Role of Chromatin Modifying Complexes and Therapeutic Opportunities in Bladder Cancer
Abstract:
BACKGROUND: Chromatin modifying enzymes, mainly through post translational modifications, regulate chromatin architecture and by extension the underlying transcriptional kinetics in normal and malignant cells. Muscle invasive bladder cancer (MIBC) has a high frequency of alterations in chromatin modifiers, with 76% of tumors exhibiting mutation in at least one chromatin modifying enzyme [1]. Additionally, clonal expansion of cells with inactivating mutations in chromatin modifiers has been identified in the normal urothelium, pointing to a currently unknown role of these proteins in normal bladder homeostasis.
OBJECTIVE: To review current knowledge of chromatin modifications and enzymes regulating these processes in Bladder cancer (BCa).
METHODS: By reviewing current literature, we summarize our present knowledge of external stimuli that trigger loss of equilibrium in the chromatin accessibility landscape and emerging therapeutic interventions for targeting these processes.
RESULTS: Genetic lesions in BCa lead to altered function of chromatin modifying enzymes, resulting in coordinated dysregulation of epigenetic processes with disease progression.
CONCLUSION: Mutations in chromatin modifying enzymes are wide-spread in BCa and several promising therapeutic targets for modulating activity of these genes are currently in clinical trials. Further research into understanding how the epigenetic landscape evolves as the disease progresses, could help identify patients who might benefit the most from these targeted therapies.
Reduced Dose Intravesical Bacillus Calmette-Guérin: Why It Might Not Matter
ABSTRACT:
When it comes to the treatment of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical bacillus Calmette-Guérin (BCG), two questions must be considered: 1) what dose to give, and 2) for how long? The issue of optimal dose and duration has been the subject of several randomized trials and is especially pertinent in the context of a global BCG shortage. Despite this, there appears to be uncertainty as to whether BCG dose or duration may be compromised in the event of shortage. As such, we wish to summarize the available evidence as an aid to the practicing urologist.
Head-to-Head Comparison between High-Resolution Microultrasound Imaging and Multiparametric MRI in Detecting and Local Staging of Bladder Cancer: The BUS-MISS Protocol
Abstract:
BACKGROUND: MRI has been proposed as a new staging tool for bladder cancer (BC), but use is limited by its high costs and low availability. 29-MHz high-resolution micro-ultrasound (mUS) technology has been suggested as an alternative to detect BC and distinguish between muscle-invasive and non-muscle invasive BC.
OBJECTIVE: The aim was to compare the diagnostic accuracy of mUS vs. magnetic resonance imaging (MRI) in differentiating NMIBC and MIBC at definitive pathological examination.
METHODS: This is a prospective study of patients with a primary diagnosis of BC with either positive urine cytology (UC) or negative UC and a tumor size > 25 mm from a tertiary care high volume center. mUS, with the ExactVu system with an EV29L 29 MHz side-fire transducer, and a 3-Tesla MRI were performed before transurethral resection of bladder tumor (TURBT) in every patient before undergoing TURBT. We compared the imaging results with pathological reports.
RESULTS: The analyzed population consisted of 58 individuals. The reported mUS and MRI sensitivity, specificity, positive, and negative predictive values were 85.0%, 76.3%, 65.4%, and 90.6%, versus 85.0%, 50.0%, 47.2%, and 86.4%, respectively. In accuracy analysis, the AUC for mUS and MRI were respectively 0.807 and 0.675.
CONCLUSIONS: In our population mUS seems to have a better performance in distinguishing NMIBC from MIBC. The main limitation of mUS is the probe shape that makes its use problematic in cases with a large prostate and inadequate rectal preparation. Further studies with a larger population are ongoing to compare and validate these techniques in this setting.
Association between Smoking and Overall and Specific Mortality in Patients with Bladder Cancer: A Population-based Study
Abstract:
BACKGROUND: The role of smoking in the prognosis of bladder cancer may significantly impact clinical management. It is also a considerable burden to Taiwan’s economy and health of its citizens.
OBJECTIVE: To search Taiwan’s National Health Insurance Research Database to determine whether smoking affected overall and cancer-specific mortality of patients with bladder cancer.
METHODS: We collected data on basic information, tumor stage, and comorbidities. Each smoking case was propensity score-matched by age, sex, and diagnosis year to one control individual among bladder cancer patients. The study comprised a never-smoke and an ever-smoke group, with each group including 4,728 patients after matching. We evaluated the association between smoking and mortalities in patients with bladder cancer. Cox proportional regression modeling was used to estimate hazard ratios (HRs) of overall and cancer-specific mortality rates. Stratified analysis was also performed to estimate risk ratios of overall and cancer-specific mortalities in bladder cancer patients with and without a history of smoking history among different subgroups.
RESULTS: The overall and specific mortality ratio of patients who were ever smokers were 1.15-fold and 1.16-fold, respectively, compared with those of never smokers (overall: 95% confidence interval [CI], 1.06–1.26, P = 0.0014; specific: 95% CI, 1.03–1. 03, P = 0.0176). Patients with bladder cancer who smoked and had significantly higher overall and specific mortality rates were those with Charlson Comorbidity Index (CCI)≥3 (overall: P = 0.0119; specific: P = 0.0092), diabetes mellitus (DM; overall: P = 0.0046; specific: P = 0.0419), and non-muscle-invasive bladder cancer (NMIBC; overall: P = 0.0038; specific: P = 0.0014).
CONCLUSIONS: Overall and specific mortality rates were significantly higher in the ever-smoke group than in the never-smoke group. The ever-smoke group with male sex, CCI≥3, DM, and NMIBC had increased risks for overall and specific mortality.
Association between Smoking and Overall and Specific Mortality in Patients with Bladder Cancer: A Population-based Study
Abstract:
BACKGROUND: The role of smoking in the prognosis of bladder cancer may significantly impact clinical management. It is also a considerable burden to Taiwan’s economy and health of its citizens.
OBJECTIVE: To search Taiwan’s National Health Insurance Research Database to determine whether smoking affected overall and cancer-specific mortality of patients with bladder cancer.
METHODS: We collected data on basic information, tumor stage, and comorbidities. Each smoking case was propensity score-matched by age, sex, and diagnosis year to one control individual among bladder cancer patients. The study comprised a never-smoke and an ever-smoke group, with each group including 4,728 patients after matching. We evaluated the association between smoking and mortalities in patients with bladder cancer. Cox proportional regression modeling was used to estimate hazard ratios (HRs) of overall and cancer-specific mortality rates. Stratified analysis was also performed to estimate risk ratios of overall and cancer-specific mortalities in bladder cancer patients with and without a history of smoking history among different subgroups.
RESULTS: The overall and specific mortality ratio of patients who were ever smokers were 1.15-fold and 1.16-fold, respectively, compared with those of never smokers (overall: 95% confidence interval [CI], 1.06–1.26, P = 0.0014; specific: 95% CI, 1.03–1. 03, P = 0.0176). Patients with bladder cancer who smoked and had significantly higher overall and specific mortality rates were those with Charlson Comorbidity Index (CCI)≥3 (overall: P = 0.0119; specific: P = 0.0092), diabetes mellitus (DM; overall: P = 0.0046; specific: P = 0.0419), and non-muscle-invasive bladder cancer (NMIBC; overall: P = 0.0038; specific: P = 0.0014).
CONCLUSIONS: Overall and specific mortality rates were significantly higher in the ever-smoke group than in the never-smoke group. The ever-smoke group with male sex, CCI≥3, DM, and NMIBC had increased risks for overall and specific mortality.
The Impact of the COVID-19 Pandemic on Bladder Cancer Care in the Netherlands
Abstract:
BACKGROUND: The COVID-19 pandemic has disrupted regular health care with potential consequences for non-COVID diseases like cancer. To ensure continuity of oncological care, guidelines were temporarily adapted.
OBJECTIVE: To evaluate the impact of the COVID-19 outbreak on bladder cancer care in the Netherlands.
METHODS: The number of bladder cancer (BC) diagnoses per month during 2020-2021 was compared to 2018-2019 based on preliminary data from the Netherlands Cancer Registry (NCR). Additionally, detailed data were retrieved from the NCR for the cohort diagnosed between March 1st-May 31st 2020 (first COVID wave) and 2018-2019 (reference cohort). BC diagnoses, changes in age and stage at diagnosis, and time to first-line treatment were compared between both periods. Changes in treatment were evaluated using logistic regression.
RESULTS: During the first COVID wave (week 9–22), the number of BC diagnoses decreased by 14%, corresponding with approximately 300 diagnoses, but increased again in the second half of 2020. The decline was most pronounced from week 13 onwards in patients≥70 years and patients with non-muscle invasive BC. Patients with muscle-invasive disease were less likely to undergo a radical cystectomy (RC) in week 17–22 (OR = 0.62, 95% CI = 0.40–0.97). Shortly after the start of the outbreak, use of neoadjuvant chemotherapy decreased from 34% to 25% but this (non-significant) effect disappeared at the end of April. During the first wave, 5% more RCs were performed compared to previous years. Time from diagnosis to RC became 6 days shorter. Overall, a 7% reduction in RCs was observed in 2020.
CONCLUSIONS: The number of BC diagnoses decreased steeply by 14% during the first COVID wave but increased again to pre-COVID levels by the end of 2020 (i.e. 600 diagnoses/month). Treatment-related changes remained limited and followed the adapted guidelines. Surgical volume was not compromised during the first wave. Altogether, the impact of the first COVID-19 outbreak on bladder cancer care in the Netherlands appears to be less pronounced than was reported for other solid tumors, both in the Netherlands and abroad. However, its impact on bladder cancer stage shift and long-term outcomes, as well as later pandemic waves remain so far unexamined.
Comorbidity Scores and Machine Learning Methods Can Improve Risk Assessment in Radical Cystectomy for Bladder Cancer
Abstract:
BACKGROUND: Pre-operative risk assessment in radical cystectomy (RC) is an ongoing challenge especially in elderly patients.
OBJECTIVE: To evaluate the ability of comorbidity indices and their combination with clinical parameters in machine learning models to predict mortality and morbidity after RC.
METHODS: In 392 patients who underwent open RC, complication and mortality rates were reported. The predictive values of the age-adjusted Charlson Comorbidity index (aCCI), the Elixhauser Index (EI), the Physical Status Classification System (ASA) and Gagne’s combined comorbidity Index (GCI) were evaluated using regression analyses. Various machine learning models (Gaussian naïve bayes, logistic regression, neural net, decision tree, random forest) were additionally investigated.
RESULTS: The aCCI, ASA and GCI showed significant results for the prediction of complications (χ2 = 8.8, p < 0.01, χ2 = 15.7, p < 0.01 and χ2 = 4.6, p = 0.03) and mortality (χ2 = 21.1, p < 0.01, χ2 = 25.8, p < 0.01 and χ2 = 2.4, p = 0.04) after RC while the EI showed no significant prediction. However, areas under receiver characteristic curves (AUROCs) revealed good performance only for the prediction of mortality by the aCCI and ASA (0.81 and 0.78, CGI 0.63) while the prediction of complications was poor (aCCI 0.6, ASA 0.63, CGI 0.58). The combination of ASA, age, body mass index and sex in machine learning models showed a better prediction. Gaussian naïve bayes (0.79) and logistic regression (0.76) showed the best performance using a hold-out test set.
CONCLUSIONS: The ASA and aCCI show good prediction of mortality after RC but fail predicting complications accurately. Here, the combination of comorbidity indices and clinical parameters in machine learning models seems promising.
A New Functional Gene, Zinc Finger Protein 485 (ZNF485), is Involved in Bladder Cancer Proliferation
Abstract:
BACKGROUND: Bladder cancer is the second most common urological cancer worldwide, with low early diagnosis and high mortality. The limited progress in diagnostics and treatment greatly impedes the survival of bladder cancer patients.
OBJECTIVE: Potential therapeutic biomarkers are urgently needed for future clinical treatment.
METHODS: We analyzed the sequencing data and corresponding clinicopathological features and survival information of bladder cancer patients in the TCGA database and identified a new zinc finger protein 485 gene, termed ZNF485, which is highly expressed in the tissues of bladder cancer patients and was verified in cells, animal models and tissue microarrays.
RESULTS: We found that inhibition of ZNF485 in the bladder cancer cell lines T24 and 5637 obviously inhibited proliferation and promoted the apoptosis of cancer cells. Furthermore, wound healing and invasion assays showed that downregulation of ZNF485 significantly decreased the mobility and invasion of T24 and 5637 cells. In addition, ZNF485-shRNA transfection obviously inhibited tumor growth in nude mice. Immunohistochemical results of clinical samples showed that the expression level of ZNF485 protein in cancer tissues was higher than that in adjacent tissues. Mechanistic analysis identified possible downstream target genes.
CONCLUSIONS: Taken together, the results provide evidence that ZNF485 is involved in bladder cancer proliferation and might be a potential therapeutic biomarker for the treatment of this disease
A Phase 2 Study of S-588410 Maintenance Monotherapy for Platinum-Treated Advanced or Metastatic Urothelial Carcinoma
Abstract:
BACKGROUND: Effective maintenance therapy for urothelial carcinoma (UC) is needed to delay progression after first-line chemotherapy.
OBJECTIVE: To evaluate S-588410, a cancer peptide vaccine containing five human leukocyte antigen (HLA)-A*24:02-restricted epitope peptides derived from five cancer-testis antigens (DEPDC1, MPHOSPH1, URLC10, CDCA1, and KOC1) in chemotherapy-treated, clinically stable patients with advanced or metastatic UC.
MATERIALS AND METHODS: This open-label, international, phase 2 trial enrolled patients with UC who had completed≥4 cycles of first-line platinum-containing chemotherapy without disease progression. Forty-five HLA-A*24:02-positive patients received subcutaneous injections of S-588410 (Montanide ISA 51 VG with 1 mg/mL of each peptide) weekly for 12 weeks then once every 2 weeks thereafter for up to 24 months. Thirty-six HLA-A*24:02-negative patients did not receive S-588410 (observation group). The primary endpoint was the rate of cytotoxic T-lymphocyte (CTL) induction against≥1 of the peptides at 12 weeks.
RESULTS: The CTL induction rate in the S-588410 group was 93.3% (p < 0.0001, one-sided binomial test with a rate of≤50% as the null hypothesis). The antitumor response rate was 8.9% in the S-588410 group and 0% in the observation group; median progression-free survival was 18.1 versus 12.5 weeks and median overall survival was 71.0 versus 99.0 weeks, respectively. The most frequent treatment-emergent adverse event was injection-site reactions (47 events, grades 1–3) reported in 93.3% (n = 42/45) of participants.
CONCLUSIONS: S-588410 demonstrated a high CTL induction rate, acceptable safety profile, and modest clinical response, as maintenance therapy in participants with advanced or metastatic UC who had received first-line platinum-based chemotherapy (EudraCT 2013-005274-22).
Efficacy of Surgery on the Primary Tumour in Patients with Metastatic Bladder Cancer: A Comprehensive Review
Abstract:
BACKGROUND: The benefit of surgery of the primary tumor in metastatic bladder cancer is unknown.
OBJECTIVE: Perform a comprehensive contemporary literature review on the benefit of surgery of the primary tumor in metastatic bladder cancer.
METHODS: Ovid MEDLINE, Ovid EMBASE, and Cochrane Library from January 1, 1990 to April 20, 2020 were queried for relevant articles published in English. Each article was evaluated by at least two content experts prior to inclusion which were blinded to the other’s evaluation. A third content expert was used when there was not a unanimous decision. Additional articles were added at the discretion of the authors.
RESULTS: Long-term survival is possible in patients with initially unresectable and/or limited metastatic disease. Multi-modal therapy with chemotherapy and surgery have the most favorable outcomes when compared to single treatment modalities in selected populations. Patients who demonstrate a robust response to pre-surgical therapy are likely to benefit the most from consolidative surgery. Patients with distant metastatic disease may benefit from consolidative surgery; however, this benefit may only be seen in those with metastatic disease limited to one site.
CONCLUSIONS: Surgery of the primary tumor in metastatic bladder cancer either in the setting of surgery alone, consolidative therapy or coupled with adjuvant therapy may be beneficial in well selected patients and should generally be limited to those who have a response to primary chemotherapy. Randomized clinical control trials are needed to further our understanding of the role of surgery in metastatic bladder cancer.
The Effect of Metformin on Bladder Cancer Incidence and Outcomes: A Systematic Review and Meta-Analysis
Abstract:
BACKGROUND: Effective oral treatment options for urothelial bladder cancer (BC) are lacking. Metformin, the most frequently used oral drug in type II diabetes mellitus, has putative anticancer properties and could, therefore, influence BC incidence and treatment outcomes. We systematically reviewed the current literature regarding the effect of metformin on BC incidence and oncological outcomes in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC).
METHODS: This review was conducted according to the PRISMA guidelines. Literature was gathered through a systematic search in PubMed/Medline, EMBASE and the Cochrane library. Risk of bias was determined using the Cochrane risk-of-bias tool for randomized trials and the Newcastle-Ottawa Scale for non-randomized trials. Hazard ratios (HRs) were extracted and pooled in a random-effects meta-analysis.
RESULTS: We reviewed 13 studies, including 3,315,320 patients, considering the risk of developing BC after metformin exposure and 9 studies, including 4,006 patients, on oncological outcomes of patients with BC. Metformin did not affect BC incidence (HR 0.97, 95% CI 0.87 –1.09) or oncological outcomes for NMIBC but did show a reduced risk of recurrence (HR 0.52, 95% CI 0.32 –0.84), cancer-specific mortality (HR 0.58, 95% CI 0.43 –0.78) and overall mortality (HR 0.66, 95% CI 0.47 –0.92) in MIBC.
CONCLUSIONS: The role of metformin in the prevention and treatment of BC in patients remains unclear. Although a beneficial effect of metformin on treatment outcomes of certain stages of BC may exist, a definitive conclusion cannot be drawn. Prospective clinical trials are needed to assess the efficacy of metformin for BC treatment.
