The aim of this multicenter study was to investigate the prognostic impact of residual T1 high-grade (HG)/G3 tumors at re-transurethral resection (TUR of bladder tumor) in a large multi-institutional ...cohort of patients with primary T1 HG/G3 bladder cancer (BC).
The study period was from January 2002 to -December 2012. A total of 1,046 patients with primary T1 HG/G3 and who had non-muscle invasive BC (NMIBC) on re-TUR followed by adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with maintenance were included. Endpoints were time to disease recurrence, progression, and overall and cancer-specific death.
A total of 257 (24.6%) patients had residual T1 HG/G3 tumors. The presence of concomitant carcinoma in situ, multiple and large tumors (> 3 cm) at first TUR were associated with residual T1 HG/G3. Five-year recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) were 17% (CI 11.8-23); 58.2% (CI 50.7-65); 73.7% (CI 66.3-79.7); and 84.5% (CI 77.8-89.3), respectively, in patients with residual T1 HG/G3, compared to 36.7% (CI 32.8-40.6); 71.4% (CI 67.3-75.2); 89.8% (CI 86.6-92.3); and 95.7% (CI 93.4-97.3), respectively, in patients with NMIBC other than T1 HG/G3 or T0 tumors. Residual T1 HG/G3 was independently associated with RFS, PFS, OS, and CSS in multivariable analyses.
Residual T1 HG/G3 tumor at re-TUR confers worse prognosis in patients with primary T1 HG/G3 treated with maintenance BCG. Patients with residual T1 HG/G3 for primary T1 HG/G3 are very likely to fail BCG therapy alone.
The intravesical route permits site-specific delivery of drugs with a reduced side-effect profile as compared to oral delivery systems, either by avoiding first-pass metabolism or by obtaining a ...local effect. We investigated mechanisms related to urothelium permeability and new physical and chemical developments in intravesical drug delivery that potentially permit successful treatment of several bladder dysfunction.
A literature review.
Pharmacologic agents increasing urothelial permeability and useful for clinical purposes have been described, such as dimethylsulfoxide, protamine sulphate, chitosan, and nystatin. Among physical approaches, electromotive drug administration appears to be more effective than intravesical passive diffusion in delivering drugs through the urothelium into deeper layers of the bladder. Experimental and clinical reports demonstrated that electric current significantly increases the transport of local anaesthetics, mytomicin C, oxybutynin, resiniferatoxin, epinephrine, and dexamethasone. Among new chemical approaches, cell-penetrating peptides posses the ability to translocate macromolecular drugs across membranes of urothelial cells. The therapeutic benefits of sustained delivery afforded by thermosensitive hydrogel, which forms a depot for hydrophilic and hydrophobic drugs, have been demonstrated by delivering anti-inflammatory drugs. Liposomes improve the aqueous solubility of several hydrophobic drugs such as taxol, amphotericin, and capsaicin.
Electromotive drug administration, new in situ delivery systems, and bioadhesive liposomes may make it possible to extend intravesical therapy and drug administration to many bladder diseases. Research to expand knowledge of the chemical and physical properties of the bladder and processes regulating drug transport across biologic membranes is needed to make this a reality.
We investigated the effects of BTX-A on visceral afferent nerve transmission by measuring bladder tissue NGF levels in patients with neurogenic detrusor overactivity before and after intravesical ...treatment with BTX-A. We also compared the bladder tissue NGF content with clinical and urodynamic data.
A total of 23 patients underwent clinical evaluation and urodynamics with detection of the UDC threshold, maximum pressure and maximum cystometric capacity before, and at the 1 and 3-month followups. Endoscopic bladder wall biopsies were also obtained at the same time points. NGF levels were measured in tissue homogenate by enzyme-linked immunosorbent assay (Promega, Madison, Wisconsin).
At 1 and 3 months mean catheterization and incontinent episodes were significantly decreased (p <0.05 and <0.001, respectively). On urodynamics we detected a significant increase in the UDC threshold and maximum cystometric capacity, and a significant decrease in UDC maximum pressure at the 1 and 3-month followups compared to baseline (each p <0.001). At the same time points we detected a significant decrease in NGF bladder tissue content (each p <0.02).
BTX-A intravesical treatment induces a state of NGF deprivation in bladder tissue that persists at least up to 3 months. As caused by BTX-A, the decrease in acetylcholine release at the presynaptic level may induce a decrease in detrusor contractility and in NGF production by the detrusor muscle. Alternatively BTX-A can decrease the bladder level of neurotransmitters that normally modulate NGF production and release.
The physiology and anatomy of female sexual function are poorly understood. The differences in sexual function among women may be partly attributed to anatomical factors.
The purpose of this study ...was to use ultrasonography to evaluate the anatomical variability of the urethrovaginal space in women with and without vaginal orgasm.
Twenty healthy, neurologically intact volunteers were recruited from a population of women who were a part of a previous published study. All women underwent a complete urodynamic evaluation and those with clinical and urodynamic urinary incontinence, idiopathic detrusor overactivity, or micturition disorders, as well as postmenopausal women and those with sexual dysfunction were excluded. The reported experience of vaginal orgasm was investigated.
The urethrovaginal space thickness as measured by ultrasound was chosen as the indicator of urogenital anatomical variability. Designated evaluators carried out the measurements in a blinded fashion.
The urethrovaginal space and distal, middle, and proximal urethrovaginal segments were thinner in women without vaginal orgasm. A direct correlation between the presence of vaginal orgasm and the thickness of urethrovaginal space was found. Women with a thicker urethrovaginal space were more likely to experience vaginal orgasm (r=0.884; P=0.015). A direct and significant correlation between the thickness of each urethrovaginal segment and the presence of vaginal orgasm was found, with the best correlation observed for the distal segment (r=0.863; P<0.0001). Interobserver agreement between the designated evaluators was excellent (r=0.87; P<0.001).
The measurement of the space within the anterior vaginal wall by ultrasonography is a simple tool to explore anatomical variability of the human clitoris-urethrovaginal complex, also known as the G-spot, which can be correlated to the ability to experience the vaginally activated orgasm. Gravina GL, Brandetti F, Martini P, Carosa E, Di Stasi SM, Morano S, Lenzi A, and Jannini EA. Measurement of the thickness of the urethrovaginal space in women with or without vaginal orgasm.
Serum levels of neutrophils, platelets, and lymphocytes have been recognized as factors related to poor prognosis for many solid tumors, including bladder cancer (BC).
To evaluate the prognostic role ...of the combination of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) in patients with high-risk non–muscle-invasive urothelial BC (NIMBC).
A total of 1151 NMIBC patients who underwent first transurethral resection of the bladder tumor (TURBT) at 13 academic institutions between January 1, 2002 and December 31, 2012 were included in this analysis. The median follow-up was 48 mo.
TURBT with intravesical chemotherapy or immunotherapy.
Multivariable Cox regression analysis was performed to identify factors predictive of recurrence, progression, cancer-specific mortality, and overall mortality. A systemic inflammatory marker (SIM) score was calculated based on cutoffs for NLR, PLR, and LMR.
The 48-mo recurrence-free survival was 80.8%, 47.35%, 20.67%, and 17.06% for patients with an SIM score of 0, 1, 2, and 3, respectively (p<0.01, log-rank test) while the corresponding 48-mo progression free-survival was 92.0%, 75.67%, 72.85%, and 63.1% (p<0.01, log-rank test). SIM scores of 1, 2, and 3 were associated with recurrence (hazard ratio HR 3.73, 7.06, and 7.88) and progression (HR 3.15, 4.41, and 5.83). Limitations include the lack of external validation and comparison to other clinical risk models.
Patients with high-grade T1 stage NMIBC with high SIM scores have worse oncologic outcomes in terms of recurrence and progression. Further studies should be conducted to stratify patients according to SIM scores to identify individuals who might benefit from early cystectomy.
In this study, we defined a risk score (the SIM score) based on the measurement of routine systemic inflammatory markers. This score can identify patients with high-grade bladder cancer not invading the muscular layer who are more likely to suffer from tumor recurrence and progression. Therefore, the score could be used to select patients who might benefit from early bladder removal.
Patients with high-risk non–muscle-invasive bladder cancer (BC) experienced greater recurrence and progression according to systemic inflammatory markers. This score could be used to select patients who might benefit from early cystectomy. The availability of these biomarkers in routine clinical practice gives further relevance to identification of the prognostic role of immune cells in patients with BC. These results could be translated into clinical practice to stratify patients who might benefit from early cystectomy.
Clinical trials have shown that hexaminolevulinate (HAL) fluorescence cystoscopy improves the detection of bladder tumors compared with standard white-light cystoscopy, resulting in more efficacious ...treatment. However, some recent meta-analyses report controversially on recurrence-free rates with this procedure. A systematic review of literature was performed from December 2014 to January 2015 using the PubMed, Embase and Cochrane databases for controlled trials on photodynamic diagnosis (PDD) with HAL. A total of 154 publications were found up to January 2015. Three of the authors separately reviewed the records to evaluate eligibility and methodological quality of clinical trials. A total of 16 publications were considered eligible for analysis. HAL–PDD-guided cystoscopy increased overall tumor detection rate (proportion difference 19%, 95% confidence interval CI 0.152–0.236) although the benefit was particularly significant in patients with carcinoma in situ (CIS) lesion (proportion difference 15.7%, 95% CI 0.069–0.245) and was reduced in papillary lesions (Ta proportion difference 5.9%, 95% CI 0.014–0.103 and T1 proportion difference 1.2%, 95% CI 0.033–0.057). Moreover, there were 15% of patients (95% CI 0.098–0.211) with at least one additional tumor seen with PDD. With regard to recurrence rates, the data sample was insufficient for a statistical analysis, although the evaluation of raw data showed a trend in favor of HAL–PDD. This meta-analysis confirms the increased tumor detection rate by HAL–PDD with a most pronounced benefit for CIS lesion.
In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk ...superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment.
Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed.
The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p = 0.036) and 58% versus 31% (p = 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p = 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC ((43 vs 8 ng/ml), consistent with bladder content absorption.
Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer.
objective Lack of sexual activity due to erectile dysfunction (ED) decreases testosterone (T) levels through a central effect on the hypothalamic–pituitary axis. In this paper we studied the effect ...of different type V phosphodiesterase (PDE5) inhibitor treatments for ED on the reversibility of this endocrine pattern.
design Open‐label, retrospective study.
patients Seventy‐four consecutive patients were treated on demand with sildenafil (Sild) (50 mg) and tadalafil (Tad) 20 mg.
measurements The success in sexual intercourse was recorded and total (tT) and free testosterone (fT) levels were studied before and after 3 months of treatment.
results Basal level of tT and fT were at the bottom of the normal range and LH levels were at the top of the high normal range. After treatments, this endocrine pattern was reversed in both groups. However, the T increase in Sild‐treated patients was significantly lower than in those treated with Tad (4·7 ± 2·7 vs. 5·1 ± 0·9, P < 0·001). fT levels followed a directly proportional pattern, while the inverse was found when LH production was studied. The intercourse rate reflected this effect: in fact, the Sild group showed a 4·9 ± 2·9/month full sexual intercourse rate while in the Tad group a significantly higher rate of sexual intercourse was found (6·9 ± 4·6/month, P = 0·04). However, drug consumption was comparable between the groups (Sild 4·9 ± 2·9 vs. Tad 4·4 ± 2·8 pills/month, P = 0·72).
conclusions As it is unlikely that the two drugs have a different direct effect on the pituitary–testis axis, this effect is probably due to the higher frequency of full sexual intercourse in the Tad‐treated group, because of the drug's longer half‐life.
We investigated the effectiveness and safety of intravesical resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) and botulinum-A toxin injections into the detrusor muscle in a group of spinal ...cord injured patients with neurogenic detrusor overactivity unresponsive to conventional anticholinergic therapy.
A total of 25 patients were randomly assigned to receive intravesically 0.6 μM resiniferatoxin in 50 ml of 0.9% NaCl or injections into the detrusor muscle of 300 units botulinum A-toxin diluted in 30 ml 0.9% NaCl. Clinical evaluation and urodynamics were performed at baseline, and at 6, 12 and 18 months after treatment.
In both arms there was a significant decrease in catheterization and incontinent episodes, and a significant increase in first detrusor contraction and maximum bladder capacity at 6, 12 and 18-month followup. There were no local side effects with either treatment. Botulinum-A toxin induced a significant decrease in the frequency of daily incontinence episodes (p <0.05), a significant increase in first uninhibited detrusor contraction (p <0.01) in maximum bladder capacity (p <0.01), and a significant decrease in maximum pressure of uninhibited detrusor contractions (p <0.01) compared to resiniferatoxin at 6, 12 and 18-month followup.
In spinal cord injured patients with refractory neurogenic detrusor overactivity, intravesical resiniferatoxin and botulinum-A toxin injections into the detrusor muscle provided beneficial clinical and urodynamic results with decreases in detrusor overactivity and restoration of urinary continence in a large proportion of patients. Botulinum-A toxin injections provided superior clinical and urodynamic benefits compared to those of intravesical resiniferatoxin.
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