Publications by authors named "Yair Lotan"

646 Publications

A Systematic Review and Meta-Analysis of Prognostic Nomograms After UTUC Surgery.

Front Oncol 2022 1;12:907975. Epub 2022 Jul 1.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: Current guidelines recommend assessing the prognosis in high-risk upper tract urothelial carcinoma patients (UTUC) after surgery. However, no specific method is endorsed. Among the various prognostic models, nomograms represent an easy and accurate tool to predict the individual probability for a specific event. Therefore, identifying the best-suited nomogram for each setting seems of great interest to the patient and provider.

Objectives: To identify, summarize and compare postoperative UTUC nomograms predicting oncologic outcomes. To estimate the overall performance of the nomograms and identify the most reliable predictors. To create a reference tool for postoperative UTUC nomograms, physicians can use in clinical practice.

Design: A systematic review was conducted following the recommendations of Cochrane's Prognosis Methods Group. Medline and EMBASE databases were searched for studies published before December 2021. Nomograms were grouped according to outcome measurements, the purpose of use, and inclusion and exclusion criteria. Random-effects meta-analyses were performed to estimate nomogram group performance and predictor reliability. Reference tables summarizing the nomograms' important characteristics were created.

Results: The systematic review identified 26 nomograms. Only four were externally validated. Study heterogeneity was significant, and the overall Risk of Bias (RoB) was high. Nomogram groups predicting overall survival (OS), recurrence-free survival (RFS), and intravesical recurrence (IVR) had moderate discrimination accuracy (c-Index summary estimate with 95% confidence interval [95% CI] and prediction interval [PI] > 0.6). Nomogram groups predicting cancer-specific survival (CSS) had good discrimination accuracy (c-Index summary estimate with 95% CI and PI > 0.7). Advanced pathological tumor stage (≥ pT3) was the most reliable predictor of OS. Pathological tumor stage (≥ pT2), age, and lymphovascular invasion (LVI) were the most reliable predictors of CSS. LVI was the most reliable predictor of RFS.

Conclusions: Despite a moderate to good discrimination accuracy, severe heterogeneity discourages the uninformed use of postoperative prognostic UTUC nomograms. For nomograms to become of value in a generalizable population, future research must invest in external validation and assessment of clinical utility. Meanwhile, this systematic review serves as a reference tool for physicians choosing nomograms based on individual needs.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=282596, identifier PROSPERO [CRD42021282596].
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http://dx.doi.org/10.3389/fonc.2022.907975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283688PMC
July 2022

Clinical validation of IsoPSA, a single parameter, structure-focused assay for improved detection of prostate cancer: A prospective, multicenter study.

Urol Oncol 2022 Jul 12. Epub 2022 Jul 12.

Cleveland Diagnostics, Inc., Cleveland, OH.

Background: IsoPSA is a blood-based test that assesses prostate cancer (CaP) risk by partitioning and detecting cancer-specific structural isoforms of prostate specific antigen (PSA) with an aqueous 2- phase system.

Objective: To validate the diagnostic performance of IsoPSA for High-Grade CaP and Any CaP risk on biopsy in men age ≥ 50 with total PSA ≥ 4 ng/ml.

Design, Setting, And Participants: Prospective, multicenter study of 888 men scheduled for prostate biopsy at 8 academic and community sites between August 2015 and August 2020.

Intervention: IsoPSA test.

Outcome Measurements And Statistical Analysis: Receiver operating characteristic and likelihood ratio analysis used to validate diagnostic performance for previously established IsoPSA Index cutoffs for High-Grade CaP (Gleason Score ≥ 7) and Any CaP (Gleason Score ≥ 6), compare IsoPSA to total PSA and % free PSA, and evaluate subgroups (total PSA 4-10 ng/ml, total PSA > 10 ng/ml, biopsy naïve, prior negative biopsy).

Results And Limitations: The disease prevalence was 35.6% (High-Grade CaP) and 58.9% (Any CaP). The area under the receiver operating characteristic curve was 0.783 (High-Grade CaP) and 0.770 (Any CaP). IsoPSA outperformed total PSA and % free PSA on area under the receiver operating characteristic curve, specificity, positive and negative predictive value at similar sensitivity. Using selected IsoPSA Index cutoffs, an estimated 46% (High-Grade CaP) and 42% (Any CaP) of biopsies could be avoided in low-risk patients. IsoPSA displayed statistically informative likelihood ratio-based predictive characteristics. IsoPSA maintained accuracy in clinically relevant subgroups.

Conclusions: IsoPSA diagnostic performance and predictive value is validated for High-Grade CaP and Any CaP in men age ≥ 50 with total PSA ≥ 4 ng/ml undergoing diagnostic biopsy. IsoPSA outperforms total and % free PSA in discriminating the risk of prostate cancer on biopsy.

Patient Summary: IsoPSA has the potential to reduce unnecessary biopsies and improve the risk-benefit ratio for CaP early detection.
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http://dx.doi.org/10.1016/j.urolonc.2022.06.002DOI Listing
July 2022

Safety of repeat blue light cystoscopy with hexaminolevulinate (HAL) in the management of bladder cancer: Results from a phase III, comparative, multi-center study.

Urol Oncol 2022 Aug 22;40(8):382.e1-382.e6. Epub 2022 Jun 22.

Department of Urology, University of Southern California, Los Angeles, CA.

Purpose: The therapeutic benefit of intravesical instillation of hexaminolevulinate (HAL) at the time of transurethral resection of bladder tumor (TURBT) has been demonstrated in multiple studies. The purpose of this study was to prospectively assess the safety of repeated administration of HAL from a phase III pre-trial planned analysis.

Materials And Methods: All patients evaluated in the study received at least 1 dose of HAL at the time of office cystoscopy, and a subset of these patients (n = 103, 33.2%) received a second dose a few weeks later at the time of TURBT. Adverse events (AEs) were recorded, and the safety of repeat use of HAL was determined by comparing the proportion of patients with AEs considered causally related to HAL in the surveillance examination compared to the OR examination. Association between categorical variables was tested using Fisher's Exact Test, and a P < 0.05 was considered statistically significant.

Results: HAL-related AEs were experienced by 6 patients (2.2%) during surveillance cystoscopy and 3 patients (3.4%) following TURBT (P = 0.76); 181 patients (59.5%) had prior exposure to HAL before enrolling in the study with no difference in the number of AEs when comparing prior exposure to HAL to no prior exposure (P = 0.76). Of the patients who previously received intravesical therapy, 8 (2.9%) had at least 1 AE during surveillance compared to 3 (9.7%) who had no prior intravesical therapy (P = 0.09).

Conclusions: Repeat use of HAL is safe even when administered within a few weeks of receiving a dose of intravesical therapy.
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http://dx.doi.org/10.1016/j.urolonc.2022.04.012DOI Listing
August 2022

Lipidomic Profiling Identifies a Novel Lipid Signature Associated with Ethnicity-Specific Disparity of Bladder Cancer.

Metabolites 2022 Jun 14;12(6). Epub 2022 Jun 14.

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Bladder Cancer (BLCA) is the ninth most frequently diagnosed cancer globally and the sixth most common cancer in the US. African Americans (AA) exhibit half the BLCA incidence compared to European Americans (EA), but they have a 70% higher risk of cancer-related death; unfortunately, this disparity in BLCA mortality remains poorly understood. In this study, we have used an ethnicity-balanced cohort for unbiased lipidomics profiling to study the changes in the lipid fingerprint for AA and EA BLCA tissues collected from similar geographical regions to determine a signature of ethnic-specific alterations. We identified 86 lipids significantly altered between self-reported AA and EA BLCA patients from Augusta University (AU) cohort. The majority of altered lipids belong to phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), ly sophosphatidylcholines (lysoPCs), phosphatidylserines (PSs), and diglycerides (DGs). Interestingly, levels of four lysoPCs (lyso PCs 20:3, lyso PCs 22:1, lyso PCs 22:2, and lyso PCs 26:1) were elevated while, in contrast, the majority of the PCs were reduced in AA BLCA. Significant alterations in long-chain monounsaturated (MonoUN) and polyunsaturated (PolyUN) lipids were also observed between AA and EA BLCA tumor tissues. These first-in-field results implicate ethnic-specific lipid alterations in BLCA.
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http://dx.doi.org/10.3390/metabo12060544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230655PMC
June 2022

Pathologic fracture in metastatic kidney cancer: Identifying widening disparities and opportunity for quality improvement.

Urol Oncol 2022 Aug 31;40(8):384.e1-384.e8. Epub 2022 May 31.

Department of Urology, UT Southwestern Medical Center, Dallas, TX.

Background: Management and palliation of pathologic fracture (PFx) secondary to metastatic prostate (mCaP) and renal cancer (mRCa) is hospital resource intensive. Using a national all-payer database, we assessed the burden of PFx secondary to mCaP and mRCa nationwide. Admission rates, mortality, surgical fixation rates, and risk factors for high-cost admissions for pathologic fractures were assessed METHODS: National Inpatient Sample was queried from 2013 to 2015 for mCaP and mRCa admissions. Hospitalization costs of PFx was assessed over time by cancer type. Hospitalization outcomes were stratified by cancer type. Multivariable logistic regression models were constructed to examine predictors of high-cost admission for PFx (>75th percentile).

Results: From 2013 to 2015, there were 21,466 and 6,334 admissions for mCaP and mRCa with bone metastasis, respectively. Proportion of admissions for PFx was greater in mRCa than mCaP (15.9% vs. 7.2%, P < 0.01). PFx secondary to mRCa was associated with longer length of stay, hospitalization cost, and greater rate of surgical fixation. Costs of admission for PFx increased by $4,005 dollars from 2013 to 2015 for mRCa (P = 0.03), but did not increase for mCaP (P = 0.5). On multivariable analysis, mRCa was associated with greater odds of PFx (OR:2.12, P < 0.01), and high-cost hospitalization for mRCa associated PFx (OR:1.37, P = 0.02).

Conclusions: PFx secondary to mRCa represents a significant health care burden. mRCa was associated with greater odds of PFx compared to mCaP, as well as greater inpatient morbidity and cost. Formalized guidelines on screening and management of bone lesions in mRCa may be needed to mitigate this under-recognized health care burden.
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http://dx.doi.org/10.1016/j.urolonc.2022.05.002DOI Listing
August 2022

Safety and Feasibility of Telehealth Only Preoperative Evaluation Before Minimally Invasive Robotic Urologic Surgery.

J Endourol 2022 Aug 5;36(8):1070-1076. Epub 2022 Jul 5.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Telehealth utilization has increased dramatically over the past few years due to improvement in technology and the COVID-19 pandemic. To date, no study has examined whether a telehealth visit alone for preoperative evaluation is safe and sufficient before surgery. We examined the safety and feasibility of preoperative telehealth visits alone before minimally invasive urologic surgery. Single institution retrospective review of robotic prostate, kidney, and cystectomy procedures between April and December 2020. Cases were dichotomized into those who underwent preoperative evaluation by telehealth only traditional in-person visits. Outcomes included complications, blood loss, conversion to open surgery rates, and operative times. We assessed efficiency of care by measuring time from preoperative visit to surgery. Three hundred fourteen patients were included in the study, with 14% of cases ( = 45) being performed after a preoperative telehealth visit. The majority of cases included in analysis were robotic surgeries of the prostate (56.1% of all cases,  = 176) and the kidney (35.0% of all cases,  = 110). Patients seen via telehealth alone preoperatively had no significant differences in any grade of complications, perioperative outcomes, blood loss, operative time, and length of stay. There was no difference in change in anticipated procedure between the groups, and there was no case of conversion to open surgery in the telehealth only group. Time from preoperative visit to surgery was significantly shorter for the telehealth group by 13 days. Our study is the first to analyze the safety of telehealth only preoperative visits before minimally invasive urologic surgery. We found no difference in perioperative outcomes including conversion to open surgery or change in planned procedure. Furthermore, telehealth preoperative visits appeared to facilitate shorter time to surgery. This study has important implications for expediting patient care and medicolegal considerations.
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http://dx.doi.org/10.1089/end.2021.0819DOI Listing
August 2022

The Search for the Optimal cut-off Value of p53-Immunohistochemistry to Predict Prognosis of Invasive Bladder Cancer: A Multi-Center, Multi-Laboratory Analysis.

Int J Surg Pathol 2022 Apr 24:10668969221095173. Epub 2022 Apr 24.

Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Mutations in the gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and mutation status. The Kaplan-Meier method was used to estimate DSS. Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.
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http://dx.doi.org/10.1177/10668969221095173DOI Listing
April 2022

Progress in the development of tissue-based biomarkers for urothelial cancer.

Expert Rev Anticancer Ther 2022 Jun 29;22(6):605-619. Epub 2022 Apr 29.

Department of Urology, University of Texas Southwestern, Dallas, Texas 75390.

Introduction: As the understanding of molecular mechanisms of bladder cancer advances, molecularly-guided precision medicine becomes increasingly relevant. Biomarkers play a critical role in this setting, predicting treatment response and identifying candidates for targeted therapies.

Areas Covered: Current literature on biomarkers in their role in disease prognosis and response to neoadjuvant and adjuvant therapies. In non-muscle invasive bladder cancer, particular focus is on markers of disease progression, and response to intravesical therapy. In muscle invasive and advanced bladder cancer, particular emphasis is on markers associated with neoadjuvant chemotherapy, as well as systemic immunotherapy. We discuss current shortcomings and pitfalls in contemporary markers, and future avenues of prospective research.

Expert Opinion: The focus on biomarkers has moved from immunohistochemical analysis and tumor-related phenotypic changes to examining genetic alterations. Single marker analysis has been shown to be insufficient in predicting both disease course and response to therapy, and studies have shifted toward examining marker combinations and genetic classifiers. Ultimately, significant progress in implementing biomarkers into clinical guidelines remains elusive, largely due to lack of prospective studies in well-defined patient cohorts and with clinically meaningful endpoints. Until then, despite their promising value, tissue markers should be limited to experimental settings and clinical trials.
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http://dx.doi.org/10.1080/14737140.2022.2070154DOI Listing
June 2022

Predictive factors of diagnostic delay and effect on treatment patterns in testicular germ cell tumor patients.

Urol Oncol 2022 05 7;40(5):201.e1-201.e7. Epub 2022 Apr 7.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address:

Background: Increased time from clinical symptom onset to diagnosis of testicular germ cell tumor (GCT), termed diagnostic delay (DD), is associated with an increased likelihood of metastatic disease at presentation. We assessed the association of patient factors on DD and subsequent treatment patterns.

Methods: The records for patients undergoing orchiectomy at a tertiary care hospital and safety net county hospital between 2006 and 2018 were obtained. Demographic variables, clinical symptoms, and post-diagnosis parameters were queried. Patient factors were assessed for association with DD by using both univariate and multivariable analyses. The effect of the Patient Protection and Affordable Care Act (PPACA) on DD was also studied.

Results: 201 patients received orchiectomy, and median DD was 38 days (IQR 14.5-122.5). Patients with metastatic disease had increased DD compared to those with localized disease (76 vs. 31 days, P < 0.001). Increased DD was associated with presentation to the safety net hospital (P = 0.001), non-white (P = 0.025), emergency department presentation (P = 0.025), uninsured (P = 0.01), testicular pain (P = 0.019), and presentation before 2014 (P = 0.047). DD was independently associated with presentation before 2014 (P = 0.004) on multivariate analysis. DD >38 days (i.e., above the median) was associated with increased receipt of adjuvant therapy (P = 0.001).

Conclusion: PPACA implementation is associated with earlier detection of testicular cancer. Our findings highlight the impact of health care legislation on improving access of care to young men with cancer. Delay in diagnosis can lead to increased stage at presentation and need for adjuvant treatment. Further research to identify and overcome sociodemographic factors associated with diagnostic delay may lead to decreased treatment-related morbidity.
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http://dx.doi.org/10.1016/j.urolonc.2022.02.019DOI Listing
May 2022

Prognostic impact of insulin-like growth factor-I and its binding proteins, insulin-like growth factor-I binding protein-2 and -3, on adverse histopathological features and survival outcomes after radical cystectomy.

Int J Urol 2022 07 2;29(7):676-683. Epub 2022 Apr 2.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Objectives: Insulin-like growth factor-I and its binding proteins are involved in cancer development, progression, and metastasis. In urothelial carcinoma, the impact of this pathway is still poorly investigated. The present large cohort study aimed to evaluate the association of preoperative circulating levels of insulin-like growth factor-I, insulin-like growth factor-I binding protein-2 and -3 on outcomes after radical cystectomy.

Methods: A retrospective cohort study of the plasma specimens from 1036 consecutive urothelial carcinoma patients who were treated with radical cystectomy. The primary and secondary outcomes were adverse histopathological features and survival outcomes. Binominal logistic regression and multivariable Cox regression analyses were performed to assess the association of plasma levels of insulin-like growth factor-I, insulin-like growth factor-I binding protein-2 and -3 with outcomes.

Results: On multivariable analysis adjusting for the effects of preoperative variables, lower insulin-like growth factor-I binding protein-2 levels were associated with an increased risk of lymph node metastasis and (any non-organ confined disease) any non-organ confined disease. Insulin-like growth factor-I binding protein-3 levels were also inversely independently associated with lymph node metastasis. Receiver operating characteristic curve analysis showed that the addition of insulin-like growth factor-I binding proteins biomarkers to a reference model significantly improved the discriminating ability for the prediction of lymph node metastasis (+10.0%, P < 0.001). On multivariable Cox regression models, lower levels of both insulin-like growth factor-I binding protein-2 and -3 plasma levels were associated with recurrence-free survival, cancer-specific survival, and overall survival. insulin-like growth factor-I binding protein-2 and -3 levels and improved the discrimination of a standard reference model for the prediction of recurrence-free survival, cancer-specific survival, and overall survival (+4.9%, 4.9%, 2.3%, respectively).

Conclusions: Preoperative insulin-like growth factor-I binding protein-2 and -3 are significantly associated with features of biologically and clinically aggressive urothelial carcinoma. These biomarkers improved prognostic urothelial carcinoma models.
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http://dx.doi.org/10.1111/iju.14869DOI Listing
July 2022

Prognostic Role of Preoperative Vascular Cell Adhesion Molecule-1 Plasma Levels in Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy.

Ann Surg Oncol 2022 Aug 26;29(8):5307-5316. Epub 2022 Mar 26.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Background: Angiogenesis-related marker vascular cell adhesion molecule-1 (VCAM-1) has been shown to be elevated in urothelial carcinoma of the bladder (UCB), but its predictive/prognostic role has not been determined. Thus, this study aimed to investigate the predictive/prognostic role of VCAM-1 for patients who have UCB treated with radical cystectomy (RC).

Methods: The study enrolled 1036 patients with clinically non-metastatic advanced UCB who underwent RC, and plasma VCAM-1 was evaluated preoperatively. The correlation of plasma VCAM-1 with pathologic and survival outcomes was assessed using binominal logistic regression and multivariable Cox regression analyses. Discrimination was assessed using the area under the curve and concordance indices. The clinical net benefit was evaluated using decision curve analysis (DCA).

Results: Preoperative VCAM-1 was significantly elevated in patients with adverse pathologic features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node-metastasis (LNM), ≥pT3 disease, and non-organ-confined disease (NOCD (p < 0.001 for each). Preoperative plasma VCAM-1 was independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in pre- and postoperative multivariable models. Adding VCAM-1 to these predictive models improved their discriminatory ability to predict all outcomes by a significant margin. In the DCA, VCAM-1 addition to the reference models for prediction of LNM, NOCD, RFS, and CSS resulted in relevant improvement.

Conclusions: Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from intensified/multimodal therapy. In addition, VCAM-1 improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making.
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http://dx.doi.org/10.1245/s10434-022-11575-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246812PMC
August 2022

Dose-Intensified Stereotactic Ablative Radiation for Localized Prostate Cancer.

Front Oncol 2022 21;12:779182. Epub 2022 Feb 21.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States.

Purpose: Stereotactic ablative radiation (SAbR) has been increasingly used in prostate cancer (PCa) given its convenience and cost efficacy. Optimal doses remain poorly defined with limited prospective comparative trials and long-term safety/efficacy data at higher dose levels. We analyzed toxicity and outcomes for SAbR in men with localized PCa at escalated 45 Gy in 5 fractions.

Methods And Materials: This study retrospectively analyzed men from 2015 to 2019 with PCa who received linear-accelerator-based SAbR to 45 Gy in 5 fractions, along with perirectal hydrogel spacer, fiducial placement, and MRI-based planning. Disease control outcomes were calculated from end of treatment. Minimally important difference (MID) assessing patient-reported quality of life was defined as greater than a one-half standard deviation increase in American Urological Association (AUA) symptom score after SAbR.

Results: Two-hundred and forty-nine (249) low-, intermediate-, and high-risk PCa patients with median follow-up of 14.9 months for clinical toxicity were included. Acute urinary grade II toxicity occurred in 20.4% of patients. Acute grade II GI toxicity occurred in 7.3% of patients. For follow-up > 2 years (n = 69), late GU and GI grade ≥III toxicity occurred in 5.8% and 1.5% of patients, respectively. MID was evident in 31.8%, 23.4%, 35.8%, 37.0%, 33.3%, and 26.7% of patients at 3, 6, 12, 24, 36, and 48 months, respectively. The median follow-up for biochemical recurrence was 22.6 months with biochemical failure-free survival of 100% at 1 year (n = 226) and 98.7% for years 2 (n = 113) and 3 (n = 54).

Conclusions: SAbR for PCa at 45 Gy in 5 fractions shows an encouraging safety profile. Prospective studies with longer follow-up are warranted to establish this dose regimen as standard of care for PCa.
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http://dx.doi.org/10.3389/fonc.2022.779182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899031PMC
February 2022

Outcomes of patients undergoing concurrent radical cystectomy and nephroureterectomy: A single-institution series.

Can Urol Assoc J 2022 Jul;16(7):E363-E369

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, United States.

Introduction: Radical cystectomy (RC) and radical nephroureterectomy (RNU) are commonly performed in urological oncology. Concurrent disease in the upper tract and bladder is rare, so performing both procedures in the same setting is uncommon. Here, we report the perioperative and oncological outcomes of a single-institution series of concurrent RC+RNU.

Methods: We retrospectively reviewed the charts of patients who underwent concurrent RC+RNU for bladder and/or upper tract urothelial carcinoma between 2006 and 2020. Patient demographic and clinical factors, perioperative parameters, and oncological outcomes were obtained.

Results: Twenty-seven patients underwent RC+RNU during the study period; 22 (81%) were male. Median (interquartile range) patient age was 71 (67-75) years. All had a diagnosis of bladder cancer. Concurrent upper tract urothelial carcinoma (UTUC) was the indication for RNU in 12 cases (44%) and non-functional renal unit in the remainder. Two patients (7%) experienced early postoperative mortality. Eight patients (30%) experienced major complications (Clavien-Dindo >3). Complications did not vary significantly between those rendered anephric (5/16, 31%) and those who were not (3/11, 27%) (p=0.82, Chi-squared test). Median (95% confidence interval) and five-year overall survival were 47 (41-52) months and 42%, respectively. Six of 22 male patients (27%) experienced a urethral recurrence and three of 14 patients (21%) with non-functional kidneys had occult UTUC discovered on final pathology.

Conclusions: Combined RC+RNU carries an elevated perioperative risk, primarily in highly comorbid patients. Striking rates of occult UTUC in non-functional kidneys and of urethral recurrence after cystectomy were noted. RC+RNU is an appropriate option in select patients.
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http://dx.doi.org/10.5489/cuaj.7612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328854PMC
July 2022

TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells.

Eur Urol Oncol 2022 Feb 22. Epub 2022 Feb 22.

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA. Electronic address:

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.
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http://dx.doi.org/10.1016/j.euo.2021.11.005DOI Listing
February 2022

Prognostic value of hepatocyte growth factor for muscle-invasive bladder cancer.

J Cancer Res Clin Oncol 2022 Jan 8. Epub 2022 Jan 8.

Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: The HGF/MET pathway is involved in cell motility, angiogenesis, proliferation, and cancer invasion. We assessed the clinical utility of plasma HGF level as a prognostic biomarker in patients with MIBC.

Methods: We retrospectively analyzed 565 patients with MIBC who underwent radical cystectomy. Logistic regression and Cox regression models were used, and predictive accuracies were estimated using the area under the curve and concordance index. To estimate the clinical utility of HGF, DCA and MCID were applied.

Results: Plasma HGF level was significantly higher in patients with advanced pathologic stage and LN metastasis (p = 0.01 and p < 0.001, respectively). Higher HGF levels were associated with an increased risk of harboring LN metastasis and non-organ-confined disease (OR1.21, 95%CI 1.12-1.32, p < 0.001, and OR1.35, 95%CI 1.23-1.48, p < 0.001, respectively) on multivariable analyses; the addition of HGF improved the predictive accuracies of a standard preoperative model (+ 7%, p < 0.001 and + 8%, p < 0.001, respectively). According to the DCA and MCID, half of the patients had a net benefit by including HGF, but the absolute magnitude remained limited. In pre- and postoperative predictive models, a higher HGF level was significant prognosticator of worse RFS, OS, and CSS; in the preoperative model, the addition of HGF improved accuracies by 6% and 5% for RFS and CSS, respectively.

Conclusion: Preoperative HGF identified MIBC patients who harbored features of clinically and biologically aggressive disease. Plasma HGF could serve, as part of a panel, as a biomarker to aid in preoperative treatment planning regarding intensity of treatment in patients with clinical MIBC.
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http://dx.doi.org/10.1007/s00432-021-03887-xDOI Listing
January 2022

International Bladder Cancer Group Consensus Statement on Clinical Trial Design for Patients with Bacillus Calmette-Guérin-exposed High-risk Non-muscle-invasive Bladder Cancer.

Eur Urol 2022 Jul 23;82(1):34-46. Epub 2021 Dec 23.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. Electronic address:

Context: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive disease. As multiple therapeutic agents move into this gray area, there is a critical need to define the disease state and establish recommendations for optimal trial design.

Objective: To develop a consensus on optimal trial design for patients with BCG-exposed NMIBC, defined as high-grade recurrence after BCG treatment that does not meet the criteria for BCG-unresponsive disease.

Evidence Acquisition: We conducted a literature review using the Cochrane Library, Medline, and Embase and a review of clinical trials in ClinicalTrials.gov as a basis to generate consensus recommendations for clinical trial design in BCG-exposed NMIBC.

Evidence Synthesis: BCG-exposed NMIBC encompasses BCG resistance (presence of high-grade Ta or carcinoma in situ [CIS] at 3-mo evaluation after induction BCG) and delayed relapse. Randomized controlled trials are required to compare experimental therapies to a control arm receiving additional BCG, although ongoing BCG shortages may impact our ability to follow an optimal trial design. A placebo should be used in combination with BCG if the treatment arm includes BCG plus a study drug. Trials will either need to separate patients with and without CIS into two cohorts, or stratify by the presence of CIS at the time of randomization. If two cohorts are used, the primary endpoint for CIS patients should be complete response within a predetermined time. The primary endpoint in a cohort with Ta/T1 only, or if a single combined cohort is used, should be the duration of event-free survival. Suggested efficacy thresholds and corresponding sample sizes are provided.

Conclusions: The International Bladder Cancer Group has developed recommendations regarding definitions, endpoints, and clinical trial design for BCG-exposed NMIBC to encourage uniformity among studies in this disease state.

Patient Summary: Our consensus provides a precise definition of the disease state for bladder cancer not invading the bladder muscle and exposed to bacillus Calmette-Guérin (BCG) treatment. Clear guidance for conducting optimal clinical trials in this disease setting was established and we believe that this will promote further progress in this field.
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http://dx.doi.org/10.1016/j.eururo.2021.12.005DOI Listing
July 2022

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

Eur Urol 2022 03 18;81(3):223-228. Epub 2021 Dec 18.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.
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http://dx.doi.org/10.1016/j.eururo.2021.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891058PMC
March 2022

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients.

Urol Oncol 2022 03 11;40(3):110.e1-110.e9. Epub 2021 Dec 11.

Dept. Pathology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort.

Patients And Methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS).

Results: pT-stage was
Conclusion: The FGFR3 mutation selectively identified patients with favorable BC at RC while p53 and Ki-67 were only associated with adverse tumor characteristics. Our results suggest that, besides tumor-stage, nodal-status and LVI, the oncogenic FGFR3 mutation may represent a valuable tool to guide adjuvant treatment and follow-up strategies after RC.
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http://dx.doi.org/10.1016/j.urolonc.2021.10.010DOI Listing
March 2022

Prognostic Factors for Contralateral Recurrence of Upper Tract Urothelial Carcinoma after Nephroureterectomy: A Large Multiregional Study.

Cancers (Basel) 2021 Nov 25;13(23). Epub 2021 Nov 25.

Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.

This study aimed to examine the prognostic significance of preoperative inflammation-associated blood cell markers in the metachronous contralateral recurrence of upper tract urothelial carcinoma (UTUC). Patients with nonmetastatic UTUC treated in Taiwan and the U.S. between 1990 and 2017 were included. The Kaplan-Meier method was used to calculate the contralateral recurrence rate, and multivariate logistic regression was performed to study the association of blood cell markers and clinicopathological characteristics with contralateral recurrence. Overall, a total of 1039 patients were included in this study, 52 of whom (5.0%) developed metachronous recurrence of the contralateral side. Kaplan-Meier analysis indicated that a history of bladder cancer ( = 0.006), multiple tumors ( = 0.016), advanced chronic kidney disease (CKD; < 0.001), elevated serum white blood cell (WBC) count ( < 0.001), and decreased hemoglobin levels ( = 0.001) significantly reduced the contralateral recurrence-free survival. Multivariate analysis showed that multiple tumors (hazard ratio (HR), 1.87; = 0.030), advanced CKD (HR, 2.63; = 0.002) and increased WBC count (HR, 2.60; = 0.001) were independent risk factors for higher contralateral recurrence rate. Notably, advanced CKD was a significant factor regardless of the patient's region. In summary, multiple tumors, advanced CKD and elevated serum WBC count are independent predictors of contralateral recurrence in patients with UTUC. It is recommended that patients with these adverse characteristics be closely followed up to monitor the opposite upper urinary tract.
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http://dx.doi.org/10.3390/cancers13235935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657377PMC
November 2021

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

Int J Radiat Oncol Biol Phys 2022 06 11;113(2):290-301. Epub 2021 Nov 11.

Departments of Radiation Oncology; Neurosurgery, Simmons Comprehensive Cancer Center, University of Texas at Southwestern Medical Center, Dallas, Texas.

Purpose: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.

Methods And Materials: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.

Results: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.

Conclusions: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2021.10.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091061PMC
June 2022

Diagnostic Accuracy of Novel Urinary Biomarker Tests in Non-muscle-invasive Bladder Cancer: A Systematic Review and Network Meta-analysis.

Eur Urol Oncol 2021 12 6;4(6):927-942. Epub 2021 Nov 6.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Context: During the past decade, several urinary biomarker tests (UBTs) for bladder cancer have been developed and made commercially available. However, none of these is recommended by international guidelines so far.

Objective: To assess the diagnostic estimates of novel commercially available UBTs for diagnosis and surveillance of non-muscle-invasive bladder cancer (NMIBC) using diagnostic test accuracy (DTA) and network meta-analysis (NMA).

Evidence Acquisition: PubMed, Web of Science, and Scopus were searched up to April 2021 to identify studies addressing the diagnostic values of UBTs: Xpert bladder cancer, Adxbladder, Bladder EpiCheck, Uromonitor and Cxbladder Monitor, and Triage and Detect. The primary endpoint was to assess the pooled diagnostic values for disease recurrence in NMIBC patients using a DTA meta-analysis and to compare them with cytology using an NMA. The secondary endpoints were the diagnostic values for high-grade (HG) recurrence as well as for the initial detection of bladder cancer.

Evidence Synthesis: Twenty-one studies, comprising 7330 patients, were included in the quantitative synthesis. In most of the studies, there was an unclear risk of bias. For NMIBC surveillance, novel UBTs demonstrated promising pooled diagnostic values with sensitivities up to 93%, specificities up to 84%, positive predictive values up to 67%, and negative predictive value up to 99%. Pooled estimates for the diagnosis of HG recurrence were similar to those for the diagnosis of any-grade recurrence. The analysis of the number of cystoscopies potentially avoided during the follow-up of 1000 patients showed that UBTs might be efficient in reducing the number of avoidable interventions with up to 740 cystoscopies. The NMA revealed that diagnostic values (except specificity) of the novel UBTs were significantly higher than those of cytology for the detection of NMIBC recurrence. There were too little data on UBTs in the primary diagnosis setting to allow a statistical analysis.

Conclusions: Our analyses support high diagnostic accuracy of the studied novel UBTs, supporting their utility in the NMIBC surveillance setting. All of these might potentially help prevent unnecessary cystoscopies safely. There are not enough data to reliably assess their use in the primary diagnostic setting. These results have to be confirmed in a larger cohort as well as in head-to-head comparative studies. Nevertheless, our study might help policymakers and stakeholders evaluate the clinical and social impact of the implementation of these tests into daily practice.

Patient Summary: Novel urinary biomarker tests outperform cytology with the potential of improving routine clinical practice by preventing unnecessary cystoscopic examinations during the surveillance of non-muscle-invasive bladder cancer.
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http://dx.doi.org/10.1016/j.euo.2021.10.003DOI Listing
December 2021

Validation of testicular germ cell tumor staging in nationwide cancer registries.

Urol Oncol 2021 12 26;39(12):838.e1-838.e6. Epub 2021 Oct 26.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address:

Introduction: Nationwide cancer registries such as the National Cancer Database and Surveillance, Epidemiology, and End Results rely on accurate data from tumor registries to formulate hypotheses and report outcomes and treatment patterns. We evaluated the accuracy of our institutional registry for testicular germ cell tumors by comparing data abstracted by urologists with data abstracted by registry.

Methods: We performed a retrospective review of patients receiving initial diagnosis and treatment for germ cell tumors at our hospital system from 2005 to 2016. We compared coding for American Joint Committee on Cancer TNMS staging, overall composite stage, and first-line treatment between urologists and tumor registry at the time of diagnosis.

Results: Paired staging from registry and urologist was available for 80 patients. T, N, M, and S-staging were accurate for 90%, 81%, 94%, and 54% of records, respectively. Composite staging and first-line treatment were concordant for 39% and 90% of patients, respectively. A separate review of 33 Stage IS patients per registry for composite staging revealed 15% concordance.

Conclusion: Our institutional tumor registry had substantial inconsistencies in accurately staging N stage, S stage, and thus, composite stage for testicular cancer. An educational intervention to improve abstraction by registry led to increased concordance. Assuming similar discrepancies may exist at other institutions and for other cancer types, caution should be used when interpreting staging data in nationwide cancer registries. This sheds light on the need for improved clarification of staging guidelines, dynamic institutional internal auditing, and training reform within cancer registries.
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http://dx.doi.org/10.1016/j.urolonc.2021.09.011DOI Listing
December 2021

Utility of Blue Light Cystoscopy for Post-bacillus Calmette-Guérin Bladder Cancer Recurrence Detection: Implications for Clinical Trial Recruitment and Study Comparisons.

J Urol 2022 Mar 25;207(3):534-540. Epub 2021 Oct 25.

The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG.

Materials And Methods: Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence.

Results: Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15).

Conclusions: BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.
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http://dx.doi.org/10.1097/JU.0000000000002308DOI Listing
March 2022

The early impact of medicaid expansion on urologic malignancies in the United States.

Urol Oncol 2022 03 17;40(3):103.e1-103.e8. Epub 2021 Oct 17.

Department of Urology, UT Southwestern Medical Center, Dallas, TX. Electronic address:

Purpose: To assess the effects of variable adoption of Medicaid Expansion (ME) of the Affordable Care Act among different states on urologic malignancies using a new variable that defines ME status of patient's residence in a nationwide cancer registry.

Basic Procedures: The National Cancer Database was queried for urologic malignancies (bladder, prostate, kidney and testis) from 2011 to 2016, spanning the period surrounding the primary ME which took place in 2014. Trends in insurance status at time of diagnosis and effects on stage at presentation and survival after ME were evaluated using a difference-in-differences estimator and stratified Cox proportional hazards regression model.

Main Findings: The percentage of patients with Medicaid coverage at the time of diagnosis increased significantly after adoption of ME in ME states across all urologic malignancies. Concurrently, there was a significant decrease in percentage of uninsured patients diagnosed with testis cancer, but not other urologic malignancies, in ME states. A change in the stage at presentation was not observed across all urologic malignancies for patients in ME states after adoption of ME. No difference in overall survival was noted among patients living in a ME state compared to non-ME states with adoption of ME in 2014.

Principal Conclusions: Despite increases in the proportion of patients with Medicaid coverage after 2014 in states that enrolled in ME, there was not an associated change in stage at presentation or survival for patients with genitourinary malignancy.
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http://dx.doi.org/10.1016/j.urolonc.2021.09.002DOI Listing
March 2022

Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy.

J Urol 2022 03 13;207(3):541-550. Epub 2021 Oct 13.

Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with nonmetastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5%-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC.

Materials And Methods: Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan-Meier curves. Cox proportional hazards models were used to evaluate the primary and secondary study end points of overall survival (OS) and cancer-specific survival, respectively.

Results: A total of 601 patients with MIBC were included, of whom 247 had been treated with NAC and RC, and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and cancer-specific survival at 3 years was 7% and 5%, respectively. After controlling for clinicopathological variables, nonluminal tumors had greatest benefit from NAC, with 10% greater OS at 3 years (71% vs 61%), while luminal tumors had minimal benefit (63% vs 65%) for NAC vs non-NAC.

Conclusions: In patients with MIBC, a commercially available molecular subtyping assay revealed nonluminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.
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http://dx.doi.org/10.1097/JU.0000000000002261DOI Listing
March 2022

Role of blue-light cystoscopy in detecting invasive bladder tumours: data from a multi-institutional registry.

BJU Int 2022 07 26;130(1):62-67. Epub 2021 Oct 26.

Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

Objectives: To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC).

Patients And Methods: Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected.

Results: Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease.

Conclusions: A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach.
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http://dx.doi.org/10.1111/bju.15614DOI Listing
July 2022

A Randomized Feasibility Trial Comparing Surveillance Regimens for Patients with Low and Low-Intermediate Risk Non-Muscle Invasive Bladder Cancer.

Bladder Cancer 2021 ;7(3):285-295

Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA.

Background: Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown.

Objectives: To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens.

Methods: A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of = 35 patients per arm provided a one-sided 95% exact Clopper-Pearson confidence lower-limit of 60%.

Results: Of 70 patients approached, 45 (64.3%) agreed to participate and 25 (35.7%) declined enrollment due to preference for HF. Twelve biopsies were performed, including 4 (19%) of 21 patients in the HF group and 8 (33.3%) of 24 patients in the LF group. Disease recurrence (low grade Ta) was observed in 3 (14.3%) and 5 (20.8%) patients in the HF and LF groups, respectively. No patients experienced high grade recurrence or progression. Both groups had similar patient-reported procedure-related discomfort and quality of life measures over time. Patient out-of-pocket cost and healthcare systems costs were $383.80 more per patient annually in the HF group.

Conclusions: Randomization to variable frequency surveillance is challenging as over a third of patients declined participation. However, these data provide important preliminary insights into the potential effects of surveillance frequency on oncologic and economic outcomes in patients with low and low-intermediate risk bladder cancer.
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http://dx.doi.org/10.3233/blc-201535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494135PMC
January 2021

Performance of Narrow Band Imaging (NBI) and Photodynamic Diagnosis (PDD) Fluorescence Imaging Compared to White Light Cystoscopy (WLC) in Detecting Non-Muscle Invasive Bladder Cancer: A Systematic Review and Lesion-Level Diagnostic Meta-Analysis.

Cancers (Basel) 2021 Aug 30;13(17). Epub 2021 Aug 30.

Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Despite early detection and regular surveillance of non-muscle invasive bladder cancer (NMIBC), recurrence and progression rates remain exceedingly high for this highly prevalent malignancy. Limited visualization of malignant lesions with standard cystoscopy and associated false-negative biopsy rates have been the driving force for investigating alternative and adjunctive technologies for improved cystoscopy. The aim of our systematic review and meta-analysis was to compare the sensitivity, specificity, and oncologic outcomes of photodynamic diagnosis (PDD) fluorescence, narrow band imaging (NBI), and conventional white light cystoscopy (WLC) in detecting NMIBC. Out of 1,087 studies reviewed, 17 prospective non-randomized and randomized controlled trials met inclusion criteria for the study. We demonstrated that tumor resection with either PDD and NBI exhibited lower recurrence rates and greater diagnostic sensitivity compared to WLC alone. NBI demonstrated superior disease sensitivity and specificity as compared to WLC and an overall greater hierarchical summary receiver operative characteristic. Our findings are consistent with emerging guidelines and underscore the value of integrating these enhanced technologies as a part of the standard care for patients with suspected or confirmed NMIBC.
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http://dx.doi.org/10.3390/cancers13174378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431313PMC
August 2021

The Value of Preoperative Plasma VEGF Levels in Urothelial Carcinoma of the Bladder Treated with Radical Cystectomy.

Eur Urol Focus 2021 Aug 25. Epub 2021 Aug 25.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Background: Elevated preoperative plasma levels of the angiogenesis-related marker VEGF have been associated with worse oncological outcomes in various malignancies.

Objective: To investigate the predictive/prognostic role of VEGF in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC).

Design, Setting, And Participants: VEGF plasma levels were measured preoperatively in 1036 patients with UCB who underwent RC.

Outcome Measurements And Statistical Analysis: The correlation between plasma VEGF levels and pathological and survival outcomes was assessed using logistic regression and Cox regression analyses. Discrimination was assessed using the concordance index (C index). The clinical net benefit was evaluated using decision curve analysis (DCA).

Results And Limitations: Patients with higher pretreatment plasma VEGF levels had poorer recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) according to log-rank tests (all p < 0.001). Higher VEGF levels were not independently associated with higher risk of lymph node metastasis, ≥pT3 disease, or non-organ-confined disease (all p > 0.05). Preoperative plasma VEGF levels were independently associated with RFS, CSS, and OS in preoperative and postoperative multivariable models. However, in all cases the C index increased by <0.02 and there was no improvement in net benefit on DCA. A limitation is that none of the patients received current elements of standard of care such as neoadjuvant chemotherapy.

Conclusions: Elevated plasma VEGF levels were associated with features of biologically and clinically aggressive disease such as worse survival outcomes among patients with UCB treated with RC. However, VEGF appears to have relatively limited incremental additive value in clinical use. Further study of VEGF for UCB prognostication is warranted before routine use in clinical algorithms.

Patient Summary: Currently available models for predicting outcomes in bladder cancer are less than optimal. A protein called vascular endothelial growth factor (VEGF), which is a marker of the formation of blood vessels (angiogenesis), may have a role in predicting survival outcomes in bladder cancer.

Take Home Message: Elevated plasma VEGF levels are associated with worse survival outcomes for patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy. VEGF could be used as a part of a biomarker panel to enhance tools currently used for risk stratification for patients with UCB.
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http://dx.doi.org/10.1016/j.euf.2021.08.006DOI Listing
August 2021
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