Bladder Cancer Screening Research Articles

Generic Isolated Cell Image Generator.

Building automated cancer screening systems based on image analysis is currently a hot topic in computer vision and medical imaging community. One of the biggest challenges of such systems, especially those using state‐of‐the‐art deep learning techniques, is that they usually require a large amount of training data to be accurate. However, in the medical field, the confidentiality of the data and the need for medical expertise to label them significantly reduce the amount of training data available. A common practice to overcome this problem is to apply data set augmentation techniques to artificially increase the size of the training data set. Classical data set augmentation methods such as geometrical or color transformations are efficient but still produce a limited amount of new data. Hence, there has been interest in data set augmentation methods using generative models able to synthesize a wider variety of new data. VitaDX is actually developing an automated bladder cancer screening system based on the analysis of cell images contained in urinary cytology digital slides. Currently, the number of available labeled cell images is limited and therefore exploitation of the full potential of deep learning techniques is not possible. In an attempt to increase the number of labeled cell images, a new generic generator for 2D cell images has been developed and is described in this article. This framework combines previous works on cell image generation and a recent style transfer method referred to as doodle‐style transfer in this article. To the best of our knowledge, we are the first to use a doodle‐style transfer method for synthetic cell image generation. This framework is quite modular and could be applied to other cell image generation problems. A statistical evaluation has shown that features of real and synthetic cell images followed roughly the same distribution. Finally, the realism of the synthetic cell images has been assessed through a visual evaluation performed with the help of medical experts. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Abstract 997: Three-dimensional high-throughput drug screening for bladder cancer

Abstract Recent progress in understanding the molecular mechanisms that underlie bladder cancer carcinogenesis offers the prospect of specifically targeting signaling pathways to achieve more effective and rational treatment. In a novel, 3-dimensional high-throughput drug screening (3D HTS) platform to identify novel agents affecting bladder cancer cells, 24 molecularly-targeted agents were screened in seven human bladder cancer cell lines (UCUM3, T24, SW780, RT4, J82, 5637 and 253J-BV). The efficacy of 24 targeted agents on the bladder cell lines varied dramatically on their genomic alterations. BEZ235 (mTOR and PI3K inhibitor) showed antitumor effect in most of cell lines except UMUC3. Another mTOR inhibitor, AZD2014 (inhibitors of mTORC1 and mTORC2) also had IC50 <2 μM in 3 cell lines (5637, J82 and RT4). However, FGFR targeted agents (AZD4547 and BGJ398) did not show the efficacy in cell lines with FGFR3 alterations (J82, SW780 and RT4). In HER2 mutated/amplified cell line (5637), dacomitinib, lapatinib and neratinib showed anti-tumor effect. Immunoblot assay showed that lapatinib and neratinib suppressed phosphorylated HER2 and downstream molecules such as p-AKT or p-ERK. In conclusion, 3D HTS drug screening platform could be a useful preclinical tool to evaluate various kinds of drugs rapidly, and eventually provide a valuable insight into precision medicine along with comprehensive genomic analysis. Note: This abstract was not presented at the meeting. Citation Format: Sang-Cheol Lee, Young Saing Kim, In Gyu Hwang, Su Jin Lee, Se Hoon Park. Three-dimensional high-throughput drug screening for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 997.

Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells

Many patients with muscle-invasive bladder cancer (BC) are either ineligible for or do not benefit from cisplatin-based chemotherapy, and there is an unmet need to estimate individuals’ drug sensitivities. We investigated the suitability of conditionally reprogrammed (CR) cells for the characterization of BC properties and their feasibility for personalized drug sensitivity screening. The CR cultures were established from six BC tumors with varying histology and stage. Four cultures were successfully propagated for genomic, transcriptomic, and protein expression profiling and compared to the parental tumors. Two out of four CR cultures (urothelial carcinoma and small cell neuroendocrine carcinoma [SmCC]) corresponded well to their parental tumors and underwent drug sensitivity screening to identify novel drugs for the respective tumors. Both cultures were sensitive to standard BC chemotherapy agents (eg cisplatin and gemcitabine) and to conventional drugs such as taxanes and inhibitors of topoisomerase and proteasome. The SmCC cells were also sensitive to statins (eg, atorvastatin and pitavastatin). In summary, after confirming their representativeness and origin, we conclude that CR cells are a feasible platform for personalized drug sensitivity testing and might thus add to the approaches used to personalize BC treatment strategies. Patient summaryWe investigated the conditional reprogramming method for generating patient-derived bladder cancer cell cultures and studied their feasibility for planning personalized treatment strategies.

Fight for men’s health: Call of bladder cancer and prostate cancer screening

Not applicable

Mutations in CDKN2A and the FGFR3 genes on bladder cancer diagnosis: a systematic review and meta-analysis.

To determine the association between mutations in CDKN2A and FGFR3 genes and the diagnosis of bladder carcinoma (BCa). A systematic search strategy was carried out through MEDLINE, EMBASE, LILACS, CENTRAL and unpublished literature. We included RCTs, cohort, case-control and cross-sectional studies that involved patients > 18-year-old assessing the association between CDKN2A and FGFR3 mutated genes and BCa. The primary outcome was bladder cancer defined by histology of the sample. We assessed the risk of bias with QUADAS2 and performed a meta-analysis with Review Manager v5.3. We found 97 records with the search strategies. After duplicates were removed, six studies were included in meta-analysis. Regarding the association between mutated FGFR3 and bladder cancer, we found an OR 31 95% CI (15-64). However, there was no association for CDKN2A and BCa. There is a strong association between FGFR3 mutated gene and the diagnosis of bladder cancer, which has not been observed with CDKN2A. Such a result supports FGFR3 mutated gene as a promissory bladder cancer screening and monitoring biomarker.

Hopes and Challenges: Translational Medical Research in Bladder Cancer

Bladder cancer is a complex disease and could be classified into non-muscle-invasive or muscle-invasive subtypes according to the distinct genetic background and clinical prognosis. It is necessary to find a non-invasive, economical and efficient method for the diagnosis and treatment of bladder cancer. Translational medicine provides such an opportunity. Genomics, proteomics, molecular biology, bioinformatics and the like that aid in studying and exploring the mechanism of bladder cancer development, bladder cancer-related genes, signalling pathways, key molecules or targets can be clearly used for the diagnosis and treatment of bladder cancer. Biomarkers have been developed as part of a new detection kit for the early screening, diagnosis and recurrence monitoring of bladder cancer through translational medicine. Additionally, targeted drugs and immunological preparations can be used for the treatment of bladder cancer and further improve its existing diagnosis, treatment and prognosis.

Epidemiology, aetiology and screening of bladder cancer.

Bladder cancer (BC) is a common, significant and expensive health condition. Understanding the risk factors for this disease is paramount to improving disease prevention and increasing public awareness. Historically BC has been a disease of industrialized regions and the most responsible carcinogens are tobacco smoke and occupational chemical exposure. BC incidence and mortality differ dramatically by region and reflect differences in risk factor exposure, healthcare behaviour, and population demographics. Screening studies have suggested a survival benefit amongst screened non-symptomatic populations with known risk factors, but this has not become standard practice.

Bladder cancer detection by urinary extracellular vesicle mRNA analysis.

ObjectiveUrinary extracellular vesicles (EV) could be promising biomarkers for urological diseases. In this retrospective feasibility study, we conducted biomarker screening for early stage bladder cancer using EV mRNA analysis.MethodsBiomarker candidates were identified through RNA-seq analysis of urinary EV from patients with non-muscle invasive bladder cancer (N=3), advanced urothelial cancer (N=3), no residual tumor after TURBT (N=2), and healthy and disease controls (N=4). Diagnostic performance was evaluated by RT-qPCR in a larger patient group including bladder cancer (N=173), renal pelvis and ureter cancer (N=33), no residual tumor and non-cancer disease control (N=36).ResultsUrinary EV SLC2A1, GPRC5A and KRT17 were overexpressed in pT1 and higher stage bladder cancer by 20.6-fold, 18.2-fold and 29.5-fold, respectively. These genes allowed detection of non-muscle invasive bladder cancer (AUC: 0.56 to 0.64 for pTa, 0.62 to 0.80 for pTis, and 0.82 to 0.86 for pT1) as well as pT2 and higher muscle invasive bladder cancer (AUC: 0.72 to 0.90). Subgroup analysis indicated that these markers could be useful for the detection of cytology-negative/-suspicious and recurrent bladder cancers.ConclusionThree urinary EV mRNA were discovered to be elevated in bladder cancer. Urinary EV mRNA are promising biomarkers of urothelial cancer and worth further investigation.

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Microchips for detection of exfoliated tumor cells in urine for identification of bladder cancer

Bladder cancer (BC) is a common malignancy, and it accounts for one of the highest management costs among urogenital cancers. As a non-invasive method, urine cytology plays an important role in the detection of exfoliated tumor cells (ETCs) for early diagnosis of BC. However, urine cytology suffers from its low sensitivity and reliance on microscopic examination. To address this issue, an integrated filtration device was developed with a pore size of 5 μm that isolated and enriched ETCs from discarded urine samples, and then quantified ETCs using a microchip ELISA method. The results revealed that the number of urinary ETCs from BC patients (n = 35) was obviously higher than the number of ETCs from healthy donors (n = 20). The ROC curve showed that the integrated filtration microfluidic device had a sensitivity of 77.1% when the specificity was set at 90% in identifying BC patients. Thus, the integrated filtration device holds great potential for the screening of BC or the follow-up analysis of treatment efficacy in point-of-care (POC) settings.

Role of ultrasonography in the diagnosis of gall-bladder carcinoma: A boon for low-resource settings

Abstract Purpose: The present study was done with an aim to evaluate the usefulness of ultrasonography (USG) in early diagnosis of gall-bladder carcinoma for low-resource settings. Materials and Methods: A total of 264 clinically suspicious cases were enrolled in the study. The patients underwent USG followed by computed tomography (CT). Histopathological specimens were obtained from 208 cases. Final diagnosis was confirmed histopathologically/CT. Sensitivity, specificity, positive predictive, and negative predictive values of USG were calculated. Results: A total of 29 cases were confirmed as gall-bladder carcinoma, 58.6% were diagnosed at advanced stage (Stage III/IV). USG diagnosed 42 cases as neoplastic, however, 24 were true positive and 18 were false positive. USG was 82.8% sensitive and 92.5% specific. The positive and negative predictive values were 57.1% and 97.8%, respectively, diagnostic efficacy was 91.5%. 94.1% advanced stage gall bladder cancers were diagnosed correctly by USG. Sensitivity for early stages was promising (61.9%), however false positive was higher. Cost of USG was nearly five times lesser as compared to that of CT. Conclusion: USG was a useful economical imaging modality for the screening of gall bladder cancer in low-resource settings, especially for advanced stages. However, for early stages too, it seemed useful. We recommend to encourage the use of USG in early detection of gall-bladder carcinoma in socially and economically disadvantaged settings.

Promoting Long-Term Health among People with Spinal Cord Injury: What's New?

A key ingredient to successful health promotion is a primary care provider who can offer an informed first response to lifestyle issues, emerging problems and chronic challenges. This article aims to assist family physicians to play their role in promoting the health of people with SCI, by summarizing the latest evidence in the management of spinal cord injury in primary care. This study used a scoping review methodology to survey peer-reviewed journal articles and clinical guidelines published between January 2012 to June 2016. This search strategy identified 153 articles across 20 topics. A prevention framework is used to identify five primary, nine secondary, four tertiary, and two quaternary prevention issues about which family physicians require current information. Major changes in the management of SCI in primary care were noted for 8 of the 20 topics, specifically in the areas of pharmacological management of neuropathic pain and urinary tract infection; screening for bowel and bladder cancer; improvements in wound care; and clarification of dietary fibre recommendations. All of these changes are represented in the 3rd edition of Actionable Nuggets—an innovative tool to assist family physicians to be aware of the best practices in primary care for spinal cord injury.

The contemporary role and impact of urine-based biomarkers in bladder cancer.

Despite advances in the surgical and medical treatment of bladder cancer, there have only been minor improvements in mortality and morbidity rates over the past decades. Urine-based markers help to improve diagnosing bladder cancer with the aim of complementing or probably in future replacing cystoscopy. Biomarkers may allow individualized risk stratification and support decision-making regarding therapy and follow-up. This review summarizes the existing urine-based biomarkers in bladder cancer. We conducted a comprehensive review of the literature. We conducted a PubMed/Medline based research on English language articles and selected original articles and review articles that provided both description and assessment of urinary markers at time of screening, initial diagnosis, monitoring and prognostic evaluation of urothelial bladder cancer. Our research covered studies published between 2000 and 2017. The aim of this study was to give clinicians keys to understand the existing or promising urinary markers that may become alternatives to cytology/cystoscopy pair in the near future. Many urinary markers are now available, often with superior sensitivity to cytology. Their uses have been evaluated in numerous clinical situations in addition to the time of initial diagnosis and surveillance such as cases of isolated macroscopic hematuria or atypical cytology discordant with the rest of the explorations. However, their superiority over the cytology/cystoscopy association is not demonstrated. These new markers are lacking for the most part of standardization and simplicity making their use in common practice difficult. the types and forms of these new markers are very heterogeneous among themselves and between the studies that evaluate them. Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of urine- and blood-based biomarkers into clinical decision-making will be of value for bladder cancer detection and screening in the future.

Microdevices for Non-Invasive Detection of Bladder Cancer

Bladder cancer holds the record for the highest lifetime cost on a per-patient basis. This is due to high recurrence rates, which necessitate invasive and costly long-term evaluation methods such as cystoscopy and imaging. Microfluidics is emerging as an important approach to contribute to initial diagnosis and follow-up, by enabling the precise manipulation of biological samples. Specifically, microdevices have been used for the isolation of cells or genetic material from blood samples, sparking significant interest as a versatile platform for non-invasive bladder cancer detection with voided urine. In this review, we revisit the methods of bladder cancer detection and describe various types of markers currently used for evaluation. We detail cutting-edge technologies and evaluate their merits in the detection, screening, and diagnosis of bladder cancer. Advantages of microscale devices over standard methods of detection, as well as their limitations, are provided. We conclude with a discussion of criteria for guiding microdevice development that could deepen our understanding of prognoses at the level of individual patients and the underlying biology of bladder cancer development. Collectively, the development and widespread application of improved microfluidic devices for bladder cancer could drive treatment breakthroughs and establish widespread, tangible outcomes on patients’ long-term survival.

Review of the Clinical Approaches to the Use of Urine-based Tumor Markers in Bladder Cancer.

Bladder cancer is a common disease with a stable incidence for the past few decades despite advancements in molecular and genetic determinants of cancer development and progression. Cystoscopy remains the standard for detection and surveillance of bladder cancer, but it is an invasive and potentially costly procedure. With the knowledge of molecular alterations associated with bladder cancer numerous urine-based tumor markers have become commercially available. These urine markers have been evaluated in all clinical scenarios for the detection of bladder cancer including screening, hematuria, atypical cytology evaluation, and surveillance, but given the relative lack of impactful trials they are not routinely utilized. The efforts to develop markers with increased sensitivity to replace cystoscopy for the detection of bladder cancer have thus far been unsuccessful as well. This review addresses role of urine markers for screening, detection, and surveillance of bladder cancer.

Reliability of urinary cytology and cystoscopy for the screening and diagnosis of bladder cancer in patients with neurogenic bladder: A systematic review

To assess the reliability of urinary cytology and cystoscopy to screen and diagnose bladder cancer in patients with NB. A systematic literature search of the Medline and Embase databases was performed in April 2017. Data extraction was performed by two independent reviewers. A narrative synthesis was made. Out of 220 records assessed, 15 were included in this systematic review. All studies were prospective or retrospective series with no control group. Cystoscopy allowed the detection of asymptomatic bladder cancer in 0-10 patients, with a screening sensitivity (available in only one study) of 0%, a screening specificity ranging from 65% to 90%, and a yield in detecting asymptomatic bladder cancer of 0% in all series where it could be calculated. Urinary cytology allowed the detection of bladder cancer in asymptomatic patients in 0-12 patients, with a screening sensitivity of 71%, a screening specificity ranging from 92% to 97% and a yield ranging from 0% to 1.25%. Sensitivity of cystoscopy for diagnosis of bladder cancer ranged from 27% to 81% and specificity was 54% in the only study where it could be calculated. Sensitivity of urinary cytology for diagnosis of bladder cancer was 0-72% and specificity was 100%. There is currently insufficient data to support formal recommendations of using both tools in the screening of bladder cancer in patients with neurogenic bladder. Urinary cytology outperformed cystoscopy for screening and might be the best tool currently available.

Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics.

Purpose: The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance.Experimental Design: RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients (n = 13) and controls (n = 10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines.Results: A total of 418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (PBC) based on expression of three markers (ROBO1, WNT5A, and CDC42BPB). Setting PBC = 0.45 as the cutoff for a positive test, urine testing using the three-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the three-marker panel in the independent validation cohort yielded an AUC of 0.87 and overall 83% sensitivity and 89% specificity.Conclusions: Urine-based molecular diagnostics using this three-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis. Clin Cancer Res; 23(14); 3700-10. ©2017 AACR.

Epigenetic regulation in bladder cancer: development of new prognostic targets and therapeutic implications

: Epigenetic and genetic alterations contribute to cancer initiation and progression. Epigenetics refers to heritable alterations in gene expression without DNA sequence changes. Epigenetic changes include reversible alterations in DNA methylation, chromatin modification, nucleosome positioning, and non-coding RNA profiles. In bladder cancer, many epigenetic changes have been reported to exhibit correlation with cancer progression and malignances. In particular, both DNA hypermethylation and hypomethylation have been reported to be associated with higher bladder cancer rates or advanced tumor stages. The association of changes in histone modifying enzyme expression with bladder cancer stages has been extensively studied. MicroRNA (miRNA) expression also has been studied in bladder cancer diagnosis and disease progression. The use of epigenetics for the diagnosis of and therapeutic target screening in bladder cancer is an emerging and rapidly evolving field. The reversible nature of epigenetic changes may facilitate additional therapeutic options in the future.

MicroRNAs in biofluids are novel tools for bladder cancer screening.

MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in basic cellular processes, including differentiation, proliferation, apoptosis and autophagy. They are also involved in various stages of tumorigenesis and play key roles in bladder cancer initiation and progression. Notably, the altered expression of miRNAs in the tumors is reflected in body fluids, including blood and urine, which opens avenues for non-invasive diagnosis and prognosis. Many studies have demonstrated that epigenetic changes extensively alter tumoral microRNA expression. The high reproducibility, specificity and sensitivity of miRNA levels in body fluids suggest their potential use as biomarkers for cancer screening and diagnosis. For example, recent technological advances have made it possible to detect miRNAs in urine for bladder cancer screening. In this review, we focus mainly on the current knowledge and future challenges for incorporating miRNAs in body fluids, like urine and blood, for making clinical diagnoses and assessing prognoses in bladder cancer.

Development of a Dual-Label Time-Resolved Fluorescence Immunoassay (TRFIA) for Screening of Bladder Cancer based on Simultaneous Detection of BLCA-4 and NMP52 in Urine

Bladder cancer is a heterogeneous disease and occupies highest incidence in developed country. Time-resolved fluoroimmunoassays (TRFIA) is a new detection technique with a feature of sensitive, simple and inexpensive. The aim of this study is to establish a dual-label TRFIA for the simultaneous detection of BLCA-4 and NMP52 in urine in a single run. The sandwich immunoassay was used to detect the concentration of BLCA-4 and NMP52 in urine. BLCA- 4 and NMP52 in urine were captured by anti-BLCA-4 and anti-NMP52 antibodies immobilized on microtiter wells, and then banded together with another anti-BLCA-4 and anti-NMP52 labeled with europium(III) Sm3+ and samarium(III) Eu3+ chelates, followed by fluorescence measurement using time resolved fluorometry. To assess the performance of this assay, clinical urine samples were used, and then commercialized kits were compared. The sensitivity for BLCA-4 and NMP52 detection of this assay were 2 U/mL (dynamic range, 5-300 U/L) and 1 μg/ml (dynamic range, 2-150 μg/ml) respectively. The correlation coefficients (R) between the present dual-label TRFIA and commercially available kits were high. R-values were 0.99 for BLCA-4 and NMP52. The cross-reactivity seems not to influence the results. The present dual-label TRFIA, allowing the simultaneous detection ofBLCA-4 and NMP52, has high sensitivity, specificity, and accuracy in clinical sample analysis. Therefore, it has good prospects of application.