Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus.

Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future.

Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis.

BACKGROUND: Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision-making. METHODS: The current study included 2222 patients who had a history of nonmuscle-invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle-invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true-positives), subtracting the harms (false-positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy. RESULTS: After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design. CONCLUSIONS: For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision-making. For less risk-averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure.

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy.

OBJECTIVE: To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium-lined space. RESULTS: LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft-tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer-specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer-specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer-specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node-positive patients, LVI only marginally improved the prediction of cancer-specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%). CONCLUSIONS: LVI is strongly associated with clinical outcome in node-negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.

A delay in radical nephroureterectomy can lead to upstaging.

STUDY TYPE: Prognosis (case series). LEVEL OF EVIDENCE: 4. OBJECTIVE: To examine the association between the delay from diagnosis of upper-tract urothelial carcinoma (UTUC) to radical nephroureterectomy (RNU), and the pathological features and outcomes, as the decision to proceed to RNU for an individual patient is complex. PATIENTS AND METHODS: The records of 187 patients who had RNU were reviewed; the interval from diagnosis to RNU was analysed as both a continuous (months) and categorical variable (<3 vs > or =3 months). Logistic regression and survival analyses were used to evaluate the association between time from diagnosis to RNU with pathological characteristics and clinical outcomes. RESULTS: The median time from diagnosis to RNU was 45 days (interquartile range 68). A delay from diagnosis to RNU analysed as a continuous variable was associated with advanced stage, higher grade, previous endoscopic procedure, tumour necrosis, infiltrative tumour architecture, and lymphovascular invasion (P = 0.034), but not disease recurrence or cancer-specific mortality. In the subgroup of patients (90, 48.1%) who had muscle-invasive disease (> or =pT2) a longer delay from diagnosis to RNU as a continuous variable was associated with advanced stage (P = 0.030), higher grade (P = 0.014), infiltrative tumour architecture (P = 0.044), lymphovascular invasion (P = 0.034), disease recurrence (P = 0.02), and cancer-specific mortality (P = 0.03). CONCLUSIONS: Our data suggest that a delay in the interval from diagnosis to RNU is associated with more advanced disease stage. These findings might have important implications for trial design in the ongoing evaluation of neoadjuvant regimens. Timely consideration of definitive treatment for patients with high-risk UTUC is of high importance. Further studies are necessary to validate these hypothesis-generating findings.

Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma.

OBJECTIVE: To assess the value of nuclear matrix protein-22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non-TCC). PATIENTS AND METHODS: We tested the sensitivity, specificity and the predictive accuracy of NMP22 in the context of non-TCC bladder cancer recurrence, and compared it to the performance of urinary cytology. The study group comprised 2687 patients with history of non-muscle-invasive bladder cancer from 10 centres across four continents. RESULTS: The mean patient age was 64.8 years and 75.4% were men; of all patients, 513 (19.1%) had positive urinary cytology, 906 (33.7%) had a positive NMP22 test (>or=10 units/mL) and 80 (3.0%) had non-TCC recurrence. Most of these, i.e. 60 (75%), were stage >or=T2. The sensitivity and specificity of urinary cytology were, respectively, 20.0% and 94.8%, vs 77.5% and 81.8% for NMP22 of >or=10 units/mL. The predictive accuracy of urinary cytology was 57.5%, vs 87.1% for NMP22 >or= 10 units/mL. A combined model that included dichotomized NMP22 and urinary cytology was 85.3% accurate. CONCLUSION: The ability of a NMP22 level of >or=10 units/mL to predict non-TCC recurrence was better than that of urinary cytology, suggesting that NMP22 might have a role in the surveillance of patients at risk of non-TCC recurrence.

A novel approach to energy ablative therapy of small renal tumours: laparoscopic high-intensity focused ultrasound.

OBJECTIVE: High-intensity focused ultrasound (HIFU) permits targeted homogeneous ablation of tissue. The objective of this phase 1 study was to evaluate the feasibility of HIFU ablation of small renal tumours under laparoscopic control. PATIENTS AND METHODS: Ten kidneys with solitary renal tumours were treated with a newly developed 4.0 MHz laparoscopic HIFU probe. In the first two patients with 9-cm tumours, a defined marker lesion was placed prior to laparoscopic radical nephrectomy. In eight patients with a mean tumour size of 22 mm (range, 11-40), the tumour was completely ablated as in curative intent, followed by laparoscopic partial nephrectomy in seven tumours. One patient had post-HIFU biopsies and was followed radiologically. Specimens were studied by detailed and whole-mount histology, including NADH stains. RESULTS: Mean HIFU insonication time was 19 min (range, 8-42), with a mean targeted volume of 10.2 cm3 (range, 9-23). At histological evaluation both marker lesions showed irreversible and homogeneous thermal damage within the targeted site. Of the seven tumours treated and removed after HIFU, four showed complete ablation of the entire tumour. Two had a 1- to 3-mm rim of viable tissue immediately adjacent to where the HIFU probe was approximated, and one tumour showed a central area with about 20% vital tissue. There were no intra- or postoperative complications related to HIFU. CONCLUSION: The morbidity of laparoscopic partial nephrectomy mainly comes from the need to incise highly vascularized parenchyma. Targeted laparoscopic HIFU ablation may render this unnecessary, but further studies to refine the technique are needed.

Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer.

PURPOSE: We assessed variability in the diagnostic performance of NMP22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS transitional cell carcinoma of the bladder in a large international cohort. MATERIALS AND METHODS: NMP22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1 and/or CIS transitional cell carcinoma at 12 participating institutions. RESULTS: Patient characteristics varied considerably among institutions. Overall 1,045 patients (36.4%) had recurrent transitional cell carcinoma (range across institutions 13.6% to 54.3%). Median NMP22 was 5.5 U/ml (range across institutions 2.5 to 18.8). Of the patients 33.5% had grade III tumors (range across institutions 20.6% to 54.0%) and 22.4% had muscle invasive tumors (range across institutions 3.2% to 38.2%). Area under the ROC curve for bladder TCC detection was 0.735 (95% CI 0.715 to 0.755, range across institutions 0.676 to 0.889). The manufacturer recommended cutoff of 10 U/ml detected 57% of cases with a 19% false-positive rate. AUC for grade III and stage T2 or greater disease was 0.806 (95% CI 0.780 to 831) and 0.864 (95% CI 0.839 to 0.890), respectively. For each NMP22 cutoff NMP22 had higher sensitivity for detecting grade III and stage T2 or greater bladder transitional cell carcinoma than for detecting any cancer. No optimal cutoffs for detecting any or aggressive bladder transitional cell carcinoma could be derived based on NMP22 values. CONCLUSIONS: There is a substantial degree of heterogeneity in the diagnostic performance of NMP22 applied to populations from different institutions. There is no clearly defined NMP22 cutoff but there is a continuum of risk for recurrence and progression.

Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder.

OBJECTIVE: To assess the contemporary inter-institutional accuracy of urinary cytology in predicting the recurrence of transitional cell carcinoma (TCC) of the bladder, in a large multi-institutional cohort from four continents, as cystoscopy and urinary cytology represent the 'gold standards' for surveillance of TCC recurrences, but the ability of cytology to predict recurrence varies. PATIENTS AND METHODS: Ten institutions contributed 2542 patients with a history of superficial TCC, of whom 898 had TCC recurrence. Age- and gender-adjusted logistic regression models were used to evaluate the association between urine cytology and TCC recurrence. The predictive accuracy derived from the logistic regression model was tested using the area under the receiver operating characteristic curve. The resulting predictive accuracy estimates were internally validated with 200 bootstrap re-samples. RESULTS: The mean (range across institutions) age of the patients was 65 (48-69) years and 75 (67-87)% were men. Cytology was positive in 19 (10-38)% of patients; recurrence was identified in 35 (27-54)% of patients. The sensitivity was 38-65% across institutions. Urinary cytology varied significantly in its ability to predict recurrence of bladder cancer. Institution-specific predictive accuracy adjusted for gender and age was 0.627-0.893. Stratifying by grade and stage only partly attenuated the discrepancies between centres. CONCLUSIONS: The variability of urinary cytology results was very appreciable among the 10 centres and ranged from poor (63%) to excellent (89%).

Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder.

PURPOSE: We developed and validated nomograms that accurately predict disease recurrence and progression in patients with Ta, T1, or CIS transitional cell carcinoma (TCC) of the bladder using a large international cohort. METHODS: Univariate and multivariate logistic regression models targeted histologically confirmed disease recurrence, and focused on 2,542 patients with bladder TCC from 10 participating centers. Variables consisted of pre-cystoscopy voided urine Nuclear Matrix Protein 22 (NMP22) assay, urine cytology, age and gender. Resulting nomograms were internally validated with bootstrapping. Nomogram performance was explored graphically with Loess smoothing plots. RESULTS: Overall 957 patients had recurrent TCC. Tumor grade and stage was available for 898 patients, including 24% grade I, 43% grade II, and 33% grade III; 45% stage Ta, 32% T1 and/or CIS, and 23% T2 or greater. Bootstrap corrected predictive accuracy for any TCC recurrence was 0.842; grade III Ta/T1 or CIS was 0.869; and T2 or higher stage TCC of any grade was 0.858. Virtually perfect performance characteristics were observed for the nomograms predicting any TCC recurrence or grade III Ta/T1 or CIS. The nomogram predicting T2 or higher stage TCC overestimated the observed probability for predicted values greater than 45%. CONCLUSIONS: We developed and internally validated nomograms that incorporate urinary NMP22, cytology, age and gender to predict with high accuracy the probability of disease recurrence and progression in patients with Ta, T1, and/or CIS bladder TCC. These nomograms could provide a means for individualizing followup in patients with Ta, T1, CIS bladder TCC.

Comparison of open versus laparoscopic pyeloplasty techniques in treatment of uretero-pelvic junction obstruction.

PURPOSE: Open dismembering pyeloplasty has high success rates but is associated with significant morbidity and moderate cosmetic results. Aim of this study was to evaluate laparoscopic dismembering pyeloplasty compared with other laparoscopic techniques and open surgery in this respect. MATERIAL AND METHODS: Between September 1999 and September 2002 we performed 25 laparoscopic dismembering (LDP), 15 laparoscopic non-dismembering (LNDP) and 15 open pyeloplasties (ODP) in 55 patients. For laparoscopy two 12 mm and two 5mm ports were used, a ureteric stent remained in place for 4 weeks. ODP was performed via a flank incision, a percutaneous ureteric stent and a nephrostomy remained for 10 days. Postoperative morbidity was assessed by visual analogue scale (VAS). Mean follow-up was 23.4+/-9.1 months (range 7-42) for laparoscopy vs. 21.9+/-8.8 (range 9-41) months for open surgery. Success was evaluated with postoperative i.v. pyelogram or diuretic nephrography. RESULTS: A crossing vessel could be identified in 82.5% (33/40) with laparoscopy vs. 47.0% (7/15) in ODP. Postoperative VAS score was lower in the laparoscopic group (day 1 3.5+/-1.6 vs. 5.4+/-3.1, day 5 0.9+/-1.2 vs. 3.1+/-1.8, p=0.001). Length of skin incision was 4.1+/-0.7 vs. 23.8+/-9.1 cm and hospital stay was 5.9+/-2.1 vs. 13.4+/-3.8 days for laparoscopy and ODP respectively. Success rate was 96.0% (24/25) for LDP, 73.3% (11/15) for LNDP and 93.4% (14/15) for ODP. Two patients with LNDP and one with ODP required re-operation. Clot retention was observed in two with LDP and one with ODP. Two abdominal wall herniations and one thromboembolism occurred with ODP. CONCLUSION: Short-term results demonstrate that dismembering laparoscopic pyeloplasty has the same success rates as open surgery but morbidity and complications are significantly decreased. Non-dismembering techniques have the least favourable results. This finding may suggest that LDP has the potential to replace open surgery as the gold standard for treatment of uretero-pelvic junction obstruction.

Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate.

INTRODUCTION AND OBJECTIVES: To investigate factors involved in inflammation of the prostate besides IL-15, we screened prostatic cells and tissues for IL-17 and IL-17 receptor expression. METHODS: Normal prostate (n = 1), BPH (n = 19), and carcinoma (CaP, n = 12) specimens were screened for IL-17, IL-17 receptor, CD45, IL-6, and IL-8 mRNA expression. The carcinoma cell lines DU145, PC3, LNCaP, and BPH-epithelial (EC), stromal cell (SC) preparations, and BPH-T-cell lines were analyzed for IL-17 production by RT-PCR and ELISA. The effect of IL-17 on IL-6, IL-8, TGF-beta1, and fibroblast growth factor (FGF-2) mRNA expression and/or release of SC was analyzed using real-time PCR and/or ELISA. Immunohistochemistry was used to localize both IL-17 and IL-17 receptor. RESULTS: In the normal prostate, IL-17 expression was very weak and restricted to lymphocytes. In 79% of BPH and 58% of CaP specimens, IL-17 mRNA and protein expression was increased. IL-17 mRNA expression could be shown for activated BPH-T-cells and to some extend for BPH-EC. Expression of IL-17 receptor was ubiquitous. Release of IL-17 was shown only for activated BPH-T-cells. IL-17 stimulated expression of IL-6 (13-fold) and IL-8 (26-fold) by prostatic BPH-SC. In situ, however, the amount of IL-17mRNA in BPH-tissue did not correlate with the amount of IL-6 and IL-8 mRNA. In CaP tissue, significant correlation was found only between the amount of IL-6 and IL-8 mRNA. CONCLUSIONS: Activated BPH-T-cells abundantly express IL-17. The increase of IL-17 in BPH-tissues goes hand in hand with elevated levels of IL-15, a pro-inflammatory cytokine with T-cell growth factor properties. A clinical relevance of increased IL-17 expression under pathological conditions is suggested by the demonstration of significant upregulation of IL-6 and IL-8 production of prostatic SC by IL-17.