Does the sequence of high-dose rate brachytherapy boost and IMRT for prostate cancer impact early toxicity outcomes? Results from a single institution analysis.

BACKGROUND: We present the first report comparing early toxicity outcomes with high-dose rate brachytherapy (HDR-BT) boost upfront versus intensity modulated RT (IMRT) upfront combined with androgen deprivation therapy (ADT) as definitive management for intermediate risk or higher prostate cancer. METHODS AND MATERIALS: We reviewed all non-metastatic prostate cancer patients who received HDR-BT boost from 2014 to 2019. HDR-BT boost was offered to patients with intermediate-risk disease or higher. ADT use and IMRT target volume was based on NCCN risk group. IMRT dose was typically 45 Gy in 25 fractions to the prostate and seminal vesicles ± pelvic lymph nodes. HDR-BT dose was 15 Gy in 1 fraction, delivered approximately 3 weeks before or after IMRT. The sequence was based on physician preference. Biochemical recurrence was defined per ASTRO definition. Gastrointestinal (GI) and Genitourinary (GU) toxicity was graded per CTCAE v5.0. Pearson Chi-squared test and Wilcoxon tests were used to compare toxicity rates. P-value < 0.05 was significant. RESULTS: Fifty-eight received HDR-BT upfront (majority 2014-2016) and 57 IMRT upfront (majority 2017-2018). Median follow-up was 26.0 months. The two cohorts were well-balanced for baseline patient/disease characteristics and treatment factors. There were differences in treatment sequence based on the year in which patients received treatment. Overall, rates of grade 3 or higher GI or GU toxicity were <1%. There was no significant difference in acute or late GI or GU toxicity between the two groups. CONCLUSION: We found no significant difference in GI/GU toxicity in intermediate-risk or higher prostate cancer patients receiving HDR-BT boost upfront versus IMRT upfront combined with ADT. These findings suggest that either approach may be reasonable. Longer follow-up is needed to evaluate late toxicity and long-term disease control.

A Prospective, Single-Blind, Randomized, Phase III Study to Evaluate the Safety and Efficacy of Fibrin Sealant Grifols as an Adjunct to Hemostasis During Soft Tissue Open Surgery.

BACKGROUND/PURPOSE: Rapid hemostasis, an essential prerequisite of good surgical practice during surgical bleeding, including soft tissue open surgery, often requires adjunctive treatment. We evaluated the safety and hemostatic effectiveness of a human plasma-derived fibrin sealant (FS Grifols) in soft tissue open surgery. METHODS: Patients with moderate soft tissue bleeding during open, urologic, gynecologic or general surgery were studied. The trial consisted of a preliminary phase (to familiarize investigators with the technique for FS Grifols application and the intraoperative procedures required by the clinical protocol) and a primary phase: in both phases, patients were randomized 1:1 to FS Grifols or Surgicel®. The primary efficacy endpoint, based on analysis of subjects in the primary phase of the study, was to evaluate whether FS Grifols was non-inferior to Surgicel® in achieving hemostasis, based on the proportion of subjects in both treatment groups who achieved hemostasis at the target bleeding site (TBS) by 4 min (T4) following the start of treatment application. Safety assessments included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests, viral markers, and immunogenicity. RESULTS: A total of 224 subjects were randomized (primary phase): FS Grifols (N = 116), Surgicel® (N = 108). The 95% CI at T4 for the ratio of the proportion of patients achieving hemostasis in the two treatment groups was 1.064 (0.934, 1.213), indicating non-inferiority for FS Grifols vs. Surgicel®. The rate of hemostasis at the TBS by T4 in both phases of the study was higher in the FS Grifols treatment group (preliminary phase: 90.2%; primary phase: 82.8%) than in the Surgicel® treatment group (preliminary phase: 78.8%; primary phase: 77.8%). Overall, reported AEs were as expected in surgical patients and were similar between the two treatment groups. CONCLUSIONS: This study shows the non-inferiority in time to hemostasis of FS Grifols vs. Surgicel as an adjunct to hemostasis in patients undergoing soft tissue open surgery, and a similar rate of AEs.

A Novel Video-Based Patient Education Program to Reduce Penile Prosthetic Surgery Cancellations.

Penile prosthetic surgery is an effective treatment for men with erectile dysfunction. Cancellation of surgery is disruptive and costly to patients, physicians, and the healthcare system. This pilot study sought to analyze surgery cancellations and implement a video-based patient education program to decrease surgery noncompletion. Baseline penile prosthetic surgery completion, rescheduling, and cancellation rates among consecutively scheduled surgeries were determined using a national cohort. Selected prosthetic surgeons then implemented Vidscrip, a video-based patient education program. Prerecorded videos were delivered via text message 14 days, 7 days, and 1 day preoperatively, as well as 1 day postoperatively. Subsequent analysis determined noncompletion rates, reasons for noncompletion, surgeon volume, and video utilization. Two-hundred twenty-six surgeries were scheduled in the baseline cohort; 141 were completed, and 85 were rescheduled or canceled. Among the intervention cohort, 290 patients completed, 7 rescheduled, and 37 canceled surgery. After program implementation, the surgery noncompletion rate was reduced compared to baseline (13.2% vs. 37.6%, p < .05), corresponding to a number needed to treat of 4.1. When stratified by surgeon volume, there was no difference in noncompletion rate (>20 cases vs. ≤20 cases: 8.20% vs. 32.0%, p = .35). Video utilization was widely variable among practices (median viewing time 58.6 min, IQR 5.09-113). Penile prosthetic surgery is frequently rescheduled or canceled. Implementing a video-based patient education program reduces surgery noncompletion, improving efficiency and quality of care. Wider implementation is needed to validate these findings, while cost-effectiveness analyses may further support their broad adoption.

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer.

BACKGROUND: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. METHODS: We identified ≥ pT3pN0-3M0 LABC patients in the National Cancer Database diagnosed 2004-2014 who underwent RC ± PORT. OS was calculated using Kaplan-Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. RESULTS: 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2-21.8) for PORT vs 20.8 months (95% CI, 20.3-21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008. A one-to-three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity-matched cohort, median OS was 19.8 months (95% CI, 18.0-21.6) for PORT vs 16.9 months (95% CI, 15.6-18.1) for no PORT (P = 0.030). In the propensity-matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P < 0.01 all). CONCLUSION: In this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted.

A propensity analysis comparing definitive chemo-radiotherapy for muscle-invasive squamous cell carcinoma of the bladder vs. urothelial carcinoma of the bladder using the National Cancer Database.

INTRODUCTION: Squamous cell carcinoma (SqCC) is the second most common histology of primary bladder cancer, but still very limited information is known about its treatment outcomes. Most bladder cancer trials have excluded SqCC, and the current treatment paradigm for localized SqCC is extrapolated from results in urothelial carcinoma (UC). In particular, there is limited data on the efficacy of definitive chemo-radiotherapy (CRT). In this study, we compare overall survival outcomes between SqCC and UC patients treated with definitive CRT. MATERIALS/METHODS: We queried the National Cancer Database (NCDB) for muscle-invasive (cT2-T4 N0 M0) bladder cancer patients diagnosed from 2004 to 2013 who underwent concurrent CRT. Propensity matching was performed to match patients with SqCC to those with UC. OS was analyzed using the Kaplan-Meier survival method, and the log-rank test and Cox regression were used for analyses. RESULTS: 3332 patients met inclusion criteria of which 79 (2.3%) had SqCC. 73.4% of SqCC patients had clinical T2 disease compared to 82.5% of UC patients. Unadjusted median OS for SqCC patients was 15.6 months (95% CI, 11.7-19.6) versus 29.1 months (95% CI, 27.5-30.7) for those with UC (P < 0.0001). On multivariable analysis, factors associated with worse OS included: SqCC histology [HR: 1.53 (95% CI, 1.19-1.97); P = 0.001], increasing age [HR: 1.02 (95% CI, 1.02-1.03); P < 0.0001], increasing clinical T-stage [HR: 1.21 (95% CI, 1.13-1.29); P < 0.0001], and Charlson-Deyo comorbidity index [HR: 1.26 (95% CI, 1.18-1.33); P < 0.0001]. Seventy-seven SqCC patients were included in the propensity-matched analysis (154 total patients) with a median OS for SqCC patients of 15.1 months (95% CI, 11.1-18.9) vs. 30.4 months (95% CI, 19.4-41.4) for patients with UC (P = 0.013). CONCLUSIONS: This is the largest study to-date assessing survival outcomes for SqCC of the bladder treated with CRT. In this study, SqCC had worse overall survival compared to UC patients. Histology had a greater impact on survival than increasing T-stage, suggesting that histology should be an important factor when determining a patient's treatment strategy and that treatment intensification in this subgroup may be warranted.

Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.

Surgical Management for Prostate Cancer.

For prostate cancer, radical prostatectomy remains the gold standard for surgical management. Given the side effects associated with surgery, patients at low risk of prostate cancer-specific mortality should consider active surveillance under the guidance of a urologist to safely delay intervention. For patients with an intermediate risk of cancer-specific mortality and otherwise healthy life expectancy, radical prostatectomy has been demonstrated to improve survival. Finally, even for select patients with advanced prostate cancer-metastatic disease to the lymph nodes or distant sites-radical prostatectomy may provide a survival benefit.

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.

Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.

Sperm recovery and IVF after testicular sperm extraction (TESE): effect of male diagnosis and use of off-site surgical centers on sperm recovery and IVF.

OBJECTIVE: Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation. PATIENTS: One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm. OUTCOME MEASURES: Successful sperm recovery defined as 1-2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and "other"(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician's office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm. RESULTS: Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%). CONCLUSION: Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization.

A comparison of chlorhexidine-alcohol versus povidone-iodine for eliminating skin flora before genitourinary prosthetic surgery: a randomized controlled trial.

PURPOSE: We defined the relevant skin flora during genitourinary prosthetic surgery, evaluated the safety of chlorhexidine-alcohol for use on the male genitalia and compared chlorhexidine-alcohol to povidone-iodine in decreasing the rate of positive bacterial skin cultures at the surgical skin site before prosthetic device implantation. MATERIALS AND METHODS: In this single institution, prospective, randomized, controlled study we evaluated 100 consecutive patients undergoing initial genitourinary prosthetic implantation. Patients were randomized to a standard skin preparation with povidone-iodine or chlorhexidine-alcohol. Skin cultures were obtained from the surgical site before and after skin preparation. RESULTS: A total of 100 patients were randomized, with 50 in each arm. Pre-preparation cultures were positive in 79% of the patients. Post-preparation cultures were positive in 8% in the chlorhexidine-alcohol group compared to 32% in the povidone-iodine group (p = 0.0091). Coagulase-negative staphylococci were the most commonly isolated organisms in post-preparation cultures in the povidone-iodine group (13 of 16 patients) as opposed to propionibacterium in the chlorhexidine-alcohol group (3 of 4 patients). Clinical complications requiring additional operations or device removal occurred in 6 patients (6%) with no significant difference between the 2 groups. No urethral or genital skin complications occurred in either group. CONCLUSIONS: Chlorhexidine-alcohol was superior to povidone-iodine in eradicating skin flora at the surgical skin site before genitourinary prosthetic implantation. There does not appear to be any increased risk of urethral or genital skin irritation with the use of chlorhexidine compared to povidone-iodine. Chlorhexidine-alcohol appears to be the optimal agent for skin preparation before genitourinary prosthetic procedures.

Laparascopic capsulotomy to treat autoinflation of inflatable penile prostheses.

INTRODUCTION: Inflatable penile prosthetic implants are a reliable treatment for erectile dysfunction. Mechanical failures now are the most common reason for revision of this type of device, and autoinflation is a common cause for device revision. There are currently no published surgical treatments for this malfunction. AIM: To describe a simple outpatient surgical revision for an automatically inflating device using laparascopic dissection. MAIN OUTCOME MEASURES: Complete deflation of penile prosthesis on follow-up visit, intraoperative and postsurgical complications, and length of procedure. METHODS: We performed a retrospective review of patients treated for inflatable penile prosthesis autoinflation with laparascopic capsulotomy to release constricting connective tissue rind surrounding the device reservoir at a single institution. We collected information about etiology of impotence, surgical procedures relating to implant and revision of prosthetic devices, and follow-up evaluations. RESULTS: Four patients underwent laparascopic capsulotomy to treat autoinflation. Mean operative time was 45 minutes, and no adverse surgical or perioperative outcomes occurred. All four patients had deflated corporal cylinders at the time of follow-up evaluation. CONCLUSIONS: Laparascopic capsulotomy is an easy and reliable method of treating inflatable penile prosthesis autoinflation that can be performed in the outpatient setting.

Positive margin during partial nephrectomy: does cancer remain in the renal remnant?

OBJECTIVE: To examine the outcomes of patients with a positive surgical margin by gross and/or frozen examination during partial nephrectomy, in whom a re-resection of the margin or a completion nephrectomy was performed. METHODS: Patients with renal cancer who underwent partial nephrectomy were considered. If the patient had a positive margin and underwent completion nephrectomy or re-excision of the margin, they were included. Patients with planned enucleation were excluded from the study. Clinical and pathologic information were reviewed to examine for residual cancer in the additionally resected tissue. RESULTS: In the final cohort, 29 patients with a positive margin and subsequent complete parenchymal re-resection or completion nephrectomy were identified. Eight patients underwent nephrectomy, after which no residual cancer was found in the renal remnant. Twenty-one patients underwent total re-resection of the margin, of which two were found to have carcinoma. Renal functional outcomes revealed a decrease in estimated glomerular filtration rate of 25 mL/min/1.73 m(2) in patients who underwent radical nephrectomy, and 4 mL/min/1.73 m(2) in patients who underwent re-resection of the margin with preservation of the renal unit. CONCLUSIONS: A positive surgical margin does not necessarily mean that cancer remains in the renal remnant in most cases. Therefore, radical nephrectomy or re-resection of the margin is overtreatment in many cases, but a small percentage of patients will harbor residual malignancy. Clinical correlation is recommended before reexcision or completion nephrectomy after a positive surgical margin, with careful consideration of the impact on subsequent renal function weighed against the possibility of residual disease.

Update on male urinary stress incontinence.

Urinary incontinence after prostate surgery is a rare, but potentially devastating problem. Guidelines for the evaluation and treatment of male stress urinary incontinence have evolved over the years. A review of current behavioral, medical and surgical approaches (male sling, artificial urinary sphincter) for post prostatectomy incontinence is reviewed in this manuscript.

Prostate-specific antigen density predicts adverse pathology and increased risk of biochemical failure.

OBJECTIVES: To determine whether the prostate-specific antigen (PSA) density (PSAD), measured using either ultrasound (US) or prostatic weight (PW), is an independent predictor of adverse pathologic findings or biochemical-free survival and whether it outperformed PSA. METHODS: The data were obtained prospectively from 1327 patients undergoing radical prostatectomy from 1990 to 2003. The US PSAD was calculated by dividing the preoperative PSA level in nanograms per milliliter by the US measured prostate volume in cubic centimeters. The PW PSAD was calculated by dividing the PSA value in nanograms per milliliter by the measured PW of the prostatectomy specimen in grams. Logistic regression analysis was performed to determine whether the US or PW PSAD was more accurate than the PSA level in predicting for adverse pathologic findings. A proportional hazards model was used to determine whether PSAD more accurately predicted for biochemical failure (PSA level greater 0.2 ng/mL). RESULTS: Multivariate analysis demonstrated that US and PW PSAD were independent predictors of positive margins (odds ratio [OR] 5.00, 95% confidence interval [CI] 2.65 to 9.47 and OR 29.75, 95% CI 10.18 to 86.96, respectively), extracapsular disease (OR 10.89, 95% CI 5.32 to 22.32 and OR 126.62, 95% CI 37.99 to 422.07, respectively), seminal vesical invasion (OR 6.06, 95% CI 2.96 to 12.41 and OR 33.72, 95% CI 9.79 to 116.15, respectively), and biochemical failure (hazard ratio 3.32, 95% CI 2.38 to 4.63 and hazard ratio 8.70, 95% CI 5.21 to 14.52, respectively). The C-index demonstrated that both US and PW PSAD appeared more discriminant for adverse pathologic findings and biochemical failure than did the PSA level. CONCLUSIONS: The US and PW PSAD are strong predictors of advanced pathologic features and biochemical failure after radical prostatectomy. The incorporation of PSAD into the risk assessment could provide additional prognostic information beyond grade, stage, and PSA level; therefore, the inclusion of PSAD into nomograms should be considered.

Surgical treatment of renal neoplasia: evolving toward a laparoscopic standard of care.

OBJECTIVES: To determine the extent to which laparoscopy has replaced open surgery for renal malignancy. METHODS: The records of all 537 patients at Washington University who underwent surgery for localized renal malignancies from January 1997 to December 2001 were examined for clinical and pathologic information. RESULTS: The total procedures per year increased from 1997 to 2001, but the distribution of pathologic stages throughout the 5 years was similar. In 1997, laparoscopic approaches were used in 15% of cases; this increased to 65% by 2001. Nephron-sparing surgery (NSS) was used in 31% to 42% of patients yearly, but laparoscopic NSS increased in frequency. By 2001, only 3.3% of T1 tumors were removed by open radical nephrectomy compared with 55% treated by laparoscopic nephrectomy. The rest of the T1 tumors in 2001 were treated by open partial nephrectomy (20.2%) or laparoscopic NSS (21.3%). In 2001, 61% of T2 lesions were treated laparoscopically, an increase from 37% in 1997. Most open radical nephrectomies in 2001 were performed for T3 disease. The number of surgeons performing laparoscopic renal surgery has increased at our institution, from two in 1997, both endourologists, to eight in 2001, representing the entire urology faculty that treats renal cancer. CONCLUSIONS: Laparoscopic radical nephrectomy has replaced open radical nephrectomy for low-stage renal neoplasia. Although laparoscopic NSS is increasing in frequency, it has not yet replaced open partial nephrectomy. At our institution, the laparoscopic approach has become the standard of care when radical nephrectomy is needed for T1 or T2 renal cancer.