Does previous transurethral prostate surgery affect oncologic and continence outcomes after RARP?

We examined the effect of previous transurethral resection of the prostate (TURP) on multiple oncologic and continence outcomes after robotic-assisted radical prostatectomy (RARP). We performed a retrospective cohort study of a total of 2693 patients from 2007 to 2014 who underwent RARP. Patients were stratified into 49 patients who had previous TURP prior to RARP (group 1) and 2644 patients who had no TURP prior to RARP (group 2). We collected operative variables including estimated blood loss, operative time, and positive surgical margin (PSM) rates. Urinary continence, defined as 0 pads per day (PPD), and social continence, defined as 1-PPD, were also assessed. American Urological Association Symptoms Score (AUASS), overall ability to function sexually, and Expanded Prostate Cancer Index Composite (EPIC) questionnaire were evaluated at 3 and 12 months after RARP. Weakness of urinary stream (EPIC #4d) at 12 months imposed a greater problem for group 1 patients with prior TURP compared to group 2 patients without prior TURP (p = 0.012). PSM was not statistically significant between the two groups (p = 0.110). Group 1 patients had a greater PSM rate (30.61 %) as compared to group 2 (20.95 %). PSM locations in group 1 patients showed the most common locations at the posterior and apex. The difference between the two groups for AUASS, overall sexual function, estimated blood loss, operative time, urinary continence, and social continence was not statistically significant. We examined the effect of previous TURP on postoperative RARP continence and oncologic outcomes. This data can be used to counsel those with prior TURP before RARP.

TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia.

Mechanosensitive ion channels at stereocilia tips mediate mechanoelectrical transduction (MET) in inner ear sensory hair cells. Transmembrane channel-like 1 and 2 (TMC1 and TMC2) are essential for MET and are hypothesized to be components of the MET complex, but evidence for their predicted spatiotemporal localization in stereocilia is lacking. Here, we determine the stereocilia localization of the TMC proteins in mice expressing TMC1-mCherry and TMC2-AcGFP. Functionality of the tagged proteins was verified by transgenic rescue of MET currents and hearing in Tmc1(Δ/Δ);Tmc2(Δ/Δ) mice. TMC1-mCherry and TMC2-AcGFP localize along the length of immature stereocilia. However, as hair cells develop, the two proteins localize predominantly to stereocilia tips. Both TMCs are absent from the tips of the tallest stereocilia, where MET activity is not detectable. This distribution was confirmed for the endogenous proteins by immunofluorescence. These data are consistent with TMC1 and TMC2 being components of the stereocilia MET channel complex.

Functional and oncologic outcomes of graded bladder neck preservation during robot-assisted radical prostatectomy.

PURPOSE: To describe our bladder neck dissection during robot-assisted radical prostatectomy (RARP), to describe the degrees of robot-assisted bladder neck preservation (R-BNP) we have encountered, and to determine the effect of increasing R-BNP on postoperative continence and positive surgical margin (PSM) rates. PATIENTS AND METHODS: We performed a retrospective analysis of 599 patients who underwent robot-assisted radical prostatectomy (RARP) by a single surgeon (DIL). All bladder neck dissections were graded between 1 and 4; higher grades corresponded to an increasing degree of robot-assisted bladder neck preservation (R-BNP). After grouping patients by R-BNP grade, postoperative continence and positive surgical margin (PSM) rates were compared. The association between R-BNP and continence was also assessed using multivariate binary logistic regression models. RESULTS: Similar outcomes were seen for two definitions of continence (0 pads per day [ppd]; 0 ppd or security pad, respectively). A higher proportion of patients were continent at 3 months postoperatively who received grade 4 compared with grade 1 (P=0.043; P=0.001) and grade 2 (P=0.006; P=0.009); and grade 3 compared with grade 1 (P=0.048; P=0.002) and grade 2 (P=0.009; P=0.030) R-BNP. There was no difference between grade 1 and 2 (P=0.541; P=0.064), and grade 3 and 4 (P=0.898; P=0.584) R-BNP. At 1 year postoperatively, there was no difference among the four groups in continence rate (P=0.771; P=0.411). R-BNP was an independent predictor of continence at 3 months (odds ratio [OR] [95% confidence interval (CI)]=1.33 [1.06-1.67]; OR [95% CI]=1.45 [1.1-1.82]), but not at 1 year (OR [95% CI]=1.07 [0.82-1.39]; OR (95% CI)=1.30 [0.92-1.85]). There was no difference among the four groups in PSM rates (P=0.946). CONCLUSIONS: R-BNP is a graded, rather than all-or-none outcome. An increasing degree of R-BNP is associated with an earlier return to continence, without compromising oncologic outcomes.

Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition.

Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO3- into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated hearing loss.

A noncoding point mutation of Zeb1 causes multiple developmental malformations and obesity in Twirler mice.

Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelial cell identity. This developmental pathway is disrupted in inner ears of Tw/Tw mice. The purpose of our study was to comprehensively characterize the Twirler phenotype and to identify the causative mutation. The Tw/+ inner ear phenotype includes irregularities of the semicircular canals, abnormal utricular otoconia, a shortened cochlear duct, and hearing loss, whereas Tw/Tw ears are severely malformed with barely recognizable anatomy. Tw/+ mice have obesity associated with insulin-resistance and have lymphoid organ hypoplasia. We identified a noncoding nucleotide substitution, c.58+181G>A, in the first intron of the Tw allele of Zeb1 (Zeb1(Tw)). A knockin mouse model of c.58+181G>A recapitulated the Tw phenotype, whereas a wild-type knockin control did not, confirming the mutation as pathogenic. c.58+181G>A does not affect splicing but disrupts a predicted site for Myb protein binding, which we confirmed in vitro. In comparison, homozygosity for a targeted deletion of exon 1 of mouse Zeb1, Zeb1(ΔEx1), is associated with a subtle abnormality of the lateral semicircular canal that is different than those in Tw mice. Expression analyses of E13.5 Twirler and Zeb1(ΔEx1) ears confirm that Zeb1(ΔEx1) is a null allele, whereas Zeb1(Tw) RNA is expressed at increased levels in comparison to wild-type Zeb1. We conclude that a noncoding point mutation of Zeb1 acts via a gain-of-function to disrupt regulation of Zeb1(Tw) expression, epithelial-mesenchymal cell fate or interactions, and structural development of the inner ear in Twirler mice. This is a novel mechanism underlying disorders of hearing or balance.

Bladder neck plication stitch: a novel technique during robot-assisted radical prostatectomy to improve recovery of urinary continence.

BACKGROUND AND PURPOSE: Efforts to improve postprostatectomy incontinence have led to many modifications in surgical technique. We present our experience with a novel technique to improve continence outcomes in patients who are undergoing robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: A consecutive series of 159 patients after initiation of a bladder neck plication stitch was compared with the most recent group before the change. After completion of the vesicourethral anastomosis, a single suture was used to plicate the distal bladder neck. A structured questionnaire was used for follow-up. Continence criteria used were 1 pad per day for social continence and 0 pad per day for total continence. RESULTS: A total of 334 patients were included in the study: 159 in the plication stitch group vs 175 in the control group. Average age was 59.1 vs 59.6 years, average body mass index was 27.9 vs 28.3 kg/m(2), and average prostate volume was 58.1 vs 60.9 cc, respectively. The mean time to reach social continence was 3.63±3.01 vs 5.33±4.89 weeks (P=0.004), and total continence was 5.10±3.80 vs 8.49±6.32 weeks (P=0.002), respectively. Chance of total continence improved with the bladder plication stitch: Odds ratio of 1.95±0.72 (P<0.001) at 1 month, 1.25±0.56 (P=0.113) at 3 months, and 2.07±0.66 (P=0.005) at 12 months. There were no bladder neck contractures or other urinary complications noted in either group. CONCLUSIONS: The bladder plication stitch is a simple and effective technical modification for shortening the period of recovery of urinary continence in RARP patients. Randomized controlled trials are under way to further evaluate this technique.

Rectal injury during robot-assisted radical prostatectomy: incidence and management.

PURPOSE: Rectal injury during robot-assisted radical prostatectomy is a rare but significant complication. Since the Clavien grading classification of complications does not include intraoperative injury without further sequelae, rectal injury may be underreported in the literature. We present what is to our knowledge the largest retrospective review to date of rectal injury and subsequent management. MATERIALS AND METHODS: We reviewed the records of 6,650 patients who underwent robot-assisted radical prostatectomy at a total of 6 institutions. Patient characteristics, perioperative parameters, pathological findings and rectal injury management were tabulated and analyzed for intraoperative predictors of outcome and subsequent management. RESULTS: A total of 11 rectal injury cases were identified of the 6,650 robot-assisted radical prostatectomies for a combined 0.17% incidence of rectal injury. Of rectal injuries 72.7% were identified intraoperatively and most did well with primary closure. Delayed recognition injury presented as rectourethral fistula without septic complications and required delayed fistula repair after primary diversion. We found no conclusive association of rectal injury with any patient parameter, intraoperative differences, pathological finding or surgeon experience. Posterior prostate plane dissection, including seminal vesicle dissection, is the crucial stage when rectal injury can occur and be identified. CONCLUSIONS: Our review of the records at 6 centers revealed a combined 0.17% incidence of rectal injury. This compares favorably to the incidence in modern open and laparoscopic radical prostatectomy series. No preoperative, intraoperative or pathological differences correlated with injury. Cases in which rectal injury was identified intraoperatively required fewer surgical repeat interventions but ultimately each group had acceptable long-term urinary and bowel function results.

Pelvic anatomy on preoperative magnetic resonance imaging can predict early continence after robot-assisted radical prostatectomy.

BACKGROUND AND PURPOSE: Postoperative incontinence is multifactorial after radical prostatectomy. Using endorectal coil MRI, we examined features of the male urethra and accompanying muscular sphincter to predict continence after robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: 80 patients underwent preoperative 1.5 Tesla endorectal coil MRI. Urethral length was measured in the coronal plane. All patients underwent RARP. Questionnaires were completed by patients at monthly intervals. The primary end point was time to continence defined as necessitating 0 to 1 pad per day (PPD). Statistical analysis was performed using Cox regression models to create both univariate and multivariate survival models. RESULTS: Mean age was 59.7 (standard deviation [SD] 7.1); 98% had bilateral nerve sparing. Mean urethral length was 17.1 mm (SD 4.5 mm). Mean prostate size was 34.7 g (SD 17.8). By 3 months, 60 patients achieved 1 PPD (mean 8.1 weeks, SD 9.4) and 34 patients achieved 0 PPD (mean 10.5 weeks, SD 8.0). Time to social continence was significantly related to prostate size both as a continuous variable (P=0.01), and as a dichotomized variable of ≥ 50 vs<50 g (P=0.02). Increased urethral length was related to decreased time to continence both as a continuous variable (P=0.06), and when dichotomized to ≥ 20 vs<20 mm (P=0.08). In addition to larger prostate size (hazard ratio [HR] 0.97, P<0.04), older age (0.95 P<0.025) was also associated with a longer time to achieve 0 PPD. Multivariate analysis revealed that longer urethral length was associated with a faster recovery of continence (HR 1.11, P<0.01). After controlling for age and urethral length, patients with a prostate size ≥ 50 g had 75% lower likelihood of achieving continence at all time points when compared with patients with prostate size <50 g (HR 0.25; 95% confidence interval: 0.06, 1.06; P=0.06). CONCLUSIONS: Longer urethral length increased the likelihood of achieving continence at all time points postoperatively. Advanced age and larger prostate size were negatively associated with continence outcomes.

Surgeon perception is not a good predictor of peri-operative outcomes in robot-assisted radical prostatectomy.

Surgeons have always used their cognitive intuition for the execution of skilled tasks and real-time perception of intra-operative outcomes. We attempted to measure the overall accuracy of intra-operative surgeon perception on the functional outcome of early continence after robot-assisted radical prostatectomy (RARP). A single experienced surgeon (D.I.L.) used a scoring sheet to prospectively capture his subjective opinion of how well a particular portion of the RARP procedure was completed. Surgeon perception of factors affecting post-operative continence such as quality of bladder neck preservation, nerve sparing, urethral length, anastomosis, striated sphincter thickness, quality of Rocco repair and bladder neck plication suture (total 7 variables) were graded as "poor", "average" or "good". Urinary continence was graded as either total continence [0 pads per day (PPD) or social continence (security pad or one PPD)]. A total of 273 (39 patients × 7 variables) responses were recorded: 58.6% were rated as "good", 32.2% as "average" and 8.4% as "poor". A log-rank test for all perception variables showed no significant differences in subsequent achievement of continence (either 0 or 1 PPD) (P > 0.05) at both the 1- and 3-month time points. In the case of some perception variables, patients with "bad" scores gained continence a median of 3 weeks sooner than patients with "good" scores. Surgeon perception of intra-operative performance during RARP is a poor predictive indicator of subsequent functional outcome in terms of urinary continence. Inter-surgeon variability of perception may vary and needs further investigation.

Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment.

Two different missense mutations, p.D572N and p.D572H, affecting the same nucleotide and codon of the TMC1 gene were earlier reported to cause autosomal dominant hearing impairment at locus DFNA36 in two North American families. No other dominant mutations of human TMC1 have been published. We ascertained a third North American family segregating autosomal dominant nonsyndromic hearing impairment at the DFNA36 locus. We identified the p.D572N mutation of TMC1 co-segregating with hearing loss in our study family. A comparative haplotype analysis of linked single nucleotide polymorphisms and short tandem repeats in the two families segregating p.D572N was not consistent with a founder effect. These findings can be explained in two ways. Either nucleotide 1714 is a hot spot for mutations or, alternatively, missense mutations at this site confer a specific pathogenic gain-of-function or dominant-negative effect.