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Objectives: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). Materials and Methods: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox’ regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as ‘organ-confined’ (≤pT2N0), ‘locally advanced’ (pT3-4N0) and ‘node-positive’ (pTanyN1-3). Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

Contains fulltext : 237666.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered.

OBJECTIVE To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery. PATIENTS AND METHODS Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses. RESULTS A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P

Objectives To compare the prognostic value of the World Health Organization (WHO) 1973 and 2004 classification systems for grade in T1 bladder cancer (T1-BC), as both are currently recommended in international guidelines. Patients and methods Three uro-pathologists re-revised slides of 601 primary (first diagnosis) T1-BCs, initially managed conservatively (bacille Calmette-Guerin) in four hospitals. Grade was defined according to WHO1973 (Grade 1-3) and WHO2004 (low-grade [LG] and high-grade [HG]). This resulted in a lack of Grade 1 tumours, 188 (31%) Grade 2, and 413 (69%) Grade 3 tumours. There were 47 LG (8%) vs 554 (92%) HG tumours. We determined the prognostic value for progression-free survival (PFS) and cancer-specific survival (CSS) in Cox-regression models and corrected for age, sex, multiplicity, size and concomitant carcinoma in situ. Results At a median follow-up of 5.9 years, 148 patients showed progression and 94 died from BC. The WHO1973 Grade 3 was negatively associated with PFS (hazard ratio [HR] 2.1) and CSS (HR 3.4), whilst WHO2004 grade was not prognostic. On multivariable analysis, WHO1973 grade was the only prognostic factor for progression (HR 2.0). Grade 3 tumours (HR 3.0), older age (HR 1.03) and tumour size >3 cm (HR 1.8) were all independently associated with worse CSS. Conclusion The WHO1973 classification system for grade has strong prognostic value in T1-BC, compared to the WHO2004 system. Our present results suggest that WHO1973 grade cannot be replaced by the WHO2004 classification in non-muscle-invasive BC guidelines.

Objective To investigate the effect of neoadjuvant chemotherapy (NAC) on the incidence of lymph node (LN) metastases in clinically node-negative (cN0) patients with carcinoma invading the bladder muscle (MIBC). Patients and Methods Between 1990 and 2012, 828 consecutive patients underwent radical cystectomy (RC) with extended pelvic LN dissection (ePLND), of whom 441 had cT2–4N0M0 stage disease. A total of 83 patients received NAC then underwent RC and 358 patients underwent RC only. The ePLND template and the indication for NAC remained the same during the study period. The incidence of occult LN metastases was compared between the groups. Unadjusted and adjusted odds ratios (ORs) were calculated to investigate the influence of NAC, cT stage, gender and the preoperative staging technique used (computed tomography [CT] or positron emission tomography/CT) on the occurrence of LN metastases. Overall survival (OS) and disease-specific survival were analysed using the Kaplan–Meier method. Results Patients in the NAC group more often had locally advanced MIBC than patients in the non-NAC group (cT3–4: 88.0 vs 30.2%). In the NAC group, 19.3% of patients had LN metastases vs 28.5% of the patients in the non-NAC group (P = 0.099). In the patients with cT3–4 disease, the occurrence of LN metastases was significantly lower in the NAC group than in the non-NAC group (21.9 vs 40.7%, respectively, P = 0.002). In multivariable analysis, adjusting for cT stage, gender and staging method, NAC was independently associated with a lower likelihood of LN metastases (OR: 0.41, 95% CI 0.21–0.79; P = 0.008). Among the patients with cT3–4 disease, the median OS was significantly longer in the NAC group than in the non-NAC group (68.0 vs 23.0 months, P = 0.047) Conclusion These data suggest that, along with a downstaging effect on the primary bladder tumour, NAC is associated with a lower incidence of occult LN metastases at the time of RC.

Objective To evaluate the clinical impact of 18F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT) scanning, compared with conventional staging with contrast-enhanced CT imaging (CECT). Patients and Methods The FDG-PET/CT results of 96 consecutive patients with bladder cancer were analysed. Patients included in this study underwent standard CECT imaging of the chest and abdomen/pelvis

Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC. OBJECTIVE To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette-Guerin. PATIENTS AND METHODS The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. T1 sub-staging was done in two separate rounds, using a new system that identifies micro-invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). The EORTC risk scores for recurrence and progression were calculated. Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression). RESULTS The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. Molecular markers were significant in univariable and in multivariable analyses for recurrence. EORTC risk scores were not significant. CONCLUSIONS CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. The additional value of molecular markers was modest. Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node-metastasis classifications.

UNLABELLED: What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ-confined (OC) to non-organ-confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0-8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6-4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES: To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS: Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992-2010) and University of Turku, Turku, Finland (1986-2005) were analysed. RESULTS: Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ-confined (OC) to non-organ-confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44-4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21-6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48-7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38-0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6-4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10-year disease-specific mortality, P < 0.001). CONCLUSIONS: Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

Study Type – Aetiology (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Smoking is well described among the most important risk factors for bladder cancer. It is also known that higher quantity of tobacco exposure is associated with higher bladder cancer risk and that smoking cessation is known to be associated with lower risk of bladder cancer. Furthermore, among patients with non-muscle invasive bladder cancer, smoking cessation decreases the risk of tumour recurrence. On the other hand, the effect of smoking on tumour stages at presentation and especially on prognosis is not well studied. The current study describes the presentation and outcome of 564 patients (64% smokers, 36% non-smokers) treated with radical cystectomy. Patients with smoking history have more advanced outcome at the time of radical surgery and significantly worse outcome after surgery when compared to non-smokers, although the effect of smoking was not significant when survival was studied in multivariable analysis including classic prognostic parameters such as tumour grade, stage and adjuvant chemotherapy. Finally, there was a surprising finding that history of smoking affected outcome among male patients but such effect was not noted among female patients. OBJECTIVE • To study the effect of smoking on bladder cancer presentation and outcome in a large cystectomy population. PATIENTS AND METHODS • A database including 546 patients from the University Health Network (Toronto, Canada) and Turku University Hospital (Turku, Finland) was studied. • In addition to the association of smoking with clinicopathological parameters, the effect of smoking on survival was analyzed. • Categorical data were analyzed by the chi-squared test and numerical data were analyzed by Student's t-test. • The Kaplan–Meier method, log-rank test and a proportional hazards model were used to estimate the effect of smoking on survival. RESULTS • In total, 352 patients (64%) were smokers and 194 (36%) were non-smokers. • Smokers had more frequently advanced tumours and nodal metastasis. • The 10-year disease-specific survival (DSS) was 52% vs 66% for smokers and non-smokers, respectively (P= 0.039). • Smokers also had significantly worse overall survival (10-year overall survival 37% vs 62%; P= 0.015). • Smoking affected significant DSS among men (P= 0.012), although no effect was observed among women. • In a univariate model smoking was associated with a hazard ratio (HR) of 1.4 (95% confidence interval, CI, 1.0–1.9) for bladder cancer specific mortality and 1.4 (95% CI, 1.1–1.8) for overall mortality. • In a multivariate model, smoking did not impact on DSS (HR, 1.1; 95% CI, 0.8–1.6; P= 0.41). • In addition to advanced stage and nodal metastasis, female sex was an independent risk factor for DSS (HR, 1.6; 95% CI, 1.1–2.3; P= 0.007). CONCLUSIONS • Smokers appear to have worse outcomes after radical cystectomy for bladder cancer; however, it does not appear to be an independent prognostic factor for survival. • Smoking affected survival only among men. • Women had poorer survival but smoking was not a contributing factor to this.

Study Type – Prognosis (multi-centre cohort) Level of Evidence 1b What’s known on the subject? and What does the study add? More men than women develop bladder cancer (BC) but reasons why are unclear. Recent findings have implicated androgens, androgen receptors (AR) and AR expression in BC. Previous studies showed that a significant loss of AR expression was associated with aggressive BC. However, these results have been gathered on limited series of patients. We analyzed the expression of AR in BC and its correlation with gender, grade, stage and clinical outcome on a large multi-institutional (Toronto/Dallas) cohort. In contrast to previous reports, our data do not suggest that loss of AR expression is gender-related nor associated with invasive BC. In fact, in this large cohort, we showed that AR positivity is actually uncommon in BC, that there are no differences in expression among high and low grade tumours and no statistically significant differences between muscle-invasive AR-positive and AR-negative cases in time to death, or time to recurrence. OBJECTIVE • To investigate androgen receptor (AR) expression in a large series of patients with bladder cancer (BC) because data on a limited number of patients showed that loss of AR expression was associated with invasive BC. PATIENTS AND METHODS • A total of 472 patients with urothelial bladder carcinoma (UBC) from two institutional centres (Toronto and Dallas) were analysed. Tissue microarrays comprising both non-muscle-invasive UBC (n= 167) and muscle-invasive UBC (n= 305) were accrued and immunohistochemical staining for AR was performed. • We used bright-field microscopy imaging coupled with advanced colour detection software to detect, classify and count stained cellular objects and manual scoring. • Results obtained in Dallas were blindly reviewed and validated in Toronto and samples randomly chosen were further analysed in Rochester, NY, USA. RESULTS • The AR were positively expressed in 61/472 (12.9%) bladder tumours. No statistically significant difference in AR expression between men and women was observed. • Only 9.0% of non-muscle-invasive BC expressed the AR compared with 15.1% of muscle-invasive tumours (P= 0.059). The highest percentage of AR positivity (28.9% of cases) was found in T2 tumours. • There was no statistically significant difference in death from BC, time to death, or time to recurrence between AR-positive and AR-negative cases. CONCLUSION • In contrast to previous reports, based on our large BC series, we did not observe a decrease in AR protein expression in bladder tumours with increased pathological stage. Our data do not suggest that loss of AR expression is gender-related nor is it associated with invasive BC.

What’s known on the subject? and What does the study add? This is a short series of unclassified RCC with positivity for TFE3 staining an association with poor outcome on those patients’ follow-up. The paper supports the idea of TFE3 positivity as a marker for poor outcome in RCC patients. It has already been stated in some manuscripts; however, not in this number of patients. OBJECTIVES • To evaluate the clinical and pathologic features and the prognostic relevance of unclassified RCC with – TFE3 over-expression in our adult series. • Recent studies suggest that renal cell carcinomas (RCCs) associated with the newly recognized Xp11.2 translocation (transcription factor E3 [TFE3] gene fusions) can be found among adults with RCC showing a very aggressive disease-course. MATERIAL AND METHODS • We evaluated tumour specimens from 25 patients with unclassified RCC morphology out of 298 RCCs in the last 12 years in a tertiary academic centre. • Immunohistochemistry was performed using monoclonal antibody for TFE3 C-terminal section, taking nuclear label into consideration. RT-PCR technique was performed for ASPL-TFE3 gene fusion on two tumours with available frozen tissue. RESULTS • Of the 25 cases analyzed, 8 (32%) showed positivity for TFE3 and 17 were negative for TFE3 staining. Two tumors with ASPL-TFE3 gene fusion also showed TFE3 over-expression. • Fifty percent of the positive patients had lymph node metastatic disease, whereas only one TFE3-negative patient (5.8%) showed evidence of lymph node spread and cava thrombus at diagnosis. Of the TFE3-positive patients, three had a vena cava thrombus (37.5%). Seven of the eight positive cases (87.5%) were diagnosed with a high Fuhrman grade (III/IV). In comparison, five of 17 (29.4%) TFE3-negative patients had a high Fuhrman grade. Five of eight TFE3-positive patients relapsed rapidly at 3 month follow-up; conversely none of the negative cases relapsed. At 36-month mean follow-up, 5-year cancer-specific survival was 15.6% for TFE3-positive patients and 87.5% for TFE3-negative patients (P

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? High-grade non muscle invasive bladder cancer is a very aggressive disease, potentially lethal if not managed adequately, because of the ability of these tumours to invade surrounding tissues and become metastatic. Treatment with intravesical BCG has been shown to delay progression to muscle invasive or/and metastatic disease, preserve the bladder, and decrease the risk of death from bladder cancer. However, most studies have analyzed patients with short follow-up, and long-term data about the real efficacy of BCG to prevent tumour recurrence, progression and impact mortality are lacking. This study has analyzed a large series of patients with high-grade non muscle invasive bladder cancer treated with intravesical BCG in two University Institutions (Toronto and Rotterdam), with a central pathology review by a very experienced uro-pathologist. It provides further insight into the long-term risks of progression of patients harbouring high-grade T1 bladder cancer treated with BCG, demonstrating that about 30% of patients are at risk of progression and that late progressions even more than 3 years after the initial resection and BCG treatment are rare but not exceptional. OBJECTIVE To report the long-term results of bacille Calmette-Guerin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS In all, 136 patients from two university centres (Rotterdam, n= 49; Toronto, n= 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS Mean (range) follow-up was 6.5 (0.3–21.6) years. There were no significant differences for recurrence (P= 0.52), progression (P= 0.35) and disease-specific survival (DSS) (P= 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred ≥3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P= 0.011). No independent predictors were found for progression. CONCLUSIONS Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring ≥3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected.

BJU Int 2010; 106: 206–211. Objective: To evaluate the effect of a pathology review on the clinical outcome of patients with primary pT1 bladder cancer (BC), as the clinical course of such patients is variable. Patients and Methods: The slides of 164 primary (first diagnosis) pT1 bladder tumours from two university hospitals were reviewed by one pathologist for stage and grade (World Health Organization 1973 and 2004). Patients were initially managed conservatively with bacille Calmette-Guerin (BCG). Uni- and multivariate analyses compared the predictive value of age, gender, hospital, carcinoma in situ (CIS), tumour-size, reviewed grade and reviewed stage. Results: With a mean follow-up of 6.4 years, there was disease progression in 48 (29%) patients and 26 (16%) died from BC. Associated CIS was found in 55 (34%) patients. After reviewing the slides, 24 (15%) tumours were downstaged to pTa, 134 (82%) remained pT1 and six (4%) were upstaged to or pT2. The grade review resulted in 74 G2, 90 G3, 37 low-grade and 127 high-grade lesions for the two systems used. In multivariate analyses, reviewed stage (both P 0.001) and CIS (P 0.017 and 0.023) had independent significance for progression and disease-specific survival, respectively. Conclusion: A stage review is indicated in pT1 BC, as almost 20% of pT1 tumours were up- or downstaged, and the reviewed stage predicted the patient’s prognosis. Hence, pathology review identified patients with different prognoses who might benefit from other treatment strategies than BCG. We confirmed that CIS is an unfavourable sign in pT1 bladder cancer. Editorial Comment: This article is unique in that instead of evaluating whether review of cases from a community hospital is beneficial, the authors reviewed cases from 2 major universities with expertise in urological pathology. Of T1 tumors 20% were either upstaged or down-staged, and the reviewed stage was an independent predictor of disease specific survival. It appears that even if an expert pathologist reads a case, review of all T1 tumors by more than 1 pathologist is important.

OBJECTIVE To determine how good microsatellite analysis (MA) markers in voided urine samples should be to make a surveillance procedure cost-effective in which cystoscopy is partly replaced by MA for patients with non-muscle-invasive urothelial carcinoma (NMI-UC). PATIENTS AND METHODS We constructed a semi-Markov model with a time horizon of 2 years, and a man aged 65 years as reference case. Data were used from a randomized trial (including 448 patients with NMI-UC from 10 hospitals), and from other data sources. The costs and effects (probability of being in a specific health state) were compared for two surveillance strategies: (i) cystoscopy of the urinary bladder every 3 months (conventional arm), and (ii) semi-automated MA of voided urine samples to identify loss of heterozygosity every 3 months, with a control cystoscopy at 3, 12 and 24 months (test arm). Various sensitivity analyses were used to determine the sensitivity, specificity, and costs of MA of urine for which the test arm was as cost-effective as the conventional arm. RESULTS The probability of being without recurrence after 2 years of surveillance was similar (86.6% conventional arm vs 86.3% test arm) with currently available MA markers (sensitivity of 58% and specificity of 73%). However, the test arm led to higher costs (€4104 vs €3433 per head). The test arm would be as effective and cost the same as the conventional arm if the sensitivity of the currently available MA markers was increased at ≥61%, had a specificity of 73%, and decreased the costs of the MA test per follow-up sample from €158 to