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Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 23615

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Special Issue Editors

Dr. Hideki Furuya

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Guest Editor

1. Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Interests: urinary biomarkers for early detection, prognostics, and prediction of the response to treatment of bladder cancer; the role of sphingolipid signaling cascade in cancers, such as colon, breast, and bladder
Special Issues, Collections and Topics in MDPI journals

Dr. Charles Rosser

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Guest Editor

Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Interests: molecular diagnostics and experimental therapeutics; specifically bladder cancer biomarkers for early detection, clinical diagnosis and prognosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Despite improvements in the diagnosis and treatment of bladder cancer, the death rates of bladder cancer have been increasing over the past two decades. In addition, bladder cancer has one of the highest recurrence rates of any tumor type. Although treatment, such as administration of intravesical immunologic or chemotherapeutic agents, helps lower the risk of recurrence, the risk still remains 31%–78% after 5 years. Unfortunately, up to 45% of non-muscle invasive bladder cancer (NMIBC) progresses to muscle invasive bladder cancer (MIBC) after 5 years, leading to dismal survival rates associated with more advance disease. When diagnosed early as NMIBC, including stage 0 or I, a cure with surgical resection is possible in a high percentage of cases: a 5-year survival rate of 98% and 88%, respectively. However, once it becomes MIBC or metastatic including stage II, III, and IV, it is fatal, with an estimated 5-year survival rate of 63%, 46%, and 15%, respectively. Thus, there is an urgent need to develop novel strategies for prevention and treatment of bladder cancer. The forthcoming Special Issue will welcome submissions on, but not limited to, the following topics:

Risk factors (epidemiological and biological factors including the mechanism);
Non-invasive detection biomarkers, such as blood- and urine-based biomarkers;
Novel DNA, RNA, and protein biomarkers;
Extracellular vesicles;
Precision medicine;
Immunotherapy including immune checkpoint inhibitors;
Predictive biomarkers.

Dr. Hideki Furuya
Dr. Charles Rosser
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Personalized medicine
Molecular diagnosis
Biomarkers (early detection, grading, staging, prognosis, prediction of response to chemo- and immuno-therapies)
Novel therapies (gene, cell, and molecular therapy)
Genotype-phenotype correlation and modifier genes
Preclinical models (cell and tissue, organoids, animal models)
OMICS
Immunotherapy
Targeted therapy

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Published Papers (8 papers)

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Research

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8 pages, 434 KiB

Open AccessArticle

Influencing Factors on the Oncuria™ Urinalysis Assay: An Experimental Model

by Kaoru Murakami, Ian Pagano, Runpu Chen, Yijun Sun, Steve Goodison, Charles J. Rosser and Hideki Furuya

Diagnostics 2021, 11(6), 1023; https://doi.org/10.3390/diagnostics11061023 - 3 Jun 2021

Cited by 4 | Viewed by 2458

Abstract

Background: The Oncuria™ urine test for the detection of bladder cancer measures a multiplex protein signature. In this study, we investigated the influence of urinary cellularity, protein, and hematuria on the performance of the Oncuria™ test in an ex vivo experimental model. Materials and Methods: Pooled urine from healthy subjects was spiked with cultured benign (UROtsa) or malignant cells (T24), cellular proteins, or whole blood. The resulting samples were analyzed using the Oncuria™ test following the manufacturer’s instructions. Results: Urine samples obtained from healthy subjects were negative for bladder cancer by Oncuria™ test criteria. The majority of the manipulated conditions did not result in a false-positive test. The addition of whole blood (high concentration) did result in a false-positive result, but this was abrogated by sample centrifugation prior to analysis. The addition of cellular proteins (high concentration) resulted in a positive Oncuria™ test, and this was unaffected by pre-analysis sample centrifugation. Conclusions: The Oncuria™ multiplex test performed well in the ex vivo experimental model and shows promise for clinical application. The identification of patients who require additional clinical evaluation could reduce the need to subject patients who do not have bladder cancer to frequent, uncomfortable and expensive cystoscopic examinations, thus benefiting both patients and the healthcare system. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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10 pages, 827 KiB

Open AccessArticle

Impact of Lymphovascular Invasion on Prognosis in the Patients with Bladder Cancer—Comparison of Transurethral Resection and Radical Cystectomy

by Kei Yoneda, Naoto Kamiya, Takanobu Utsumi, Ken Wakai, Ryo Oka, Takumi Endo, Masashi Yano, Nobuyuki Hiruta, Tomohiko Ichikawa and Hiroyoshi Suzuki

Diagnostics 2021, 11(2), 244; https://doi.org/10.3390/diagnostics11020244 - 4 Feb 2021

Cited by 10 | Viewed by 2178

Abstract

(1) Background: This study aimed to evaluate the associations of lymphovascular invasion (LVI) at first transurethral resection of bladder (TURBT) and radical cystectomy (RC) with survival outcomes, and to evaluate the concordance between LVI at first TURBT and RC. (2) Methods: We analyzed 216 patients who underwent first TURBT and 64 patients who underwent RC at Toho University Sakura Medical Center. (3) Results: LVI was identified in 22.7% of patients who underwent first TURBT, and in 32.8% of patients who underwent RC. Univariate analysis identified ≥cT3, metastasis and LVI at first TURBT as factors significantly associated with overall survival (OS) and cancer-specific survival (CSS). Multivariate analysis identified metastasis (hazard ratio (HR) 6.560, p = 0.009) and LVI at first TURBT (HR 9.205, p = 0.003) as significant predictors of CSS. On the other hand, in patients who underwent RC, ≥pT3, presence of G3 and LVI was significantly associated with OS and CSS in univariate analysis. Multivariate analysis identified inclusion of G3 as a significant predictor of OS and CSS. The concordance rate between LVI at first TURBT and RC was 48.0%. Patients with positive results for LVI at first TURBT and RC displayed poorer prognosis than other patients (p < 0.05). (4) Conclusions: We found that the combination of LVI at first TURBT and RC was likely to provide a more significant prognostic factor. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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10 pages, 11970 KiB

Open AccessArticle

Photodynamic Diagnosis-Assisted Transurethral Resection Using Oral 5-Aminolevulinic Acid Decreases the Risk of Repeated Recurrence in Non-Muscle-Invasive Bladder Cancer: A Cumulative Incidence Analysis by the Person-Time Method

by Makito Miyake, Nobutaka Nishimura, Yasushi Nakai, Tomomi Fujii, Takuya Owari, Shunta Hori, Yosuke Morizawa, Daisuke Gotoh, Satoshi Anai, Kazumasa Torimoto, Nobumichi Tanaka, Yoshihiko Hirao and Kiyohide Fujimoto

Diagnostics 2021, 11(2), 185; https://doi.org/10.3390/diagnostics11020185 - 28 Jan 2021

Cited by 21 | Viewed by 2811

Abstract

Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome (p = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16–0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact p = 0.011; incidence rate ratio 0.37, Clopper–Pearson confidence interval 0.15–0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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14 pages, 1945 KiB

Open AccessArticle

Soluble Syndecan-1 Levels Are Associated with Survival in Platinum-Treated Bladder Cancer Patients

by Csilla Olah, Stephan Tschirdewahn, Michèle J. Hoffmann, Ulrich Krafft, Boris Hadaschik, Peter Nyirady, Attila Szendröi, Orsolya Módos, Anita Csizmarik, Ilona Kovalszky, Henning Reis and Tibor Szarvas

Diagnostics 2020, 10(11), 864; https://doi.org/10.3390/diagnostics10110864 - 23 Oct 2020

Cited by 8 | Viewed by 2068

Abstract

Cisplatin-containing chemotherapy represents the first-line treatment for patients with locally advanced or metastatic muscle-invasive bladder cancer. Recently, novel therapies have become available for cisplatin-ineligible or -resistant patients. Therefore, prediction of cisplatin response is required to optimize therapy decisions. Syndecan-1 (SDC1) tissue expression and serum concentration may be associated with cisplatin resistance. Thus, pre-treatment serum levels of SDC1 and its expression in chemo-naïve tissues were assessed in 121 muscle-invasive bladder cancer patients who underwent postoperative platinum-based chemotherapy. SDC1 concentrations were evaluated by ELISA in 52 baseline and 90 follow-up serum samples and tissue expressions were analyzed by immunohistochemistry in an independent cohort of 69 formalin-fixed paraffin-embedded tumor samples. Pre-treatment SDC1 serum levels were significantly higher in lymph node metastatic (p = 0.009) and female patients (p = 0.026). SDC1 tissue expression did not correlate with clinicopathological parameters. High pre-treatment SDC1 serum level and the presence of distant metastasis were independent risk factors for overall survival (Hazard ratio (HR): 1.439, 95% Confidence interval (CI): 1.003–2.065, p = 0.048; HR: 2.269, 95%CI: 1.053–4.887, p = 0.036). Our results demonstrate an independent association between high baseline serum SDC1 concentration and poor survival in platinum-treated patients. Analyzing baseline serum SDC1 levels may help to predict platinum-containing chemotherapy and could help to optimize therapeutic decision-making. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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11 pages, 738 KiB

Open AccessArticle

Clinical Validation of a Urine Test (Uromonitor-V2^®) for the Surveillance of Non-Muscle-Invasive Bladder Cancer Patients

by Caroline A. Sieverink, Rui P. M. Batista, Hugo J. M. Prazeres, João Vinagre, Cristina Sampaio, Ricardo R. Leão, Valdemar Máximo, J. Alfred Witjes and Paula Soares

Diagnostics 2020, 10(10), 745; https://doi.org/10.3390/diagnostics10100745 - 24 Sep 2020

Cited by 30 | Viewed by 3984

Abstract

The costly and burdensome nature of the current follow-up methods in non-muscle-invasive bladder cancer (NMIBC) drives the development of new methods that may alternate with regular cystoscopy and urine cytology. The Uromonitor-V2^® is a new urine-based assay in the detection of hotspot mutations in three genes (TERT, FGFR3, and KRAS) for evaluation of disease recurrence. The aim of this study was to investigate the Uromonitor-V2^®’s performance in detecting NMIBC recurrence and compare it with urine cytology. From February 2018 to September 2019 patients were enrolled. All subjects underwent a standard-of-care (SOC) cystoscopy, either as part of their follow-up for NMIBC or for a nonmalignant urological pathology. Urine cytology was performed in NMIBC patients. Out of the 105 patients enrolled, 97 were eligible for the study. Twenty patients presented nonmalignant lesions, 29 had a history of NMIBC with disease recurrence, and 49 had a history of NMIBC without recurrence. In NMIBC, the Uromonitor-V2^® displayed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. Urine cytology was available for 52 patients, and the sensitivity, specificity, PPV, and NPV were 26.3%, 90.9%, 62.5%, and 68.2%, respectively. With its high NPV of 95.3%, the Uromonitor-V2^® revealed promising properties for the follow-up of patients with NMIBC. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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15 pages, 2237 KiB

Open AccessArticle

Comparison of Pteridine Normalization Methods in Urine for Detection of Bladder Cancer

by Piotr Kośliński, Robert Pluskota, Katarzyna Mądra-Gackowska, Marcin Gackowski, Michał J. Markuszewski, Kornelia Kędziora-Kornatowska and Marcin Koba

Diagnostics 2020, 10(9), 612; https://doi.org/10.3390/diagnostics10090612 - 20 Aug 2020

Cited by 3 | Viewed by 2514

Abstract

Pterin compounds belong to the group of biomarkers for which an increase in interest has been observed in recent years. Available literature data point to this group of compounds as potential biomarkers for cancer detection, although the biochemical justification for this claim is not yet fully understood. The aim of this study was to evaluate the usefulness of pterin compounds in the diagnosis of bladder cancer, with particular emphasis on the role of creatinine and the specific gravity of urine as factors for normalizing the concentration of pterin compounds in urine. The standardization of the concentration of pterin compounds to urine specific gravity allows the building of better classification models for screening patients with potential cancer of the bladder. Of the compounds that make up the pterin profile, isoxanthopterin appears to be a compound that can potentially be described as a biomarker of bladder cancer. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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Review

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15 pages, 2721 KiB

Open AccessReview

Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies

by Massimiliano Creta, Giuseppe Celentano, Luigi Napolitano, Roberto La Rocca, Marco Capece, Gianluigi Califano, Claudia Collà Ruvolo, Francesco Mangiapia, Simone Morra, Carmine Turco, Lorenzo Spirito, Ferdinando Fusco, Ciro Imbimbo, Vincenzo Mirone and Nicola Longo

Diagnostics 2021, 11(2), 351; https://doi.org/10.3390/diagnostics11020351 - 20 Feb 2021

Cited by 21 | Viewed by 2195

Abstract

Bladder cancer (BCa) is an endocrine-related tumour and the activation of androgen signalling pathways may promote bladder tumorigenesis. We summarized the available preclinical and clinical evidence on the implications of the manipulation of androgen signalling pathways on the outcomes of BCa therapies. A systematic review was performed in December 2020. We included papers that met the following criteria: original preclinical and clinical research; evaluating the impact of androgen signalling modulation on the outcomes of BCa therapies. Six preclinical and eight clinical studies were identified. The preclinical evidence demonstrates that the modulation of androgen receptor-related pathways has the potential to interfere with the activity of the Bacillus Calmette Guerin, doxorubicin, cisplatin, gemcitabine, and radiotherapy. The relative risk of BCa recurrence after transurethral resection of the bladder tumour (TURBT) is significantly lower in patients undergoing therapy with 5 alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT) (Relative risk: 0.50, 95% CI: 0.30–0.82; p = 0.006). Subgroup analysis in patients receiving 5-ARIs revealed a relative risk of BCa recurrence of 0.46 (95% CI: 0.22–0.95; p = 0.040). A significant negative association between the ratio of T1 BCa patients in treated/control groups and the relative risk of BCa recurrence was observed. Therapy with 5-ARIs may represent a potential strategy aimed at reducing BCa recurrence rate, mainly in patients with low stage disease. Further studies are needed to confirm these preliminary data. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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10 pages, 1059 KiB

Open AccessReview

Urinary Cell-Free DNA in Bladder Cancer Detection

by Ryan Tsz-Hei Tse, Hongda Zhao, Christine Yim-Ping Wong, Carol Ka-Lo Cheng, Angel Wing-Yan Kong, Qiang Peng, Peter Ka-Fung Chiu, Chi-Fai Ng and Jeremy Yuen-Chun Teoh

Diagnostics 2021, 11(2), 306; https://doi.org/10.3390/diagnostics11020306 - 14 Feb 2021

Cited by 12 | Viewed by 4380

Abstract

Urinary bladder cancer is a common urological cancer. Although flexible cystoscopy is widely employed in bladder cancer detection, it is expensive, invasive, and uncomfortable to the patients. Recently, urinary cell-free DNA (ucfDNA) isolated from urine supernatant has been shown to have great potential in bladder cancer detection and surveillance. Molecular features, such as integrity and concentration of ucfDNA, have been shown to be useful for differentiating bladder cancer patients from healthy controls. Besides, bladder cancer also exhibits unique genetic features that can be identified from sequencing and expression of ucfDNA. Apart from bladder cancer detection, ucfDNA is also useful for molecular classification. For example, ucfDNA exhibits significant differences, both molecularly and genetically, in non-muscle-invasive and muscle-invasive bladder cancers. There is no doubt that ucfDNA is a very promising tool for future applications in the field of bladder cancer. Full article

(This article belongs to the Special Issue Early Detection, Diagnosis, and Management of Bladder Cancer – Importance of Biomarkers)

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