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Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy. Radioresistance remains a challenge in the treatment of bladder cancer. In this study, the authors show in mice that radiation increases deposits of neutrophil extracellular traps (NETs) via a TLR4-dependent mechanism and that NETs-targeting strategies can improve the response to radiotherapy.

Immune checkpoint inhibitors (ICIs) are commonly used to treat patients with advanced urothelial cancer. However, a significant number of patients do not respond to ICI, and the lack of validated predictive biomarkers impedes the success of the ICI strategy alone or in combination with chemotherapy or targeted therapies. In addition, some patients experience potentially severe adverse events with limited clinical benefit. Therefore, identifying biomarkers of response to ICI is crucial to guide treatment decisions. The most evaluated biomarkers to date are programmed death ligand 1 expression, microsatellite instability/defective mismatch repair phenotype, and tumor mutational burden. Other emerging biomarkers, such as circulating tumor DNA and microbiota, require evaluation in clinical trials. This review aims to examine these biomarkers for ICI response in urothelial cancer and assess their analytical and clinical validation.

Background There are no published studies on the simultaneous effect of extent and location of positive surgical margins (PSMs) on biochemical recurrence (BCR) after robot-assisted laparoscopic prostatectomy (RALP). The aim was to report the incidence, extent, and location of PSMs over the inclusion period as well as the rates of BCR and cancer-related mortality, and determine if BCR is associated with PSM extent and/or location. Methods Retrospective review of 530 consecutive patients who underwent RALP between 2003 and 2012. Kaplan-Meier (KM) survival analyses and Cox regressions were performed to determine variables associated with BCR. Results For the 530 operated patients, evaluated at a median of 92 months (IQR, 87–99), PSMs were observed in 156 (29%), of which 24% were focal. Out of 172 PSMs, 126 (73%) were focal and 46 (27%) were extensive. The KM survival using BCR as endpoint was 0.81 (CI, 0.78–0.85) at 5 years and was 0.67 (CI, 0.61–0.72) at 10 years; and using cancer-related mortality as endpoint was 0.99 (CI, 0.99–1.00) at 5 years and 0.95 (CI, 0.92–0.98) at 10 years. Multi-variable analysis revealed the strongest predictors of BCR to be Gleason score ≥ 8 (HR = 7.97; CI, 4.38–14.51) and 4 + 3 (HR = 3.88; CI, 2.12–7.07), lymph nodes invasion (HR = 3.42; CI, 1.70–6.91), pT stage 3b or 4 (HR = 3.07; CI, 1.93–4.90), and extensive apical PSMs (HR = 2.62; CI, 1.40–4.90) but not focal apical PSMs (HR = 0.86; CI, 0.49–1.50; p  = 0.586). Conclusion Extensive apical PSMs significantly increased the risk of BCR, independently from pT stage, Gleason score and lymph nodes invasion, while focal apical PSMs had no significant effect on BCR.

PurposeRadiotherapy (RT), as part of trimodal therapy, is an attractive alternative treatment in patients with urothelial muscle-invasive bladder cancer (MIBC). There is accumulating evidence suggesting the immunomodulatory effects of RT and its potential synergy when combined with immunotherapy. The aim of this review was to report on the most recent advances on this combination, including the mechanisms of RT immunomodulation, practical approach to combining RT and immunotherapy, and ongoing clinical trials in bladder cancer.MethodsUsing the PubMed database, we identified articles published between March 2004 and April 2020 on the combination of RT with immunotherapy in localized or metastatic MIBC. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu/ retrieved ongoing clinical trials on the topic as well.ResultsCombination of RT with immunotherapy leads to immunogenic cell death and an increase in immune markers thus leading to improved tumor control. For localized MIBC, there are safety concerns related to the use of concurrent immunotherapy with hypofractionated RT, thus neoadjuvant or adjuvant immunotherapy is preferred. In the metastatic setting, the combination of multi-site RT with SBRT-like doses (≥ 6 Gy per fraction) and concurrent immunotherapy seems most efficacious at harnessing the abscopal effect. At least 25 clinical trials combining immunotherapy and RT in MIBC are currently ongoing and will answer pending questions on safety, efficacy, and practical considerations on RT scheduling, fractionation, and targets volumes.ConclusionRT has the potential to synergize with immunotherapy to improve oncological outcomes in patient with localized or metastatic MIBC. Clinical trials results are eagerly awaited.

Background: The Vesical Imaging-Reporting and Data System (VI-RADS) score is a novel standardized approach to image and report bladder cancer (BC) with multiparametric MRI (mpMRI). Objectives: To describe and evaluate the performance of the VI-RADS score using mpMRI and assess its potential clinical applications and limitations. Methods: A systematic review was conducted using the MEDLINE and EMBASE electronic bibliographic databases between June 2020 and December 2020. All reports deemed relevant to describe the VI-RADS score and assess its performance and applications were retrieved. Results presentation stands as narrative, purely descriptive synthesis based on aggregate studies data. Results: A total of 20 relevant studies were retrieved: three meta-analyses, five prospective studies, and twelve retrospective studies. The retrospective studies covered 1676 patients, while the prospective studies included a total number of 468 patients. Pooled sensitivity, specificity to differentiate muscle-invasive from non-muscle-invasive bladder cancer, ranged from 74.1% to 97.3%, and 77% to 100%, respectively. The chosen VI-RADS score thresholds for this discrimination varied across studies. The interreader agreement ranged from 0.73 to 0.95. Currently, the potential clinical applications of VI-RADS consist of initial BC risk stratification, assessment of neoadjuvant therapies response, and bladder sparing approaches, although further validation is required. Conclusions: The VI-RADS score helps to discriminate muscle invasive from non-muscle invasive BC with good performance and reproducibility. A simple algorithm based on four basic questions may enhance its popularization. Further studies are required to validate the clinical applications.

Background: In an era of Bacillus of Calmette-Guérin (BCG) shortages, the comparative efficacy from different adjuvant intravesical BCG strains in non-muscle invasive bladder cancer (NMIBC) has not been clearly elucidated. We aim to compare, through a systematic review and meta-analysis, the cumulative BC recurrence rates and the best efficacy profile of worldwide available BCG strains over the last forty years. Methods: PubMed, Scopus, Web of Science, Embase, and Cochrane databases were searched from 1982 up to 2022. A meta-analysis of pooled BC recurrence rates was stratified for studies with ≤3-y vs. >3-y recurrence-free survival (RFS) endpoints and the strain of BCG. Sensitivity analysis, sub-group analysis, and meta-regression were implemented to investigate the contribution of moderators to heterogeneity. A random-effect network meta-analysis was performed to compare BCG strains on a multi-treatment level. Results: In total, n = 62 series with n = 15,412 patients in n = 100 study arms and n = 10 different BCG strains were reviewed. BCG Tokyo 172 exhibited the lowest pooled BC recurrence rate among studies with ≤3-y RFS (0.22 (95%CI 0.16–0.28). No clinically relevant difference was noted among strains at >3-y RFS outcomes. Sub-group and meta-regression analyses highlighted the influence of NMIBC risk-group classification and previous intravesical treated categories. Out of the n = 11 studies with n = 7 BCG strains included in the network, BCG RIVM, Tice, and Tokyo 172 presented with the best-predicted probability for efficacy, yet no single strain was significantly superior to another in preventing BC recurrence risk. Conclusion: We did not identify a BCG stain providing a clinically significant lower BC recurrence rate. While these findings might discourage investment in future head-to-head randomized comparison, we were, however, able to highlight some potential enhanced benefits from the genetically different BCG RIVM, Tice, and Tokyo 172. This evidence would support the use of such strains for future BCG trials in NMIBCs.

Background: We aimed to provide a comprehensive literature review on the best practice management of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) using neoadjuvant chemotherapy (NAC). Method: Between July and September 2018, we conducted a systematic review using MEDLINE and EMBASE electronic bibliographic databases. The search strategy included the following terms: Neoadjuvant Therapy and Urinary Bladder Neoplasms. Results: There is no benefit of a single-agent platinum-based chemotherapy. Platinum-based NAC is the gold standard therapy and mainly consists of a combination of cisplatin, vinblastine, methotrexate, doxorubicin, gemcitabine or even epirubicin (MVAC). At 5 years, the absolute overall survival benefit of MVAC was 5% and the absolute disease-free survival was improved by 9%. This effect was observed independently of the type of local treatment and did not vary between subgroups of patients. Moreover, a ypT0 stage (complete pathological response) after radical cystectomy was a surrogate marker for improved oncological outcomes. High-density MVAC has been shown to decrease toxicity (with a grade 3–4 toxicity ranging from 0% to 26%) without impacting oncological outcomes. To date, there is no role for carboplatin administration in the neoadjuvant setting in patients that are unfit for cisplatin-based NAC administration. So far, there is no published trial evaluating the role of immunotherapy in a neoadjuvant setting, but many promising studies are ongoing. Conclusion: There is a strong level of evidence supporting the clinical use of a high-dose-intensity combination of methotrexate, vinblastine, doxorubicin and cisplatin in a neoadjuvant setting. The landscape of MIBC therapies should evolve in the near future with emerging immunotherapies.

Following publication of the original article [1], we have been notified that the authors' last names have been incorrectly tagged as first names and vice-versa. The original publication has been corrected.

Nonmuscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. It is common and costly. Cost and detriment to patient outcomes and quality of life are driven by high recurrence rates and the need for regular invasive surveillance and repeat treatments. There is evidence that the quality of the initial surgical procedure (transurethral resection of bladder tumor [TURBT]) and administration of postoperative bladder chemotherapy significantly reduce cancer recurrence rates and improve outcomes (cancer progression and mortality). There is surgeon-reported evidence that TURBT practice varies significantly across surgeons and sites. There is limited evidence from clinical trials of intravesical chemotherapy that NMIBC recurrence rate varies significantly between sites and that this cannot be accounted for by differences in patient, tumor, or adjuvant treatment factors, suggesting that how the surgery is performed may be a reason for the variation. This study primarily aims to determine if feedback on and education about surgical quality indicators can improve performance and secondarily if this can reduce cancer recurrence rates. Planned secondary analyses aim to determine what surgeon, operative, perioperative, institutional, and patient factors are associated with better achievement of TURBT quality indicators and NMIBC recurrence rates. This is an observational, international, multicenter study with an embedded cluster randomized trial of audit, feedback, and education. Sites will be included if they perform TURBT for NMIBC. The study has four phases: (1) site registration and usual practice survey; (2) retrospective audit; (3) randomization to audit, feedback, and education intervention or to no intervention; and (4) prospective audit. Local and national ethical and institutional approvals or exemptions will be obtained at each participating site. The study has 4 coprimary outcomes, which are 4 evidence-based TURBT quality indicators: a surgical performance factor (detrusor muscle resection); an adjuvant treatment factor (intravesical chemotherapy administration); and 2 documentation factors (resection completeness and tumor features). A key secondary outcome is the early cancer recurrence rate. The intervention is a web-based surgical performance feedback dashboard with educational and practical resources for TURBT quality improvement. It will include anonymous site and surgeon-level peer comparison, a performance summary, and targets. The coprimary outcomes will be analyzed at the site level while recurrence rate will be analyzed at the patient level. The study was funded in October 2020 and began data collection in April 2021. As of January 2023, there were 220 hospitals participating and over 15,000 patient records. Projected data collection end date is June 30, 2023. This study aims to use a distributed collaborative model to deliver a site-level web-based performance feedback intervention to improve the quality of endoscopic bladder cancer surgery. The study is funded and projects to complete data collection in June 2023. ClinicalTrials.org NCT05154084; https://clinicaltrials.gov/ct2/show/NCT05154084. DERR1-10.2196/42254.

Background To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC). Materials and Methods We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFR < 60 mL/minute per 1.73 m2. Results Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (P = .052). The concordance between calculated eGFR formulas was rated substantial (Cohen’s kappa (k): 0.66-0.95). Among the subgroup (n = 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60 mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59 mL/minute exhibited a measured CrCI ≥ 60 mL/minute. Conclusions Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59 mL/minute. This study examined the agreement of different calculated estimated glomerular filtration rate formulas and measured creatinine clearance at the primary diagnosis of muscle-invasive bladder cancer. Graphical Abstract Graphical Abstract