Academic Appointments

Administrative Appointments

  • Chief of Urology Division, VA Palo Alto Health Care System (2021 - Present)
  • Director of Urologic Oncology, VA Palo Alto Health Care System (2010 - Present)
  • Cancer Liason Physician, Commission on Cancer - VA Palo Alto Health Care System (2010 - 2020)

Honors & Awards

  • Faculty Mentor Award, Stanford Biodesign Program (2012)
  • Developmental Cancer Research Award, Stanford Cancer Institute (2011 - 2013)
  • Career Development Award (K23), The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2010 - 2015)

Professional Education

  • MS, Stanford University School of Medicine, Epidemiology (2013)
  • Fellowship, UCLA, Minimally Invasive Surgery / Endourology (2008)
  • Residency, UCLA, Urology (2007)
  • Internship, UCLA, Surgery (2002)
  • MD, Northwestern University Medical School, Honors Program Medical Education (2001)
  • BA, Northwestern University, Biology (1996)

Current Research and Scholarly Interests

Our research aims to improve the global quality of care for patients with Urologic Cancer with a particular focus on kidney cancer. We are investigating novel proteomic platforms and assays to diagnose kidney cancer and predict response to therapy. We are evaluating the comparative effectiveness of various kidney cancer surgeries and their impact on chronic kidney disease and its downstream effects. We are applying epidemiology, bioinformatics, and health services methods to urologic conditions.

2021-22 Courses

Stanford Advisees

All Publications

  • Removing Race from eGFR calculations: Implications for Urologic Care. Urology Vilson, F. L., Schmidt, B., White, L., Soerensen, S. J., Ganesan, C., Pao, A. C., Enemchukwu, E., Chertow, G. M., Leppert, J. T. 2021


    Equations estimating the glomerular filtration rate are important clinical tools in detecting and managing kidney disease. Urologists extensively use these equations in clinical decision making. For example, the estimated glomerular function rate is used when considering the type of urinary diversion following cystectomy, selecting systemic chemotherapy in managing urologic cancers, and deciding the type of cross-sectional imaging in diagnosing or staging urologic conditions. However, these equations, while widely accepted, are imprecise and adjust for race which is a social, not a biologic construct. The recent killings of unarmed Black Americans in the US have amplified the discussion of racism in healthcare and has prompted institutions to reconsider the role of race in eGFR equations and raced-based medicine. Urologist should be aware of the consequences of removing race from these equations, potential alternatives, and how these changes may affect Black patients receiving urologic care.

    View details for DOI 10.1016/j.urology.2021.03.018

    View details for PubMedID 33798557

  • Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS). Urologic oncology Velaer, K., Thomas, I. C., Yang, J., Kapphahn, K., Metzner, T. J., Golla, A., Hoerner, C. R., Fan, A. C., Master, V., Chertow, G. M., Brooks, J. D., Patel, C. J., Desai, M., Leppert, J. T. 2021


    Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test.The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24-1.48), leukocyte count (HR 1.40, 95%CI 1.30-1.51), platelet count (HR 1.36, 95%CI 1.27-1.51), and hemoglobin (HR 0.79, 95%CI 0.72-0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61-0.72), ferritin (HR 1.25, 95%CI 1.08-1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23-1.40), and C-reactive protein (HR 1.70, 95%CI 1.14-2.53).Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies.

    View details for DOI 10.1016/j.urolonc.2021.08.011

    View details for PubMedID 34580027

  • Laboratory-wide association study of survival with prostate cancer. Cancer Sohlberg, E. M., Thomas, I., Yang, J., Kapphahn, K., Velaer, K. N., Goldstein, M. K., Wagner, T. H., Chertow, G. M., Brooks, J. D., Patel, C. J., Desai, M., Leppert, J. T. 2020


    BACKGROUND: Estimates of overall patient health are essential to inform treatment decisions for patients diagnosed with cancer. The authors applied XWAS methods, herein referred to as "laboratory-wide association study (LWAS)", to evaluate associations between routinely collected laboratory tests and survival in veterans with prostate cancer.METHODS: The authors identified 133,878 patients who were diagnosed with prostate cancer between 2000 and 2013 in the Veterans Health Administration using any laboratory tests collected within 6 months of diagnosis (3,345,083 results). Using the LWAS framework, the false-discovery rate was used to test the association between multiple laboratory tests and survival, and these results were validated using training, testing, and validation cohorts.RESULTS: A total of 31 laboratory tests associated with survival met stringent LWAS criteria. LWAS confirmed markers of prostate cancer biology (prostate-specific antigen: hazard ratio [HR], 1.07 [95% confidence interval (95% CI), 1.06-1.08]; and alkaline phosphatase: HR, 1.22 [95% CI, 1.20-1.24]) as well laboratory tests of general health (eg, serum albumin: HR, 0.78 [95% CI, 0.76-0.80]; and creatinine: HR, 1.05 [95% CI, 1.03-1.07]) and inflammation (leukocyte count: HR, 1.23 [95% CI, 1.98-1.26]; and erythrocyte sedimentation rate: HR, 1.33 [95% CI, 1.09-1.61]). In addition, the authors derived and validated separate models for patients with localized and advanced disease, identifying 28 laboratory markers and 15 laboratory markers, respectively, in each cohort.CONCLUSIONS: The authors identified routinely collected laboratory data associated with survival for patients with prostate cancer using LWAS methodologies, including markers of prostate cancer biology, overall health, and inflammation. Broadening consideration of determinants of survival beyond those related to cancer itself could help to inform the design of clinical trials and aid in shared decision making.LAY SUMMARY: This article examined routine laboratory tests associated with survival among veterans with prostate cancer. Using laboratory-wide association studies, the authors identified 31 laboratory tests associated with survival that can be used to inform the design of clinical trials and aid patients in shared decision making.

    View details for DOI 10.1002/cncr.33341

    View details for PubMedID 33237577

  • Analysis of Primary Hyperparathyroidism Screening Among US Veterans With Kidney Stones. JAMA surgery Ganesan, C., Weia, B., Thomas, I., Song, S., Velaer, K., Seib, C. D., Conti, S., Elliott, C., Chertow, G. M., Kurella Tamura, M., Leppert, J. T., Pao, A. C. 2020


    Importance: Approximately 3% to 5% of patients with kidney stones have primary hyperparathyroidism (PHPT), a treatable cause of recurrent stones. However, the rate of screening for PHPT in patients with kidney stones remains unknown.Objectives: To estimate the prevalence of parathyroid hormone (PTH) testing in veterans with kidney stones and hypercalcemia and to identify the demographic, geographic, and clinical characteristics of veterans who were more or less likely to receive PTH testing.Design, Setting, and Participants: This cohort study obtained Veterans Health Administration (VHA) health records from the Corporate Data Warehouse for veterans who received care in 1 of the 130 VHA facilities across the United States from January 1, 2008, through December 31, 2013. Historical encounters, medical codes, and laboratory data were assessed. Included patients had diagnostic or procedural codes for kidney or ureteral stones, and excluded patients were those with a previous serum PTH level measurement. Data were collected from January 1, 2006, to December 31, 2014. Data analysis was conducted from June 1, 2019, to January 31, 2020.Exposures: Elevated serum calcium concentration measurement between 6 months before and 6 months after kidney stone diagnosis.Main Outcomes and Measures: Proportion of patients with a serum PTH level measurement and proportion of patients with biochemical evidence of PHPT who underwent parathyroidectomy.Results: The final cohort comprised 7561 patients with kidney stones and hypercalcemia and a mean (SD) age of 64.3 (12.3) years. Of these patients, 7139 were men (94.4%) and 5673 were white individuals (75.0%). The proportion of patients who completed a serum PTH level measurement was 24.8% (1873 of 7561). Across the 130 VHA facilities included in the study, testing rates ranged from 4% to 57%. The factors associated with PTH testing included the magnitude of calcium concentration elevation (odds ratio [OR], 1.07 per 0.1 mg/dL >10.5 mg/dL; 95% CI, 1.05-1.08) and the number of elevated serum calcium concentration measurements (OR, 1.08 per measurement >10.5 mg/dL; 95% CI, 1.06-1.10) as well as visits to both a nephrologist and a urologist (OR, 6.57; 95% CI, 5.33-8.10) or an endocrinologist (OR, 4.93; 95% CI, 4.11-5.93). Of the 717 patients with biochemical evidence of PHPT, 189 (26.4%) underwent parathyroidectomy within 2 years of a stone diagnosis.Conclusions and Relevance: This cohort study found that only 1 in 4 patients with kidney stones and hypercalcemia were tested for PHPT in VHA facilities and that testing rates varied widely across these facilities. These findings suggest that raising clinician awareness to PHPT screening indications may improve evaluation for parathyroidectomy, increase the rates of detection and treatment of PHPT, and decrease recurrent kidney stone disease.

    View details for DOI 10.1001/jamasurg.2020.2423

    View details for PubMedID 32725208

  • The Urine Albumin-Creatinine Ratio and Kidney Function after Nephrectomy. The Journal of urology Sun, A. J., Thomas, I., Velaer, K. N., Ganesan, C., Song, S., Pao, A. C., Wagner, T. H., Brooks, J. D., Chertow, G. M., Leppert, J. T. 2020: 101097JU0000000000001005


    BACKGROUND: Patients with kidney cancer are at risk of developing chronic kidney disease (CKD) after radical and partial nephrectomy. We sought to determine if the urine albumin-creatinine ratio (UACR) is independently associated with progressive CKD after nephrectomy.METHODS: We performed a cohort study based within a large, integrated health care system. We identified patients who underwent radical or partial nephrectomy from 2004 to 2014 with UACR measured in the 12 months prior to surgery. We fit multivariable models to determine if the UACR was associated with the time to CKD progression (defined as reaching stage 4 or 5 CKD, eGFR <30 mL/min/1.73m2). We performed a parallel analysis measuring the time to stage 3b, 4 or 5 CKD (eGFR <45 mL/min/1.73m2) among patients with normal or near-normal preoperative kidney function (eGFR ≥60 mL/min/1.73 m2). We also examined the association between UACR and survival.RESULTS: 1930 patients underwent radical or partial nephrectomy and had preoperative UACR and pre- and post-operative eGFR. Of these, 658 (34%) and 157 (8%) had moderate (UACR 30-300mg/g) or severe albuminuria (UACR > 300mg/g), respectively. Albuminuria severity was independently associated with progressive CKD after radical (moderate albuminuria HR 1.7, 95%CI 1.4-2.2; severe albuminuria HR 2.3, 95%CI 1.7-3.1) and partial nephrectomy (moderate albuminuria HR 1.8, 95%CI 1.2-2.7; severe albuminuria HR 4.3, 95%CI 2.7-7.0). Albuminuria was also associated with survival following radical and partial nephrectomy.CONCLUSIONS: In patients undergoing radical or partial nephrectomy, the severity of albuminuria can stratify risk of progressive CKD.

    View details for DOI 10.1097/JU.0000000000001005

    View details for PubMedID 32125227

  • Development of a DNA Methylation-Based Diagnostic Signature to Distinguish Benign Oncocytoma From Renal Cell Carcinoma. JCO precision oncology Brennan, K. n., Metzner, T. J., Kao, C. S., Massie, C. E., Stewart, G. D., Haile, R. W., Brooks, J. D., Hitchins, M. P., Leppert, J. T., Gevaert, O. n. 2020; 4


    A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma.We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC.Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma.This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens.

    View details for DOI 10.1200/PO.20.00015

    View details for PubMedID 33015531

    View details for PubMedCentralID PMC7529536

  • The m6A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America Xiao, Y. n., Thakkar, K. N., Zhao, H. n., Broughton, J. n., Li, Y. n., Seoane, J. A., Diep, A. N., Metzner, T. J., von Eyben, R. n., Dill, D. L., Brooks, J. D., Curtis, C. n., Leppert, J. T., Ye, J. n., Peehl, D. M., Giaccia, A. J., Sinha, S. n., Rankin, E. B. 2020


    Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.

    View details for DOI 10.1073/pnas.2000516117

    View details for PubMedID 32817424

  • Organoid Modeling of the Tumor Immune Microenvironment. Cell Neal, J. T., Li, X., Zhu, J., Giangarra, V., Grzeskowiak, C. L., Ju, J., Liu, I. H., Chiou, S., Salahudeen, A. A., Smith, A. R., Deutsch, B. C., Liao, L., Zemek, A. J., Zhao, F., Karlsson, K., Schultz, L. M., Metzner, T. J., Nadauld, L. D., Tseng, Y., Alkhairy, S., Oh, C., Keskula, P., Mendoza-Villanueva, D., De La Vega, F. M., Kunz, P. L., Liao, J. C., Leppert, J. T., Sunwoo, J. B., Sabatti, C., Boehm, J. S., Hahn, W. C., Zheng, G. X., Davis, M. M., Kuo, C. J. 2018; 175 (7): 1972


    Invitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor Tcell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.

    View details for PubMedID 30550791

  • Multiregion Quantification of Extracellular Signal-regulated Kinase Activity in Renal Cell Carcinoma. European urology oncology Hoerner, C. R., Massoudi, R., Metzner, T. J., Stell, L., O'Rourke, J. J., Kong, C. S., Liliental, J. E., Brooks, J. D., Sabatti, C., Leppert, J. T., Fan, A. C. 2018


    To personalize treatment for renal cell carcinoma (RCC), it would be ideal to confirm the activity of druggable protein pathways within individual tumors. We have developed a high-resolution nanoimmunoassay (NIA) to measure protein activity with high precision in scant specimens (eg, fine needle aspirates [FNAs]). Here, we used NIA to determine whether protein activation varied in different regions of RCC tumors. Since most RCC therapies target angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) receptor, we quantified phosphorylation of extracellular signal-regulated kinase (ERK), a downstream effector of the VEGF signaling pathway. In 90 ex vivo FNA biopsies sampled from multiple regions of 38 primary clear cell RCC tumors, ERK phosphorylation differed among patients. In contrast, within individual patients, we found limited intratumoral heterogeneity of ERK phosphorylation. Our results suggest that measuring ERK in a single FNA may be representative of ERK activity in different regions of the same tumor. As diagnostic and therapeutic protein biomarkers are being sought, NIA measurements of protein signaling may increase the clinical utility of renal mass biopsy and allow for the application of precision oncology for patients with localized and advanced RCC. PATIENT SUMMARY: In this report, we applied a new approach to measure the activity of extracellular signal-regulated kinase (ERK), a key cancer signaling protein, in different areas within kidney cancers. We found that ERK activity varied between patients, but that different regions within individual kidney tumors showed similar ERK activity. This suggests that a single biopsy of renal cell carcinoma may be sufficient to measure protein signaling activity to aid in precision oncology approaches.

    View details for DOI 10.1016/j.euo.2018.09.011

    View details for PubMedID 31412000

  • Incident CKD after Radical or Partial Nephrectomy. Journal of the American Society of Nephrology : JASN Leppert, J. T., Lamberts, R. W., Thomas, I. C., Chung, B. I., Sonn, G. A., Skinner, E. C., Wagner, T. H., Chertow, G. M., Brooks, J. D. 2017


    The comparative effectiveness of partial nephrectomy versus radical nephrectomy to preserve kidney function has not been well established. We determined the risk of clinically significant (stage 4 and higher) CKD after radical or partial nephrectomy among veterans treated for kidney cancer in the Veterans Health Administration (2001-2013). Among patients with preoperative eGFR≥30 ml/min per 1.73 m(2), the incidence of CKD stage 4 or higher after radical (n=9759) or partial nephrectomy (n=4370) was 7.9% overall. The median time to stage 4 or higher CKD after surgery was 5 months, after which few patients progressed. In propensity score-matched cohorts, partial nephrectomy associated with a significantly lower relative risk of incident CKD stage 4 or higher (hazard ratio, 0.34; 95% confidence interval [95% CI], 0.26 to 0.43, versus radical nephrectomy). In a parallel analysis of patients with normal or near-normal preoperative kidney function (eGFR≥60 ml/min per 1.73 m(2)), partial nephrectomy was also associated with a significantly lower relative risk of incident CKD stage 3b or higher (hazard ratio, 0.15; 95% CI, 0.11 to 0.19, versus radical nephrectomy) in propensity score-matched cohorts. Competing risk regression models produced consistent results. Finally, patients treated with a partial nephrectomy had reduced risk of mortality (hazard ratio, 0.55; 95% CI, 0.49 to 0.62). In conclusion, compared with radical nephrectomy, partial nephrectomy was associated with a marked reduction in the incidence of clinically significant CKD and with enhanced survival. Postoperative decline in kidney function occurred mainly in the first year after surgery and appeared stable over time.

    View details for PubMedID 29018140

  • Renal Morbidity Following Radical Cystectomy in Patients with Bladder Cancer. European urology open science Schmidt, B., Velaer, K. N., Thomas, I., Ganesan, C., Song, S., Pao, A. C., Thong, A. E., Liao, J. C., Chertow, G. M., Skinner, E. C., Leppert, J. T. 1800; 35: 29-36


    Background: Patients with chronic kidney disease (CKD) are poor candidates for standard treatments for muscle-invasive bladder cancer (MIBC) and may be more likely to experience adverse outcomes when diagnosed with MIBC.Objective: To investigate factors associated with the development of advanced CKD following radical cystectomy.Design setting and participants: Using national Veterans Health Administration utilization files, we identified 3360 patients who underwent radical cystectomy for MIBC between 2004 and 2018.Outcome measurements and statistical analysis: We examined factors associated with the development of advanced CKD (estimated glomerular filtration rate [eGFR] of <30 ml/min/1.73 m2) after radical cystectomy using multivariable logistic and proportional hazard regression, with and without consideration of competing risks. We examined survival using Kaplan-Meier product limit estimates and proportional hazard regression.Results and limitations: The median age at surgery was 67 yr and the mean preoperative eGFR was 69.1 ± 20.3 ml/min/1.73 m2. Approximately three out of ten patients (n = 962, 29%) progressed to advanced CKD within 12 mo. Older age (hazard ratio [HR] per 5-yr increase 1.15, 95% confidence interval [CI] 1.10-1.20), preoperative hydronephrosis (HR 1.50, 95% CI 1.29-1.76), adjuvant chemotherapy (HR 1.19, 95% CI 1.00-1.41), higher comorbidity index (HR 1.13, 95% CI 1.11-1.16 per point), and lower baseline kidney function (HR 0.75, 95% CI 0.73-0.78) were associated with the development of advanced CKD. Baseline kidney function at the time of surgery was associated with survival. Generalizability is limited due to the predominantly male cohort.Conclusions: Impaired kidney function at baseline is associated with progression to advanced CKD and mortality after radical cystectomy. Preoperative kidney function should be incorporated into risk stratification algorithms for patients undergoing radical cystectomy.Patient summary: Impaired kidney function at baseline is associated with progression to advanced chronic kidney disease and mortality after radical cystectomy.

    View details for DOI 10.1016/j.euros.2021.11.001

    View details for PubMedID 35024629

  • Twenty-four-hour Urine Testing and Urinary Stone Disease Recurrence in Veterans UROLOGY Song, S., Thomas, I., Ganesan, C., Velaer, K. N., Chertow, G. M., Pao, A. C., Leppert, J. T. 2022; 159: 33-40
  • Learning from the "tail end" of de-implementation: the case of chemical castration for localized prostate cancer. Implementation science communications Skolarus, T. A., Forman, J., Sparks, J. B., Metreger, T., Hawley, S. T., Caram, M. V., Dossett, L., Paniagua-Cruz, A., Makarov, D. V., Leppert, J. T., Shelton, J. B., Stensland, K. D., Hollenbeck, B. K., Shahinian, V., Sales, A. E., Wittmann, D. A. 2021; 2 (1): 124


    BACKGROUND: Men with prostate cancer are often treated with the suppression of testosterone through long-acting injectable drugs termed chemical castration or androgen deprivation therapy (ADT). In most cases, ADT is not an appropriate treatment for localized prostate cancer, indicating low-value care. Guided by the Theoretical Domains Framework (TDF) and the Behavior Change Wheel's Capability, Opportunity, Motivation Model (COM-B), we conducted a qualitative study to identify behavioral determinants of low-value ADT use to manage localized prostate cancer, and theory-based opportunities for de-implementation strategy development.METHODS: We used national cancer registry and administrative data from 2016 to 2017 to examine the variation in low-value ADT use across Veterans Health Administration facilities. Using purposive sampling, we selected high- and low-performing sites to conduct 20 urology provider interviews regarding low-value ADT. We coded transcripts into TDF domains and mapped content to the COM-B model to generate a conceptual framework for addressing low-value ADT practices.RESULTS: Our interview findings reflected provider perspectives on prescribing ADT as low-value localized prostate cancer treatment, including barriers and facilitators to de-implementing low-value ADT. We characterized providers as belonging in 1 of 3 categories with respect to low-value ADT use: 1) never prescribe 2); willing, under some circumstances, to prescribe: and 3) prescribe as an acceptable treatment option. Provider capability to prescribe low-value ADT depended on their knowledge of localized prostate cancer treatment options (knowledge) coupled with interpersonal skills to engage patients in educational discussion (skills). Provider opportunity to prescribe low-value ADT centered on the environmental resources to inform ADT decisions (e.g., multi-disciplinary review), perceived guideline availability, and social roles and influences regarding ADT practices, such as prior training. Provider motivation involved goals of ADT use, including patient preferences, beliefs in capabilities/professional confidence, and beliefs about the consequences of prescribing or not prescribing ADT.CONCLUSIONS: Use of the TDF domains and the COM-B model enabled us to conceptualize provider behavior with respect to low-value ADT use and clarify possible areas for intervention to effect de-implementation of low-value ADT prescribing in localized prostate cancer.TRIAL REGISTRATION: , NCT03579680.

    View details for DOI 10.1186/s43058-021-00224-8

    View details for PubMedID 34711274

  • Postoperative opioid-free ureteroscopy discharge: A quality initiative pilot protocol. Current urology Kasman, A. M., Schmidt, B., Spradling, K., Chow, C., Hunt, R., Wu, M., Sockol, A., Liao, J., Leppert, J. T., Shah, J., Conti, S. L. 2021; 15 (3): 176-180


    Background: Opioids are commonly prescribed after ureteroscopy. With an increasing adoption of ureteroscopy for management of urolithiasis, this subset of patients is at high risk for opioid dependence. We sought to pilot an opioid-free discharge protocol for patients undergoing ureteroscopy for urolithiasis.Materials and methods: A prospective cohort study was performed of all patients undergoing ureteroscopy for urolithiasis and compared them to a historical control group. An opioid-free discharge protocol was initiated targeting all areas of surgical care from June 20th, 2019 to September 20th, 2019 as part of an institutional quality improvement initiative. Demographic and surgical data were collected as were morphine equivalent doses (MEDs) prescribed at discharge, postoperative measures including phone calls, clinic visits, and emergency room visits for pain.Results: Between October 1st, 2017 and February 1st, 2018, a total of 54 patients who underwent ureteroscopy were identified and comprised the historical control cohort while 54 prospective patients met the inclusion criteria since institution of the quality improvement initiative. There were no statistically significant differences in baseline patient demographics or surgical characteristics between the 2 patient groups. Total 37% of the intervention group had a preexisting opioid prescription versus 42.6% of the control group with no difference in preoperative MED (p = 0.55). The intervention group had a mean MED of 12.03 at discharge versus 110.5 in the control cohort (p ≤ 0.001). At discharge 3.7% of the intervention group received an opioid prescription versus 88.9% of the control group (p < 0.001). Overall, there was no difference in postoperative pain related phone calls (p = 1.0) or emergency room visits (p = 1.0).Conclusions: An opioid-free discharge protocol can dramatically reduce opioid prescription at discharge following ureteroscopy for urinary calculi without affecting postoperative measures such as phone calls, clinic visits, or subsequent prescriptions.

    View details for DOI 10.1097/CU9.0000000000000025

    View details for PubMedID 34552459



    To determine whether 24-hour urine testing in Veterans with USD (urinary stone disease) reduces or delays urinary stone recurrence.Cohort study of national health record data from Veterans Health Administration from 2007 through 2013. We utilized a study population of 130,129 Veterans with USD based on diagnostic or procedural codes and excluded those with USD claims in the two years before cohort entry. We then created a propensity-score matched cohort of 14,854 Veterans based on completion of 24-hour urine testing within 6 months of stone diagnosis. Primary outcome was time-to-next clinically significant stone event, defined as an emergency department visit, inpatient admission related to a urinary stone, or urologic stone procedure with 5-year follow up.Of 14,854 Veterans in the propensity-score matched cohort, 8,560 (57.6%) experienced a recurrent USD event. Completion of 24-hour urine testing was associated with a higher risk of developing a second stone event (hazard ratio (HR) 1.17, 95% confidence interval (95% CI) 1.12-1.22). Among Veterans with known recurrent disease, we examined time to a third stone event. In this cohort of 4,736 patients, completion of 24-hour urine testing was not associated with a higher risk of developing a third stone event (HR 1.06, 95% CI 0.99-1.12).Completion of 24-hour urine testing was not associated with a reduction in urinary stone recurrence. These findings challenge the validity of a longstanding recommendation in general medicine, nephrology, and urology practice.

    View details for Web of Science ID 000693688000745

    View details for PubMedID 34688771

  • Risk of Postpartum Urinary Stone Disease in Women with History of Urinary Stone Disease During Pregnancy. Journal of endourology Spradling, K., Zhang, C. A., Pao, A. C., Liao, J. C., Leppert, J. T., Elliott, C. S., Conti, S. L. 2021


    OBJECTIVE: To determine the risk of postpartum urinary stone disease in women with a history of stone disease during pregnancy.METHODS: Using the Optum de-identified Clinformatics Datamart we identified pregnant women with urinary stone disease in the United States between January 2003 to December 2017 by standardized ICD-9, ICD-10, and CPT code criteria. We limited the cohort to include women without evidence of urinary stone disease prior to pregnancy. We abstracted patient demographic characteristics, clinical risk factors for stone disease, and data for urinary stone disease encounters and related procedures after pregnancy. Encounters occurring within 1 year of pregnancy were excluded. Cox proportional hazard models were used to analyze for significance.RESULTS: We identified a total of 1,395,783 pregnant women with a median postpartum follow-up of 4.0 years, including 5,971 (0.4%) women diagnosed with a urinary stone during pregnancy. Of these, 736 (12.3%) had an additional urinary stone diagnosis claim after pregnancy, compared with 13,275 (0.95%) women without a history of stone disease during pregnancy (p < 0.0001). In multivariable proportional hazards models urinary stone disease during pregnancy (HR 12.8, 95% CI [11.8 - 13.8]) was independently associated with a higher hazard of urinary stone disease after pregnancy.CONCLUSION: Women urinary stone disease during pregnancy were more likely to present with recurrent urinary stone disease after pregnancy. Given the 1 in 8 chance of needing further care, women with history of stone disease during pregnancy may benefit from risk counseling, surveillance, or secondary prevention efforts in the postpartum period.

    View details for DOI 10.1089/end.2021.0223

    View details for PubMedID 34235965

  • Interaction between race and prostate cancer treatment benefit in the Veterans Health Administration. Cancer Rude, T., Walter, D., Ciprut, S., Kelly, M. D., Wang, C., Fagerlin, A., Langford, A. T., Lepor, H., Becker, D. J., Li, H., Loeb, S., Ravenell, J., Leppert, J. T., Makarov, D. V. 2021


    BACKGROUND: Studies have demonstrated that Black men may undergo definitive prostate cancer (CaP) treatment less often than men of other races, but it is unclear whether they are avoiding overtreatment of low-risk disease or experiencing a reduction in appropriate care. The authors' aim was to assess the role of race as it relates to treatment benefit in access to CaP treatment in a single-payer population.METHODS: The authors used the Veterans Health Administration (VHA) Corporate Data Warehouse to perform a retrospective cohort study of veterans diagnosed with low- or intermediate-risk CaP between 2011 and 2017.RESULTS: The authors identified 35,427 men with incident low- or intermediate-risk CaP. When they controlled for covariates, Black men had 1.05 times the odds of receiving treatment in comparison with non-Black men (P < .001), and high-treatment-benefit men had 1.4 times the odds of receiving treatment in comparison with those in the low-treatment-benefit group (P < .001). The interaction of race and treatment benefit was significant, with Black men in the high-treatment-benefit category less likely to receive treatment than non-Black men in the same treatment category (odds ratio, 0.89; P < .001).CONCLUSIONS: Although race does appear to influence the receipt of definitive treatment in the VHA, this relationship varies in the context of the patient's treatment benefit, with Black men receiving less definitive treatment in high-benefit situations. The influence of patient race at high treatment benefit levels invites further investigation into the driving forces behind this persistent disparity in this consequential group.

    View details for DOI 10.1002/cncr.33643

    View details for PubMedID 34184271

  • Reply to the Editorial Comment on: Using an Automated Electronic Health Record Score To Estimate Life Expectancy In Men Diagnosed With Prostate Cancer In The Veterans Health Administration. Urology. 2021. Urology Soerensen, S. J., Thomas, I., Schmidt, B., Daskivich, T., Skolarus, T. A., Jackson, C., Osborne, T. F., Chertow, G. M., Brooks, J. D., Rehkopf, D., Leppert, J. T. 2021


    OBJECTIVES: To determine if an automatically calculated electronic health record score can estimate intermediate-term life expectancy in men with prostate cancer to provide guideline concordant care.METHODS: We identified all men (n=36,591) diagnosed with prostate cancer in 2013-2015 in the VHA. Of the 36,591, 35,364 (96.6%) had an available Care Assessment Needs (CAN) score (range: 0-99) automatically calculated in the 30 days prior to the date of diagnosis. It was designed to estimate short-term risks of hospitalization and mortality. We fit unadjusted and multivariable Cox proportional hazards regression models to determine the association between the CAN score and overall survival among men with prostate cancer. We compared CAN score performance to two established comorbidity measures: The Charlson Comorbidity Index and Prostate Cancer Comorbidity Index (PCCI).RESULTS: Among 35,364 men, the CAN score correlated with overall stage, with mean scores of 46.5 (±22.4), 58.0 (±24.4), and 68.1 (±24.3) in localized, locally advanced, and metastatic disease, respectively. In both unadjusted and adjusted models for prostate cancer risk, the CAN score was independently associated with survival (HR=1.23 95%CI 1.22-1.24 & adjusted HR=1.17 95%CI 1.16-1.18 per 5-unit change, respectively). The CAN score (overall C-Index 0.74) yielded better discrimination (AUC=0.76) than PCCI (AUC=0.65) or Charlson Comorbidity Index (AUC=0.66) for 5-year survival.CONCLUSIONS: The CAN score is strongly associated with intermediate-term survival following a prostate cancer diagnosis. The CAN score is an example of how learning health care systems can implement multi-dimensional tools to provide fully automated life expectancy estimates to facilitate patient-centered cancer care.

    View details for DOI 10.1016/j.urology.2021.05.056

    View details for PubMedID 34139251

  • Association of parathyroidectomy with 5-year clinically significant kidney stone events in patients with primary hyperparathyroidism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Seib, C. D., Ganesan, C., Arnow, K. D., Suh, I., Pao, A. C., Leppert, J. T., Tamura, M. K., Trickey, A. W., Kebebew, E. 2021


    OBJECTIVE: Patients with primary hyperparathyroidism (PHPT) are at increased risk of kidney stones. Guidelines recommend parathyroidectomy in PHPT patients with a history of stone disease. This study aimed to compare the 5-year incidence of clinically significant kidney stone events in patients with PHPT treated with parathyroidectomy vs. non-operative management.METHODS: We performed a longitudinal cohort study of patients with PHPT in a national commercial insurance claims database (2006-2019). Propensity score inverse probability weighting-adjusted multivariable regression models were calculated.RESULTS: We identified 7,623 patients ≥35 years-old with continuous enrollment >1 year before and >5 years after PHPT diagnosis. 2,933 patients (38.5%) were treated with parathyroidectomy. The cohort had a mean age of 66.5 years, 78.1% were female, 72.4% were White. Over 5 years, the unadjusted incidence of ≥1 kidney stone event was higher in patients managed with parathyroidectomy compared to those managed non-operatively overall (5.4% vs. 4.1%) and among those with a history of kidney stones at PHPT diagnosis (17.9% vs. 16.4%). On multivariable analysis, parathyroidectomy was associated with no statistically significant difference in the odds of 5-year kidney stone event among patients with a history of kidney stones (OR 1.03, 95%CI 0.71-1.50) or those without history of kidney stones (OR 1.16, 95%CI 0.84-1.60).CONCLUSION: Based on this claims analysis, there was no difference in the odds of 5-year kidney stone events in PHPT patients treated with parathyroidectomy vs. non-operative management. Time-horizon for benefit should be considered when making treatment decisions for PHPT based on risk of kidney stone events.

    View details for DOI 10.1016/j.eprac.2021.06.004

    View details for PubMedID 34126246

  • Development and Validation of an Interpretable Artificial Intelligence Model to Predict 10-Year Prostate Cancer Mortality CANCERS Bibault, J., Hancock, S., Buyyounouski, M. K., Bagshaw, H., Leppert, J. T., Liao, J. C., Xing, L. 2021; 13 (12)


    Prostate cancer treatment strategies are guided by risk-stratification. This stratification can be difficult in some patients with known comorbidities. New models are needed to guide strategies and determine which patients are at risk of prostate cancer mortality. This article presents a gradient-boosting model to predict the risk of prostate cancer mortality within 10 years after a cancer diagnosis, and to provide an interpretable prediction. This work uses prospective data from the PLCO Cancer Screening and selected patients who were diagnosed with prostate cancer. During follow-up, 8776 patients were diagnosed with prostate cancer. The dataset was randomly split into a training (n = 7021) and testing (n = 1755) dataset. Accuracy was 0.98 (±0.01), and the area under the receiver operating characteristic was 0.80 (±0.04). This model can be used to support informed decision-making in prostate cancer treatment. AI interpretability provides a novel understanding of the predictions to the users.

    View details for DOI 10.3390/cancers13123064

    View details for Web of Science ID 000666025900001

    View details for PubMedID 34205398

  • Accurate differentiation of renal tumour pathological subtypes using a machine learning model of epigenetic markers Rossi, S., Newsham, I., Pita, S., Park, G., Lach, R., Babbage, A., Smith, C., Brennan, K., Mitchell, T., Warren, A., Gevaert, O., Leppert, J., Stewart, G. D., Massie, C. E., Samarajiwa, S. A. ELSEVIER. 2021: S811
  • Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Yin, Q., Yu, W., Grzeskowiak, C. L., Li, J., Huang, H., Guo, J., Chen, L., Wang, F., Zhao, F., von Boehmer, L., Metzner, T. J., Leppert, J. T., Chien, Y., Kuo, C. J., Davis, M. M. 2021; 118 (21)
  • Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities. Proceedings of the National Academy of Sciences of the United States of America Yin, Q., Yu, W., Grzeskowiak, C. L., Li, J., Huang, H., Guo, J., Chen, L., Wang, F., Zhao, F., von Boehmer, L., Metzner, T. J., Leppert, J. T., Chien, Y., Kuo, C. J., Davis, M. M. 2021; 118 (21)


    Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.

    View details for DOI 10.1073/pnas.2016168118

    View details for PubMedID 34021082

  • Osteoporosis, Fractures, and Bone Mineral Density Screening in Veterans With Kidney Stone Disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Ganesan, C., Thomas, I., Romero, R., Song, S., Conti, S., Elliott, C., Chertow, G. M., Tamura, M. K., Leppert, J. T., Pao, A. C. 2021


    Whether a link exists between kidney stone disease and osteoporosis or fractures remains an open question. In this retrospective cohort study, we sought to determine the prevalence of osteoporosis and fractures and rate of bone mineral density screening by dual-energy X-ray absorptiometry (DXA) in patients with kidney stone disease. We examined nationwide data from the Veterans Health Administration and identified 531,431 patients with kidney stone disease between 2007 and 2015. Nearly 1 in 4 patients (23.6%, 95% confidence interval [CI] 23.5-23.7) with kidney stone disease had a prevalent diagnosis of osteoporosis or fracture. In patients with no prior history of osteoporosis or bone mineral density assessment before a kidney stone diagnosis, 9.1% were screened with DXA after their kidney stone diagnosis, of whom 20% were subsequently diagnosed with osteoporosis. Our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, a group less well recognized as at risk for osteoporosis or fractures. © 2021 American Society for Bone and Mineral Research (ASBMR).

    View details for DOI 10.1002/jbmr.4260

    View details for PubMedID 33655611

  • Costs of Robotic-Assisted Radical Prostatectomy 1 Year After Surgery: Pay Now and Save Later? JAMA network open Schmidt, B., Leppert, J. T. 2021; 4 (3): e212548

    View details for DOI 10.1001/jamanetworkopen.2021.2548

    View details for PubMedID 33749763

  • The Impact of Comorbidity and Age on Timing of Androgen Deprivation Therapy in Men with Biochemical Recurrence after Radical Prostatectomy Editorial Comment UROLOGY PRACTICE Schmidt, B., Leppert, J. T. 2021; 8 (2): 245
  • In Search of Clinical Biomarkers of Response to Checkpoint Inhibitor Therapy in Renal Cell Carcinoma. JAMA network open Fan, A. C., Leppert, J. T. 2021; 4 (1): e2035120

    View details for DOI 10.1001/jamanetworkopen.2020.35120

    View details for PubMedID 33496791

  • Facility-Level Variation in Dialysis Use and Mortality Among Older Veterans With Incident Kidney Failure. JAMA network open Bradshaw, C. n., Thomas, I. C., Montez-Rath, M. E., Lorenz, K. A., Asch, S. M., Leppert, J. T., Wang, V. n., O'Hare, A. M., Kurella Tamura, M. n. 2021; 4 (1): e2034084


    Current guidelines lack consensus regarding the treatment of patients who may not benefit from dialysis; this lack of consensus may be associated with the substantial variation in dialysis use and outcomes across health care facilities.To assess the degree to which variation in dialysis use and mortality was associated with patient rather than facility characteristics and to distinguish which features identified the US Department of Veterans Affairs (VA) facilities with high rates of dialysis use.This cohort study analyzed data of veterans with stage 3 or 4 chronic kidney disease that progressed to kidney failure between January 1, 2011, and December 31, 2014. These patients received care from VA facilities across the US. Data sources included laboratory and administrative records from the VA, Medicare, and United States Renal Data System. Data analysis was conducted from August 1, 2019, to September 1, 2020.The primary exposure was the VA facility in which patients received most of their care before the onset of incident kidney failure defined as the first occurrence of either a sustained estimated glomerular filtration rate of less than 15 mL/min/1.73 m2 or the initiation of maintenance dialysis.The primary outcomes were dialysis use and mortality within 2 years of incident kidney failure. Median rate ratio was used to quantify facility-level variation, and variance partition coefficient was used to quantify the sources of unexplained variation.The cohort included 8695 older veterans with a mean (SD) age of 78.8 (7.5) years who were predominantly male (8573 [99%]) and White (6102 [70%]) individuals treated at 108 VA facilities. The observed frequency of dialysis use across facilities ranged from 25.0% to 81.4%, with a median (interquartile range [IQR]) rate of 51.7% (48.4%-60.0%). The observed frequency of mortality across facilities ranged from 27.2% to 60.0%, with a median (IQR) rate of 45.2% (41.2%-48.6%). The median rate ratio (adjusted for multiple patient and facility characteristics) was 1.40 for dialysis use and 1.08 for mortality. The unexplained variation in both outcomes mainly derived from patient characteristics rather than facility characteristics. No correlation was found between dialysis use and mortality at the facility level (correlation coefficient = 0.03).This study found sizable variation in dialysis use for older adults that was poorly correlated with facility-level mortality rates and was not accounted for by differences in measured patient and facility characteristics. These findings suggest opportunities to improve the degree to which dialysis use practices align with the values, goals, and preferences of older adults with kidney failure.

    View details for DOI 10.1001/jamanetworkopen.2020.34084

    View details for PubMedID 33449098

  • AUTHOR REPLY. Urology Soerensen, S. J., Thomas, I. C., Schmidt, B., Daskivich, T. J., Skolarus, T. A., Jackson, C., Osborne, T. F., Chertow, G. M., Brooks, J. D., Rehkopf, D. H., Leppert, J. T. 2021; 155: 76

    View details for DOI 10.1016/j.urology.2021.05.058

    View details for PubMedID 34489006

  • Association of 152 Biomarker Reference Intervals with All-Cause Mortality in Participants of a General United States Survey from 1999 to 2010. Clinical chemistry Pho, N. n., Manrai, A. K., Leppert, J. T., Chertow, G. M., Ioannidis, J. P., Patel, C. J. 2021; 67 (3): 500–507


    Physicians sometimes consider whether or not to perform diagnostic testing in healthy people, but it is unknown whether nonextreme values of diagnostic tests typically encountered in such populations have any predictive ability, in particular for risk of death. The goal of this study was to quantify the associations among population reference intervals of 152 common biomarkers with all-cause mortality in a representative, nondiseased sample of adults in the United States.The study used an observational cohort derived from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the United States population consisting of 6 survey waves from 1999 to 2010 with linked mortality data (unweighted N = 30 651) and a median followup of 6.1 years. We deployed an X-wide association study (XWAS) approach to systematically perform association testing of 152 diagnostic tests with all-cause mortality.After controlling for multiple hypotheses, we found that the values within reference intervals (10-90th percentiles) of 20 common biomarkers used as diagnostic tests or clinical measures were associated with all-cause mortality, including serum albumin, red cell distribution width, serum alkaline phosphatase, and others after adjusting for age (linear and quadratic terms), sex, race, income, chronic illness, and prior-year healthcare utilization. All biomarkers combined, however, explained only an additional 0.8% of the variance of mortality risk. We found modest year-to-year changes, or changes in association from survey wave to survey wave from 1999 to 2010 in the association sizes of biomarkers.Reference and nonoutlying variation in common biomarkers are consistently associated with mortality risk in the US population, but their additive contribution in explaining mortality risk is minor.

    View details for DOI 10.1093/clinchem/hvaa271

    View details for PubMedID 33674838

  • "Following up on an improperly drawn screening test: The PSA Dilemma". The American journal of medicine Bergman, J., Schmidt, B., Leppert, J. T. 2020

    View details for DOI 10.1016/j.amjmed.2020.10.013

    View details for PubMedID 33171101

  • Evaluation of Patient Treatment Preferences for 15-20mm Kidney Stones: A Conjoint Analysis. Journal of endourology Spradling, K., Bhambhvani, H. P., Chang, T. C., Pao, A. C., Liao, J. C., Leppert, J. T., Welk, B., Harris, C. R., Conti, S. L., Elliott, C. S. 2020


    INTRODUCTION AND OBJECTIVE: Ureteroscopy (URS) and percutaneous nephrolithotomy (PCNL) are standard surgical treatments for intermediate-size (15-20mm) kidney stones but differ in their postoperative recovery, stone-free rates, and complication risks. We aimed to evaluate what affects patient treatment preferences.METHODS: Patients with urinary stone disease completed a choice-based conjoint analysis exercise assessing four treatment attributes associated with URS and PCNL. A sensitivity analysis using a market simulator was performed and the relative importance of each attribute was calculated. Differences in treatment preferences by demographic subgroup were assessed.RESULTS: A total of 58 patients completed the conjoint analysis exercise. Stone-free rate was the most important treatment attribute while length of hospital stay and cosmesis were less important. Overall, sensitivity analysis based on market simulation scenarios predicted almost equal preference for URS (52.4%) compared to PCNL (47.6%) for treatment of an intermediate-size stone. Older patients (>65 yo) expressed stronger preferences for lower infection rates and shorter hospital stays, and were more likely to prefer URS (67.2%, 95% CI: 52 - 82.5%) compared to younger patients (20-34 yo) (20.3%, 95% CI: 0 - 41.5%) who preferred higher procedure success rates and fewer repeat procedures.CONCLUSION: Conjoint analysis predicts nearly equal patient preference for URS or PCNL for the treatment of intermediate-size kidney stones. Older patients prefer the lower UTI risk and shorter hospital stay associated with URS, while younger patients prefer higher stone-free rates associated with PCNL. These results can help guide urologists in counseling patients and improve the shared decision-making process.

    View details for DOI 10.1089/end.2020.0370

    View details for PubMedID 32867549

  • Life expectancy estimates for patients diagnosed with prostate cancer in the Veterans Health Administration. Urologic oncology Sohlberg, E. M., Thomas, I., Yang, J., Kapphahn, K., Daskivich, T. J., Skolarus, T. A., Shelton, J. B., Makarov, D. V., Bergman, J., Bang, C. K., Goldstein, M. K., Wagner, T. H., Brooks, J. D., Desai, M., Leppert, J. T. 2020


    PURPOSE: Accurate life expectancy estimates are required to inform prostate cancer treatment decisions. However, few models are specific to the population served or easily implemented in a clinical setting. We sought to create life expectancy estimates specific to Veterans diagnosed with prostate cancer.MATERIALS AND METHODS: Using national Veterans Health Administration electronic health records, we identified Veterans diagnosed with prostate cancer between 2000 and 2015. We abstracted demographics, comorbidities, oncologic staging, and treatment information. We fit Cox Proportional Hazards models to determine the impact of age, comorbidity, cancer risk, and race on survival. We stratified life expectancy estimates by age, comorbidity and cancer stage.RESULTS: Our analytic cohort included 145,678 patients. Survival modeling demonstrated the importance of age and comorbidity across all cancer risk categories. Life expectancy estimates generated from age and comorbidity data were predictive of overall survival (C-index 0.676, 95% CI 0.674-0.679) and visualized using Kaplan-Meier plots and heatmaps stratified by age and comorbidity. Separate life expectancy estimates were generated for patients with localized or advanced disease. These life expectancy estimates calibrate well across prostate cancer risk categories.CONCLUSIONS: Life expectancy estimates are essential to providing patient-centered prostate cancer care. We developed accessible life expectancy estimation tools for Veterans diagnosed with prostate cancer that can be used in routine clinical practice to inform medical-decision making.

    View details for DOI 10.1016/j.urolonc.2020.05.015

    View details for PubMedID 32674954

  • Association of renal cell carcinoma subtypes with race/ethnicity and comorbid medical conditions Lichtensztajn, D. Y., Hofer, B. M., Leppert, J. T., Brooks, J. D., Chung, B., Shah, S. A., DeRouen, M. C., Gomez, S. L., Cheng, I. AMER ASSOC CANCER RESEARCH. 2020
  • Testicular cancer in Hispanics: Incidence of subtypes over time according to neighborhood sociodemographic factors in California DeRouen, M. C., McKinley, M., Shah, S. A., Borno, H. T., Aoki, R., Lichtensztajn, D. Y., Leppert, J. T., Brooks, J. D., Chung, B., Gomez, S. L., Cheng, I. AMER ASSOC CANCER RESEARCH. 2020
  • Testicular cancer in Hispanics: incidence of subtypes over time according to neighborhood sociodemographic factors in California. Cancer causes & control : CCC DeRouen, M. C., McKinley, M., Shah, S. A., Borno, H. T., Aoki, R., Lichtensztajn, D. Y., Leppert, J. T., Brooks, J. D., Chung, B. I., Gomez, S. L., Cheng, I. 2020


    PURPOSE: Hispanic men in the USA experience the second-highest incidence rate of testicular germ cell tumors (TGCTs), behind non-Hispanic (NH) White men, and have experienced steep increases in TGCT in recent decades. It is unknown whether increases in incidence differ according to neighborhood sociodemographic factors.METHODS: We conducted a population-based study of n=3759 Hispanic and n=8469 NH White men (n=12,228 total) diagnosed with TGCT in California during the three most recent pericensal periods. We calculated incidence rates according to neighborhood socioeconomic status (nSES) and among Hispanics, according to ethnic enclave. We calculated incidence rate ratios to compare rates across nSES and ethnic enclave and to examine changes in rates over pericensal time periods according to these neighborhood factors for major histologic types (i.e., seminoma and nonseminoma).RESULTS: Hispanic men residing in high SES, compared to low SES, neighborhoods had greater incidence of seminoma and nonseminoma testicular cancer across pericensal periods, as did Hispanic men in low enclave (less ethnic), compared to high enclave, neighborhoods. Between the periods 1998-2002 and 2008-2012, Hispanic men residing in low SES neighborhoods experienced a 39% increased incidence of seminoma, while those residing in low and middle SES neighborhoods experienced 87% and 48% increased incidence of nonseminoma, respectively.CONCLUSION: While TGCT incidence has increased among all Hispanic men, incidence increases appear to be driven disproportionately by those residing in lower SES and lower enclave neighborhoods, particularly for nonseminoma.

    View details for DOI 10.1007/s10552-020-01311-2

    View details for PubMedID 32440828

  • Screening Rates for Primary Aldosteronism in Resistant Hypertension: A Cohort Study. Hypertension (Dallas, Tex. : 1979) Jaffe, G., Gray, Z., Krishnan, G., Stedman, M., Zheng, Y., Han, J., Chertow, G. M., Leppert, J. T., Bhalla, V. 2020: HYPERTENSIONAHA11914359


    Resistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 persons with hypertension and excluded persons with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 persons ages 18 to <90 from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in persons with resistant hypertension was 2.1%. Screened persons were younger (55.9±13.3 versus 65.5±11.6 years; P<0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; P=0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; P<0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; P=0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; P=0.04) than unscreened persons. Screened persons had significantly higher rates of prescription for calcium channel blockers, mixed alpha/beta-adrenergic receptor antagonists, sympatholytics, and vasodilators, and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (P=0.20). In conclusion, only 2.1% of eligible persons received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.

    View details for DOI 10.1161/HYPERTENSIONAHA.119.14359

    View details for PubMedID 32008436

  • Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U.S. Veterans : A Retrospective Cohort Study. Annals of internal medicine Cohen, J. B., Cohen, D. L., Herman, D. S., Leppert, J. T., Byrd, J. B., Bhalla, V. n. 2020


    Primary aldosteronism is a common cause of treatment-resistant hypertension. However, evidence from local health systems suggests low rates of testing for primary aldosteronism.To evaluate testing rates for primary aldosteronism and evidence-based hypertension management in patients with treatment-resistant hypertension.Retrospective cohort study.U.S. Veterans Health Administration.Veterans with apparent treatment-resistant hypertension (n = 269 010) from 2000 to 2017, defined as either 2 blood pressures (BPs) of at least 140 mm Hg (systolic) or 90 mm Hg (diastolic) at least 1 month apart during use of 3 antihypertensive agents (including a diuretic), or hypertension requiring 4 antihypertensive classes.Rates of primary aldosteronism testing (plasma aldosterone-renin) and the association of testing with evidence-based treatment using a mineralocorticoid receptor antagonist (MRA) and with longitudinal systolic BP.4277 (1.6%) patients who were tested for primary aldosteronism were identified. An index visit with a nephrologist (hazard ratio [HR], 2.05 [95% CI, 1.66 to 2.52]) or an endocrinologist (HR, 2.48 [CI, 1.69 to 3.63]) was associated with a higher likelihood of testing compared with primary care. Testing was associated with a 4-fold higher likelihood of initiating MRA therapy (HR, 4.10 [CI, 3.68 to 4.55]) and with better BP control over time.Predominantly male cohort, retrospective design, susceptibility of office BPs to misclassification, and lack of confirmatory testing for primary aldosteronism.In a nationally distributed cohort of veterans with apparent treatment-resistant hypertension, testing for primary aldosteronism was rare and was associated with higher rates of evidence-based treatment with MRAs and better longitudinal BP control. The findings reinforce prior observations of low adherence to guideline-recommended practices in smaller health systems and underscore the urgent need for improved management of patients with treatment-resistant hypertension.National Institutes of Health.

    View details for DOI 10.7326/M20-4873

    View details for PubMedID 33370170

  • Urinary Stone Disease in Pregnancy: Current Management Practices in a Large National Cohort. Urology Spradling, K. n., Sohlberg, E. M., Li, S. n., Zhang, C. A., Brubaker, W. D., Dallas, K. n., Pao, A. C., Liao, J. n., Leppert, J. T., Elliott, C. S., Chung, B. I., Min, G. E., Conti, S. L. 2020


    To define current national practice patterns of imaging modalities and urologic procedures in pregnant women with urinary stone disease.Using the IBM® MarketScan® national insurance claims database, we identified pregnant women with urinary stone disease and their corresponding gestational age between 2011-2016 using administrative claims data. We then assessed each encounter for urinary stone disease or stone-related urologic procedure during their pregnancy. We abstracted demographic information as well as codes for stone procedures and imaging.We identified 14,298 pregnant women with urinary stone disease during the study period. Of the 12,315 undergoing abdominal imaging (86.1%), magnetic resonance imaging (MRI) in 2.8%, x-ray in 9%, and ultrasound in 74.3%. Computed tomography was not used as a diagnostic modality during pregnancy. Procedural intervention was performed in 749 women (5.2%): 476 (3.3%) ureteral stent placement without definitive stone treatment, 93 (0.6%) percutaneous nephrostomy placement, and 180 (1.3%) ureteroscopy (URS) for definitive stone treatment. URS was most commonly performed before 34 weeks gestation with only 27 cases (15%) performed after.This large national cohort reveals the current imaging and procedural practice patterns for urinary stone disease during pregnancy and provides a critical baseline as these practice patterns evolve in the future.

    View details for DOI 10.1016/j.urology.2020.03.050

    View details for PubMedID 32311447

  • Urinary Stone Disease in Pregnancy: A Claims-Based Analysis of 1.4 Million Patients. The Journal of urology Sohlberg, E. M., Brubaker, W. D., Zhang, C. A., Anderegg, L. D., Dallas, K., Song, S., Ganesan, C., Chertow, G., Pao, A., Liao, J., Leppert, J. T., Elliott, C. S., Conti, S. L. 2019: 101097JU0000000000000657


    PURPOSE: Urinary stone disease during pregnancy is poorly understood but is thought to be associated with increased maternal and fetal morbidity. We sought to determine the prevalence of urinary stone disease in pregnancy and whether urinary stone disease during pregnancy is associated with adverse pregnancy outcomes.MATERIALS AND METHODS: We identified all pregnant women from 2003 through 2017 in the Optum national insurance claims database. We used diagnosis claims to identify urinary stone disease and assess medical comorbidity. We established the prevalence of urinary stone disease during pregnancy, stratified by week of pregnancy. We further evaluated associations among urinary stone disease and maternal complications and pregnancy outcomes in both univariable and multivariable analyses.RESULTS: Urinary stone disease affects 8/1000 pregnancies and is more common in white women and women with more comorbid conditions. In fully adjusted models, pregnancies complicated by urinary stone disease had higher rates of adverse fetal outcomes, including prematurity and spontaneous abortions. This analysis is limited by its retrospective administrative claims design.CONCLUSIONS: The rate of urinary stone disease during pregnancy is higher than previously reported. Urinary stone disease is associated with adverse pregnancy outcomes.

    View details for DOI 10.1097/JU.0000000000000657

    View details for PubMedID 31738114

  • Association between PSA values and surveillance quality after prostate cancer surgery. Cancer medicine Chapman, C. H., Caram, M. E., Radhakrishnan, A., Tsodikov, A., Deville, C., Burns, J., Zaslavsky, A., Chang, M., Leppert, J. T., Hofer, T., Sales, A. E., Hawley, S. T., Hollenbeck, B. K., Skolarus, T. A. 2019


    BACKGROUND: Although prostate-specific antigen (PSA) testing is used for prostate cancer detection and posttreatment surveillance, thresholds in these settings differ. The screening cutoff of 4.0ng/mL may be inappropriately used during postsurgery surveillance, where 0.2ng/mL is typically used, creating missed opportunities for effective salvage radiation treatment. We performed a study to determine whether guideline concordance with annual postoperative PSA surveillance increases when PSA values exceed 4ng/mL, which represents a screening threshold that is not relevant after surgery.METHODS: We used US Veterans Health Administration data to perform a retrospective longitudinal cohort study of men diagnosed with nonmetastatic prostate cancer from 2005 to 2008 who underwent radical prostatectomy. We used logistic regression to examine the association between postoperative PSA levels and receipt of an annual PSA test.RESULTS: Among 10400 men and 38901 person-years of follow-up, annual guideline concordance decreased from 95% in year 1 to 79% in year 7. After adjustment, guideline concordance was lower for the youngest and oldest men, Black, and unmarried men. Guideline concordance significantly increased as PSA exceeded 4ng/mL (adjusted odds ratio 2.20 PSA>4-6ng/mL vs PSA>1-4ng/mL, 95% confidence interval 1.20-4.03; P=.01).CONCLUSIONS: Guideline concordance with prostate cancer surveillance increased when PSA values exceeded 4ng/mL, suggesting a screening threshold not relevant after prostate cancer surgery, where 0.2ng/mL is considered treatment failure, is impacting cancer surveillance quality. Clarification of PSA thresholds for early detection vs cancer surveillance, as well as emphasizing adherence for younger and Black men, appears warranted.

    View details for DOI 10.1002/cam4.2663

    View details for PubMedID 31691526

  • Diabetes Medications, Prostate-Specific Antigen Values, and the Chemoprevention of Prostate Cancer. JAMA network open Velaer, K. N., Leppert, J. T. 2019; 2 (11): e1914644

    View details for DOI 10.1001/jamanetworkopen.2019.14644

    View details for PubMedID 31693117

  • The Harms of Overdiagnosis and Overtreatment in Patients with Small Renal Masses: A Mini-review EUROPEAN UROLOGY FOCUS Sohlberg, E. M., Metzner, T. J., Leppert, J. T. 2019; 5 (6): 943–45
  • Ultra-low-dose CT: An Effective Follow-up Imaging Modality for Ureterolithiasis. Journal of endourology Cheng, R. Z., Shkolyar, E., Chang, T. C., Spradling, K., Ganesan, C., Song, S., Pao, A. C., Leppert, J. T., Elliott, C. S., To'o, K., Conti, S. L. 2019


    BACKGROUND AND PURPOSE: Classically, abdominal X-ray (KUB), ultrasound or a combination of both have been routinely used for ureteral stone surveillance after initial diagnosis. More recently, ultra-low-dose CT (ULD CT) has emerged as a CT technique that reduces radiation dose while maintaining high sensitivity and specificity for urinary stone detection. We aim to evaluate our initial experience with ULD CT for patients with ureterolithiasis, measuring real-world radiation doses and stone detection performance.METHODS: We reviewed all ULD CT scans performed at the Veterans Affairs Palo Alto Health Care System between 2016 and 2018. We included patients with ureteral stones and calculated the mean effective radiation dose per scan. We determined stone location and size, if the stone was visible on the associated KUB or CT scout film, and if hydronephrosis was present. We performed logistic regression to identify variables associated with visibility on KUB or CT scout film and hydronephrosis.RESULTS: One-hundred and eighteen ULD scans were reviewed, of which 50 detected ureteral stones. The mean effective radiation dose was 1.04 ± 0.41 mSv. Of the ULD CTs that detected ureterolithiasis, 38% lacked visibility on KUB/CT scout film and had no associated hydronephrosis, suggesting they would be missed with a combination of KUB and ultrasound. Larger stones (OR: 1.40, 95% CI: 1.08-1.96 for every 1mm increase in stone size) were more likely to be detected by KUB/CT scout or ultrasound, while stones in the distal ureter (OR: 0.18, 95% CI: 0.03-0.81) were more likely to be missed by KUB/CT scout or hydronephrosis.CONCLUSION: Based on our institutions' initial experience with ULD CT, ULD CT detects small and distal ureteral stones that would likely be missed by KUB or ultrasound, while maintaining a low effective radiation dose. An ULD CT protocol should be considered when re-imaging for ureteral stones is necessary.

    View details for DOI 10.1089/end.2019.0574

    View details for PubMedID 31663371

  • Operating room preparedness for active shooter events. Surgery Leppert, J. T., Wren, S. M., Bergman, J. 2019

    View details for DOI 10.1016/j.surg.2019.08.009

    View details for PubMedID 31606195

  • Reply to Letter to the Editor Re: External Validation of the Prostate Cancer-specific Comorbidity Index (PCCI), a Claims-Based Tool for Prediction of Life Expectancy in Men with Prostate Cancer. The Journal of urology Daskivich, T. J., Thomas, I. C., Leppert, J. T. 2019: 101097JU0000000000000586

    View details for DOI 10.1097/JU.0000000000000586

    View details for PubMedID 31596670

  • S100A10 is a critical mediator of GAS6/AXL-induced angiogenesis in renal cell carcinoma. Cancer research Xiao, Y., Zhao, H., Tian, L., Nolley, R., Diep, A. N., Ernst, A., Fuh, K. C., Miao, Y. R., von Eyben, R., Leppert, J. T., Brooks, J. D., Peehl, D. M., Giaccia, A. J., Rankin, E. B. 2019


    Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC.

    View details for DOI 10.1158/0008-5472.CAN-19-1366

    View details for PubMedID 31585940

  • External Validation of the Prostate Cancer Specific Comorbidity Index: A Claims Based Tool for the Prediction of Life Expectancy in Men with Prostate Cancer JOURNAL OF UROLOGY Daskivich, T. J., Thomas, I., Luu, M., Shelton, J. B., Makarov, D., Skolarus, T. A., Leppert, J. T. 2019; 202 (3): 518–24
  • Postmarketing Analysis of Sipuleucel-T-The Importance of Real-World Data. JAMA network open Fan, A. C., Leppert, J. T. 2019; 2 (8): e199233

    View details for DOI 10.1001/jamanetworkopen.2019.9233

    View details for PubMedID 31411706

  • Prostate Magnetic Resonance Imaging Interpretation Varies Substantially Across Radiologists EUROPEAN UROLOGY FOCUS Sonn, G. A., Fan, R. E., Ghanouni, P., Wang, N. N., Brooks, J. D., Loening, A. M., Daniel, B. L., To'o, K. J., Thong, A. E., Leppert, J. T. 2019; 5 (4): 592–99
  • Characterising potential bone scan overuse amongst men treated with radical prostatectomy BJU INTERNATIONAL Kirk, P. S., Borza, T., Caram, M. V., Shumway, D. A., Makarov, D. V., Burns, J. A., Shelton, J. B., Leppert, J. T., Chapman, C., Chang, M., Hollenbeck, B. K., Skolarus, T. A. 2019; 124 (1): 55–61

    View details for DOI 10.1111/bju.14551

    View details for Web of Science ID 000471830900012

  • External Validation of the Prostate Cancer-Specific Comorbidity Index (PCCI), a Claims-Based Tool for Prediction of Life Expectancy in Men with Prostate Cancer. The Journal of urology Daskivich, T. J., Thomas, I., Luu, M., Shelton, J. B., Makarov, D. V., Skolarus, T. A., Leppert, J. T. 2019: 101097JU0000000000000287


    BACKGROUND: Accurate assessment of life expectancy (LE) is critical to treatment decision making for men with prostate cancer. We sought to externally validate the Prostate Cancer Comorbidity Index (PCCI) for prediction of long-term mortality in men with prostate cancer and operationalize it using claims data.METHODS: We conducted an observational study of 181,009 men with prostate cancer from the Veterans Affairs Health System diagnosed from 2000-2013. Overall mortality across PCCI scores was analyzed using Kaplan-Meier and Cox proportional hazards analysis. Discrimination and calibration were measured using c-index and mean prediction error, respectively.RESULTS: Among men with PCCI scores of 0, 1-2, 3-4, 5-6, 7-9, and 10+, 10-year overall mortality was 15%, 26%, 36%, 41%, 52%, and 69%, respectively. Multivariable Cox analysis showed an increasing hazard of mortality (95%CI) with higher PCCI scores: 1.22 (1.18-1.27), 1.69 (1.61-1.76), 2.08 (2.00-2.17), 2.88 (2.76-3.00), 4.50 (4.32-4.69) for scores of 1-2, 3-4, 5-6, 7-9, and 10+, respectively. C-index for prediction of overall mortality was 0.773. Mean absolute error for prediction of 10-year overall mortality was 0.032. Among men with clinically localized, Gleason ≤6 disease with LE<10 years and Gleason ≤7 disease with LE<5 years as defined by the PCCI, 3,999/12,185 (33%) and 1,038/3,930 (26%) men were treated with definitive local treatment, respectively.CONCLUSIONS: The PCCI is a claims-based, externally validated tool that predicts mortality in men with prostate cancer. Integration of the PCCI into clinical pathways may improve prostate cancer management through more accurate LE assessment.

    View details for PubMedID 31009286

  • The Harms of Overdiagnosis and Overtreatment in Patients with Small Renal Masses: A Mini-review. European urology focus Sohlberg, E. M., Metzner, T. J., Leppert, J. T. 2019


    Overdiagnosis and overtreatment refer to the detection and treatment of conditions that would not ultimately affect an individual's health. With increasing detection of small renal masses there is growing awareness of the overdiagnosis and overtreatment of these tumors, supported by studies showing that 15-30% of nephrectomy specimens are pathologically benign, and that many small renal cell carcinomas are indolent. The harms of overdiagnosis and overtreatment are numerous, including psychosocial stressors and renal morbidity, in addition to unnecessary surgical complications. A greater understanding of the potential harms of overdiagnosis and overtreatment is crucial as clinicians focus on optimizing patient selection for renal mass biopsy, active surveillance protocols, and minimally invasive surgery. PATIENT SUMMARY: In this mini-review we discuss the issues of overdiagnosis and overtreatment in patients with kidney cancer. We enumerate the risks of overdiagnosis and overtreatment, and examine the next steps towards preventing these harms.

    View details for PubMedID 30905599

  • Vasectomy and the risk of prostate cancer in a prospective US Cohort: Data from the NIH-AARP Diet and Health Study ANDROLOGY Davenport, M. T., Zhang, C. A., Leppert, J. T., Brooks, J. D., Eisenberg, M. L. 2019; 7 (2): 178–83

    View details for DOI 10.1111/andr.12570

    View details for Web of Science ID 000461886700007

  • Vasectomy and the risk of prostate cancer in a prospective US Cohort: Data from the NIH-AARP Diet and Health Study. Andrology Davenport, M. T., Zhang, C. A., Leppert, J. T., Brooks, J. D., Eisenberg, M. L. 2019


    BACKGROUND: Several studies have linked vasectomy with the risk of prostate cancer; however, this association has been attributed to selection bias. Since vasectomy is a common and effective form of contraception, these implications are significant. Therefore, we sought to test this association in a large observational cohort.OBJECTIVE: To evaluate the potential association between prior vasectomy and the risk of developing prostate cancer.MATERIALS AND METHODS: We evaluated the relationship between vasectomy and prostate cancer in the NIH-AARP Diet and Health Study. Of the 111,914 men, prostate cancer was identified in 13,885 men and vasectomies were performed in 48,657. We used multivariate analysis to examine the relationship between prostate cancer and vasectomy. We also performed propensity score-adjusted and propensity score-matched analysis.RESULTS: Men utilizing vasectomy were more likely to be ever married, fathers, educated, white, and screened for prostate cancer. During 4,251,863 person-years of follow-up, there was a small association between vasectomy and incident prostate cancer with a hazard ratio of 1.05 (95% CI, 1.01-1.11). However, no significant association was found when looking separately at prostate cancer by grade or stage. Conclusions were similar when using propensity adjustment and matching. Importantly, a significant interaction between vasectomy and PSA screening was identified.DISCUSSION: Estimates of the association between vasectomy and prostate cancer are sensitive to analytic method underscoring the tenuous nature of the connection. Given the differences between men who do and do not utilize vasectomy, selection bias appears likely to explain any identified association between vasectomy and prostate cancer.CONCLUSIONS: With over 20years of follow-up, no convincing relationship between vasectomy and prostate cancer of any grade was identified.

    View details for PubMedID 30714352

  • Comparative Effectiveness of Non-cisplatin First-line Therapies for Metastatic Urothelial Carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration EUROPEAN UROLOGY ONCOLOGY Vander Velde, N., Guerin, A., Ionescu-Ittu, R., Shi, S., Wu, E. Q., Lin, S., Hsu, L., Saum, K., de Ducla, S., Wang, J., Li, S., Thastrom, A., Liu, S., Shi, L., Leppert, J. T. 2019; 2 (1): 12–20
  • Comparative Effectiveness of Non-cisplatin First-line Therapies for Metastatic Urothelial Carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration. European urology oncology Vander Velde, N., Guerin, A., Ionescu-Ittu, R., Shi, S., Wu, E. Q., Lin, S., Hsu, L., Saum, K., de Ducla, S., Wang, J., Li, S., Thastrom, A., Liu, S., Shi, L., Leppert, J. T. 2019; 2 (1): 12–20


    BACKGROUND: First-line treatments for cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC) include carboplatin-based chemotherapy and checkpoint inhibitors such as atezolizumab (anti-PD-L1).OBJECTIVE: To compare overall survival (OS) among patients with mUC treated in the first-line setting with atezolizumab versus carboplatin-based chemotherapies (any carboplatin-based regimens or carboplatin-gemcitabine).DESIGN, SETTING, AND PARTICIPANTS: Cisplatin-ineligible patients with mUC from the phase 2 trial IMvigor210 ( NCT02951767) treated with atezolizumab and patients from the Veterans Health Administration (VHA) health care system (2006-2017, with IMvigor210 eligibility criteria applied using proxy measurements) treated according to normal clinical practice.INTERVENTIONS: IMvigor210 cohort 1 patients were treated with atezolizumab, and real-world VHA cohorts were treated with carboplatin-based regimens.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Entropy-balance weighting was applied to balance prespecified baseline patient characteristics. OS was analyzed using weighted Kaplan-Meier and Cox methods.RESULTS AND LIMITATIONS: The median OS was 15.0 mo with atezolizumab (n = 110), 12.1 mo with any carboplatin-based chemotherapy (n = 282), and 8.7 mo with carboplatin-gemcitabine (n = 120). An OS benefit occurred with atezolizumab versus carboplatin-based regimens after 9 mo (hazard ratio [HR] 0.43; p = 0.004) and with atezolizumab versus carboplatin-gemcitabine after 5 mo (HR 0.52; p = 0.005). Study limitations include a predominantly male VHA cohort and ≤24-mo follow-up. Adjustment for confounding, a potential limitation of nonrandomized studies, was limited by the availability of clinical measurements in the VHA data, which allowed for replication of IMvigor210 exclusions in the VHA cohorts.CONCLUSIONS: First-line atezolizumab for cisplatin-ineligible mUC may provide an OS benefit over carboplatin-based treatments after 5-9 mo, depending on the regimen.PATIENT SUMMARY: Many patients with metastatic urothelial carcinoma are ineligible for cisplatin-based chemotherapy. This study compared patients from a clinical trial receiving the immunotherapeutic agent atezolizumab with those in Veterans Health Administration clinical practice receiving carboplatin-based chemotherapy. Atezolizumab provided a survival benefit over chemotherapy after 5-9 mo.

    View details for PubMedID 30929841

  • Applying the PRECISION approach in biopsy naïve and previously negative prostate biopsy patients. Urologic oncology Wang, N. N., Teslovich, N. C., Fan, R. E., Ghanouni, P. n., Leppert, J. T., Brooks, J. D., Ahmadi, S. n., Sonn, G. A. 2019


    The PRECISION trial provides level 1 evidence supporting prebiopsy multiparametric magnetic resonance imaging (mpMRI) followed by targeted biopsy only when mpMRI is abnormal [1]. This approach reduced over-detection of low-grade cancer while increasing detection of clinically significant cancer (CSC). Still, important questions remain regarding the reproducibility of these findings outside of a clinical trial and quantifying missed CSC diagnoses using this approach. To address these issues, we retrospectively applied the PRECISION strategy in men who each underwent prebiopsy mpMRI followed by systematic and targeted biopsy.Clinical, imaging, and pathology data were prospectively collected from 358 biopsy naïve men and 202 men with previous negative biopsies. To apply the PRECISION approach, a retrospective analysis was done comparing the cancer yield from 2 diagnostic strategies: (1) mpMRI followed by targeted biopsy alone for men with Prostate Imaging Reporting and Data System ≥ 3 lesions and (2) systematic biopsy alone for all men. Primary outcomes were biopsies avoided and the proportion of CSC cancer (Grade Group 2-5) and non-CSC (Grade Group 1).In biopsy naïve patients, the mpMRI diagnostic strategy would have avoided 19% of biopsies while detecting 2.5% more CSC (P= 0.480) and 12% less non-CSC (P< 0.001). Thirteen percent (n= 9) of men with normal mpMRI had CSC on systematic biopsy. For previous negative biopsy patients, the mpMRI diagnostic strategy avoided 21% of biopsies, while detecting 1.5% more CSC (P= 0.737) and 13% less non-CSC (P< 0.001). Seven percent (n= 3) of men with normal mpMRI had CSC on systematic biopsy.Our results provide external validation of the PRECISION finding that mpMRI followed by targeted biopsy of suspicious lesions reduces biopsies and over-diagnosis of low-grade cancer. Unlike PRECISION, we did not find increased diagnosis of CSC. This was true in both biopsy naïve and previously negative biopsy cohorts. We have incorporated this information into shared decision making, which has led some men to choose to avoid biopsy. However, we continue to recommend targeted and systematic biopsy in men with abnormal MRI.

    View details for DOI 10.1016/j.urolonc.2019.05.002

    View details for PubMedID 31151788

  • Optical biopsy of penile cancer with in vivo confocal laser endomicroscopy. Urologic oncology Shkolyar, E. n., Laurie, M. A., Mach, K. E., Trivedi, D. R., Zlatev, D. V., Chang, T. C., Metzner, T. J., Leppert, J. T., Kao, C. S., Liao, J. C. 2019


    Surgical management of penile cancer depends on accurate margin assessment and staging. Advanced optical imaging technologies may improve penile biopsy and organ-sparing treatment. We evaluated the feasibility of confocal laser endomicroscopy for intraoperative assessment of benign and malignant penile tissue.With institutional review board approval, 11 patients were recruited, 9 with suspected penile cancer, and 2 healthy controls. Confocal laser endomicroscopy using a 2.6-mm fiber-optic probe was performed at 1 or 2 procedures on all subjects, for 13 imaging procedures. Fluorescein was administered intravenously approximately 3 minutes prior to imaging for contrast. Video sequences from in vivo (n = 12) and ex vivo (n = 6) imaging were obtained of normal glans, suspicious lesions, and surgical margins. Images were processed, annotated, characterized, and correlated with standard hematoxylin and eosin histopathology.No adverse events related to imaging were reported. Distinguishing features of benign and malignant penile tissue could be identified by confocal laser endomicroscopy. Normal skin had cells of uniform size and shape, with distinct cytoplasmic membranes consistent with squamous epithelium. Malignant lesions were characterized by disorganized, crowded cells of various size and shape, lack of distinct cytoplasmic membranes, and hazy, moth-eaten appearance. The transition from normal to abnormal squamous epithelium could be identified.We report the initial feasibility of intraoperative confocal laser endomicroscopy for penile cancer optical biopsy. Pending further evaluation, confocal laser endomicroscopy could serve as an adjunct or replacement to conventional frozen section pathology for management of penile cancer.

    View details for DOI 10.1016/j.urolonc.2019.08.018

    View details for PubMedID 31537485

  • Twenty-Four Hour Urine Testing and Prescriptions for Urinary Stone Disease-Related Medications in Veterans. Clinical journal of the American Society of Nephrology : CJASN Song, S. n., Thomas, I. C., Ganesan, C. n., Sohlberg, E. M., Chertow, G. M., Liao, J. C., Conti, S. n., Elliott, C. S., Pao, A. C., Leppert, J. T. 2019


    Current guidelines recommend 24-hour urine testing in the evaluation and treatment of persons with high-risk urinary stone disease. However, how much clinicians use information from 24-hour urine testing to guide secondary prevention strategies is unknown. We sought to determine the degree to which clinicians initiate or continue stone disease-related medications in response to 24-hour urine testing.We examined a national cohort of 130,489 patients with incident urinary stone disease in the Veterans Health Administration between 2007 and 2013 to determine whether prescription patterns for thiazide diuretics, alkali therapy, and allopurinol changed in response to 24-hour urine testing.Stone formers who completed 24-hour urine testing (n=17,303; 13%) were significantly more likely to be prescribed thiazide diuretics, alkali therapy, and allopurinol compared with those who did not complete a 24-hour urine test (n=113,186; 87%). Prescription of thiazide diuretics increased in patients with hypercalciuria (9% absolute increase if urine calcium 201-400 mg/d; 21% absolute increase if urine calcium >400 mg/d, P<0.001). Prescription of alkali therapy increased in patients with hypocitraturia (24% absolute increase if urine citrate 201-400 mg/d; 34% absolute increase if urine citrate ≤200 mg/d, P<0.001). Prescription of allopurinol increased in patients with hyperuricosuria (18% absolute increase if urine uric acid >800 mg/d, P<0.001). Patients who had visited both a urologist and a nephrologist within 6 months of 24-hour urine testing were more likely to have been prescribed stone-related medications than patients who visited one, the other, or neither.Clinicians adjust their treatment regimens in response to 24-hour urine testing by increasing the prescription of medications thought to reduce risk for urinary stone disease. Most patients who might benefit from targeted medications remain untreated.

    View details for DOI 10.2215/CJN.03580319

    View details for PubMedID 31712387

  • Prevalence of twenty-four hour urine testing in Veterans with urinary stone disease. PloS one Ganesan, C. n., Thomas, I. C., Song, S. n., Sun, A. J., Sohlberg, E. M., Kurella Tamura, M. n., Chertow, G. M., Liao, J. C., Conti, S. n., Elliott, C. S., Leppert, J. T., Pao, A. C. 2019; 14 (8): e0220768


    The American Urological Association guidelines recommend 24-hour urine testing in patients with urinary stone disease to decrease the risk of stone recurrence; however, national practice patterns for 24-hour urine testing are not well characterized. Our objective is to determine the prevalence of 24-hour urine testing in patients with urinary stone disease in the Veterans Health Administration and examine patient-specific and facility-level factors associated with 24-hour urine testing. Identifying variations in clinical practice can inform future quality improvement efforts in the management of urinary stone disease in integrated healthcare systems.We accessed national Veterans Health Administration data through the Corporate Data Warehouse (CDW), hosted by the Veterans Affairs Informatics and Computing Infrastructure (VINCI), to identify patients with urinary stone disease. We defined stone formers as Veterans with one inpatient ICD-9 code for kidney or ureteral stones, two or more outpatient ICD-9 codes for kidney or ureteral stones, or one or more CPT codes for kidney or ureteral stone procedures from 2007 through 2013. We defined a 24-hour urine test as a 24-hour collection for calcium, oxalate, citrate or sulfate. We used multivariable regression to assess demographic, geographic, and selected clinical factors associated with 24-hour urine testing.We identified 130,489 Veterans with urinary stone disease; 19,288 (14.8%) underwent 24-hour urine testing. Patients who completed 24-hour urine testing were younger, had fewer comorbidities, and were more likely to be White. Utilization of 24-hour urine testing varied widely by geography and facility, the latter ranging from 1 to 40%.Fewer than one in six patients with urinary stone disease complete 24-hour urine testing in the Veterans Health Administration. In addition, utilization of 24-hour urine testing varies widely by facility identifying a target area for improvement in the care of patients with urinary stone disease. Future efforts to increase utilization of 24-hour urine testing and improve clinician awareness of targeted approaches to stone prevention may be warranted to reduce the morbidity and cost of urinary stone disease.

    View details for DOI 10.1371/journal.pone.0220768

    View details for PubMedID 31393935

  • Spinal anesthesia increases the rate of opioid-free recovery after transurethral urologic surgery. Journal of clinical anesthesia Tien, M. n., Kou, A. n., Leppert, J. T., Mariano, E. R., Mudumbai, S. C. 2019; 60: 109–10

    View details for DOI 10.1016/j.jclinane.2019.09.013

    View details for PubMedID 31614296

  • De-implementation of low value castration for men with prostate cancer: protocol for a theory-based, mixed methods approach to minimizing low value androgen deprivation therapy (DeADT). Implementation science : IS Skolarus, T. A., Hawley, S. T., Wittmann, D. A., Forman, J., Metreger, T., Sparks, J. B., Zhu, K., Caram, M. E., Hollenbeck, B. K., Makarov, D. V., Leppert, J. T., Shelton, J. B., Shahinian, V., Srinivasaraghavan, S., Sales, A. E. 2018; 13 (1): 144


    BACKGROUND: Men with prostate cancer are often castrated with long-acting injectable drugs termed androgen deprivation therapy (ADT). Although many benefit, ADT is also used in patients with little or nothing to gain. The best ways to stop this practice are unknown, and range from blunt pharmacy restrictions to informed decision-making. This study will refine and pilot two different de-implementation strategies for reducing ADT use among those unlikely to benefit in preparation for a comparative effectiveness trial.METHODS/DESIGN: This innovative mixed methods research program has three aims. Aim 1: To assess preferences and barriers for de-implementation of chemical castration in prostate cancer. Guided by the theoretical domains framework (TDF), urologists and patients from facilities with the highest and lowest castration rates across the VA will be interviewed to identify key preferences and de-implementation barriers for reducing castration as prostate cancer treatment. This qualitative work will inform Aim 2 while gathering rich information for two proposed pilot intervention strategies. Aim 2: To use a discrete choice experiment (DCE), a novel barrier prioritization approach, for de-implementation strategy tailoring. The investigators will conduct national surveys of urologists to prioritize key barriers identified in Aim 1 for stopping incident castration as localized prostate cancer treatment using a DCE experiment design. These quantitative results will identify the most important barriers to be addressed through tailoring of two pilot de-implementation strategies in preparation for Aim 3 piloting. Aim 3: To pilot two tailored de-implementation strategies to reduce castration as localized prostate cancer treatment. Building on findings from Aims 1 and 2, two de-implementation strategies will be piloted. One strategy will focus on formulary restriction at the organizational level and the other on physician/patient informed decision-making at different facilities. Outcomes will include acceptability, feasibility, and scalability in preparation for an effectiveness trial comparing these two widely varying de-implementation strategies.DISCUSSION: Our innovative approach to de-implementation strategy development is directly aligned with state-of-the-art complex implementation intervention development and implementation science. This work will broadly advance de-implementation science for low value cancer care, and foster participation in our de-implementation evaluation trial by addressing barriers, facilitators, and concerns through pilot tailoring.TRIAL REGISTRATION: Identifier: NCT03579680 , First Posted July 6, 2018.

    View details for PubMedID 30486836

  • Performance of multiparametric MRI appears better when measured in patients who undergo radical prostatectomy. Research and reports in urology Wang, N. N., Fan, R. E., Leppert, J. T., Ghanouni, P., Kunder, C. A., Brooks, J. D., Chung, B. I., Sonn, G. A. 2018; 10: 233-235


    Utilization of pre-biopsy multiparametric MRI (mpMRI) is increasing. To optimize the usefulness of mpMRI, physicians should accurately quote patients a numerical risk of cancer based on their MRI. The Prostate Imaging Reporting and Data System (PIRADS) standardizes interpretation of mpMRI; however, reported rates of clinically significant prostate cancer (CSC) stratified by PIRADS score vary widely. While some publications use radical prostatectomy (RP) specimens as gold standard, others use biopsy. We hypothesized that much of the variation in CSC stems from differences in cancer prevalence in RP cohorts (100% prevalence) vs biopsy cohorts. To quantify the impact of this selection bias on cancer yield according to PIRADS score, we analyzed data from 614 men with 854 lesions who underwent targeted biopsy from 2014 to 2018. Of these, 125 men underwent RP. We compared the PIRADS detection rates of CSC (Gleason ≥7) on targeted biopsy between the biopsy-only and RP cohorts. For all PIRADS scores, CSC yield was much greater in patients who underwent RP. For example, CSC was found in 30% of PIRADS 3 lesions in men who underwent RP vs 7.6% in men who underwent biopsy. Our results show that mpMRI performance appears to be better in men who undergo RP compared with those who only receive biopsy. Physicians should understand the effect of this selection bias and its magnitude when discussing mpMRI results with patients considering biopsy, and take great caution in quoting CSC yields from publications using RP as gold standard.

    View details for DOI 10.2147/RRU.S178064

    View details for PubMedID 30538970

    View details for PubMedCentralID PMC6254536

  • Crowd Sourced Assessment of Ureteroscopy with Laser Lithotripsy video feed does not correlate with Trainee Experience. Journal of endourology Conti, S. L., Brubaker, W., Chung, B. I., Sofer, M., Hsi, R. S., Shinghal, R., Elliott, C. S., Caruso, T., Leppert, J. T. 2018


    OBJECTIVES: We sought to validate the use of crowd sourced surgical video evaluation in the evaluation of flexible ureteroscopic laser lithotripsy videos using a modified global assessment scale previously validated for ureteroscopic skills.METHODS: We collected video feeds from 30 intra-renal ureteroscopic laser lithotripsy cases where residents post graduate year(PGY) 2 through 6 handled the ureteroscope. The video feeds were annotated to represent the overall performance and to contain the parts of the procedure being scored. The videos were submitted to a commercially available surgical video evaluation platform. We used a validated ureteroscopic laser lithotripsy global assessment tool that was modified to account for the fact that this scoring system looked at the video feed only. Videos were evaluated by crowd workers recruited using Amazon's Mechanical Turk as well as 5 Endourology trained experts. Mean scores were calculated and intraclass correlation coefficients(ICCs) were computed for the expert domain and total scores. The ICCs were estimated using a linear mixed-effects model. Spearman rank correlation coefficients were calculated as a measure of the strength of the relationships between the crowd mean and the expert average scores.RESULTS: 30 videos were reviewed 2,488 times by 487 crowd workers and five expert endourologists. ICCs between expert raters were all below accepted levels of correlation(0.30) with the overall score having an ICC of .000. Overall the crowd scores did not correlate with expert scores except for the stone retrieval domain (0.60 p = 0.015). Crowd sourced scores had a negative correlation with PGY level(-0.44 p=0.019).CONCLUSIONS: Given the poor agreement between experts and poor correlation between expert and crowd scores when evaluating video feeds of ureteroscopic laser lithotripsy, assessment of skills using intraoperative video feeds may not be reliable. This is further supported by the inverse correlation between crowd scores and PGY level.

    View details for PubMedID 30450963

  • Payer Type, Race/Ethnicity, and the Timing of Surgical Management of Urinary Stone Disease JOURNAL OF ENDOUROLOGY Brubaker, W. D., Dallas, K. B., Elliott, C. S., Pao, A. C., Chertow, G. M., Leppert, J. T., Conti, S. L. 2019; 33 (2): 152–58
  • Undertreatment of High-Risk Localized Prostate Cancer in the California Latino Population. Journal of the National Comprehensive Cancer Network : JNCCN Lichtensztajn, D. Y., Leppert, J. T., Brooks, J. D., Shah, S. A., Sieh, W., Chung, B. I., Gomez, S. L., Cheng, I. 2018; 16 (11): 1353–60


    Background: The NCCN Clinical Practice Guidelines in Oncology recommend definitive therapy for all men with high-risk localized prostate cancer (PCa) who have a life expectancy >5 years or who are symptomatic. However, the application of these guidelines may vary among ethnic groups. We compared receipt of guideline-concordant treatment between Latino and non-Latino white men in California. Methods: California Cancer Registry data were used to identify 2,421 Latino and 8,636 non-Latino white men diagnosed with high-risk localized PCa from 2010 through 2014. The association of clinical and sociodemographic factors with definitive treatment was examined using logistic regression, overall and by ethnicity. Results: Latinos were less likely than non-Latino whites to receive definitive treatment before (odds ratio [OR], 0.79; 95% CI, 0.71-0.88) and after adjusting for age and tumor characteristics (OR, 0.84; 95% CI, 0.75-0.95). Additional adjustment for sociodemographic factors eliminated the disparity. However, the association with treatment differed by ethnicity for several factors. Latino men with no health insurance were considerably less likely to receive definitive treatment relative to insured Latino men (OR, 0.34; 95% CI, 0.23-0.49), an association that was more pronounced than among non-Latino whites (OR, 0.63; 95% CI, 0.47-0.83). Intermediate-versus high-grade disease was associated with lower odds of definitive treatment in Latinos (OR, 0.75; 95% CI, 0.59-0.97) but not non-Latino whites. Younger age and care at NCI-designated Cancer Centers were significantly associated with receipt of definitive treatment in non-Latino whites but not in Latinos. Conclusions: California Latino men diagnosed with localized high-risk PCa are at increased risk for undertreatment. The observed treatment disparity is largely explained by sociodemographic factors, suggesting it may be ameliorated through targeted outreach, such as that aimed at younger and underinsured Latino men.

    View details for PubMedID 30442735

  • Payer Type, Race/Ethnicity, and the Timing of Surgical Management of Urinary Stone Disease. Journal of endourology Brubaker, W. D., Dallas, K., Elliott, C. S., Pao, A. C., Chertow, G., Leppert, J. T., Conti, S. L. 2018


    PURPOSE: Surgery for upper tract urinary stone disease is often reserved for symptomatic patients and those whose stone does not spontaneously pass after a trial of passage. Our objective was to determine whether payer type or race/ethnicity is associated with the timeliness of kidney stone surgery.MATERIALS AND METHODS: Population-based cohort study using the California Office of Statewide Health Planning and Development dataset from 2010 to 2012. We identified patients who were discharged from an emergency department with a stone diagnosis and who subsequently underwent a stone surgery. Primary outcome was time from emergency department discharge to urinary stone surgery in days. Secondary outcomes included potential harms resulting from delayed stone surgery.RESULTS: Over the study period, 15,193 patients met the inclusion criteria. Median time from emergency department discharge to stone surgery was 28 days. On multivariable analysis patients with Medicaid, Medicare, and self-pay coverage experienced adjusted mean increases of 46%, 42%, and 60% in time to surgery, respectively, when compared with private insurance. Additionally, patients of Black and Hispanic race/ethnicity, respectively experienced adjusted mean increases of 36% and 20% in time to surgery relative to their white counterparts. Prior to a stone surgery, underinsured patients were more likely to revisit an emergency department three or more times, undergo two or more CT imaging studies, and receive upper urinary tract decompression.CONCLUSIONS: Underinsured and minority patients are more likely to experience a longer time to stone surgery after presenting to an emergency department and experience potential harm from this delay.

    View details for PubMedID 30343603

  • Characterising potential bone scan overuse amongst men treated with radical prostatectomy. BJU international Kirk, P. S., Borza, T., Caram, M. E., Shumway, D. A., Makarov, D. V., Burns, J. A., Shelton, J. B., Leppert, J. T., Chapman, C., Chang, M., Hollenbeck, B. K., Skolarus, T. A. 2018


    OBJECTIVES: To characterise bone scan use, and potential overuse, after radical prostatectomy (RP) using data from a large, national integrated delivery system. Overuse of imaging is well documented in the setting of newly diagnosed prostate cancer, but whether overuse persists after RP remains unknown.PATIENTS AND METHODS: We identified 12 269 patients with prostate cancer treated with RP between 2005 and 2008 using the Veterans Administration Central Cancer Registry. We used administrative and laboratory data to examine rates of bone scan use, including preceding prostate-specific antigen (PSA) levels, and receipt of adjuvant or salvage therapy. We then performed multivariable logistic regression to identify factors associated with post-RP bone scan use.RESULTS: At a median follow-up of 6.8 years, one in five men (22%) underwent a post-RP bone scan at a median PSA level of 0.2 ng/mL. Half of bone scans (48%) were obtained in men who did not receive further treatment with androgen-deprivation or radiation therapy. After adjustment, post-RP bone scan was associated with a prior bone scan (adjusted odds ratio [aOR] 1.55, 95% confidence interval [CI] 1.32-1.84), positive surgical margin (aOR 1.68, 95% CI 1.40-2.01), preoperative PSA level (aOR 1.02, 95% CI 1.01-1.03), as well as Hispanic ethnicity, Black race, and increasing D'Amico risk category, but not with age or comorbidity.CONCLUSION: We found a substantial rate of bone scan utilisation after RP. The majority were performed for PSA levels of <1 ng/mL where the likelihood of a positive test is low. More judicious use of imaging appears warranted in the post-RP setting.

    View details for PubMedID 30246937

  • Re: Brandon A. Mahal, David D. Yang, Natalie Q. Wang, et al. Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer. Eur Urol. In press. European urology Leppert, J. T., Brooks, J. D. 2018

    View details for PubMedID 30017399

  • Ethical Pitfalls When Estimating Life Expectancy For Patients with Prostate Cancer. The Journal of urology Leppert, J. T., Asch, S. M., Bergman, J. 2018

    View details for PubMedID 29885322

  • Minimizing the Cost of Treating Asymptomatic Ureterolithiasis UROLOGY PRACTICE Lamberts, R. W., Lines, E., Conti, S. L., Leppert, J. T., Elliott, C. S. 2018; 5 (3): 172–78
  • The Research Implications of PSA Registry Errors: Data from the Veterans Health Administration. The Journal of urology Guo, D. P., Thomas, I., Mittakanti, H. R., Shelton, J. B., Makarov, D. V., Skolarus, T. A., Cooperberg, M. R., Sonn, G. A., Chung, B. I., Brooks, J. D., Leppert, J. T. 2018


    INTRODUCTION: We sought to characterize the effects of PSA registry errors on clinical research by comparing cohorts based on cancer registry PSA values with those based directly on results in the electronic health record.METHODS: We defined example cohorts of men with prostate cancer using data from the Veterans Health Administration: those with a PSA values less than 4.0 ng/mL, 4.0 to 10.0 ng/mL, 10.0 to 20.0 ng/mL, and 20.0 to 98.0 ng/mL. We compared the composition of each cohort and overall patient survival when using PSA values from either the VA Central Cancer Registry versus the gold standard electronic health record laboratory file results.RESULTS: There was limited agreement between cohorts defined using either the cancer registry PSA values versus the laboratory file of the electronic health record. The least agreement was seen in patients with PSA values < 4.0 ng/mL (58%) and greatest among patients with PSA values between 4.0 and 10.0 ng/mL (89%). In each cohort, patients assigned to a cohort based only on the cancer registry PSA value had significantly different overall survival when compared with patients assigned based on both the registry and laboratory file PSA values.CONCLUSIONS: Cohorts based exclusively on cancer registry PSA values may have high rates of misclassification that can introduce concerning differences in key characteristics and result in measurable differences in clinical outcomes.

    View details for PubMedID 29630980

  • The implications of baseline bone-health assessment at initiation of androgen-deprivation therapy for prostate cancer BJU INTERNATIONAL Kirk, P. S., Borza, T., Shahinian, V. B., Caram, M. V., Makarov, D. V., Shelton, J. B., Leppert, J. T., Blake, R. M., Davis, J. A., Hollenbeck, B. K., Sales, A., Skolarus, T. A. 2018; 121 (4): 558–64


    To assess bone-density testing (BDT) use amongst prostate cancer survivors receiving androgen-deprivation therapy (ADT), and downstream implications for osteoporosis and fracture diagnoses, as well as pharmacological osteoporosis treatment in a national integrated delivery system.We identified 17 017 men with prostate cancer who received any ADT between 2005 and 2014 using the Veterans Health Administration cancer registry and administrative data. We identified claims for BDT within a 3-year period of ADT initiation. We then used multivariable regression to examine the association between BDT use and incident osteoporosis, fracture, and use of pharmacological treatment.We found that a minority of patients received BDT (n = 2 502, 15%); however, the rate of testing increased to >20% by the end of the study period. Men receiving BDT were older at diagnosis and had higher-risk prostate cancer (both P < 0.001). Osteoporosis and fracture diagnoses, use of vitamin D ± calcium, and bisphosphonates were all more common in men who received BDT. After adjustment, BDT, and to a lesser degree ≥2 years of ADT, were both independently associated with incident osteoporosis, fracture, and osteoporosis treatment.BDT is rare amongst patients with prostate cancer treated with ADT in this integrated delivery system. However, BDT was associated with substantially increased treatment of osteoporosis indicating an underappreciated burden of osteoporosis amongst prostate cancer survivors initiating ADT. Optimising BDT use and osteoporosis management in this at-risk population appears warranted.

    View details for PubMedID 29124881

    View details for PubMedCentralID PMC5878705

  • The Predictive Value of Inflammation-Related Peripheral Blood Measurements in Cancer Staging and Prognosis FRONTIERS IN ONCOLOGY Sylman, J. L., Mitrugno, A., Atallah, M., Tormoen, G. W., Shatzel, J. J., Yunga, S., Wagner, T. H., Leppert, J. T., Mallick, P., McCarty, O. T. 2018; 8: 78


    In this review, we discuss the interaction between cancer and markers of inflammation (such as levels of inflammatory cells and proteins) in the circulation, and the potential benefits of routinely monitoring these markers in peripheral blood measurement assays. Next, we discuss the prognostic value and limitations of using inflammatory markers such as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and C-reactive protein measurements. Furthermore, the review discusses the benefits of combining multiple types of measurements and longitudinal tracking to improve staging and prognosis prediction of patients with cancer, and the ability of novel in silico frameworks to leverage this high-dimensional data.

    View details for PubMedID 29619344

  • Preclinical Testing of a Combination Stone Basket and Ureteral Balloon to Extract Ureteral Stones JOURNAL OF ENDOUROLOGY Massoudi, R., Metzner, T. J., Bonneau, B., Ngo, T. C., Shinghal, R., Leppert, J. T. 2018; 32 (2): 96–99


    We have developed the Peralta Stone Extraction System to increase the safety of ureteral stone extraction. The device combines a nitinol stone basket and low-pressure balloon into a single device. After visualization, the stone is captured in the tipless nitinol basket and enveloped by a low-pressure balloon. We tested the performance of device prototypes in a porcine model using stone mimics with diameters ranging from 4.2 to 6.2 mm. Stones extracted with the device required less force when compared with stones in a standard ureteral stone basket. The force reduction was most pronounced for stones greater than 4.2 mm in diameter, and when traversing a ureteral stenosis model. In conclusion, a combination stone basket and balloon device may provide a new and safer way to extract ureteral stones.

    View details for PubMedID 29216731

  • Unplanned Emergency Department Visits and Hospital Admissions Following Ureteroscopy: Do Ureteral Stents Make a Difference? Urology Mittakanti, H. R., Conti, S. L., Pao, A. C., Chertow, G. M., Liao, J. C., Leppert, J. T., Elliott, C. S. 2018


    The comparative effectiveness of ureteral stents placed during ureteroscopy for urinary stone disease is widely debated. We sought to evaluate unplanned medical visits within the early post-operative period after ureteroscopy in patients with and without ureteral stent placement.We identified all ureteroscopic procedures for urinary stone disease in the California Office of Statewide Health Planning and Development (OSHPD) database from 2010-2012. The primary outcome was any emergency department visit or inpatient hospital admission in the first 7 days following ureteroscopy. Patients were sub-categorized by type of ureteroscopy (i.e. laser lithotripsy versus basket retrieval) and analyzed for significant differences between stented and unstented patients. Multivariable logistic regression was performed to determine if ureteral stent placement was independently associated with unplanned visits.Our analytic cohort included 16,060 patients undergoing 17,716 ureteroscopy procedures. A ureteral stent was placed in 86.2% of patients undergoing laser lithotripsy, and 70.5% of patients receiving basket retrieval. In the 7 days following ureteroscopy, 6.6% of patients were seen in the emergency department and 2.2% of patients were admitted to a hospital. In a fully adjusted model, the utilization of a ureteral stent was not associated with emergency department visits or inpatient admissions.Ureteral stent placement during ureteroscopy is not associated with an increased odds of emergency department visits and inpatient admissions in the early post-operative period.

    View details for PubMedID 29601836

  • Performance of multiparametric MRI appears better when measured in patients who undergo radical prostatectomy RESEARCH AND REPORTS IN UROLOGY Wang, N. N., Fan, R. E., Leppert, J. T., Ghanouni, P., Kunder, C. A., Brooks, J. D., Chung, B., Sonn, G. A. 2018; 10: 233–35
  • A Temporal Examination of Platelet Counts as a Predictor of Prognosis in Lung, Prostate, and Colon Cancer Patients. Scientific reports Sylman, J. L., Boyce, H. B., Mitrugno, A. n., Tormoen, G. W., Thomas, I. C., Wagner, T. H., Lee, J. S., Leppert, J. T., McCarty, O. J., Mallick, P. n. 2018; 8 (1): 6564


    Platelets, components of hemostasis, when present in excess (>400 K/μL, thrombocytosis) have also been associated with worse outcomes in lung, ovarian, breast, renal, and colorectal cancer patients. Associations between thrombocytosis and cancer outcomes have been made mostly from single-time-point studies, often at the time of diagnosis. Using laboratory data from the Department of Veterans Affairs (VA), we examined the potential benefits of using longitudinal platelet counts in improving patient prognosis predictions. Ten features (summary statistics and engineered features) were derived to describe the platelet counts of 10,000+ VA lung, prostate, and colon cancer patients and incorporated into an age-adjusted LASSO regression analysis to determine feature importance, and predict overall or relapse-free survival, which was compared to the previously used approach of monitoring for thrombocytosis near diagnosis (Postdiag AG400 model). Temporal features describing acute platelet count increases/decreases were found to be important in cancer survival and relapse-survival that helped stratify good and bad outcomes of cancer patient groups. Predictions of overall and relapse-free survival were improved by up to 30% compared to the Postdiag AG400 model. Our study indicates the association of temporally derived platelet count features with a patients' prognosis predictions.

    View details for PubMedID 29700384

  • Applying Precision Oncology to Renal Cell Carcinoma: Emerging Challenges. European urology Leppert, J. T. 2017; 72 (4): 565-566

    View details for DOI 10.1016/j.eururo.2017.04.032

    View details for PubMedID 28499618

  • Defining the Rate of Negative Ureteroscopy in the General Population Treated for Upper Tract Urinary Stone Disease. Journal of endourology Lamberts, R. W., Conti, S. L., Leppert, J. T., Elliott, C. S. 2017; 31 (3): 266-271


    Ureteroscopy is increasingly used to treat upper tract urinary stone disease. A negative ureteroscopy is a ureteroscopy performed with the intent of removing a kidney or ureteral stone, but in which ultimately no stone is removed. Negative ureteroscopy may occur when the stone is found to have already passed, or the presumed stone is found to be outside of the collecting system. We sought to determine the rate of negative ureteroscopy in a large population-based sample as well as factors associated with its use.We examined nonpublic data from the Office of Statewide Health Planning and Development (OSHPD) Database for all patients in California undergoing outpatient surgery from 2010 to 2012. We identified all patients with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for upper tract urinary stone disease, who underwent a ureteroscopic procedure. After excluding patients undergoing second look procedures or who had diagnosis codes for separate urologic pathology, the negative ureteroscopy rate was defined as the proportion of those ureteroscopy cases coded as a diagnostic ureteroscopy. We fit logistic regression models to evaluate patient factors associated with negative ureteroscopy.During the years 2010 to 2012, 20,236 eligible patients underwent ureteroscopic procedures for upper tract stone disease. Of these, 1287 patients underwent diagnostic ureteroscopy and 19,039 underwent ureteroscopy with stone removal accounting for a negative ureteroscopy rate of 6.3%. The odds of receipt of a negative ureteroscopy rate were higher in females compared to males (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.25, 1.58) and lower in self-pay patients compared with insured patients (OR = 0.55, 95% CI 0.33, 0.91).Negative ureteroscopy is common, occurring in nearly 1 in 16 procedures to treat urinary stone disease.

    View details for DOI 10.1089/end.2016.0751

    View details for PubMedID 28049343

  • Contemporary Use of Partial Nephrectomy: Are Older Patients With Impaired Kidney Function Being Left Behind? UROLOGY Leppert, J. T., Mittakanti, H. R., Thomas, I., Lamberts, R. W., Sonn, G. A., Chung, B. I., Skinner, E. C., Wagner, T. H., Chertow, G. M., Brooks, J. D. 2017; 100: 65-71
  • Editorial Comment. Urology Metzner, T. J., Leppert, J. T. 2017; 100: 156-157

    View details for DOI 10.1016/j.urology.2016.10.048

    View details for PubMedID 27988153

  • Redefining the Stone Belt: Precipitation is Associated with Increased Risk of Urinary Stone Disease. Journal of endourology Dallas, K. B., Conti, S. L., Liao, J. C., Sofer, M. n., Pao, A. C., Leppert, J. T., Elliott, C. S. 2017


    Objectives The American Southeast has been labeled the "Stone Belt" due to its relatively high burden of urinary stone disease, presumed to be related to its higher temperatures. However, other regions with high temperatures (e.g. the Southwest) do not have the same disease prevalence as the southeast. We seek to explore the association of stone disease to other climate-associated factors beyond temperature including precipitation and temperature variation.We identified all patients who underwent a surgical procedure for urinary stone disease from the California Office of Statewide Health Planning and Development (OSHPD) databases (2010-2012). Climate data obtained from the National Oceanic and Atmospheric Administration was compared to population adjusted county operative stone burden, controlling for patient and county demographic data as potential confounders.A total of 63,994 unique patients underwent stone procedures in California between 2010-2012. Multivariate modeling revealed higher precipitation (0.019 average increase in surgeries per 1000 persons per inch, p<0.01) and higher mean temperature (0.029 average increase in surgeries per 1000 persons per degree, p<0.01) were both independently associated with an increased operative stone disease burden. Controlling for county level patient factors did not change these observed effects. Conclusion In the state of California, higher precipitation and higher mean temperature are associated with increased rates of stone surgery. Our results appear to agree with the larger trends seen throughout the United States where the areas of highest stone prevalence have warm wet climates, and not warm arid, climates.

    View details for PubMedID 28830242

  • Prostate Magnetic Resonance Imaging Interpretation Varies Substantially Across Radiologists. European urology focus Sonn, G. A., Fan, R. E., Ghanouni, P. n., Wang, N. N., Brooks, J. D., Loening, A. M., Daniel, B. L., To'o, K. J., Thong, A. E., Leppert, J. T. 2017


    Multiparametric magnetic resonance imaging (mpMRI) interpreted by experts is a powerful tool for diagnosing prostate cancer. However, the generalizability of published results across radiologists of varying expertise has not been verified.To assess variability in mpMRI reporting and diagnostic accuracy across radiologists of varying experience in routine clinical care.Men who underwent mpMRI and MR-fusion biopsy between 2014-2016. Each MRI scan was read by one of nine radiologists using the Prostate Imaging Reporting and Data System (PIRADS) and was not re-read before biopsy. Biopsy histopathology was the reference standard.Outcomes were the PIRADS score distribution and diagnostic accuracy across nine radiologists. We evaluated the association between age, prostate-specific antigen, PIRADS score, and radiologist in predicting clinically significant cancer (Gleason ≥7) using multivariable logistic regression. We conducted sensitivity analyses for case volume and changes in accuracy over time.We analyzed data for 409 subjects with 503 MRI lesions. While the number of lesions (mean 1.2 lesions/patient) did not differ across radiologists, substantial variation existed in PIRADS distribution and cancer yield. The significant cancer detection rate was 3-27% for PIRADS 3 lesions, 23-65% for PIRADS 4, and 40-80% for PIRADS 5 across radiologists. Some 13-60% of men with a PIRADS score of <3 on MRI harbored clinically significant cancer. The area under the receiver operating characteristic curve varied from 0.69 to 0.81 for detection of clinically significant cancer. PIRADS score (p<0.0001) and radiologist (p=0.042) were independently associated with cancer in multivariable analysis. Neither individual radiologist volume nor study period impacted the results. MRI scans were not retrospectively re-read by all radiologists, precluding measurement of inter-observer agreement.We observed considerable variability in PIRADS score assignment and significant cancer yield across radiologists. We advise internal evaluation of mpMRI accuracy before widespread adoption.We evaluated the interpretation of multiparametric magnetic resonance imaging of the prostate in routine clinical care. Diagnostic accuracy depends on the Prostate Imaging Reporting and Data System score and the radiologist.

    View details for PubMedID 29226826

  • Overall Survival in Patients with Localized Prostate Cancer in the US Veterans Health Administration: Is PIVOT Generalizable? EUROPEAN UROLOGY Barbosa, P. V., Thomas, I., Srinivas, S., Buyyounouski, M. K., Chung, B. I., Chertow, G. M., Asch, S. M., Wagner, T. H., Brooks, J. D., Leppert, J. T. 2016; 70 (2): 227-230


    A better understanding of overall survival among patients with clinically localized prostate cancer (PCa) in the US Veterans Health Administration (VHA) is critical to inform PCa treatment decisions, especially in light of data from the Prostate Intervention Versus Observation Trial (PIVOT). We sought to describe patterns of survival for all patients with clinically localized PCa treated by the VHA. We created an analytic cohort of 35 954 patients with clinically localized PCa diagnosed from 1995 to 2001, approximating the PIVOT inclusion criteria (age of diagnosis ≤75 yr and clinical stage T2 or lower). Mean patient age was 65.9 yr, and median follow-up was 161 mo. Overall, 22.5% of patients were treated with surgery, 16.6% were treated with radiotherapy, and 23.1% were treated with androgen deprivation. Median survival of the entire cohort was 14 yr (25th, 75th percentiles, range: 7.9-20 yr). Among patients who received treatment with curative intent, median survival was 17.9 yr following surgery and 12.9 yr following radiotherapy. One-third of patients died within 10 yr of diagnosis compared with nearly half of the participants in PIVOT. This finding sounds a note of caution when generalizing the mortality data from PIVOT to VHA patients and those in the community.More than one-third of patients diagnosed with clinically localized prostate cancer treated through the US Veterans Health Administration from 1995 to 2001 died within 10 yr of their diagnosis. Caution should be used when generalizing the estimates of competing mortality data from PIVOT.

    View details for DOI 10.1016/j.eururo.2016.02.037

    View details for PubMedID 26948397

  • Intraoperative Optical Biopsy during Robotic Assisted Radical Prostatectomy Using Confocal Endomicroscopy JOURNAL OF UROLOGY Lopez, A., Zlatev, D. V., Mach, K. E., Bui, D., Liu, J., Rouse, R. V., Harris, T., Leppert, J. T., Liao, J. C. 2016; 195 (4): 1110-1117


    Intraoperative optical biopsy technologies may aid identification of important anatomic landmarks and improve surgical outcomes of robotic-assisted radical prostatectomy (RARP). We sought to evaluate the feasibility of confocal laser endomicroscopy (CLE) during RARP.Twenty-one patients with biopsy-proven prostate cancer scheduled for RARP were recruited. After intravenous administration of fluorescein, 15 patients underwent in vivo intraoperative CLE of prostatic and periprostatic structures using either a 2.6-mm or 0.85-mm imaging probe. Standard robotic instruments were used to grasp and maneuver the CLE probes for image acquisition. CLE imaging was performed ex vivo on fresh prostate specimens from 20 patients. Confocal video sequences acquired in vivo and ex vivo were reviewed and analyzed, with additional image processing using a mosaicing algorithm. Processed confocal images were compared with standard hematoxylin and eosin analysis of imaged regions.CLE was successfully integrated with robotic surgery, including co-registration of confocal video sequences with white light and probe handling with standard robotic instrumentation. Intraoperative CLE imaging of the neurovascular bundle prior to and following nerve-sparing dissection revealed characteristic features including dynamic vascular flow and intact axon fibers. Ex vivo confocal imaging of the prostatic parenchyma demonstrated the normal prostatic glands, stroma, and prostate carcinoma.We report the initial feasibility of optical biopsy of prostatic and periprostatic tissue during RARP. Image guidance and tissue interrogation using CLE offers a new intraoperative imaging method that has the potential to improve the functional and oncologic outcomes of prostate cancer surgery.

    View details for DOI 10.1016/j.juro.2015.10.182

    View details for Web of Science ID 000373401200108

  • A Protective Role for Androgen Receptor in Clear Cell Renal Cell Carcinoma Based on Mining TCGA Data. PloS one Zhao, H., Leppert, J. T., Peehl, D. M. 2016; 11 (1)


    Androgen receptor (AR) is expressed in normal murine and human kidneys of both genders, but its physiologic role is uncertain. Several studies showed loss of AR in renal cell carcinoma (RCC) in conjunction with increasing clinical stage and pathological grade, but others found that higher AR expression correlated with worse outcomes. Limited functional studies with renal cell lines suggested tumor-promoting activity of AR. In this study, we queried transcriptomic, proteomic, epigenetic and survival data from The Cancer Genome Atlas (TCGA) to evaluate AR expression and its association with overall survival in three subtypes of RCC (clear cell [ccRCC], papillary [pRCC], and chromophobe [chRCC]). We found that although there was no significant difference in AR mRNA expression in ccRCC of males vs. females, AR protein expression in ccRCC was significantly higher in male compared to female patients. More importantly, higher expression of AR at both transcript and protein levels was associated with improved overall survival in both genders with ccRCC, but did not predict survival of either gender with pRCC or chRCC. Genes whose transcript levels were associated with AR mRNA levels significantly overlapped between ccRCC and pRCC, but not with chRCC, suggesting a similar transcriptional program mediated by AR in ccRCC and pRCC. Ingenuity pathway analysis also identified overlapping pathways and upstream regulators enriched in AR-associated genes in ccRCC and pRCC. Hypermethylation of CpG sites located in the promoter and first exon of AR was associated with loss of AR expression and poor overall survival. Our findings support a tumor suppressor role for AR in both genders that might be exploited to decrease the incidence or progression of ccRCC.

    View details for DOI 10.1371/journal.pone.0146505

    View details for PubMedID 26814892

    View details for PubMedCentralID PMC4729482

  • Perspective: Beyond the genome. Nature Leppert, J., Patel, C. 2016; 537 (7620): S105-?

    View details for DOI 10.1038/537S105a

    View details for PubMedID 27626778

  • Accuracy of Prostate-Specific Antigen Values in Prostate Cancer Registries. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mittakanti, H. R., Thomas, I. C., Shelton, J. B., Makarov, D. V., Skolarus, T. A., Cooperberg, M. R., Chung, B. I., Sonn, G. A., Brooks, J. D., Leppert, J. T. 2016

    View details for PubMedID 27458297

  • A Pilot Study of In Vivo Confocal Laser Endomicroscopy of Upper Tract Urothelial Carcinoma JOURNAL OF ENDOUROLOGY Bui, D., Mach, K. E., Zlatev, D. V., Rouse, R. V., Leppert, J. T., Liao, J. C. 2015; 29 (12): 1418-1423


    Tissue diagnosis of upper tract urothelial carcinoma (UTUC) is limited by variance in tumor sampling by standard ureteroscopic biopsy. Optical imaging technologies can potentially improve UTUC diagnosis, surveillance, and endoscopic treatment. We previously demonstrated in vivo optical biopsy of urothelial carcinoma of the bladder using confocal laser endomicroscopy (CLE). In this study, we evaluated a new 0.85-mm imaging probe in the upper urinary tract and demonstrated feasibility and compatibility with standard ureteroscopes to achieve in vivo optical biopsy of UTUC.Fourteen patients scheduled for ureteroscopy of suspected upper tract lesions or surveillance of UTUC were recruited. After intravenous (IV) administration of fluorescein, CLE was performed using a 0.85-mm-diameter imaging probe inserted through the working channel of standard ureteroscopes. Acquired confocal video sequences were reviewed and analyzed. A mosaicing algorithm was used to compile a series of images into a single larger composite image. Processed CLE images were compared with standard histopathologic analysis.Optical biopsy of the UTUC using CLE was effectively achieved during standard ureteroscopy. There were no adverse events related to IV fluorescein administration or image acquisition. Confocal imaging of UTUC showed characteristic features similar to urothelial carcinoma of the bladder, including papillary structure, fibrovascular stalks, and pleomorphism. Lamina propria in normal areas of the renal pelvis and ureter was also identified.We report an initial feasibility of CLE of UTUC. Pending further clinical investigation, CLE may become a useful adjunct to ureteroscopic biopsy, endoscopic ablation, and surveillance of UTUC.

    View details for DOI 10.1089/end.2015.0523

    View details for Web of Science ID 000366602600015

    View details for PubMedID 26413927

  • Biochemical Measures of Diabetes are Not Independent Predictors of Urinary Incontinence in Women JOURNAL OF UROLOGY Weinberg, A. E., Leppert, J. T., Elliott, C. S. 2015; 194 (6): 1668-1674

    View details for DOI 10.1016/j.juro.2015.06.074

    View details for PubMedID 26087382

  • Editorial Comment. Urology Mittakanti, H. R., Leppert, J. T. 2015; 86 (5): 899-?

    View details for DOI 10.1016/j.urology.2015.06.060

    View details for PubMedID 26590035

  • Biologic Differences Between Peripheral and Transition Zone Prostate Cancer PROSTATE Lee, J. J., Thomas, I., Nolley, R., Ferrari, M., Brooks, J. D., Leppert, J. T. 2015; 75 (2): 183-190


    Prostate cancer arises in the transition zone (TZ) in approximately 20-25% of cases. Modern biopsy and surveillance protocols, and advances in prostate cancer imaging, have renewed interest in TZ prostate cancers. We compared TZ and PZ prostate cancer to determine if cancer location is independently associated with better outcomes.We evaluated an expanded cohort of 1354 men who underwent radical prostatectomy between 1983 and 2003 with updated long-term clinical follow-up. Regression models were used to compare the volume of high-grade (Gleason 4 or 5) cancer and total cancer volume by location. Uni- and multi-variable logistic regression models tested the associations between cancer location and adverse pathologic features. Multivariable proportional hazard models were fit to examine cancer recurrence.Patients with TZ cancer presented with higher pre-operative serum PSA values (11.07 vs. 7.86 ng/ml) and larger total cancer volume (7.1 vs. 3.8 cc). Patients with TZ cancer had decreased odds of seminal vesicle invasion (OR 0.08, 95% CI 0.03, 0.21), extra-capsular extension (OR 0.56, 95% CI 0.35, 0.92), and lymphovascular invasion (OR 0.48, 95% CI 0.27, 0.87) in multivariable models. TZ cancers were independently associated with decreased hazard of tumor recurrence (HR 0.62, 95% CI 0.43, 0.90).TZ cancer prostate is associated with favorable pathologic features and better recurrence-free survival despite being diagnosed with larger cancers and higher PSA values. Tumor location should be taken into account when stratifying patient risk before and after prostatectomy, particularly with the evolving role of imaging in prostate cancer management. Prostate 75:183-190, 2015. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.22903

    View details for PubMedID 25327466

  • Editorial comment. Urology Barbosa, P. V., Leppert, J. T. 2014; 83 (6): 1291-1292

    View details for DOI 10.1016/j.urology.2014.01.052

    View details for PubMedID 24862393

  • Trends and perioperative outcomes for laparoscopic and robotic nephrectomy using the National Surgical Quality Improvement Program (NSQIP) database UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Liu, J., Leppert, J. T., Maxwell, B. G., Panousis, P., Chung, B. I. 2014; 32 (4): 473-479


    We sought to examine the trends in perioperative outcomes of kidney cancer surgery stratified by type (radical nephrectomy [RN] vs. partial nephrectomy [PN]) and approach (open vs. minimally invasive).We queried the National Surgical Quality Improvement Program database to identify kidney cancer operations performed from 2005 to 2011. We examined 30-day perioperative outcomes including operative time, transfusion rate, length of stay, major morbidity (cardiovascular, pulmonary, renal, and infectious), and mortality.A total of 2,902 PN and 5,459 RN cases were identified. The use of PN increased over time, accounting for 39% of all nephrectomies in 2011. Minimally invasive approaches also increased over time for both RN and PN. Open surgery was associated with increased length of stay, receipt of transfusion, major complications, and perioperative mortality. Resident involvement and open approach were independent predictors of major complications for both PN and RN. Additionally, the presence of a medical comorbidity was also a risk factor for complications after RN. The overall complication rates decreased for all approaches over the study period.Minimally invasive approaches to kidney cancer renal surgery have increased with favorable outcomes. The safety of open and minimally invasive PN improved significantly over the study period. Although pathologic features cannot be determined from this data set, these data show that complications from renal surgical procedures are decreasing in an era of increasing use.

    View details for DOI 10.1016/j.urolonc.2013.09.012

    View details for Web of Science ID 000335422300015

    View details for PubMedID 24332644

  • Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. International journal of cancer. Journal international du cancer Conti, S. L., Thomas, I., Hagedorn, J. C., Chung, B. I., Chertow, G. M., Wagner, T. H., Brooks, J. D., Srinivas, S., Leppert, J. T. 2014; 134 (9): 2245-2252


    We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy. We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy. The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of cytoreductive nephrectomy. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0.41, 95% confidence interval 0.34 to 0.43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference-in-difference analysis showed a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era. Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies. © 2013 Wiley Periodicals, Inc.

    View details for PubMedID 24135850

  • Reply. Urology Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Brooks, J. D., Srinivas, S., Chertow, G. M., Saigal, C. S. 2014; 83 (4): 779-780

    View details for DOI 10.1016/j.urology.2013.10.077

    View details for PubMedID 24529590

  • Utilization of renal mass biopsy in patients with renal cell carcinoma. Urology Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Srinivas, S., Chertow, G. M., Brooks, J. D., Saigal, C. S. 2014; 83 (4): 774-780


    To examine the patient, tumor, and temporal factors associated with receipt of renal mass biopsy (RMB) in a contemporary nationally representative sample.We queried the Surveillance, Epidemiology, and End Results-Medicare data set for incident cases of renal cell carcinoma diagnosed between 1992 and 2007. We tested for associations among receipt of RMB and patient and tumor characteristics, type of therapy, and procedure type. Temporal trends in receipt of RMB were characterized over the study period.Approximately 1 in 5 (20.7%) patients diagnosed with renal cell carcinoma (n = 24,702) underwent RMB before instituting therapy. There was a steady and modest increase in RMB utilization, with the highest utilization (30%) occurring in the final study year. Of patients who underwent radical (n = 15,666) or partial (n = 2211) nephrectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. Sixty-five percent of patients who underwent ablation (n = 314) underwent RMB before or in conjunction with the procedure. Roughly half of patients (50.4%) treated with systemic therapy alone underwent RMB. Factors independently associated with use of RMB included younger age, black race, Hispanic ethnicity, tumor size <7 cm, and metastatic disease at presentation.At present, most patients who eventually undergo radical or partial nephrectomy do not undergo RMB, whereas most patients who eventually undergo ablation or systemic therapy do. The optimal use of RMB in the evaluation of kidney tumors has yet to be determined.

    View details for DOI 10.1016/j.urology.2013.10.073

    View details for PubMedID 24529579

  • Diabetic Severity and Risk of Kidney Stone Disease EUROPEAN UROLOGY Weinberg, A. E., Patel, C. J., Chertow, G. M., Leppert, J. T. 2014; 65 (1): 242-247


    BACKGROUND: The prevalence of kidney stone disease is rising along with increasing rates of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. OBJECTIVE: To investigate the associations among the presence and severity of T2DM, glycemic control, and insulin resistance with kidney stone disease. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional analysis of all adult participants in the 2007-2010 National Health and Nutrition Examination Survey (NHANES). A history of kidney stone disease was obtained by self-report. T2DM was defined by self-reported history, T2DM-related medication usage, and reported diabetic comorbidity. Insulin resistance was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) definition. We classified glycemic control using glycosylated hemoglobin A1c (HbA1c) and fasting plasma-glucose levels (FPG). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (OR) for having kidney stone disease were calculated for each individual measure of T2DM severity. Logistic regression models were fitted adjusting for age, sex, race/ethnicity, smoking history, and the Quételet index (body mass index), as well as laboratory values and components of metabolic syndrome. RESULTS AND LIMITATIONS: Correlates of kidney stone disease included a self-reported history of T2DM (OR: 2.44; 95% confidence interval [CI], 1.84-3.25) and history of insulin use (OR: 3.31; 95% CI, 2.02-5.45). Persons with FPG levels 100-126mg/dl and >126mg/dl had increased odds of having kidney stone disease (OR 1.28; 95% CI, 0.95-1.72; and OR 2.29; 95% CI, 1.68-3.12, respectively). Corresponding results for persons with HbA1c 5.7-6.4% and =6.5% were OR 1.68 (95% CI, 1.17-2.42) and OR 2.82 (95% CI, 1.98-4.02), respectively. When adjusting for patient factors, a history of T2DM, the use of insulin, FPI, and HbA1c remained significantly associated with kidney stone disease. The cross-sectional design limits causal inference. CONCLUSIONS: Among persons with T2DM, more-severe disease is associated with a heightened risk of kidney stones.

    View details for DOI 10.1016/j.eururo.2013.03.026

    View details for PubMedID 23523538

  • Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States National Health and Nutrition Examination Survey. International journal of epidemiology Patel, C. J., Rehkopf, D. H., Leppert, J. T., Bortz, W. M., Cullen, M. R., Chertow, G. M., Ioannidis, J. P. 2013; 42 (6): 1795-1810


    Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.

    View details for DOI 10.1093/ije/dyt208

    View details for PubMedID 24345851

  • Diabetes Severity, Metabolic Syndrome, and the Risk of Erectile Dysfunction JOURNAL OF SEXUAL MEDICINE Weinberg, A. E., Eisenberg, M., Patel, C. J., Chertow, G. M., Leppert, J. T. 2013; 10 (12): 3102-3109


    Erectile dysfunction (ED) is more common in men with type 2 diabetes mellitus (T2DM), obesity, and/or the metabolic syndrome (MetS).The aim of this study is to investigate the associations among proxy measures of diabetic severity and the presence of MetS with ED in a nationally representative U.S. data sample.We performed a cross-sectional analysis of adult participants in the 2001-2004 National Health and Nutrition Examination Survey.ED was ascertained by self-report. T2DM severity was defined by calculated measures of glycemic control and insulin resistance (IR). IR was estimated using fasting plasma insulin (FPI) levels and the homeostasis model assessment of IR (HOMA-IR) definition. We classified glycemic control using hemoglobin-A1c (HbA1c) and fasting plasma glucose (FPG) levels. MetS was defined by the American Heart Association and National Heart, Lung, and Blood Institute criteria. Logistic regression models, adjusted for sociodemographics, risk factors, and comorbidities, were fitted for each measure of T2DM severity, MetS, and the presence of ED.Proxy measures of glycemic control and IR were associated with ED. Participants with FPG between 100-126 mg/dL (5.6-7 mmol/L) and ≥ 126 mg/dL (>7 mmol/L) had higher odds of ED, odds ratio (OR) 1.22 (confidence interval or CI, 0.83-1.80), and OR 2.68 (CI, 1.48-4.86), respectively. Participants with HbA1c 5.7-6.4% (38.8-46.4 mmol/mol) and ≥ 6.5% (47.5 mmol/mol) had higher odds of ED (OR 1.73 [CI, 1.08-2.76] and 3.70 [CI, 2.19-6.27], respectively). When FPI and HOMA-IR were evaluated by tertiles, there was a graded relation among participants in the top tertile. In multivariable models, a strong association remained between HbA1c and ED (OR 3.19 [CI,1.13-9.01]). MetS was associated with >2.5-fold increased odds of self reported ED (OR 2.55 [CI, 1.85-3.52]).Poor glycemic control, impaired insulin sensitivity, and the MetS are associated with a heightened risk of ED.

    View details for DOI 10.1111/jsm.12318

    View details for PubMedID 24010555

  • Estimating the risk of chronic kidney disease after nephrectomy CANADIAN JOURNAL OF UROLOGY Ngo, T. C., Hurley, M. P., Thong, A. E., Jeon, S. H., Leppert, J. T., Chung, B. I. 2013; 20 (6): 7035-7041


    To identify factors associated with the development of chronic kidney disease (CKD) after nephrectomy and to create a clinical model to predict CKD after nephrectomy for kidney cancer for clinical use.We identified 144 patients who had normal renal function (eGFR > 60) prior to undergoing nephrectomy for kidney cancer. Selected cases occurred between 2007 and 2010 and had at least 30 days follow up. Sixty-six percent (n = 95) underwent radical nephrectomy and 62.5% (n = 90) developed CKD (stage 3 or higher) postoperatively. We used univariable analysis to screen for predictors of CKD and multivariable logistic regression to identify independent predictors of CKD and their corresponding odds ratios. Interaction terms were introduced to test for effect modification. To protect against over-fitting, we used 10-fold cross-validation technique to evaluate model performance in multiple training and testing datasets. Validation against an independent external cohort was also performed.Of the variables associated with CKD in univariable analysis, the only independent predictors in multivariable logistic regression were patient age (OR = 1.27 per 5 years, 95% CI: 1.07-1.51), preoperative glomerular filtration rate (GFR), (OR = 0.70 per 10 mL/min, 95% CI: 0.56-0.89), and receipt of radical nephrectomy (OR = 4.78, 95% CI: 2.08-10.99). There were no significant interaction terms. The resulting model had an area under the curve (AUC) of 0.798. A 10-fold cross-validation slightly attenuated the AUC to 0.774 and external validation yielded an AUC of 0.930, confirming excellent model discrimination.Patient age, preoperative GFR, and receipt of a radical nephrectomy independently predicted the development of CKD in patients undergoing nephrectomy for kidney cancer in a validated predictive model.

    View details for Web of Science ID 000328717300007

    View details for PubMedID 24331345

  • Utilization of renal mass biopsy in patients with renal cell carcinoma 12th International Kidney Cancer Symposium Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Srinivas, S., Chertow, G. M., Brooks, J. D., Saigal, C. S. WILEY-BLACKWELL. 2013: 14–14
  • Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era 12th International Kidney Cancer Symposium Conti, S. L., Thomas, I., Hagedorn, J. C., Chung, B. I., Chertow, G. M., Wagner, T. H., Brooks, J. D., Srinivas, S., Leppert, J. T. WILEY-BLACKWELL. 2013: 14–16
  • Turning on the lights: new technologies in optical diagnostics and therapeutics. journal of urology Liao, J. C., Leppert, J. T. 2013; 190 (2): 381-382

    View details for DOI 10.1016/j.juro.2013.05.026

    View details for PubMedID 23688641

  • Interobserver agreement of confocal laser endomicroscopy for bladder cancer. Journal of endourology Chang, T. C., Liu, J., Hsiao, S. T., Pan, Y., Mach, K. E., Leppert, J. T., McKenney, J. K., Rouse, R. V., Liao, J. C. 2013; 27 (5): 598-603


    Emerging optical imaging technologies such as confocal laser endomicroscopy (CLE) hold promise in improving bladder cancer diagnosis. The purpose of this study was to determine the interobserver agreement of image interpretation using CLE for bladder cancer.Experienced CLE urologists (n=2), novice CLE urologists (n=6), pathologists (n=4), and nonclinical researchers (n=5) were recruited to participate in a 2-hour computer-based training consisting of a teaching and validation set of intraoperative white light cystoscopy (WLC) and CLE video sequences from patients undergoing transurethral resection of bladder tumor. Interobserver agreement was determined using the κ statistic.Of the 31 bladder regions analyzed, 19 were cancer and 12 were benign. For cancer diagnosis, experienced CLE urologists had substantial agreement for both CLE and WLC+CLE (90%, κ 0.80) compared with moderate agreement for WLC alone (74%, κ 0.46), while novice CLE urologists had moderate agreement for CLE (77%, κ 0.55), WLC (78%, κ 0.54), and WLC+CLE (80%, κ 0.59). Pathologists had substantial agreement for CLE (81%, κ 0.61), and nonclinical researchers had moderate agreement (77%, κ 0.49) in cancer diagnosis. For cancer grading, experienced CLE urologists had fair to moderate agreement for CLE (68%, κ 0.64), WLC (74%, κ 0.67), and WLC+CLE (53%, κ 0.33), as did novice CLE urologists for CLE (53%, κ 0.39), WLC (66%, κ 0.50), and WLC+CLE (61%, κ 0.49). Pathologists (65%, κ 0.55) and nonclinical researchers (61%, κ 0.56) both had moderate agreement for CLE in cancer grading.CLE is an adoptable technology for cancer diagnosis in novice CLE observers after a short training with moderate interobserver agreement and diagnostic accuracy similar to WLC alone. Experienced CLE observers may be capable of achieving substantial levels of agreement for cancer diagnosis that is higher than with WLC alone.

    View details for DOI 10.1089/end.2012.0549

    View details for PubMedID 23072435

    View details for PubMedCentralID PMC3643225

  • TEMPORAL TRENDS IN UTILIZATION OF CYTOREDUCTIVE NEPHRECTOMY AND PATIENT SURVIVAL IN THE TARGETED THERAPY ERA Annual Meeting of the American-Urological-Association (AUA) Conti, S. L., Hagedorn, J., Chung, B. I., Srinivas, S., Leppert, J. ELSEVIER SCIENCE INC. 2013: E753–E753
  • Editorial Comment. Urology Lee, J. J., Leppert, J. T. 2013

    View details for DOI 10.1016/j.urology.2013.02.066

    View details for PubMedID 23706590

  • The use of mannitol in partial and live donor nephrectomy: an international survey. World journal of urology Cosentino, M., Breda, A., Sanguedolce, F., Landman, J., Stolzenburg, J. U., Verze, P., Rassweiler, J., Van Poppel, H., Klingler, H. C., Janetschek, G., Celia, A., Kim, F. J., Thalmann, G., Nagele, U., Mogorovich, A., Bolenz, C., Knoll, T., Porpiglia, F., Alvarez-Maestro, M., Francesca, F., Deho, F., Eggener, S., Abbou, C., Meng, M. V., Aron, M., Laguna, P., Mladenov, D., D'Addessi, A., Bove, P., Schiavina, R., De Cobelli, O., Merseburger, A. S., Dalpiaz, O., D'Ancona, F. C., Polascik, T. J., Muschter, R., Leppert, T. J., Villavicencio, H. 2012


    PURPOSE: Animal studies have shown the potential benefits of mannitol as renoprotective during warm ischemia; it may have antioxidant and anti-inflammatory properties and is sometimes used during partial nephrectomy (PN) and live donor nephrectomy (LDN). Despite this, a prospective study on mannitol has never been performed. The aim of this study is to document patterns of mannitol use during PN and LDN. MATERIALS AND METHODS: A survey on the use of mannitol during PN and LDN was sent to 92 high surgical volume urological centers. Questions included use of mannitol, indications for use, physician responsible for administration, dosage, timing and other renoprotective measures. RESULTS: Mannitol was used in 78 and 64 % of centers performing PN and LDN, respectively. The indication for use was as antioxidant (21 %), as diuretic (5 %) and as a combination of the two (74 %). For PN, the most common dosages were 12.5 g (30 %) and 25 g (49 %). For LDN, the most common doses were 12.5 g (36.3 %) and 25 g (63.7 %). Overall, 83 % of centers utilized mannitol, and two (percent or centers??) utilized furosemide for renoprotection. CONCLUSIONS: A large majority of high-volume centers performing PN and LDN use mannitol for renoprotection. Since there are no data proving its value nor standardized indication and usage, this survey may provide information for a randomized prospective study.

    View details for DOI 10.1007/s00345-012-1003-1

    View details for PubMedID 23242033

  • Clinical, Molecular, and Genetic Correlates of Lymphatic Spread in Clear Cell Renal Cell Carcinoma EUROPEAN UROLOGY Kroeger, N., Seligson, D. B., Klatte, T., Rampersaud, E. N., Birkhaeuser, F. D., Rao, P. N., Leppert, J. T., Zomorodian, N., Kabbinavar, F. F., Belldegrun, A. S., Pantuck, A. J. 2012; 61 (5): 888-895


    While it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood.Define the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas.A retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively.Fisher exact test or the χ(2) test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread.In clinical analyses, a predictive model consisting of smoking history (p=0.040), T stage (p<0.0001), Fuhrman grade (p<0.0001), Eastern Cooperative Oncology Group performance status (p<0.0001), and microvascular invasion (p<0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p=0.043) and high epithelial vascular endothelial growth factor receptor 2 (p=0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p<0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience.The low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation.

    View details for DOI 10.1016/j.eururo.2012.01.012

    View details for Web of Science ID 000302267900016

    View details for PubMedID 22269604

  • Standardized Linear Port Configuration to Improve Operative Ergonomics in Laparoscopic Renal and Adrenal Surgery: Experience with 1264 cases JOURNAL OF ENDOUROLOGY Harper, J. D., Leppert, J. T., Breda, A., Schulam, P. G. 2011; 25 (11): 1769-1773


    Traditional laparoscopic port placement for upper urinary tract surgery involves camera access via the umbilicus with working ports placed on either side of the camera at various locations. This diamond configuration requires the camera operator to cross hands with the surgeon, resulting in poor ergonomics. A standardized linear port configuration has been used for nearly all transperitoneal urologic surgery at our institution. The purpose of this article is to describe our experience with this simplified approach and its advantages.A retrospective review was conducted of all laparoscopic cases by a single surgeon from 2000 to June 2009. The linear port configuration includes three ports placed along the ipsilateral pararectal line with the most superior port one fingerbreadth below the costal margin and the inferior port at the level of the umbilicus. A 5-mm camera is used through the most superior port. A low transverse extraction site is typically used, if necessary.There were 1264 laparoscopic cases performed using the linear port configuration. Of these, there were 1038 donor/radical/simple and 60 partial nephrectomies, 35 nephroureterectomies, 49 adrenalectomies, 50 pyeloplasties, 20 renal cryoablations, and 12 miscellaneous renal procedures. Of these, 98.2% were performed successfully via this port configuration. Three cases needed an additional port. The intraoperative complication rate was 0.9%, and mean estimated blood loss was 60 mL. There were 20 (1.6%) open conversions: 16 were elective and 4 secondary to complications.Simplifying port placement via a linear configuration for both right and left renal and adrenal surgery is feasible, easy to learn, simplifies strategic planning preoperatively, and provides excellent exposure. Using camera access through the superior port allows for direct visualization and minimizes interaction between the camera holder and surgeon's working envelope.

    View details for DOI 10.1089/end.2011.0127

    View details for Web of Science ID 000296788100011

    View details for PubMedID 21864025

  • Laparoendoscopic Single-Site Porcine Nephrectomy Using A Novel Valveless Trocar System JOURNAL OF ENDOUROLOGY Leppert, J. T., Breda, A., Harper, J. D., Schulam, P. G. 2011; 25 (1): 119-122


    The AirSeal™ access system is a novel laparoscopic trocar that uses airflow to create insufflation pressure without the need for a physical seal or valve. By eliminating all valve elements within the lumen of the canula, the port provides a platform that accommodates multiple instruments of any diameter, shape, or combination and is ideally suited for laparoendoscopic single-site surgery (LESS). We present our initial experience with valveless trocars in traditional urologic laparoscopic cases and a porcine LESS nephrectomy series.Nine transperitoneal LESS nephrectomies were performed in a live porcine model using the 27-mm oval valveless trocar. All working instruments were placed through the single port, and the specimen was extracted through the 4-cm port site.All cases were completed without technical or operative complications. The porcine single-port nephrectomy (n=9) was successfully performed in a mean operative time of 24 minutes through the single 27-mm oval trocar. This accommodated a 5-mm laparoscope, multiple 5-mm instruments, the Endo GIA stapler, and the 15-mm Endocatch bag without loss of insufflation pressure. Condensation and smudging of the laparoscope were minimized, improving visualization and efficiency. The system allowed for use of suction without significant loss of insufflation pressure.The initial experience with the AirSeal valveless trocar system in LESS is encouraging. This technology may offer significant benefits over traditional laparoscopic trocars and single -port platforms and appears particularly suited to facilitate LESS.

    View details for DOI 10.1089/end.2010.0199

    View details for Web of Science ID 000286377200023

    View details for PubMedID 20977374

  • Experience With 750 Consecutive Laparoscopic Donor Nephrectomies-Is it Time to Use a Standardized Classification of Complications? JOURNAL OF UROLOGY Harper, J. D., Breda, A., Leppert, J. T., VEALE, J. L., Gritsch, H. A., Schulam, P. G. 2010; 183 (5): 1941-1946


    Laparoscopic living donor nephrectomy offers patients the benefits of decreased morbidity and improved cosmesis, while maintaining equivalent graft outcomes and complication rates similar to those of open donor surgery. With expressed concern for donor safety, using a standardized complication scale would allow combining data in a donor registry so potential donors could be adequately followed and counseled. We present the largest series to our knowledge of laparoscopic living donor nephrectomy by a single surgeon.The institution's initial 750 laparoscopic living donor nephrectomies were included in the study, and a retrospective and prospective chart and database analysis was performed.Mean donor age was 40.5 years and average body mass index was 25.7 kg/m(2). There were 175 patients (23%) with 2 or more renal arteries while 161 (21.5%) had early arterial bifurcations. There were 3 open conversions (0.4%) and the overall complication rate was 5.46%. Median hospital stay was 1 day and the readmission rate was 1.2%. There were 5 reoperations (0.67%), none of which was for the control of bleeding. No patients required a blood transfusion and there were no mortalities. Using a modified Clavien classification of complications for living donor nephrectomy 65.8% were grade 1, 31.7% grade 2 (12.2% grade 2a, 14.6% grade 2b, 4.9% grade 2c) and 2.4% grade 3. There were no grade 4 complications.With appropriate patient selection and operative experience, laparoscopic living donor nephrectomy is a safe procedure associated with low morbidity. The use of a standardized complication system specific for this procedure is encouraged and could aid in counseling potential donors in the future.

    View details for DOI 10.1016/j.juro.2010.01.021

    View details for Web of Science ID 000276747600112

    View details for PubMedID 20303114

  • Percutaneous Cystolithotomy for Calculi in Reconstructed Bladders: Initial UCLA Experience JOURNAL OF UROLOGY Breda, A., Mossanen, M., Leppert, J., Harper, J., Schulam, P. G., Churchill, B. 2010; 183 (5): 1989-1993


    Following bladder augmentation, patients are at significant risk for bladder calculi. We present our experience with a minimally invasive treatment approach using endoscopically assisted percutaneous cystolithotomy.A retrospective chart review identified 74 patients who underwent percutaneous cystolithotomy following bladder augmentation between 2002 and 2009. Cystogram was performed to determine the ideal location for percutaneous bladder access and a guidewire was inserted in the bladder through a bile needle. A balloon dilator was used to place a 30Fr sheath. Rigid cystoscopy with a 26Fr nephroscope allowed stone treatment by basketing and ultrasonic lithotripsy. A suprapubic 22Fr catheter was then placed. Patients were seen on postoperative day 14 and abdominal ultrasound was performed. If no significant residual calculi were visualized, the suprapubic tube was removed.Mean +/- SD patient age at operation was 20 +/- 10.7 months (range 4 to 40). Mean +/- SD time between bladder augmentation and percutaneous cystolithotomy was 4.8 +/- 2.05 years. Of the patients 38 (51%) were male and 36 (49%) were female. Mean +/- SD number of stones per patient was 4.6 +/- 7.8 (range 1 to 60). Ultrasonic lithotripsy was performed in 49 cases (66%). In 25 cases (34%) only stone basketing was performed. A total of 70 patients (95%) were stone-free on abdominal plain film at 14 days. Of the procedures 24 (32%) were performed on an outpatient basis and 50 were performed on an inpatient basis with a mean +/- SD hospital stay of 1.3 +/- 2.7 days (range 1 to 21). There were 9 minor complications noted (12%).Endoscopic percutaneous cystolithotomy offers a safe and effective treatment option for bladder calculi in reconstructed bladders and is the preferred method at our institution.

    View details for DOI 10.1016/j.juro.2010.01.033

    View details for Web of Science ID 000276747600133

    View details for PubMedID 20303534

  • Comparison of accuracy of 14-, 18-and 20-G needles in ex-vivo renal mass biopsy: a prospective, blinded study BJU INTERNATIONAL Breda, A., Treat, E. G., Haft-Candell, L., Leppert, J. T., Harper, J. D., Said, J., Raman, S., Smith, R. B., Belldegrun, A. S., Schulam, P. G. 2010; 105 (7): 940-945


    To prospectively determine the accuracy of 14-, 18- and 20-G core needle biopsies to render the appropriate histological diagnosis of solid, enhancing renal masses, using a controlled, ex-vivo biopsy technique.From March 2007 to September 2007, 31 patients undergoing partial or radical nephrectomy were randomly selected for biopsy. After extirpative surgery, three ex-vivo biopsies were taken from each lesion with 14-, 18- and 20-G biopsy needles. One experienced genitourinary pathologist, unaware of patient identifiers and final pathology results, determined the biopsy histology and tumour grade, based on standard haematoxylin and eosin (H&E) techniques and immunohistochemistry.The final pathological evaluation classified 21 masses (68%) as clear cell renal cell carcinoma (RCC), three (10%) as papillary RCC, three (10%) as chromophobe RCC, three (10%) as oncocytoma and one (3%) as a benign lymphoid infiltrate. The biopsy histology correlated with the final pathology in 29/31 cases (94%) with the 14-G, 30/31 cases (97%) with the 18-G and 25/31 cases (81%) with the 20-G needles. In two cases chromophobe RCC was misdiagnosed with oncocytoma, and vice versa.In this study a minimum of an 18-G biopsy needle was the most accurate in determining the histological diagnosis. Clear cell and papillary RCCs were accurately diagnosed on biopsy using an 18-G, whereas oncocytoma and chromophobe RCC were difficult to differentiate using standard H&E techniques and immunohistochemistry.

    View details for DOI 10.1111/j.1464-410X.2009.08989.x

    View details for Web of Science ID 000275204900012

    View details for PubMedID 19888984

  • Flexible Ureteroscopy and Laser Lithotripsy for Multiple Unilateral Intrarenal Stones EUROPEAN UROLOGY Breda, A., Ogunyemi, O., Leppert, J. T., Schulam, P. G. 2009; 55 (5): 1190-1196


    External shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) have been the standard of care for the treatment of intrarenal calculi.We sought to determine the safety and efficacy of flexible ureteroscopy and holmium laser lithotripsy for the treatment of multiple intrarenal calculi and further stratify the efficacy by stone burden less than and greater than 20mm.Patients with multiple unilateral renal calculi treated between 2000 and 2006 at a single tertiary academic center were retrospectively evaluated.All patients underwent retrograde flexible ureteroscopy and holmium laser lithotripsy.Stone-free status was determined by ureteroscopy 15 d after the last procedure and was defined as the absence of stones in the kidney or residual fragments <1mm. A renal ultrasound was performed 30 d after the last treatment to confirm the absence of stones and hydronephrosis.Fifty-one patients were identified for a total of 161 intrarenal calculi with a mean stone size per patient of 6.6+/-3mm (range: 2-15). The mean number of stones per patient was 3.1+/-1 (range: 2-6). The mean number of primary procedures was 1.4+/-0.6 (range: 1-3). The overall stone-free rates after one and two procedures were 64.7% and 92.2%, respectively. The stone-free rates for patients with a stone burden greater than and less than 20mm were 85.1% and 100%, respectively. The overall complication rate was 13.6%; 97.6% of cases were performed as outpatient procedures. There are some limitations to this study, however: This is a retrospective review from a single institution, and our results are based on a relatively small sample size.For select patients with multiple intrarenal calculi, flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to ESWL or PNL, with acceptable efficacy and low morbidity.

    View details for DOI 10.1016/j.eururo.2008.06.019

    View details for Web of Science ID 000265592300035

    View details for PubMedID 18571315

  • Flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater - Is this the new frontier? JOURNAL OF UROLOGY Breda, A., Ogunyemi, O., Leppert, J. T., Lam, J. S., Schulam, P. G. 2008; 179 (3): 981-984


    Percutaneous nephrolithotomy has been the standard of care for intrarenal calculi greater than 2 cm. Flexible ureteroscopy with holmium laser lithotripsy is a minimally invasive treatment modality that is able to treat large intrarenal calculi with the potential to decrease morbidity, while maintaining a high level of efficacy.A total of 15 patients with a single intrarenal calculus 2 cm or greater were treated with retrograde ureteroscopic nephrolithotripsy. Lithotripsy was performed with a 7.2Fr flexible ureteroscope and 200 micron laser fiber. The stone-free rate was defined as the absence of any stones in the kidney or residual stone fragments less than 1 mm, which is too small to be extracted with a basket or a grasper. All patients underwent followup ureteroscopy within 15 days after the last procedure and renal ultrasound 30 days after the last treatment.There were a total of 15 intrarenal calculi 20 to 25 mm (mean 22) in diameter. The mean number of procedures was 2.3 (range 2 to 4). The overall stone-free rate was 93.3%. One patient (6.6%) had a residual 5 mm stone fragment in the lower pole of the kidney, which was followed expectantly for 2 years with no change in size. There were no major complications. There were 3 minor complications (20%), including 1 emergency room visit for fever and pain, and 2 cases of gross hematuria. All cases were performed on an outpatient basis.In select patients with a single intrarenal calculus 2 cm or greater small diameter flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to standard percutaneous nephrolithotomy with acceptable efficacy and low morbidity.

    View details for DOI 10.1016/j.juro.2007.10.083

    View details for Web of Science ID 000253176000056

    View details for PubMedID 18207179

  • The chemokine receptor CXCR3 is an independent prognostic factor in patients with localized clear cell renal cell carcinoma JOURNAL OF UROLOGY Klatte, T., Seligson, D. B., Leppert, J. T., Riggs, S. B., Yu, H., Zomorodian, N., Kabbinavar, F. F., Strieter, R. M., Belldegrun, A. S., Pantuck, A. J. 2008; 179 (1): 61-66


    Through its binding with interferon inducible angiostatic chemokines the chemokine receptor CXCR3 has an important role in regulating tumor mediating immunity, angiogenesis and metastatic spread. To evaluate its role in the biology of clear cell renal cell carcinoma we performed a tissue microarray based study.The tissue microarray comprised 154 patients who underwent nephrectomy for localized (N0M0) clear cell renal cell carcinoma at UCLA from 1989 to 2000. Immunohistochemical staining was evaluated by 2 anatomical pathologists who were blinded to outcome. The end point of this study was disease-free survival. Median followup was 5.9 years.A total of 96% of the tumor specimens stained positive for CXCR3. The mean percent of cells staining positive was 68% (range 0 to 100%). CXCR3 expression was not associated with other common clinicopathological features, such as Eastern Cooperative Oncology Group performance status, T stage, Fuhrman grade, vascular invasion or sarcomatoid features. Patients with low CXCR3 expression (less than 30%) had a significantly worse prognosis than patients with high CXCR3 expression with a 5-year disease-free survival rate of 57% vs 82% (p = 0.009). Multivariate Cox regression analysis retained T stage, Eastern Cooperative Oncology Group performance status, sarcomatoid features and CXCR3 as independent prognostic factors.CXCR3 is a novel molecular marker in patients with clear cell renal cell carcinoma. Its higher expression is an independent predictor of improved disease-free survival following nephrectomy for localized disease. Since CXCR3 is not associated with other clinicopathological prognostic factors, it may represent an ideal complementary molecular marker for identifying patients who are at higher risk for recurrence after nephrectomy.

    View details for DOI 10.1016/j.juro.2007.08.148

    View details for Web of Science ID 000251650200015

    View details for PubMedID 17997430

  • In vivo efficacy of laparoscopic assisted percutaneous renal cryotherapy: Evidence based guidelines for the practicing urologist JOURNAL OF UROLOGY Breda, A., Lam, J. S., Riggs, S., Leppert, J. T., Gui, D., Said, J. W., Schulam, P. G., Belldegrun, A. S. 2008; 179 (1): 333-337


    The treatment of small renal tumors continues to evolve in parallel with advances in ablative technology. We compared the lesion geometry of 3, 17 gauge cryoneedles to determine the most effective distance and configuration of the cryoneedles in an in vivo porcine kidney model.Argon gas based renal cryoablation was performed in 6 pigs using a laparoscopically assisted percutaneous approach. Cryoablation using a single cryoneedle and a template of 3 cryoneedles with various ice ball shapes, including elliptical, bulb-shaped and standard 17 gauge cryoneedles (Galil Medical, Plymouth Meadow, Pennsylvania) was performed in 3 pigs. Three additional pigs underwent renal cryoablation using elliptical cryoneedles in 3 triangular template configurations with the cryoneedles spaced 1, 1.5 and 2 cm apart, respectively. The animals were sacrificed a minimum of 2 weeks following treatment.Elliptical cryoneedles achieved the largest area of necrosis when used in single and template configurations. When used in a template configuration of 3 needles 1, 1.5 and 2 cm apart from each other the calculated volume of necrosis was 4.3 x 4.5 x 2.5, 4.9 x 4.1 x 2.5 and 4.0 x 4.5 x 2.5 cm, respectively.Using a single 17 gauge cryoneedle is inadequate for treating most small renal tumors. Cryoneedles with an elliptical ice ball are most effective for achieving consistent and reliable tissue destruction. The 1.5 cm template configuration generated the largest area of necrosis. Our data suggest that with the current technology renal cryoablation should be limited to lesions not greater than 4 cm.

    View details for DOI 10.1016/j.juro.2007.08.089

    View details for Web of Science ID 000251650200084

    View details for PubMedID 18006012

  • Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma CLINICAL CANCER RESEARCH Klatte, T., Seligson, D. B., Riggs, S. B., Leppert, J. T., Berkman, M. K., Kleid, M. D., Yu, H., Kabbinavar, F. F., Pantuck, A. J., Belldegrun, A. S. 2007; 13 (24): 7388-7393


    Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1 alpha in renal cell carcinoma (RCC).Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.HIF-1 alpha expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1 alpha was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1 alpha expression predicted outcome in metastatic patients: patients with high HIF-1 alpha expression (>35%) had significantly worse survival than patients with low expression (< or =35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1 alpha and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.HIF-1 alpha is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1 alpha and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

    View details for DOI 10.1158/1078-0432.CCR-07-0411

    View details for Web of Science ID 000251954200025

    View details for PubMedID 18094421

  • Complications of laparoscopic renal surgery. Minerva urologica e nefrologica = The Italian journal of urology and nephrology Bergman, J., Leppert, J. T., Breda, A. 2007; 59 (4): 417-423


    Initial excitement for laparoscopy's potential to decrease patient morbidity and convalescence by avoiding a flank incision was initially tempered by concerns for increased operative time, technical complexity and the suitability of laparoscopy approaches to oncologic surgery. With experience, the benefits of laparoscopic approaches to renal surgery have become clear. As laparoscopic techniques are mastered and the indications expanded, it is important to remember that minimally invasive surgery remains associated with significant risks and potential complications. Several complications are theoretically more difficult to control laparoscopically than with open exposure. Control of bleeding, identification of injury to solid organs, and positive margins due to the lack of haptic feedback have been of special concern during the rapid advancement of laparoscopic surgical technique between 1991 and today. It is critical for the urologist to be familiar with these complications in order to maximize patients' clinical outcomes through appropriate patient selection and intraoperative planning. Know-ledge of the complications of laparoscopic renal surgery will also aid in providing patients with true informed consent and realistic surgical expectations. The purpose of this manuscript is to review the complications associated with laparoscopic renal surgery in general, with specific attention paid to laparoscopic radical, partial, pediatric, and donor nephrectomy.

    View details for PubMedID 17947959

  • Prognostic relevance of the mTOR pathway in renal cell carcinoma - Implications for molecular patient selection for targeted therapy CANCER Pantuck, A. J., Seligson, D. B., Klatte, T., Yu, H., Leppert, J. T., Moore, L., O'Toole, T., Gibbons, J., Belldegrun, A. S., Figlin, R. A. 2007; 109 (11): 2257-2267


    The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended.

    View details for DOI 10.1002/cncr.22677

    View details for Web of Science ID 000246679100013

    View details for PubMedID 17440983

  • The role of molecular markers in the staging of renal cell carcinoma BJU INTERNATIONAL Leppert, J. T., Pantuck, A. J., Figlin, R. A., Belldegrun, A. S. 2007; 99 (5): 1208-1211
  • Prognostic relevance of capsular involvement and collecting system invasion in stage I and II renal cell carcinoma BJU INTERNATIONAL Klatte, T., Chung, J., Leppert, J. T., Lam, J. S., Pantuck, A. J., Figlin, R. A., Belldegrun, A. S. 2007; 99 (4): 821-824


    To define the prognostic relevance of capsular involvement (invasion with no penetration) and collecting-system invasion in patients with stage I (pT1N0M0) and stage II (pT2N0M0) renal cell carcinoma (RCC), by evaluating the outcome of patients treated with nephrectomy.In all, 519 patients from a kidney cancer database treated with nephrectomy for stage I and II RCC between 1985 and 2005 were assessed retrospectively. The primary endpoint was recurrence-free survival time. The prognostic relevance of capsular involvement and collecting-system invasion were examined using univariate and multivariate survival analysis.Capsular involvement and collecting-system invasion were evident in 112 (21.6%) and 39 (7.5%) patients, respectively. Capsular involvement was associated with higher Fuhrman grades and larger tumours. The incidence of collecting-system invasion was higher in patients with microvascular invasion. The median follow-up was 49 months. In univariate analysis, patients with capsular involvement and collecting-system invasion had a worse prognosis than patients without (P = 0.007 and <0.001, respectively). In multivariate analysis, capsular involvement (hazard ratio 1.84, P = 0.036) and collecting-system invasion (3.78, P < 0.001) were independent prognostic factors of recurrence-free survival. Interestingly, there was no survival difference between patients with capsular involvement in stage I/II and patients with invasion of perinephric tissue (pT3aN0M0).These findings suggest that capsular involvement and collecting-system invasion are poor prognostic findings in stage I and II RCC. They should both be considered when planning the follow-up. A revised pT3a stage including patients with capsular involvement could improve its prognostic validity.

    View details for DOI 10.1111/j.1464=410X.2006.06729x

    View details for Web of Science ID 000244977500025

    View details for PubMedID 17244281

  • Is the testis a chemo-privileged site? Is there a blood-testis barrier? Reviews in urology Dave, D. S., Leppert, J. T., Rajfer, J. 2007; 9 (1): 28-32


    The incidence of testicular cancer, primarily seminoma, has been increasing in many countries, including the United States. The testis is often the site of residual cancer after adequate treatment with systemic chemotherapy. The blood-testis barrier is commonly cited as the explanation for residual tumor within the gonad after chemotherapy and as the indication for delayed orchiectomy. Conversely, complete eradication of viable tumor from the primary site is common and argues against the testis as a "tumor sanctuary." Residual tumor is also demonstrated within metastatic foci, and the disparity between the histopathologic response of the primary tumor and metastatic sites may be best explained by tumor heterogeneity and multiple tumor clones. Regardless of the scientific and academic arguments, delayed radical orchiectomy remains an important part of treatment for patients undergoing primary chemotherapy.

    View details for PubMedID 17396169

  • Renca/carbonic anhydrase-IC: A murine model of a carbonic anhydrase-IX-expressing renal cell carcinoma UROLOGY Shvarts, O., Janzen, N., Lam, J. S., Leppert, J. T., Caliliw, R., Figlin, R. A., Belldegrun, A. S., Zeng, G. 2006; 68 (5): 1132-1138


    Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC.A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models.Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining.RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line.

    View details for DOI 10.1016/j.urology.2006.08.1073

    View details for Web of Science ID 000242592500059

    View details for PubMedID 17095063

  • Determining the prognosis of patients with renal cell carcinoma: is it time for a re-evaluation? NATURE CLINICAL PRACTICE UROLOGY Leppert, J. T., Pantuck, A. J. 2006; 3 (10): 510-511

    View details for DOI 10.1038/ncpuro0598

    View details for Web of Science ID 000240938400002

    View details for PubMedID 17031370

  • The sensitivity of testosterone immunoassays and their role in monitoring antiandrogen therapy UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Leppert, J. T., Lam, J. S., Butch, A. W., Belldegrun, A. S. 2006; 24 (4): 277-278
  • Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer CLINICAL CANCER RESEARCH Pantuck, A. J., Leppert, J. T., Zomorodian, N., Aronson, W., Hong, J., Barnard, R. J., Seeram, N., Liker, H., Wang, H., Elashoff, R., Heber, D., Aviram, M., Ignarro, L., Belldegrun, A. 2006; 12 (13): 4018-4026


    Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy.A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels.The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption.We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

    View details for DOI 10.1158/1078-0432.CCR-05-2290

    View details for Web of Science ID 000238930500023

    View details for PubMedID 16818701

  • Implants of noninvasive papillary urothelial carcinoma in peritoneum and ileocolonic neobladder: Support for "seed and soil" hypothesis of bladder recurrence UROLOGY Herawi, M., Leppert, J. T., Thomas, G. V., de Kernion, J. B., Epstein, J. I. 2006; 67 (4): 746-750


    To explore the underlying mechanism of tumor regrowth in cases of noninvasive urothelial carcinoma that recur in unusual anatomic locations.The pathology files of our institution and the consult service of one of us were searched for cases of noninvasive nonmetastatic urothelial carcinoma with involvement of unusual anatomic sites. Cases in which the mode of spread included direct spread to the adjacent tissue and lymphovascular metastases were excluded. Medical history, including presenting symptoms, and follow-up data were obtained.Two cases of noninvasive urothelial carcinoma were identified. One had presented as an implant in the peritoneal investment of the bladder dome and the other as multiple implants growing on the benign surface of the colonic mucosa of an orthotopic neobladder distant from the anastomosis site. Both cases had initially presented as noninvasive papillary urothelial carcinoma of the renal pelvis. Although the urinary bladder was free of neoplastic changes at nephroureterectomy, both patients also developed several papillary tumors within the bladder shortly after the removal of the kidney.After clinicopathologic correlation, the mode of tumor spread in these cases was best explained by the "seeding/implantation" theory. The urothelial tumor cells in each of these cases demonstrated the ability to implant themselves not only in the urothelium of the bladder but also in the colonic mucosa of a constructed neobladder and on the peritoneal surface.

    View details for DOI 10.1016/j.urology.2005.10.023

    View details for Web of Science ID 000237054800025

    View details for PubMedID 16566991

  • Prevention of bladder cancer: A review EUROPEAN UROLOGY Leppert, J. T., Shvarts, O., Kawaoka, K., LIEBERMAN, R., Belldegrun, A. S., Pantuck, A. J. 2006; 49 (2): 226-234


    Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention.A literature review of peer-reviewed articles which address bladder cancer prevention was performed.Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects.While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

    View details for DOI 10.1016/j.eururo.2005.12.011

    View details for Web of Science ID 000235511100007

    View details for PubMedID 16413099

  • Significance of gene expression analysis of renal cell carcinoma EXPERT REVIEW OF ANTICANCER THERAPY T Leppert, J., Pantuck, A. J. 2006; 6 (2): 293-299


    Renal cell carcinoma (RCC) describes a family of epithelial tumors arising from within the kidney. Each subtype of RCC presents a unique clinical picture with varied tumor biology, patient prognosis and response to treatment. Gene expression profiling offers the ability to analyze thousands of candidate genes in high-throughput arrays and has led to a greater knowledge of the molecular genetics of RCC. This powerful technology can identify RCC subtypes, recapitulating and refining the current histological classifications. Gene expression data also promise to advance current staging systems and improve prognostic information for patients and clinicians. Understanding the genetic signature of RCC tumors will allow for sophisticated application of systemic and targeted therapies, improving patient response and minimizing unnecessary exposure of patients to treatment toxicities. This article reviews the significance of gene expression analysis in the understanding of tumor biology and RCC treatment.

    View details for DOI 10.1586/14737140.6.2.293

    View details for Web of Science ID 000240922500019

    View details for PubMedID 16445381

  • Secondary hormonal therapy for advanced prostate cancer JOURNAL OF UROLOGY Lam, J. S., Leppert, J. T., Vemulapalli, S. N., Shvarts, O., Belldegrun, A. S. 2006; 175 (1): 27-34


    Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer.A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer.Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents.Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.

    View details for DOI 10.1016/S0022-5347(05)00034-0

    View details for Web of Science ID 000234001100007

    View details for PubMedID 16406864

  • Open surgical management of renal cell carcinoma in the era of minimally invasive kidney surgery BJU INTERNATIONAL Dave, D. S., Lam, J. S., Leppert, J. T., Belldegrun, A. S. 2005; 96 (9): 1268-1274
  • Role of molecular markers in the diagnosis and therapy of renal cell carcinoma. Urology Lam, J. S., Leppert, J. T., Figlin, R. A., Belldegrun, A. S. 2005; 66 (5): 1-9


    Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma (RCC) have paved the way for developments that may enhance early diagnosis, better predict prognosis, and improve survival. Reliable predictive factors are essential for the stratification of patients into clinically meaningful categories that can be used to provide patients with counseling regarding prognosis, select treatment modalities, and determine eligibility for clinical trials. The TNM (tumor, nodes, metastasis) staging system is currently the most extensively used staging system for RCC, but it has undergone systematic revisions as a result of emerging data. Comprehensive integrated staging systems that combine important clinical and pathological variables have been created in an attempt to improve prognostication. Although staging has improved with the development of integrated systems, the incorporation of molecular tumor markers are expected to revolutionize the staging of RCC. This article reviews the important molecular markers in RCC to date and discusses their role in the diagnosis, prognostication, and therapy of patients with RCC.

    View details for PubMedID 16194700

  • Role of molecular markers in the diagnosis and therapy of renal cell carcinoma UROLOGY Lam, J. S., Leppert, J. T., Figlin, R. A., Belldegrun, A. S. 2005; 66 (5A): 1-9
  • Adjuvant therapy of renal cell carcinoma: patient selection and therapeutic options BJU INTERNATIONAL Lam, J. S., Leppert, J. T., Belldegrun, A. S., Figlin, R. A. 2005; 96 (4): 483-488
  • Predicting response to interleukin-2 therapy among patients with renal cell carcinoma JOURNAL OF IMMUNOTHERAPY Leppert, J. T., Lam, J. S., Belldegrun, A. S. 2005; 28 (5): 427-429

    View details for Web of Science ID 000231481800001

    View details for PubMedID 16113598

  • Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma BJU INTERNATIONAL Leppert, J. T., Lam, J. S., Pantuck, A. J., Figlin, R. A., Belldegrun, A. S. 2005; 96 (3): 281-285


    The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.

    View details for DOI 10.1111/j.1464-410X.2005.05615.x

    View details for Web of Science ID 000230726000011

    View details for PubMedID 16042714

  • Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system JOURNAL OF UROLOGY Lam, J. S., Shvarts, O., Leppert, J. T., Pantuck, A. J., Figlin, R. A., Belldegrun, A. S. 2005; 174 (2): 466-472


    We created an evidence based postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma (RCC) based on a risk group stratification system.559 patients undergoing surgery for localized and ocally advanced RCC were stratified into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the University of California-Los Angeles Integrated Staging System (UISS). Tumor recurrences were identified and categorized according to time and location.Patients with localized disease had a lower 5-year recurrence rate than patients with locally advanced (nodal) disease (27.6% vs 64%, p <0.0001). Patients in the LR, IR, and HR groups following nephrectomy demonstrated 5-year recurrence-free rates of 90.4%, 61.8%, and 41.9%, respectively (p <0.0001), and median times to recurrence of 28.9, 17.8 and 9.5 months, respectively (p <0.0001). Chest and abdomen recurrences comprised of 75% and 37.5%, 77.4% and 58.1%, and 45.2% and 67.7% of recurrences in the LR, IR and HR groups, respectively. In patients with node positive disease, chest and abdomen comprised of 58.8% and 76.5% of recurrences, respectively. Patients undergoing partial nephrectomy did not demonstrate a greater rate of local or distant recurrence compared with patients undergoing radical nephrectomy.Significant differences in incidence and time to recurrence following surgical resection for RCC mandates unique surveillance protocols for patients in each of the UISS risk groups. LR group patients should be followed for at least 5 years, whereas IR and HR group patients require longer surveillance. HR group patients require more stringent abdominal surveillance, whereas LR group patients should emphasize the chest. Patients with nodal disease also require stringent followup. Patients undergoing partial nephrectomy for localized disease can be followed according to the same UISS risk group based protocol.

    View details for DOI 10.1097/01.ju.0000165572.38887.da

    View details for Web of Science ID 000230604300016

    View details for PubMedID 16006866

  • Novel approaches in the therapy of metastatic renal cell carcinoma WORLD JOURNAL OF UROLOGY Lam, J. S., Leppert, J. T., Belldegrun, A. S., Figlin, R. A. 2005; 23 (3): 202-212


    Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.

    View details for DOI 10.1007/s00345-004-0466-0

    View details for Web of Science ID 000230806900010

    View details for PubMedID 15812574

  • Renal cell carcinoma 2005: New frontiers in staging, prognostication and targeted molecular therapy JOURNAL OF UROLOGY Lam, J. S., Shvarts, O., Leppert, J. T., Figlin, R. A., Belldegrun, A. S. 2005; 173 (6): 1853-1862


    Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC.A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC.A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting.Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.

    View details for DOI 10.1097/01.ju.0000165693.68449.c3

    View details for Web of Science ID 000229051700006

    View details for PubMedID 15879764

  • Surveillance following radical or partial nephrectomy for renal cell carcinoma. Current urology reports Lam, J. S., Leppert, J. T., Figlin, R. A., Belldegrun, A. S. 2005; 6 (1): 7-18


    Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease and up to 50% treated for localized disease have a recurrence. Although the prognosis generally is poor in these patients, some may respond to immunotherapy and a subset of patients who develop solitary metastases can achieve long-term survival. Therefore, the timely identification of recurrences following surgical extirpation is imperative in the treatment of patients.

    View details for PubMedID 15610692

  • Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75 JOURNAL OF COMPARATIVE NEUROLOGY Peterson, D. A., Dickinson-Anson, H. A., Leppert, J. T., Lee, K. F., Gage, F. H. 1999; 404 (1): 1-20


    The neurotrophin receptor p75 is a low-affinity receptor that binds neurotrophins. To investigate the role of p75 in the survival and function of central neurons, p75 null-mutant and wild type litter mate mice were tested on behavioral tasks. Null mutants showed significant performance deficits on water maze, inhibitory avoidance, motor activity, and habituation tasks that may be attributed to cognitive dysfunction or may represent a global sensorimotor impairment. The p75 null-mutant and wild type litter mate mice were assessed for central cholinergic deficit by using quantitative stereology to estimate the total neuronal number in basal forebrain and striatum and for subpopulations expressing the high-affinity tyrosine receptor kinase A (trkA) neurotrophin receptor and choline acetyltransferase (ChAT). In the adult brain, cholinergic neurons of the basal forebrain receive target-derived trophic support, whereas cholinergic striatal neurons do not. Adult p75 null-mutant mice had significant reduction of basal forebrain volume by 25% and had a corresponding significant loss of 37% of total basal forebrain neurons. The basal forebrain population of ChAT-positive neurons in p75-deficient mice declined significantly by 27%, whereas the trkA-positive population did not change significantly. There was no significant change in striatal volume or in striatal neuronal number either in total or by cholinergic subpopulation. These results demonstrate vulnerability to the lack of p75 in adult central neurons that are neurotrophin dependent. In addition, the loss of noncholinergic central neurons in mice lacking p75 suggests a role for p75 in cell survival by an as yet undetermined mechanism. Possible direct and indirect effects of p75 loss on neuronal survival are discussed.

    View details for Web of Science ID 000077748200001

    View details for PubMedID 9886021

  • Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75 SCIENCE Peterson, D. A., Leppert, J. T., Lee, K. F., Gage, F. H. 1997; 277 (5327): 837-838

    View details for Web of Science ID A1997XQ24700050

    View details for PubMedID 9273702