Niels Harving

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

Alfuzosin 10 mg once daily improves sexual function in men with lower urinary tract symptoms and concomitant sexual dysfunction

Associate Editor

Alfuzosin 10 mg once daily for treating benign prostatic hyperplasia: a 3-year experience in real-life practice

To assess the 3‐year efficacy and safety of the selective α1‐blocker alfuzosin at 10 mg once daily in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in ‘real‐life practice’. The influence of treatment response on the risk of acute urinary retention (AUR) and BPH‐related surgery was also analysed.

Long-term efficacy and safety of alfuzosin 10 mg once daily: a 2-year experience in ‘real-life’ practice

To assess the 2‐year efficacy and safety of alfuzosin 10 mg once daily, a selective α1‐adrenoceptor antagonist, in men complaining of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH), in ‘real life’ practice.

Completeness of bladder cancer staging in the Danish Cancer Registry, 2004-2009

Objective To investigate the completeness of TNM (Tumor-Node-Metastasis) staging for prostate cancer (PC) in the Danish Cancer Registry (DCR). Methods We identified 20,184 men registered with first-time PC in the DCR between 2004 and 2009. These patients were linked to the Danish National Patient Register to obtain data on comorbidity according to the Charlson Comorbidity Index (CCI). We calculated the completeness and corresponding 95% confidence intervals (CI) of TNM staging overall and by the individual components. We also defined a clinically-based algorithm classifying PC into four stage categories: localized, regional, distant, and unknown. Results The overall completeness of TNM staging was 34.2% (95% CI: 0.34–0.35). TNM completeness improved gradually over time reaching 41.2% in 2009. TNM completeness decreased substantially with age from 75.0% among patients 0–39 years to 11.3% among patients 80 years or older. Similarly, completeness decreased with increasing comorbidity level from 37.6% among patients with low CCI to 20.3% among those with high CCI. When classifying T1 cancer as a complete registration regardless of missing N or M stage, the overall TNM completeness increased to 48.7% (95% CI: 0.48–0.49). According to the clinically-based staging algorithm, 70.5% of PC cases could be categorized into a definite clinical stage. Conclusion One-third of PC patients had a complete registration of all TNM components in the DCR. Although TNM completeness improved over time, older age and high comorbidity were consistently associated with missing TNM staging. Research and monitoring based on cancer registries such as the DCR should account for missing TNM staging. Failing to do so could otherwise lead to biased results of stage-specific analyses.

Age, Comorbidity and Hypertensive Co-Medication do Not Affect Cardiovascular Tolerability of 10 Mg Alfuzosin Once Daily

PURPOSE We assessed in real-life practice the impact of age, cardiovascular comorbidity and co-medication on the tolerability and efficacy of 10 mg alfuzosin OD in men with lower urinary tract symptoms suggestive of benign prostatic obstruction. MATERIALS AND METHODS A total of 6,523 men with a mean age of 64.7 years were enrolled in a 6-month open label study of 10 mg alfuzosin OD. They were stratified by age quartile (younger than 60, 60 to 64, 65 to 70 and older than 70 years), comorbidity (hypertension, ischemic heart disease and diabetes) and antihypertensive co-medication (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II inhibitors and calcium channel antagonists). RESULTS Alfuzosin was effective and well tolerated. Despite an increased prevalence of cardiovascular comorbidity and antihypertensive co-medication with age changes in blood pressure did not significantly differ among age groups. In controls, ie those with no cardiovascular comorbidity or co-medication, alfuzosin produced minimal decreases in sitting systolic (mean -2.6 to -2.8 mm Hg) and diastolic (mean -1.7 to -1.8 mm Hg) blood pressure. In men with cardiovascular comorbidity mean decreases in systolic (-3.5 to 5.8 mm Hg) and diastolic (-2.0 to -3.3 mm Hg) blood pressure remained marginal. Of the 6,523 exposed patients 19.3% withdrew from the study, mainly for adverse events (6.4%) or a lack of efficacy (5.3%), while 229 (3.5%) experienced serious adverse events and 1,558 (23.9%) reported at least 1 treatment emergent adverse event. The most commonly reported adverse event was dizziness/postural dizziness (4.8%). Hypotension/postural hypotension was uncommon (0.7%). Age, cardiovascular comorbidity and antihypertensive co-medication had no impact on the safety profile of 10 mg alfuzosin OD. CONCLUSIONS Alfuzosin (10 mg) OD is effective and well tolerated, and it has marginal effects on blood pressure, including in elderly patients and those with hypertension, ischemic heart disease or diabetes and those receiving antihypertensive agents.

Positive urinary cytology after tumor resection: an indicator for concomitant carcinoma in situ

Concomitant urothelial atypia (grade II atypia or carcinoma in situ) is predictive of new tumor growth after transurethral tumor resection. Concomitant urothelial atypia can be demonstrated by pre-selected site mucosal biopsies. However, a number of patients have new tumors despite normal pre-selected site biopsies. To investigate whether urinary cytology is a better indicator for concomitant urothelial atypia than pre-selected site biopsies, we studied in bladder tumor patients the correlation between the findings of pre-selected site biopsies (8 per patient) at tumor resection and urinary cytology (2 per patient) after successful resection. Concomitant urothelial atypia was demonstrated by biopsies in 52 per cent of the patients, of whom 60 per cent had grade II atypia and 40 per cent had carcinoma in situ. All patients with concomitant carcinoma in situ in biopsies had positive cytology findings. Of the patients with concomitant grade II atypia in biopsies 15 per cent had negative cytology studies. In 48 per cent of the patients no urothelial atypia in pre-selected site biopsies was demonstrable. However, cytology was positive, that is neoplastic cells were present, in 64 per cent of these specimens (19 patients). Of the 19 patients 16 currently have had demonstrable urothelial atypia in pre-selected site mucosal biopsies at a later occasion. We conclude that urinary cytology seems to be a better indicator for the presence of concomitant urothelial atypia than pre-selected site mucosal biopsies and, therefore, it can be used as a screening procedure for patients without demonstrable concomitant carcinoma in situ at tumor resection.

Prognostic Impact of a 12-gene Progression Score in Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study

BACKGROUND Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Prognostic impact of a 12-gene progression score in non-muscle invasive bladder cancer: A prospective multicenter validation study

Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed.To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study.We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values.We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions.The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guerin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R(2)=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients).The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens.Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Molecular markers increase precision of the European Association of Urology non-muscle invasive bladder cancer progression risk groups

Purpose: The European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%). Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586–93. ©2018 AACR.