Charles C. Peyton

Halofuginone infused keratin hydrogel attenuates adhesions in a rodent cecal abrasion model.

BACKGROUND Postoperative adhesion formation continues to be a significant surgical complication, and methods for preventing abdominopelvic adhesions remain limited. Halofuginone (HF) is a type-1 collagen synthesis inhibitor and may enhance the effects of a physical barrier in preventing adhesion formation. We evaluated the effectiveness of a HF infused keratin hydrogel on preventing adhesions in a rat cecal abrasion model. MATERIAL AND METHODS Laparotomy and standardized cecal abrasion was performed on 58 retired-breeder Sprague Dawley female rats to induce intra-abdominal adhesions. Rats were randomized to: no treatment; Interceed absorbable adhesion barrier; keratin hydrogel alone; or keratin hydrogel infused with 22 μg/mL of HF. Necropsies were performed at postop d-14 to assess the extent and tenacity of adhesions and grade histologic inflammation and fibrosis using a standard scoring system. Serum, liver, kidneys, and lungs were harvested to evaluate tissue HF concentrations. Protein and drug elution curves were generated to assess the release of HF from the hydrogel. RESULTS Treatment with Keratin-HF hydrogel resulted in significantly fewer abdominal adhesions than any other treatment, and significantly less dense adhesions compared with Interceed or keratin hydrogel alone. Subset histologic analysis did not reveal qualitative differences. HF was undetectable in serum and kidneys, and detected at negligible concentrations in liver and lungs. Keratin-HF hydrogel drug release in phosphate-buffered solution (PBS) was sustained over 7 d and correlated with keratin protein degradation. CONCLUSIONS Keratin-HF hydrogel is a novel therapeutic agent that may provide a better method for preventing the development of postoperative adhesions using a combined physical barrier and pharmacologic approached.

Dedicated Research Time in Urology Residency: Current Status

OBJECTIVE To gauge the importance of dedicated research time during urology residency and how this influences rank-list preferences when applying for residency. METHODS An American Urological Association survey was emailed to US resident members. The online form consisted of 14 questions addressing demographics, career plans, and training program characteristics. Two additional Likert-scale question series evaluated rank-list preferences and the value of dedicated research time during residency. RESULTS A total of 263 of 956 urology residents (27.5%) responded to the survey. More than 70% responders valued the opportunity to be involved with scholarly research and agreed that doing so will enhance their education and/or training. About 88.2% interviewed with at least 1 program with a dedicated research year. About 33.5% preferred or were indifferent to applying to 6-year programs with dedicated research time vs a traditional 5-year program. About 76.4% residents preferred doing an extra year of research in fellowship as opposed to residency. CONCLUSION Dedicated research time is one of many components influencing rank-list preference. Residents value the opportunity to participate in research, but there is limited interest in an additional year during residency. However, one-third of applicants favor or are willing to accept an additional year of research in urology residency.

Current controversies and developments on the role of lymphadenectomy for penile cancer

Penile squamous cell carcinoma is a rare cancer in men. The main prognosticators of survival for penile cancer patients remain the presence and the extent of lymph node metastasis. While radical inguinal lymphadenectomy has been the cornerstone of regional lymph node management for many years, it is still associated with significant morbidity and psychological distress. Recent developments in penile squamous cell carcinoma management have been met with some controversy in the urologic oncology community. Herein, we review the current controversies and developments on the role of inguinal lymphadenectomy for penile cancer.

Estimating Minimally Important Differences for the Bladder Cancer Index Using Distribution- and Anchor-Based Approaches

Purpose: The BCI (Bladder Cancer Index) is a validated, condition specific health questionnaire assessing urinary, bowel and sexual function and quality of life among patients with bladder cancer. We aimed to establish minimally important difference score thresholds that signal clinical importance. Materials and Methods: For 1 year after surgery we followed a prospective cohort of 150 patients who underwent radical cystectomy between 2013 and 2016. Usable data on 138 patients were analyzed. The BCI and the Medical Outcomes Study SF-36 (36-Item Short Form Health Survey) questionnaires were completed prior to cystectomy, and 3, 6 and 12 months postoperatively. Distribution based, minimally important differences were estimated at ⅓ and ½ SD for each index domain across time points. Changes in index domain scores anchored to changes in a SF-36 overall health assessment question were used to estimate anchor based, minimally important differences. Pooled averages are reported between time points and methods. Results: The distribution based, minimally important difference of ⅓ SDs for urinary, bowel and sexual domains ranged between 5.3 and 7.3, 4.6 and 5.6, and 6.0 and 8.9 points, respectively. Ranges of ½ SDs were 8.8 and 10.9, 6.8 and 8.4, and 8.9 and 13.5 points, respectively. The anchor based approach resulted in minimally important difference estimates of 6.2, 7.3 and 6.8 points, respectively. Aggregated results across the 2 approaches resulted in minimally important differences of 6 to 9, 5 to 8 and 7 to 11 points for urinary, bowel and sexual domains, respectively. Conclusions: Using 2 independent approaches to our knowledge we established the first minimally important difference estimates for the BCI. Defining patient reported outcome thresholds is important to interpret changes or differences in BCI scores.

Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ≥1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

Downstaging and Survival Outcomes Associated With Neoadjuvant Chemotherapy Regimens Among Patients Treated With Cystectomy for Muscle-Invasive Bladder Cancer

Importance Neoadjuvant chemotherapy (NAC) followed by radical cystectomy improves survival compared with cystectomy alone for patients with bladder cancer. Although gemcitabine with cisplatin has become a standard NAC regimen, a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) is being adopted at some institutions. Objective To assess the association of neoadjuvant ddMVAC vs standard regimens with downstaging and overall survival among patients treated with radical cystectomy for bladder cancer. Design, Setting, and Participants Cross-sectional analysis of data extracted from the medical records of a consecutive sample, after exclusions, of 1113 patients with bladder cancer of whom 824 had disease stage T2 or greater, who were treated with cystectomy at the Moffitt Cancer Center in Tampa, Florida, a tertiary care cancer center, between January 1, 2007, and May 31, 2017. Data were collected between November 14, 2016, and July 21, 2017, and analyzed between August 21, 2017, and December 8, 2017. Patients were compared based on type of NAC. Those who did not receive NAC were included as controls. Main Outcomes and Measures Comparative rates and the association of any downstaging, complete response, and overall survival with ddMVAC and other NAC regimens and surgery alone. Outcomes were examined using Kaplan-Meier, adjusted logistic, Cox regression, and propensity-weighted models. Results Of the 1113 patients who underwent cystectomy for bladder cancer, 861 (77.4%) were male, the median (interquartile range) age was 67 (60-74) years, 1051 (94.4%) were white, 27 (2.4%) black, 37 (3.3%) Hispanic/Latino, and 35 (3.1%) other race/ethnicity. Of 824 patients with muscle-invasive bladder cancer, 332 (40%) received NAC. Downstaging rates were 52.2% for ddMVAC, 41.3% for gemcitabine-cisplatin, and 27.0% for gemcitabine with carboplatin, and complete response (pT0N0) rates were 41.3% for ddMVAC, 24.5% for gemcitabine-cisplatin, and 9.4% for gemcitabine-carboplatin (2-sided P < .001). Adjusted analysis comparing ddMVAC with gemcitabine-cisplatin demonstrated a higher likelihood of downstaging (odds ratio [OR], 1.84; 95% CI, 1.10-3.09) and complete response (OR, 2.67; 95% CI, 1.50-4.77) with ddMVAC. Similar results were achieved with propensity score matching (OR, 1.52; 95% CI, 0.99-2.35). Patients who received ddMVAC had better overall survival than those treated with other chemotherapy regimens, although the observed survival benefit did not reach statistical significance in adjusted or propensity-matched models (hazard ratio, 0.44; 95% CI, 0.14-1.38; P = .16). Conclusions and Relevance This study suggest that neoadjuvant ddMVAC followed by cystectomy is associated with a higher complete response (ypT0N0) rate than standard NAC. These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion.

The Value of Neutrophil to Lymphocyte Ratio in Patients Undergoing Cytoreductive Nephrectomy with Thrombectomy

BACKGROUND The neutrophil-lymphocyte ratio (NLR) is an established signature of inflammation used for evaluating renal cell carcinoma (RCC). OBJECTIVE To determine the utility of NLR and its relationship with known risk factors associated with poor survival in patients with metastatic RCC and tumor thrombus undergoing cytoreductive nephrectomy (CN). DESIGN, SETTING, AND PARTICIPANTS Prognostic variables were reviewed for patients undergoing CN with thrombectomy between 2000 and 2014 from six different institutions. Patients were stratified for NLR >4.0 based on cut point analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Kaplan-Meier curves compared overall survival of the total cohort and established risk models (Memorial Sloan Kettering Cancer Center [MSKCC], International Metastatic Renal-Cell Carcinoma Database Consortium [IMDC], and M.D. Anderson Cancer Center [MDACC]) stratified by NLR. Multivariable Cox regression determined predictors of overall survival. Receiver operator characteristic curves tested the predictive accuracy of survival ≥12 mo, and area under the curve (AUC) was compared between models. RESULTS AND LIMITATIONS In total, 332 patients were identified. Patients with NLR ≤4.0 had longer median survival (24.7 vs 15.2 mo, p=0.004). NLR >4.0 distinguished patients with significantly shorter survival for non-poor-risk groups defined by MSKCC, IMDC, and MDACC criteria. Systemic symptoms, low hemoglobin, elevated lactate dehydrogenase, retroperitoneal adenopathy, level IV thrombus, elevated absolute neutrophil count, and NLR >4 were independent predictors of decreased survival (p<0.05). These factors had higher predictive accuracy for survival at 12 mo (AUC=0.755) than MKSCC, IMDC, and MSKCC models. CONCLUSIONS NLR >4.0 independently predicts poor survival and further distinguishes established risk model survival curves. We identified seven preoperative risk factors related to poor survival for patients with metastatic RCC with tumor thrombus undergoing CN. PATIENT SUMMARY The neutrophil-lymphocyte ratio and six additional preoperative variables can be used to better council patients regarding survival after surgery for metastatic renal cell carcinoma with tumor thrombus.

Impact of PI3K-AKT-mTOR Signaling Pathway Up-regulation on Prognosis of Penile Squamous-Cell Carcinoma: Results From a Tissue Microarray Study and Review of the Literature

Purpose To assess the prognostic value of PI3K‐AKT‐mTOR signaling pathway up‐regulation in a contemporary cohort of penile squamous‐cell carcinoma (PSCC) patients. Patients and Methods Tissue microarrays were constructed for 57 patients with invasive PSCC treated at our institution between 2000 and 2013. Immunohistochemical staining was performed for PTEN, AKT, and S6. Human papillomavirus (HPV) in‐situ hybridization for high‐risk subtypes was also performed. Biomarker expression was evaluated by a semiquantitative H score. Overall survival, disease‐specific survival and recurrence‐free survival stratified by biomarker expression (low vs. high) were estimated by the Kaplan‐Meier method. Multivariable Cox regression models were used to determine predictors of mortality and recurrence. Results HPV in‐situ hybridization was positive in 23 patients (40%). PTEN was down‐regulated in 43 patients (75%), while phosphorylated‐AKT (p‐AKT) and phosphorylated‐S6 (p‐S6) were up‐regulated in 27 (47%) and 12 patients (21%), respectively. In multivariable Cox regression models, patients with low expression of p‐AKT had an increased risk of recurrence (hazard ratio [HR] = 3.95; 95% confidence interval [CI], 1.47‐10.59; P = .02), while those with low expression of p‐S6 had an increased risk of overall mortality (HR = 6.15; 95% CI, 1.55‐24.36; P = .01). HPV status was an independent predictor of overall survival (HR = 6.99; 95% CI, 2.42‐20.16; P < .001) and disease‐specific survival (HR = 6.74; 95% CI, 2.02‐22.48; P = .002). Conclusion PI3K‐AKT‐mTOR signaling pathway up‐regulation and HPV coinfection in PSCC are associated with favorable disease. mTOR pathway biomarkers along with HPV status may represent novel prognosticators for risk stratification of PSCC patients and may help guide treatment decisions and follow‐up strategies. These findings require further investigation. Micro‐Abstract PI3K‐AKT‐mTOR signaling pathway dysregulation has been linked to the development of various malignancies, with only limited and conflicting reports in penile squamous‐cell carcinoma (PSCC). Tissue microarrays of 57 cases of invasive PSCC were immunohistochemically stained for 3 proteins of the mTOR pathway: PTEN, AKT, and S6. Up‐regulation of PI3K‐AKT‐mTOR and human papillomavirus coinfection in PSCC were associated with favorable disease.

Survival Outcomes Associated With Female Primary Urethral Carcinoma: Review of a Single Institutional Experience

Micro‐Abstract Female primary urethral carcinoma is rare, and treatment standards are nonexistent, particularly for the use of multimodal therapy in locally advanced disease. We reviewed 39 patients with primary urethral carcinoma in regard to presentation, treatment, and outcomes. Multimodal therapy shows a nonsignificant interval increase in overall and recurrence‐free survival, but the sequence, type, and delivery of multimodal therapy is poorly defined. Background Primary urethral carcinoma (PUC) is rare, and standard treatment recommendations are lacking. We examined the variation in treatments and survival outcomes of female PUC at a single, tertiary referral cancer center. Methods Records of women with PUC referred to our multidisciplinary genitourinary oncology service between 2003 and 2017 were reviewed. Clinical, demographic, pathologic, primary and salvage therapy details, and overall (OS) and recurrence‐free survival (RFS) were recorded. Survival outcomes were analyzed for the entire cohort, and cases of locally‐advanced (≥ T2 tumor), non‐metastatic PUC were evaluated according to treatment intensity. Multimodal treatment (cystourethrectomy + concomitant therapy) was compared with non‐multimodal therapy. Contingency analyses and Kaplan‐Meier estimates were performed. Results Thirty‐nine women with PUC were identified. In total, median OS was 36 months (95% confidence interval, 10.6‐61.4 months). Twenty‐four had T3 to T4 disease, 12 were node‐positive, and 3 had distant metastases. Histology included 22 adenocarcinomas, 11 urothelial, 5 squamous, and 1 neuroendocrine. Patients with locally advanced, non‐metastatic disease (n = 25) had significantly reduced OS (36 vs. 99 months; P = .016) and RFS (46 months vs. unmet; P = .011) compared with patients with locally confined tumors. Approximately one‐half of locally advanced cases were managed with multimodal therapy (4 with neoadjuvant therapy + cystourethrectomy, 8 with cystourethrectomy + adjuvant therapy, and 1 with chemoradiation + consolidative cystourethrectomy). Multimodal therapy had nonsignificant longer OS (36 vs. 16 months) and RFS (58 vs. 16 months), P > .05. Conclusions Locally advanced female PUC has relatively poor survival outcomes. Although we observed a nonsignificant interval improvement in survival with multimodality therapy, the treatment paradigm is inconsistent. Because it is a rare disease, collaborative multi‐institutional studies are needed.

Bone Preservation Strategies for Men on Androgen Deprivation Therapy

Bone metastases are common in many men with advanced prostate cancer. Maintaining bone health related to the management of prostate cancer is important. Skeletal related events (SRE) are a major source of morbidity for prostate cancer patients. Furthermore, men receiving androgen deprivation therapy (ADT) are at considerably higher risk for debilitating skeletal events. Abnormal bone remodeling secondary to irregular osteoclast activity is a favorable therapeutic target. Bisphosphonates, such as zoledronic acid, can increase bone mineral density of men on ADT and significantly decrease the risk of skeletal complications at risk patients. Denosumab is a human monoclonal antibody that specifically binds and inactivates the RANK ligand, a molecular activation switch for osteoclasts. This osteoclast specific therapy can increase bone mineral density and decrease the risk of fracture. Both therapies have proven benefit in preventing SREs for men with metastatic castration resistant prostate cancer (mCRPC). No agents are currently approved for prevention of bone metastasis, although recent phase III studies are promising. Radium-223, abiraterone and enzalutamide are several mechanistically distinct agents that diminished tumor growth and also decrease the rate of SRE in men with mCRPC. Incorporation and optimization of these bone targeted agents into primary therapy for metastatic prostate cancer investigation is currently on going.