Special Issue "Biomarkers and Therapeutic Advances in Bladder Cancer"

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 14266

Special Issue Editors

Department of Urology, University of Foggia School of Medicine, 71121 Foggia, Italy
Interests: prostate cancer; bladder cancer; BPH and male infertility
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Precision medicine requires the stratification of patients into subpopulations with known features in terms of responsiveness to certain treatments. In this setting, novel biomarkers that provide reliable information on the patients’ prognosis and likely response to therapy are of pivotal importance.

Bladder cancer (BC), ranking 7th among the most prevalent human cancers worldwide, is a heterogeneous disease, encompassing a wide spectrum of entities from a clinical, histological, and molecular viewpoint; because of this, each type of BC is amenable to different treatments, which in turn results in distinct outcomes, eventually with inherent side effects.

This Special Issue will focus on papers, both original and review articles, dealing with a spectrum of topics, including recent updates in the development, implementation, and validation of diagnostic, prognostic, and predictive biomarkers, as well as novel treatment and management approaches.

Prof. Dr. Francesca Sanguedolce
Dr. Matteo Ferro
Prof. Dr. Gian Maria Busetto
Guest Editors

Manuscript Submission Information

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Keywords

  • Bladder cancer
  • Biomarker
  • Prognosis
  • Therapeutic advances
  • Precision medicine

Published Papers (8 papers)

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11 pages, 1855 KiB  
Article
A Diagnostic Gene Expression Signature for Bladder Cancer Can Stratify Cases into Prescribed Molecular Subtypes and Predict Outcome
Diagnostics 2022, 12(8), 1801; https://doi.org/10.3390/diagnostics12081801 - 25 Jul 2022
Cited by 2 | Viewed by 1446
Abstract
Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a [...] Read more.
Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a bladder cancer diagnostic signature composed of 10 biomarkers, which has been incorporated into a multiplex immunoassay bladder cancer test, Oncuria™. In this study, we evaluate whether these 10 biomarkers can assist in the prediction of bladder cancer clinical outcomes. Tumor gene expression and patient survival data from bladder cancer cases from The Cancer Genome Atlas (TCGA) were analyzed. Alignment between the mRNA expression of 10 biomarkers and the TCGA 2017 subtype classification was assessed. Kaplan–Meier analysis of multiple gene expression datasets indicated that high expression of the combined 10 biomarkers correlated with a significant reduction in overall survival. The analysis of three independent, publicly available gene expression datasets confirmed that multiplex prognostic models outperformed single biomarkers. In total, 8 of the 10 biomarkers from the Oncuria™ test were significantly associated with either luminal or basal molecular subtypes, and thus, the test has the potential to assist in the prediction of clinical outcome. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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12 pages, 1210 KiB  
Article
Modified Glasgow Prognostic Score as a Predictor of Recurrence in Patients with High Grade Non-Muscle Invasive Bladder Cancer Undergoing Intravesical Bacillus Calmette–Guerin Immunotherapy
Diagnostics 2022, 12(3), 586; https://doi.org/10.3390/diagnostics12030586 - 25 Feb 2022
Cited by 10 | Viewed by 1936
Abstract
Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We [...] Read more.
Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We retrospectively reviewed patient’s medical data from multicenter institutions. A total of 1382 patients with HG/G3 T1 NMIBC have been administered adjuvant intravesical BCG therapy, every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. The analysis of mGPS for recurrence and progression was performed using multivariable and univariable Cox regression models. Results: During follow-up, 659 patients (47.68%) suffered recurrence, 441 (31.91%) suffered progression, 156 (11.28%) died of all causes, and 67 (4.84%) died of bladder cancer. At multivariable analysis, neutrophil to lymphocyte ratio [hazard ratio (HR): 7.471; p = 0.0001] and erythrocyte sedimentation rate (ESR) (HR: 0.706; p = 0.006 were significantly associated with recurrence. mGPS has no statistical significance for progression (p = 0.076). Kaplan–Meier survival analysis showed a significant difference in survival among patients from different mGPS subgroups. Five-year OS was 93% (CI 95% 92–94), in patients with mGPS 0, 82.2% (CI 95% 78.9–85.5) in patients with mGPS 1 and 78.1% (CI 95% 60.4–70) in mGPS 2 patients. Five-year CSS was 98% (CI 95% 97–99) in patients with mGPS 0, 90% (CI 95% 87–94) in patients with mGPS 1, and 100% in mGPS 2 patients. Limitations are applicable to a retrospective study. Conclusions: mGPS may have the potential to predict recurrence in HG/G3 T1 NMIBC patients, but more prospective, with large cohorts, studies are needed to study the influence of systemic inflammatory markers in prediction of outcomes in NMIBC for a definitive conclusion. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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14 pages, 1826 KiB  
Article
A Comparative Study of the Triglycerides/HDL Ratio and Pseudocholinesterase Levels in Patients with Bladder Cancer
Diagnostics 2022, 12(2), 431; https://doi.org/10.3390/diagnostics12020431 - 07 Feb 2022
Cited by 20 | Viewed by 2300
Abstract
Background: Lipid alterations may serve as potential tumour biomarkers. The ratio of triglycerides to HDL cholesterol (TG/HDL ratio) is associated with various cancers. Pseudocholinesterase (PChE) activity, involved in TG hydrolysis, plays an important role in the metabolism of lipoprotein. There is scarce data [...] Read more.
Background: Lipid alterations may serve as potential tumour biomarkers. The ratio of triglycerides to HDL cholesterol (TG/HDL ratio) is associated with various cancers. Pseudocholinesterase (PChE) activity, involved in TG hydrolysis, plays an important role in the metabolism of lipoprotein. There is scarce data assessing the reliability of both the TG/HDL ratio and PChE levels in correctly classifying patients suffering from bladder cancer. Methods: Three hundred and ninety-six patients undergoing cystoscopy or transurethral resection of the bladder (TURB), broken into two major groups, i.e., patients with histologically confirmed, non-metastatic bladder cancer (n = 208) and without bladder cancer (no bladder cancer, n = 188), formed the study population. The last group was split into two subgroups consisting of a cohort of patients never suffering from bladder cancer but with other bladder diseases (no CaBD, n = 100) and another cohort formed by patients characterised by eradicated bladder cancer after TURB with no recurrence during a three-month follow-up (previous bladder cancer, n = 88). Pieces of information by both metabolic derangement (the presence of type 2 diabetes mellitus), hypertension and lipid profile were retrieved from patient records upon entry to the study. Sensitivity, specificity, areas under the ROC (AUROC) of the TG/HDL ratio, and PChE levels were used in diagnostic decision making. Results: The TG/HDL ratio as well as PChE concentrations of bladder cancer patients were significantly different when compared to those with previous bladder cancer and the no CaBD patients (p = 0.023 and 0.0004, respectively). There was an independent role of both the TG/HDL ratio and PChE levels in predicting the presence of bladder cancer (OR: 1.22 and 0.99, respectively), but the reliability of the TG/HDL ratio (AUROC: 0.587) was superior to that of PChE levels (AUROC: 0.374). The AUROC of a new parameter resulting from the combination of the TG/HDL ratio with PChE levels showed a further increment in the discriminant power of the bladder cancer presence (0.6298), interestingly with a negative predictive value (89%) according to the Bayesian approach. The cut-off of the TG/HDL ratio, the main marker of the present study that better distinguishes bladder cancer from no bladder cancer patients, was 2.147. Discussion and Conclusions: The reliability of the TG/HDL ratio is based on the fact that this parameter likely mirrors the insulin resistance (IR) underlying bladder cancer patients. Furthermore, PChE levels evidence both IR and the associated non-alcoholic fatty liver disease. The TG/HDL ratio and PChE levels as well as their combined use could help physicians to assess/confirm the presence of this very common cancer, where early detection is important to ensure the best therapeutical approach. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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10 pages, 9442 KiB  
Article
N-OH-AABP Modifications in Human DNA May Lead to Auto-Antibodies in Bladder Cancer Subjects
Diagnostics 2022, 12(2), 337; https://doi.org/10.3390/diagnostics12020337 - 28 Jan 2022
Viewed by 1649
Abstract
4-Aminobiphenyl (4-ABP) and other related arylamines have emerged to be responsible for human urinary bladder tumors and cancers. Hemoglobin-ABP adducts have been recognized in the blood of smokers, and it builds up in the circulatory system over the period of years that might [...] Read more.
4-Aminobiphenyl (4-ABP) and other related arylamines have emerged to be responsible for human urinary bladder tumors and cancers. Hemoglobin-ABP adducts have been recognized in the blood of smokers, and it builds up in the circulatory system over the period of years that might lead to a bladder tumor. N-hydroxy-Acetyl 4-Aminobiphenyl (N-OH-AABP) is one of the reactive forms of 4-ABP which has a potential to initiate tumor growth and causes cancer rapidly. In the present study, commercially available human DNA was modified by N-OH-AABP, and its modifications were analyzed biophysically from fluorescence spectroscopy and thermal denaturation studies. Further, Sera and IgG from bladder cancer patients’ blood were assessed for affinity to native and N-OH-AABP modified human DNA using ELISA. The study showed N-OH-AABP caused damage in the structure of the DNA macromolecule and the perturbations resulting from damage leads to change in the Tm of the DNA molecule. Bladder cancer auto-antibodies, particularly in smoker group, showed preferential binding to N-OH-AABP modified human DNA. This study shows that N-OH-AABP modified DNA could be an antigenic stimulus for the generation of autoantibodies in the sera of bladder cancer patients. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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10 pages, 2317 KiB  
Article
One-Day Prostate Cancer Diagnosis: Biparametric Magnetic Resonance Imaging and Digital Pathology by Fluorescence Confocal Microscopy
Diagnostics 2022, 12(2), 277; https://doi.org/10.3390/diagnostics12020277 - 21 Jan 2022
Cited by 3 | Viewed by 1805
Abstract
In this prospective observational study, we tested the feasibility and efficacy of a novel one-day PCa diagnosis path based on biparametric magnetic resonance (bpMRI) and digital pathology by fluorescence confocal microscopy (FCM). Patients aged 55–70 years scheduled for PBx due to increased PSA [...] Read more.
In this prospective observational study, we tested the feasibility and efficacy of a novel one-day PCa diagnosis path based on biparametric magnetic resonance (bpMRI) and digital pathology by fluorescence confocal microscopy (FCM). Patients aged 55–70 years scheduled for PBx due to increased PSA levels (3–10 ng/mL) and/or abnormal digitorectal examination were enrolled. All patients underwent bpMRI and PBx with immediate FCM evaluation of biopsy cores. Patients were asked to fill out a dedicated Patient Satisfaction Questionnaire. Patients’ satisfaction rates and concordance between digital pathology and standard HE evaluation were the outcomes of interest. Twelve patients completed our one-day PCa diagnosis path. BpMRI showed suspicious lesions in 7 patients. Digital pathology by FCM identified PCa in 5 (41.7%) of the 12 patients. Standard pathology confirmed the diagnosis made through digital pathology in all the cases. At a per patient level, high concordance between the methods was achieved in Gleason Grading (4 out of 5 patients). The level of agreement in the number of positive cores was lower but did not affect the choice of treatment in any of the 5 PCa cases. At a per core level, the agreement was very high for the diagnosis of anyPCa (96.2%) and csPCa (97.3%), with a k coefficient of 0.90 and 0.92, respectively (near perfect agreement). In conclusion, one-day PCa diagnosis by FCM represents a feasible, reliable, and fast diagnostic method that provides significant advantages in optimizing time and resources, leading to patients having a higher quality standard of care perception. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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9 pages, 1038 KiB  
Article
Usefulness of Preoperative High Systemic Immune-Inflammation Index as a Prognostic Biomarker in Patients Who Undergo Radical Cystectomy for Bladder Cancer: Multicenter Analysis
Diagnostics 2021, 11(12), 2194; https://doi.org/10.3390/diagnostics11122194 - 25 Nov 2021
Cited by 7 | Viewed by 1250
Abstract
Evidence of the prognostic value of pretreatment systemic immune-inflammation index (SII) after radical cystectomy (RC) for bladder cancer is limited. This study aims to assess the association between preoperative SII and prognosis after RC for bladder cancer. In this multicenter retrospective study, we [...] Read more.
Evidence of the prognostic value of pretreatment systemic immune-inflammation index (SII) after radical cystectomy (RC) for bladder cancer is limited. This study aims to assess the association between preoperative SII and prognosis after RC for bladder cancer. In this multicenter retrospective study, we calculated preoperative SII as well as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in 237 patients who underwent RC for bladder cancer between March 2009 and March 2018. Patients were classified into high SII and low SII groups by using the optimal cutoff value (438 × 109/L) based on receiver operating characteristic curve analysis for cancer-specific death. We compared cancer-specific survival (CSS) and overall survival (OS) between the two groups. To evaluate the prognostic impact of preoperative SII, we also performed Cox proportional regression analyses for CSS and OS. Of 237 patients, 127 patients were classified into the high SII group and 110 patients into the low SII group. During the follow-up period, 70 patients died of bladder cancer (30%) and 21 patients died from other causes (9%). Patients with high SII had significantly lower rates of CSS and OS than those with low SII (p < 0.01 and p < 0.01, respectively). Multivariable Cox proportional hazard analysis showed that high SII was independently associated with poor CSS (p = 0.01) and poor OS (p < 0.01). In conclusion, high SII could be an independent significant predictor of poor prognosis after RC in patients with bladder cancer. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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10 pages, 1034 KiB  
Article
Mitofusin-2 Down-Regulation Predicts Progression of Non-Muscle Invasive Bladder Cancer
Diagnostics 2021, 11(8), 1500; https://doi.org/10.3390/diagnostics11081500 - 20 Aug 2021
Cited by 3 | Viewed by 1410
Abstract
Identification of markers predicting disease outcome is a major clinical issue for non-muscle invasive bladder cancer (NMIBC). The present study aimed to determine the role of the mitochondrial proteins Mitofusin-2 (Mfn2) and caseinolytic protease P (ClpP) in predicting the outcome of NMIBC. The [...] Read more.
Identification of markers predicting disease outcome is a major clinical issue for non-muscle invasive bladder cancer (NMIBC). The present study aimed to determine the role of the mitochondrial proteins Mitofusin-2 (Mfn2) and caseinolytic protease P (ClpP) in predicting the outcome of NMIBC. The study population consisted of patients scheduled for transurethral resection of bladder tumor upon the clinical diagnosis of bladder cancer (BC). Samples of the main bladder tumor and healthy-looking bladder wall from patients classified as NMIBC were tested for Mfn2 and ClpP. The expression levels of these proteins were correlated to disease recurrence, progression. Mfn2 and ClpP expression levels were significantly higher in lesional than in non-lesional tissue. Low-risk NMIBC had significantly higher Mfn2 expression levels and significantly lower ClpP expression levels than high-risk NMIBC; there were no differences in non-lesional levels of the two proteins. Lesional Mfn2 expression levels were significantly lower in patients who progressed whereas ClpP levels had no impact on any survival outcome. Multivariable analysis adjusting for the EORTC scores showed that Mfn2 downregulation was significantly associated with disease progression. In conclusion, Mfn2 and ClpP proteins were found to be overexpressed in BC as compared to non-lesional bladder tissue and Mfn2 expression predicted disease progression. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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11 pages, 548 KiB  
Systematic Review
The Role of Adjuvant Single Postoperative Instillation of Gemcitabine for Non-Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis
Diagnostics 2022, 12(5), 1154; https://doi.org/10.3390/diagnostics12051154 - 06 May 2022
Cited by 2 | Viewed by 1361
Abstract
Bladder cancer is a heterogeneous disease with variable natural history. Non-muscle-invasive bladder cancer has a favorable prognosis following transurethral resection, but the optimal adjuvant chemotherapy plan is still in debate. The aim of this study was to evaluate the effect of the adjuvant [...] Read more.
Bladder cancer is a heterogeneous disease with variable natural history. Non-muscle-invasive bladder cancer has a favorable prognosis following transurethral resection, but the optimal adjuvant chemotherapy plan is still in debate. The aim of this study was to evaluate the effect of the adjuvant intravesical administration of a single dose of gemcitabine in the outcome of this disease. For that purpose, we performed a systematic review and meta-analysis on available randomized control trials on MEDLINE, EMBASE, Cochrane, Scopus, and Google Scholar databases. Ultimately, two studies were included with a total number of 654 patients. The statistical analysis performed showed that a single post-operative intravesical dose of gemcitabine does not affect the recurrence rate of non-muscle-invasive bladder cancer compared to placebo. Therefore, this therapeutic strategy does not offer any significant improvement on the outcomes of the disease. Nonetheless, due to the plethora of available therapeutic agents and treatment strategies, further research is needed to establish the optimal treatment in this category of patients. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Advances in Bladder Cancer)
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