Early vs Delayed Transurethral Surgery in Acute Urinary Retention: Does Timing Make a Difference?

PURPOSE: Our goal was to compare outcomes of early vs delayed transurethral surgery for benign prostatic hyperplasia after an episode of acute urinary retention compared to men without preoperative acute retention. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from the New York Statewide Planning and Research Cooperative System from 2002-2016. We identified men ≥40 years old who underwent primary ambulatory transurethral resection or photoselective vaporization of the prostate, assessing surgical failure as time to reoperation or recatheterization. We categorized presurgical acute urinary retention by number of episodes: none (reference), 1, or ≥2 precatheterizations, and time from first retention episode to surgery: none (reference), 0-6 months, and >6 months. We used Fine-Gray competing-risk models to predict surgical failure at 10 years, with presurgical acute retention as the primary predictor, adjusted for age, race, insurance, Charlson Comorbidity Index score, preoperative urinary infection, and procedure type, with death as the competing risk. RESULTS: Among 17,474 patients undergoing transurethral surgery, 10% had preoperative acute retention with a median time to surgery of 2.4 months (IQR: 1-18). Among men with preoperative retention, 37% had ≥6 months of delay to surgery. The 10-year cumulative treatment failure rate was 17.2% among catheter naïve men vs 34.0% with ≥2 precatheterizations and 32.9% with ≥6 months delay to surgery. Delays from catheterization to surgery were associated with higher rates of treatment failure (<6 months SHR 1.49, P < .001; ≥6 months SHR 2.11, P < .001) vs catheter naïve men. CONCLUSIONS: Preoperative acute urinary retention and delay to surgery once catheterized are associated with poorer long-term postoperative outcomes after surgery for benign prostatic hyperplasia.

A Scoping Review of the Economic Burden of Non-Cancerous Genitourinary Conditions.

OBJECTIVE: To provide a scoping review of the economic burden of non-cancerous genitourinary conditions (NCGUC). METHODS: A scoping review of the economic costs associated with NCGUC was conducted for literature published between 1990-2020. The articles were screened and relevant articles were selected for review. These articles were abstracted with information pertaining to the costs surrounding NCGUC. A descriptive analysis of the data was conducted. RESULTS: We found 3,298 articles in our scoping review. Of these, we found 39 relevant articles related to pelvic floor dysfunction and pelvic organ prolapse, interstitial cystitis, neurogenic bladder, nocturia, urinary tract infections, urolithiasis, urinary incontinence, benign prostatic hyperplasia, overactive bladder, and erectile dysfunction of which the data was reviewed. CONCLUSION: Although the data in estimating the economic burden is limited, existing evidence demonstrates a significant component of health care spending on NCGUC. Much of the spending is out-of-pocket and indirect costs that are difficult to measure which may increase the magnitude of the costs. There is a need for future research that takes a holistic look at the economic impact of NCGUC.

Efficiency of cell-type specific and generic promoters in transducing oxytocin neurons and monitoring their neural activity during lactation.

Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of several physiological and behavioral studies. Advances in viral vector biology and the development of transgenic rodent models have allowed for targeted gene expression to study the functions of specific cell populations and brain circuits. In this study, we compared the efficiency of various adeno-associated viral vectors in these cell populations and demonstrated that none of the widely used promoters were, on their own, effective at driving expression of a down-stream fluorescent protein in OXT or AVP neurons. As anticipated, the OXT promoter could efficiently drive gene expression in OXT neurons and this efficiency is solely attributed to the promoter and not the viral serotype. We also report that a dual virus approach using an OXT promoter driven Cre recombinase significantly improved the efficiency of viral transduction in OXT neurons. Finally, we demonstrate the utility of the OXT promoter for conducting functional studies on OXT neurons by using an OXT specific viral system to record neural activity of OXT neurons in lactating female rats across time. We conclude that extreme caution is needed when employing non-neuron-specific viral approaches/promoters to study neural populations within the paraventricular nucleus of the hypothalamus.

A Claims Based Assessment of Reoperation and Acute Urinary Retention after Ambulatory Transurethral Surgery for Benign Prostatic Hyperplasia.

PURPOSE: We evaluated real-world use of common transurethral prostate procedures in the ambulatory surgical setting and compare subsequent rates of tr!eatment failure. MATERIALS AND METHODS: Using the New York Statewide Planning and Research Cooperative System database we identified men 40 years old or older undergoing ambulatory surgeries categorized as transurethral resection of the prostate, photoselective vaporization of the prostate, endoscopic enucleation or other (transurethral incision, microwave/radiofrequency ablation) from 2010 to 2016. Multivariate Cox proportional hazards regression was used to predict treatment failure, defined as reoperation or postoperative acute urinary retention greater than 30 days after procedure. RESULTS: We identified 15,982 men, median age 69 years (IQR 63-76), 61% of whom underwent photoselective vaporization of the prostate, 36% transurethral resection of the prostate, 1.5% endoscopic enucleation and 1.5% other transurethral prostate procedures from 2010 to 2016. At 7 years cumulative failure rates were 15.3% (transurethral resection of the prostate), 13.9% (photoselective vaporization of the prostate), 6.7% (endoscopic enucleation) and 17.8% (other procedures). Compared to transurethral resection of the prostate, photoselective vaporization of the prostate was not associated with increased hazards of treatment failure HR 1.07 (95% CI 0.93-1.22). Compared to transurethral resection of the prostate, endoscopic enucleation was associated with a nonsignificant trend toward lower treatment failure (HR 0.67, 95% CI 0.36-1.22), while other surgical modalities were associated with significantly higher treatment failure (HR 1.68. 95% CI 1.12-2.52). Among men treated from 2011 to 2012, endoscopic enucleations were associated with significantly lower failure than transurethral resection of the prostate (HR: 0.24, 95% CI 0.06-0.97). CONCLUSIONS: Supporting the generalizability of previous randomized trial findings, in real-world practice we found no differences in treatment failure up to 7 years after photoselective vaporization of the prostate or transurethral resection of the prostate. By comparison, endoscopic enucleation, although underused, may be associated with lower rates of treatment failure than transurethral resection of the prostate.

Outcomes in Patients Treated with Laser Interstitial Thermal Therapy for Primary Brain Cancer and Brain Metastases.

Laser interstitial thermal therapy (LITT) is an emerging modality to treat benign and malignant brain lesions. LITT is a minimally invasive method to ablate tissue using laser-induced tissue heating and serves as both a diagnostic and therapeutic modality for progressive brain lesions. We completed a single-center retrospective analysis of all patients with progressive brain lesions treated with LITT since its introduction at our center in August of 2015. Twelve patients have been treated for a total of 13 procedures, of which 10 patients had brain metastases and 2 patients had primary malignant gliomas. Biopsies were obtained immediately prior to laser-induced tissue heating in 10 procedures (76.9%), of which seven biopsies showed treatment-related changes without viable tumor. After laser ablation, two of three patients previously on steroids were successfully weaned on first attempt. The results of this analysis indicate that LITT is a well-tolerated procedure enabling some patients to discontinue steroids that may be effective for diagnosing and treating radiation necrosis and tumor progression.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Tetrahydroisoquinoline-Based CXCR4 Antagonists with Favorable ADME Properties.

CXCR4 is a G-protein-coupled receptor that interacts with its cognate ligand, CXCL12, to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small-molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal-chemistry efforts toward the redesign of TIQ15 as a result of high mouse-microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability. Guided by the in vitro ADME data of TIQ15, structural modifications were executed to provide compound 12a, which demonstrated a reduced potential for first-pass metabolism while maintaining CXCR4 potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist possessing good intestinal permeability and low risk of CYP-mediated drug-drug interactions.

Herbal Supplements for Prostate Enlargement: Current State of the Evidence.

OBJECTIVE: To provide a comprehensive review of the current state of herbal supplement market for lower urinary tract symptoms (LUTS) and correlate the ingredients of each product with available scientific evidence. MATERIALS AND METHODS: Twenty-seven products from Amazon.com that were advertised as herbal supplements for LUTS and had listed their active ingredients were selected. Active ingredients were reviewed on Google Scholar. Product price, warranty, and consumer review information were also collected. RESULTS: A total of 58 unique active ingredients were identified. The mean number of ingredients was 8.26 (standard deviation 5.25). Whereas 17 (63%) products had an ingredient with a systematic review to support their use, 20 (74%) had an ingredient with conflicting evidence based on systematic reviews. Out of the supplements that contained ingredients supported by literature, all (100%) products simultaneously had other ingredients with no, conflicting, or refuting evidence. There was no (0%) product that contained only scientifically proven ingredients. There is no scientific study to evaluate these supplements as a whole. CONCLUSION: Despite the widespread use of herbal supplements for LUTS, there is scant scientific evidence to support their safety and efficacy. Lack of adequate regulation and government support for research and development are some of the factors that disincentivize researchers to study safety and efficacy of these products. We encourage physicians to warn their patients on the lack of adequate evidence to support the safety and efficacy of many of these supplements.

ALD1613, a Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology.

Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.

Outcomes of intense pulsed light therapy for treatment of evaporative dry eye disease.

OBJECTIVE: To determine the clinical outcomes of intense pulsed light (IPL) therapy for the treatment of evaporative dry eye disease (DED). DESIGN: Multicentre cohort study. PARTICIPANTS: Patients with a diagnosis of meibomian gland dysfunction (MGD) and dry eye presenting to the ophthalmology clinic at either the Duke Eye Center, Durham, NC, or Matossian Eye Associates' private practice in Pennington, NJ, and Doylestown, PA. METHODS: Clinical data were reviewed from 100 patients with diagnosis of MGD and DED who underwent IPL therapy from September 2012 through December 2014 at 1 of 2 centres (Duke Eye Center or Matossian Eye Associates). Demographics, clinical history, examination findings (eyelid and facial vascularity, eyelid margin edema, meibomian gland oil flow, and quality score-all graded on a scale of 0 to 4), tear break up time (TBUT), and ocular surface disease index (OSDI) scoring data were collected from each visit. RESULTS: On average, patients underwent 4 IPL sessions. There was significant decrease in scoring of lid margin edema (mean = -0.3; range -1.5 to 0), facial telangiectasia (mean = -0.7; range -2.5 to 0), lid margin vascularity (mean = -1.2; range -2.5 to 0), meibum viscosity (mean = -1.1; range -3 to 0), and OSDI score (mean = -9.6), all with p < 0.001. There was a significant increase in oil flow score (mean = 0.9, range -0.5 to 2) and TBUT (mean = 3.4 seconds, range -2 to 7), both p < 0.001. No significant changes in intraocular pressure or acuity were noted. There were no cases of adverse ocular effects. CONCLUSIONS: IPL therapy for evaporative DED is a safe procedure. The positive change in objective clinical examination findings and subjective OSDI scoring data suggest that IPL is an effective treatment for patients with evaporative DED.

Voiding Dysfunction in Multiple Sclerosis.

Voiding dysfunction is a common and debilitating consequence of multiple sclerosis (MS). The prevalence and severity of voiding dysfunction increases with the increasing severity of MS, but even the mildest forms of the disease are associated with urinary symptoms in 30% of patients. Every component of the central nervous system is involved in regulating voiding; as a result, MS can lead to a wide variety of urinary symptoms and urologic complications. The effect of MS on voiding can be classified according to the resulting function of the bladder and the urethral sphincter during storage and emptying of urine. Therapy is targeted to the specific bladder and sphincter abnormalities that occur. The primary goals of therapy are prevention of injury to the upper urinary tract (kidneys), reduction in urinary tract infections, and maintenance of urinary continence. These goals can be achieved by interventions ranging from behavioral modification to major reconstructive surgery.

Anti-inflammatory effect of hexane fraction from Myagropsis myagroides ethanolic extract in lipopolysaccharide-stimulated BV-2 microglial cells.

OBJECTIVES: Microglial activation has been implicated in neurological disorders for its inflammatory and neurotrophic effects. We investigated the anti-inflammatory effect of the hexane fraction from Myagropsis myagroides (Mertens ex Turner) Fensholt ethanolic extract and its underlying molecular mechanism in lipopolysaccharide-stimulated microglia. METHODS: Various solvent fractions prepared from the ethanolic extract of M. myagroides were analysed for total phenolic content, 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity and inhibitory effect on nitric oxide (NO) production in activated BV-2 microglia. We measured prostaglandin E2 (PGE2 ) and pro-inflammatory cytokine levels by enzyme-linked immunosorbent assay. Expression of inflammatory enzymes was analysed by Western blot. Nuclear translocation and activation of nuclear factor-kappaB (NF-κB) were determined by immunofluorescence and reporter gene assay, respectively. KEY FINDINGS: Among the fractions, the hexane fraction (MMH), rich in fatty acid, showed the highest inhibitory activity on NO generation. Pretreatment with MMH decreased mRNA and protein levels of inducible NO synthase and cyclooxygenase-2, resulting in a decrease in NO and PGE2 in LPS-stimulated BV-2 cells. Furthermore, MMH inhibited the production of inducible pro-inflammatory cytokines at their transcriptional level via inactivation of NF-κB. MMH inhibited the activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. CONCLUSIONS: These results indicate that MMH has a strong anti-inflammatory activity in LPS-stimulated microglia, suggesting that MMH can be used as a therapeutic agent against neuroinflammatory diseases.

Prostate cancer-specific mortality after definitive radiation therapy: who dies of disease?

BACKGROUND: A competing risks analysis was undertaken to identify subgroups at greatest risk of dying from prostate cancer (PC) after definitive external beam radiation therapy (RT)±androgen deprivation therapy (ADT) in the prostate specific antigen (PSA) era. METHODS: Outcomes of 2675 men with localised PC treated with RT±ADT from 1987-2007 were analysed. Prostate cancer-specific mortality (PCSM) and non-PCSM rates were calculated after stratifying patients according to National Comprehensive Cancer Network (NCCN) risk-group, RT dose, use of ADT and age at treatment. RESULTS: Only 0.2% of low-risk men died of PC 10 years after treatment. All of these deaths occurred in patients treated with < 72 Gy, and only one patient ≥ 70 years old who received ≥ 72 Gy died of PC at last follow-up. Likewise, none of the patients with intermediate-risk disease treated with ≥ 72 Gy and ADT died of PC at 10 years, and the highest 10-year rate of PCSM was seen in men ≥ 70 years old treated with < 72 Gy without ADT (5.1%). Among high-risk men < 70 years old, treatment with RT dose < 72 Gy without ADT yielded similar 10-year rates of PCSM (15.2%) and non-PCSM (18.5%), whereas men treated with ≥ 72 Gy and ADT were twice as likely to die from other causes (16.2%) than PC (9.4%). In high-risk men ≥ 70 years old, dose-escalation with ADT reduced 10-year PCSM from 14% to 4%, and most deaths were due to other causes. CONCLUSION: Low- and intermediate-risk patients treated with definitive RT are unlikely to die of PC. PCSM is higher in men with high-risk disease but may be reduced with dose-escalation and ADT, although patients are still twice as likely to die of other causes.

Improvement in prostate cancer survival over time: a 20-year analysis.

PURPOSE: This study aimed to evaluate the changes in outcome for men with localized prostate cancer treated with definitive external beam radiation therapy during a 20-year period at a comprehensive cancer center. METHODS: We categorized 2675 men with prostate cancer treated at MD Anderson Cancer Center with definitive external beam radiation therapy with or without androgen deprivation therapy into 3 treatment eras: 1987 to 1993 (n = 722), 1994 to 1999 (n = 828), and 2000 to 2007 (n = 1125). To help adjust for stage migration, patients were stratified according to risk group as defined by the National Comprehensive Cancer Network. Biochemical (Phoenix definition), local, distant, and any clinical failure, prostate-cancer specific survival, and overall survival were analyzed according to the Kaplan-Meier method. RESULTS: Median age was 68.5 years and median follow-up was 6.4 years. Fewer men in the most recent era had high-risk disease, and a higher proportion received 72 Gy or higher (99% vs 4%) and androgen deprivation therapy (60% vs 6%) than the earliest era. All risk groups treated in the modern era experienced improved rates of biochemical, local, and distant failure. In high-risk patients, decreased rates of distant failure and clinical failure led to improved prostate cancer-specific survival and overall survival. Local control was improved for intermediate- and high-risk patients, with a trend toward improvement in low-risk patients. On multivariate analysis, recent treatment era was closely correlated with a dose of 72 Gy or higher and treatment with androgen deprivation therapy and predicted for lower rates of biochemical, local, and distant failure. Androgen deprivation therapy, higher dose, and more recent treatment era predicted for improved prostate cancer-specific survival. DISCUSSION: During the last 20 years of prostate cancer irradiation, disease control outcomes have improved in all patients, leading to improved prostate cancer-specific survival and overall survival for men with high-risk disease. This may reflect advances in workup, staging accuracy, and prostate cancer treatment in the modern era.

Sinomenine suppresses TNF-alpha-induced VCAM-1 expression in human umbilical vein endothelial cells.

Sinomenine (SN), an alkaloid prepared from the root of Sinomenium acutum Rehd. Et wils, is used to alleviate the symptoms of rheumatism in Chinese medicine. In the present study, the potential inhibition of TNF-alpha-induced VCAM-1 expression on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. HUVECs were isolated from freshly collected umbilical cords. Positive controls were stimulated with TNF-alpha, omitting SN. Negative controls were cultured omitting TNF-alpha and SN. Experimental groups were co-cultured with TNF-alpha and SN at different concentrations (0.25, 0.5, and 1.0 mol/L), or TNF-alpha and Dexamethasone (Dex) at a concentration of 1.0 x 10(-6) mol/L. Cells were harvested after culturing with the above drugs for 12 h. VCAM-1 mRNA expression was detected by real-time quantitative PCR, and VCAM-1 expression was detected by flow cytometry. The experimental data indicated that VCAM-1 mRNA and VCAM-1 were induced by TNF-alpha. The relative VCAM-1 mRNA expression decreased in the experimental groups (p<0.05). Concentrations of SN at 0.5 and 1.0 mol/L inhibited expression of VCAM-1 (p<0.05). SN at concentration of 0.25 mol/L and Dex at concentration of 1.0 x 10(-6) mol/L did not show an inhibitory effect on VCAM-1 expression in TNF-alpha-induced HUVECs. Our preliminary data indicates that SN has an inhibitory effect in vitro on TNF-alpha-induced VCAM-1 expression at both mRNA level and protein level in HUVECs, and suggests that SN may be a novel method of immunotherapy for rheumatic carditis or rheumatic heart disease.