Thomas W. Fuller

Differential Capture of Serum Proteins for Expression Profiling and Biomarker Discovery in Pre‐ and Posttreatment Head and Neck Cancer Samples

Introduction: A long‐term goal of our group is to develop proteomic‐based approaches to the detection and use of protein biomarkers for improvement in diagnosis, prognosis, and tailoring of treatment for head and neck squamous cell cancer (HNSCC). We have previously demonstrated that protein expression profiling of serum can identify multiple protein biomarker events that can serve as molecular fingerprints for the assessment of HNSCC disease state and prognosis.

Clinical collection and protein properties of expressed prostatic secretions as a source for biomarkers of prostatic disease.

The prostate gland secretes many proteins in a prostatic fluid that combines with seminal vesicle derived fluids to promote sperm activation and function. Proximal fluids of the prostate that can be collected clinically are seminal plasma and expressed-prostatic secretion (EPS) fluids. EPS represents the fluid being secreted by the prostate following a digital rectal prostate massage, which in turn can be collected in voided urine post-exam. This collection is not disruptive to a standard urological exam, and it can be repeatedly collected from men across all prostatic disease states. A direct EPS fluid can also be collected under anesthesia prior to prostatectomy. While multiple genetic assays for prostate cancer detection are being developed for the shed epithelial cell fraction of EPS urines, the remaining fluid that contains many prostate-derived proteins has been minimally characterized. Approaches to optimization and standardization of EPS collection consistent with current urological exam and surgical practices are described, and initial proteomic and glycomic evaluations of the of EPS fluid are summarized for prostate specific antigen and prostatic acid phosphatase. Continued characterization of the prostate specific protein components of EPS urine combined with optimization of clinical collection procedures should facilitate discovery of new biomarkers for prostate cancer.

Challenges to Developing Proteomic-Based Breast Cancer Diagnostics

Over the past decade, multiple genetic and histological approaches have accelerated development of new breast cancer diagnostics and treatment paradigms. Multiple distinct genetic subtypes of breast cancers have been defined, and this has progressively led toward more personalized medicine in regard to treatment options. There still remains a deficiency in the development of molecular diagnostic assays that can be used for breast cancer detection and pretherapy clinical decisions. In particular, the type of cancer-specific biomarker typified by a serum or tissue-derived protein. Progress in this regard has been minimal, especially in comparison to the rapid advancements in genetic and histological assays for breast cancers. In this review, some potential reasons for this large gap in developing protein biomarkers will be discussed, as well as new strategies for improving these approaches. Improvements in the study design of protein biomarker discovery strategies in relation to the genetic subtypes and histology of breast cancers is also emphasized. The current successes in use of genetic and histological assays for breast cancer diagnostics are summarized, and in that context, the current limitations of the types of breast cancer-related clinical samples available for protein biomarker assay development are discussed. Based on these limitations, research strategies emphasizing identification of glycoprotein biomarkers in blood and MALDI mass spectrometry imaging of tissues are described.

Contribution of GABAA, Glycine, and Opioid Receptors to Sacral Neuromodulation of Bladder Overactivity in Cats.

In α-chloralose–anesthetized cats, we examined the role of GABAA, glycine, and opioid receptors in sacral neuromodulation-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.5% acetic acid (AA). AA irritation significantly (P < 0.01) reduced bladder capacity to 59.5 ± 4.8% of saline control. S1 or S2 dorsal root stimulation at threshold intensity for inducing reflex twitching of the anal sphincter or toe significantly (P < 0.01) increased bladder capacity to 105.3 ± 9.0% and 134.8 ± 8.9% of saline control, respectively. Picrotoxin, a GABAA receptor antagonist administered i.v., blocked S1 inhibition at 0.3 mg/kg and blocked S2 inhibition at 1.0 mg/kg. Picrotoxin (0.4 mg, i.t.) did not alter the inhibition induced during S1 or S2 stimulation, but unmasked a significant (P < 0.05) poststimulation inhibition that persisted after termination of stimulation. Naloxone, an opioid receptor antagonist (0.3 mg, i.t.), significantly (P < 0.05) reduced prestimulation bladder capacity and removed the poststimulation inhibition. Strychnine, a glycine receptor antagonist (0.03–0.3 mg/kg, i.v.), significantly (P < 0.05) increased prestimulation bladder capacity but did not reduce sacral S1 or S2 inhibition. After strychnine (0.3 mg/kg, i.v.), picrotoxin (0.3 mg/kg, i.v.) further (P < 0.05) increased prestimulation bladder capacity and completely blocked both S1 and S2 inhibition. These results indicate that supraspinal GABAA receptors play an important role in sacral neuromodulation of bladder overactivity, whereas glycine receptors only play a minor role to facilitate the GABAA inhibitory mechanism. The poststimulation inhibition unmasked by blocking spinal GABAA receptors was mediated by an opioid mechanism.

Surgical Management of Adult Acquired Buried Penis: Escutcheonectomy, Scrotectomy, and Penile Split-thickness Skin Graft

OBJECTIVE To demonstrate the surgical management of adult acquired buried penis (AABP). Affected patients have poor sexual function, urinary dribbling with subsequent skin breakdown, mood disturbance, lichen sclerosus with subsequent urethral stricture, and poor quality of life. Previous efforts have described limited repairs including an isolated resection of the escutcheon, which unfortunately often leads to reburying. We present a more extensive surgical repair including escutcheonectomy, scrotoplasty, and penile split-thickness skin graft (STSG) to provide a durable definitive repair. METHODS A retrospective review was conducted of patients managed in 2015-2016. Twelve patients who underwent escutcheonectomy, scrotoplasty, and penile STSG were identified. All patients had morbid obesity as a sole etiology or a significant contributing factor. Outcomes evaluated were surgical complications, reburying of the penis, and graft take rates. RESULTS Twelve patients underwent repair of AABP. All patients had durable unburying at the intermediate-term follow-up (mean of 8 months). The mean patient body mass index was 45.4 ± 13.8. The operative times, the length of stay, and the estimated blood loss were 312 ± 59 minutes, 5.3 ± 1.1 days, and 304 ± 133 cc, respectively. The STSG take rate was 80%-100% (mean of 91.7%). CONCLUSION AABP is a challenging condition to treat. Limited surgical repairs can lead to a reburying of the penis and a progression of urethral disease. Escutcheonectomy, scrotoplasty, and STSG have encouraging intermediate-term outcomes with durable unburying of the penis and good STSG take rates. Further follow-up in larger series is needed, but results are thus far encouraging.

MP25-07 SURGICAL MANAGEMENT OF ADULT ACQUIRED BURIED PENIS: IMPACT ON URINARY AND SEXUAL QUALITY OF LIFE OUTCOMES

OBJECTIVE To assess postoperative patient-reported quality of life outcomes after surgical management of adult-acquired buried penis (AABP). We hypothesize that surgical treatment of AABP results in improvements in urinary and sexual quality of life. METHODS Patients that underwent surgical treatment of AABP were retrospectively identified. The Expanded Prostate Cancer Index (EPIC) questionnaire was completed at ≥3 months postoperatively, and completed retrospectively to define preoperative symptoms. EPIC is validated for local treatment of prostate cancer. Urinary and sexual domains were utilized. Questions are scored on a 5-point Likert scale, with higher scores indicating better quality of life. Preoperative scores were compared with postoperative scores. RESULTS Sixteen patients completed pre- and postoperative questionnaires. Mean time from surgery to questionnaire was 12.6 months. There was a significant improvement in 10 of 12 urinary domain questions and 10 of 13 sexual domain questions. Fourteen of 16 patients (87.5%) reported significant improvement in overall sexual function (median score changed from 1.5 to 5, P <.0001). Similarly, 14 of 16 patients (87.5%) reported significant improvement in overall urinary function (median score changed from 1 to 4, P <.0001). CONCLUSION AABP is a challenging condition to treat and often requires surgical intervention to improve hygiene and function. There are limited data on patient-reported quality of life outcomes. We found that surgical management of AABP results in significant improvements in both urinary and sexual quality of life outcomes.

Surgical Management of Adult Acquired Buried Penis

Purpose of ReviewAdult acquired buried penis is a morbid condition characterized by complete entrapment of the phallus as a result of morbid obesity, post-surgical cicatrix formation, or primary genital lymphedema. Hygienic voiding is not possible and urinary dribbling is frequent with accompanying inflammation, skin breakdown, and infection from the chronic moisture. The end result is penile skin fibrosis resulting in permanent functional loss. Herein, we describe the etiology of adult acquired buried penis, advances in its surgical management, and quality of life outcomes with treatment.Recent FindingsAdult acquired buried penis is increasing in incidence as morbid obesity becomes more prevalent. Frequently comorbid conditions affect treatment including those affecting wound healing such a diabetes mellitus. Functional and cosmetic surgical outcomes are being published in greater volume in recent years leading to more refined treatment algorithms. Patient quality of life is greatly improved by definitive surgical management.SummaryAdult acquired buried penis is a morbid condition that is increasing in incidence as obesity becomes more commonplace. Surgical management often necessitates surgical lipectomy of the suprapubic fat pad, scrotoplasty, and penile split thickness skin graft. Substantial quality of life improvements have been consistently reported after surgical treatment.

Safety and Surgical Outcomes of Same-day Anterior Urethroplasty

OBJECTIVE To evaluate the safety and feasibility of same-day anterior urethroplasty at our institution and define predictors of postoperative admission and surgical failure. METHODS We retrospectively reviewed the charts of 118 consecutive anterior urethroplasties performed at a tertiary care center. Data were analyzed to detect predictors of postoperative admission and urethroplasty failure. The 30-day complications and long-term outcomes were compared between same-day and admitted patients. RESULTS Ninety-two patients (78%) were discharged on the day of surgery. A penile stricture location compared with a bulbar stricture location (odds ratio: 13.4, P = .009) and having undergone more than 3 prior endoscopic stricture interventions (odds ratio: 10.2, P = .001) were significantly associated with postoperative admission. Patients with a ventral onlay approach were more likely to be discharged home (P = .03), whereas patients with combined repairs were more likely to be admitted (P = .04). Same-day urethroplasty did not increase 30-day postoperative complications, patient emergency room visits, unplanned clinic visits, or phone calls. Success rates did not differ between same-day (89%) and admitted (79%) cohorts, and no individual stricture characteristic was predictive of urethroplasty failure. CONCLUSION Same-day anterior urethroplasty is safe and feasible and could help increase utilization of urethroplasty for urethral stricture disease.

Lumbosacral spinal segmental contributions to tibial and pudendal neuromodulation of bladder overactivity in cats

To determine the spinal segmental afferent contributions to tibial and pudendal inhibition of bladder overactivity.

Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats

The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly (P < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly (P < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly (P < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01-1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.