Bladder Cancer Journal Vol. 6 Issue 3
The Urinary Microbiome and Bladder Cancer: Susceptibility and Immune Responsiveness
ABSTRACT: Bladder cancer is a highly prevalent disease worldwide and is associated with a high mortality rate. Across all stages of bladder cancer, immunotherapy has now become the cornerstone of treatment. The commensal microbiome has become a major focus of research given its impact on numerous states of human health and disease. Many links between commensal microbes and immune function have been reported. Recently a commensal urinary microbiome has been identified and characterized in healthy individuals by several research groups. The urinary microbiome is now emerging as an important factor influencing bladder cancer development and therapeutic responsiveness. In this report, we identify findings from important clinical and mechanistic studies on the urinary microbiome and future opportunities to impact prevention and treatment of bladder cancer.
Review: Brain Metastases in Bladder Cancer
ABSTRACT: Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.
Mutations in Non-Tumoral Human Urothelium: Disease Prelude or Epilogue?
ABSTRACT: Bladder cancer is characterized by high rates of recurrence and multifocality, features which have commonly been associated with the colonization of widespread areas of non-neoplastic urothelium by mutant cells, a phenomenon known as field change. Whether mutant fields in the bladder arise from tumor cells or develop from the accumulation of somatic mutations followed by clonal expansions of non-transformed progenitor cells during lifetime remains unanswered. In this issue, Strandgaard et al. perform a deep-sequencing analysis of paired samples of tumor and histologically normal-appearing urothelium from four patients with advanced bladder cancer. By using a careful validation process, they report several mutations exclusive of normal, non-neoplastic tissue, suggesting that multiple fields precede (or develop independently from) the disease. Here, we discuss the main results from this work and elaborate on the biological implications and open questions in the context of normal somatic clonal evolution and cancer risk. We finish providing some general guidelines for future experiments to resolve the role of field changes in bladder carcinogenesis and its possible clinical relevance.
Mutational Analysis of Field Cancerization in Bladder Cancer
ABSTRACT
BACKGROUND:
Morphologically normal tissue, adjacent to tumors, contains multiple molecular changes, the so-called field cancerization. The multifocal and recurrent nature of bladder cancer has been hypothesized to originate from this. However, further studies are required to explore the mutational composition of normal tissue adjacent to tumors.
OBJECTIVE:
To analyze field cancerization in bladder cancer patients using a non-tumor guided approach.
METHODS:
We investigated the mutational landscape of normal appearing urothelium and paired bladder tumors from four patients by applying deep-targeted sequencing.
RESULTS:
Sequencing of 509 cancer driver genes revealed the presence of 2– 13 mutations exclusively localized in normal tissue (average target read depth 634×). Furthermore, 6– 13 mutations were shared between tumor and normal samples and 8– 75 mutations were exclusively detected in tumor samples. More mutations were observed in normal samples from patients with multifocal disease compared to patients with unifocal disease. Mutations in normal samples had lower variant allele fractions (VAF) compared to tumor mutations (p < 2.2*10–16). Furthermore, significant differences in the type of nucleotide changes between tumor, normal and shared mutations (p = 2.2*10–5) were observed, and mutations in APOBEC context were observed primarily among tumor mutations (p = 0.02). No differences in functional impact between normal, shared and tumor mutations were observed (p = 0.61).
CONCLUSION:
Overall, these findings support the presence of more than one field in the bladder, and document non-tumor specific driver mutations to be present in normal appearing bladder tissue.
ABSTRACT
PURPOSE:
Data have indicated that residual disease after neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) may be associated with poor outcomes.
OBJECTIVE:
Analyze differences in overall survival (OS) of patients with residual MIBC treated with NAC + Radical cystectomy (RC), RC alone, or RC + Adjuvant Chemotherapy(AC).
MATERIALS AND METHODS:
The National Cancer Database was queried for patients who underwent RC alone, NAC + RC, or RC + AC for MIBC stage cT2-4aN0M0 from 2004-2015. Covariates were balanced using propensity score (PS) weighting. Time to death was evaluated from diagnosis. Weighted cox proportional hazards models and Kaplan-Meier survival curves were created to analyze differences in OS.
RESULTS:
8,288 patients were included for analysis, 1,899 (23%) received NAC + RC, 5,529 (67%) received RC alone, and 860 (10%) received RC + AC. Patients were sub-stratified based on pathological staging (≤pT2 or >pT2) and compared against treatment with RC alone. In the ≤pT2 cohort, NAC + RC was associated with a decreased risk of death (HR:0.85, 95% CI:0.79–0.91) and RC + AC was associated with an increased risk of death (HR:1.46, 95% CI:1.34–1.60, both p < 0.001) compared to RC alone. In the >pT2 cohort, these associations reversed, with an increased risk of death seen in the NAC + RC group (HR:1.11, 95% CI:1.05–1.18) and a decreased risk of death in the RC + AC group (HR:0.74, 95% CI:0.7–0.77, both p < 0.001).
CONCLUSIONS:
Patients with >ypT2 disease after NAC experienced a significant increased risk of death when compared to pathological stage-matched patients who underwent RC alone or RC + AC. Biomarkers predictive of NAC resistance may be important to optimize NAC usage and establish treatment algorithms.
Recurrence in Non-Muscle Invasive Bladder Cancer Patients: External Validation of the EORTC, CUETO and EAU Risk Tables and Towards a Non-Linear Survival Model
ABSTRACT
BACKGROUND:
EORTC, CUETO and EAU are the most commonly used risk stratification models for recurrence and progression in non-muscle invasive bladder cancer (NMIBC).
OBJECTIVE:
We assessed the predictive value of the EORTC, CUETO and EAU risk group stratification methods for our population and explore options to improve the predictive value using Cox Proportional Hazards (CPH), Boosted Cox regression and a non-linear Random Survival Forest (RSF) model.
MATERIALS:
Our retrospective database included of 452 NMIBC patients who underwent a transurethral resection of bladder tumor (TURBT) between 2000 and 2018 in our hospital. The cumulative incidence of recurrence was calculated at one- and five-years for all risk stratification methods. A customized CPH, Boosted Cox and RSF models were trained in order to predict recurrence, and the performances were compared.
RESULTS:
Risk stratification using the EORTC, CUETO and EAU showed small differences in recurrence probabilities between the risk groups as determined by the risk stratification. The concordance indices (C-index) were low and ranged between 0.51 and 0.57. The predictive accuracies of CPH, Boosted Cox and RSF models were also moderate, with C-indices ranging from 0.61 to 0.64.
CONCLUSIONS:
Prediction of recurrence in patients with NMIBC based on patient characteristics is difficult. Alternative (non-linear) approaches have the potential to improve the predictive value. Nonetheless, the currently used characteristics are unable to properly stratify between the recurrence risks of patients.
Establishment of Real-Time Multispectral Imaging for the Detection of Bladder Cancer Using a Preclinical in Vivo Model
ABSTRACT
BACKGROUND:
Emerging imaging technologies such as real-time multispectral imaging (rMSI) hold great potential for simultaneous visualization of multiple target structures using fluorophores on various tumours including bladder cancer (BC). These technologies, however, require a multi-step preclinical evaluation process, including mouse models.
OBJECTIVE:
To demonstrate the suitability of the new rMSI technology for the detection of premalignant lesions and malignant BC in a preclinical mouse model using contrast agents.
METHODS:
Tumours were induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), which is known to induce BC in rodent models. In total, 30 mice (C57BL/6) were fed with 0.1% BBN ad libitum in drinking water for up to 5 months. Bladders were excised at 3 (n = 6) and 5 months (n = 24) of treatment and incubated ex vivo with Hexaminolevulinat (HAL, Hexvix®), CD47-FITC, CD90.2-FITC or a combination of CD90.2-FITC/CD47-FITC and HAL. The bladders were analyzed by an endoscopic rMSI prototype system equipped with a spectral filter (Chroma), a 4 mm endoscope (Karl Storz) with 30° optic, a LED light source and a PC with a microcontroller board.
RESULTS:
5-month treatment of mice with 0.1% BBN led to the formation of squamous carcinoma (46%, n = 11) while urothelial carcinoma was observed only in one mouse (4%, n = 1). Carcinoma in situ (CIS) was detectable in twelve out of twenty-four mice (50%, n = 12) treated for 5 month and in three out of six mice (50%, n = 3) treated for 3 months.The metabolite of HAL, protoporphyrin IX (PpIX), could be reliably and specifically detected in all of mouse bladder tumours and CIS. However, detection of the CD90.2 surface marker was less reliable, potentially due to species- or tumour-subtype specificity.
CONCLUSIONS:
This model offers the potential for preclinical imaging studies with combined fluorescence targets, e.g. HAL, in combination with BC-specific antibodies.
Optimizing Sequence of PD-L1 Immune-Checkpoint Inhibitors and Radiation Therapy in Bladder Cancer
ABSTRACT
BACKGROUND:
New bladder preserving strategies are needed for muscle invasive bladder cancer (MIBC). Combined therapy of immune-checkpoint inhibitors and radiation was shown to have synergistic antitumoral effects in preclinical studies.
OBJECTIVES:
We aim to evaluate whether the sequence of administration of this combined therapy impacts antitumoral response.
METHODS:
We developed an in-vivo syngeneic MIBC mouse model where murine bladder cancer cells (MB49) were injected subcutaneously in the right flank of C57BL/6 mice. Mice were then randomized to the following treatments: control, anti-programmed cell death ligand 1 (PD-L1) alone, radiation alone (XRT) consisting of 6.25 Gy x2 fractions, concurrent anti-PD-L1 with XRT, neoadjuvant anti-PD-L1 followed by XRT, or XRT followed by adjuvant anti-PD-L1 therapy. Tumor growth, survival, and rate of response were analyzed.
RESULTS:
Total of 60 mice were randomized. One-way analysis of variance showed statistically significant difference in tumor growth rate across the treatment arms (p = 0.029). Importantly, timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) did not alter either tumor growth or survival (p > 0.05). The rate of response was also similar in each combination arm (p > 0.05).
CONCLUSION:
Combining anti-PD-L1 immunotherapy and radiation therapy offers optimal antitumoral responses. Timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) does not appear to affect outcomes. Whether the toxicity profile differs across various sequential deliveries of combination therapy requires further evaluation.
Evaluation of a Novel Cystoscopic Compatible Cryocatheter for the Treatment of Bladder Cancer
ABSTRACT
BACKGROUND:
As the acceptance of cryoablative therapies for the treatment of non-metastatic cancers continues to grow, avenues for novel cryosurgical technologies and approaches have opened. Within the field of genitourinary tumors, cryosurgical treatments of bladder cancers remain largely investigational. Current modalities employ percutaneous needles or transurethral cryoballoons or sprays, and while results have been promising, each technology is limited to specific types and stages of cancers.
OBJECTIVE:
This study evaluated a new, self-contained transurethral cryocatheter, FrostBite-BC, for its potential to treat bladder cancer.
METHODS:
Thermal characteristics and ablative capacity were assessed using calorimetry, isothermal analyses, in vitro 3-dimensional tissue engineered models (TEMs), and a pilot in vivo porcine study.
RESULTS:
Isotherm assessment revealed surface temperatures below – 20°C within 9 sec. In vitro TEMs studies demonstrated attainment of ≤– 20°C at 6.1 mm and 8.2 mm in diameter following single and double 2 min freezes, respectively. Fluorescent imaging 24 hr post-thaw revealed uniform, ablative volumes of 326.2 mm3 and 397.9 mm3 following a single or double 2 min freeze. In vivo results demonstrated the consistent generation of ablative areas. Lesion depth was found to correlate with freeze time wherein 15 sec freezes resulted in ablation confined to the sub-mucosa and ≥30 sec full thickness ablation of the bladder wall.
CONCLUSIONS:
These studies demonstrate the potential of the FrostBite-BC cryocatheter as a treatment option for bladder cancer. Although preliminary, the outcomes of these studies were encouraging, and support the continued investigation into the potential of the FrostBite-BC cryocatheter as a next generation, minimally invasive cryoablative technology.
Diagnostic Performance of Novel Urine-Based mRNA Tests (Xpert and Urinary Metabolomics Markers Assay) for Bladder Cancer Detection in Patients with Hematuria
ABSTRACT
BACKGROUND:
Hematuria is the most frequent presenting symptom in the vast majority of bladder cancer (BC) patients. The current recommended evaluation of hematuria includes cross sectional imaging and cystoscopy with possible high negative results, expensive costs and substantial patient burden.
OBJECTIVES:
To validate novel urine-based mRNA-dependant tests; Xpert test and urinary metabolomics assay (CRAT and SLC 25A20genes expression) for BC detection in patients with hematuria.
METHODS:
Patients presented with hematuria to our tertiary care hospital were evaluated by CT urogram and office white light cystoscopy with subsequent inpatient biopsy for positive findings. Voided precystoscopy urine samples were prospectively collected. Xpert test, assay of targeted urinary metabolomics and cytology, were performed. The tests characteristics presumably were calculated based on the ability to identify BC noninvasively.
RESULTS:
Between March 2018 and June 2019, 181 patients were included in the final analysis with mean (±SD) age 62 (±10) years with 168 (92.8%) males. Macroscopic hematuria was encountered in 153 (84.5%) patients with irritative bladder symptoms in 48 (26.5%) patients. BC was confirmed by cystoscopy/biopsy in 36 (19.9%) patients. The performance characteristics of Xpert alone (SN: 73%, SP: 83%, NPV: 92%, PPV: 52%) (AUC 0.84, 95% CI 0.75–0.93, p = 0.001), metabolomics assay alone (SN: 89%, SP: 93%, NPV: 97%, PPV: 78%) (AUC 0.91, 95% CI 0.85–0.98, p < 0.001) and combination of both test results (SN: 66%, SP: 98%, NPV: 92%, PPV: 97%) (AUC 0.83, 95% CI 0.74–0.93, p = 0.001) were notably superior to urine cytology (SN: 30%, SP: 84%, NPV: 83%, PPV: 33%) (AUC 0.58, 95% CI 0.47–0.69, p = 0.154) for BC prediction. Cystoscopy-negative patients (CNP) were followed-up for a median (range) 12 (2–19) months. Re-cystoscopy was done for 35 patients with persistent symptoms. BC was diagnosed in 6 patients. Xpert and urinary metabolomics results were observably positive in those 6 patients.
CONCLUSION:
Xpert test and assay of urinary metabolomics (CRAT and SLC 25A20 genes expression) have the potential for BC detection in hematuria patients. These non invasive urine based tests can help prioritization of the use of invasive diagnostic tests in systems with long waiting times.
Functional Outcomes After Robotic Radical Cystectomy with Intracorporeal Diversion: A Systematic Review
ABSTRACT
BACKGROUND:
Robotic assisted radical cystectomy (RARC) is considered a safe and feasible technique in patients with bladder cancer who are candidates for curative treatment. Intracorporeal urinary diversions (ICUD) represents one step forward into moving to an utterly minimal invasive procedure with the thought that it may improve patients outcomes and time to recovery after the surgical procedure. Overall, RARC has shown to provide similar oncological outcomes as other procedures. The impact of such approach in continence and sexual function of the patients is an important part of an integral health care of this subset of patients.
OBJECTIVE:
To describe the functional outcomes of RARC with ICUD across different manuscript evaluating this field.
METHODS:
A systematic literature search related to functional outcomes and diversion technique in RARC with ICUD, was performed on June 2019 using PubMed
RESULTS:
Out of 22 manuscripts evaluated we included 11 in our analysis. Although the functional outcomes in the studies we have included in this analysis seem to be adequate and consistent, the evidence is poor when comparing RARC with ICUD versus other approaches
CONCLUSION:
We consider that studies with better designs aiming to elucidate the impact of RARC with ICUD in the quality of life of the patients may improve the quality of the outcomes and would help to draw stronger conclusions
Radiomics and Bladder Cancer: Current Status
ABSTRACT
PURPOSE:
To systematically review the current literature and discuss the applications and limitations of radiomics and machine-learning augmented radiomics in the management of bladder cancer.
METHODS:
Pubmed ®, Scopus ®, and Web of Science ® databases were searched systematically for all full-text English-language articles assessing the impact of Artificial Intelligence OR Radiomics OR Machine Learning AND Bladder Cancer AND (staging OR grading OR prognosis) published up to January 2020.
RESULTS:
Of the 686 articles that were identified, 13 studies met the criteria for quantitative analysis. Staging, Grading and Tumor Classification, Prognosis, and Therapy Response were discussed in 7, 3, 2 and 7 studies, respectively. Data on cost of implementation were not reported. CT and MRI were the most common imaging approaches.
CONCLUSION:
Radiomics shows potential in bladder cancer detection, staging, grading, and response to therapy, thereby supporting the physician in personalizing patient management. Extension and validation of this promising technology in large multisite prospective trials is warranted to pave the way for its clinical translation.
Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada
ABSTRACT
BACKGROUND:
Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns.
OBJECTIVE:
To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer.
METHODS:
A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence.
RESULTS:
Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted.
CONCLUSIONS:
This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.
