Publications by authors named "Stephen A Boorjian"

388 Publications

Incidence and predictors of occult preoperative deep vein thrombosis at radical cystectomy for urothelial carcinoma.

Can Urol Assoc J 2021 Feb 12. Epub 2021 Feb 12.

Department of Urology, Mayo Clinic, Rochester, MN, United States.

Introduction: Patients undergoing radical cystectomy are at high perioperative risk for deep vein thrombosis due to age, malignancy, recent transurethral resection, and neoadjuvant chemotherapy. We, therefore, evaluated the incidence and predictors of occult preoperative deep vein thrombosis prior to radical cystectomy for urothelial carcinoma.

Methods: We prospectively screened 52 asymptomatic patients with urothelial carcinoma undergoing radical cystectomy at our institution with lower extremity ultrasound and D-dimer assay within two weeks prior to surgery. Patients with a prior history of deep vein thrombosis and those on systemic anticoagulation were excluded.

Results: We identified 4/52 patients (7.7%) with preoperative asymptomatic deep vein thrombosis prior to radical cystectomy. Median D-dimer for patients with and without preoperative deep vein thrombosis was 787 ng/ml(interquartile range [IQR] 365-1257) and 260 ng/ml(IQR 158-498), respectively. A D-dimer threshold of >250 ng/ml had a sensitivity of 100% and specificity of 50%, resulting in a negative predictive value of 100% and positive predictive value of 14.8% for preoperative deep vein thrombosis. Increasing the D-dimer threshold to >1000 ng/ml created a sensitivity of 50% and specificity of 85%, resulting in a negative predictive value of 92% and positive predictive value of 33%. D-dimer values did not significantly vary with neoadjuvant chemotherapy or days since transurethral resection.

Conclusions: Approximately 8% of patients had an occult deep vein thrombosis prior to radical cystectomy. D-dimer can provide sensitive diagnostic utility for deep vein thrombosis in the pre- radical cystectomy setting and could help guide use of preoperative lower extremity ultrasound in this high-risk patient population.
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http://dx.doi.org/10.5489/cuaj.6852DOI Listing
February 2021

Collaborative Review: Factors Influencing Treatment Decisions for Patients with a Localized Solid Renal Mass.

Eur Urol 2021 Feb 5. Epub 2021 Feb 5.

Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Context: With the addition of active surveillance and thermal ablation (TA) to the urologist's established repertoire of partial (PN) and radical nephrectomy (RN) as first-line management options for localized renal cell carcinoma (RCC), appropriate treatment decision-making has become increasingly nuanced.

Objective: To critically review the treatment options for localized, nonrecurrent RCC; to highlight the patient, renal function, tumor, and provider factors that influence treatment decisions; and to provide a framework to conceptualize that decision-making process.

Evidence Acquisition: A collaborative critical review of the medical literature was conducted.

Evidence Synthesis: We identify three key decision points when managing localized RCC: (1) decision for surveillance versus treatment, (2) decision regarding treatment modality (TA, PN, or RN), and (3) decision on surgical approach (open vs minimally invasive). In evaluating factors that influence these treatment decisions, we elaborate on patient, renal function, tumor, and provider factors that either directly or indirectly impact each decision point. As current nomograms, based on preselected patient datasets, perform poorly in prospective settings, these tools should be used with caution. Patient decision aids are an underutilized tool in decision-making.

Conclusions: Localized RCC requires highly nuanced treatment decision-making, balancing patient- and tumor-specific clinical variables against indirect structural influences to provide optimal patient care.

Patient Summary: With expanding treatment options for localized kidney cancer, treatment decision is highly nuanced and requires shared decision-making. Patient decision aids may be helpful in the treatment discussion.
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http://dx.doi.org/10.1016/j.eururo.2021.01.021DOI Listing
February 2021

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients.

Mayo Clin Proc 2021 Jan 29. Epub 2021 Jan 29.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Objective: To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).

Patients And Methods: The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).

Results: A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.

Conclusion: The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.
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http://dx.doi.org/10.1016/j.mayocp.2020.11.004DOI Listing
January 2021

The association of salvage intravesical therapy following BCG with pathologic outcomes and survival after radical cystectomy for patients with high-grade non-muscle invasive bladder cancer: A multi-institution analysis.

Urol Oncol 2021 Jan 20. Epub 2021 Jan 20.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Introduction: While numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC).

Methods: We identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST.

Results: Patients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60-2.09, P = 0.7). Results were unchanged on sensitivity analysis.

Conclusions: These data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.
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http://dx.doi.org/10.1016/j.urolonc.2021.01.004DOI Listing
January 2021

The evolving role of lymphadenectomy for bladder cancer: why, when, and how.

Transl Androl Urol 2020 Dec;9(6):3082-3093

Department of Urology, Mayo Clinic, Rochester, MN, USA.

Radical cystectomy (RC) represents a standard treatment for non-metastatic muscle-invasive and select high-risk non-muscle invasive bladder cancer. Lymphadenectomy performed at time of RC identifies nodal metastases in up to 25% of patients despite normal imaging. There has been an increasing utilization of pelvic lymph node dissection (PLND) with RC since 1950, and in fact lymph node dissection is now recommended in contemporary National Comprehensive Cancer Network (NCCN) guidelines. Benefits of removing of nodal disease include improved staging, guidance for adjuvant treatment, and potentially improved oncologic outcomes. Advantages of dissection have been suggested among both node-negative and node-positive patients. Numerous studies have attempted to define the optimal dissection characteristics of lymphadenectomy with regard to nodal yield and anatomic boundaries of dissection. The ideal extent of lymphadenectomy remains uncertain due to the retrospective and non-randomized nature of the majority of existing reports, which are thereby limited by significant confounding and selection bias. Two randomized controlled trials have investigated this issue, one of which LEA AUO AB 25/02 recently reported its outcomes, demonstrating no significant improvement in 5-year outcomes with an extended dissection. Meanwhile, the Southwest Oncology Group 1011 trial has completed enrollment and data are maturing. While current data preclude definitive recommendations, herein we review the why, when, and how to perform a PLND for bladder cancer.
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http://dx.doi.org/10.21037/tau.2019.06.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807370PMC
December 2020

Differential prognostic impact of different Gleason patterns in grade group 4 in radical prostatectomy specimens.

Eur J Surg Oncol 2020 Dec 24. Epub 2020 Dec 24.

Department of Urology, Medical University of Vienna, Vienna, Austria; Departments of Pathology, The Jikei University School of Medicine, Tokyo, Japan; Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; European Association of Urology Research Foundation, Arnhem, Netherlands. Electronic address:

Introduction: There are questions regarding whether grade group (GG) 4 prostate cancer (PC) is heterogeneous in terms of prognosis. We assessed prognostic differences in PC patients within GG 4 treated with radical prostatectomy (RP).

Material And Methods: Biochemical recurrence (BCR)-free, cancer-specific, and overall survival were analyzed in 787 PC patients with GG 4 based on RP pathology (Gleason score (GS) 3 + 5: 189, GS 4 + 4: 500, and GS 5 + 3: 98). Logistic regression analysis was performed to assess factors predictive of high-risk surgical pathological features. Cox regression models were used to evaluate potential prognostic factors of survival.

Results: Within a median follow-up of 86 months, 378 patients (48.0%) experienced BCR and 96 patients (12.2%) died, 42 of whom (5.3%) died of PC. GS 5 + 3 was significantly associated with worse BCR-free and cancer-specific survival, as well as higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates, than GS 3 + 5 and higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates than GS 4 + 4 (P < 0.05). GS 4 + 4 was significantly associated with worse BCR-free survival and higher extraprostatic extension, and non-organ-confined disease rates than GS 3 + 5 (P < 0.05). Inclusion of the different Gleason patterns improved the discrimination of a model for prediction of all survival outcomes compared to standard prognosticators.

Conclusions: There is considerable heterogeneity within GG 4 in terms of oncological and surgical pathological outcomes. Primary and secondary Gleason patterns should be considered to stratify high-risk PC patients after RP.
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http://dx.doi.org/10.1016/j.ejso.2020.12.014DOI Listing
December 2020

Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria.

J Urol 2020 Dec 24:101097JU0000000000001550. Epub 2020 Dec 24.

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

Purpose: Microhematuria is a prevalent condition and the American Urological Association has developed a new risk-stratified approach for the evaluation of patients with microhematuria. Our objective was to provide the first evaluation of this important guideline.

Materials And Methods: This multinational cohort study combines contemporary patients from 5 clinical trials and 2 prospective registries who underwent urological evaluation for hematuria. Patients were stratified into American Urological Association risk strata (low, intermediate, or high risk) based on sex, age, degree of hematuria, and smoking history. The primary endpoint was the incidence of bladder cancer within each risk stratum.

Results: A total of 15,779 patients were included in the analysis. Overall, 727 patients (4.6%) were classified as low risk, 1,863 patients (11.8%) were classified as intermediate risk, and 13,189 patients (83.6%) were classified as high risk. The predominance of high risk patients was consistent across all cohorts. A total of 857 bladder cancers were diagnosed with a bladder cancer incidence of 5.4%. Bladder cancer was more prevalent in men, smokers, older patients, and patients with gross hematuria. The cancer incidence for low, intermediate, and high risk groups was 0.4% (3 patients), 1.0% (18 patients), and 6.3% (836 patients), respectively.

Conclusions: The new risk stratification system separates hematuria patients into clinically meaningful categories with differing likelihoods of bladder cancer that would justify evaluating the low, intermediate and high risk groups with incremental intensity. Furthermore, it provides the relative incidence of bladder cancer in each risk group which should facilitate patient counseling regarding the risks and benefits of evaluation for bladder cancer.
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http://dx.doi.org/10.1097/JU.0000000000001550DOI Listing
December 2020

Cost-Effectiveness Analysis of Pembrolizumab for BCG-Unresponsive Carcinoma in Situ of the Bladder.

J Urol 2020 Dec 21:101097JU0000000000001515. Epub 2020 Dec 21.

Department of Urology, Mayo Clinic, Rochester, Minnesota.

Purpose: Patients with BCG-unresponsive carcinoma in situ (CIS) are treated with radical cystectomy (RCx) or salvage intravesical chemotherapy (SIC). Recently, pembrolizumab was approved for BCG-unresponsive CIS.

Materials And Methods: We used a decision-analytic Markov model to compare pembrolizumab, SIC (with gemcitabine-docetaxel induction+monthly maintenance), and RCx for patients with BCG-unresponsive CIS who are RCx candidates (index patient 1) or are unwilling/unable to undergo RCx (index patient 2). The model used a US Medicare perspective with a 5-year time horizon. One-way and probabilistic sensitivity analyses were performed. Incremental Cost-Effectiveness Ratios(ICERs) were compared using a willingness-to-pay threshold of $100,000/Quality-adjusted life year(QALY).

Results: For index patient 1, pembrolizumab was not cost-effective relative to RCx(ICER $1,403,008/QALY) or SIC(ICER $2,011,923/QALY). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to RCx with a >93% price reduction. Relative to RCx, SIC was cost-effective for time horizons <5 years and nearly cost-effective at 5 years(ICER $118,324/QALY). One-way sensitivity analysis revealed that SIC became cost-effective relative to RCx if risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required >90% price reduction to be cost-effective(ICER $1,073,240/QALY). Pembrolizumab was cost-effective in 0% of 100,000 microsimulations in probabilistic sensitivity analyses for both index patients.

Conclusions: At its current price, pembrolizumab is not cost-effective for BCG-unresponsive CIS relative to RCx or SIC. Although gemcitabine-docetaxel is not cost-effective relative to RCx at 5 years, further studies may validate its cost-effectiveness if recurrence and metastasis thresholds are met.
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http://dx.doi.org/10.1097/JU.0000000000001515DOI Listing
December 2020

Creation of a primary tumor tissue expression biomarker-augmented prognostic model for patients with metastatic renal cell carcinoma.

Urol Oncol 2021 Feb 9;39(2):135.e1-135.e8. Epub 2020 Dec 9.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Background: Clinical and pathological factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). Bim, a downstream pro-apoptotic molecule in the PD-1 signaling pathway, has recently been associated with survival in other malignancies. We sought to determine if tissue biomarkers including Bim, added to a previously reported clinical metastases score, improved prediction of cancer-specific survival (CSS) for patients with metastatic ccRCC.

Methods: Patients with metastatic ccRCC who underwent nephrectomy between 1990 and 2004 were identified using our institutional registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for Bim, PD-1, B7-H1 (PD-L1), B7-H3, CA-IX, IMP3, Ki67, and survivin. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index.

Results: The cohort included 602 patients: 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up was 9.6 years (IQR 4.2-12.8), during which 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score, and were eligible for biomarker-specific model inclusion. After variable selection, high Bim (hazard ratio [HR] = 1.44; 95% confidence interval [CI] 1.16-1.78; P <0.001), high survivin (HR = 1.35; 95% CI 1.08-1.68; P = 0.008), and the metastases score (HR = 1.13 per 1 point; 95% CI 1.10-1.16; P <0.001) were retained in the final multivariable model (c-index = 0.69).

Conclusion: We created a prognostic model combining the clinical metastases score and 2 primary tumor tissue expression biomarkers, Bim and survivin, for patients with metastatic renal cell carcinoma who underwent nephrectomy.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.028DOI Listing
February 2021

Association of intraoperative hypothermia with oncologic outcomes following radical cystectomy.

Urol Oncol 2020 Dec 8. Epub 2020 Dec 8.

Department of Urology, Mayo Clinic, Rochester, MN.

Introduction: Intraoperative hypothermia (IOH) has been suggested to adversely impact outcomes following surgery. The objective of this study was to evaluate the association between IOH and survival following radical cystectomy (RC).

Methods: Patients who underwent RC for bladder cancer from 2003 to 2018 were identified in our cystectomy registry. Intraoperative temperatures were extracted from the anesthesia record. IOH was defined as a median intraoperative temperature <36°C, and severe IOH as ≤ 35°C. Time under 36°C was assessed as a continuous variable. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Associations between IOH and outcomes were assessed with multivariable Cox proportional hazards models.

Results: A total of 852 patients were identified, among whom 274 (32%) had IOH. Median follow up among survivors was 4.9 years (IQR 2.4-8.7), during which time 483 patients died, including 343 from bladder cancer. Two-year survival was not significantly different between patients with and without IOH (CSS: 74% vs. 71%, P= 0.31; OS: 68% vs. 67%, P= 0.13). Following multivariable adjustment, neither IOH nor time under 36°C was significantly associated with survival. A total of 37 patients (4.3%) had severe IOH. These patients were observed to have significantly lower 2-year OS (56% vs. 68%, P= 0.005); however, this association did not remain statistically significant after multivariable adjustment (P= 0.92).

Conclusion: IOH was not independently associated with survival following RC. These data do not support IOH as a prognostic factor for cancer outcomes among patients undergoing RC.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.036DOI Listing
December 2020

Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.

BJU Int 2020 Dec 11. Epub 2020 Dec 11.

Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Objectives: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-β (MSP) adds predictive value.

Patients And Methods: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore.

Results: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold.

Conclusion: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.
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http://dx.doi.org/10.1111/bju.15320DOI Listing
December 2020

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

Lancet Oncol 2021 01 27;22(1):107-117. Epub 2020 Nov 27.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.

Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.

Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.

Funding: FKD Therapies Oy.
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http://dx.doi.org/10.1016/S1470-2045(20)30540-4DOI Listing
January 2021

Grading Chromophobe Renal Cell Carcinoma: Evidence for a Four-tiered Classification Incorporating Coagulative Tumor Necrosis.

Eur Urol 2021 Feb 7;79(2):225-231. Epub 2020 Nov 7.

Department of Urology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Although grading systems have been proposed for chromophobe renal cell carcinoma (ChRCC), including a three-tiered system by Paner et al (Paner GP, Amin MB, Alvarado-Cabrero I, et al. A novel tumor grading scheme for chromophobe renal cell carcinoma: prognostic utility and comparison with Fuhrman nuclear grade. Am J Surg Pathol 2010;34:1233-40), none have gained clinical acceptance, and the World Health Organization (WHO) currently recommends against grading ChRCC.

Objective: To validate a previously published grading scheme and propose a scheme that includes tumor necrosis.

Design, Setting, And Participants: A total of 266 patients who underwent nephrectomy for nonmetastatic ChRCC between 1970 and 2012 were reviewed for ChRCC grade according to the Paner system and coagulative tumor necrosis.

Outcome Measurements And Statistical Analysis: Associations with cancer-specific survival (CSS) were evaluated using Cox proportional hazard regression models and summarized with hazard ratios (HRs).

Results And Limitations: Twenty-nine patients died from RCC; the median follow-up was 11.0 (interquartile range 7.9-15.9) yr. ChRCC grade according to the Paner system was significantly associated with CSS, including the difference in outcome between grade 1 and 2 tumors. Among patients with grade 2 tumors, the presence of tumor necrosis helped delineate patients with worse CSS. As such, the Paner system was expanded to four tiers separating grade 2 into those with and without tumor necrosis. HRs for associations of the proposed grade 2, 3, and 4 tumors with CSS were 4.63 (p=0.007), 17.8 (p<0.001), and 20.9 (p<0.001), respectively. The study is limited by the lack of multivariable analysis including additional pathologic features.

Conclusions: The expansion of a previously reported ChRCC grading system from three to four tiers by the inclusion of tumor necrosis helps further delineate patient outcome and can, therefore, enhance patient counseling following surgery. It also aligns the number of ChRCC grades with the WHO/International Society of Urologic Pathology four-tiered grading systems for clear cell and papillary RCC.

Patient Summary: Chromophobe renal cell carcinoma is the third most common type of renal cancer, and unlike other renal cancers, there is no accepted prognostic grading system. In this study, we found that a grading system that included a pathologic feature of tumor necrosis could better define outcomes for patients with chromophobe renal cell carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2020.10.007DOI Listing
February 2021

Renal neoplasia with papillary architecture involving the pelvicalyceal system.

Hum Pathol 2021 Jan 6;107:46-57. Epub 2020 Nov 6.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.

Pelvicalyceal system (PS) involvement by renal cell carcinoma (RCC) is staged as pT3a disease (American Joint Committee on Cancer [AJCC], 8th edition). As papillary RCC (PRCC) has been infrequently represented in studies looking at the prognostic impact of PS involvement, we reviewed our institutional cohort of 8225 cases for PS involvement by PRCC. Nine such cases were subjected to histopathologic review and immunohistochemistry. Fluorescence in situ hybridization for TFE3/TFEB alterations was performed if indicated. One case each (1 of 9, 11%) was classified as TFE3-rearranged and FH-deficient RCC. The majority were high grade (World Health Organization/International Society of Urologic Pathology grade 3: 8 of 9, 89%) or had features of aggressive disease, including hilar fat (6 of 9, 67%) and regional lymph node involvement (5 of 7, 71%). One low-grade 3.3-cm tumor with isolated PS involvement with a germline heterozygous FH p.Lys477dup alteration with retained FH, lack of increased S-(2-succino)-cysteine expression, BRAF V600E immunohistochemistry positivity, and lack of trisomy 7/17 on chromosomal microarray was identified, arguing against an FH-deficient and conventional PRCC. Our study shows that PS involvement by renal neoplasia with papillary architecture is a rare event. Aside from PRCC, it is important to note that these may include other aggressive and nonaggressive subtypes of renal neoplasia with papillary architecture. One case of isolated PS involvement by a low-grade, noninvasive tumor that we refer to as nephrogenic papillary neoplasm was identified. At present, there are insufficient data to stage such tumors as pT3a (AJCC, 8th edition), and additional studies are needed to address this question.
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http://dx.doi.org/10.1016/j.humpath.2020.10.013DOI Listing
January 2021

Development of a technique for evaluating the presence of malignant cells in prostatic fluid during robotic prostatectomy.

Urol Oncol 2021 Mar 29;39(3):192.e1-192.e6. Epub 2020 Aug 29.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Introduction: To develop a technique to collect fluid expressed during robot-assisted radical prostatectomy (RARP) to assess whether malignant cells may have been inadvertently introduced into the surgical field.

Methods: Men with clinically localized grade group 2 to 5 prostate adenocarcinoma undergoing RARP were identified. Following bladder neck division, fluid expressed via prostatic urethra during seminal vesicle dissection was aspirated (specimen A). After specimen removal, an ex vivo seminal vesicle aspiration was performed as well (specimen B). Specimens were prepared with ThinPrep (Hologic, Marlborough, MA) and stained with 4 immunohistochemical markers: keratin-7, PAX-8, prostate-specific antigen (PSA), and prostatic acid phosphatase (PACP).

Results: Between December 2018 and May 2019, 15 men undergoing RARP were included. Median age was 60 years (range: 47-77), median PSA 8.5 ng/ml (range 5.1-24), and 7 (47%) had AUA high-risk disease. Specimen A had adequate cellularity in 13 patients (87%). Five patients were excluded from assessment of malignancy due to acellularity of specimen A (n = 2) or specimen B (n = 3). Three of the remaining 10 patients (30%) had cytologic features suspicious for malignancy on specimen A. Immunohistochemistry supported prostatic origin with positive PSA and PACP staining and negative PAX8 stains. Specimen B was not suspicious in any patient.

Conclusion: We report a technique for intraoperative collection of fluid expressed during RARP. Three patients with adverse pathologic features had evidence of cancer cells within the operative field. Further work is needed to confirm this observation and to determine whether these cells are associated with adverse oncologic outcomes.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.007DOI Listing
March 2021

Does Ureteral Stent Drainage Prior to Cystectomy Increase the Risk of Subsequent Upper Tract Urothelial Carcinoma and Ureteral Complications?

Urology 2020 Aug 5. Epub 2020 Aug 5.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To guide management of preoperative hydronephrosis prior to radical cystectomy (RC), we compared post-RC risks of upper tract urothelial carcinoma (UTUC) and ureteroenteric anastomotic complications between ureteral stent and percutaneous nephrostomy tube drainage.

Methods: Patients who underwent RC for urothelial carcinoma without a prior diagnosis of UTUC at our institution between 2000 and 2015 were included and divided into 4 patient groups: (1) no hydronephrosis (75%, N = 787); (2) hydronephrosis without preoperative upper tract drainage (13%, N = 132); (3) hydronephrosis treated with nephrostomy tube (3%, N = 36); (4) hydronephrosis treated with ureteral stent (9%, N = 94). The incidence of post-RC UTUC and ureteral complications was compared using Kaplan-Meier analyses and multivariable Cox proportional hazard modeling.

Results: We identified a total of 1049 patients who underwent RC (median postoperative follow-up 4.3 years). Five-year post-RC UTUC incidence was 6.6%, 10.2%, 17%, 18.7% for groups 1-4, respectively (P= .13). On multivariable analysis, nephrostomy tube drainage (hazard ratio [HR] 4.10, P = .02) and preoperative ureteral stenting (HR 2.35, P = .04) were both associated with UTUC after RC, but ureteral stenting did not have a significantly higher association with UTUC than nephrostomy tube drainage. Severe hydronephrosis was also associated with development of UTUC (HR 4.03, P = .02). The incidence of ureteroenteric anastomotic complications did not vary by drainage modality.

Conclusion: Preoperative hydronephrosis was associated with UTUC after RC, but ureteral stent placement did not increase the risk of UTUC or ureteral complications relative to nephrostomy tube placement. The choice of hydronephrosis drainage pre-RC should not be guided by concern for UTUC risk.
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http://dx.doi.org/10.1016/j.urology.2020.07.034DOI Listing
August 2020

Microhematuria: AUA/SUFU Guideline.

J Urol 2020 10 23;204(4):778-786. Epub 2020 Jul 23.

University of California, San Francisco, California.

Purpose: Patients presenting with microhematuria represent a heterogeneous population with a broad spectrum of risk for genitourinary malignancy. Recognizing that patient-specific characteristics modify the risk of underlying malignant etiologies, this guideline sought to provide a personalized diagnostic testing strategy.

Materials And Methods: The systematic review incorporated evidence published from January 2010 through February 2019, with an updated literature search to include studies published up to December 2019. Evidence-based statements were developed by the expert Panel, with statement type linked to evidence strength, level of certainty, and the Panel's judgment regarding the balance between benefits and risks/burdens.

Results: Microhematuria should be defined as ≥ 3 red blood cells per high power field on microscopic evaluation of a single specimen. In patients diagnosed with gynecologic or non-malignant genitourinary sources of microhematuria, clinicians should repeat urinalysis following resolution of the gynecologic or non-malignant genitourinary cause. The Panel created a risk classification system for patients with microhematuria, stratified as low-, intermediate-, or high-risk for genitourinary malignancy. Risk groups were based on factors including age, sex, smoking and other urothelial cancer risk factors, degree and persistence of microhematuria, as well as prior gross hematuria. Diagnostic evaluation with cystoscopy and upper tract imaging was recommended according to patient risk and involving shared decision-making. Statements also inform follow-up after a negative microhematuria evaluation.

Conclusions: Patients with microhematuria should be classified based on their risk of genitourinary malignancy and evaluated with a risk-based strategy. Future high-quality studies are required to improve the care of these patients.
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http://dx.doi.org/10.1097/JU.0000000000001297DOI Listing
October 2020

Long-term outcomes of incidental prostate cancer at radical cystectomy.

Urol Oncol 2020 Nov 2;38(11):848.e17-848.e22. Epub 2020 Jul 2.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: We evaluated the natural history and long-term outcomes of incidentally detected prostate cancer (PCa) at radical cystectomy (RC) for bladder cancer (BCa).

Patients And Methods: We identified 1,640 male patients who underwent RC between 1992 and 2012. Patients were stratified as clinically insignificant and clinically significant PCa, based on Grade Group (GG) 1 and ≥2, respectively. Survival was assessed using the Kaplan-Meier method.

Results: There were 329 (20%) patients with incidentally detected PCa at RC: 245 (15%) GG1, 52 (3.2%) GG2, 20 (1.2%) GG3, 6 (0.4%) GG4, and 6 (0.4%) GG5. Median follow-up among survivors was 9.6 years (interquartile range 7.5-13.3), during which time 253 patients died, of whom 127 died of BCa and 1 died of PCa. Nine patients experienced biochemical recurrence (BCR), 4 underwent salvage PCa therapies, and 2 developed PCa metastases. Patients with clinically significant PCa were significantly more likely to experience BCR (6% vs. 1.6%; P = 0.04) and had shorter median time to BCR (1.8 vs. 10.4 years; P = 0.01) than those with clinically insignificant PCa. No patients with BCR had greater than pT2N0 BCa or positive BCa margins. Ten-year PCa-specific survival, BCa-specific survival, other cause-specific survival, and overall survival were 99%, 57%, 63%, and 35%, respectively.

Conclusions: In a large RC series, we note a 20% rate of incidental PCa, the majority of which are clinically insignificant. On long-term follow-up, we determined that BCR and PCa mortality are extremely rare events among these patients. Pending validation, future guidelines may consider omission of PCa surveillance for some patients with incidental PCa at RC.
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http://dx.doi.org/10.1016/j.urolonc.2020.05.018DOI Listing
November 2020

Treatment Outcomes in Patients With Symptomatic Lymphoceles Following Radical Prostatectomy Depend Upon Size and Presence of Infection.

Urology 2020 Sep 17;143:181-185. Epub 2020 Jun 17.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To guide treatment decisions for symptomatic lymphoceles after radical prostatectomy. We examined our experience to create a treatment algorithm.

Materials And Methods: We evaluated all patients that underwent radical prostatectomy at our institution from 2003 to 2012. Presenting signs, management and treatment outcomes were evaluated.

Results: Of the 8081 patients who underwent radical prostatectomy from 2003 to 2012, we identified 123 (1.5%) patients who developed a symptomatic lymphocele, 70 sterile and 53 infected. Percutaneous aspiration was performed in 26 of 123 (21%) patients, of those, 100% recurred. A drain was placed in 86 of 123 (70%) patients for a median of 13 vs 33 days for the infected and sterile lymphocele groups, respectively (P <.001). The median duration of drainage for sterile lymphoceles was 15 vs 58 days for lymphoceles <10 cm vs ≥10 cm (P <.001). Percutaneous drainage was successful in 93% and 86% of patients with infected and sterile lymphoceles, respectively. Laparoscopic unroofing was performed in 18 sterile lymphocele patients (15%) with a success rate of 94%.

Conclusion: Aspiration of symptomatic lymphoceles should be reserved for diagnostic purposes due to a high risk of recurrence. Infected lymphoceles are optimally treated with drain placement and antibiotics, and have excellent resolution rates. While sterile lymphoceles <10 cm can be successfully managed with drain placement, if drainage and sclerotherapy fail, laparoscopic unroofing should be considered. For patients with sterile lymphoceles ≥10 cm there should be a shared decision-making process to weigh the risk of a protracted course if a drain is utilized vs upfront laparoscopic unroofing.
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http://dx.doi.org/10.1016/j.urology.2020.06.004DOI Listing
September 2020

Hemosiderin deposition in papillary renal cell carcinoma and its potential to mask enhancement on MRI: analysis of 110 cases.

Eur Radiol 2020 Nov 9;30(11):6033-6041. Epub 2020 Jun 9.

Department of Diagnostic Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Objectives: To evaluate the relationship between imperceptible T1 enhancement of papillary renal cell carcinoma (pRCC) on MR and intratumoral hemosiderin deposition.

Methods: One hundred ten pRCCs (≤ 7 cm) were evaluated by MR with in- and opposed-phase spoiled gradient echo (GRE) and T1-weighted spoiled GRE with fat suppression before and after contrast. Hemosiderin deposition was assessed by SI and D on in- and opposed-phase images. SI and D are calculated as (SI - SI)/(SI) × 100, where SI and SI are tumor signal intensities on in- and opposed-phase images and (D)/(D), where D and D are tumor diameters on in- and opposed-phase images, respectively. The degree of tumor enhancement was classified as grade 1 (no), grade 2 (subtle), or grade 3 (definite). Tumor enhancement on CT was assessed when available.

Results: Five (5%), 10 (9%), and 95 (86%) tumors were categorized as grades 1, 2, and 3 enhancement, respectively. The mean SI was - 33.9, - 25.3, and 1.00, whereas the mean D was 1.26, 1.05, and 1.00 in tumors with grades 1, 2, and 3 enhancement, respectively. Tumors with grade 1 enhancement had significantly lower SI (p = 0.001) and higher D (p = 0.005) than those with grade 3 enhancement. Among six tumors with grade 1 or 2 enhancement and available CT, four tumors showed > 20 HU enhancement.

Conclusions: pRCC with no subjective enhancement on contrast-enhanced MR showed hemosiderin deposition evident by lower SI and higher D. Hemosiderin deposition might mask the tumor enhancement on MR.

Key Points: • 5% of papillary renal cell carcinoma showed imperceptible enhancement on contrast-enhanced MR. • Hemosiderin deposition in papillary renal cell carcinoma might mask the tumor enhancement on contrast-enhanced MR due to T2/T2*-shortening effects. • A renal lesion with extensive hemosiderin deposition but no perceptible enhancement on MR should be considered suspicious for papillary renal cell carcinoma.
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http://dx.doi.org/10.1007/s00330-020-06994-4DOI Listing
November 2020

Reply by Authors.

J Urol 2020 08 27;204(2):246. Epub 2020 May 27.

Decipher Biosciences Inc., Vancouver, British Columbia.

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http://dx.doi.org/10.1097/JU.0000000000000798.03DOI Listing
August 2020

Safety and Efficacy of Retrograde Pyeloperfusion for Ureteral Protection during Renal Tumor Cryoablation.

J Vasc Interv Radiol 2020 08 23;31(8):1249-1255. Epub 2020 May 23.

Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Purpose: To determine safety and efficacy of retrograde pyeloperfusion for ureteral protection during cryoablation of adjacent renal tumors.

Materials And Methods: Retrospective review of 155 patients treated with renal cryoablation, including adjunctive retrograde pyeloperfusion, from 2005 to 2019 was performed. Ice contacted the ureter in 67 of the 155 patients who represented the study cohort. Median patient age was 68 years old (interquartile range [61, 74]), 52 patients (78%) were male, and 37 tumors (55%) were clear cell histology. Mean tumor size was 3.4 ± 1.3 cm, and 42 tumors (63%) were located at the lower pole. Treatment-related complication and oncologic outcomes were recorded based on a review of post-procedural images and chart review.

Results: Technical success of cryoablation was attained in 67 cases (100%), and technical success of pyeloperfusion was attained in 66 cases (99%). A total of 13 patients (19.4%) experienced SIR major C or D complications related to the procedure, including hemorrhage (n = 4), urine leak (n = 3), transient urinary obstruction (n = 2), pulmonary embolism (n = 1), hypertensive urgency (n = 1), acute respiratory failure (n = 1), and ureteropelvic junction (UPJ) stricture (n = 1). No complications were attributable to pyeloperfusion. Three of 45 patients with biopsy-proven renal cell carcinoma experienced local recurrence resulting in local recurrence-free survival of 92% (95% confidence interval, 81.5%-100%) 3 years after ablation.

Conclusions: Retrograde pyeloperfusion of the renal collecting system is a relatively safe and efficacious option for ureteral protection during renal tumor cryoablation. This adjunctive procedure should be considered for patients in whom cryoablation of a renal mass could potentially involve the ureter.
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http://dx.doi.org/10.1016/j.jvir.2019.11.039DOI Listing
August 2020

Timing and distribution of early renal cell carcinoma recurrences stratified by pathological nodal status in M0 patients at the time of nephrectomy.

Int J Urol 2020 Jul 18;27(7):618-622. Epub 2020 May 18.

Departments of, Department of, Urology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: To evaluate the timing and distribution of first renal cell carcinoma metastasis after nephrectomy stratified by nodal status.

Methods: We evaluated patients treated with nephrectomy for sporadic, unilateral renal cell carcinoma between 1970 and 2011 who subsequently developed distant metastasis to three or fewer sites. Site-specific metastases-free 2-year survival rates were estimated using the Kaplan-Meier method. Associations of nodal status with time to metastasis were evaluated using multivariable Cox regression models.

Results: A total of 1049 patients met the inclusion criteria (135 pN1, 914 pN0/x patients). The median time to identification of first distant metastasis for pN1 patients was 0.4 years (interquartile range 0.2-1.1 years) versus 2.2 years (interquartile range 0.6-6.0 years) in pN0/x patients. The most common site of metastasis was to the lung, but this occurred earlier in pN1 patients (median 0.3 years vs 2.0 years). pN1 was associated with significantly lower site-specific 2-year metastases-free survival when compared with pN0/x for lung (37% vs 70%, P < 0.001), bone (63% vs 87%, P < 0.001), non-regional lymph nodes (60% vs 96%, P < 0.001) and liver metastases (79% vs 91%, P < 0.001). On multivariable analysis, pN1 status remained significantly associated with lung, bone, and non-regional lymph node (all P < 0.001) metastases, but it was no longer associated with liver metastases (P = 0.3).

Conclusions: pN1 nodal status in M0 patients treated with nephrectomy for renal cell carcinoma is associated with more frequent early metastasis to sites conferring poor prognosis when compared with pN0/x. Our findings highlight the importance of rigorous, early surveillance though the multimodal use of a comprehensive history, physical, laboratory and radiological studies, as outlined in societal guidelines.
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http://dx.doi.org/10.1111/iju.14261DOI Listing
July 2020

Simultaneous versus staged partial nephrectomies for bilateral synchronous solid renal masses.

Urol Oncol 2020 07 10;38(7):640.e13-640.e22. Epub 2020 May 10.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Objectives: The optimal management approach for synchronous bilateral renal masses is unknown, particularly regarding surgical sequencing of bilateral partial nephrectomy (PN). We evaluated the impact of simultaneous vs. staged bilateral PN on renal functional, perioperative, and oncologic outcomes.

Patients And Methods: We reviewed our institutional nephrectomy registry to identify patients who underwent simultaneous or staged (within 6 months) bilateral PN for nonmetastatic bilateral synchronous solid renal masses between 1980 and 2015. Short-term and long-term renal function changes were assessed at 3 and 12 months, respectively. Perioperative outcomes were pooled across staged surgeries by taking the sum of each outcome. Local recurrence-free, distant metastases-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method. Outcomes were compared by surgical sequencing approach. A sensitivity analysis was performed that grouped approaches by preoperative intent.

Results: Among the 107 patients studied, 77 (72%) underwent simultaneous and 30 (28%) underwent staged PN. The majority of PN were performed by open approach. Clinicopathologic features were similar between groups. Patients who underwent simultaneous PN had lower mean short-term (-6% vs. -24%, P = 0.015) and median long-term (-4% vs. -22%, P < 0.001) reduction in eGFR vs. staged PN, respectively. Furthermore, patients with simultaneous PN had lower pooled length of stay (median 6 vs. 8 days, P < 0.001), rate of urine leak (3% vs. 17%, P = 0.018), and rate of high-grade complications (8% vs. 23%, P = 0.044), relative to staged PN, respectively. However, on sensitivity analysis, only differences in long term reduction in estimated glomerular filtration rate and length of stay remained. There were no significant differences in oncologic outcomes between groups.

Conclusions: Our results suggest that when technically feasible, simultaneous PN yields comparable outcomes vs. staged PN, offering a reasonable surgical sequencing approach for patients presenting with bilateral synchronous renal masses.
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http://dx.doi.org/10.1016/j.urolonc.2020.04.002DOI Listing
July 2020

Sporadic Angiomyolipomas Growth Kinetics While on Everolimus: Results of a Phase II Trial.

J Urol 2020 Sep 6;204(3):531-537. Epub 2020 Apr 6.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas.

Materials And Methods: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus.

Results: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects.

Conclusions: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.
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http://dx.doi.org/10.1097/JU.0000000000001065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695484PMC
September 2020

Distribution of Molecular Subtypes in Muscle-invasive Bladder Cancer Is Driven by Sex-specific Differences.

Eur Urol Oncol 2020 08 20;3(4):420-423. Epub 2020 Mar 20.

Department of Urology, University of California San Francisco, San Francisco, CA, USA. Electronic address:

Muscle-invasive bladder cancer (MIBC) is a sex-biased cancer with a higher incidence in men but worse outcomes in women. The root cause behind these observations remains unclear. To investigate whether sex-specific tumor biology could explain the differences in clinical behavior of MIBC, we analyzed the transcriptome profiles from transurethral resected bladder tumors of 1000 patients. Female tumors expressed higher levels of basal- and immune-associated genes, while male tumors expressed higher levels of luminal markers. Using molecular subtyping, we found that the rates of the basal/squamous subtype were higher in females than in males. Males were enriched with tumors of the luminal papillary (LumP) and neuroendocrine-like subtypes. Male MIBC tumors had higher androgen response activity across all luminal subtypes and male patients with LumP tumors were younger. Taken together, these data confirm differences in molecular subtypes based on sex. The role of the androgen response pathway in explaining subtype differences between men and women should be studied further. PATIENT SUMMARY: We explored the sex-specific biology of bladder cancer in 1000 patients and found that women had more aggressive cancer with higher immune activity. Men tended toward less aggressive tumors that showed male hormone signaling, suggesting that male hormones may influence the type of bladder cancer that a patient develops.
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http://dx.doi.org/10.1016/j.euo.2020.02.010DOI Listing
August 2020

Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non-muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis.

Eur Urol Oncol 2020 06 20;3(3):318-340. Epub 2020 Mar 20.

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Context: Currently, there is no standard of care for patients with non-muscle-invasive bladder cancer (NMIBC) who recur despite bacillus Calmette-Guerin (BCG) therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.

Objective: To systematically synthesize and describe the efficacy and safety of current and emerging treatments for NMIBC patients after treatment with BCG.

Evidence Acquisition: A systematic literature search of MEDLINE, Embase, and the Cochrane Controlled Register of Trials (period limited to January 2007-June 2019) was performed. Abstracts and presentations from major conference proceedings were also reviewed. Randomized controlled trials were assessed using the Cochrane risk of bias tool. Data for single-arm trials were pooled using a random-effect meta-analysis with the proportions approach. Trials were grouped based on the minimum number of prior BCG courses required before enrollment and further stratified based on the proportion of patients with carcinoma in situ (CIS).

Evidence Synthesis: Thirty publications were identified with data from 23 trials for meta-analysis, of which 17 were single arm. Efficacy and safety outcomes varied widely across studies. Heterogeneity across trials was reduced in subgroup analyses. The pooled 12-mo response rates were 24% (95% confidence interval [CI]: 16-32%) for trials with two or more prior BCG courses and 36% (95% CI: 25-47%) for those with one or more prior BCG courses. In a subgroup analysis, inclusion of ≥50% of patients with CIS was associated with a lower response.

Conclusions: The variability in efficacy and safety outcomes highlights the need for consistent endpoint reporting and patient population definitions. With promising emerging treatments currently in development, efficacious and safe therapeutic options are urgently needed for this difficult-to-treat patient population.

Patient Summary: We examined the efficacy and safety outcomes of treatments for non-muscle-invasive bladder cancer after bacillus Calmette-Guerin therapy. Outcomes varied across studies and patient populations, but emerging treatments currently in development show promising efficacy.
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http://dx.doi.org/10.1016/j.euo.2020.02.006DOI Listing
June 2020

Cost-Effectiveness of Maintenance bacillus Calmette-Guérin for Intermediate and High Risk Nonmuscle Invasive Bladder Cancer.

J Urol 2020 Sep 19;204(3):442-449. Epub 2020 Mar 19.

Department of Urology, Mayo Clinic, Rochester, Minnesota.

Purpose: While guidelines support the use of maintenance bacillus Calmette-Guérin for patients with intermediate and high risk nonmuscle invasive bladder cancer, in an era of bacillus Calmette-Guérin shortage we explored the cost-effectiveness of maintenance bacillus Calmette-Guérin.

Materials And Methods: A Markov model compared the cost-effectiveness of maintenance bacillus Calmette-Guérin to surveillance after induction bacillus Calmette-Guérin for intermediate/high risk nonmuscle invasive bladder cancer from a U.S. Medicare perspective. Five-year oncologic outcomes, toxicity rates and utility values were extracted from the literature. Univariable and multivariable sensitivity analyses were conducted. A willingness to pay threshold of $100,000 per quality adjusted life year was considered cost-effective.

Results: At 5 years mean costs per patient were $14,858 and $13,973 for maintenance bacillus Calmette-Guérin and surveillance, respectively, with quality adjusted life years of 4.046 for both, making surveillance the dominant strategy. On sensitivity analysis full dose and 1/3 dose maintenance bacillus Calmette-Guérin became cost-effective if the absolute reduction in 5-year progression was greater than 2.1% and greater than 0.76%, respectively. On further sensitivity analysis full dose and 1/3 dose maintenance bacillus Calmette-Guérin became cost-effective when maintenance bacillus Calmette-Guérin toxicity equaled surveillance toxicity. In multivariable sensitivity analyses using 100,000 Monte-Carlo microsimulations, full dose and 1/3 dose maintenance bacillus Calmette-Guérin was cost-effective in 17% and 39% of microsimulations, respectively.

Conclusions: Neither full dose nor 1/3 dose maintenance bacillus Calmette-Guérin appears cost-effective for the entire population of patients with intermediate/high risk nonmuscle invasive bladder cancer. These data support prioritizing maintenance bacillus Calmette-Guérin for the subset of patients with high risk nonmuscle invasive bladder cancer most likely to experience progression, in particular those who tolerated induction bacillus Calmette-Guérin well. Overall, our findings support the American Urological Association policy statement to allocate bacillus Calmette-Guérin for induction rather than maintenance therapy during times of bacillus Calmette-Guérin shortage.
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http://dx.doi.org/10.1097/JU.0000000000001023DOI Listing
September 2020

Emulating Target Clinical Trials of Radical Nephrectomy With or Without Lymph Node Dissection for Renal Cell Carcinoma.

Urology 2020 Jun 4;140:98-106. Epub 2020 Mar 4.

Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, MA. Electronic address:

Objective: To emulate two target clinical trials of radical nephrectomy (RN) with lymph node dissection (LND) vs radical nephrectomy alone.

Methods: Using the National Cancer Database, we separately emulated an index trial of patients with cT1-3cN0cM0 renal cell carcinoma (RCC), designed to resemble EORTC 30881 ("index trial emulation"), and a hypothetical trial of patients at increased risk for lymph node metastases with cT1-4cN0-1cM0 RCC ("high-risk trial emulation"). A propensity score for LND was estimated using preoperative features (Model 1) or preoperative and pathologic features (Model 2). The associations of LND with overall survival (OS) were estimated using Cox regression with stabilized inverse probability weights.

Results: A total of 67,388 patients were included in the index trial emulation. Median follow-up was 49.2 (interquartile range 27.2-74.3) months. LND was not associated with improved OS when adjusting using either Model 1 (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.20-1.33; P <.0001) or Model 2 (HR 1.13; 95% CI 1.07-1.20; P <.0001). A total of 69,477 patients were included in the high-risk trial emulation. Median follow-up was 48.6 (interquartile range 26.6-73.8) months. LND was not associated with improved OS when adjusting using either Model 1 (HR 1.24; 95% CI 1.18-1.30; P <.0001) or Model 2 (HR 1.09; 95% CI 1.04-1.16; P = .001). In sensitivity analyses, LND was not associated with improved OS across cN stage, pT stage, tumor grade, histologic subtype, or probability of pN1 disease.

Conclusion: In observational analyses, that emulate target trials representing EORTC 30881 and a trial of LND in high-risk RCC, LND was not associated with improved OS.
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http://dx.doi.org/10.1016/j.urology.2020.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255934PMC
June 2020