The SIGHT questionnaire: A novel assessment tool for Satisfaction In Genital Hypospadias Treatment.

PURPOSE: Psychosexual development is currently underrepresented in hypospadias outcome research. The aim of this study was to develop and validate a questionnaire addressing psychosexual long-term satisfaction, specifically of adolescent patients, after hypospadias repair. MATERIALS AND METHODS: In a multistep participative design we identified key interests of adolescent patients with hypospadias. Next, a questionnaire addressing specifically the psychosexual satisfaction of adolescents after hypospadias repair was established. A population of 109 former patients with hypospadias was then assessed using this questionnaire. Furthermore, functional and cosmetic aspects, behavioural anomalies, and sexual activity were investigated. Age-matched patients undergoing circumcision served as control patients. Possible influence factors on patient satisfaction were investigated. Clinical trial registry site: German Registry of Clinical Trials DRKS, Freiburg, Germany (Reference: DRKS00003432). RESULTS: Key interests of adolescent patients were "normal appearance of the penis", "normal function of the penis regarding voiding and sexual activity", "no limitations regarding cosmetic appearance to others", "no limitations to sexual activity", and an "unimpaired masculine identity". The "Satisfaction In Genital Hypospadias Treatment" (SIGHT) questionnaire was developed using these items and using previously published evaluation systems. Nine questions address psychosexual aspects and two additional questions address current sexual activity. Internal consistency was high and retest reliability acceptable. The patient population showed a normal strength and difficulties score (SDQ). Overall satisfaction was high and similar to that of the control group. In a Spearman correlation a high SDQ value, erectile problems, and complications correlated negatively with satisfaction. CONCLUSION: To date, few studies have examined patients' satisfaction and psychosexuality. To our knowledge, the SIGHT questionnaire is the first to be developed participatively and in a stepwise fashion in collaboration with a paediatric psychologist and an open approach to determine items specifically important for adolescents. The SIGHT questionnaire can thus offer a relevant assessment of patients' psychosexual satisfaction. It is most suitable to supplement current strategies that so far mostly neglect the impact on psychosexual wellbeing.

Urothelial Cancer in Renal Transplant Recipients: Incidence, Risk Factors, and Oncological Outcome.

OBJECTIVE: To evaluate the incidence and risk factors for urothelial cancer (UC) as well as the oncological outcome and allograft function in renal transplant recipients. SUBJECTS/PATIENTS: We conducted a retrospective analysis of 1855 consecutive patients undergoing renal transplantation (TX) between February 1982 and May 2014 at a single center. UC incidence, overall and cancer-specific survival, recurrence and progression rates, risk factors for UC, and renal function were determined. Fisher's exact test and log-rank Mantel-Cox test were used as appropriate. RESULTS: In renal transplant recipients, incidence of de novo UC was 1.35% (25/1855). Deceased donor transplantation (P = .002), increased age at transplantation (P = .011), and analgesic abuse (P = .005) were significant risk factors for the development of UC post-TX. Progression rate and recurrence rate were doubled for post-TX-UC but stable for patients with pre-TX-UC compared with the general population. Analgesic abuse was associated with worse cancer specific and overall survival in post-TX patients. The overall survival status was significantly lower for post-TX patients at a median of 34 months vs 222 months in control patients. Adjuvant treatment was scarcely used. UC had no significant influence on graft function. CONCLUSION: A higher incidence of UC was identified in renal transplant recipients compared with that for the general population. These observations justify screening for UC in renal transplant patients, especially considering that in a large proportion, a tentative diagnosis was possible with noninvasive urine analysis. Prudent adjuvant treatment for UC should be used. Limitations of this study were the retrospective design and the single-center experience.

An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder.

BACKGROUND: To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. RESULTS: We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. CONCLUSIONS: This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.

The glandular resection and central embedding modification (GRACE) in Duckett and Barcat hypospadias repair.

INTRODUCTION: We recently reported a novel modification of the Barcat technique termed glandular resection and central embedding (GRACE). Here, we report results from a large patient population and apply this modification also to Duckett hypospadias repair. PATIENTS AND METHODS: We retrospectively evaluated 488 patients who had undergone primary or secondary hypospadias repair by Barcat or Duckett using the GRACE modification. RESULTS: For all GRACE repairs, cosmetic appearance was favorable regarding meatal position, shape and overall appearance. Maximum and average flow were above the 5th percentile in at least 95%. In Barcat and Duckett repairs, urethrocutaneous fistulas occurred in 5 and 30.7%, urethral strictures in 3 and 20.8%, and meatal strictures in 5 and 25.3%, respectively. CONCLUSIONS: The initially reported favorable cosmetic and functional results were confirmed both for Duckett and Barcat repair using the GRACE modification. Complication rates were favorably low for Barcat and higher, but consistent with published results, for Duckett repair.

Glandular resection and central embedding in hypospadias repair--a novel modification of the Barcat technique.

PURPOSE: Urethrocutaneous fistula and urethral or meatal stricture, to date, remain the commonest complications of hypospadias repair, with increased tissue tension being a major cause of failure. We developed a novel technique comprising glandular resection and central embedding of the neourethra to specifically address this critical issue. We report the results of the first 112 procedures, of which 7 cases were a secondary hypospadias repair. MATERIALS AND METHODS: All patients who underwent hypospadias repair using the glandular resection and central embedding technique over a period of 10 years were included into this retrospective single-surgeon case series. An independent third-party observer carried out follow-up examinations including urometric evaluation. RESULTS: The median follow-up was 37 months (range, 7-147 months). In the group of primary hypospadias repair, urethrocutaneous fistulas were observed in 4%, all requiring surgical revision, and meatal or urethral stricture were observed in 4% of the patients, treated either surgically or by dilatation. In 98% of the patients, the neomeatus was located at the tip of the glans. A cosmetically impeccable slitlike appearance of the meatus was achieved in 84%, and a cosmetically acceptable oval shape was achieved in 10% of the patients. Both maximum and average urinary flow rates were within the standard ranges for the respective age groups in 93.7% and 96%, respectively. There was no significant residual urine in 92% of the patients. In the group of secondary hypospadias repairs, both cosmetic and functional results were similar, and no complications were noted. CONCLUSIONS: Glandular resection and central embedding is a promising expansion of the repertoire of Barcat modifications. It allows safe embedding of the neourethra and glandular closure without detrimental tension. The cosmetic and functional results are encouraging.

The efferent segment in continent cutaneous urinary diversion: a comprehensive review of the literature.

OBJECTIVE: To critically assess the biophysical properties and current status of outlet formation in heterotopic intestinal urinary diversion. As despite three decades of clinical experience with continent cutaneous urinary diversion through bowel segments, no consensus has been reached for the optimal efferent segment although its function largely determines patient satisfaction. METHODS: A comprehensive Medline literature search using the Medical Subject Headings database (search terms: continent urinary diversion followed by either efferent segment, nipple, Mitrofanoff, Yang-Monti, Benchekroun, tapered ileum, intussuscepted ileum, Kock pouch, T-valve, or Ghonheim) was conducted to identify all full-length original articles addressing the various principles and techniques of outlet formation as well as their outcomes and complications. Examined series were published in English between 1966 and 2010. All studies were systematically evaluated using a checklist (study design, number of patients, etc.) and rated according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence (LoE). RESULTS: While there was a continuous flow of publications over the last three decades, the vast majority of studies were retrospective case series with numerous confounding factors and poorly defined, non-standardized outcomes (LoE, 3). Only a few investigations compare different efferent segments (LoE, 2a). No randomized studies exist. The major biophysical principles are based on the use of flap, nipple, and hydraulic valves. Vermiform appendix, intussuscepted ileal nipple, and the Yang-Monti tube are the most popular techniques and have well-established data on outcomes, complications, and failure rates. Artificial sphincter systems and tissue engineering have provided disappointing results thus far. Most reconstructive strategies are subject to a process of on-going improvement. CONCLUSIONS: The continuous quest for optimization has not led to a single universally applicable efferent segment in continent cutaneous urinary diversion. While all techniques have their unique set of advantages and disadvantages, they will always remain a compromise. Success depends on selecting the optimal strategy for individual patients. A major change in principles in the near future is unlikely.

Reactive antibodies against bacillus Calmette-Guerin heat-shock protein-65 potentially predict the outcome of immunotherapy for high-grade transitional cell carcinoma of the bladder.

BACKGROUND: Intravesical immunotherapy with Mycobacterium bovis (M. bovis) bacillus Calmette-Guerin (BCG) is the current standard of care against superficial, high-grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle-invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG-induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy. METHODS: Because host immunoresponse mediates BCG activity, the authors screened a combinatorial random peptide library on the circulating pool of immunoglobulins (Igs) purified from an index patient after successful BCG immunotherapy to identify the corresponding target antigen(s). RESULTS: An immunogenic peptide motif was selected, isolated, and validated from M. bovis BCG heat-shock protein 65 (HSP-65) as a dominant epitope of the humoral response to treatment. Increasing IgA and IgG anti-HSP-65 titers specifically predicted a positive patient outcome in a cohort of patients with bladder cancer relative to several cohorts of control patients. CONCLUSIONS: The current results indicated that antibody production against M. bovis BCG HSP-65 can serve as a serologic marker for the predictive outcome of BCG immunotherapy. Subsequent studies will determine the value of this candidate marker to modify BCG-based treatment for individual patients with bladder cancer.

Design and validation of a bifunctional ligand display system for receptor targeting.

Here we developed a bacteriophage display particle designed to serve as a bifunctional entity that can target tumors while delivering an agent. We engineered a chimera phage vector containing a pIII-displayed alphav integrins-targeting moiety and a pVIII-displayed streptavidin binding adaptor moiety. By using the chimeric phage particle, targeting of alphav integrins on cells in culture and tumor-related blood vessels was shown through different applications, including luminescent quantum dots localization, surface plasmon resonance-based binding detection, and an in vivo tumor model. The strategy validated here will accelerate the discovery and characterization of receptor-ligand binding events in high throughput, and cell-specific delivery of diagnostics or therapeutics to organs of choice without the need for chemical conjugation.

Targeting urothelium: ex vivo assay standardization and selection of internalizing ligands.

PURPOSE: With the goal of targeting the human bladder using phage display technology we designed and tested a tissue binding assay on intact urothelium ex vivo. This approach may form the molecular basis for clinical development of peptide or peptidomimetic guided intravesical compounds. MATERIALS AND METHODS: We screened 2 phage display random peptide libraries on human urothelium. Select peptides were tested for their binding ability to human urothelium, 2 human transitional cell carcinoma cell lines and a nontransitional cell carcinoma cell line. Next we standardized an ex vivo binding assay, validated binding of selected phage to whole urothelium, and evaluated whether receptor mediated internalization into urothelium derived cells occurred. Finally we tested if the presence of the glycosaminoglycan layer had any effect on the binding of the urothelium targeted phage. RESULTS: Phage selected and recovered in the screening were isolated and sequenced. Displayed peptide sequences were searched against online protein databases. Five classes of peptide motifs were characterized based on their ability to bind to normal urothelium but not to control cell lines. Remarkable consistency and reproducibility were observed in the ex vivo binding assays. Two classes of peptide motifs sharing the sequence Ile/Leu-Ser-Gly-Leu bound to normal urothelium and to 2 transitional cell carcinoma cells but not to nontransitional cell carcinoma cells in a glycosaminoglycan independent manner and mediated internalization into cells of urothelial origin. CONCLUSIONS: We introduce a strategy for screening combinatorial peptide libraries on bladder mucosa, a standard model for ex vivo intact urothelium binding assays and a panel of urothelium binding peptides that may be suitable for translation into targeted intravesical therapy applications.

Steps toward mapping the human vasculature by phage display.

The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This large-scale screening indicates that the tissue distribution of circulating peptides is nonrandom. High-throughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand-receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.