is the commonest form of anaesthesia. Most urologists take 8-10 cores per biopsy.

Submucosal endocervicosis of the bladder: an ectopic, glandular structure of Müllerian origin.

Endocervicosis of the bladder is a rare, benign variant of endometriosis. The lesions are characterized by ectopic, glandular structures of Müllerian origin with intracytoplasmic mucin production. During placement of a ureteral stent, a cystic tumor in the posterior bladder wall was discovered in a 47-year-old woman with nephroureterolithiasis. CT and MRI revealed a 5 x 1.6 cm(2) mass in the posterior bladder wall protruding into the lumen of the bladder. Urine culture and cytological analyses showed no malignancy. Transurethral biopsy of the tumor confirmed the diagnosis of endocervicosis. Complete transurethral resection was rejected due to the absence of symptoms and the benign condition of the lesion.

Scrotal hysterectomy in a male patient with mixed gonadal dysgenesis 46,XY(75%)/45,X(25%).

We report on a 20-year-old man in whom endocrinological investigation owing to dysmorphic signs characteristic for Turner syndrome revealed mixed gonadal dysgenesis. The patient was referred to us for further diagnostic investigations on a right intrascrotal tumour. Both testes were intrascrotal and hypotrophic with normal testosterone production. Surgical investigation showed a circumscribed tumor that proved to be a rudimentary uterus without evidence of malignancy at histological examination. Biopsies from both tested showed no signs of malignant disease. After removal of the tumor, we decided not to remove the testes prophylactically because of the male phenotype and the sufficient testosterone production.

Sacral magnetic stimulation in non-inflammatory chronic pelvic pain syndrome.

OBJECTIVES: To prospectively evaluate sacral magnetic high-frequency stimulation as a treatment option for patients with non-inflammatory chronic pelvic pain syndrome (CPPS, category IIIB). PATIENTS AND METHODS: Fourteen men with CPPS IIIB were treated with high-frequency sacral magnetic stimulation, with 10 treatment sessions once a week for 30 min at a frequency of 50 Hz. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and quality-of-life index were determined before and after treatment. RESULTS: All patients tolerated the stimulation well and 12 of 14 reported agreeable sensations during stimulation. There were no complications; only one patient did not complete the treatment course. The mean (range) total NIH-CPSI score did not change with treatment, at 27 (18-38) before and 27 (4-40) after treatment. Moreover, there was no sustained effect on the mean scores for pain, micturition complaints or quality of life. CONCLUSIONS: High-frequency sacral magnetic stimulation in patients with CPPS IIIB only reduces pain during stimulation, with no sustained relief of symptoms. Therefore, intermittent sacral magnetic stimulation cannot be recommended as a treatment option for CPPS IIIB.

Chronic scrotal pain syndrome: management among urologists in Switzerland.

INTRODUCTION AND OBJECTIVES: Management of patients presenting with chronic or recurrent pain located in the scrotum is often very challenging. Evidence-based literature and clinical practice guidelines for the management of chronic scrotal pain syndrome (CSPS) are not available. We assessed the current perception and management of chronic scrotal pain syndrome by urologists in Switzerland. METHODS: In July 2004, all the members of the Swiss Society of Urology received a questionnaire focusing on diagnostic and treatment practices for the management of chronic scrotal pain syndrome. The questionnaire consisted of 6 topics concerning practice setting, incidence, aetiology, diagnostics, therapy and treatment success rate. RESULTS: 103 questionnaires were completed (63%). All but 2 (2%) responding Swiss urologists see a mean of 6.5 new patients per month (range 1-30). 79% of Swiss urologists consider CSPS to be infectious or post-infectious in nature. Furthermore, a history of vasectomy, psychosomatic disorders, chronic prostatitis, neuromuscular disorders, a history of inguinal surgery, and idiopathic aetiology were mentioned in decreasing order. The most commonly used examinations are urinalysis in 96% and ultrasound in 93%. Additional assessments include blood sampling, duplex ultrasound, assessment for coexisting chronic prostatitis, and referral to an Orthopaedist, Rheumatologist or Psychiatrist. The predominant medication prescribed for CSPS is a non-steroidal anti-inflammatory agent given for a mean of 15.5 days. An antibiotic trial is prescribed by 82% for a mean of 20.5 days. 74% consider epididymectomy the treatment option of choice in recurrence. Inguinal orchiectomy is performed by 7%, microsurgical spermatic cord denervation is performed by 6% of surgeons. Mean estimated recurrence rate after conservative treatment is 48% and thus higher than after epididymectomy with 18%. CONCLUSIONS: Chronic pain located in the scrotum is a common clinical condition in Switzerland. Most urologists consider an infection or post-infectious alterations as the predominant aetiology for CSPS. Consequently, an antibiotic trial in combination with an anti-inflammatory agent is prescribed as first-line therapy. Recurrence rates for conservative treatment are estimated high which is in contradiction to the presumed aetiology. Therefore, further evaluation of this poorly described disease complex is required.

Botulinum toxin as a new therapy option for voiding disorders: current state of the art.

Botulinum toxin is a presynaptic neuromuscular blocking agent inducing selective and reversible muscle weakness up to several months when injected intramuscularly in minute quantities. Different medical disciplines have discovered the toxin to treat mainly muscular hypercontraction. In urology, indications for botulinum-A toxin have been neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, motor and sensory urge and, more recently, chronic prostatic pain. The available literature was reviewed using Medline Services. The keywords "botulinum-A toxin", "detrusor-sphincter dyssynergia", "neurogenic bladder", "spinal cord injury", "denervation", "chronic prostatic pain", "chronic urinary retention" were used to obtain references. A toxin injection is effective to treat detrusor-sphincter dyssynergia when injected either transurethrally or transperineally. After treatment, external urethral sphincter pressure, voiding pressure and post-void residual volume decreased. The effect lasts between 2 to 9 months depending on the number of injections. Best indications seem to be multiple sclerosis and incomplete spinal cord injury patients suffering from neurogenic detrusor overactivity and detrusor-sphincter dyssynergia. According to the previous results, the use of botulinum-A toxin injections into the external urethral sphincter has been extended to a variety of bladder obstructions and to decrease outlet resistance in patients with acontractile detrusor. In cases of successful treatment, spontaneous voiding re-occurs and catheterization can be resumed. Injections of the toxin into the external urethral sphincter also seem to have a beneficial effect on chronic prostatic pain, presumably by reducing hypertonicity and hyperactivity of the external urethral sphincter. Injections of botulinum-A toxin into the detrusor muscle has first been tested to treat neurogenic detrusor activity in spinal cord injured patients and in myelomeningocele children. Long lasting (mean 9 months) detrusor relaxation occurs after injection of usually 300 units of Botox). Continence is restored in about 95% of the patients and anticholinergic drugs can be markedly reduced or even stopped. Excellent results of botulinum-A toxin injections into the detrusor in neurogenic detrusor overactivity have lead to an expansion of this treatment to incontinence due to idiopathic detrusor overactivity. Although preliminary results are promising, adequate dosage of the toxin required for this indication is not yet known. In conclusion, it appears that botulinum toxin injection into either the external urethral sphincter or the detrusor offers new promising treatment options for many different urological dysfunctions. However, large controlled trials are absolutely required to establish the role of botulinum-A toxin injections in the fields of urology and neurourology on evidence based medicine.