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The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative symposium dedicated to optimizing sexual function and preserving cardiovascular health. The Fourth Princeton Consensus Conference was convened on March 10-11, 2023, at the Huntington Medical Research Institutes in Pasadena, California. Princeton panels I to III addressed the clinical management of men with erectile dysfunction (ED) who also had cardiovascular disease. Thirteen years since Princeton III, Princeton IV builds on previous foundations in several key areas. Mounting evidence supports the need for providers to treat men with ED as being at risk for cardiac events until proven otherwise. Algorithms for the diagnosis and treatment of ED are updated with new recommendations for coronary artery calcium scoring for advanced cardiovascular risk stratification. Optimization of oral phosphodiesterase type 5 inhibitors in the treatment of men with ED and cardiovascular disease is thoroughly explored, including recent evidence of potential cardioprotective effects of these drugs.
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INTRODUCTION: Prior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023. OBJECTIVES: Our meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area. METHODS: An expert panel reviewed existing research and clinical practice guidelines. RESULTS: Key findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications. CONCLUSION: Studies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.
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OBJECTIVE: To report urinary bother, urinalysis changes, disease-free survival (DFS), and overall survival (OS) over 2 years for subjects enrolled in a phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab for recurrent or persistent high-grade non-muscle invasive bladder cancer (HGNMIBC). METHODS: Eighteen patients consented to the study. Five were screen failures. Clinical activity was determined using cystoscopy and cytology with a biopsy of suspicious lesions. Urinalysis and International Prostate symptom score were assessed at pre-treatment, Week 10 (during combined BCG and pembrolizumab treatment), and 3 and 6 months from treatment completion. IPSS was analyzed using a mixed-model repeated measures analysis. A Chi-square test was used to compare urinalysis results at each interval. RESULTS: The pathologic disease stage after restaging transurethral resection and before treatment was pTa in 6 (46.2%), CIS in 6 (46.2%), and pT1 in 1 (7.7%). There was no increase in reported urinary bother throughout treatment. Quality of life measurements demonstrated no change in subjective burden. On urinalysis, we did not observe significant differences at 3 months compared to baseline evaluation. At 12 months, the DFS and OS were 69.23% and 92.31%, respectively. At 24 months, the DFS and OS were 38.46% and 92.31%, respectively. CONCLUSIONS: Treatment with BCG combined with intravenous pembrolizumab is not showing increased urinary bother or adverse urinalysis changes. Two-year response data is promising and await confirmation in the phase III study (Keynote 676).
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Anticorpos Monoclonais Humanizados , Vacina BCG , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Vacina BCG/administração & dosagem , Vacina BCG/uso terapêutico , Masculino , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Administração Intravesical , Pessoa de Meia-Idade , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Seguimentos , Resultado do Tratamento , Urinálise , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Neoplasias não Músculo Invasivas da BexigaRESUMO
BACKGROUND: The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with erectile dysfunction (ED), initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle and increased collagen, which alter penile architecture and make corpora cavernosa smooth muscle less able to relax in response to neurotransmitters, resulting in ED. AIM: Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses penile remodeling after CN injury through an unknown mechanism; we examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1). METHODS: Primary cultures of smooth muscle cells were established from prostatectomy, diabetic, hypertension and Peyronie's (control) (N = 18) patients. Cultures were characterized by ACTA2, CD31, P4HB, and nNOS immunohistochemical analysis. Patient smooth muscle cell growth was quantified in response to BMP4 and GREM1 treatment. Adult Sprague Dawley rats underwent 1 of 3 surgeries: (1) uninjured or CN-injured rats were treated with BMP4, GREM1, or mouse serum albumin (control) proteins via Affi-Gel beads (N = 16) or peptide amphiphile (PA) (N = 26) for 3 and 14 days, and trichrome stain was performed; (2) rats underwent sham (N = 3), CN injury (N = 9), or CN injury and SHH PA treatment for 1, 2, and 4 days (N = 9). OUTCOMES: Western analysis for BMP4 and GREM1 was performed; (3) rats were treated with 5E1 SHH inhibitor (N = 6) or IgG (control; N = 6) for 2 and 4 days, and BMP4 and GREM1 localization was examined. Statistics were performed by analysis of variance with Scheffé's post hoc test. RESULTS: BMP4 increased patient smooth muscle cell growth, and GREM1 decreased growth. In rats, BMP4 treatment via Affi-Gel beads and PA increased smooth muscle at 3 and 14 days of treatment. GREM1 treatment caused increased collagen and smooth muscle at 3 days, which switched to primarily collagen at 14 days. CN injury increased BMP4 and GREM1, while SHH PA altered Western band size, suggesting alternative cleavage and range of BMP4 and GREM1 signaling. SHH inhibition in rats increased BMP4 and GREM1 in fibroblasts. CLINICAL IMPLICATIONS: Understanding how SHH PA preserves and regenerates penile morphology after CN injury will aid development of ED therapies. STRENGTHS AND LIMITATIONS: SHH treatment alters BMP4 and GREM1 localization and range of signaling, which can affect penile morphology. CONCLUSION: Part of the mechanism of how SHH regulates corpora cavernosa smooth muscle involves BMP4 and GREM1.
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Proteína Morfogenética Óssea 4 , Proteínas Hedgehog , Peptídeos e Proteínas de Sinalização Intercelular , Pênis , Animais , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Citocinas , Disfunção Erétil/etiologia , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Induração Peniana/patologia , Prostatectomia , Ratos Sprague-DawleyRESUMO
BACKGROUND: Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment. AIM: We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and examined the relationship between SHH, BMP4, GREM1, and collagen in penis of ED patients and rat models of CN injury, SHH inhibition, and SHH, BMP4, and GREM1 treatment. METHODS: Corpora cavernosa of Peyronie's disease (control), prostatectomy, and diabetic ED patients were obtained (N = 30). Adult Sprague Dawley rats (n = 90) underwent (1) CN crush (1-7 days) or sham surgery; (2) CN injury and BMP4, GREM1, or mouse serum albumin (control) treatment via Affi-Gel beads or peptide amphiphile (PA) for 14 days; (3) 5E1 SHH inhibitor, IgG, or phosphate-buffered saline (control) treatment for 2 to 4 days; or (4) CN crush with mouse serum albumin or SHH for 9 days. OUTCOMES: Immunohistochemical and Western analysis for BMP4 and GREM1, and collagen analysis by hydroxyproline and trichrome stain were performed. RESULTS: BMP4 and GREM1 proteins were identified in corpora cavernosa smooth muscle of prostatectomy, diabetic, and Peyronie's patients, and in rat smooth muscle, sympathetic nerve fibers, perineurium, blood vessels, and urethra. Collagen decreased 25.4% in rats with CN injury and BMP4 treatment (P = .02) and increased 61.3% with CN injury and GREM1 treatment (P = .005). Trichrome stain showed increased collagen in rats treated with GREM1. Western analysis identified increased BMP4 and GREM1 in corpora cavernosa of prostatectomy and diabetic patients, and after CN injury (1-2 days) in our rat model. Localization of BMP4 and GREM1 changed with SHH inhibition. SHH treatment increased the monomer form of BMP4 and GREM1, altering their range of signaling. CLINICAL IMPLICATIONS: A better understanding of penile remodeling and how fibrosis occurs with loss of innervation is essential for development of novel ED therapies. STRENGTHS AND LIMITATIONS: The relationship between SHH, BMP4, GREM1, and collagen is complex in the penis. CONCLUSION: BMP4 and GREM1 are downstream targets of SHH that impact collagen and may be useful in collaboration with SHH to prevent penile remodeling and ED.
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Proteína Morfogenética Óssea 4 , Colágeno , Disfunção Erétil , Proteínas Hedgehog , Peptídeos e Proteínas de Sinalização Intercelular , Pênis , Transdução de Sinais , Animais , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Proteína Morfogenética Óssea 4/metabolismo , Colágeno/metabolismo , Citocinas , Modelos Animais de Doenças , Disfunção Erétil/metabolismo , Disfunção Erétil/etiologia , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Induração Peniana/metabolismo , Pênis/inervação , Pênis/metabolismo , Prostatectomia , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: To determine the safety and effectiveness of water vapor thermal therapy (Rezum) in men with large prostate volumes of at least 80cm3. METHODS: We performed systematic searches for studies of Rezum therapy in men with prostate volume of at least 80â¯cm3. Meta-analysis outcomes included the International Prostate Symptom Score (IPSS), IPSS Quality of Life (IPSS-QOL), Qmax, postvoid residual, International Index of Erectile Function-Erectile Function (IIEF-EF), and serious (Clavien-Dindo grade III-V) complications, surgical retreatments. Outcomes were analyzed using a random effects meta-analysis model. RESULTS: The review included 15 studies (11 retrospective) of 471 men with prostate volume at least 80â¯cm3 treated with Rezum therapy and followed for a median of 6months (range: 3-17months). Rezum therapy resulted in statistically significant improvements in IPSS (mean change: -11.0; 95% CI: -12.2, -9.7; Pâ¯<â¯.001), IPSS-QOL (mean change: -2.9; 95% CI: -3.5, -2.4; Pâ¯<â¯.001), Qmax (mean change: 6.5â¯mL/s; 95% CI: 4.8, 8.2â¯mL/s; Pâ¯<â¯.001), and postvoid residual (mean change: -101â¯mL; 95% CI: -145, -57; Pâ¯<â¯.001). No change in IIEF-EF was observed (mean change: 0.3; 95% CI: -1.1, 1.6; Pâ¯=â¯.71). Serious complications occurred in <0.1% (95% CI: 0.0%, 0.4%) and surgical retreatment in 1.2% (95% CI: 0.0%, 3.5%) of patients. CONCLUSION: Rezum therapy provides a statistically significant and clinically important short-term improvement in lower urinary tract symptoms with low complication rates in men with prostate volume of at least 80â¯cm3. Long-term outcomes with Rezum therapy in large prostates remain unclear.
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Disfunção Erétil , Próstata , Masculino , Humanos , Qualidade de Vida , Vapor , Estudos RetrospectivosRESUMO
BACKGROUND: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs. AIM: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. METHOD: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. OUTCOMES: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. RESULTS: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. CLINICAL IMPLICATIONS: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. STRENGTHS AND LIMITATIONS: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. CONCLUSION: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.
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Doenças Cardiovasculares , Disfunção Erétil , Masculino , Humanos , Feminino , Inibidores da Fosfodiesterase 5/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate the incidence and risk factors of persistent lower urinary tract symptoms (LUTS) 1 month and later following convective water vapor thermal therapy (CWVTT) in men with LUTS secondary to benign prostatic hyperplasia (BPH). METHODS: Patients who underwent CWVTT from 11/2018-5/2021 at a single institution were eligible for inclusion and retrospectively identified. Pertinent patient, operative, and outcomes data were extracted. The primary outcome was clinically significant LUTS improvement at 4 weeks following CWVTT. Persistent LUTS was defined as failure to reach a minimally clinical important difference of 25% reduction on International Prostate Symptom Score at 4 weeks. RESULTS: One hundred nine patients qualified. Fifty percent of patients experienced persistent LUTS at 1 month. Eighty-two percent of men ultimately reached the minimally clinical important difference. For each additional month following CWVTT, the odds of achieving clinically significant LUTS improved by 9% (Odds ratio (OR) = 0.91, P = .0033). Bladder outlet obstruction index and prior surgical BPH therapy were associated with persistent LUTS on multivariate logistic regression. Every 10-unit increase in Bladder outlet obstruction index noted at baseline was associated with a 15% increased likelihood of achieving minimally clinical important difference in LUTS at 4 weeks following CWVTT (OR = 0.85, P = .01). Patients receiving prior surgical BPH therapy were 3.5 times more likely to experience persistent LUTS at 1 month (OR = 3.47, P = .01). CONCLUSION: Fifty percent of men experienced persistent LUTS 1 month following CWVTT. However, LUTS improved with time and the majority of men ultimately achieved clinically significant LUTS improvement. A lower baseline Bladder outlet obstruction index and prior BPH procedures are risk factors for persistent LUTS following CWVTT.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Obstrução do Colo da Bexiga Urinária , Masculino , Humanos , Hiperplasia Prostática/complicações , Hiperplasia Prostática/terapia , Hiperplasia Prostática/diagnóstico , Vapor , Obstrução do Colo da Bexiga Urinária/complicações , Estudos Retrospectivos , Sintomas do Trato Urinário Inferior/epidemiologia , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/terapia , Fatores de RiscoRESUMO
OBJECTIVES: Convective water vapor thermal therapy (CWVTT-Rezum) is a minimally invasive surgical therapy that is being increasingly utilized for bladder outlet obstruction. Most patients leave the site of care with a Foley catheter in place for a mean reported duration of 3-4 days. A minority of men will fail their trial without catheter (TWOC). We aim to identify the frequency of TWOC failure following CWVTT and its associated risk factors. METHODS: Patients who underwent CWVTT at a single institution from October 2018 to May 2021 were retrospectively identified and pertinent data extracted. The primary endpoint was TWOC failure. Descriptive statistics were performed, and rate of TWOC failure was determined. Potential risk factors for failed TWOC were assessed through univariate and multivariate logistic regression. RESULTS: A total of 119 patients were analyzed. Seventeen percent (20/119) had a failed TWOC on their first attempt. Of those, 60% (12/20) failed in a delayed fashion. In patients who failed, the median number of total TWOC attempts required for success was two (interquartile range [IQR] = 2-3). All patients eventually had a successful TWOC. The median preoperative postvoid residual for successful and failed TWOC was 56 mL (IQR = 15-125) and 87 mL (IQR = 25-367), respectively. Preoperative elevated postvoid residual (unadjusted odds ratio [OR] 1.02, 95% CI: 1.01-1.04; adjusted OR 1.02, 95% CI: 1.01-1.04) was associated with TWOC failure. CONCLUSIONS: Seventeen percent of patients failed their initial TWOC after CWVTT. Elevated postvoid residual was associated with TWOC failure.
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Hiperplasia Prostática , Retenção Urinária , Masculino , Humanos , Retenção Urinária/etiologia , Vapor , Hiperplasia Prostática/complicações , Estudos Retrospectivos , Resultado do Tratamento , Doença Aguda , Catéteres/efeitos adversos , Fatores de RiscoRESUMO
INTRODUCTION: Patients with a prostatectomy are at high risk of developing erectile dysfunction (ED) that is refractory to phosphodiesterase type 5 inhibitors. The cavernous nerve (CN) is frequently damaged during prostatectomy, causing loss of innervation to the penis. This initiates corpora cavernosal remodeling (apoptosis and fibrosis) and results in ED. AIM: To aid in the development of novel ED therapies, the current aim was to obtain a global understanding of how signaling mechanisms alter in the corpora cavernosa with loss of CN innervation that results in ED. METHODS: Microarray and pathway analysis were performed on the corpora cavernosal tissue of patients with a prostatectomy (n = 3) or Peyronie disease (control, n = 3). Results were compared with an analysis of a Sprague-Dawley rat CN injury model (n = 10). RNA was extracted by TRIzol, DNase treated, and purified by a Qiagen Mini Kit. Microarray was performed with the Human Gene 2.0 ST Array and the RU34 rat array. Differentially expressed genes were identified through several analytic tools (ShinyGO, Ingenuity, WebGestalt) and databases (GO, Reactome). A 2-fold change was used as the threshold for differential expression. OUTCOMES: Pathways that were altered (up- or downregulated) in response to CN injury in the prostatectomy patients and a rat CN injury model were determined. RESULTS: Microarray identified 197 differentially expressed protein-coding genes in the corpora cavernosa from the prostatectomy cohort, with 100 genes upregulated and 97 genes downregulated. Altered signaling pathways that were identified that affect tissue morphology included the following: neurologic disease, cell death and survival, tissue and cellular development, skeletal and muscle development and disorders, connective tissue development and function, tissue morphology, embryonic development, growth and proliferation, cell-to-cell signaling, and cell function and maintenance. These human pathways have high similarity to those observed in the CN-injured rat ED model. CLINICAL IMPLICATIONS: Significant penile remodeling continues in patients long after the acute surgical injury to the CN takes place, offering the opportunity for clinical intervention to reverse penile remodeling and improve erectile function. STRENGTHS AND LIMITATIONS: Understanding how signaling pathways change in response to CN injury and how these changes translate to altered morphology of the corpora cavernosa and ensuing ED is critical to identify strategic targets for therapy development. CONCLUSION: Altered signaling in pathways that regulate tissue homeostasis, morphogenesis, and development was identified in penes of patients with a prostatectomy, and competitive forces of apoptosis and proliferation/regeneration were found to compete to establish dominance after CN injury. How these pathways interact to regulate penis tissue homeostasis is a complex process that requires further investigation.
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Disfunção Erétil , Induração Peniana , Traumatismos do Sistema Nervoso , Masculino , Humanos , Ratos , Animais , Ratos Sprague-Dawley , Ereção Peniana , Pênis , Traumatismos do Sistema Nervoso/complicações , Prostatectomia/efeitos adversos , Modelos Animais de DoençasRESUMO
BACKGROUND: Urinary microbiota is implicated in many diseases of the urinary tract. The aim of this study was to perform a systematic review of the role of urinary microbiota in prostatic diseases. METHODS: A PubMed/Medline search was undergone from inception through June 2022 for studies investigating urinary microbiota alterations in prostatic diseases, subdivided into benign prostatic hyperplasia (BPH), prostate cancer (PCa), and chronic prostatitis (CP). Study selection followed the PRISMA statement. Phylum, family, genus and species of each bacterium in cancer patients and controls were recorded. Quality of included studies was evaluated using the Critical Appraisal Skills Program (CASP) checklist for non-randomized studies. RESULTS: A total of 16 studies (4 studies on BPH, 9 studies on PCa and 3 studies on CP) comprising 1486 patients were included in our final analysis. Patients with BPH had a different urinary microbial composition, with a certain pattern proven to be associated with a higher lower urinary tract symptoms severity. Regarding PCa, some bacterial phyla/genera/classes/species were more abundant in PCa and others predicted a higher grade disease. In patients with CP, a different microbiota composition and a higher diversity were found, with the symptom severity being influenced mainly by microbiota composition, favoring aerobic microorganisms. CONCLUSION: Urinary microbiota is implicated in prostatic diseases, especially in BPH, PCa and CP. However, given the relative heterogeneity among published studies, this implication suggests better delineation is needed. Further studies are needed to confirm these findings.
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Sintomas do Trato Urinário Inferior , Microbiota , Hiperplasia Prostática , Neoplasias da Próstata , Prostatite , Masculino , Humanos , Hiperplasia Prostática/complicações , Neoplasias da Próstata/complicações , Doença CrônicaRESUMO
PURPOSE: To create a prospective, multicenter coordinated registry network (CRN) of robust "real world" data for benign prostatic hyperplasia (BPH) that links surgical practices to objective and subjective outcomes of patients who undergo surgery for the improvement in lower urinary tract symptoms (LUTS) secondary to BPH. METHODS: We gathered a group of BPH experts from various institutions to identify the minimum core data elements needed to assess BPH procedures. To achieve consensus on the data elements, we used a Delphi method adaptation, in which a series of surveys were answered by the expert panel individually and anonymously. Survey results were collected and analyzed. Questions for the following round were based on response analysis from the prior survey. This process was repeated until consensus was achieved. RESULTS: Participation rates in the first and second rounds were 100% and 90%, respectively. The expert panel reached consensus on 148 data elements out of the 182 proposed, capturing patient medical and surgical history, procedure, discharge, short- and long-term follow-up, device factors, surgery, and surgeon factors. CONCLUSION: We have successfully developed a set of core data elements to support the study of BPH surgical therapies by gathering an expert panel on BPH and using the Delphi method. These data elements influence provider decisions about treatment and include important outcomes related to efficacy and safety.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/complicações , Hiperplasia Prostática/cirurgia , Hiperplasia Prostática/diagnóstico , Estudos Prospectivos , Sintomas do Trato Urinário Inferior/cirurgia , Sintomas do Trato Urinário Inferior/complicações , Sistema de Registros , América do NorteRESUMO
OBJECTIVE: To investigate voiding time (VT) in asymptomatic and symptomatic men, and compare VT to other parameters such as maximum flow rates (Qmax) as a possible solution to disparity related lack of access to standard urodynamic testing. METHODS: We conducted a controlled prospective study on a total of 30 patients. Exclusion criteria included ongoing medical therapy for lower urinary tract symptoms (LUTS) or a history of invasive therapy for LUTS. Patients completed International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry, and post-void residual (PVR) testing. Symptomatic LUTS was defined as an IPSS ≥8. RESULTS: On univariate analysis, men with a symptomatic LUTS had a significantly longer VT than asymptomatic men (30.6 seconds (Interquartile rage [IQR] 24.2-42.4) vs 20.5 seconds (IQR 16.6-40.5), Pâ¯=â¯.04). VT was not otherwise associated with age, race, or primary complaint. There was trend towards lower Qmax in symptomatic patients (13.4 vs 20.5 seconds, Pâ¯=â¯.07), although this was not statistically significant. Our study demonstrated that the sensitivity of a VT ≥23.5 seconds, or probability of observing a VT exceeding 23.5 seconds when the patient has a symptomatic IPSS, is 85%. On sensitivity and specificity analysis, there was no difference between the abilities of VT and Qmax to predict that a patient would have symptomatic LUTS (Pâ¯=â¯.80). CONCLUSION: In this controlled prospective study, we found that VT was as accurate as Qmax in predicting symptomatic IPSS scores. This novel finding might improve the ability to diagnose and treat LUTS, especially in primary care offices and underserved areas.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Humanos , Masculino , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/terapia , Estudos Prospectivos , Hiperplasia Prostática/complicações , Projetos de Pesquisa , Inquéritos e Questionários , UrodinâmicaRESUMO
PURPOSE: With the ubiquity of lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) in older men, costs related to this highly prevalent disease are likely significant but not well defined. With this study, we hoped to define costs related to LUTS/BPH care. METHODS: We utilized the Optum© de-identified Clinformatics® Data Mart Database (CDM) for privately insured male enrollees aged 40-64 years with LUTS/BPH (N ≈ 100,300 annually) and the Centers for Medicare and Medicaid Services Medicare 5% Sample for male beneficiaries aged 65 + years with LUTS/BPH (N ≈ 147,800 annually). Annual LUTS/BPH-related expenditures from 2004 to 2013 were age standardized and calculated overall and by age and service location. RESULTS: The Medicare cohort demonstrated a 23% increase in total costs over the study period with a 28% decrease in CDM costs. Decreases in inpatient hospital charges (45% for Medicare, 55% for CDM) were offset by increasing hospital-based outpatient fees (120% for Medicare, 87% for CDM). Overall, we estimated a total cost of at least $1.9 billion for treatment of men with LUTS/BPH for 2013. Per person expenditures increased with age within cohorts with an average per-person cost of $269 (CDM) and $248 (Medicare) in 2013. CONCLUSION: The distribution of healthcare expenditures for LUTS/BPH shifted across practice settings from 2004 to 2013, with increasing outpatient relative to inpatient expenditures. Total direct costs for LUTS/BPH in 2013 were at least $1.9 billion, not accounting for indirect costs or certain unmeasured populations.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Idoso , Estudos de Coortes , Custos de Cuidados de Saúde , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/terapia , Masculino , Medicare , Hiperplasia Prostática/diagnóstico , Estados UnidosRESUMO
BACKGROUND: Cavernous nerve (CN) injury causes penile remodeling, including smooth muscle apoptosis and increased collagen, which results in erectile dysfunction (ED), and prevention of this remodeling is critical for novel ED therapy development. AIM: We developed 2 peptide amphiphile (PA) hydrogel delivery vehicles for Sonic hedgehog (SHH) protein to the penis and CN, which effectively suppress penile distrophic remodeling (apoptosis and fibrosis), in vivo in a rat CN injury model, and the aim of this study is to determine if SHH PA can be used to regenerate human corpora cavernosal smooth muscle deriving from multiple ED origins. METHODS: Corpora cavernosal tissue was obtained from prostatectomy, diabetic, hypertension, cardiovascular disease and Peyronie's (control) patients (n = 21). Primary cultures (n = 21) were established, and corpora cavernosal cells were treated with SHH protein, MSA (control), 5E1 SHH inhibitor, and PBS (control). Growth was quantified by counting the number of cells at 3-4 days. Statistics were performed by ANOVA with Scheffe's post hoc test. Concentration of SHH protein for maximal growth was optimized, and a more active SHH protein examined. OUTCOMES: Cultures were characterized by immunohistochemical analysis with ACTA2, CD31, nNOS and P4HB, and smooth muscle was quantified in comparison to DAPI. RESULTS: Cultures established were >97% smooth muscle. SHH protein increased growth of smooth muscle cells from prostatectomy, diabetic, and Peyronie's patients in a similar manner (49%-51%), and SHH inhibition decreased growth (20%-33%). There was no difference in growth using 25 ug and 10 ug SHH protein, suggesting a threshold concentration of SHH protein above which smooth muscle growth is enhanced. A more active lipid modified SHH peptide further enhanced growth (15%), indicating a more robust growth response. SHH increased growth in smooth muscle cells from hypertension (37%) and cardiovascular disease (32%) patients. SHH protein increased growth under normal and high glucose conditions, suggesting that high glucose conditions that may be present in under controlled diabetic patients would not detract from SHH regenerative capacity. CLINICAL IMPLICATIONS: SHH PA would be beneficial to enhance smooth muscle regeneration in patients with ED of multiple etiologies. STRENGTHS AND LIMITATIONS: Understanding how human corpora cavernosal tissue responds to SHH treatment is critical for clinical translation of SHH PA to ED patients. CONCLUSION: Corpora cavernosal smooth muscle from all ED patients responded to SHH treatment with increased growth. Stupp, SI. Sonic Hedgehog Signaling in Primary Culture of Human Corpora Cavernosal Tissue From Prostatectomy, Diabetic, and Peyronie's Patients. J Sex Med 2022;19:1228-1242.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Disfunção Erétil , Hipertensão , Animais , Doenças Cardiovasculares/complicações , Glucose , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapêutico , Humanos , Hipertensão/complicações , Masculino , Pênis , Peptídeos/farmacologia , Prostatectomia/efeitos adversos , RatosRESUMO
Treatment options for men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) have variable efficacy, safety, and retreatment profiles, contributing to variations in patient quality of life and healthcare costs. This study examined the long-term cost-effectiveness of generic combination therapy (CT), prostatic urethral lift (PUL), water vapor thermal therapy (WVTT), photoselective vaporization of the prostate (PVP), and transurethral resection of the prostate (TURP) for the treatment of BPH. A systematic literature review was performed to identify clinical trials of CT, PUL, WVTT, PVP, and TURP that reported change in International Prostate Symptom Score (IPSS) for men with BPH and a prostate volume ≤80 cm3. A random-effects network meta-analysis was used to account for the differences in patient baseline clinical characteristics between trials. An Excel-based Markov model was developed with a cohort of males with a mean age of 63 and an average IPSS of 22 to assess the cost-effectiveness of these treatment options at 1 and 5 years from a US Medicare perspective. Procedural and adverse event (AE)-related costs were based on 2021 Medicare reimbursement rates. Total Medicare costs at 5 years were highest for PUL ($9,580), followed by generic CT ($8,223), TURP ($6,328), PVP ($6,152), and WVTT ($2,655). The total cost of PUL was driven by procedural ($7,258) and retreatment ($1,168) costs. At 5 years, CT and PUL were associated with fewer quality-adjusted life years (QALYs) than WVTT, PVP, and TURP. Compared to WVTT, the incremental cost-effectiveness ratios (ICERs) for both TURP and PVP were above a willingness-to-pay threshold of $50,000/QALY (TURP: $64,409/QALY; PVP: $87,483/QALY). This study provides long-term cost-effectiveness evidence for several common treatment options for men with BPH. WVTT is an effective and economically viable treatment in resource-constrained environments.
Assuntos
Hiperplasia Prostática , Ressecção Transuretral da Próstata , Idoso , Análise Custo-Benefício , Humanos , Masculino , Medicare , Pessoa de Meia-Idade , Hiperplasia Prostática/complicações , Qualidade de Vida , Ressecção Transuretral da Próstata/efeitos adversos , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Erectile dysfunction (ED) is a debilitating medical condition in which current treatments are minimally effective in diabetic patients due to neuropathy of the cavernous nerve, a peripheral nerve that innervates the penis. Loss of innervation causes apoptosis of penile smooth muscle, remodeling of corpora cavernosa (penile erectile tissue) morphology, and ED. AIM: In this study, microarray and pathway analysis were used to obtain a global understanding of how signaling mechanisms are altered in diabetic patients and animal models as ED develops, in order to identify novel targets for disease management, and points of intervention for clinical therapy development. METHODS AND OUTCOMES: Human corpora cavernosal tissue was obtained from diabetic (n = 4) and Peyronie's (control, n = 3) patients that were undergoing prosthesis implant to treat ED, and BB/WOR diabetic (n = 5) and resistant (n = 5) rats. RNA was extracted using TRIzol, DNase treated, and purified by Qiagen mini kit. Microarray was performed using the Human Gene 2.0 ST Array. (i) Alterations in patient and diabetic rat pathway signaling were examined using several analytical tools (ShinyGO, Metascape, WebGestalt, STRING) and databases, (ii) Strengths/weaknesses of the different pathway analysis tools were compared, and (iii) Comparison of human and rat (BB/WOR and Streptozotocin) pathway analysis was performed. Two technical replicates were performed. P value (FDR) < .15 was used as threshold for differential expression. FDR < 0.05 was considered significant. RESULTS: Microarray identified 182 differentially expressed protein-coding genes. Pathway analysis revealed similar enrichments with different analytical tools. Down regulated pathways include development, tubular structure, sprouting, cell death, ischemia, angiogenesis, transcription, second messengers, and stem cell differentiation. ED patients, who have diabetes, incur significant loss of normal regulatory processes required for repair and replacement of injured corpora cavernosal tissue. Combined with loss of apoptotic regulatory mechanisms, this results in significant architectural remodeling of the corpora cavernosa, and loss of regenerative capacity in the penis. CLINICAL TRANSLATION: This first report of microarray and pathway analysis in human corpora cavernosa, is critical for identification of novel pathways pertinent to ED and for validating animal models. STRENGTHS AND LIMITATIONS: The analysis of tissue specific gene expression profiles provides a means of understanding drivers of disease and identifying novel pathways for clinical intervention. CONCLUSION: Penis from diabetic ED patients lacks capacity for maintenance of corpora cavernosal architecture and regeneration, which are critical points for intervention for therapy development. Searl T, Ohlander S, McVary KT, et al., Pathway Enrichment Analysis of Microarray Data Fom Human Penis of Diabetic and Peyronie's Patients, in Comparison With Diabetic Rat Erectile Dysfunction Models. J Sex Med 2022;19:37-53.
Assuntos
Diabetes Mellitus , Disfunção Erétil , Induração Peniana , Animais , Apoptose , Disfunção Erétil/etiologia , Humanos , Masculino , Músculo Liso , Pênis , RatosRESUMO
BACKGROUND: The American Urological Association makes recommendations for evaluation and testing for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) to help primary care providers and specialists identify LUTS/BPH and harmful related conditions including urinary retention and prostate or bladder cancer. Our understanding of provider adherence to these Guidelines is limited to single-site or nonrepresentative settings. METHODS: We analyzed two insurance claims databases: the Optum® de-identified Clinformatics® Data Mart database for privately insured males aged 40-64 years (N ≈ 1,650,900 annually) and the Medicare 5% Sample for males aged ≥65 years (N ≈ 546,000 annually). We calculated the annual prevalence of LUTS/BPH and comorbid bladder cancer and bladder stones from 2004 to 2013. We additionally examined LUTS/BPH incidence and adherence to testing guidelines in a cohort of men newly diagnosed with LUTS/BPH in 2009. RESULTS: While LUTS/BPH prevalence and incidence increased with increasing age, evaluation testing became less common. Urinalysis was the most common testing type but was performed in <60% of incident patients. Serum prostate-specific antigen (PSA) was the second most common test across age groups (range: 15-34%). Prevalence of comorbid bladder cancer (range: 0-4%), but not bladder stones (range: 1-2%), increased with increasing age. CONCLUSIONS: Although older men were at greater risk of LUTS/BPH than younger men, they were less likely to undergo testing at diagnosis. Recommended testing with urinalysis was poor despite higher prevalence of bladder cancer in older men and a standard recommendation for urinalysis since 1994. Providers should be more cognizant of AUA Guidelines when assessing LUTS/BPH patients.
Assuntos
Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Neoplasias da Próstata , Neoplasias da Bexiga Urinária , Idoso , Fidelidade a Diretrizes , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/epidemiologia , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Medicare , Hiperplasia Prostática/complicações , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/epidemiologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Erectile dysfunction (ED) and ejaculatory dysfunction (EjD) are known outcomes of traditional surgery and some pharmacotherapies for treatment of benign prostatic hyperplasia (BPH). Minimally invasive treatment options, including water vapor thermal therapy (WVTT), are now available to treat lower urinary tract symptoms (LUTS) due to BPH. AIM: The objective of this analysis was to evaluate long-term impact of a single water vapor thermal therapy procedure on erectile and ejaculatory function in subjects enrolled in the Rezum II prospective, multicenter, randomized, blinded controlled trial. METHODS: Fifteen centers enrolled 197 subjects with International Prostate Symptom Score (IPSS) ≥ 13, maximum flow rate (Qmax) ≤ 15 mL/s, and prostate volume 30-80 cc. Subjects were randomized (2:1) to (WVTT) or sham procedure (control) and followed for 5 years. Erectile and ejaculatory functions were quantitatively assessed at baseline and yearly thereafter. After 3 months, control subjects could opt to requalify for cross-over to WVTT and were followed for 5 years. Results of the per protocol analysis were reported previously. The current post hoc analysis was performed on all treated subjects who were sexually active at baseline with no other surgical or medical management for BPH during the 5-year study period. OUTCOMES: LUTS was evaluated using IPSS, Benign Prostatic Hyperplasia Impact Index (BPHII), and Qmax. Sexual function was assessed using the International Index of Erectile Function (IIEF-EF) and Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD). RESULTS: A total of 197 subjects (136 treated, 61 control) were enrolled in the study, and 53 control subjects opted to cross-over and receive WVTT. All subgroups experienced significant, durable improvement in IPSS (P < .0001). Subjects with normal sexual function at baseline had little change in function over 5 years (IIEF-EF: -2.4 ± 8.9, P = .1414; MSHQ-EjD Function: -1.6 ± 3.2, P = .0083; MSHQ-EjD Bother: -0.5 ± 1.6, P = .1107). Subjects with baseline medical history of ED and EjD showed slight decline over time that was not clinically significant (ED, IIEF-EF: -3.0 ± 10.1, P = .1259; MSHQ EjD Function: -2.3 ± 4.7, P = .0158; MSHQ-EjD Bother: -0.1 ± 2.6, P = .7764; EjD, IIEF-EF: -4.1 ± 9.2, P = .0127; MSHQ EjD Function: -1.6 ± 4.8, P = .1970; MSHQ-EjD Bother: -0.4 ± 2.6, P = .440). CLINICAL IMPLICATIONS: Treatment for BPH with Rezum durably improved IPSS without clinically significant impact on sexual function. Patients with baseline ED/EjD may expect continued decline from other causes but are unimpacted by the therapy. STRENGTHS & LIMITATIONS, CONCLUSION: The results are limited by the post-hoc nature of the analysis and attrition over the 5-year follow-up but provide long-term evidence of durable outcomes after treatment with Rezum without impact on sexual function scores. McVary KT, El-Arabi A, Roehrborn C. Preservation of Sexual Function 5 Years After Water Vapor Thermal Therapy for Benign Prostatic Hyperplasia. Sex Med 2021;9:100454.