Spencer Kozinn

Management of Complex Anterior Urethral Strictures With Multistage Buccal Mucosa Graft Reconstruction

OBJECTIVE To describe the indications and outcomes of salvage urethral reconstruction using the combination of urethrectomy and buccal graft replacement. MATERIALS AND METHODS We retrospectively identified 91 consecutive patients who had undergone multistage urethral reconstruction from 2003 to 2009. The demographic and surgical outcomes data, including the need for first stage revision, pre- and postoperative urine flow rates, and reconstruction failure was collected for all patients. RESULTS Of the 91 patients, 51 (56%) subsequently underwent urethral tubularization, 17 (19%) were pending closure, and 23 (25%) had undergone the first stage only, with no plan for completion. The stricture etiology included hypospadias in 41 (45.1%), lichen sclerosus in 29 (31.9%), and a combination of the 2 in 10 (11%). Of the 91 patients, 54.9% had panurethral disease, with the remaining involving varying lengths of the anterior urethra. The mean follow-up was 15 months (range 12-69). A total of 17 patients (18.7%) required revision of their first stage, with 4 requiring ≥2 repairs. Seven patients (7.7%) required revision of their second stage, with 2 undergoing multiple revisions. The urine flow rates increased on average from 6.7 mL/s preoperatively to 21.5 mL/s postoperatively (P <.00001). In 9 patients (9.9%) reconstruction failed, and they required scheduled balloon dilation or a chronic indwelling catheter to maintain urethral patency. CONCLUSION Urethrectomy with salvage reconstruction using buccal mucosal grafts in a staged fashion is the optimal option for complex anterior urethral stricture resolution in these challenging patients. Surgical revision of the first or second stage could be required in up to 25% of challenging patients. Despite the high complexity and severity of the urethral stricture burden, a 90% success rate was achieved.

Urological Complications and Vesicoureteral Reflux Following Pediatric Kidney Transplantation

PURPOSE Ureteral complications of renal transplantation can dramatically impact renal outcomes. We studied whether complications are associated with preexisting genitourinary pathology or transplant using a deceased donor allograft. MATERIALS AND METHODS We retrospectively reviewed all patients undergoing renal transplantation at our institution between 2000 and 2010. We abstracted patient demographic details, donor type (living vs deceased), end-stage renal disease etiology, reimplant technique, stent use, preoperative and postoperative imaging, history of lower genitourinary pathology and postoperative complication management. RESULTS A total of 211 kidneys were transplanted into 206 patients (mean age 13.7 years, mean followup 4.6 years). Most patients (89%) underwent extravesical ureteroneocystostomy without stenting (97%), with roughly half (47%) of transplants being from living donors. Preexisting urological pathology was present in 34% of cases. Postoperative obstruction or extravasation occurred in 16 cases (7.6%), of which 15 were acute. Complications were not associated with donor type, preexisting urological pathology other than posterior urethral valves, surgical technique, etiology of end-stage renal disease or patient age. However, posterior urethral valves or other preexisting genitourinary pathology was not associated with an increased likelihood of genitourinary complications. Posterior urethral valves were associated with development of postoperative vesicoureteral reflux (OR 6.7, p = 0.004) but were not associated with stent placement, surgical technique, donor type or etiology of end-stage renal disease. CONCLUSIONS Patients with posterior urethral valves undergoing renal transplantation are at increased risk for postoperative vesicoureteral reflux but not for other acute surgical complications. There is no association between donor type, etiology of end-stage renal disease, surgical technique or patient age and increased complications.

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines

MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in development, differentiation, cell proliferation, and death as well as the complex process of acquired drug resistance. The goal of this study was to identify specific miRNAs and their potential protein targets that confer acquired resistance to gemcitabine in urothelial carcinoma of the bladder (UCB) cell lines. Gemcitabine-resistant cells were established from 6 cell lines following exposure to escalating concentrations of the drug and by passaging cells in the presence of the drug over a 2- to 3-month period. Differential miRNA expression was identified in a microarray format comparing untreated controls with resistant cell lines, representing the maximum tolerated concentration, and results were validated via qRT-PCR. The involvement of specific miRNAs in chemoresistance was confirmed with transfection experiments, followed by clonogenic assays and Western blot analysis. Gemcitabine resistance was generated in 6 UCB cell lines. Microarray analysis comparing miRNA expression between gemcitabine-resistant and parental cells identified the differential expression of 66 miRNAs. Confirmation of differential expression was recorded via qRT-PCR in a subset of these miRNAs. Within this group, let-7b and let-7i exhibited decreased expression, while miR-1290 and miR-138 displayed increased expression levels in gemcitabine-resistant cells. Transfection of pre-miR-138 and pre-miR-1290 into parental cells attenuated cell death after exposure to gemcitabine, while transfection of pre-miR-let-7b and pre-miR-let-7i into the resistant cells augmented cell death. Mucin-4 was up-regulated in gemcitabine-resistant cells. Ectopic expression of let-7i and let-7b in the resistant cells resulted in the down-regulation of mucin-4. These results suggest a role for miRNAs 1290, 138, let-7i, and let-7b in imparting resistance to gemcitabine in UCB cell lines in part through the modulation of mucin-4. Alterations in these miRNAs and/or mucin-4 may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine in UCB.

Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy.

OBJECTIVE We compared positive surgical margin (PSM) rates for patients with high risk prostate cancer (HRCaP) who underwent open radical retropubic (RRP), robotic (RALP), and laparoscopic (LRP) prostatectomy at a single institution. MATERIALS AND METHODS We performed a retrospective review of our prospectively maintained IRB approved database identifying prostate cancer patients who underwent RRP, RALP, or LRP between January 2000 and March 2010. Patients were considered to have HRCaP if they had biopsy or final pathologic Gleason score ≥ 8, or preoperative PSA ≥ 20, or pathologic stage ≥ T3a. A positive surgical margin (PSM) was defined by the presence of tumor at the inked surface of the specimen. Patients who received neoadjuvant hormonal therapy and those who underwent a perineal prostatectomy were excluded from the study. RESULTS Of the 445 patients in this study, surgical technique for prostatectomy included RRP (n = 153), RALP (n = 152), and LRP (n = 140). PSM rate for the three groups were not different: 52.9% RRP, 50% RALP, and 41.4% LRP, (p = 0.13). The PSM rate did not differ when comparing RRP to a combined group of RALP and LRP (p = 0.16). Among patients with a PSM, there was no statistical difference between the three groups in terms of the number of patients with a pathologic stage of T3 or higher (p = 0.83). On univariate analysis, a higher preoperative PSA value was associated with a positive margin (p = 0.04). CONCLUSION In this HRCaP series, the PSM rate did not differ based on the surgical approach. On univariate analysis, patients with a higher preoperative PSA value were more likely to have a PSM.

Abstract 1161: Detection and identification of a miRNA expression profile from cell-free urine: Potential utility in bladder cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction/Objective: MicroRNAs are small, non-coding RNAs that have been shown to play an important role in tumorigenesis. There is differential expression of miRNA in cancer progression, and profiling of miRNA is promising for both diagnosis and treatment of malignant tumors. In this study we isolated RNA from cell-free urine in an attempt to characterize miRNA profiles indicating the presence of urothelial carcinoma and its potential use as a non-invasive assay to identify patients with cancer progression. Methods: Urine was collected from patients diagnosed with bladder cancer and control patients with no history of cancer under an IRB-approved protocol. Urine was centrifuged and total RNA was isolated from the supernatants using the mirVana Paris™ kit. A total of 178 samples were grouped according to grade and stage (healthy controls (35), TaG1 (19), T1G3 (16), ≥T2 (30), carcinoma in situ (CIS; 28) and no evidence of disease following therapy (50). Seven hundred and thirty miRNAs were profiled by qRT-PCR on pooled samples within each group. Validation of selected miRNAs was performed on individual samples using qRT-PCR. Results: Cell-free RNA was isolated from urine of 35 healthy controls and 143 patients with bladder cancer. Of the 730 miRNAs tested, 236 were detected in at least one of the pooled samples using a Ct cutoff of 35. The number of miRNAs detected in the pooled samples correlated with disease progression where the healthy control group and the ≥T2 group expressed 8 and 228 miRNAs, respectively. qRT-PCR of individual samples revealed a gradual increase of some miRNAs with disease progression. Statistical analysis adjusted for multiple comparisons demonstrated differences between groups based on miRNA expression levels. In addition, a panel of miRNAs was identified which discriminated between cancer and cancer-free patients. Conclusion: This study demonstrates the successful isolation of miRNAs from cell-free urine. Utilizing non-invasive urine based assays, we identified a miRNA panel that can discriminate between cancer-free patients and patients with urinary carcinoma of the bladder. These findings provide evidence that profiling of miRNAs from cell-free urine holds the promise for the development of valuable clinical tools. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2011-1161