Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Incidence of complications and urinary incontinence following endoscopic enucleation of the prostate in men with a prostate volume of 80 ml and above: results from a multicenter, real-world experience of 2512 patients.

PURPOSE: To evaluate complications and urinary incontinence (UI) after endoscopic enucleation of the prostate (EEP) stratified by prostate volume (PV). METHODS: We retrospectively reviewed patients with benign prostatic hyperplasia who underwent EEP with different energy sources in 14 centers (January 2019-January 2023). INCLUSION CRITERIA: prostate volume ≥ 80 ml. EXCLUSION CRITERIA: prostate cancer, previous prostate/urethral surgery, pelvic radiotherapy. PRIMARY OUTCOME: complication rate. SECONDARY OUTCOMES: incidence of and factors affecting postoperative UI. Patients were divided into 3 groups. Group 1: PV = 80-100 ml; Group 2 PV = 101-200 ml; Group 3 PV > 200 ml. Multivariable logistic regression analysis was performed to evaluate independent predictors of overall incontinence. RESULTS: There were 486 patients in Group 1, 1830 in Group 2, and 196 in Group 3. The most commonly used energy was high-power Holmium laser followed by Thulium fiber laser in all groups. Enucleation, morcellation, and total surgical time were significantly longer in Group 2. There was no significant difference in overall 30-day complications and readmission rates. Incontinence incidence was similar (12.1% in Group 1 vs. 13.2% in Group 2 vs. 11.7% in Group 3, p = 0.72). The rate of stress and mixed incontinence was higher in Group 1. Multivariable regression analysis showed that age (OR 1.019 95% CI 1.003-1.035) was the only factor significantly associated with higher odds of incontinence. CONCLUSIONS: PV has no influence on complication and UI rates following EEP. Age is risk factor of postoperative UI.

The effect of gestational diabetes mellitus on carotid artery intima-media thickness in and after pregnancy: a systematic review and meta-analysis.

AIMS: The association between gestational diabetes mellitus (GDM) and common carotid artery (CCA) intima-media thickness (IMT) is still controversial. This systematic review and meta-analysis was performed to assess the correlation between GDM and CCA-IMT in and after pregnancy. METHODS: PubMed and EMBASE databases were systematically reviewed on April 2023. Studies measuring CCA-IMT in both pregnant women with GDM and women with previous history of GDM (pGDM) vs. healthy controls were included. The subtotal and overall standardized mean differences (SMDs) of CCA-IMT were calculated using the random-effect model. RESULTS: Nineteen studies with a total of 302 GDM and 861 pGDM women were analyzed. The average value of CCA-IMT measured in GDM/pGDM (0.59 ± 0.12 mm) was slightly increased in comparison to the accepted reference limits of IMT according to age classes. Substantial heterogeneity was detected for the studies involving both GDM and pGDM women, with an overall statistic I2 of 86.0% (p < 0.001). Large SMDs were obtained for the studies conducted on both GDM and pGDM women, with an overall SMD of 0.89 (95%CI 0.63-1.15, p < 0.001). Egger's test for a regression intercept gave a p-value of 0.37, indicating no publication bias. On meta-regression analysis, all potential confounders (number of patients, age at pregnancy, body mass index, measuring time, follow-up duration and GDM criteria) were not significantly associated with effect modification. CONCLUSIONS: GDM in and after pregnancy is independently associated with subclinical atherosclerosis. The association between GDM and carotid remodeling is potentially mediated by the longstanding underlying risk.

Influence of gestational diabetes mellitus on subclinical myocardial dysfunction during pregnancy: A systematic review and meta-analysis.

OBJECTIVE: The correlation between gestational diabetes mellitus (GDM) and subclinical myocardial dysfunction has been poorly investigated. Accordingly, we performed a meta-analysis to examine the influence of GDM on left ventricular (LV) global longitudinal strain (GLS), assessed by speckle tracking echocardiography (STE), during pregnancy. STUDY DESIGN: All echocardiographic studies assessing conventional echoDoppler parameters and LV-GLS in GDM women vs. healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case-Control Studies. The subtotal and overall standardized mean differences (SMDs) of LV-GLS were calculated using the random-effect model. RESULTS: The full-texts of 10 studies with 1147 women with GDM and 7706 pregnant women without diabetes were analyzed. GDM women enrolled in the included studies were diagnosed with a small reduction in LV-GLS in comparison to controls (average value -19.4 ± 2.5 vs -21.8 ± 2.5 %, P < 0.001) and to the accepted reference values (more negative than -20 %). Substantial heterogeneity was detected for the included studies, with an overall statistic value I2 of 94.4 % (P < 0.001). Large SMDs were obtained for the included studies, with an overall SMD of -0.97 (95 %CI -1.32, -0.63, P < 0.001). Egger's test for a regression intercept gave a P-value of 0.99, indicating no publication bias. On meta-regression analysis, all moderators and/or potential confounders (age at pregnancy, BMI, systolic blood pressure and ethnicity) were not significantly associated with effect modification (all P < 0.05). CONCLUSIONS: GDM is independently associated with subclinical myocardial dysfunction in pregnancy. STE analysis allows to identify, among GDM women, those who might benefit of targeted non-pharmacological and/or pharmacological interventions, aimed at reducing the risk of developing type 2 diabetes and cardiovascular complications later in life.

One-Year Outcomes of Transurethral Treatment of Bladder Neck Stenosis Following Transurethral Resection of the Prostate. Results from a Large, Multicenter Series.

Purpose: To assess management and outcomes of bladder neck stenosis (BNS) post-transurethral resection of the prostate (TURP) in 12 centers. Patients and Methods: A retrospective analysis of patients who underwent transurethral BN incision for stenosis following TURP from January 2015 and January 2023 was performed. Inclusion criteria included endoscopic diagnosis of BNS associated with obstruction and/or lower urinary tract symptoms. Data are presented as median and interquartile range. Two distinct univariable logistic regression analyses were performed to identify factors associated with overall urinary incontinence and recurrent stenosis. Results: Three hundred and seventy-two men were included. 95.2% of patients developed BNS following bipolar TURP. 21.0% of patients were on an indwelling catheter before BNS incision. Bipolar electrocautery was the most commonly employed energy for incision (66.5%). Collings knife was the most commonly employed (61.2%) instrument for incision, followed by end-firing holmium lasering (35.3%). Median operation time was 30 (25-45) minutes. The overall complication rate was 12.4%, with 19 (5.1%) patients suffering from acute urinary retention, 6 (1.6%) patients requiring prolonged irrigation due to persistent hematuria, and a surgical hemostasis was necessary in 8 cases (2.2%). Overall postoperative incontinence rate was 17.2%, with urge incontinence accounting for the most common type (45.3%). Incontinence lasted more than 3 months in 9/46 (14.3%) patients. Recurrent BNS occurred in 29 (7.8%) patients and was managed by re-endoscopic incision in 21 (5.6%) patients and dilatation only in 6 (1.6%) patients. Two (0.5%) patients underwent urethroplasty for recalcitrant stenosis. Logistic regression analysis showed that Collings knife was associated with higher odds of having postoperative incontinence (OR 3.93 95% CI 1.45-11.13, p=0.008) and BN recurrence (OR 3.589 95% CI 1.157-15.7, p=0.047). Conclusion: Transurethral BN incision provides satisfactory short-term results with an acceptable rate of complications.

Long-term PSA-free survival and castration-free survival with delayed antiandrogen therapy in patients with one versus two or more positive nodes at prostatectomy.

PURPOSE: To analyze time in relation to biochemical recurrence (BCR) and antiandrogen therapy (ADT) in patients with node metastasis at retropubic prostatectomy (RRP) and to identify prognostic factors of BCR- and ADT-free survival. METHODS: Positive node patients at RRP and extended pelvic lymph node dissection (ePLND) were recruited retrospectively. Neoadjuvant and adjuvant therapy were exclusion criteria. BR was defined as PSA ≥ 0.3 ng/ml or the beginning of salvage radiotherapy or, ADT. RESULTS: Between 1995 and 2008, 70 node-positive patients after RRP were followed without ADT. Overall, BCR-free survival was 77.9% at 2 years and 29.7% at 8 years. The median time to BCR was 59.2 months for patients with only one node compared to 27.7 months for those with ≥2 nodes. The number of positive nodes was the only independent predictor of BCR in Cox regression multivariable analysis. ADT-free survival was 78% at 2 years and 39% at 8 years. The median time to ADT for patients with only one positive node was 115 months, and the 5 years ADT-free survival was 68.8%. Gleason score and the number of positive nodes were the only independent prognostic factors of time to ADT in the Cox regression multivariable analysis. CONCLUSIONS: The prognosis of patients with positive nodes after RRP and ePNLD is good in terms of BCR- and ADT-free survival. After 8 years, 29.7% were still free from BCR, and 39% did not receive ADT. The number of positive nodes was the most important predictor of BCR- and ADT-free survival.

Transperineal US-MRI Fusion-Guided Biopsy for the Detection of Clinical Significant Prostate Cancer: A Systematic Review and Meta-Analysis Comparing Cognitive and Software-Assisted Technique.

INTRODUCTION: We aimed to find potential differences in clinically significant prostate cancer (csPCa) detection rates between transperineal software-assisted fusion biopsy (saFB) and cognitive fusion biopsies (cFB). METHODS: A systematic review of the literature was performed to identify comparative studies using PubMed, EMBASE, and Scopus according to the PICOS criteria. Cancer detection and complication rates were pooled using the Cochran-Mantel-Haenszel method with the random effect model and reported as odds ratios (ORs), 95% confidence intervals (CI), and p-values. A meta-analysis was performed using Review Manager (RevMan) 5.4 software by Cochrane Collaboration. The quality assessment of the included studies was performed using the Cochrane Risk of Bias tool, using RoB 2 for randomized studies and ROBINS-I for retrospective and nonrandomized ones. RESULTS: Eight studies were included for the meta-analysis, including 1149 cases in software-based and 963 cases in cognitive fusion biopsy. The detection rates of csPCa were similar between the two groups (OR 1.01, 95% CI 0.74-1.37, p = 0.95). Study heterogeneity was low (I2 55%). CONCLUSION: There is no actual evidence of the superiority of saFB over cFB in terms of the csPCa detection rate. Operator experience and software availability can drive the choice of one fusion technique over the other.

Vacuum erection device for erectile function rehabilitation after radical prostatectomy: which is the correct schedule? Results from a systematic, scoping review.

Vacuum erection device (VED), for its capacity to improve the peak flow and elasticity of cavernous arteries, is a well-known tool to improve recovery of erectile function (EF) after radical prostatectomy. Aim of this study is to compare the different therapeutic schemes proposed in literature to find the most effective timing for VED treatment and to evaluate its efficacy alone or associated with phosphodiesterase 5 inhibitors (PDE5i). We performed a systematic review of Literature in October 2022 using MEDLINE, EMBASE, and Cochrane Central Controlled Register of Trials to retrieve all articles dealing with EF rehabilitation after radical prostatectomy (excluding non-English papers, reviews, or meeting abstracts). Patients were divided among those receiving VED alone or combined with other treatments. Study outcomes were compared dividing them between those with follow-up shorter or longer than 12 months. Sixteen papers were included according to selection criteria. Among them, seven were randomized-controlled trials, five were prospective observational studies and four were retrospective. VED alone was evaluated in eight articles, while the remaining papers evaluated the combination of VED with PDE5i. Regarding VED therapeutic protocol, 7/16 studies used it daily. Rehabilitation protocol lasted less than 1 year in 4 studies, up to 12 months in 6 studies and more than 1 year in 6 studies. All the studies show improvement in International Index of Erectile Function Questionnaire (IIEF-5), conservation of penile length and satisfactory intercourses when compared to controls. VED results appear to increase when patients were addressed to VED-dedicated programs to enhance their compliance with the device.

Improving Outcomes of Same-sitting Bilateral Flexible Ureteroscopy for Renal Stones in Real-world Practice-Lessons Learnt from Global Multicenter Experience of 1250 Patients.

Background: Bilateral kidney stones are commonly treated in staged procedures. Objective: To evaluate outcomes after same-sitting bilateral retrograde intrarenal surgery (SSB-RIRS) for renal stones. Design setting and participants: Data from adults who underwent bilateral RIRS in 21 centers were retrospectively reviewed (from January 2015 to June 2022). The inclusion criteria were unilateral/bilateral symptomatic bilateral stone(s) of any size/location in both kidneys and bilateral stones on follow-up with symptom/stone progression. Stone-free rate (SFR) was defined as absence of any fragment >3 mm at 3 mo. Outcome measurements and statistical analysis: Continuous variables are presented as medians and 25-75th percentiles. A multivariable logistic regression analysis was performed to evaluate independent predictors of sepsis and bilateral SFR. Results and limitations: A total of 1250 patients were included. The median age was 48.0 (36-61) yr. Of the patients, 58.2% were prestented. The median stone diameter was 10 mm on both sides. Multiple stones were present in 45.3% and 47.9% of the left and right kidneys, respectively. Surgery was stopped in 6.8% of cases. The median surgical time was 75.0 (55-90) min. Complications were transient fever (10.7%), fever/infection needing prolonged stay (5.5%), sepsis (2%), and blood transfusion (1.3%). Bilateral and unilateral SFRs were 73.0% and 17.4%, respectively. Female (odds ratio [OR] 2.97, 95% confidence interval [CI] 1.18-7.49, p = 0.02), no antibiotic prophylaxis (OR 5.99, 95% CI 2.28-15.73, p < 0.001), kidney anomalies (OR 5.91, 95% CI 1.96-17.94, p < 0.001), surgical time ≥100 min (OR 2.86, 95% CI 1.12-7.31, p = 0.03) were factors associated with sepsis. Female (OR 1.88, 95% CI 1.35-2.62, p < 0.001), bilateral prestenting (OR 2.16, 95% CI 1.16-7.66, p = 0.04), and the use of high-power holmium:YAG laser (OR 1.63, 95% CI 1.14-2.34, p < 0.01) and thulium fiber laser (OR 2.50, 95% CI 1.32-4.74, p < 0.01) were predictors of bilateral SFR. Limitations were retrospective study and no cost analysis. Conclusions: SSB-RIRS is an effective treatment with an acceptable complication rate in selected patients with kidney stones. Patient summary: In this large multicenter study, we looked at outcomes after same-sitting bilateral retrograde intrarenal surgery (SSB-RIRS) for renal stones in a large cohort. We found that SSB-RIRS was associated with acceptable morbidity and good stone clearance after a single session.

En bloc transurethral resection of bladder lesions: a trick to retrieve specimens up to 4.5 cm.

The present technique maintains the integrity of voluminous lesions during extraction. Pathological analysis is consequently improved and a proper evaluation of the surgical margins is also possible. Papillary lesions of up to 4.5 cm are amenable to en bloc resection and extraction, while solid lesions comply less well with the urethra and sometimes are very difficult to extract. Nevertheless, the main limitation of the technique remains that lesions originating from the bladder neck are not amenable to en bloc resection,while particular attention should be paid during resection of lesions involving the ureteric orifice to avoid ureteric stripping.

Development and external validation of lymph node density cut-off points in prospective series of radical cystectomy and pelvic lymph node dissection.

OBJECTIVE: To identify lymph node density thresholds and their prognostic role in patients who underwent radical cystectomy and pelvic lymph node dissection, and to validate findings in an external series. METHODS: Between May 2001 and September 2009, data from 750 radical cystectomies carried out at "Regina Elena" National Cancer Institute (Rome, Italy) were collected in a prospectively-maintained database. Once patients who had undergone neoadjuvant treatments and those who had undergone salvage radical cystectomy were excluded from the 210 pN+ patients, 156 patients with urothelial carcinoma were selected for analysis. Optimal cut-off points for age, lymph node count and lymph node density were identified by considering these variables as continuous. External validation of findings was carried out by using data of 154 pN+ patients selected from two prospective series. RESULTS: The optimal identified cut-off points were 11% and 30% for lymph node density, nine and 30 nodes for lymph node count, and 73 years for age. Median cancer-specific survival of patients were significantly different in patients with lymph node density <12%, between 12% and 30%, and >30% (71 months, 24 months and 11 months, respectively; P < 0.001). Cancer-specific survival was independently predicted by lymph node density cut-off points (12-30% vs <12%: hazard ratio 1.51, P = 0.047; >30% vs <12%: hazard ratio 2.89, P < 0.001). In the external series, the prognostic effect of lymph node density according to tertiary distribution of risk based on these lymph node density cut-off points was confirmed at Cox multivariable analysis (12-30% vs <12%: hazard ratio 1.5, P = 0.048; >30% vs <12%: hazard ratio 2.5, P = 0.004). CONCLUSIONS: Lymph node density is the strongest predictor of cancer-specific survival. Identified lymph node density thresholds have shown to be independent predictors of cancer-specific survival in the external validation series.

Does power setting impact surgical outcomes of holmium laser enucleation of the prostate? A systematic review and meta-analysis.

Introduction: The aim of this article was to enumerate the differences in immediate and postoperative outcomes for holmium laser enucleation of the prostate (HoLEP) performed with low-power (LP) or high-power (HP) laser settings through a systematic review of comparative studies. Material and methods: We performed a systematic literature review using MEDLINE, EMBASE, and Cochrane Central Controlled Register of Trials. Potential clinical differences among LP and HP HoLEP were determined using the PICOS (Patient Intervention Comparison Outcome Study type) model, where outcomes were surgical time, operative efficiency, postoperative catheterization time, length of hospital stay, blood transfusion, incontinence rate, maximum urinary flow rate (QMax) and International Prostatic Symptom score (IPSS). Retrospective, prospective nonrandomized, randomized studies, and meeting abstracts were considered. Results: A total of five studies were included for meta-analysis. No significant differences between LP and HP HoLEP were evidenced in terms of intraoperative variables (surgical time, surgical efficiency); postoperative outcomes (length of stay, length of catheterization); postoperative complications; functional results (IPSS; Qmax). Urinary incontinence rate did not differ between the two groups (OR 0.95, 95% CI 0.362.47, p = 0.91). Conclusions: The study shows equal outcomes in outcomes from HoLEP performed with LP or HP energy settings. Even if further comparative studies are still needed to increase the level of evidence, those results encourage a further clinical adoption of LP HoLEP.

Late-onset incontinence in a cohort of radical prostatectomy patients.

A cohort of 235 subjects, who underwent radical prostatectomy from 1994 to 2002, completely continent at the 2-year follow up and with the last follow-up visit in 2009, was examined to assess incidence and risk factors of late-onset incontinence. Median follow up was 100 months, range 84-176. At the last follow-up visit, 209 (89%) maintained continence, and 26 (11%) became incontinent. Specifically 14 out of 26 (6%) used one pad and 12 (5%) used two or more pads daily. Incidence of age ≥ 65 years at radical prostatectomy was greater in the subgroup who developed late incontinence, 109/209 (52%) vs 19/26 (73%). Incidence of adjuvant or salvage radiotherapy, of hormonal manipulation and of extraprostatic disease was similar in the two subgroups. Univariate and multivariate analysis did not disclose any difference. Late-onset incontinence is to be expected in about 10% of subjects who became completely continent after radical prostatectomy. The cause is likely to be related to ageing. Patients should be informed about the long-term risk of becoming incontinent.

Narrow band imaging for detecting residual/recurrent cancerous tissue during second transurethral resection of newly diagnosed non-muscle-invasive high-grade bladder cancer.

OBJECTIVE: To determine if narrow-band imaging (NBI) can be used to detect high-grade cancerous lesions missed with the white light at the time of a second transurethral resection (TUR) of high-grade non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Consecutive patients with newly diagnosed high-grade NMIBC were enrolled in a prospective observational study. Patients with incomplete resection or absence of muscle tissue in the specimen were excluded. About 1 month after the first TUR, NBI cold-cup biopsies were taken from areas suspicious for urothelial cancer at the end of an extensive white-light second TUR protocol including: (i) resection of the scar of the primary tumour; (ii) resection of any overt or suspected urothelial lesions; and (iii) six random cold-cup biopsies of healthy mucosa. RESULTS: In 2008, 47 consecutive patients were recruited after giving written consent (median age 62 years, range 49-83, 39 men and eight women). Nine patients (19%) had macroscopic or microscopic high-grade NMI urothelial cancer, whereas one was reassessed as having muscle-invasive disease at the white-light second TUR plus the six random biopsies. NBI biopsies were taken in 40 of the 47 patients and detected six more patients with high-grade cancerous tissue (13%). In all 16 of the 47 patients (34%) were found to have residual/recurrent cancer using our extensive protocol of second TUR followed by NBI biopsies. CONCLUSIONS: Adding NBI biopsies at the end of an extensive second TUR protocol in patients with newly diagnosed high-grade NMIBC can lead to the identification of patients with otherwise missed high-grade residual/recurrent urothelial carcinoma.

New Italian guidelines on bladder cancer, based on the World Health Organization 2004 classification.

OBJECTIVE To provide evidence-based recommendations on bladder cancer management METHODS A multidisciplinary guideline panel composed of urologists, medical oncologists, radiotherapists, general practitioners, radiologists, epidemiologists and methodologists conducted a structured review of previous reports, searching the Medline database from 1 January 2004 to 31 December 2008. The milestone papers published before January 2004 were accepted for analysis. The level of evidence and the grade of the recommendations were established using the GRADE system. RESULTS In all, 15 806 references were identified, 1940 retrieved, 1712 eliminated (specifying the reason for their elimination) and 971 included in the analysis, as well as 241 milestone reports. A consensus conference held to discuss the discrepancies between the scientific evidence and the clinical practice was then attended by 122 delegates of various specialities. CONCLUSION Recommendations on bladder cancer management are provided.