Morpho-molecular ex vivo detection and grading of non-muscle-invasive bladder cancer using forward imaging probe based multimodal optical coherence tomography and Raman spectroscopy.

Non-muscle-invasive bladder cancer affects millions of people worldwide, resulting in significant discomfort to the patient and potential death. Today, cystoscopy is the gold standard for bladder cancer assessment, using white light endoscopy to detect tumor suspected lesion areas, followed by resection of these areas and subsequent histopathological evaluation. Not only does the pathological examination take days, but due to the invasive nature, the performed biopsy can result in significant harm to the patient. Nowadays, optical modalities, such as optical coherence tomography (OCT) and Raman spectroscopy (RS), have proven to detect cancer in real time and can provide more detailed clinical information of a lesion, e.g. its penetration depth (stage) and the differentiation of the cells (grade). In this paper, we present an ex vivo study performed with a combined piezoelectric tube-based OCT-probe and fiber optic RS-probe imaging system that allows large field-of-view imaging of bladder biopsies, using both modalities and co-registered visualization, detection and grading of cancerous bladder lesions. In the present study, 119 examined biopsies were characterized, showing that fiber-optic based OCT provides a sensitivity of 78% and a specificity of 69% for the detection of non-muscle-invasive bladder cancer, while RS, on the other hand, provides a sensitivity of 81% and a specificity of 61% for the grading of low- and high-grade tissues. Moreover, the study shows that a piezoelectric tube-based OCT probe can have significant endurance, suitable for future long-lasting in vivo applications. These results also indicate that combined OCT and RS fiber probe-based characterization offers an exciting possibility for label-free and morpho-chemical optical biopsies for bladder cancer diagnostics.

Budget impact of incorporating one instillation of hexaminolevulinate hydrochloride blue-light cytoscopy in transurethral bladder tumour resection for patients with non-muscle-invasive bladder cancer in Sweden.

OBJECTIVES: To explore the cost impact on Swedish healthcare of incorporating one instillation of hexaminolevulinate hydrochloride (HAL) blue-light cystoscopy into transurethral resection of bladder tumour (TURBT) in patients with suspected new or recurrent non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: A decision tree model was built based on European Association of Urology guidelines for the treatment and management of NMIBC. Input data were compiled from two recent studies comparing recurrence rates of bladder cancer in patients undergoing TURBT with either the current standard of care (SOC) of white-light cystoscopy, or with the SOC and HAL blue-light cystoscopy. Using these published data with clinical cost data for surgical and outpatient procedures and pharmaceutical costs, the model reported on the clinical and economic differences associated with the two treatment options. RESULTS: This model demonstrates the significant clinical benefits likely to be observed through the incorporation of HAL blue-light cystoscopy for TURBT in terms of reductions in recurrences of bladder cancer. Analysis of economic outputs of the model found that the use of one instillation of HAL for TURBT in all Swedish patients with NMIBC is likely to be cost-neutral or cost-saving over 5 years relative to the current SOC of white-light cystoscopy. CONCLUSIONS: The results of this analysis provide additional health economic rationale for the incorporation of a single instillation of HAL blue-light cystoscopy for TURBT in the treatment of patients with NMIBC in Sweden.

A five-factor biomarker profile obtained week 4-12 of treatment for improved prognostication in metastatic renal cell carcinoma: Results from DARENCA study 2.

BACKGROUND: Several biomarkers of treatment efficacy have been associated with a better prognosis in patients with metastatic renal cell carcinoma (mRCC). The prognostic significance of biomarkers in the early treatment phase is unclear. MATERIAL AND METHODS: In a complete national cohort of mRCC patients receiving first-line tyrosine kinase inhibitors (TKI) or interleukin-2 based immunotherapy (IT) from 2006 to 2010, overall survival (OS) was analysed for baseline International mRCC Database Consortium (IMDC) classification factors and on-treatment time-dependent biomarkers obtained day 1 each cycle week 4-12 after treatment initiation with multivariate analysis and bootstrap validation. RESULTS: A total of 735 patients received first-line TKI (59%) or IT (41%). Median OS was overall 14.0 months and 33.4, 18.5, and 5.8 months for baseline IMDC favourable, intermediate, and poor risk groups, respectively (p < 0.0001). Systolic blood pressure ≥140 mmHg, neutrophils < lower level of normal (LLN), platelets < LLN, sodium ≥ LLN, and LDH ≤1.5 times upper level of normal after treatment initiation were significantly associated with favourable OS independent of baseline IMDC risk group in multivariate analyses stratified for TKI and IT (p ≤ 0.04). Concordance (C)-index for IMDC classification alone was 0.625 (95% CI 0.59-0.66) and combined with the five-factor biomarker profile 0.683 (95% CI 0.64-0.72). For patients with good (3-5 factors) and poor (0-2 factors) biomarker profile median OS were 23.5 and 9.6 months, respectively (p < 0.0001). Adding the five-factor biomarker profile significantly improved prognostication in IMDC intermediate (25.7 vs. 12.0 months, p < 0.0001) and poor (12.8 vs. 6.4 months, p < 0.0001) risk groups. A trend was seen in IMDC favourable risk group (38.9 vs. 28.7 months, p = 0.112). CONCLUSION: On-treatment hypertension, neutropenia, thrombocytopenia, LDH below 1.5 times upper level of normal, and normal sodium, obtained week 4-12 of treatment, are independent biomarkers of favourable outcome in mRCC, independent of treatment type.

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

BACKGROUND AND OBJECTIVE: 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. STUDY DESIGN/PATIENTS AND METHODS: An in vitro model was developed to examine the dose/response relationship between laser power, treatment time, and distance between laser fibre and target, using a 980 nm diode laser and chicken meat. The relationship between depth and extent of tissue destruction and the laser settings was measured using microscopy and non-parametric statistical analysis. A patient with low grade stage Ta tumour and multiple comorbidity, and therefore not fit for general anaesthesia, had a tumour devascularised using the laser at the tumour base, in the outpatient department. The tumour was left in the bladder. RESULTS: In the in vitro model, depth of tissue destruction increased with laser illumination up to 30 seconds, where median depth was 4.1 mm. With longer illumination the tissue destruction levelled off. The width of tissue destruction was 2-3 mm independent of laser illumination time. The in vivo laser treatments devascularised the tumour, which was later shed from the mucosa and passed out with the urine in the days following treatment. Pain score was 0 on a visual log scale (0-10). The tumour had completely disappeared two weeks after treatment. CONCLUSION: This diode laser technique may provide almost pain-free office-based treatment of low grade urothelial cancer using flexible cystoscopes in conscious patients. A prospective randomised study will be scheduled to compare the technique with standard TUR-BT in the operating theatre.

Exploration of two methods for quantitative Mitomycin C measurement in tumor tissue in vitro and in vivo.

: Two methods of quantifying Mitomycin C in tumor tissue are explored. A method of ultraviolet-visible absorption microscopy is developed and applied to measure the concentration of Mitomycin C in preserved mouse tumor tissue, as well as in gelatin samples. Concentrations as low as 60 µM can be resolved using this technique in samples that do not strongly scatter light. A novel method for monitoring the Mitomycin C concentrations inside a tumor is developed, based on microdialysis and ultraviolet-visible spectroscopy. A pump is used to perfuse a microdialysis probe with Ringer's solution, which is fed to a flow cell to determine intratumor concentrations in real time to within a few µM. The success and limitations of these techniques are identified, and suggestions are made as to further development. To the authors' knowledge these are the first attempts made to quantify Mitomycin C concentrations in tumor tissue.

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

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.

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.

External Validation of the 2003 Leibovich Prognostic Score in Patients Randomly Assigned to SORCE, an International Phase III Trial of Adjuvant Sorafenib in Renal Cell Cancer.

PURPOSE: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC. METHODS: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas. RESULTS: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC. CONCLUSION: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC.

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

OBJECTIVES: •To compare the bladder tumour recurrence rate in stage Ta and T1 tumours after conventional transurethral resection of the bladder in white light (WL TURB) and after fluorescence-guided TURB (HAL TURB) using hexaminolaevulinate (HAL: Hexvix®, Photocure, Norway) for photodynamic diagnosis during 12 months of follow-up. •As secondary objectives, to relate the tumour recurrence rate to fluorescence-detected residual tumour after WL TURB and to assess the false positive rate. PATIENTS AND METHODS: •This was a prospective, comparative, randomized, open-label study carried out in hospital outpatient urology clinics and the operating theatre. A total of 233 patients presenting with suspected superficial bladder tumour were recruited. Both patients with new tumours and patients with recurrent tumours were included. •The study duration was 2.5 years with follow-up cystoscopic investigations at 4, 8 and 12 months. •Patients were randomized to cystoscopy and WL TURB (118 patients) or WL TURB followed immediately by HAL TURB (115 patients). Cystoscopy/TURB and bladder biopsies were performed under general anaesthesia. No patients had intravesical chemotherapy immediately after TURB. •Recurrences were verified histologically. RESULTS: •The two groups were similar regarding age and previous bladder cancer history. •In all, 90 patients from the HAL TURB group had bladder tumour. Fluorescence-guided cystoscopy after complete WL TURB identified residual tumour tissue in 44 of 90 patients (49%). In 37 of 83 (45%) residual Ta tumour was found; in three of seven residual T1 was found and in four cases carcinoma in situ. •True (and false) positive detection rate of photodynamic diagnosis was 64% (25%) and of white light 83% (16%). •In all, 145 patients were eligible for analysis of tumour recurrence. Twelve patients had their last follow-up after 4 months. The recurrence rate in patients followed for 12 months was 47.3% (35/74) after WL TURB and 30.5% (18/59) after HAL TURB (P= 0.05). •Kaplan-Meier analyses comprising data from all 145 patients showed that the recurrence-free period was significantly longer in the HAL TURB group than in the WL TURB group (P= 0.02). CONCLUSION: •WL TURB often leaves residual tumour in the bladder. HAL TURB improves the detection of Ta/T1 tumours of the bladder resulting in more complete TURB procedures and thus a reduced recurrence rate.

Morpho-molecular signal correlation between optical coherence tomography and Raman spectroscopy for superior image interpretation and clinical diagnosis.

The combination of manifold optical imaging modalities resulting in multimodal optical systems allows to discover a larger number of biomarkers than using a single modality. The goal of multimodal imaging systems is to increase the diagnostic performance through the combination of complementary modalities, e.g. optical coherence tomography (OCT) and Raman spectroscopy (RS). The physical signal origins of OCT and RS are distinctly different, i.e. in OCT it is elastic back scattering of photons, due to a change in refractive index, while in RS it is the inelastic scattering between photons and molecules. Despite those diverse characteristics both modalities are also linked via scattering properties and molecular composition of tissue. Here, we investigate for the first time the relation of co-registered OCT and RS signals of human bladder tissue, to demonstrate that the signals of these complementary modalities are inherently intertwined, enabling a direct but more importantly improved interpretation and better understanding of the other modality. This work demonstrates that the benefit for using two complementary imaging approaches is, not only the increased diagnostic value, but the increased information and better understanding of the signal origins of both modalities. This evaluation confirms the advantages for using multimodal imaging systems and also paves the way for significant further improved understanding and clinically interpretation of both modalities in the future.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Bladder tissue characterization using probe-based Raman spectroscopy: Evaluation of tissue heterogeneity and influence on the model prediction.

Existing approaches for early-stage bladder tumor diagnosis largely depend on invasive and time-consuming procedures, resulting in hospitalization, bleeding, bladder perforation, infection and other health risks for the patient. The reduction of current risk factors, while maintaining or even improving the diagnostic precision, is an underlying factor in clinical instrumentation research. For example, for clinic surveillance of patients with a history of noninvasive bladder tumors real-time tumor diagnosis can enable immediate laser-based removal of tumors using flexible cystoscopes in the outpatient clinic. Therefore, novel diagnostic modalities are required that can provide real-time in vivo tumor diagnosis. Raman spectroscopy provides biochemical information of tissue samples ex vivo and in vivo and without the need for complicated sample preparation and staining procedures. For the past decade there has been a rise in applications to diagnose and characterize early cancer in different organs, such as in head and neck, colon and stomach, but also different pathologies, for example, inflammation and atherosclerotic plaques. Bladder pathology has also been studied but only with little attention to aspects that can influence the diagnosis, such as tissue heterogeneity, data preprocessing and model development. The present study presents a clinical investigative study on bladder biopsies to characterize the tumor grading ex vivo, using a compact fiber probe-based imaging Raman system, as a crucial step towards in vivo Raman endoscopy. Furthermore, this study presents an evaluation of the tissue heterogeneity of highly fluorescent bladder tissues, and the multivariate statistical analysis for discrimination between nontumor tissue, and low- and high-grade tumor.

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

Can routine outpatient follow-up of patients with bladder cancer be improved? A multicenter prospective observational assessment of blue light flexible cystoscopy and fulguration.

BACKGROUND: The aim of this prospective cohort study was to determine the feasibility of incorporating blue light flexible cystoscopy (BLFC) and biopsy/fulguration into routine outpatient follow-up of non-muscle invasive bladder cancer patients. METHODS: The study included patients with non-muscle-invasive bladder cancer (NMIBC) who were scheduled for routine follow-up. Hexaminolevulinate was instilled in the outpatient department, and the bladder was examined under white light and then with BLFC. Biopsies were taken from all suspicious lesions. Small tumors and suspicious lesions were fulgurated on site; patients with larger lesions were referred to the operating room for resection. RESULTS: The study included 69 patients, with a mean age of 70 years (range 33-89 years) and a mean duration since NMIBC diagnosis of 8 years. Most patients had high-grade cancer at initial diagnosis (52/69) and were at high risk of recurrence (48/69). Two patients per hour could be assessed using outpatient BLFC. Preparation and instillation of hexaminolevulinate took less than 10 minutes per patient, and patients had an additional waiting time of 45-60 minutes following instillation, while the hexaminolevulinate solution was retained in the bladder before examination. Eleven patients had histologically confirmed tumors that were identified using both white light flexible cystoscopy and BLFC. An additional three patients had tumors that were identified by BLFC only: two with Ta tumors and one with carcinoma in situ. Of the 14 patients with confirmed tumors, 11 could be managed on site with fulguration, whereas three were referred to the operating room. No adverse events attributable to BLFC were reported. CONCLUSION: Routine outpatient management of patients with NMIBC using BLFC and on-site biopsy/fulguration is feasible, despite the additional time required for hexaminolevulinate instillation, and appears to allow early detection of recurrent lesions, which can be fulgurated without the need for hospitalization.

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.

Non-muscle-invasive bladder cancer: a vision for the future.

The management of non-muscle-invasive bladder cancer (NMIBC) has evolved from the first reports on bladder endoscopy and transurethral resection to the introduction of adjuvant intravesical treatment. However, disease recurrence and progression remain an ongoing risk, placing a heavy burden on healthcare resources and on patients' quality of life. Deeper understanding of the molecular basis of the disease and developments in optics, lasers and computer science are already offering opportunities to revolutionize care and improve long-term prognosis. This article discusses developments likely to cause a paradigm shift towards the delivery of personalized care and reduced burden of disease in 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.

An optical method for reducing green fluorescence from urine during fluorescence-guided cystoscopy.

Photodynamic diagnosis (PDD) of bladder tumour tissue significantly improves endoscopic diagnosis and treatment of bladder cancer in rigid cystoscopes in the operating theatre and thus reduces tumour recurrence. PDD comprises the use of blue light, which unfortunately excites green fluorescence from urine. As this green fluorescence confounds the desired red fluorescence of the PDD, methods for avoiding this situation particularly in cystoscopy using flexible cystoscopes are desirable. In this paper we demonstrate how a tailor made high power LED light source at 525 nm can be used for fluorescence assisted tumour detection using both a flexible and rigid cystoscope used in the outpatient department (OPD) and operating room (OR) respectively. It is demonstrated both in vitro and in vivo how this light source can significantly reduce the green fluorescence problem with urine. At the same time this light source also is useful for exciting autofluorescence in healthy bladder mucosa. This autofluorescence then provides a contrast to the sensitized fluorescence (PDD) of tumours in the bladder.

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

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.

Investigation of the mechanisms of action behind Electromotive Drug Administration (EMDA).

OBJECTIVE: Bladder cancer is a cause of considerable morbidity worldwide. Electromotive Drug Administration is a method that combines intravesical chemotherapy with local electric field application. Electroporation has been suggested among other mechanisms as having a possible role in the therapy, so the goal of the present study was to investigate the electric fields present in the bladder wall during the treatment to determine which mechanisms might be involved. MATERIAL AND METHODS: Electromotive Drug Administration involves applying intravesical mitomycin C with direct current of 20 mA delivered through a catheter electrode for 30 min. For numerical electric field computation we built a 3-D nonhomogeneous patient specific model based on CT images and used finite element method simulations to determine the electric fields in the whole body. RESULTS: Results indicate that highest electric field in the bladder wall was 37.7 V/m. The mean electric field magnitude in the bladder wall was 3.03 V/m. The mean magnitude of the current density in the bladder wall was 0.61 A/m(2). CONCLUSIONS: The present study shows that electroporation is not the mechanism of action in EMDA. A more likely explanation of the mechanism of action is iontophoretic forces increasing the mitomycin C concentration in the bladder wall.