Exploring the DNA Methylation Profile of Genes Associated with Bladder Cancer in Bladder Tissue of Patients with Neurogenic Lower Urinary Tract Dysfunction.

DNA methylation is an epigenetic process that commonly occurs in genes' promoters and results in the transcriptional silencing of genes. DNA methylation is a frequent event in bladder cancer, participating in tumor initiation and progression. Bladder cancer is a major health issue in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD), although the pathogenetic mechanisms of the disease remain unclear. In this population, bladder cancer is characterized by aggressive histopathology, advanced stage during diagnosis, and high mortality rates. To assess the DNA methylation profiles of five genes' promoters previously known to be associated with bladder cancer in bladder tissue of NLUTD patients, we conducted a prospective study recruiting NLUTD patients from the neuro-urology unit of a public teaching hospital. Cystoscopy combined with biopsy for bladder cancer screening was performed in all patients following written informed consent being obtained. Quantitative methylation-specific PCR was used to determine the methylation status of RASSF1, RARß, DAPK, hTERT, and APC genes' promoters in bladder tissue samples. Twenty-four patients suffering from mixed NLUTD etiology for a median duration of 10 (IQR: 12) years were recruited in this study. DNA hypermethylation was detected in at least one gene of the panel in all tissue samples. RAR-ß was hypermethylated in 91.7% samples, RASSF and DAPK were hypermethylated in 83.3% samples, APC 37.5% samples, and TERT in none of the tissue samples. In 45.8% of the samples, three genes of the panel were hypermethylated, in 29.2% four genes were hypermethylated, and in 16.7% and in 8.3% of the samples, two and one gene were hypermethylated, respectively. The number of hypermethylated genes of the panel was significantly associated with recurrent UTIs (p = 0.0048). No other significant association was found between DNA hypermethylation or the number of hypermethylated genes and the clinical characteristics of the patients. Histopathological findings were normal in 8.3% of patients, while chronic inflammation was found in 83.3% of patients and squamous cell metaplasia in 16.7% of patients. In this study, we observed high rates of DNA hypermethylation of genes associated with bladder cancer in NLUTD patients, suggesting an epigenetic field effect and possible risk of bladder cancer development. Recurrent UTIs seem to be associated with increased DNA hypermethylation. Further research is needed to evaluate the impact of recurrent UTIs and chronic inflammation in DNA hypermethylation and bladder cancer etiopathogenesis in NLUTD patients.

Testosterone castration levels in patients with prostate cancer: Is there a difference between GnRH agonist and GnRH antagonist? Primary results of an open-label randomized control study.

PURPOSE: To compare testosterone castration levels between patients treated with the gonadotropin-releasing hormone (GnRH) antagonist, degarelix, and GnRH agonist. MATERIALS AND METHODS: Patients with prostate cancer (PCa) of a single outpatient clinic were randomized (2:1) to receive degarelix (group A) or GnRH agonist (group B). The study evaluated testosterone and prostate-specific antigen (PSA) levels, patients' age, Gleason score and the presence of metastases (nodal or bone). Testosterone and PSA levels were measured at 1st, 6th, 12th, and 18th months. Mann-Whitney test and Spearman correlation were used to investigate independent variable while standard multiple regression was performed to explore statistically significant correlations. Kruskal-Wallis test was used to compare testosterone levels at follow-up. RESULTS: The study included 168 patients, 107 in group A and 61 in group B. Testosterone levels at 1st month were significantly lower in patients under GnRH antagonist than those receiving GnRH agonist (group A: 22 ng/dL vs. group B: 29 ng/dL, p=0.011). However, PSA values did not differ significantly between groups (group A: 0.130 ng/mL vs. group B: 0.067 ng/mL, p=0.261). In multivariate analysis, treatment with degarelix was an independent factor of lower testosterone levels at 1st month (p=0.013). Comparison of testosterone levels at 6, 12, and 18 months did not reveal any significant difference within each group. CONCLUSIONS: In patients with PCa who are candidates for androgen deprivation therapy, the administration of GnRH antagonist seems to achieve significantly lower testosterone levels compared to treatment with GnRH agonist at 1st month of treatment.

A Study of DNA Methylation of Bladder Cancer Biomarkers in the Urine of Patients with Neurogenic Lower Urinary Tract Dysfunction.

Background: Bladder cancer (BCa) in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) is a significant concern due to its advanced stage at diagnosis and high mortality rate. Currently, there is a scarcity of specific guidelines for BCa screening in these patients. The development of urine biomarkers for BCa seems to be an attractive non-invasive method of screening or risk stratification in this patient population. DNA methylation is an epigenetic modification, resulting in the transcriptional silencing of tumor suppression genes, that is frequently detected in the urine of BCa patients. Objectives: We aimed to investigate DNA hypermethylation in five gene promoters, previously associated with BCa, in the urine of NLUTD patients, and in comparison with healthy controls. Design, setting and participants: This was a prospective case-control study that recruited neurourology outpatients from a public teaching hospital who had suffered from NLUTD for at least 5 years. They all underwent cystoscopy combined with biopsy for BCa screening following written informed consent. DNA was extracted and DNA methylation was assessed for the RASSF1, RARß, DAPK, TERT and APC gene promoters via quantitative methylation-specific PCR in urine specimens from the patients and controls. Results: Forty-one patients of mixed NLUTD etiology and 35 controls were enrolled. DNA was detected in 36 patients' urine specimens and in those of 22 controls. In the urine specimens, DNA was hypermethylated in at least one of five gene promoters in 17/36 patients and in 3/22 controls (47.22% vs. 13.64%, respectively, p = 0.009). RASSF1 was hypermethylated in 10/17 (58.82%) specimens with detected methylation, APC in 7/17 (41.18%), DAPK in 4/17 (23.53%), RAR-ß2 in 3/17 (17.56%) and TERT in none. According to a multivariate logistic regression analysis, NLUTD and male gender were significantly associated with hypermethylation (OR = 7.43, p = 0.007 and OR = 4.21; p = 0.04, respectively). In the tissue specimens, histology revealed TaLG BCa in two patients and urothelial squamous metaplasia in five patients. Chronic bladder inflammation was present in 35/41 bladder biopsies. Conclusions: DNA hypermethylation in a panel of five BCa-associated genes in the urine was significantly more frequent in NLUTD patients than in the controls. Our results warrant further evaluation in longitudinal studies assessing the clinical implications and possible associations between DNA hypermethylation, chronic inflammation and BCa in the NLUTD population.

Role of Pelvic Ischemia in Human Lower Urinary Tract Symptoms and Sexual Function Among Patients With Common Iliac Artery Obstruction Undergoing Revascularization Surgery.

PURPOSE: In this case-control study, we explored the relationships among pelvic ischemia, lower urinary tract symptoms (LUTS), and sexual function in patients with common iliac artery steno-occlusive disease, along with the potential therapeutic role of revascularization. METHODS: We recruited 33 men diagnosed with radiologically documented common iliac artery stenosis (>80%) who underwent endovascular revascularization, and 33 healthy controls. Five patients had obstruction of the abdominal aorta (Leriche syndrome). The International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire, and International Index of Erectile Function were used to evaluate LUTS and erectile function. Medical history, anthropometrics, urinalysis, and blood tests, including levels of serum prostate-specific antigen, urea, creatinine, triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein, and hemoglobin A1c, were recorded. Uroflow (maximum flow, average flow, voided volume, and voiding time) and ultrasound parameters (prostate volume and postvoid residual [PVR]) were also measured. Patients with moderate-to-severe LUTS (IPSS>7) underwent complete urodynamic investigation. Patients were examined at baseline and 6 months postoperatively. RESULTS: Patients exhibited poorer total IPSS (P<0.001), storage (P=0.001) and voiding symptom (P<0.001) subscores, as well as worse OAB-bother (P=0.015), OAB-sleep (P<0.001), OAB-coping (P<0.001), and OAB-total (P<0.001) scores than control participants. Additionally, erectile function (P=0.002), sexual desire (P<0.001), and satisfaction from intercourse (P=0.016) deteriorated in the patient group. Six months postoperatively, significant improvements were observed in erectile function (P=0.008), orgasm (P=0.021), and desire (P=0.014). Similarly, PVR significantly improved (P=0.012), while fewer patients experienced increased bladder sensation (P=0.035) and detrusor overactivity (P=0.035) upon postoperative urodynamic study. No significant differences were found between patients with bilateral and unilateral obstruction or between either of those groups and Leriche syndrome patients. CONCLUSION: Patients with steno-occlusive disease of the common iliac artery experienced more severe LUTS and sexual dysfunction than healthy controls. Endovascular revascularization alleviated LUTS in patients with moderate-to-severe symptoms and improved bladder and erectile function.

Urine Biomarkers in the Management of Adult Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review.

BACKGROUND: Neurogenic lower urinary tract dysfunction requires lifelong surveillance and management for the perseveration of patients' quality of life and the prevention of significant morbidity and mortality. Urine biomarkers are an attractive noninvasive method of surveillance for these patients. The aim of this systematic review is to search for and critically appraise studies that investigate the clinical usefulness of urine biomarkers in the management of neurogenic lower urinary tract dysfunction (NLUTD) in adults. METHODS: This review was conducted according to PRISMA and MOOSE guidelines. Search strategy included PubMed, CENTRAL, and Scopus (until October 2022). Studies investigating potential urine biomarkers for the management of adults with NLUTD were included. RESULTS: Fifteen studies fulfilled the criteria. To date, a variety of different urine molecules have been investigated for the diagnosis and management of neurogenic overactive bladder and detrusor overactivity (nerve growth factor, brain-derived neurotrophic factor, prostaglandin E2, prostaglandin F2α, transformation growth factor ß-1, tissue inhibitor metalloproteinase-2, matrix metalloproteinase-2, substance P, microRNA), diagnosis of vesicoureteral reflux (exosomal vitronectin), urinary tract infection (neutrophil gelatinase-associated lipocalin, interleukin 6) and bladder cancer screening (cytology, BTA stat, survivin) in neurological patients. CONCLUSION: Further studies are needed to specify the utility of each molecule in the management algorithm of adult NLUTD.

Pure single-port retzius-sparing robot-assisted radical prostatectomy with the da Vinci SP: Initial experience and technique description.

Objective: To assess the feasibility and safety of pure single-port (SP) retzius-sparing robot-assisted radical prostatectomy (RARP) using the da Vinci SP and describe the technique. Materials and Methods: From August 2020 to November 2020, data of 10 consecutive patients with localized prostate cancer, who underwent SP retzius-sparing RARP, were prospectively collected. Patients demographics, intraoperative variables, postoperative complications, early oncological, and functional outcomes were assessed. Results: The patients were aged 46-73 years with a body mass index between 20.3 and 27.4 kg/m2. Prostate volumes ranged from 15 to 47.2 ml, with a median (interquartile range, IQR) PSA level of 7.4 (6.2-9.1) ng/ml. All surgeries were successfully completed without conversion. The median (IQR) operative and console time were 106 (101-109) min and 65 (63-68) min, respectively. The median (IQR) blood loss was 125 (50-150) ml, and one Clavien-Dindo grade I complication occurred. At 3 months, nine patients had undetectable PSA levels and all patients were continent. Conclusions: Pure SP retzius-sparing RARP could be safely performed using the da Vinci SP system, with acceptable surgical times and minimal complications. Future research will evaluate the advantages of this technique over the standard multiport robotic surgery.

Potential Contenders for the Leadership in Robotic Surgery.

Purpose: To summarize the scientific published literature on new robotic surgical platforms with potential use in the urological field, reviewing their evolution from presentation until the present day. Our goal is to describe the current characteristics and possible prospects for these platforms. Materials and Methods: A nonsystematic search of the PubMed, Cochrane library's Central, EMBASE, MEDLINE, and Scopus databases was conducted to identify scientific literature about new robotic platforms other than the Da Vinci® system, reviewing their evolution from inception until December 2020. Only English language publications were included. The following keywords were used: "new robotic platforms," "Revo-I robot," "Versius robot," and "Senhance robot." All relevant English-language original studies were analyzed by one author (R.F.) and summarized after discussion with an independent third party (E.M., S.Y., S.P., and M.A.). Results: Since 1995, Intuitive Surgical, Inc., with the Da Vinci surgical system, is the leading company in the robotic surgical market. However, Revo-I®, Versius®, and Senhance® are the other three platforms that recently appeared on the market with available articles published in peer-reviewed journals. Among these three new surgical systems, the Senhance robot has the most substantial scientific proof of its capacity to perform minimally invasive urological surgery and as such, it might become a contender of the Da Vinci robot. Conclusions: The Da Vinci surgical platform has allowed the diffusion of robotic surgery worldwide and showed the different advantages of this type of technique. However, its use has some drawbacks, especially its price. New robotic platforms characterized by unique features are under development. Of note, they might be less expensive compared with the Da Vinci robotic system. We found that these new platforms are still at the beginning of their technical and scientific validation. However, the Senhance robot is in a more advanced stage, with clinical studies supporting its full implementation.

Comparing Revo-i and da Vinci in Retzius-Sparing Robot-Assisted Radical Prostatectomy: A Preliminary Propensity Score Analysis of Outcomes.

Purpose: This study aims to compare perioperative and oncologic outcomes between matched cohorts of localized prostate cancer (PCa) operated on by the same surgeon using the da Vinci Si robot and the Revo-i robot. Materials and Methods: Nonmetastatic PCa patients undergoing Retzius-sparing robot-assisted laparoscopic radical prostatectomy (RS-RARP) from January 2016 to December 2020 were matched one-to-one (33:33) to da Vinci Si controls using propensity score matching according to the following covariates: age, American Society of Anesthesiology (ASA) score, body mass index, previous abdominal and endoscopic surgery, preoperative prostate specific antigen, prostate volume, Gleason grade group, tumor stage, and need for pelvic lymphadenectomy. Outcomes of interest were estimated blood loss, length of stay, complication rate, operative times, positive surgical margins, and biochemical recurrence at 6 months. Results: Both cohorts were similar in estimated blood loss, rate of margin positivity, and rate of complications. Length of stay was significantly shorter with the Revo-i cohort. The da Vinci robot showed faster console, suture, and total operation times. Positive margin rate and biochemical recurrence at 6 months were similar in both groups. Conclusion: Despite the longer suture, console, and operative time those in the da Vinci robot in the authors' institution, the Revo-i robot-assisted radical prostatectomy had equivalent short-term oncologic outcomes with the da Vinci standard.

Robot-assisted partial nephrectomy for high-complexity tumors (PADUA score ≥10): Perioperative, long-term functional and oncologic outcomes.

OBJECTIVES: To evaluate the safety and efficacy, and long-term functional and oncologic outcomes of robot-assisted partial nephrectomy in high-complexity tumors. METHODS: Data of 155 patients with a high-complexity tumor (PADUA score ≥10) were reviewed. Trifecta achievement, intra-, perioperative, functional, and oncologic outcomes were analyzed and compared between patients with increasing complexity. RESULTS: Of the 155 patients, 65 (41.9%) patients had a PADUA score of 10, 55 (35.5%) had a PADUA score of 11, and 35 (22.6%) had a PADUA score of 12-13, respectively. The median (interquartile range) operative time, warm ischemia time and estimated blood loss were 150 min (112-186 min), 26 min (23-32 min) and 250 mL (100-500 mL), respectively. Postoperatively, complications occurred in 25 (16.1%) patients, and positive surgical margins in 15 (10.5%) patients. Trifecta was achieved in 67 (43.2%) patients. At a median follow-up period of 58 months, the median estimated glomerular filtration rate preservation was 87% (78-110), and 12 (7.7%) patients developed new-onset chronic kidney disease. Recurrence-free survival and overall survival rates were 93.6% and 96.7%, respectively. Positive surgical margins were statistically different between the groups of PADUA score 10, 11 and 12-13 (P = 0.017), whereas functional and oncologic outcomes were similar. In multivariate logistic regression analysis, increasing tumor size (odds ratio 1.48, 95% confidence interval 1.21-1.87; P < 0.001) and the American Society of Anesthesiologists score 2/3 (odds ratio 0.48, 95% confidence interval 0.24-0.96; P = 0.041) were independent predictors of trifecta failure. CONCLUSIONS: Robot-assisted partial nephrectomy is a safe and effective treatment for high-complexity tumors providing excellent long-term functional and oncologic outcomes.

Robotic surgical systems in urology: What is currently available?

Robotic assistance in laparoscopic surgery was introduced at the turn of this millennium, marking a milestone in the history of surgery. Urologists were early adopters of robotic technology and the indications of robot-assisted surgery in urology are expanding. Over the last 20 years, the da Vinci surgical system was the dominant system in the robotic surgical market. However, the recent expiration of Intuitive patents has allowed new systems to enter the market more freely. We performed a nonsystematic literature review using the PubMed/MEDLINE search engines. The aim of this review was to briefly summarize the currently available robotic surgical systems for laparoscopic urologic surgery. New surgical devices have already been launched in the robotic market and the da Vinci systems have some competition. The innovation of robotic technology is continuing, and new features such as an open-console design, haptic feedback, smaller instruments, and separately mounted robotic arms have been introduced. A new robotic era is rising, and new systems and technologies enhancing patient care are welcomed.

Systemic therapy for chromophobe renal cell carcinoma: A systematic review.

BACKGROUND: Chromophobe renal cell carcinoma (chRCC) subtype accounts for almost 5% of total RCC cases. It carries the best prognosis among the rest of RCC types. However, patients with metastatic chRCC disease have worse prognosis than patients with advanced clear cell RCC. Furthermore, available data regarding systemic therapy for chRCC patients are scarce and confusing. AIM: The aim of this systematic review is to search for and critically appraise studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. METHODS: Search strategy included PUBMED, CENTRAL, clinicaltrials.gov databases, and abstracts of major conferences with a focus on urologic oncology (till March 2019). Studies investigating patients that were treated with systemic therapy for advanced chRCC disease were included. Primary outcomes were progression-free survival and objective response rate. Secondary outcome was overall survival. Screening of available studies was carried out by 2 groups of reviewers, as well as the quality assessment of the included studies. RESULTS: The systematic search yielded 369 studies, of which 15 studies (2 randomized control trials and 13 cohort studies), involving 183 patients, met the eligibility criteria. The 2 randomized control trials that directly compared sunitinib vs. everolimus, suggested an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of objective response rate. Regarding mTOR inhibitors, they may have a role in a specific subset of chRCC patients, that needs to be further explored. Finally, as far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors, since just a few tumor responses were observed with the administered immunotherapy regiments. CONCLUSION: The optimum therapy for metastatic chRCC is still missing, as results from ongoing trials are awaited. More studies, of high quality and adequate sample size, that will be based on the specific biology of chRCC, have to be carried out in order to identify the best treatment.

A unique case of aggressive uterine cancer in a 45-year-old man with persistent Müllerian duct syndrome.

OBJECTIVE: Persistent Müllerian Duct Syndrome (PMDS), one of the causes of male pseudohermaphroditism, is a rare syndrome characterized by the presence of internal female genitalia (uterus, fallopian, tubes, cervix and upper vagina) in otherwise phenotypically and normally virilized men. METHODS: We present the 4th documented case of uterine malignancy in a 45-year-old man with PMDS presenting with lower abdominal protuberance and hematuria. RESULTS: Although testicular malignancies are common in undescended testis associated with PMDS, very few cases of müllerian duct malignancies have been reported. CONCLUSIONS: Persistent mullerian duct syndrome can be associated with aggressive non-testicular malignancies, especially uterine cancer, in normally virilized males.

OBJETIVOS: El síndrome de persistencia del Conducto de Müller (SPCM), una de las causas de pseudohermafroditismo masculino, es un síndrome raro caracterizado por la presencia de genitales internos femeninos (útero, trompas de falopio, cervix y fondo vaginal) en pacientes varones fenotipicamente y con virilización normal. MÉTODOS: Presentamos el 4º caso documentado de tumor maligno uterino en un hombre de 45 años con SPCM que presenta protuberancia abdominal inferior y hematuria. RESULTADOS: Aunque los tumores malignos testiculares son frecuentes en testículos no descendidos asociados con SPCM, se han comunicado muy pocos casos de tumores malignos del conducto de Müller. CONCLUSIONES: El síndrome de persistencia del Conducto de Müller se puede asociar con tumores malignos no testiculares agresivos, especialmente cáncer uterino en hombres normalmente virilizados.