Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers

Background

DNA methylation markers could serve as useful biomarkers, both as markers for progression and for urine-based diagnostic assays.

Objective

Identify bladder cancer (BCa)–specific methylated DNA sequences for predicting pTa-specific progression and detecting BCa in voided urine.

Design, setting, and participants

Genome-wide methylation analysis was performed on 44 bladder tumours using the Agilent 244K Human CpG Island Microarray (Agilent Technologies, Santa Clara, CA, USA). Validation was done using a custom Illumina 384-plex assay (Illumina, San Diego, CA, USA) in a retrospective group of 77 independent tumours. Markers for progression were identified in pTa (n = 24) tumours and validated retrospectively in an independent series of 41 pTa tumours by the SNaPshot method (Applied Biosystems, Foster City, CA, USA).

Measurements

The percentage of methylation in tumour and urine samples was used to identify markers for detection and related to the end point of progression to muscle-invasive disease with Kaplan-Meier models and multivariate analysis.

Results and limitations

In the validation set, methylation of the T-box 2 (TBX2), T-box 3 (TBX3), GATA binding protein 2 (GATA2), and Zic family member 4 (ZIC4) genes was associated with progression to muscle-invasive disease in pTa tumours (p = 0.003). Methylation of TBX2 alone showed a sensitivity of 100%, a specificity of 80%, a positive predictive value of 78%, and a negative predictive value of 100%, with an area under the curve of 0.96 (p < 0.0001) for predicting progression. Multivariate analysis showed that methylation of TBX3 and GATA2 are independent predictors of progression when compared to clinicopathologic variables (p = 0.04 and p = 0.03, respectively). The predictive accuracy improved by 23% by adding methylation of TBX2, TBX3, and GATA2 to the European Organisation for Research and Treatment of Cancer risk scores. We further identified and validated 110 CpG islands (CGIs) that are differentially methylated between tumour cells and control urine. The limitation of this study is the small number of patients analysed for testing and validating the prognostic markers.

Conclusions

We have identified four methylation markers that predict progression in pTa tumours, thereby allowing stratification of patients for personalised follow-up. In addition, we identified CGIs that will enable detection of bladder tumours in voided urine.     

Protein expression patterns of ezrin are predictors of progression in T1G3 bladder tumours treated with nonmaintenance bacillus Calmette-Guérin

Background

Bacillus Calmette-Guérin (BCG) is a standard treatment for reducing tumour recurrence and delaying progression of high-risk, non–muscle-invasive bladder tumours. However, it is not clear yet which patients are more likely to be responders to BCG.

Objective

To evaluate the role of ezrin expression in bladder cancer (BCa) progression in T1G3 bladder tumours treated with BCG.

Design, setting, and participants

Ezrin protein expression patterns were analysed on tumour specimens belonging to 92 patients with T1G3 non–muscle-invasive BCa undergoing nonmaintenance BCG treatment. Re-resection was not performed. The median follow-up was 90.5 mo (range: 3.0–173.0). A specific tissue array was created containing three representative cores of each of the tumour specimens belonging to these patients.

Measurements

Ezrin protein expression patterns were assessed by immunohistochemistry on this tissue array. Proliferation rates were assessed by means of Ki67 staining. Recurrence, progression into muscle-invasive tumours, and disease-specific overall survival (OS) rates were analysed using univariate and multivariate tests.

Results and limitations

Among the 92 patients analysed, 40 recurred (43.5%), 17 progressed (18.5%), and 14 died of the disease (15.2%). Log-rank survival analyses revealed that an ezrin membrane expression <20% was significantly associated with increased progression (p = 0.009) and shorter disease-specific OS (p = 0.006). Multivariate analyses showed that ezrin was an independent prognostic marker of progression (p = 0.031) and disease-specific survival (p = 0.035). Interestingly, the low ezrin membrane expression correlated with high proliferation rates (p = 0.033).

Conclusions

Immunohistochemistry analyses revealed that the membrane expression of ezrin is associated with the clinical outcome of patients with T1G3 tumours undergoing BCG treatment. Protein expression patterns of ezrin were associated with tumour progression in T1G3 disease. The differential expression of ezrin distinguished patients responding to BCG from those who may require a more aggressive therapeutic approach.     

Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin

Background

Controversy exists over the most important prognostic factors in T1 high-grade non–muscle-invasive bladder cancer (NMIBC) patients treated with bacillus Calmette-Guérin (BCG).

Objective

Evaluate prognostic factors for recurrence, progression, and disease-specific mortality after adjuvant intravesical BCG immunotherapy in patients with T1G3 NMIBC and long-term follow-up.

Design, setting, and participants

A single-institution retrospective analysis of 146 patients with primary stage T1G3 NMIBC.

Intervention

All patients were treated with complete transurethral resection (TUR) plus multiple bladder biopsies that included the prostatic urethra. No second TUR was done. Patients underwent an induction course of intravesical BCG (Connaught strain, 81 mg) without maintenance therapy.

Measurements

The variables analysed for time to recurrence, progression, and death due to bladder cancer (BCa) were gender, age, tumour multiplicity, diameter, aspect, substaging, concomitant carcinoma in situ (CIS), and CIS in the prostatic urethra. Cox regression models were used to assess the univariate and multivariate prognostic importance of these factors and estimate hazard ratios (HRs). Time-to-event distributions were estimated using cumulative incidence functions.

Results and limitations

The median follow-up was 8.7 yr. Sixty-five patients (44.5%) had recurrence, 25 patients (17.1%) had progression, and 18 patients (12.3%) died because of BCa. Female gender and presence of CIS in the prostatic urethra were associated with an increased risk of recurrence (p = 0.0003, HR: 2.53), progression (p = 0.001, HR: 3.59), and death due to BCa (p = 0.004, HR: 3.53).

Conclusions

In primary T1G3 bladder tumours treated with induction BCG, female gender or having CIS in the prostatic urethra were the only prognostic factors for time to recurrence, progression, and disease-related mortality. It is very important to perform a biopsy of the prostatic urethra in patients with primary high-grade NMIBC as a first step to obtain this prognostic information.     

Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study

Objectives

The clinical management of non–muscle-invasive urothelial cell carcinoma of the bladder (UCC) is challenging, as it has a marked tendency to recur and to progress. Aim of this study was to investigate the prognostic value of the WHO 1973 and 2004 grading systems and biomarkers FGFR3, CK20 and Ki-67.

Methods

In a prospective study, tumours from 221 patients were studied for the expression of CK20 and Ki-67 by immunohistochemistry, and FGFR3 status by SNaPshot mutation detection. Staging and grading were performed according to the WHO classification systems of 1973 and 2004.

Results

: Median follow-up was 35 mo. Recurrence occurred in 72 of 221 patients. None of the parameters was able to predict disease recurrence. CK20, Ki-67, FGFR3 mutation, molecular grade using FGFR3 mutation analysis and Ki-67, and histological grading and staging were significantly associated with disease progression in stage. In multivariable analyses, WHO 1973 and 2004 grading systems remained statistically significant and independent predictors of progression, with p = 0.005 for WHO 1973 and p = 0.004 for 2004. FGFR3 status was able to discriminate progressors from nonprogressors in a subset of patients with high-grade UCC (p = 0.009).

Conclusions

This is the first prospective study comparing the WHO 1973 and 2004 grading systems. We show that both grading systems contribute valuable independent information. Therefore, it should be considered whether a better grading system could be developed that incorporates essential elements from both. The combination of WHO 2004 grading with FGFR3 status allows a better risk stratification for patients with high-grade non–muscle-invasive UCC.     

Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience

Background

Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown.

Objective

Report long-term outcomes of patients with muscle-invasive BCa treated by CMT.

Design, setting, and participants

We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2–4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr.

Interventions

Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC—60 for less than CR and 42 for recurrent invasive tumors.

Measurements

Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method.

Results and limitations

Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2 = 74%, 67%, and 63%; T3–4 = 53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3–4 = 41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p < 0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity.

Conclusions

CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.     

A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence

Background

Narrow band imaging (NBI) is an optical enhancement technology that filters white light into two bandwidths of illumination centered on 415 nm (blue) and 540 nm (green). NBI cystoscopy can increase bladder cancer (BCa) visualization and detection at the time of transurethral resection (TUR). NBI may therefore reduce subsequent relapse following TUR.

Objective

Assess the impact of NBI modality on 1-yr non–muscle-invasive BCa (NMIBC) recurrence risk.

Design, setting, and participants

Consecutive patients with overt or suspected BCa were included in a prospective study powered to test a 10% difference in 1-yr recurrence risk in favor of cases submitted to NBI TUR. Excluding patients with muscle-invasive BCa, negative pathologic examination, or without follow-up, the study population was composed of 148 subjects randomized from August 2009 to September 2010 to NBI TUR (76 cases) or white light (WL) TUR (72 cases).

Intervention

TUR was performed in NBI or standard WL modality.

Measurements

The 1-yr recurrence risks in NBI or WL TUR groups were compared using odds ratio (OR) point and interval estimates derived from logistic regression modeling.

Results and limitations

The 1-yr recurrence-risk was 25 of 76 patients (32.9%) in the NBI and 37 of 72 patients (51.4%) in the WL group (OR = 0.62; p = 0.0141). Simple and multiple logistic regression analyses provided similar OR points and interval estimates.

Conclusions

TUR performed in the NBI modality reduces the recurrence risk of NMIBC by at least 10% at 1 yr.     

Bladder Preservation in Selected Patients with Muscle-Invasive Bladder Cancer by Complete Transurethral Resection of the Bladder Plus Systemic Chemotherapy: Long-Term Follow-up of a Phase 2 Nonrandomized Comparative Trial with Radical Cystectomy

Background

Many phase 2 bladder-sparing programmes using transurethral resection of the bladder (TURB) plus chemotherapy or radio-chemotherapy have been undertaken, but some controversies remain.

Objective

To determine the efficacy of complete TURB plus three cycles of cisplatin-based chemotherapy in selected patients with muscle-invasive bladder cancer (MIBC).

Design, setting, and participants

A phase 2 nonrandomized trial was designed that included patients with MIBC who underwent complete TURB with positive biopsies of the tumour bed. Patients with negative biopsies of the tumour bed, with macroscopically residual tumour, with hydronephrosis, or with distant metastasis were excluded from this trial. Patients included in this trial were offered three cycles of systemic chemotherapy or radical cystectomy (RC). Clinical response (cR) was denoted by either no tumour or the presence of Ta1–Tis bladder tumour at 3-mo evaluation; clinical non-response (cNR) was denoted by cases of muscle-invasive tumour or distant metastasis. Of 146 patients who entered this trial, 75 choose the bladder-sparing programme and 71 chose RC.

Measurements

At 5 yr and 10 yr, the cancer-specific survival (CSS) rate was 64.5% and 59.8%, respectively, with no significant difference compared to the RC arm (p = 0.544). The progression-free survival with bladder preserved was 52.6% and 34.5%, respectively. In multivariate analysis, cR was the only predictive factor for survival (p = 0.001) and bladder preservation (p = 0.000).

Results and limitations

This was not a randomized trial, and patients were included over 16 yr. However, no modifications were made to the therapy schedule except from chemotherapy schemes considered standard at the time.

Conclusions

Patients with microscopic residual cancer after complete TURB seem to be good candidates for the bladder-sparing programme using three cycles of systemic chemotherapy, with CSS comparable to RC.     

NRAMP1 and hGPX1 gene polymorphism and response to bacillus Calmette-Guérin therapy for bladder cancer

Background

The natural resistance-associated macrophage protein 1 (NRAMP1) gene is associated with susceptibility to Mycobacterium tuberculosis in humans and to bacillus Calmette-Guérin (BCG) in mice. The detoxification enzyme, human glutathione peroxidase 1 (hGPX1), is associated with recurrence of bladder cancer (BCa).

Objective

To determine whether NRAMP1 and hGPX1 gene polymorphisms correlate with response to BCG immunotherapy for non–muscle-invasive BCa (NMIBC).

Design, setting, and participants

DNA was obtained from the peripheral blood of 99 NMIBC patients who were prospectively randomized to receive postresection intravesical BCG (81 mg [n = 50] or 27 mg [n = 19]) or BCG (27 mg) with interferon alpha (IFN-α; n = 30). The median follow-up time was 60 mo.

Intervention

Intravesical BCG or BCG–IFN-α.

Measurements

Restriction fragment length polymorphism (RFLP) analysis was performed to identify polymorphisms in the NRAMP1 promoter region (GT repeat number) and at position 543 (aspartate [D] and/or asparagine [N] expression) within the NRAMP1 protein (D543N) and position 198 (proline and/or leucine expression) within the hGPX1 protein (Pro198Leu). Data were analyzed using χ² analysis, multivariate analysis, and Kaplan-Meier curves.

Results and limitations

On univariate analysis, the NRAMP1 D543N G:G genotype had decreased cancer-specific survival (CSS; p = 0.036). The hGPX1 CT genotype (Pro-Leu) had decreased recurrence time (p = 0.03) after BCG therapy. On multivariate analysis, patients with the NRAMP1 D543N G:G genotype and allele 3 (GT)n polymorphism had decreased recurrence time (p = 0.014 and p = 0.03) after BCG therapy. The limitation of this study was its small sample size.

Conclusions

Polymorphisms of the NRAMP1 and hGPX1 genes may be associated with recurrence of BCa after BCG immunotherapy.     

Anatomic Bladder Neck Preservation During Robotic-Assisted Laparoscopic Radical Prostatectomy: Description of Technique and Outcomes

Background

Robotic-assisted laparoscopic radical prostatectomy (RALP) has been rapidly adopted despite a daunting learning curve with bladder neck dissection as a challenging step for newcomers.

Objective

To describe an anatomic, reproducible technique of bladder neck preservation (BNP) and associated perioperative and long-term outcomes.

Design, settings, and participants

From September 2005 to May 2009, data from 619 consecutive RALP were prospectively collected and compared on the basis of bladder neck dissection technique with 348 BNP and 271 standard technique (ST).

Surgical procedure

RALP with BNP.

Measurements

Tumor characteristics, perioperative complications, and post-operative urinary control were evaluated at 4, 12 and 24 months using (1) the Expanded Prostate Cancer Index (EPIC) urinary function scale scored from 0–100; and (2) continence defined as zero pads per day.

Results and limitations

Mean age for BNP versus ST was 57.1 ± 6.6 yr versus 58.9 ± 6.7 yr (p = 0.033), while complication rates did not vary significantly by technique. Estimated blood loss was 183.7 ± 95.8 ml versus 224.6 ± 108 ml (p = 0.938) in men who underwent BNP versus ST. The overall positive margin rate was 12.8%, which did not differ at the prostate base for BNP versus ST (1.4% vs. 2.2%, p = 0.547). Mean urinary function scores for BNP versus ST at 4, 12, and 24 mo were 64.6 versus 57.2 (p = 0.037), 80.6 versus 79.0 (p = 0.495), and 94.1 versus 86.8 (p < 0.001). Similarly, BNP versus ST continence rates at 4, 12, and 24 mo were 65.6% versus 26.5% (p < 0.001), 86.4% versus 81.4% (p = 0.303), and 100% versus 96.1% (p = 0.308).

Conclusions

BNP versus ST is associated with quicker recovery of urinary function and similar cancer control.     

Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer

Background

Cancer often involves inflammatory processes. We hypothesized that immune mediators in urine may serve as biomarkers for bladder cancer (BCa).

Objective

To investigate whether BCa might be marked by urinary levels of heat shock proteins (HSPs; HSP60, HSP70, or HSP90) or cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, tumor growth factor [TGF]-β, interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, or IL-13).

Design, setting, and participants

This was a case–control study with a discovery and validation phase. We examined urine from 106 consecutive patients: healthy controls (n = 18); hematuria with no evidence of BCa (n = 20); non–muscle-invasive BCa (n = 50); and muscle-invasive BCa (n = 18). The concentrations of HSPs and cytokines were assessed by enzyme-linked immunosorbent assay. In the validation phase, independent urine samples from 40 patients were analyzed (controls [n = 19] and BCa [n = 21]).

Measurements

We used the area under the curve (AUC) of a receiver operating characteristic analysis to determine the ability of HSPs and cytokines to mark BCa and applied a multivariate logistic regression to create a formula able to diagnose BCa. The formula was applied to the validation set without recalculation, and positive and negative predictive values were calculated.

Results and limitations

Urinary concentrations of IL-8, IL-10, and IL-13 were significantly elevated in BCa; IL-13 was the most prominent marker (AUC: 0.93; 95% confidence interval [CI], 0.85–0.99). The multivariate regression analysis highlighted HSP60 (odds ratio [OR]: 1.206; 95% CI, 1.041–1.397, p = 0.003) and IL-13 (OR: 1.020; 95% CI: 1.007–1.033, p = 0.012).The validation assay was performed using HSP60 and IL-13. The overall positive predictive value was 74% (95% CI, 64–84%); and the negative predictive value was 76% (95% CI, 66–86%). Since we examined a small number of patients, the results need to be confirmed in a larger cohort.

Conclusions

These results suggest that it might be possible to develop a urinary biomarker for BCa and raise the possibility that expression of anti-inflammatory cytokines and HSPs might allow BCa to evade immune surveillance.     

Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats

Background

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF).

Objective

We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling.

Design, setting, and participants

Complete T7–T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250–275 g).

Measurements

At 21–29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n = 7) or vardenafil 1 mg/kg (n = 8) was delivered intravenously. NVCs and BANF were recorded for 45 min.

Results and limitations

In all SCI rats, BANF was already present and regular at resting conditions (26.2 ± 4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08 ± 0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186 ± 37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline (p < 0.001) and BANF (52% decrease vs 28% in saline after 45 min; p < 0.001).

Conclusions

Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.     

Transurethral Resection of Non–Muscle-Invasive Bladder Transitional Cell Cancers With or Without 5-Aminolevulinic Acid Under Visible and Fluorescent Light: Results of a Prospective,Randomised, Multicentre Study

Background

Fluorescent light (FL)–guided cystoscopy induced by 5-aminolevulinic acid (5-ALA) has been reported to detect more tumours compared with standard white-light (WL) cystoscopy. Most reports are from single centres with relatively few patients.

Objective

To evaluate whether 5-ALA–induced FL and WL cystoscopy at transurethral resection (TUR) is superior compared with standard procedures under WL only with respect to tumour recurrence and progression in patients with non–muscle-invasive bladder cancer.

Design, setting, and participants

This randomised, multicentre, observer- and pathologist-blinded, prospective phase 3 clinical trial enrolled 300 patients, and of those patients, 153 were randomised to FL cystoscopy and 147 were randomised to standard WL cystoscopy.

Intervention

All patients were first inspected under WL and all lesions were recorded. Patients randomised to FL underwent a second inspection. TUR was carried out in both groups.

Measurements

Control cystoscopy under WL was performed in all patients every 3 mo during the first year after randomisation and biannually thereafter.

Results and limitations

At the first TUR, the mean number of resection specimens per patient was 2.5 (FL: 2.5; WL: 2.4; p = 0.37) and the resulting mean number of resected tumours was 1.7 with FL and 1.8 with WL (p = 0.85). More patients were diagnosed with carcinoma in situ (CIS) in the WL group (13%) than in the FL group (4.2%). Within-patient comparison of FL patients only showed that FL detected more lesions than WL. Tumour lesions solely detected by FL cystoscopy that would not otherwise be detected by WL cystoscopy included 52% dysplasia, 33% CIS, 18% papillary neoplasms, 13% pT1, and 7% pTa. Outcome at 12 mo did not show any difference between groups with regard to recurrence-free and progression-free survival rates.

Conclusions

In this prospective, randomised, multi-institutional study, we found no clinical advantage of FL cystoscopy compared with WL cystoscopy and TUR.     

Technique of Laparoscopic-Endoscopic Single-Site Surgery Radical Nephrectomy

Background

Laparoscopic-endoscopic single-site surgery (LESS) represents the closest surgical technique to scar-free surgery.

Objective

To assess the feasibility of LESS radical nephrectomy (LESS-RN).

Design, setting, and participants

Ten patients with body mass index (BMI) ≤30 underwent LESS-RN for renal tumour by two experienced laparoscopists.

Surgical procedure

TriPort (Olympus Winter &; Ibe, Hamburg, Germany) was inserted through a transumbilical incision. A combination of standard laparoscopic instruments and flexible grasper and scissors was used. A 5-mm 30° camera was also used. The standard laparoscopic transperitoneal nephrectomy technique was performed.

Measurements

Patient demographics, operative details, and final pathology were prospectively recorded. Postoperative evaluation of pain and use of analgesic medication were recorded.

Results and limitations

Ten cases were successfully accomplished (two right-sided tumours and eight left-sided tumours; tumour diameter ranges: 4–8 cm). The mean patient age was 63.5 yr (22–77 yr), and median BMI was 23.56 (18.2–26.6). The mean operative time was 146.4 min (120–180 min), and the mean blood loss was 202 ml (50–900 ml). Pathological examination observed organ-confined T1 renal cell carcinoma in nine cases and pT3b tumour in one case. One bleeding complication occurred. Limitations regarding the intraoperative instrument ergonomics and the requirement for ambidexterity of the surgeon were noted.

Conclusions

LESS-RN proved to be safe and feasible. Further clinical investigation in comparison to the established techniques should take place to evaluate the outcome of LESS-RN.     

Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies

Context

Laparoscopic nephroureterectomy (LNU) has increasingly been used as a minimally invasive alternative to open nephroureterectomy (ONU), but studies comparing the efficacy and safety of the two surgical procedures are still limited.

Objective

Evaluate the oncologic and perioperative outcomes of LNU versus ONU in the treatment of upper urinary tract urothelial carcinoma.

Evidence acquisition

A systematic review and cumulative analysis of comparative studies reporting both oncologic and perioperative outcomes of LNU and ONU was performed through a comprehensive search of the Medline, Embase, and the Cochrane Library electronic databases. All analyses were performed using the Review Manager (RevMan) v.5 (Nordic Cochrane Centre, Copenhagen, Denmark) and Meta-analysis In eXcel (MIX) 2.0 Pro (BiostatXL) software packages.

Evidence synthesis

Twenty-one eligible studies (1235 cases and 3093 controls) were identified. A significantly higher proportion of pTa/Tis was observed in LNU compared to ONU (27.52% vs 22.59%; p = 0.047), but there were no significant differences in other stages and pathologic grades (all p > 0.05). For patients who underwent LNU, the 5-yr cancer-specific survival (CSS) rate was significantly higher, at 9% (p = 0.03), compared to those who underwent ONU, while the overall recurrence rate and bladder recurrence rate were notably lower, at 15% (p = 0.01) and 17% (p = 0.02), respectively. However, there were no statistically significant differences in 2-yr CSS, 5-yr recurrence-free survival (RFS), 5-yr overall survival (OS), 2-yr OS, and metastasis rates between LNU and ONU (all p > 0.05). Moreover, there were no significant differences between LNU and ONU in terms of intraoperative complications, postoperative complications, and perioperative mortality (all p > 0.05). The results of our study were mainly limited by the retrospective design of most of the individual studies included as well as selection biases based on different management of regional lymph nodes and pathologic characteristics.

Conclusions

Our data suggest that LNU offers reliable perioperative safety and comparable oncologic efficacy when compared to ONU. Given that some limitations cannot be overcome, well-designed prospective trials are needed to confirm our findings.     

Laparoendoscopic single-site radical nephrectomy for renal cancer: technique and surgical outcomes

Background

Laparoendoscopic single-site (LESS) surgery has been developed in attempt to further reduce the morbidity and scarring associated with surgical intervention.

Objective

To describe the technique and report the surgical outcomes of LESS radical nephrectomy (RN) in the treatment of renal cell carcinoma.

Design, setting, and participants

LESS-RN was performed in 33 patients with renal tumours. The indications to perform a LESS-RN were represented by renal tumours not greater than T2 and without evidence of lymphadenopathy or renal vein involvement.

Surgical procedure

The Endocone (Karl Storz, Tuttlingen, Germany) was inserted through a transumbilical incision. A combination of standard laparoscopic instruments and bent grasper and scissors was used. The sequence of steps of LESS-RN was comparable to standard laparoscopic RN.

Measurements

Demographic data and perioperative and postoperative variables were recorded and analysed.

Results and limitations

The mean operative time was 143.7 ± 24.3 min, with a mean estimated blood loss of 122.3 ± 34.1 ml and a mean hospital stay of 3.8 ± 0.8 d. The mean length of skin incision was 4.1 ± 0.6 cm and all patients were discharged from hospital with minimal discomfort, as demonstrated by their pain assessment scores (visual analogue scale: 1.9 ± 0.8). The definitive pathologic results revealed a renal cell carcinoma in all cases and a stage distribution of four T1a, 27 T1b, and 2 T2 tumours. All patients were very satisfied with the appearance of the scars, and at a median follow-up period of 13.2 ± 3.9 mo, all patients were alive without evidence of tumour recurrence or port-site metastasis.

Conclusions

LESS is a safe and feasible surgical procedure for RN in the treatment of renal cell carcinoma and has excellent cosmetic results.     

Real-time MRI of orthotopic ileal neobladder voiding: preliminary findings

Objectives

The purpose of this preliminary study was to analyze the dynamic changes in the configuration of the neobladder and naïve bladder during voiding using real-time MRI.

Methods

This study included 10 male patients who had a radical cystectomy and an ileal orthotopic neobladder due to organ-confined bladder cancer and had good urinary function, and 5 male control volunteers. With the subjects in the lateral decubitus position, real-time MRI was performed during micturition. A sagittal slice orientation was used to depict the bladder and the entire length of the urethra; individual movements along the X-axis and Y-axis of the bottom and top of the neobladder and the naïve bladder were recorded and analyzed. Urodynamic studies (UDS) and video voiding cystourethrography were performed in patients.

Results

Five of the 10 neobladder patients could void in the lateral decubitus position. In normal controls and patients who could void, the bladder outlet bladder moved ventrocranially during micturition. The ileal bladder outlet moved a significantly longer distance than the naïve bladder during micturition (X-axis, −13.4 ± 1.5 vs. −3.6 ± 4.3 cm, p = 0.0014; Y-axis, −10.6 ± 0.5 vs. −2.0 ± 6.5 cm, p = 0.0187). The distance that the bladder top moved between the naïve bladders and the neobladder did not differ. UDS did not show a difference between patients who could and could not void at lateral position.

Conclusions

During micturition, the neobladder was found to rotate and move more dynamically than the naïve bladder. Real-time MRI is useful for assessing dynamic voiding function of orthotopic neobladders.     

Influence of nerve transsections and combined bladder filling on intravesical electrostimulation-induced bladder contraction in the rat

Background

The exact mechanisms of action of intravesical electrical stimulation (IVES) are not yet fully understood.

Objective

To gain more insight into the underlying mechanism(s) of the direct detrusor response during IVES by transsecting the dorsal roots and the pelvic nerve consecutively at different levels and to determine whether the efficiency of IVES to induce contraction could be enhanced by simultaneous bladder filling and IVES and by changing the bladder-filling grade.

Design, Setting, and Participants

Eighteen Sprague-Dawley rats underwent IVES (square-wave pulses at 10 Hz, 20-ms pulse duration).

Measurements

In seven rats, IVES-induced bladder-pressure development was studied after the bladder nerves were consecutively sectioned bilaterally at four different levels: no lesion, L6 dorsal roots, L6 ventral roots, pelvic nerve, and major pelvic ganglion with surrounding nerves. Bladder-pressure development induced by IVES with simultaneous bladder filling, by bladder filling alone, and by IVES alone was recorded in seven other rats, and bladder-pressure development induced by IVES with different grades of bladder filling was recorded in four rats.

Results and Limitations

Contraction during IVES was significantly weaker after consecutive section of more nerves (all p < 0.001), but a small contraction (19 ± 17% of baseline) could be elicited even after total decentralization. In the neurologically intact rats, separate stimulation and bladder filling gave contraction strengths similar to those of simultaneous bladder filling and stimulation, but the latter gave contraction after a significantly shorter stimulation time (both p < 0.015).

Conclusions

IVES-induced contraction is, for the major part, a nerve-mediated process. However, a small bladder-pressure rise was induced by direct bladder-wall stimulation after all nerves were cut. Simultaneous electrical stimulation and bladder filling needed much shorter stimulation times than bladder filling alone or stimulation alone. If confirmed in humans, this could shorten IVES sessions substantially without altering the contractile results and could indicate that summation of afferent potentials from different triggers is possible.     

Effects of nitric oxide on the primary bladder afferent activities of the rat with and without intravesical acrolein treatment

Background

It has been suggested that nitric oxide (NO) affects the afferent pathways innervating the bladder. In addition, acrolein, a metabolite of cyclophosphamide, causes bladder hypersensitivity in rats.

Objective

We investigated the direct effects of an NO substrate (L-arginine) and an NO synthase inhibitor (N_ω-nitro-L-arginine methyl ester hydrochloride [L-NAME]) on single fiber activities of the primary bladder afferent nerves with or without acrolein application.

Design, setting, and participants

Female Sprague-Dawley rats were used. Under urethane anesthesia, a single nerve fiber primarily originating from the bladder was identified by electrical stimulation of the left pelvic nerve and by bladder distention, and it was divided by conduction velocity as Aδ fiber or C fiber.

Measurements

The afferent activity measurements with constant bladder filling were repeated three times, and the third measurement served as the baseline observation. After that, two experiments were performed. First, L-NAME (10 mg/ml) was instilled intravesically. Then L-arginine (300 mg/kg) was administrated intravenously to investigate the competition with L-NAME. Second, L-arginine was administrated intravenously. Then 0.003% of acrolein or saline was instilled intravesically to obtain another three cycles of instillations.

Results and limitations

Forty-two single afferent fibers (Aδ fibers: n = 19; C fibers: n = 23) were isolated in 31 rats. When the bladder was filled with L-NAME solution, afferent activities of both Aδ and C fibers increased significantly, and L-arginine administration inhibited these stimulated responses. In addition, intravenous administration of L-arginine significantly decreased the activities of both fibers during saline instillation. Intravesical acrolein instillation significantly increased the activities of both fibers, which were inhibited by pretreatment with L-arginine.

Conclusions

The results suggest that NO synthase exists in the rat urinary bladder and clearly demonstrate that L-arginine, an NO substrate, can inhibit both Aδ and C mechanosensitive afferent fibers of the bladder in the rat. In addition, L-arginine can inhibit the activated responses of both fibers to intravesical acrolein.     

FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours

Background

Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis.

Objective

To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes.

Design, setting, and participants

Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death.

Measurements

FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ², Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model.

Results and limitations

FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract.

Conclusions

FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.     

Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance

Background

The optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated.

Objective

To assess the impact of urinary prostate cancer antigen 3 (PCA3) score as an AS criterion instead of and in addition to the current criteria.

Design, setting, and participants

We prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen [PSA] ≤10 ng/ml, clinical stage T1c–T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP).

Measurements

Performance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging [MRI] findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3–4 disease; (2) overall unfavourable disease (OUD) defined by pT3–4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm³; and (4) insignificant PCa.

Results and limitations

The PCA3 score was strongly correlated with the tumour volume in a linear regression analysis (p < 0.001, r = 0.409). The risk of having a cancer ≥0.5 cm³ and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non–organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm³ (odds ratio [OR]: 5.4; p = 0.010) and significant PCa (OR: 12.7; p = 0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p = 0.030 and p = 0.025, respectively).

Conclusions

PCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.