Non-muscle-invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. ...Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e., PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in patients with NMIBC.
A cohort of 152 patients presenting with primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by IHC, and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patients' specimens.
Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in patients with NMIBC. Interestingly, downregulation of PTBP1 in bladder cancer cell lines affected prosurvival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens.
PTBP1 expression correlates with disease progression, poor prognosis, and worse survival in patients with NMIBC. Downregulation of PTBP1 expression affects prosurvival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as an outcome-predictor in this disease.
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Background:
We investigated the effectiveness and safety of mirabegron oral treatment in a group of patients with Parkinson’s disease (PD) and overactive bladder (OAB), refractory to antimuscarinics.
...Materials and methods:
Thirty patients with PD and refractory OAB were prospectively included in the study. At baseline, motor symptoms, severity of disease and cognitive status were assessed with the Hoehn–Yahr Scale, the Unified Parkinson’s disease Rating Scale, the Mini Mental State examination and the Montreal Cognitive Assessment. At baseline, urinary symptoms, satisfaction with treatment and the impact of urinary incontinence on quality of life (QoL) were assessed with the 3-day voiding diary, the Visual Analogue Scale (VAS), the Incontinence–QoL questionnaire and urodynamics. Patients started assuming mirabegron 50 mg tablets once daily. Evaluation of urinary symptoms and related questionnaires, motor symptoms, severity of PD and uroflowmetry with postvoid residual volume measurement were then repeated at the 3- and 6-month follow up. Side effects were also noted.
Results:
At baseline, the most frequently reported urinary symptoms were: urinary urgency (present in all the patients), urge urinary incontinence in 28/30 (93.3%) and increased daytime urinary frequency in 25 (83.3%) patients. At the 3-month follow up, 7 out of the 30 patients achieved a complete urinary continence. Significant improvements in VAS and Incontinence–QoL scores were observed in 24 patients. These benefits were maintained for the whole observation period. Four patients discontinued treatment due to poor efficacy, and two due to the cost of the drug.
Conclusions:
Mirabegron is a safe and effective treatment in patients with PD and OAB refractory to anticholinergics in the short-term follow up.
Summary Background The clinical effect of intravesical instillation of chemotherapy immediately after transurethral resection of bladder tumours (TURBT) has recently been questioned, despite its ...recommendation in guidelines. Our aim was to compare TURBT alone with immediate post-TURBT intravesical passive diffusion (PD) of mitomycin and immediate pre-TURBT intravesical electromotive drug administration (EMDA) of mitomycin in non-muscle invasive bladder cancer. Methods We did a multicentre, randomised, parallel-group study in patients with primary non-muscle invasive bladder cancer in three centres in Italy between Jan 1, 1994, and Dec 31, 2003. Patients were randomly assigned to receive treatment by means of stratified blocked randomisation across six strata. Patients and physicians giving the interventions were aware of assignment, but it was masked from outcome assessors and data analysts. Patients were randomly assigned to receive TURBT alone, immediate post-TURBT instillation of 40 mg PD mitomycin dissolved in 50 mL sterile water infused over 60 min, or immediate pre-TURBT instillation of 40 mg EMDA mitomycin dissolved in 100 mL sterile water with intravesical 20 mA pulsed electric current for 30 min. Our primary endpoints were recurrence rate and disease-free interval. Analyses were done by intention to treat. Follow-up for our trial is complete. This study is registered with ClinicalTrials.gov , number NCT01149174. Findings 124 patients were randomly assigned to receive TURBT alone, 126 to receive immediate post-TURBT PD mitomycin, and 124 to receive immediate pre-TURBT EMDA mitomycin. 22 patients were excluded from our analyses because they did meet our eligibility criteria after TURBT: 11 had stage pT2 disease and 11 had carcinoma in situ. Median follow-up was 86 months (IQR 57–125). Patients assigned to receive EMDA mitomycin before TURBT had a lower rate of recurrence (44 38% of 117) than those assigned to receive PD mitomycin after TURBT (70 59% of 119) and TURBT alone (74 64% of 116; log-rank p<0·0001). Patients assigned to receive EMDA mitomycin before TURBT also had a higher disease-free interval (52 months, IQR 32–184) than those assigned to receive PD mitomycin after TURBT (16 months, 12–168) and TURBT alone (12 months, 12–37; log-rank p<0·0001). We recorded persistent bladder symptoms after TURBT in 18 (16%) of 116 patients in the TURBT-alone group (duration 3–7 days), 37 (31%) of 119 in the PD mitomycin post-TURBT group (duration 20–30 days), and 24 (21%) of 117 in the EMDA mitomycin pre-TURBT group (duration 7–12 days); haematuria after TURBT in eight (7%) of 116 patients in the TURBT-alone group, 16 (13%) of 119 in the PD mitomycin post-TURBT group, and 11 (9%) of 117 in the EMDA mitomycin pre-TURBT group; and bladder perforation after TURBT in five (4%) of 116 patients in the TURBT-alone group, nine (8%) of 119 in the PD mitomycin post-TURBT group, and seven (6%) of 117 in the EMDA mitomycin pre-TURBT group. Interpretation Intravesical EMDA mitomycin before TURBT is feasible and safe; moreover, it reduces recurrence rates and enhances the disease-free interval compared with intravesical PD mitomycin after TURBT and TURBT alone. Funding None.
Abstract Background Patients with non–muscle-invasive bladder cancer with an intermediate or high risk need adjuvant intravesical therapy after surgery. Based largely on meta-analyses of previously ...published results, guidelines recommend using either bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) in these patients. Individual patient data (IPD) meta-analyses, however, are the gold standard. Objective To compare the efficacy of BCG and MMC based on an IPD meta-analysis of randomised trials. Design, setting, and participants Trials were searched through Medline and review articles. The relevant trial investigators were contacted to provide IPD. Measurements The drugs were compared with respect to time to recurrence, progression, and overall and cancer-specific death. Results and limitations Nine trials that included 2820 patients were identified, and IPD were obtained from all of them. Patient characteristics were 71% primary, 54% Ta, 43% T1, 25% G1, 58% G2, and 16% G3, and 7% had prior intravesical chemotherapy. Based on a median follow-up of 4.4 yr, 43% recurred. Overall, there was no difference in the time to first recurrence ( p = 0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found ( p < 0.0001), while there was a 28% risk increase ( p = 0.006) for BCG in the trials without maintenance. BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy. In the subset of 1880 patients for whom data on progression, survival, and cause of death were available, 12% progressed and 24% died, and, of those, 30% of the deaths were due to bladder cancer. No statistically significant differences were found for these long-term end points. Conclusions For prophylaxis of recurrence, maintenance BCG is required to demonstrate superiority to MMC. Prior intravesical chemotherapy was not a confounder. There were no statistically significant differences regarding progression, overall survival, and cancer-specific survival between the two treatments.
We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 ...months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT).
Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment.
Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio HR, 2.24 95% CI, 1.21 to 4.16; PCSM: subdistribution hazard ratio sHR, 1.82 0.51 to 6.49; OS: HR, 1.72 0.97 to 3.05; RT + stADT - MFS: HR, 1.27 1.12 to 1.44; PCSM: sHR, 2.10 1.52 to 2.92; OS: HR, 1.26 1.11 to 1.44; RT + ltADT - MFS: HR, 1.58 1.27 to 1.96; PCSM: sHR, 1.97 1.11 to 3.49; OS: HR, 1.59 1.27 to 1.99). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL.
PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.
Objective To evaluate the efficacy and safety of duloxetine hydrochloride in the treatment of patients affected by chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods Thirty-eight ...CP/CPPS patients completed the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and International Index of Erectile Function-Erectile Function-5 (IIEF-5) questionnaires, uroflowmetry, and evaluation of psychologic status using Hamilton Anxiety Scale (HAM-A) and Hamilton Depression Scale (HAM-D). Patients were randomly assigned to 2 treatments groups. Treatment in group 1 consisted of a simultaneous oral administration of tamsulosin (0.4 mg/d, 60 mg/d), saw palmetto (320 mg/d), and duloxetine (60 mg/d). Treatment in group 2 consisted of tamsulosin (0.4 mg/d) and saw palmetto (320 mg/d). NIH-CPSI and IIEF-5 questionnaires, uroflowmetry, and evaluation of the psychological status were repeated at 16 weeks of follow-up. Results At 16 weeks, a significant improvement in NIH-CPSI pain subscore, NIH-CPSI quality of life subscore, and NIH-CPSI total score were observed in group 1 patients compared with those in group 2 ( P <.01, respectively), together with a significant improvement in HAM-A and HAM-D scores ( P <.01, respectively). Patients in group 2 showed a significant improvement in NIH-CPSI total score, in the urinary symptoms subscore, and in the HAM-A total score. No significant differences were observed in IIEF-5 scores in the 2 groups. Maximum flow rate significantly increased in both groups. In group 1, 20% of patients stopped the study due to adverse effects. Conclusion The use of duloxetine in a multimodal treatment with an α-blocker medication and a saw palmetto extract allowed better results in controlling clinical symptoms, psychologic status and quality of life patients affected by CP/CPPS.
Alternative splicing (AS) is tightly coupled to transcription for the majority of human genes. However, how these two processes are linked is not well understood. Here, we unveil a direct role for ...the transcription factor FBI‐1 in the regulation of AS. FBI‐1 interacts with the splicing factor SAM68 and reduces its binding to BCL‐X mRNA. This, in turn, results in the selection of the proximal 5′ splice site in BCL‐X exon 2, thereby favoring the anti‐apoptotic BCL‐XL variant and counteracting SAM68‐mediated apoptosis. Conversely, depletion of FBI‐1, or expression of a SAM68 mutant lacking the FBI‐1 binding region, restores the ability of SAM68 to induce BCL‐XS splicing and apoptosis. FBI‐1's role in splicing requires the activity of histone deacetylases, whose pharmacological inhibition recapitulates the effects of FBI‐1 knockdown. Our study reveals an unexpected function for FBI‐1 in splicing modulation with a direct impact on cell survival.
Synopsis
The oncogenic transcription factor FBI‐1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL‐X mRNA. This increases anti‐apoptotic BCL‐X isoform expression and cell survival.
The transcription factor FBI‐1 directly interacts with the splicing regulator SAM68.
FBI‐1 impairs binding of SAM68 to BCL‐X mRNA and thus promotes production of the anti‐apoptotic BCL‐X isoform and cell survival.
FBI‐1's effect on BCL‐X splicing requires histone deacetylase activity.
The oncogenic transcription factor FBI‐1 regulates alternative splicing by preventing the splicing regulator SAM68 from binding to BCL‐X mRNA. This increases anti‐apoptotic BCL‐X isoform expression and cell survival.
Objective To evaluate the concordance and prognostic role of histologic variants of bladder urothelial carcinoma in transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) ...specimens. Methods Clinicopathologic information available at the time of RC and follow-up data from 4110 RC specimens, collected between January 2000 and December 2009 at 17 tertiary referral centers were retrospectively analyzed and evaluated for the presence or absence of uncommon variants of bladder urothelial carcinoma. The presence or absence of uncommon variants of bladder urothelial carcinoma was evaluated on previous TURBT specimens of patients undergoing RC. Cox regression was used to assess the impact of these parameters on cancer-specific survival, and the Kaplan-Meier test for disease-free survival was plotted for survival estimate. Results Of 4110 patients, 579 were found to have uncommon variants of bladder urothelial carcinoma at RC (14.1%), whereas 266 (6.4%) at TURBT. A lack of agreement about uncommon variants was observed between TURBT and RC specimens in the entire population ( P <.001). The presence of uncommon variants at TURBT was associated with an increased risk of pathologic upstage (hazard ratio, 3.24; confidence interval, 1.19-6.37; P <.003) and significant decrease in cancer-specific survival and recurrence-free survival ( P <.001). Conclusion Although the concordance of presence of uncommon histologic variants of urothelial bladder carcinoma between TURBT and RC is low, the presence of uncommon histologic variants of urothelial bladder carcinoma at TURBT is associated with a less favorable clinical outcome.
We evaluated the efficacy and tolerability of botulinum A toxin (BTX-A) intravesical injections in patients affected by painful bladder syndrome with increased urinary frequency, refractory to ...conventional treatment modalities.
Twelve women and two men were prospectively included in the study. Under short general anaesthesia patients were given injections of 200U of commercially available BTX-A diluted in 20ml 0.9% NaCl. Injections were performed submucosally in the trigone and bladder floor under cystoscopic control. Voiding chart, the Visual Analog Scale (VAS) for pain, and urodynamics were performed before treatment and 1 and 3 mo afterward.
Overall, 12 patients (85.7%) reported subjective improvement at 1 and 3 mo follow-up. The mean VAS score was significantly reduced at 1 and 3 mo after treatment (p<0.05 for both); at the same time points daytime and nighttime urinary frequency significantly decreased (p<0.01 and p<0.05, respectively), and bladder cystometric capacity significantly increased (p<0.01). Two patients reported incomplete bladder emptying. We did not detect any systemic side effects during or after treatment.
The results of this pilot study indicate that BTX-A intravesical injections are effective in the short-term management of painful bladder syndrome. By modulating afferent C-fiber activity within the bladder walls, BTX-A significantly improves urodynamic parameters and reduces bladder pain and urinary frequency.
The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and ...chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer.
After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website
http://clinicaltrials.gov.
Median follow-up was 88 months (IQR 63–110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months 95% CI 55–86
vs 21 months 15–54; difference between groups 48 months 42–54, log-rank p=0·0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41·9% 32·7–51·5
vs 57·9% 48·7–67·5; difference between groups 16·0% 2·7–29·3, log-rank p=0·0012); progression (9·3% 3·8–14·8
vs 21·9% 17·9–25·9; difference between groups 12·6% 3·0–22·2, log-rank p=0·004); overall mortality (21·5% 13·5–29·5
vs 32·4% 23·4–41·4, difference between groups 10·9% 0·6–21·2, log-rank p=0·045); and disease-specific mortality (5·6% 1·2–10·0
vs 16·2% 6·1–23·3, difference between groups 10·6% 2·5–18·7, log-rank p=0·01). Side-effects were mainly localised to the bladder.
BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.
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