The effectiveness of adjustable trans-obturator male system (ATOMS) in radiated patients is reduced: A propensity score-matched analysis.

Objectives: This study aimed to compare the effectiveness and safety of the adjustable trans-obturator male system (ATOMS®) to treat post-prostatectomy incontinence (PPI) in radiated patients compared with non-radiated patients, using propensity score-matching analysis to enhance the validity of the comparison. Patients and methods: Consecutive men with PPI treated with silicone-covered scrotal port ATOMS (A.M.I., Feldkirch, Austria) in nine different institutions between 2016 and 2022 were included. Preoperative assessment evaluated 24-h pad usage, urethroscopy and urodynamics, if indicated. Propensity score-matching analysis was based on age, length of follow-up, previous PPI treatment, previous bladder neck stricture, androgen deprivation and pad usage. The primary endpoint was dry rate, defined as no pads post-operatively with a security pad allowed. The secondary endpoints were complications, device removal and self-perceived satisfaction with the Patient Global Impression of Improvement (PGI-I) scale. Results: Of the 710 included patients, 342 were matched, and the study groups were balanced for the baseline matched variables. The mean baseline 24-h pad was 4.8 in both groups (p = 0.48). The mean follow-up was 27.5 ± 18.6 months, which was also equivalent between groups (p = 0.36). The primary outcome was achieved in 73 (42.7%) radiated patients and in 115 (67.3%) non-radiated patients (p < 0.0001). The mean pad count at the last follow-up was 1.5 and 0.8, respectively (p < 0.0001). There was no significant difference in complications (p = 0.94), but surgical revision and device explant rates were higher (p = 0.03 and p = 0.01, respectively), and the proportion of patients highly satisfied (PGI-I = 1) was lower in the radiated group (p = 0.01). At sensitivity analysis, the study was found to be reasonably robust to hidden bias. Conclusion: ATOMS implantation significantly outperformed in patients without adjuvant radiation over radiated patients.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy.

Renal cell carcinoma (RCC) ranks among the most prevalent malignancies in Western countries, marked by its notable heterogeneity, which contributes to an unpredictable clinical trajectory. The insufficiency of dependable biomarkers adds complexity to assessing this tumor progression. Imbalances of several components of the intrarenal renin-angiotensin system (iRAS) significantly impact patient prognoses and responses to first-line immunotherapies. In this study, we analyzed the immunohistochemical expression of the Mas-related G-protein-coupled receptor D (MrgD), which recognizes the novel RAS peptide alamandine (ALA), in a series of 87 clear cell renal cell (CCRCCs), 19 papillary (PRCC), 7 chromophobe (ChRCC) renal cell carcinomas, and 11 renal oncocytomas (RO). MrgD was expressed in all the renal tumor subtypes, with a higher mean staining intensity in the PRCCs, ChRCCs, and ROs. A high expression of MrgD at the tumor center and at the infiltrative front of CCRCC tissues was significantly associated with a high histological grade, large tumor diameter, local invasion, and locoregional node and distant metastasis. Patients with worse 5-year cancer-specific survival and a poorer response to antiangiogenic tyrosine-kinase inhibitors (TKIs) showed higher MrgD expression at the center of their primary tumors. These findings suggest a possible role of MrgD in renal carcinogenetic processes. Further studies are necessary to unveil its potential as a novel biomarker for CCRCC prognosis and response to frontline therapies.

Multi-Institutional Outcomes of Dorsal Onlay Buccal Mucosal Graft Urethroplasty in Patients With Postprostatectomy, Postradiation Anastomotic Stenosis.

PURPOSE: The treatment of urethral stenosis after a combination of prostatectomy and radiation therapy for prostate cancer is understudied. We evaluate the clinical and patient-related outcomes after dorsal onlay buccal mucosal graft urethroplasty (D-BMGU) in men who underwent prostatectomy and radiation therapy. MATERIALS AND METHODS: A multi-institutional, retrospective review of men with vesicourethral anastomotic stenosis or bulbomembranous urethral stricture disease after radical prostatectomy and radiation therapy from 8 institutions between 2013 to 2021 was performed. The primary outcomes were stenosis recurrence and development of de novo stress urinary incontinence. Secondary outcomes were surgical complications, changes in voiding, and patient-reported satisfaction. RESULTS: Forty-five men were treated with D-BMGU for stenosis following prostatectomy and radiation. There was a total of 7 recurrences. Median follow-up in patients without recurrence was 21 months (IQR 12-24). There were no incidents of de novo incontinence, 28 patients were incontinent pre- and postoperatively, and of the 6 patients managed with suprapubic catheter preoperatively, 4 were continent after repair. Following repair, men had significant improvement in postvoid residual, uroflow, International Prostate Symptom Score, and International Prostate Symptom Score quality-of-life domain. Overall satisfaction was +2 or better in 86.6% of men on the Global Response Assessment. CONCLUSIONS: D-BMGU is a safe, feasible, and effective technique in patients with urethral stenosis after a combination of prostatectomy and radiation therapy. Although our findings suggest this technique may result in lower rates of de novo urinary incontinence compared to conventional urethral transection and excision techniques, head-to-head comparisons are needed.

Fat Mass Accounts for Insulin Resistance Impact on Functional Decline and Mortality in Nondiabetic Older Adults.

OBJECTIVE: To assess the potential role of body composition in the association of insulin resistance (IR) with functional decline and mortality in nondiabetic older persons. DESIGN: Longitudinal population-based cohort of community-dwelling people from Toledo, Spain, aged 65 years or older. SETTING AND PARTICIPANTS: A total of 1114 nondiabetic persons from the Toledo Study of Healthy Aging cohort (mean age: 74.5, 56.10% female) with complete data at baseline were included. Only 914 participants had fully assessment of functional evaluation during the follow-up period. METHODS: IR was determined by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 2.99 years' median follow-up period. A total of 319 participants experienced functional decline (2.5-point reduction in the FTS-5 score). A total of 143 deaths were recorded (6.31 years median follow-up) from the Spanish National Death Index. Body compositions were determined using dual-energy x-ray absorptiometry. Multivariate regression models analyzed the effect of HOMA-IR on outcomes, with age, sex, Charlson index, and number of medications included in the basic adjustment model. RESULTS: A 1-logaritmic unit increment in HOMA-IR increased the risk of functional decline after basic adjustment [odds ratio (95% confidence interval): 1.41 (1.09-1.83), P = .009]. This significant association was lost when further adjusted for total fat mass [1.14 (0.86-1.50)] and trunk fat mass [1.03 (0.77-1.37)], which accounted for 62.92% and 91.49% of the association. HOMA-IR was inversely associated with mortality risk [hazard ratio 0.66 (0.49-0.87), P = .0037], an association lost after adjustment for total fat mass [0.74 (0.55-1.01)] and trunk fat mass [0.80 (0.58-1.09)], accounting for 29.05% and 45.78% of the association. Adjustment by lean mass did not modify any of the associations. CONCLUSIONS AND IMPLICATIONS: Body fat mass, especially in the trunk region, mediates the association of IR with functional decline and to a lesser extent with reduced risk of mortality in nondiabetic older subjects.

Factors Influencing Postoperative Overactive Bladder after Adjustable Trans-Obturator Male System Implantation for Male Stress Incontinence following Prostatectomy.

We aimed to determine the risk factors for postoperative overactive bladder (OAB) in patients treated with an adjustable trans-obturator male system (ATOMS) for stress incontinence after radical treatment of prostate cancer. A prospective study was performed on 56 patients implanted with an ATOMS for PPI. Clinical and urodynamic information was recorded before and after ATOMS implantation. We built a multivariate model to find out the clinical and urodynamic factors that independently influenced postoperative OAB and the prognostic factors that influenced the efficacy of medical treatment of OAB. We found that the clinical risk factors were the preoperative intensity of urinary incontinence (number of daily pads used and amount of urinary leakage), International Consultation on Incontinence Questionnaire (ICIQ) score, postoperative number of ATOMS adjustments, final cushion volume, and incontinence cure. The urodynamic data associated with OAB were cystometric bladder capacity, voided volume, volume at initial involuntary contraction (IC), maximum flow rate, bladder contractility index (BCI), and urethral resistance (URA). The prognostic factors for the efficacy of oral treatment of OAB were the volume at the first IC (direct relationship) and the maximum abdominal voiding pressure (inverse relationship). The multivariate model showed that the independent clinical risk factors were the daily pad count before the implantation and the ICIQ score at baseline and after treatment. The independent urodynamic data were the volume at the first IC (inverse relationship) and the URA value (direct relationship). Both predictive factors of treatment efficacy were found to be independent. Detrusor overactivity plays an important role in postoperative OAB, although other urodynamic and clinical factors such as the degree of urethral resistance and abdominal strength may influence this condition.

Upregulation of Orai Channels Contributes to Aging-Related Vascular Alterations in Rat Coronary Arteries.

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.

Results of Adjustable Trans-Obturator Male System in Patients with Prostate Cancer Treated with Prostatectomy and Radiotherapy: A Multicenter Study.

(1) Background: Treatment of male stress incontinence in patients with prostate cancer treated with radical prostatectomy and adjuvant pelvic radiation is a therapeutic challenge. The efficacy and safety of the adjustable trans-obturator male system (ATOMS) in these patients is not well established, despite the general belief that outcomes are worse than in patients without radiation. (2) Methods: Retrospective multicenter study evaluating patients treated with silicone-covered scrotal port (SSP) ATOMS implant after radical prostatectomy and radiotherapy in nine different institutions between 2016 and 2022. The primary endpoint was dry patient rate, defined as pad-test ≤ 20 mL/day. The secondary endpoints were complication rate (defined using Clavien-Dindo classification), device removal and self-perceived satisfaction using the Patient Global Impression of Improvement (PGI-I) scale. Wilcoxon rank-sum test, Fisher's exact test and logistic regression were performed using stepwise method with a 0.15 entry and 0.1 stay criteria. (3) Results: 223 patients fulfilled the criteria for inclusion and 12 (5.4%) received salvage prostatectomy after radiation and 27 (12.1%) previous devices for stress incontinence. After ATOMS adjustment, 95 patients (42.6%) were dry and 36 (16.1%) had complications of any grade (grade I, n = 20; grade II, n = 11; grade III, n = 5) during the first 3 months postoperatively. At a mean of 36 ± 21 months follow-up, the device was explanted in 26 (11.7%) patients. Regarding self-perceived satisfaction with the implant, 105 of 125 patients (84%) considered themselves satisfied (PGI-I 1 to 3). In the univariate analysis, dryness was associated to younger age (p = 0.06), primary prostatectomy (p = 0.08), no previous incontinence surgery (p = 0.02), absence of overactive bladder symptoms (p = 0.04), absence of bladder neck stricture (p = 0.001), no need of surgical revision (p = 0.008) and lower baseline incontinence severity (p = 0.0003). Multivariate analysis identified absence of surgical revision (p = 0.018), absence of bladder neck stricture (p = 0.05), primary prostatectomy (p = 0.07) and lower baseline incontinence severity (p < 0.0001) were independent predictors of dryness. A logistic regression model was proposed and internally validated. (4) Conclusions: ATOMS is an efficacious and safe alternative to treat male incontinence after radical prostatectomy and adjuvant radiotherapy. Factors predictive of dryness are identified in this complex scenario to allow for better patient selection.

Complications after Prostate Cancer Treatment: Pathophysiology and Repair of Post-Radiation Urethral Stricture Disease.

Radiation therapy (RT) in the management of pelvic cancers remains a clinical challenge to urologists given the sequelae of urethral stricture disease secondary to fibrosis and vascular insults. The objective of this review is to understand the physiology of radiation-induced stricture disease and to educate urologists in clinical practice regarding future prospective options clinicians have to deal with this condition. The management of post-radiation urethral stricture consists of conservative, endoscopic, and primary reconstructive options. Endoscopic approaches remain an option, but with limited long-term success. Despite concerns with graft take, reconstructive options such as urethroplasties in this population with buccal grafts have shown long-term success rates ranging from 70 to 100%. Robotic reconstruction is augmenting previous options with faster recovery times. Radiation-induced stricture disease is challenging with multiple interventions available, but with successful outcomes demonstrated in various cohorts including urethroplasties with buccal grafts and robotic reconstruction.

Update on Adjustable Trans-Obturator Male System (ATOMS) for Male Incontinence after Prostate Cancer Surgery.

(1) Background: The adjustable trans-obturator male system (ATOMS) is a surgical device developed to treat post-prostatectomy incontinence (PPI) after prostate cancer treatment. We review the current literature on this anti-incontinence device with the intention of assessing the effectiveness, safety and duration of the silicone-covered scrotal port (SSP) ATOMS, the only generation of the device that is currently available. (2) Material and Methods: Non-systematic literature review is performed. Forty-eight full-text articles are assessed for eligibility. Case reports, expert opinions or commentaries without specific data reported (n = 6), studies with patients who underwent intervention before 2014 (IP or SP ATOMS; n = 10), and studies with incontinence after transurethral resection of the prostate (TUR-P; n = 2) are excluded for analysis. Thirty studies with SSP ATOMS are included in a qualitative synthesis that incorporates systematic reviews (n = 3), articles partially overlapping with other previously published studies (e.g., follow-up or series updates; n = 9), and studies focusing on specific populations (n = 8). Only articles revealing outcomes of SSP ATOMS were included in the quantitative synthesis of results (n = 10). (3) Results: the pooled data of 1515 patients from the 10 studies with SSP ATOMS confirmed very satisfactory results with this device after adjustment: dry rate: 63-82%, improved rate: 85-100%, complication rate: 7-33%, device infection rate: 2.7-6.2% and explant rate: 0-19%. The durability of the device is reassuring, with 89% of devices in place 5 years after implantation. (4) Conclusion: Despite the absence of randomized controlled studies, the literature findings confirm results of SSP ATOMS appear equivalent to those of artificial urinary sphincters (AUSs) in terms of continence, satisfaction and complications, but with a lower rate of revision in the long-term. A prospective study identified that patients with daily pad test results <900 mL and a Male Stress Incontinence Grading Scale (MSIGS) of not 4 (i.e., early and persistent stream or urine loss) are the best candidates. Future studies centered on the elder population at higher risk of impaired cognitive ability and in patients including radiation as prostate cancer treatment are needed.

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice.

BACKGROUND AND PURPOSE: Alcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED. EXPERIMENTAL APPROACH: ED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively. KEY RESULTS: In CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre-treatment with tempol prevented alcohol-induced erectile dysfunction. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.

Impact of the COVID-19 Pandemic on Cancer Diagnosis in Madrid (Spain) Based on the RTMAD Tumor Registry (2019-2021).

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant disruption to cancer diagnosis, treatment and prevention worldwide that could have serious consequences in the near future. We intend to evaluate the weight of this backlog on a community-wide scale in Madrid during the period 2020-2021, and whether a stage shift towards the advanced stage has occurred. Cancer diagnoses in the Madrid tumor registry (RTMAD) from 2019-2021 were evaluated. Absolute and percentage differences in annual volume and observed-to-expected (O/E) volume ratios were calculated. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated using the O/E ratio. The SIR for 2020-2021 compared to 2019 was 94.5% (95% CI 93.8-95.3), with unequal gender-specific cancer diagnosis recovery (88.5% for males and 102.1% for females). Most cancer types were underdiagnosed in 2020. The tendency worsened in 2021 for colorectal and prostate cancers (87.8%), but lung cancer recovered (102.1%) and breast cancer was over-diagnosed (114.4%) compared with reference pre-COVID-19 data. These changes have modified the ranking of the most frequent malignancies diagnosed in Madrid. Breast cancer has overtaken colorectal and prostate cancers, displaced to second and third position, respectively. Not only was colorectal cancer diagnosis affected more as a consequence of the COVID-19 pandemic but diagnosis of this malignancy at the advance stage also increased by 3.6% in 2020 and 4.2% in 2021 compared to the reference period of 2019. In summary, there is a large volume of undetected cancer in Madrid caused by the reduced access to care secondary to the COVID-19 pandemic, especially regarding colorectal and prostate cancer. Strategies are needed to recover the backlog of diagnoses and effectively treat these cases in the future and solve the negative impact that will be caused by the diagnostic delay. Analyzing the impact of new diagnoses suffered by each different malignancy and their recovery will help to understand how the future allocation of resources should look.

Advances in Urological Cancer in 2022, from Basic Approaches to Clinical Management.

This Special Issue includes 12 articles and 3 reviews dealing with several basic and clinical aspects of prostate, renal, and urinary tract cancer published during 2022 in Cancers, and intends to serve as a multidisciplinary chance to share the last advances in urological neoplasms [...].

Effect of Neuro-Adaptive Electrostimulation Therapy versus Sham for Refractory Urge Urinary Incontinence Due to Overactive Bladder: A Randomized Single-Blinded Trial.

This randomized clinical trial evaluates the success rate of neuro-adaptive therapy (NAT), applied with a specific neuro-adaptive regulator device, the Self-Controlled Electro Neuro-Adaptive Regulation (SCENAR), versus a sham for urge incontinence due to an overactive bladder (OAB). From February 2019 to May 2021, 66 patients were recruited. All subjects were randomized 1:1 at the first intervention visit to the NAT or sham procedure. Inclusion criteria were females between 18 and 80 years old with leakages due to an overactive bladder with unresponsiveness to medical therapy. Subjects were scheduled to receive up to eight weekly 20 min intervention sessions to obtain a complete (CR) or partial response (PR). Patients with no response after three sessions were considered as a failure. The primary end point of this trial was to assess the efficacy of NAT compared to an inactive sham intervention, evaluated 1 month after the last session. Analysis showed 23 (70%) patients responded (20 complete and 3 partial response) in the NAT group compared to 16 (48%) patients (all complete response) in the placebo arm (p = 0.014). Significant differences were maintained after the intervention, with persistent response at 3 months in 19 (58%) patients after active treatment and 14 (42%) after the placebo (p < 0.001), and at 6 months in 18 (55%) vs. 11 (33%) (p = 0.022), respectively. The number of sessions to achieve CR was similar in both arms, with 4.3 ± 1.9 in NAT and 3.9 ± 1.8 in the sham group (NS). Significant differences were observed between both groups for patients' satisfaction (p = 0.01). The binary model selected age as a predictor of response at the last follow-up. The odds ratio indicates that each year of increase in age, the probability of a positive response to treatment at 6 months decreases 0.95 (95% CI 0.9-0.99) times (p = 0.03). In conclusion, this pilot randomized trial gives evidence that neuro-adaptive electrostimulation is effective to treat refractory urge urinary incontinence due to OAB. The security and long-term efficacy of this treatment merits further evaluation. Moreover, its favorable profile and the economic advantages of the device make the evaluation of this promising technique mandatory in a primary therapeutic scenario.

Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (≥8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.

Hyperthermic Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial.

BACKGROUND: Optimising therapeutic strategies of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) is needed. OBJECTIVE: To compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. DESIGN, SETTING, AND PARTICIPANTS: A prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. RESULTS AND LIMITATIONS: The ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C-30 min, and 43 °C-60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C-30 min, and 48% in 43 °C-60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ±â€¯7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy-Bladder domains and indexes showed no significant change. CONCLUSIONS: Four-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. PATIENT SUMMARY: We were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non-muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.

Functional Role of STIM-1 and Orai1 in Human Microvascular Aging.

The impact of aging on vascular function is heterogeneous depending on the vascular territories. Calcium regulation plays a key role in vascular function and has been implicated in aging-related hypercontractility of corpus cavernosum. We aimed to evaluate stromal interaction molecule (STIM)/Orai system involvement in aging-related vascular alterations in the human macro and microvasculature. Aortae specimens and mesenteric arteries (MA), obtained from 45 organ donors, were functionally evaluated in organ chambers and wire myographs. Subjects were divided into groups either younger or older than 65-years old. The expressions of STIM-1, Orai1, and Orai3 were determined by immunofluorescence in the aorta and MA, and by Western blot in the aorta homogenates. The inhibition of STIM/Orai with YM-58483 (20 µM) reversed adrenergic hypercontractility in MA from older subjects but did not modify aging-related hypercontractility in the aortic strips. Aging was related to an increased expression of Orai1 in human aorta, while Orai1 and STIM-1 were upregulated in MA. STIM-1 and Orai1 protein expressions were inversely correlated to endothelial function in MA. Circulating levels of Orai1 were correlated with the inflammatory factor TNF-α and with the endothelial dysfunction marker asymmetric dimethylarginine. Aging is associated with an increased expression of the STIM/Orai system in human vessels with functional relevance only in the microvascular territory, suggesting its role in aging-related microvascular dysfunction.

Onion and Apple Functional Ingredients Intake Improves Antioxidant and Inflammatory Status and Vascular Injury in Obese Zucker Rats.

The objective of this study was to investigate the effects of onion and apple functional ingredients in homozygous (fa/fa) obese Zucker rats. Rodents were fed three diets: standard diet [obese control (OC) group], standard diet containing 10% onion [obese onion 10% (OO) group] and standard diet containing 10% apple [obese apple 10% (OA) group] for 8 weeks. Food intake and body weight gain were higher in obese than in lean rats. Food efficiency was lower in OO and AO groups compared with OC group. Within the obese groups, total cholesterol, LDL-cholesterol, triacylglycerols, glucose, insulin and triglyceride-glucose index were lower in OO group than in OC group, and HDL-cholesterol was higher in OO group than in OC group. In general, antioxidant activity (ABTS•+ and FRAP), antioxidant enzyme activities (CAT, SOD, GPx), GSH/GSSG ratio, nitrate/nitrite and GLP-1 increased in OO and OA groups compared with OC. Oxidative stress biomarkers, namely protein carbonyls, 8-hydroxy-2'-deoxyguanosine, 8-epi-prostaglandin F2α, inflammatory and vascular injury biomarkers (PAI-1, TIMP-1, VEGF, sICAM-1, sE-Selectin, MCP-1) and leptin, were lower in OO and OA groups than in OC group. Endothelial impairment was partially reversed, and superoxide content and gene expression of NLRP3, NFKß1 and COX2 decreased, in OO and OA groups with respect to OC group. The study demonstrates that high pressure-processed onion and apple functional ingredients administration to obese Zucker rats causes beneficial effects on metabolic health, in particular through improving food efficiency ratio; exerting pronounced lipid-lowering effects; reducing glycemia, insulinemia, and biomarkers of hepatic injury (ALT, AST); improving antioxidant, oxidative stress, inflammatory and vascular injury biomarkers, metabolic hormones, and endothelial function; and decreasing proinflammatory gene expression of NLRP3, NFKß1 and COX2.