Kyoko Sakamoto

Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA

Urine TMPRSS2:ERG gene fusion could be used for stratification of patients at higher risk for prostate cancer. Old Gene Fusion, New Diagnostic Tricks The “PSA test” is a routine test for men over the age of 50 or for those at risk for prostate cancer. It measures the level of prostate-specific antigen (PSA) in the blood, and if that level is above a predefined cutoff, a biopsy is recommended for definitive diagnosis. This test is not perfect; benign conditions, such as an enlarged prostate, can contribute to high levels of PSA, resulting in a “false-positive” and subsequent overdiagnosis and overtreatment. Because of the high prevalence of prostate cancer (it is estimated that nearly 250,000 men will be diagnosed with the disease in 2011), it is clear that a more accurate test for prostate cancer is needed. Here, Tomlins et al. improve on the PSA test by taking a new twist on a known gene fusion, using it to stratify more than 1000 men in two multicenter cohorts based on risk for developing the disease. Recently, it was discovered that the fusion of two genes, the transmembrane protease, serine 2 (TMPRSS2) gene and the v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene, known as TMPRSS2:ERG, is overexpressed in more than 50% of PSA-screened prostate cancers. The protein product of this fusion cannot be detected in serum, so the authors decided to test for the presence of TMPRSS2:ERG mRNA in urine. First, they developed a clinical-grade, transcription-mediated amplification assay for quantifying fusion mRNA—this generated a TMPRSS2:ERG “score.” Urine TMPRSS2:ERG score was linked to the presence of cancer, tumor volume, and clinically significant cancer in patients. Then, the authors combined the TMPRSS2:ERG score with the level of prostate cancer antigen 3 (PCA3) in urine. TMPRSS2:ERG+PCA3 improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator, thus demonstrating clinical utility. Who said you can’t teach an old gene fusion new tricks? By combining the cancer-specific fusion TMPRSS2:ERG score with levels of PSA (in serum) and PCA3 (in urine), Tomlins and colleagues demonstrated more accurate, individualized stratification of men at high risk for developing clinically significant prostate cancer—an important step in streamlining diagnosis and treatment. Moreover, men with extremes of TMPRSS2:ERG+PCA3 had different risks of cancer on biopsy; in combination with other clinicopathological features, urine TMPRSS2:ERG+PCA3 might also inform the urgency of biopsy after PSA screening. More than 1,000,000 men undergo prostate biopsy each year in the United States, most for “elevated” serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.

Effects of pudendal nerve injury in the female rat

To test a neurogenic hypothesis for external urethral sphincter (EUS) dysfunction associated with urinary incontinence, the proximal pudendal nerve was crushed in anesthetized retired breeder female rats (n = 5) and compared with a sham lesion group (n = 4). Outcome measures included concentric needle electromyograms (EMGs) from the target EUS, voiding patterns during a 2‐hour dark period, and micturition data over a 24‐hour period. Fast Blue (FB) was introduced to the crush site at the time of injury and Diamidino Yellow (DY) to the EUS at the time the rats were killed (3 months post‐operative), when histological analysis of the nerve and urethra was also performed. EMG records indicated the EUS motor units undergo typical denervation changes followed by regeneration and recovery. Voiding patterns from the crush group show a significant increase of small urine marks in the front third of the cage. At 1–2 weeks post‐op, the frequency of voids was significantly increased in the crush group compared to pre‐op and late post‐op time periods. The mean volume voided in the light phase at the early post‐op time was significantly increased in the sham group. Light and electron microscopic patterns seen in nerve and muscle suggest the regenerating motor units maintain a structural integrity. Motoneurons in the lower lumbar cord were labeled with either DY (14.5 ± 6.8), FB (31.7 ± 23.7), or both (35.0 ± 17.5) tracers, indicating ∼54% of the crushed pudendal neurons regenerated to the EUS. In conclusion, several measures suggest this reversible crush lesion induces mild urinary incontinence. This animal model is promising for further development of hypotheses regarding neural injury, the pathogenesis of incontinence, and strategies aimed at prevention and treatment. Neurourol. Urodynam. 19:53–69, 2000.

MR Imaging of Scrotal Tumors and Pseudotumors

Magnetic resonance (MR) imaging is an important imaging technique in the evaluation of scrotal masses, providing a useful adjunct to ultrasonography (US). Although US is the modality of choice for initial evaluation of scrotal pathologic conditions because of its wide availability, low cost, and high sensitivity for detection of testicular and paratesticular disease processes, US findings may occasionally be inconclusive. MR imaging may provide additional information in these cases, often affecting patient management. This article reviews and illustrates the MR imaging features of solid extratesticular and intratesticular benign and malignant scrotal tumors, as well as nonneoplastic lesions that can mimic neoplasia. Normal scrotal MR anatomic features and optimal MR imaging technique are also presented.

Comparison of laparoendoscopic single-site and multiport laparoscopic radical and partial nephrectomy: a prospective, nonrandomized study.

OBJECTIVE To prospectively compare outcomes of laparoendoscopic single-site and multiport laparoscopic radical nephrectomy and partial nephrectomy, focusing on postoperative pain and analgesic requirement. METHODS Nonrandomized, prospective comparison of laparoendoscopic single-site and multiport laparoscopic radical nephrectomy and partial nephrectomy. Thirty-four patients underwent laparoendoscopic single-site (17 radical nephrectomy/17 partial nephrectomy); 42 underwent multiport laparoscopy (28 radical nephrectomy/14 partial nephrectomy) from February 2009 to February 2010. Laparoendoscopic single-site transperitoneal access was obtained by periumbilical incision through which all trocars were inserted. Laparoendoscopic radical nephrectomy/partial nephrectomy recapitulated steps of multiport laparoscopic radical nephrectomy/partial nephrectomy. Demographics/tumor characteristics, outcomes, and complications were analyzed. RESULTS Forty-two of 42 multiport laparoscopic and 32/34 laparoendoscopic single-site cases were successfully performed. Mean follow-up was 16.2 months. For laparoendoscopic single-site and multiport laparoscopy groups mean operating room time (min) was 159.3 vs 158.9 (P = .952); mean estimated blood loss (mL) was 175.7 vs 156.1 (P = .553); percent transfused was 2.9% vs 0% (P = .925). No significant differences in complications were noted (P = .745). Significant decrease in analgesic use (6 morphine equivalents vs 11.6, P < .001) and discharge pain score (1.7 vs 2.7, P < .01) were noted in laparoendoscopic single-site vs multiport laparoscopic radical nephrectomy. For laparoendoscopic single-site partial nephrectomy and multiport laparoscopic partial nephrectomy, no significant differences were noted for tumor diameter (1.8 vs 2.0 cm, P = .57), RENAL score (0.962), ischemia time (28.6 vs 27.5 minutes, P = .70), and preoperative (P = .78)/postoperative creatinine (P = .32). For laparoendoscopic single-site radical nephrectomy and multiport laparoscopic radical nephrectomy, no significant differences were noted for mean tumor diameter (5.6 vs 5.3 cm, P = .63), RENAL score (P = .815), and mean operative time (142.3 vs 155.4 minutes P = .13). CONCLUSION In this well-matched, prospective comparison, laparoendoscopic single-site is comparable with multiport laparoscopic surgery in terms of perioperative parameters and may confer benefit with respect to analgesic requirement. Randomized evaluation and longer-term follow-up are necessary.

Clinical and Microbiological Determinants of Infection After Transrectal Prostate Biopsy

BACKGROUND Increasing numbers of infections following transrectal prostate biopsy (TPB) at our hospital led us to investigate clinical and bacterial risk factors to determine if the colonizing rectal Escherichia coli population is the source. METHODS We performed an observational cohort study of men undergoing TPB (1 January 2010-6 February 2014) at the San Diego Veterans Affairs Medical Center. The primary outcome was clinically significant post-TPB infection. Rectal swabs were collected immediately before the biopsy and cultured selectively for fluoroquinolone-resistant gram-negative bacilli. Fluoroquinolone-resistant clinical and rectal E. coli isolates were compared using phylotyping, pulsed-field gel electrophoresis (PFGE) analysis, sequence typing, and virulence gene profiling. RESULTS Rectal colonization with fluoroquinolone-resistant organisms (98% E. coli) was detected in 121 of 764 subjects (15.8%). Post-TPB infection was more common among fluoroquinolone-resistant-colonized subjects than noncolonized subjects (13/121 [10.7%] vs 8/649 [1.2%]; P < .001). Presence of fluoroquinolone-resistant colonizing E. coli was the most significant host characteristic associated with post-TPB infection (odds ratio, 4.5 [95% confidence interval, 1.2-18.2]; P = .03). Escherichia coli infection isolates (n = 18) did not differ from E. coli rectal culture isolates (n = 68) for any of 49 virulence genes or ST131 status (all P > .05). The rectal and clinical isolates of all 9 men with paired isolates had indistinguishable PFGE patterns and identical antimicrobial susceptibility profiles. CONCLUSIONS The rectal colonizing E. coli population is the source for most fluoroquinolone-resistant post-TPB infections, regardless of clonal background or virulence traits. Screening cultures can identify nearly all patients at risk for fluoroquinolone-resistant post-TPB infection.

Gastrointestinal stromal tumor: involvement in urologic patients and recent therapeutic advances.

G stromal tumor (GIST) is a recently described mesenchymal cancer that can arise from any portion of the GI tract, most commonly from the stomach (39%), small intestine (32%), and colorectal regions (15%) (1). These tumors, which were often previously classified as leiomyomas or leiomyosarcomas, can invade the urinary tract, and patients with GIST can develop urologic cancers or other urologic conditions. Urologists should therefore be cognizant of the recent advances in the treatment of GIST with imatinib mesylate (also known as Gleevec or STI571), because they can directly influence patient treatment and prognosis. In addition, the development of this targeted molecular therapeutic agent provides a glimpse into the future of oncology.

ACUTE AND LONG-TERM OUTCOMES OF RADIO FREQUENCY BLADDER NECK SUSPENSION

PURPOSE A new treatment modality for women with stress urinary incontinence secondary to urethral hypermobility is radio frequency bladder neck suspension. Radio frequency energy is a form of electromagnetic energy that is reliable and highly controllable. This thermal therapy can produce well-defined areas of tissue heating. The technology has been used extensively in dermatological and orthopedic surgery for tissue shrinkage and ablation. Radio frequency thermal therapy is now being applied to the endopelvic fascia at the bladder neck and urethra for treating hypermobility in patients with stress urinary incontinence. The purported mechanism is shrinkage of the collagenated tissue that supports the bladder neck and proximal urethra. We report our acute and long-term experience with laparoscopic radio frequency bladder neck suspension for stress urinary incontinence. MATERIALS AND METHODS Enrolled in this prospective multicenter trial were 94 women with a mean age of 48.4 +/- 7.6 years who had urethral hypermobility with an average cotton swab angle change of 41 degrees and Valsalva leak point pressures greater than 90 cm. water at 250 ml. bladder capacity. Detrusor instability was excluded by cystometry. In all cases precisely controlled radio frequency energy was applied to the endopelvic fascia to heat and shrink the tissue. The primary end points were physician assessment of continence, patient reported pad use and the number of patient reported episodes of urinary incontinence daily 1, 3, 6 and 12 months after surgery. RESULTS Average operative time was less than 60 minutes and 98% of the patients were discharged home from the recovery room. Treatment surface area decreased an average of 17% in length and 21% in width. Preoperatively 78% of patients had an average of 1 or more episodes of urinary incontinence daily. At 1, 3, 6 and 12 months there was an average of 1 or fewer episodes of urinary incontinence daily in 84.7%, 85.6%, 85.9% and 77.4% of patients, respectively, and at 12 months 83.5% reported being continent or improved. Preoperatively 41.2% of patients reported using 1 pad or less daily, while at 1, 3, 6 and 12 months 85.6%, 90.4%, 87.2% and 86.9%, respectively, required 1 pad or less daily. Urodynamic evaluation at 12 months showed no leakage during the Valsalva maneuver in 78% of cases. There were no major postoperative complications and the minor complication rate was 5.3%. CONCLUSIONS Early results of thermal treatment of the endopelvic fascia indicate that radio frequency bladder neck suspension is safe and effective for improving stress urinary incontinence in women. The improvement in symptomatology appears to be durable in most patients at the 1-year followup. Longer followup is needed to assess the durability of results and it is currently in progress.

ADULT ONSET NOCTURNAL ENURESIS

PURPOSE We determined the etiology and prognostic significance of adult onset enuresis with absent daytime incontinence. Adult onset nocturnal enuresis unassociated with daytime incontinence is uncommon and there is a paucity of information about its incidence, significance, evaluation and treatment. We present a retrospective evaluation of this condition based on a database review of more than 3,000 consecutive patients referred for the evaluation of lower urinary tract symptoms. MATERIALS AND METHODS A database of 3,277 consecutive patients was searched for adult onset nocturnal enuresis. Patients with daytime incontinence were excluded from study. Evaluation consisted of history, physical examination, American Urological Association symptom score, voiding diary, uroflowmetry, estimation of post-void residual urine, video urodynamics, cystoscopy and radiographic evaluation of the upper tract. RESULTS Of 3,277 patients 8 (0.02%) had adult onset nocturnal enuresis without daytime incontinence as a primary complaint. Average American Urological Association symptom score was 12.6 (range 3 to 25), average maximum urine flow was 8.5 ml. per second (range 5 to 15) and average post-void residual urine volume was 350 ml. (range 50 to 489). All patients were men with severe prostatic or vesical neck obstruction as well as bilateral or unilateral hydronephrosis in 63%, a bladder diverticulum in 38%, vesicoureteral reflux in 50% and low bladder compliance in 50%. Transurethral prostatic resection was recommended to all patients but only 5 agreed. The other 3 cases were managed by alpha-adrenergic antagonists, including 2 by adjunctive clean intermittent self-catheterization. In all patients who underwent transurethral prostatic resection symptoms resolved, as did hydronephrosis when present. CONCLUSIONS Adult onset nocturnal enuresis with absent daytime incontinence is a serious symptom that usually heralds significant urethral obstruction, and a high incidence of bladder diverticulum, hydronephrosis and vesicoureteral reflux. It demands urological investigation and aggressive therapy.

Effects of IGF-I gene therapy on the injured rat pudendal nerve

Abstract Injured nerves and their motor units may undergo enhanced recovery when exposed to recombinant human insulin-like growth factor-I (rhIGF-I). The external anal sphincter muscle in the female rat was denervated to model incontinence. The treatment-group muscle was injected with rhIGF-1 plasmid, whereas in the control group the plasmid lacked the cDNA insert and the normal group received neither surgery nor treatment. Electromyography data at 56 days post surgery indicated more reinnervation without fibrillation potentials in the treatment group (2 of 6) than in the control group (0 of 6). The histology of the regenerated axons in the pudendal nerve distal to the crush site also suggested an improved recovery in the treatment group. The number of motor neurons retrogradely labeled with horseradish peroxidase was decreased by 50% following pudendal nerve crush in both experimental groups compared to the normal group. We conclude from these preliminary results that rhIGF-I gene therapy may improve the distal recovery of structure and function.

Rapid Identification of Rectal Multidrug-resistant Escherichia coli Before Transrectal Prostate Biopsy

OBJECTIVE To develop and evaluate a rapid multiplex-quantitative polymerase chain reaction (qPCR) to identify fecal carriers of multidrug-resistant extraintestinal pathogenic Escherichia coli (MDR-ExPEC) clonal groups. METHODS Men presenting for transrectal prostate biopsy (TPB) at the San Diego Veterans Affairs Medical Center underwent rectal culture immediately before TPB. Rectal swabs were streaked onto ciprofloxacin-supplemented (4 mg/L) MacConkey agar plates, identified, and susceptibility tested. The same swab was sent to the University of Washington for qPCR test (EST200) targeting 2 major MDR-ExPEC clonal groups--ST131 and ST69--that combined were expected to represent majority of fluoroquinolone (FQ)- and trimethoprim-sulfamethoxazole-resistant E coli. We calculate test characteristics including the area under the receiver operative curve (AUC). RESULTS We enrolled 104 men from 11/5/2013 to 6/10/2014. FQ-resistant E coli were cultured from 19.2% (20/104) of rectal swabs, and 26% (27/104) of all swabs were positive for EST200 by PCR. The test characteristics comparing the EST200 to the culture-based detection of FQ resistance were 75%, 86%, 94%, and 56%, respectively. The AUC was 0.84 for the EST200 to detect FQ resistance before TPB. CONCLUSION Compared to the reference standard rectal culture, EST200 was able to detect majority of FQ-resistant E coli on rectal swabs before prostate biopsy.