Karin Mogensen

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.

Fluorescence‐guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in T a/T1 patients: a randomized two‐centre study

Study Type – Therapy (RCT)

Outpatient diagnostic of bladder tumours in flexible cystoscopes: Evaluation of fluorescence-guided flexible cystoscopy and bladder biopsies

Abstract Objective. The aim of this study was to evaluate photodynamic diagnosis (PDD) in flexible cystoscopes and the diagnostic quality of biopsies for diagnosis of non-muscle-invasive bladder cancer in the outpatients department (OPD). Material and methods. Seventy-three patients (aged 36–91 years) with recurrent non-muscle-invasive bladder cancer and a medium to high risk of recurrence had a flexible PDD cystoscopy performed in the OPD. The bladder was first examined in standard white light followed by PDD. Results. PDD was superior to white light diagnosis; PDD was positive in 16 patients (22%) where white light showed a normal bladder mucosa. Four of these patients had bladder tumour [4/73, 6%; two carcinoma in situ (CIS), two Ta]. The diagnosis was verified by transurethral resection of the bladder tumour in the operating room. In 20 patients (20/73, 27%) PDD identified additional tumour lesions that were not identified in white light (five CIS, 15 Ta). The false-positive detection rate of PDD was 0.41. False positivity was significantly reduced by simultaneous flex biopsies disproving malignancy. Biopsies were obtained from 57 patients and diagnosis of stage and grade were possible in 55 of these (97%). In two patients (4%) the tissue material was too small for diagnostic evaluation. Biopsies from 47 patients (83%) included muscularis mucosa and from 20 patients (35%) muscularis propria. In 30 patients all but one diagnosis from the OPD was confirmed by biopsy in rigid scopes in the operating room. Conclusions. PDD-guided cystoscopy and bladder biopsy in flexible cystoscopes can be performed in an OPD setting and with reliable results for diagnosis of tumour stage Ta, CIS and T1a bladder cancer.

Role of hexaminolevulinate-guided fluorescence cystoscopy in bladder cancer: critical analysis of the latest data and European guidance

Abstract Objective. Hexaminolevulinate (HAL) is an optical imaging agent used with fluorescence cystoscopy (FC) for the detection of non-muscle-invasive bladder cancer (NMIBC). Guidelines from the European Association of Urology (EAU) and a recent, more detailed European expert consensus statement agree that HAL-FC has a role in improving detection of NMIBC and provide recommendations on situations for its use. Since the publication of the EAU guidelines and the European consensus statement, new evidence on the efficacy of HAL-FC in reducing recurrence of NMIBC, compared with white light cystoscopy (WLC), have been published. Material and methods. To consider whether these new trials have an impact on the expert guidelines and on clinical practice (e.g. supporting existing recommendations or providing evidence for a change or expansion of practice), a group of bladder cancer experts from Denmark, Finland, Norway and Sweden met to address the following questions: What is the relevance of the new data on HAL-FC for clinical practice in managing NMIBC? What impact do the new data have on European guidelines? How could HAL-FC be used in clinical practice? and What further information on HAL-FC is required to optimize the management of NMIBC? Results and conclusions. This article reports the outcomes of the discussion at the Nordic expert panel meeting, concluding that, in line with European guidance, HAL-FC has an important role in the initial detection of NMIBC and for follow-up of patients to assess tumour recurrence after WLC. It provides practical advice, with an algorithm on the use of this diagnostic procedure for urologists managing NMIBC.

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.

The load on family and primary healthcare in the first six weeks after transurethral resection of the prostate

Objective. The extent of load on spouses and primary healthcare after transurethral resection of the prostate (TURP) and the number of treatment-related symptoms in the first 6 weeks after TURP were studied. Material and method. A combined interview (qualitative) and questionnaire (quantitative) study was carried out. In the first part of the study 10 spouses underwent semi-structured interviews concerning their husbands’ treatment-related symptoms 6 weeks after TURP. Based on these interviews a questionnaire was framed. In the second part questionnaires were sent to 78 spouses whose husbands had undergone TURP 6 weeks before. Results. 69 questionnaires were returned (88.5%). The median age of spouses and their husbands was 65 years (range 43–90) and 70 years (range 46–85), respectively. Length of hospitalization, including day of operation, was 3 days (range 2–9). There were 43 (62%).unscheduled contacts with the health system after discharge. In relation to discharge, 55 (79.7%) were incontinent to some degree and 29 (42%) were incontinent for more than 4 weeks, 26 (37.7%) had urinary tract infection, 30 (40%) had long-lasting bleeding, 10 (14%) urinary retention, and 41 (59.4%) urgency. Of the spouses, 20 (34.8%) had sleep disorders, 27 (39%) an affected social life and 22 (31.9%) extra work at home; 19 (27.5%) of the spouses felt that their husbands had been discharged too early, 55 (80%) were satisfied with the information given before the operation and 46 (68%) were satisfied with the information given in relation to discharge. The treatment results after 6 months are comparable to other studies. Conclusions. Among patients discharged after TURP there is a considerable number of treatment-related symptoms in the first few weeks affecting the family as well as health services. The study has resulted in better oral and written information in relation to discharge. More pads are delivered and patients have a urine culture and telephone consultation with a nurse 1 week after discharge.

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.

Hospitalization for transurethral bladder resection reduces quality of life in Danish patients with non-muscle-invasive bladder tumour

Abstract Objective The aim of the study was to evaluate the impact of transurethral resection of bladder tumour (TURBT) on patients’ quality of life (QoL) and to validate a tool to quantify problems associated with TURBT in a Danish population. Materials and methods A prospective study was carried out using a combination of questionnaires and interviews. The study included 165 consecutive patients undergoing a TURBT owing to non-muscle-invasive bladder cancer (NMIBC) from 1 May 2011 to 30 April 2012. Seven patients were selected for interviews. The Danish translation of the QLQ-NMIBC24 Quality of Life Questionnaire for NMIBC, from the European Organisation for Research and Treatment of Cancer (EORTC), was used. The interviews were semi-structured. The reliability of the subscales quantifying QoL as defined by the EORTC was tested by computing Cronbach’s coefficient alpha and confirmatory factor analysis. The interviews were analysed using the phenomenological method. Results The questionnaire was returned by 121 (77%) patients at a mean of 12 days after hospital discharge. Over half had substantial voiding problems and one-third had emotional concerns. These results were confirmed by the interviews. The mean ± SD score for urinary symptoms was 45.21 ± 23.9 and the mean score for the future worries subscale was 39.9 ± 29.9. Cronbach’s coefficient alpha was 0.84 for the urinary symptom subscale and 0.93 for the future worries subscale, which satisfied the reliability criterion for clinical use. Conclusions This first prospective study on QoL following TURBT in patients with NMIBC shows that TURBT has a significant impact on QoL. The Danish version of the EORTC questionnaire QLQ-NMIBC24 has been validated and confirmed in a Danish population.

Office-based transurethral devascularisation of low grade non-invasive urothelial cancer using diode laser. A feasibility study

Frequent recurrence of non‐muscle invasive bladder tumours (NMIBC) requiring transurethral resection of bladder tumour (TUR‐BT) and lifelong monitoring makes the lifetime cost per patient the highest of all cancers. A new method is proposed for the removal of low grade NMIBCs in an office‐based setting, without the need for sedation and pain control and where the patient can leave immediately after treatment.

Delayed healing at transurethral resection of bladder tumour sites after immediate postoperative mitomycin C instillation.

Abstract The most common reactions to mitomycin C are dysuria and drug-related palmar and genital desquamation. This report describes two cases of delayed healing of the mucosa at resection sites after transurethral resection of bladder tumours, most likely due to immediate postoperative mitomycin C instillation of the bladder.