Clinical Focus

  • Cancer > Urologic Oncology
  • Prostate cancer screening
  • Prostate cancer - localized
  • Prostate cancer active surveillance
  • Urology

Administrative Appointments

  • Director, U54 Stanford O'Brien Urology Research Center (2021 - Present)
  • Co-Chair, Molecular and Cellular Characterization Centers NCI (2015 - 2017)
  • Nominating Committee, Society of Basic Urologic Research (2015 - 2017)
  • Vice Chair, Department of Urology (2014 - Present)
  • Associate Dean, Academic Affairs, Stanford University School of Medicine (2013 - 2019)
  • Chief, Urologic Oncology, Department of Urology (2012 - Present)
  • Acting Chair, Department of Urology (2012 - 2012)
  • Editorial Board, Andrology (2011 - Present)
  • Associate Chair, Prostate Cancer Working Group EDRN (2010 - 2015)
  • Editorial Board, Prostate Cancer (2010 - 2015)
  • Editor-in-Chief, The Open Prostate Cancer Journal (2008 - 2015)
  • Membership Committee, Society for Basic Urologic Research (2004 - 2008)
  • Editorial Board, The Prostate (2000 - Present)

Honors & Awards

  • Dornier Research Scholar, American Foundation for Urologic Disease (1995-1997)
  • Clinician Scientist Award, Doris Duke Foundation (1998-2002)
  • Eugene P. Schonfeld Medical Research Award, Kidney Cancer Association (2000-2002)
  • Leutje-Stubbs Faculty Scholar, Stanford University School of Medicine (2002-2003)
  • Best Doctors in America, Best Doctors Inc. (2004-2013)
  • Listing in Guide to America's Top Surgeons, Consumers' Research Council (2010)
  • Keith and Jan Hurlbut Professor, Stanford University (2012)

Boards, Advisory Committees, Professional Organizations

  • Executive Member, Society for Basic Urologic Research (2021 - Present)

Professional Education

  • Medical Education: Stanford University School of Medicine (1988) CA
  • Residency: Johns Hopkins University Surgery Program (1990) MD
  • Internship: Johns Hopkins University Surgery Program (1989) MD
  • Fellowship: Johns Hopkins University School of Medicine (1997) MD
  • Residency: Johns Hopkins University School of Medicine (1994) MD
  • Board Recertification, Urology, American Board of Urology (2017)
  • Board Certification: American Board of Urology, Urology (2000)
  • A. B., University of Chicago, Biology (1982)

Current Research and Scholarly Interests

Our interest is in developing diagnostic and prognostic markers for urological diseases. Our work spans discovery, measurement methodologies, and clinical validation of candidate biomarkers. We have primarily used genomic and proteomic approaches for biomarker discovery. While our primary focus has been in prostate cancer, we have also worked in kidney cancer and other malignancies. We are also working to characterize the functional roles of several of the candidate biomarkers in cancer. In the past several years our work has expanded into benign urologic diseases including benign prostatic hyperplasia, obstructive nephropathy, and androgen insensitivity syndrome. In collaboration with bioengineers and radiologists, we have active research in molecular imaging, and protein and nucleotide detection on biological samples. We also participate in several large clinical trials for development, validation and implementation of clinical biomarkers in prostate cancer.

Clinical Trials

  • Prostate Active Surveillance Study Recruiting

    The Prostate Active Surveillance Study (PASS) is a research study for men who have chosen active surveillance as a management plan for their prostate cancer. Active surveillance is defined as close monitoring of prostate cancer with the offer of treatment if there are changes in test results. This study seeks to discover markers that will identify cancers that are more aggressive from those tumors that grow slowly.

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  • Prostate Cancer Upgrading Reference Set Recruiting

    Research repository designed to establish prostate cancer upgrading reference set and development of a risk prediction tool. Repository will include clinical information and biologics on a cohort of 240 men, to predict presence of high grade cancer at time of prostatectomy (removal of prostate) among patients with a low grade cancer diagnosis at time of biopsy.

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  • A Pilot Trial Using BR55 Ultrasound Contrast Agent in the Assessment of Prostate Cancer Not Recruiting

    Pilot study to evaluate the ability of BR55 to identify prostate cancer lesions with Gleason Score ≥7 by ultrasound molecular imaging on the basis of a visual score in comparison with histopathology results

    Stanford is currently not accepting patients for this trial. For more information, please contact Phuong Pham, 650-725-9810.

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  • Hypofractionated Radiotherapy for Localized Prostate Cancer (With CyberKnife or With IMRT) Not Recruiting

    To demonstrate that a hypo-fractionated course of radiotherapy (ie. an accelerated radiotherapy course where fewer but larger doses of radiotherapy are given) is both safe and effective in the treatment of low-risk localized prostate cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Gillian McFarlane, (650) 721 - 2034.

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  • Imaging During Surgery in Diagnosing Patients With Prostate, Bladder, or Kidney Cancer Not Recruiting

    This pilot clinical trial studies imaging during surgery in diagnosing patients with prostate, bladder, or kidney cancer. New diagnostic imaging procedures, may find prostate, bladder, or kidney cancer

    Stanford is currently not accepting patients for this trial. For more information, please contact Mark Gonzalgo, 650-725-5544.

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  • Microarray Analysis of Gene Expression in Prostate Tissues Not Recruiting

    The purpose of this study is to investigate gene expression profiles and biologic features of prostate tissue and how they relate to prostate cancer development and growth.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office, 650-498-7061.

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  • Perfusion CT Monitoring to Predict Treatment Efficacy in Renal Cell Carcinoma Not Recruiting

    This pilot clinical trial studies perfusion computed tomography (CT) in predicting response to treatment in patients with advanced kidney cancer. Comparing results of diagnostic procedures done before, during, and after targeted therapy may help doctors predict a patient's response to treatment and help plan the best treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Yoriko Imae, 650-498-5186.

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  • Photoacoustic Imaging (PAI) of the Prostate: A Clinical Feasibility Study Not Recruiting

    The purpose of our study is to image human prostate tissue using a transrectal photoacoustic imaging probe.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sri-Rajasekhar Kothapalli, 650-498-7061.

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  • Prostate Artery Embolization With Embosphere Microspheres Compared to TURP for Benign Prostatic Hyperplasia Not Recruiting

    The purpose of this study is to evaluate improvement of symptoms from benign prostatic hyperplasia (BPH) as assessed by the International Prostate Symptom Score (IPSS) for prostatic artery embolization (PAE) using Embosphere Microspheres compared to conventional transurethral resection of the prostate (TURP).

    Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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  • Quality of Life Following Radical Prostatectomy Not Recruiting

    This study will utilize the Expanded Prostate Cancer Index Composite questionnaire to learn what impact the surgery has upon the participant's sense of health, sexual and urinary quality of life.

    Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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2023-24 Courses

Stanford Advisees

Graduate and Fellowship Programs

All Publications

  • Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage. Histopathology Nguyen, J. K., Harik, L. R., Klein, E. A., Li, J., Corrigan, D., Liu, S., Chan, E., Hawley, S., Auman, H., Newcomb, L. F., Carroll, P. R., Cooperberg, M. R., Filson, C. P., Simko, J. P., Nelson, P. S., Tretiakova, M. S., Troyer, D., True, L. D., Vakar-Lopez, F., Weight, C. J., Lin, D. W., Brooks, J. D., McKenney, J. K. 2024


    Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential.Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology.Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

    View details for DOI 10.1111/his.15231

    View details for PubMedID 38828674

  • Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer. JAMA Newcomb, L. F., Schenk, J. M., Zheng, Y., Liu, M., Zhu, K., Brooks, J. D., Carroll, P. R., Dash, A., de la Calle, C. M., Ellis, W. J., Filson, C. P., Gleave, M. E., Liss, M. A., Martin, F., McKenney, J. K., Morgan, T. M., Tretiakova, M. S., Wagner, A. A., Nelson, P. S., Lin, D. W. 2024


    Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making.To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort.The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022.Active surveillance for prostate cancer.Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies.Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%).In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

    View details for DOI 10.1001/jama.2024.6695

    View details for PubMedID 38814624

  • AZGP1 deficiency promotes angiogenesis in prostate cancer. Journal of translational medicine Wen, R. M., Qiu, Z., Marti, G. E., Peterson, E. E., Marques, F. J., Bermudez, A., Wei, Y., Nolley, R., Lam, N., Polasko, A. L., Chiu, C. L., Zhang, D., Cho, S., Karageorgos, G. M., McDonough, E., Chadwick, C., Ginty, F., Jung, K. J., Machiraju, R., Mallick, P., Crowley, L., Pollack, J. R., Zhao, H., Pitteri, S. J., Brooks, J. D. 2024; 22 (1): 383


    Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive.AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples.Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues.AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

    View details for DOI 10.1186/s12967-024-05183-x

    View details for PubMedID 38659028

    View details for PubMedCentralID 321763

  • Mortality Risks Associated with Depression in Men with Prostate Cancer. European urology oncology Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Sieh, W., Sundquist, K. 2024


    Men diagnosed with prostate cancer (PC) have an increased risk of depression; however, it is unclear to what extent depression affects long-term survival. A better understanding of such effects is needed to improve long-term care and outcomes for men with PC.To determine the associations between major depression and mortality in a national cohort of men with PC.A national cohort study was conducted of all 180 189 men diagnosed with PC in Sweden during 1998-2017. Subsequent diagnoses of major depression were ascertained from nationwide outpatient and inpatient records through 2018.Deaths were identified from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) for all-cause mortality associated with major depression, adjusting for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. PC-specific mortality was examined using competing risks models.In 1.3 million person-years of follow-up, 16 134 (9%) men with PC were diagnosed with major depression and 65 643 (36%) men died. After adjusting for sociodemographic factors and comorbidities, major depression was associated with significantly higher all-cause mortality in men with high-risk PC (HR, 1.50; 95% confidence interval [CI], 1.44-1.55) or low- or intermediate-risk PC (1.64; 1.56-1.71). These risks were elevated regardless of PC treatment or age at PC diagnosis, except for youngest men (<55 yr) in whom the risks were nonsignificant. Major depression was also associated with increased PC-specific mortality in men with either high-risk PC (HR, 1.35; 95% CI, 1.28-1.43) or low- or intermediate-risk PC (1.42; 1.27-1.59). This study was limited to Sweden and will need replication in other countries when feasible.In this national cohort of men with PC, major depression was associated with ∼50% higher all-cause mortality. Men with PC need timely detection and treatment of depression to support their long-term outcomes and survival.In this report, we examined the effects of depression on survival in men with prostate cancer. We found that among all men with prostate cancer, those who developed depression had a 50% higher risk of dying than those without depression. Men with prostate cancer need close monitoring for the detection and treatment of depression to improve their long-term health outcomes.

    View details for DOI 10.1016/j.euo.2024.03.012

    View details for PubMedID 38575410

  • RAPHIA: A deep learning pipeline for the registration of MRI and whole-mount histopathology images of the prostate. Computers in biology and medicine Shao, W., Vesal, S., Soerensen, S. J., Bhattacharya, I., Golestani, N., Yamashita, R., Kunder, C. A., Fan, R. E., Ghanouni, P., Brooks, J. D., Sonn, G. A., Rusu, M. 2024; 173: 108318


    Image registration can map the ground truth extent of prostate cancer from histopathology images onto MRI, facilitating the development of machine learning methods for early prostate cancer detection. Here, we present RAdiology PatHology Image Alignment (RAPHIA), an end-to-end pipeline for efficient and accurate registration of MRI and histopathology images. RAPHIA automates several time-consuming manual steps in existing approaches including prostate segmentation, estimation of the rotation angle and horizontal flipping in histopathology images, and estimation of MRI-histopathology slice correspondences. By utilizing deep learning registration networks, RAPHIA substantially reduces computational time. Furthermore, RAPHIA obviates the need for a multimodal image similarity metric by transferring histopathology image representations to MRI image representations and vice versa. With the assistance of RAPHIA, novice users achieved expert-level performance, and their mean error in estimating histopathology rotation angle was reduced by 51% (12 degrees vs 8 degrees), their mean accuracy of estimating histopathology flipping was increased by 5% (95.3% vs 100%), and their mean error in estimating MRI-histopathology slice correspondences was reduced by 45% (1.12 slices vs 0.62 slices). When compared to a recent conventional registration approach and a deep learning registration approach, RAPHIA achieved better mapping of histopathology cancer labels, with an improved mean Dice coefficient of cancer regions outlined on MRI and the deformed histopathology (0.44 vs 0.48 vs 0.50), and a reduced mean per-case processing time (51 vs 11 vs 4.5 min). The improved performance by RAPHIA allows efficient processing of large datasets for the development of machine learning models for prostate cancer detection on MRI. Our code is publicly available at:

    View details for DOI 10.1016/j.compbiomed.2024.108318

    View details for PubMedID 38522253

  • Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology. Scientific reports Eminaga, O., Abbas, M., Kunder, C., Tolkach, Y., Han, R., Brooks, J. D., Nolley, R., Semjonow, A., Boegemann, M., West, R., Long, J., Fan, R. E., Bettendorf, O. 2024; 14 (1): 5284


    Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

    View details for DOI 10.1038/s41598-024-55228-w

    View details for PubMedID 38438436

    View details for PubMedCentralID 2995775

  • 68Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial. The Lancet. Oncology Duan, H., Moradi, F., Davidzon, G. A., Liang, T., Song, H., Loening, A. M., Vasanawala, S., Srinivas, S., Brooks, J. D., Hancock, S., Iagaru, A. 2024


    National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer.This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with, NCT02624518, and is complete.Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported.68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients.The US Department of Defense.

    View details for DOI 10.1016/S1470-2045(24)00069-X

    View details for PubMedID 38423030

  • Identification and characterization of intact glycopeptides in human urine. Scientific reports Garcia-Marques, F., Fuller, K., Bermudez, A., Shamsher, N., Zhao, H., Brooks, J. D., Flory, M. R., Pitteri, S. J. 2024; 14 (1): 3716


    Glycoproteins in urine have the potential to provide a rich class of informative molecules for studying human health and disease. Despite this promise, the urine glycoproteome has been largely uncharacterized. Here, we present the analysis of glycoproteins in human urine using LC-MS/MS-based intact glycopeptide analysis, providing both the identification of protein glycosites and characterization of the glycan composition at specific glycosites. Gene enrichment analysis reveals differences in biological processes, cellular components, and molecular functions in the urine glycoproteome versus the urine proteome, as well as differences based on the major glycan class observed on proteins. Meta-heterogeneity of glycosylation is examined on proteins to determine the variation in glycosylation across multiple sites of a given protein with specific examples of individual sites differing from the glycosylation trends in the overall protein. Taken together, this dataset represents a potentially valuable resource as a baseline characterization of glycoproteins in human urine for future urine glycoproteomics studies.

    View details for DOI 10.1038/s41598-024-53299-3

    View details for PubMedID 38355753

    View details for PubMedCentralID PMC10866872

  • Response to lao, guan, wang, et al. Journal of the National Cancer Institute Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Edwards, A. C., Sundquist, K., Sieh, W. 2024

    View details for DOI 10.1093/jnci/djae033

    View details for PubMedID 38341661

  • UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas. Cell reports. Medicine Liu, S., Chai, T., Garcia-Marques, F., Yin, Q., Hsu, E. C., Shen, M., Shaw Toland, A. M., Bermudez, A., Hartono, A. B., Massey, C. F., Lee, C. S., Zheng, L., Baron, M., Denning, C. J., Aslan, M., Nguyen, H. M., Nolley, R., Zoubeidi, A., Das, M., Kunder, C. A., Howitt, B. E., Soh, H. T., Weissman, I. L., Liss, M. A., Chin, A. I., Brooks, J. D., Corey, E., Pitteri, S. J., Huang, J., Stoyanova, T. 2024: 101381


    Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

    View details for DOI 10.1016/j.xcrm.2023.101381

    View details for PubMedID 38244540

  • High expression of Trop2 is associated with aggressive localized prostate cancer and is a candidate urinary biomarker. Scientific reports Liu, S., Hawley, S. J., Kunder, C. A., Hsu, E. C., Shen, M., Westphalen, L., Auman, H., Newcomb, L. F., Lin, D. W., Nelson, P. S., Feng, Z., Tretiakova, M. S., True, L. D., Vakar-Lopez, F., Carroll, P. R., Simko, J., Gleave, M. E., Troyer, D. A., McKenney, J. K., Brooks, J. D., Liss, M. A., Stoyanova, T. 2024; 14 (1): 486


    Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and pre-operative PSA levels. More importantly, we demonstrate that elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

    View details for DOI 10.1038/s41598-023-50215-z

    View details for PubMedID 38177207

    View details for PubMedCentralID 7983799

  • ArtHiFy: Artificial Histopathology-style Features for Improving MRI-Based Prostate Cancer Detection Bhattacharya, I., Shao, W., Li, X., Soerensen, S. C., Fan, R. E., Ghanouni, P., Brooks, J. D., Sonn, G. A., Rusu, M., Chen, W., Astley, S. M. SPIE-INT SOC OPTICAL ENGINEERING. 2024

    View details for DOI 10.1117/12.3006879

    View details for Web of Science ID 001208134600061

  • Risks of Depression, Anxiety, and Suicide in Partners of Men with Prostate Cancer: A National Cohort Study. Journal of the National Cancer Institute Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Edwards, A. C., Sundquist, K., Sieh, W. 2023


    BACKGROUND: A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown.METHODS: A national cohort study was conducted of 121,530 partners of men diagnosed with PC during 1998-2017 and 1,093,304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors.RESULTS: Partners of men with high-risk PC had increased risks of major depression (adjusted HR, 1.34; 95% CI, 1.30-1.39) and anxiety disorder (1.25; 1.20-1.30), which remained elevated ≥10 years later. Suicide death was increased in partners of men with distant metastases (adjusted HR, 2.38; 95% CI, 1.08-5.22) but not other high-risk PC (1.14; 0.70-1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those aged ≥80 years (adjusted HR, 1.73; 95% CI, 1.53-1.96; and 1.70; 1.47-1.96, respectively), whereas suicide death was highest among those aged <60 years (7.55; 2.20-25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes.CONCLUSIONS: In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for ≥10 years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.

    View details for DOI 10.1093/jnci/djad257

    View details for PubMedID 38060258

  • Patient and physician perspectives on treatments for low-risk prostate cancer: a qualitative study. BMC cancer Guan, A., Santiago-Rodriguez, E. J., Chung, B. I., Shim, J. K., Allen, L., Kuo, M., Lau, K., Loya, Z., Brooks, J. D., Cheng, I., DeRouen, M. C., Frosch, D. L., Golden, T., Leppert, J. T., Lichtensztajn, D. Y., Lu, Q., Oh, D., Sieh, W., Wadhwa, M., Cooperberg, M. R., Carroll, P. R., Gomez, S. L., Shariff-Marco, S. 2023; 23 (1): 1191


    BACKGROUND: Patients diagnosed with low-risk prostate cancer (PCa) are confronted with a difficult decision regarding whether to undergo definitive treatment or to pursue an active surveillance protocol. This is potentially further complicated by the possibility that patients and physicians may place different value on factors that influence this decision. We conducted a qualitative investigation to better understand patient and physician perceptions of factors influencing treatment decisions for low-risk PCa.METHODS: Semi-structured interviews were conducted among 43 racially and ethnically diverse patients diagnosed with low-risk PCa, who were identified through a population-based cancer registry, and 15 physicians who were selected to represent a variety of practice settings in the Greater San Francisco Bay Area.RESULTS: Patients and physicians both described several key individual (e.g., clinical) and interpersonal (e.g., healthcare communications) factors as important for treatment decision-making. Overall, physicians' perceptions largely mirrored patients' perceptions. First, we observed differences in treatment preferences by age and stage of life. At older ages, there was a preference for less invasive options. However, at younger ages, we found varying opinions among both patients and physicians. Second, patients and physicians both described concerns about side effects including physical functioning and non-physical considerations. Third, we observed differences in expectations and the level of difficulty for clinical conversations based on information needs and resources between patients and physicians. Finally, we discovered that patients and physicians perceived patients' prior knowledge and the support of family/friends as facilitators of clinical conversations.CONCLUSIONS: Our study suggests that the gap between patient and physician perceptions on the influence of clinical and communication factors on treatment decision-making is not large. The consensus we observed points to the importance of developing relevant clinical communication roadmaps as well as high quality and accessible patient education materials.

    View details for DOI 10.1186/s12885-023-11679-4

    View details for PubMedID 38053037

  • Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia. JCI insight Pollack, A. S., Kunder, C. A., Brazer, N., Shen, Z., Varma, S., West, R. B., Cunha, G. R., Baskin, L. S., Brooks, J. D., Pollack, J. R. 2023


    Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were Insulin Like Growth Factor 1 (IGF1) and C-X-C Motif Chemokine Ligand 13 (CXCL13), which we confirmed by RNA in situ hybridization to be co-expressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in three-dimensional culture. Our findings partially support historic speculations on the etiology of BPH, and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.

    View details for DOI 10.1172/jci.insight.176479

    View details for PubMedID 37971878

  • Measuring the multifaceted roles of mucin-domain glycoproteins in cancer. Advances in cancer research Riley, N. M., Wen, R. M., Bertozzi, C. R., Brooks, J. D., Pitteri, S. J. 2023; 157: 83-121


    Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression and glycosylation of mucins are known hallmarks in numerous malignancies, yet mucin-domain glycoproteins remain enigmatic in the broad landscape of cancer glycobiology. Here we review the multifaceted roles of mucins in cancer through the lens of the analytical and biochemical methods used to study them. We also describe a collection of emerging tools that are specifically equipped to characterize mucin-domain glycoproteins in complex biological backgrounds. These approaches are poised to further elucidate how mucin biology can be understood and subsequently targeted for the next generation of cancer therapeutics.

    View details for DOI 10.1016/bs.acr.2022.09.001

    View details for PubMedID 36725114

  • ACAA2 is a novel molecular indicator for cancers with neuroendocrine phenotype BRITISH JOURNAL OF CANCER Shen, M., Liu, S., Toland, A., Hsu, E., Hartono, A. B., Alabi, B. R., Aslan, M., Nguyen, H. M., Sessions, C. J., Nolley, R., Shi, C., Huang, J., Brooks, J. D., Corey, E., Stoyanova, T. 2023
  • ACAA2 is a novel molecular indicator for cancers with neuroendocrine phenotype. British journal of cancer Shen, M., Liu, S., Toland, A., Hsu, E. C., Hartono, A. B., Alabi, B. R., Aslan, M., Nguyen, H. M., Sessions, C. J., Nolley, R., Shi, C., Huang, J., Brooks, J. D., Corey, E., Stoyanova, T. 2023


    Neuroendocrine phenotype is commonly associated with therapy resistance and poor prognoses in small-cell neuroendocrine cancers (SCNCs), such as neuroendocrine prostate cancer (NEPC) and small-cell lung cancer (SCLC). Expression levels of current neuroendocrine markers exhibit high case-by-case variability, so multiple markers are used in combination to identify SCNCs. Here, we report that ACAA2 is elevated in SCNCs and is a potential molecular indicator for SCNCs.ACAA2 expressions in tumour xenografts, tissue microarrays (TMAs), and patient tissues from prostate and lung cancers were analysed via immunohistochemistry. ACAA2 mRNA levels in lung and prostate cancer (PC) patients were assessed in published datasets.ACAA2 protein and mRNA levels were elevated in SCNCs relative to non-SCNCs. Medium/high ACAA2 intensity was observed in 78% of NEPC PDXs samples (N = 27) relative to 33% of adeno-CRPC (N = 86), 2% of localised PC (N = 50), and 0% of benign prostate specimens (N = 101). ACAA2 was also elevated in lung cancer patient tissues with neuroendocrine phenotype. 83% of lung carcinoid tissues (N = 12) and 90% of SCLC tissues (N = 10) exhibited medium/high intensity relative to 40% of lung adenocarcinoma (N = 15).ACAA2 expression is elevated in aggressive SCNCs such as NEPC and SCLC, suggesting it is a potential molecular indicator for SCNCs.

    View details for DOI 10.1038/s41416-023-02448-y

    View details for PubMedID 37798372

    View details for PubMedCentralID 4861069

  • Identification of age- and immune-related gene signatures for clinical outcome prediction in lung adenocarcinoma. Cancer medicine Zhou, A., Zhang, D., Kang, X., Brooks, J. D. 2023


    The understanding of the factors causing decreased overall survival (OS) in older patients compared to younger patients in lung adenocarcinoma (LUAD) remains.Gene expression profiles of LUAD were obtained from publicly available databases by Kaplan-Meier analysis was performed to determine whether age was associated with patient OS. The immune cell composition in the tumor microenvironment (TME) was evaluated using CIBERSORT. The fraction of stromal and immune cells in tumor samples were also using assessed using multiple tools including ESTIMATE, EPIC, and TIMER. Differentially expressed genes (DEGs) from the RNA-Seq data that were associated with age and immune cell composition were identified using the R package DEGseq. A 22-gene signature composed of DEGs associated with age and immune cell composition that predicted OS were constructed using Least Absolute Shrinkage and Selection Operator (LASSO).In The Cancer Genome Atlas (TCGA)-LUAD dataset, we found that younger patients (≤70) had a significant better OS compared to older patients (>70). In addition, older patients had significantly higher expression of immune checkpoint proteins including inhibitory T cell receptors and their ligands. Moreover, analyses using multiple bioinformatics tools showed increased immune infiltration, including CD4+ T cells, in older patients compared to younger patients. We identified a panel of genes differentially expressed between patients >70 years compared to those ≤70 years, as well as between patients with high or low immune scores and selected 84 common genes to construct a prognostic gene signature. A risk score calculated based on 22 genes selected by LASSO predicted 1, 3, and 5-year OS, with an area under the curve (AUC) of 0.72, 0.72, 0.69, receptively, in TCGA-LUAD dataset and an independent validation dataset available from the European Genome-phenome Archive (EGA).Our results demonstrate that age contributes to OS of LUAD patients atleast in part through its association with immune infiltration in the TME.

    View details for DOI 10.1002/cam4.6330

    View details for PubMedID 37434467

  • Risks of Alcohol and Drug Use Disorders in Prostate Cancer Survivors: National Cohort Study. JNCI cancer spectrum Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Edwards, A. C., Sieh, W., Sundquist, K. 2023


    Prostate cancer (PC) survivors may potentially use substances to cope with psychological distress or poorly-controlled physical symptoms. However, little is known about long-term risks of alcohol use disorder (AUD) or drug use disorders (DUD) in men with PC.A national cohort study was conducted in Sweden of 180,189 men diagnosed with PC during 1998-2017 and 1,801,890 age-matched population-based control men. AUD and DUD were ascertained from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors and prior psychiatric disorders. Subanalyses examined differences by PC treatment during 2005-2017.Men with high-risk PC had increased risks of both AUD (adjusted HR, 1.44; 95% CI, 1.33-1.57) and DUD (1.93; 1.67-2.24). Their AUD risk was highest in the first year and was no longer significantly elevated ≥5 years after PC diagnosis, whereas their DUD risk remained elevated ≥10 years after PC diagnosis (adjusted HR, 2.26; 95% CI, 1.45-3.52), particularly opioid use disorder (3.07; 1.61-5.84). Those treated only with androgen deprivation therapy (ADT) had the highest risks of AUD (adjusted HR, 1.91; 95% CI, 1.62-2.25) and DUD (2.23; 1.70-2.92). Low- or intermediate-risk PC was associated with modestly increased risks of AUD (adjusted HR, 1.38; 95% CI, 1.30-1.46) and DUD (1.19; 1.06-1.34).In this large cohort, men with PC had significantly increased risks of both AUD and DUD, especially those with high-risk PC and treated only with ADT. PC survivors need long-term psychosocial support and timely detection and treatment of AUD and DUD.

    View details for DOI 10.1093/jncics/pkad046

    View details for PubMedID 37389442

  • Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: a Multi-Center Retrospective Study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Patel, P., Harmon, S., Iseman, R., Ludkowski, O., Auman, H., Hawley, S., Newcomb, L. F., Lin, D. W., Nelson, P. S., Feng, Z., Boyer, H. D., Tretiakova, M. S., True, L. D., Vakar-Lopez, F., Carroll, P. R., Cooperberg, M. R., Chan, E., Simko, J., Fazli, L., Gleave, M., Hurtado-Coll, A., Thompson, I. M., Troyer, D., McKenney, J. K., Wei, W., Choyke, P. L., Bratslavsky, G., Turkbey, B., Siemens, D. R., Squire, J., Peng, Y. P., Brooks, J. D., Jamaspishvili, T. 2023: 100241


    Phosphatase and tensin homolog (PTEN) loss associates to adverse outcomes in prostate cancer and can be measured via immunohistochemistry (IHC). The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Post-surgical tissue microarray sections from the Canary Foundation (n=1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by pathologist and quantification of PTEN loss by AI (High-Risk AI-qPTEN) were significantly associated to shorted MFS in univariable analysis (cPTEN HR: 1.54, CI:1.07-2.21, p=0.019; AI-qPTEN HR: 2.55, CI:1.83,3.56), p<0.001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter metastasis-free survival (MFS) (HR:2.17, CI:1.49-3.17, p<0.001) and recurrence-free survival (HR:1.36, CI:1.06-1.75, p=0.016) when adjusting for relevant post-surgical clinical nomogram (CAPRA-S) while cPTEN does not show a statistically significant association (HR:1.33, CI:0.89-2, p=0.2 and HR:1.26, CI:0.99-1.62, p=0.063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR: 2.72, CI:1.46-5.06, p=0.002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy post-surgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding AI-qPTEN assessment workflow to clinical variables may affect post-operative surveillance or management options, particularly in low-risk patients.

    View details for DOI 10.1016/j.modpat.2023.100241

    View details for PubMedID 37343766

  • Proteomics analysis of urine and catheter-associated biofilms in spinal cord injury patients. American journal of clinical and experimental urology Garcia-Marques, F. J., Zakrasek, E., Bermudez, A., Polasko, A. L., Liu, S., Stoyanova, T., Brooks, J. D., Lavelle, J., Pitteri, S. J. 2023; 11 (3): 206-219


    After spinal cord injury (SCI), use chronic urinary catheters for bladder management is common, making these patients especially vulnerable to catheter-associated complications. Chronic catheterization is associated with bacterial colonization and frequent catheter-associated urinary tract infections (CAUTI). One determinant of infection success and treatment resistance is production of catheter-associated biofilms, composed of microorganisms and host- and microbial-derived components. To better understand the biofilm microenvironment, we performed proteomics analysis of catheter-associated biofilms and paired urine samples from four people with SCI with chronic indwelling urinary catheters. We developed a novel method for the removal of adhered cellular components on catheters that contained both human and microbial homologous proteins. Proteins from seven microbial species were identified including: Escherichia coli, Klebsiella species (spp), Enterococcus spp, Proteus mirabilis, Pseudomonas spp, Staphylococcus spp, and Candida spp. Peptides identified from catheter biofilms were assigned to 4,820 unique proteins, with 61% of proteins assigned to the biofilm-associated microorganisms, while the remainder were human-derived. Contrastingly, in urine, only 51% were assigned to biofilm-associated microorganisms and 4,554 proteins were identified as a human-derived. Of the proteins assigned to microorganisms in the biofilm and paired urine, Enterococcus, Candida spp, and P. mirabilis had greater associations with the biofilm phase, whereas E. coli and Klebsiella had greater associations with the urine phase, thus demonstrating a significant difference between the urine and adhered microbial communities. The microbial proteins that differed significantly between the biofilm and paired urine samples mapped to pathways associated with amino acid synthesis, likely related to adaptation to high urea concentrations in the urine, and growth and protein synthesis in bacteria in the biofilm. Human proteins demonstrated enrichment for immune response in the catheter-associated biofilm. Proteomic analysis of catheter-associated biofilms and paired urine samples has the potential to provide detailed information on host and bacterial responses to chronic indwelling urinary catheters and could be useful for understanding complications of chronic indwelling catheters including CAUTIs, urinary stones, and catheter blockages.

    View details for PubMedID 37441441

    View details for PubMedCentralID PMC10333135

  • Patient-level factors associated with the use of active surveillance: The talking about prostate cancer cohort. Mukand, N., Shariff-Marco, S., Brooks, J. D., Chung, B. I., Leppert, J. T., Frosh, D., Sieh, W., Guan, A., Santiago-Rodriguez, E. J., Carroll, P., Shim, J. K., Kuo, M., Allen, L., DeRouen, M., Cheng, I., Gomez, S. L., Lu, Q. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Distinguishing Renal Cell Carcinoma From Normal Kidney Tissue Using Mass Spectrometry Imaging Combined With Machine Learning. JCO precision oncology Shankar, V., Vijayalakshmi, K., Nolley, R., Sonn, G. A., Kao, C. S., Zhao, H., Wen, R., Eberlin, L. S., Tibshirani, R., Zare, R. N., Brooks, J. D. 2023; 7: e2200668


    Accurately distinguishing renal cell carcinoma (RCC) from normal kidney tissue is critical for identifying positive surgical margins (PSMs) during partial and radical nephrectomy, which remains the primary intervention for localized RCC. Techniques that detect PSM with higher accuracy and faster turnaround time than intraoperative frozen section (IFS) analysis can help decrease reoperation rates, relieve patient anxiety and costs, and potentially improve patient outcomes.Here, we extended our combined desorption electrospray ionization mass spectrometry imaging (DESI-MSI) and machine learning methodology to identify metabolite and lipid species from tissue surfaces that can distinguish normal tissues from clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC) tissues.From 24 normal and 40 renal cancer (23 ccRCC, 13 pRCC, and 4 chRCC) tissues, we developed a multinomial lasso classifier that selects 281 total analytes from over 27,000 detected molecular species that distinguishes all histological subtypes of RCC from normal kidney tissues with 84.5% accuracy. On the basis of independent test data reflecting distinct patient populations, the classifier achieves 85.4% and 91.2% accuracy on a Stanford test set (20 normal and 28 RCC) and a Baylor-UT Austin test set (16 normal and 41 RCC), respectively. The majority of the model's selected features show consistent trends across data sets affirming its stable performance, where the suppression of arachidonic acid metabolism is identified as a shared molecular feature of ccRCC and pRCC.Together, these results indicate that signatures derived from DESI-MSI combined with machine learning may be used to rapidly determine surgical margin status with accuracies that meet or exceed those reported for IFS.

    View details for DOI 10.1200/PO.22.00668

    View details for PubMedID 37285559

  • Long-term Risks of Depression and Suicide Among Men with Prostate Cancer: A National Cohort Study. European urology Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Bill-Axelson, A., Edwards, A. C., Sundquist, K., Sieh, W. 2023


    A diagnosis of prostate cancer (PC) may cause psychosocial distress that worsens quality of life; however, long-term mental health outcomes are unclear.To determine the long-term risks of major depression and death by suicide in a large population-based cohort.This was a national cohort study of 180 189 men diagnosed with PC during 1998-2017 and 1 801 890 age-matched, population-based, control men in Sweden.Major depression and death by suicide were ascertained from nationwide outpatient, inpatient, and death records up to 2018. Cox regression was used to compute hazard ratios (HRs) adjusted for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017.Men diagnosed with high-risk PC had higher relative rates of major depression (adjusted HR [aHR] 1.82, 95% confidence interval [CI] 1.75-1.89) and death by suicide (aHR 2.43, 95% CI 2.01-2.95). These associations persisted for ≥10 yr after PC diagnosis. The relative increase in major depression was lower among those treated with radiation (aHR 1.44, 95% CI 1.31-1.57) or surgery (aHR 1.60, 95% CI 1.31-1.95) in comparison to androgen deprivation therapy (ADT) alone (aHR 2.02, 95% CI 1.89-2.16), whereas the relative rate of suicide death was higher only among those treated solely with ADT (aHR 2.83, 95% CI 1.80-4.43). By contrast, men with low- or intermediate-risk PC had a modestly higher relative rate of major depression (aHR 1.19, 95% CI 1.16-1.23) and higher relative rate of suicide death at 3-12 mo after PC diagnosis (aHR 1.88, 95% CI 1.11-3.18) but not across the entire follow-up period (aHR 1.02, 95% CI 0.84-1.25). This study was limited to Sweden and will need replication in other populations.In this large cohort, high-risk PC was associated with substantially higher relative rates of major depression and death by suicide, which persisted for ≥10 yr after PC diagnosis. PC survivors need close follow-up for timely detection and treatment of psychosocial distress.In a large Swedish population, men with aggressive prostate cancer had higher long-term relative rates of depression and suicide.

    View details for DOI 10.1016/j.eururo.2023.04.026

    View details for PubMedID 37169640

  • Siglec-7/9 are novel immune checkpoints for prostate cancer Wen, R., Stark, J. C., Marti, G., Garcia-Marques, F., Zhao, H., Nolley, R., Bertozzi, C. R., Pitteri, S. J., Brooks, J. D. AMER ASSOC IMMUNOLOGISTS. 2023
  • NUSAP1 Binds ILF2 to Modulate R-Loop Accumulation and DNA Damage in Prostate Cancer. International journal of molecular sciences Chiu, C. L., Li, C. G., Verschueren, E., Wen, R. M., Zhang, D., Gordon, C. A., Zhao, H., Giaccia, A. J., Brooks, J. D. 2023; 24 (7)


    Increased expression of NUSAP1 has been identified as a robust prognostic biomarker in prostate cancer and other malignancies. We have previously shown that NUSAP1 is positively regulated by E2F1 and promotes cancer invasion and metastasis. To further understand the biological function of NUSAP1, we used affinity purification and mass spectrometry proteomic analysis to identify NUSAP1 interactors. We identified 85 unique proteins in the NUSAP1 interactome, including ILF2, DHX9, and other RNA-binding proteins. Using proteomic approaches, we uncovered a function for NUSAP1 in maintaining R-loops and in DNA damage response through its interaction with ILF2. Co-immunoprecipitation and colocalization using confocal microscopy verified the interactions of NUSAP1 with ILF2 and DHX9, and RNA/DNA hybrids. We showed that the microtubule and charged helical domains of NUSAP1 were necessary for the protein-protein interactions. Depletion of ILF2 alone further increased camptothecin-induced R-loop accumulation and DNA damage, and NUSAP1 depletion abolished this effect. In human prostate adenocarcinoma, NUSAP1 and ILF2 mRNA expression levels are positively correlated, elevated, and associated with poor clinical outcomes. Our study identifies a novel role for NUSAP1 in regulating R-loop formation and accumulation in response to DNA damage through its interactions with ILF2 and hence provides a potential therapeutic target.

    View details for DOI 10.3390/ijms24076258

    View details for PubMedID 37047232

  • PlexusNet: A neural network architectural concept for medical image classification. Computers in biology and medicine Eminaga, O., Abbas, M., Shen, J., Laurie, M., Brooks, J. D., Liao, J. C., Rubin, D. L. 2023; 154: 106594


    State-of-the-art (SOTA) convolutional neural network models have been widely adapted in medical imaging and applied to address different clinical problems. However, the complexity and scale of such models may not be justified in medical imaging and subject to the available resource budget. Further increasing the number of representative feature maps for the classification task decreases the model explainability. The current data normalization practice is fixed prior to model development and discounting the specification of the data domain. Acknowledging these issues, the current work proposed a new scalable model family called PlexusNet; the block architecture and model scaling by the network's depth, width, and branch regulate PlexusNet's architecture. The efficient computation costs outlined the dimensions of PlexusNet scaling and design. PlexusNet includes a new learnable data normalization algorithm for better data generalization. We applied a simple yet effective neural architecture search to design PlexusNet tailored to five clinical classification problems that achieve a performance noninferior to the SOTA models ResNet-18 and EfficientNet B0/1. It also does so with lower parameter capacity and representative feature maps in ten-fold ranges than the smallest SOTA models with comparable performance. The visualization of representative features revealed distinguishable clusters associated with categories based on latent features generated by PlexusNet. The package and source code are at

    View details for DOI 10.1016/j.compbiomed.2023.106594

    View details for PubMedID 36753979

  • Prosteria - National Trends and Outcomes of More Frequent than Guideline Recommended Prostate Specific Antigen Screening. Urology Peterson, D. J., Bhambhvani, H. P., Baird, D. R., Li, S., Eisenberg, M. L., Brooks, J. D. 2023


    To characterize national trends in and associated outcomes of more often than annual PSA screening, which we term "prosteria".Men in the Optum Clinformatics® Data Mart with ≥ 2 years from first PSA test to censoring at the end of insurance or available data (January 2003 to June 2019) or following exclusionary diagnoses or procedures, such as PCa treatment, were included. PSAs within 90 days were treated as one PSA. Prosteria was defined as having ≥3 PSA testing intervals of ≤270 days.9,734,077 PSAs on 2,958,923 men were included. The average inter-PSA testing interval was 1.5 years, and 4.5% of men had prosteria, which increased by 0.53% per year. Educated, wealthy, non-White patients were more likely to have prosteria. Men within the recommended screening age (i.e. 55-69) had lower rates of prosteria. Prosteria patients had higher average PSA values (2.5 vs 1.4 ng/ml), but lower values at PCa diagnosis. Prosteria was associated with biopsy and PCa diagnosis; however, there were comparable rates of treatment within 2 years of diagnosis.In this large cohort study, prosteria was common, increased over time, and was associated with demographic characteristics. Importantly, there were no clinically meaningful differences in PSA values at diagnosis or rates of early treatment, suggesting prosteria leads to both overdiagnosis and overtreatment. These results support current AUA and USPTF guidelines and can be used to counsel men seeking more frequent PSA screening.

    View details for DOI 10.1016/j.urology.2023.01.011

    View details for PubMedID 36708931

  • Fusion Gene Detection in Prostate Cancer Samples Enhances the Prediction of Prostate Cancer Clinical Outcomes from Radical Prostatectomy through Machine Learning in a Multi-institutional Analysis. The American journal of pathology Yu, Y., Liu, S., Ren, B., Nelson, J., Jarrard, D., Brooks, J. D., Michalopoulos, G., Tseng, G., Luo, J. 2023


    Prostate cancer remains one of the most fatal malignancies in men in the United States. Predicting the course of prostate cancer is challenging given that only a fraction of prostate cancer patients experience cancer recurrence after radical prostatectomy or radiation therapy. In this report, the expressions of 14 fusion genes in 607 prostate cancer samples from the University of Pittsburgh, Stanford University, and the University of Wisconsin-Madison were examined. The profiling of 14 fusion genes was integrated with Gleason score of the primary pattern of prostate cancer and serum prostate-specific antigen level to develop machine-learning models to predict the recurrence of prostate cancer after radical prostatectomy. Machine-learning algorithms were developed by analysis of the data from the University of Pittsburgh cohort as a training set using the leave-one-out cross-validation method. These algorithms were then applied to the data set from the combined Stanford/Wisconsin cohort (testing set). The results showed that the addition of fusion gene profiling consistently improved the prediction rate of prostate cancer recurrence by Gleason score, serum prostate-specific antigen level, or a combination of both. These improvements occurred in both the training and testing cohorts and were corroborated by multiple models.

    View details for DOI 10.1016/j.ajpath.2022.12.013

    View details for PubMedID 36681188

  • MIC-CUSP: Multimodal Image Correlations for Ultrasound-Based Prostate Cancer Detection Bhattacharya, I., Vesal, S., Jahanandish, H., Choi, M., Zhou, S., Kornberg, Z., Sommer, E., Fan, R., Brooks, J., Sonn, G., Rusu, M., Kainz, B., Noble, A., Schnabel, J., Khanal, B., Muller, J. P., Day, T. SPRINGER INTERNATIONAL PUBLISHING AG. 2023: 121-131
  • Original Proteomics analysis of urine and catheter-associated biofilms in spinal cord injury patients AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY Garcia-Marques, F. J., Zakrasek, E., Bermudez, A., Polasko, A. L., Liu, S., Stoyanova, T., Brooks, J., Lavelle, J., Pitteri, S. J. 2023; 11 (3): 206-219
  • Deep learning-based automated pipeline for blood vessel detection and distribution analysis in multiplexed prostate cancer images. Frontiers in bioinformatics Karageorgos, G. M., Cho, S., McDonough, E., Chadwick, C., Ghose, S., Owens, J., Jung, K. J., Machiraju, R., West, R., Brooks, J. D., Mallick, P., Ginty, F. 2023; 3: 1296667


    Introduction: Prostate cancer is a highly heterogeneous disease, presenting varying levels of aggressiveness and response to treatment. Angiogenesis is one of the hallmarks of cancer, providing oxygen and nutrient supply to tumors. Micro vessel density has previously been correlated with higher Gleason score and poor prognosis. Manual segmentation of blood vessels (BVs) In microscopy images is challenging, time consuming and may be prone to inter-rater variabilities. In this study, an automated pipeline is presented for BV detection and distribution analysis in multiplexed prostate cancer images. Methods: A deep learning model was trained to segment BVs by combining CD31, CD34 and collagen IV images. In addition, the trained model was used to analyze the size and distribution patterns of BVs in relation to disease progression in a cohort of prostate cancer patients (N = 215). Results: The model was capable of accurately detecting and segmenting BVs, as compared to ground truth annotations provided by two reviewers. The precision (P), recall (R) and dice similarity coefficient (DSC) were equal to 0.93 (SD 0.04), 0.97 (SD 0.02) and 0.71 (SD 0.07) with respect to reviewer 1, and 0.95 (SD 0.05), 0.94 (SD 0.07) and 0.70 (SD 0.08) with respect to reviewer 2, respectively. BV count was significantly associated with 5-year recurrence (adjusted p = 0.0042), while both count and area of blood vessel were significantly associated with Gleason grade (adjusted p = 0.032 and 0.003 respectively). Discussion: The proposed methodology is anticipated to streamline and standardize BV analysis, offering additional insights into the biology of prostate cancer, with broad applicability to other cancers.

    View details for DOI 10.3389/fbinf.2023.1296667

    View details for PubMedID 38323039

  • Associations of Renal Cell Carcinoma Subtype with Patient Demographics, Comorbidities, and Neighborhood Socioeconomic Status in the California Population. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Lichtensztajn, D. Y., Hofer, B. M., Leppert, J. T., Brooks, J. D., Chung, B. I., Shah, S. A., DeRouen, M. C., Cheng, I. 2022


    Renal cell carcinoma (RCC) subtypes differ in molecular characteristics and prognosis. We investigated the associations of RCC subtype with patient demographics, comorbidity, and neighborhood socioeconomic status (nSES).Using linked California Cancer Registry and Office of Statewide Health Planning and Development data, we identified history of hypertension, diabetes, and kidney disease prior to RCC diagnosis in Asian/Pacific Islander, non-Latino Black, Latino, and non-Latino White adults diagnosed with their first pathologically-confirmed RCC from 2005 through 2015. We used multinomial multivariable logistic regression to model the association of demographics, comorbidity, and nSES with clear cell, papillary, and chromophobe RCC subtype.Of the 40,016 RCC cases included, 62.6% were clear cell, 10.9% papillary, and 5.9% chromophobe. The distribution of subtypes differed strikingly by race and ethnicity, ranging from 40.4% clear cell and 30.4% papillary in non-Latino Black adults to 70.7% clear cell and 4.5% papillary in Latino adults. In multivariable analysis, non-Latino Black individuals had a higher likelihood of presenting with papillary (odds ratio (OR) 3.99, 95% confidence interval 3.61-4.42) and chromophobe (OR 1.81, 1.54-2.13) vs clear cell subtype compared to non-Latino White individuals. Both hypertension (OR 1.19, 1.10-1.29) and kidney disease (OR 2.38, 2.04-2.77 end stage disease; OR 1.52, 1.33-1.72 non end-stage disease) were associated with papillary subtype. Diabetes was inversely associated with both papillary (OR 0.63, 0.58-0.69) and chromophobe (OR 0.61, 0.54-0.70) subtypes.RCC subtype is independently associated with patient demographics, and comorbidity.Targeted RCC treatments or RCC prevention efforts may have differential impact across population subgroups.

    View details for DOI 10.1158/1055-9965.EPI-22-0784

    View details for PubMedID 36480301

  • Siglec-7/9-sialic acid interactions inhibit T cell immune response in prostate cancer Wen, R. M., Stark, J., Garcia-Marques, F., Nolley, H., Bertozzi, C. R., Pitteri, S. J., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2022
  • Factors that influence treatment decisions: A qualitative study of racially and ethnically diverse patients with low- and very-low risk prostate cancer. Cancer medicine Guan, A., Shim, J. K., Allen, L., Kuo, M., Lau, K., Loya, Z., Brooks, J. D., Carroll, P. R., Cheng, I., Chung, B. I., DeRouen, M. C., Frosch, D. L., Golden, T., Leppert, J. T., Lichtensztajn, D. Y., Lu, Q., Oh, D. L., Sieh, W., Wadhwa, M., Gomez, S. L., Shariff-Marco, S. 2022


    BACKGROUND: Factors that influence prostate cancer treatment decisions are complex, multifaceted, and personal, and may vary by race/ethnicity. Although research has been published to quantify factors involved in decision-making, these studies have been limited to primarily white, and to a lesser extent, Black patients, and quantitative studies are limited for discerning the cultural and contextual processes that shape decision-making.METHODS: We conducted 43 semi-structured interviews with a racially and ethnically diverse sample of patients diagnosed with low- and very-low risk prostate cancer who had undergone treatment for their prostate cancer. Interviews were transcribed, independently coded, and analyzed to identify themes salient for decision-making, with attention to sociocultural differences.RESULTS: We found racial and ethnic differences in three areas. First, we found differences in how socialized masculinity influenced patient's feelings about different treatment options. Second, we found that for some men, religion and spirituality alleviated anxiety associated with the active surveillance protocol. Finally, for racially and ethnically minoritized patients, we found descriptions of how historic and social experiences within the healthcare system influenced decision-making.CONCLUSIONS: Our study adds to the current literature by expounding on racial and ethnic differences in the multidimensional, nuanced factors related to decision-making. Our findings suggest that factors associated with prostate cancer decision-making can manifest differently across racial and ethnic groups, and provide some guidance for future research.

    View details for DOI 10.1002/cam4.5405

    View details for PubMedID 36404625

  • Multiparametric Magnetic Resonance Imaging and Metabolic Characterization of Patient-Derived Xenograft Models of Clear Cell Renal Cell Carcinoma. Metabolites Agudelo, J. P., Upadhyay, D., Zhang, D., Zhao, H., Nolley, R., Sun, J., Agarwal, S., Bok, R. A., Vigneron, D. B., Brooks, J. D., Kurhanewicz, J., Peehl, D. M., Sriram, R. 2022; 12 (11)


    Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are needed to evaluate novel imaging and therapeutic approaches targeting metabolism. We characterized 5 PDX from high-grade or metastatic ccRCC by multiparametric magnetic resonance imaging (MRI) and steady state metabolic profiling and flux analysis. Similar to MRI of clinical ccRCC, T2-weighted images of orthotopic tumors of most PDX were homogeneous. The increased hyperintense (cystic) areas observed in one PDX mimicked the cystic phenotype typical of some RCC. The negligible hypointense (necrotic) areas of PDX grown under the highly vascularized renal capsule are beneficial for preclinical studies. Mean apparent diffusion coefficient (ADC) values were equivalent to those of ccRCC in human patients. Hyperpolarized (HP) [1-13C]pyruvate MRI of PDX showed high glycolytic activity typical of high-grade primary and metastatic ccRCC with considerable intra- and inter-tumoral variability, as has been observed in clinical HP MRI of ccRCC. Comparison of steady state metabolite concentrations and metabolic flux in [U-13C]glucose-labeled tumors highlighted the distinctive phenotypes of two PDX with elevated levels of numerous metabolites and increased fractional enrichment of lactate and/or glutamate, capturing the metabolic heterogeneity of glycolysis and the TCA cycle in clinical ccRCC. Culturing PDX cells and reimplanting to generate xenografts (XEN), or passaging PDX in vivo, altered some imaging and metabolic characteristics while transcription remained like that of the original PDX. These findings show that PDX are realistic models of ccRCC for imaging and metabolic studies but that the plasticity of metabolism must be considered when manipulating PDX for preclinical studies.

    View details for DOI 10.3390/metabo12111117

    View details for PubMedID 36422257

  • Dietary Patterns and Risk of Gleason Grade Progression among Men on Active Surveillance for Prostate Cancer: Results from the Canary Prostate Active Surveillance Study. Nutrition and cancer Schenk, J. M., Liu, M., Neuhouser, M. L., Newcomb, L. F., Zheng, Y., Zhu, K., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Filson, C. P., Gleave, M. E., Liss, M., Martin, F. M., Morgan, T. M., Wagner, A. A., Lin, D. W. 2022: 1-9


    Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

    View details for DOI 10.1080/01635581.2022.2143537

    View details for PubMedID 36343223

  • A review of artificial intelligence in prostate cancer detection on imaging. Therapeutic advances in urology Bhattacharya, I., Khandwala, Y. S., Vesal, S., Shao, W., Yang, Q., Soerensen, S. J., Fan, R. E., Ghanouni, P., Kunder, C. A., Brooks, J. D., Hu, Y., Rusu, M., Sonn, G. A. 2022; 14: 17562872221128791


    A multitude of studies have explored the role of artificial intelligence (AI) in providing diagnostic support to radiologists, pathologists, and urologists in prostate cancer detection, risk-stratification, and management. This review provides a comprehensive overview of relevant literature regarding the use of AI models in (1) detecting prostate cancer on radiology images (magnetic resonance and ultrasound imaging), (2) detecting prostate cancer on histopathology images of prostate biopsy tissue, and (3) assisting in supporting tasks for prostate cancer detection (prostate gland segmentation, MRI-histopathology registration, MRI-ultrasound registration). We discuss both the potential of these AI models to assist in the clinical workflow of prostate cancer diagnosis, as well as the current limitations including variability in training data sets, algorithms, and evaluation criteria. We also discuss ongoing challenges and what is needed to bridge the gap between academic research on AI for prostate cancer and commercial solutions that improve routine clinical care.

    View details for DOI 10.1177/17562872221128791

    View details for PubMedID 36249889

    View details for PubMedCentralID PMC9554123

  • The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors. Cancers Chiu, C. L., Zhao, H., Chen, C. H., Wu, R., Brooks, J. D. 2022; 14 (19)


    The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells. MARCKS plays important roles in multiple cellular processes, including cell adhesion and motility, mucin secretion, exocytosis, and inflammatory response. Aberrant MARCKS signaling has been observed in the development and progression of multiple cancer types. In addition, MARCKS facilitates cancer metastasis through modulating cancer cell migration and invasion. Moreover, MARCKS contributes to treatment resistance, likely by promoting cancer stem cell renewal as well as immunosuppression. In this review, we describe MARCKS protein structure, cellular localization, and biological functions. We then discuss the role of MARCKS in cancer metastasis as well as its mechanisms of action in solid tumors. Finally, we review recent advances in targeting MARCKS as a new therapeutic strategy in cancer management.

    View details for DOI 10.3390/cancers14194925

    View details for PubMedID 36230850

  • The controversial role and therapeutic development of the m6A demethylase FTO in renal cell carcinoma. Translational oncology Zhang, D., Wornow, S., Peehl, D. M., Rankin, E. B., Brooks, J. D. 2022; 25: 101518


    Fat mass and obesity-associated (FTO) protein, the first m6A demethylase identified in 2011, regulates multiple aspects of RNA biology including splicing, localization, stability, and translation. Accumulating data show that FTO is involved in numerous physiological processes and is implicated in multiple cancers including renal cell carcinoma (RCC). However, the exact role of FTO in RCC remains controversial. Some studies demonstrated that decreased FTO expression was associated with aggressive clinical features and shorter overall survival in clear cell RCC (ccRCC) patients, while others found that FTO inhibition selectively reduced the growth and survival of VHL-deficient ccRCC cells in vitro and in vivo. Here, we review the evidence supporting either a promoting or suppressive role of FTO in kidney cancers, the mechanisms of action of FTO, and recent progress in developing FTO inhibitors.

    View details for DOI 10.1016/j.tranon.2022.101518

    View details for PubMedID 36037557

  • Impact of Prostate Health Index Results for Prediction of Biopsy Grade Reclassification During Active Surveillance. The Journal of urology Filson, C. P., Zhu, K., Huang, Y., Zheng, Y., Newcomb, L. F., Williams, S., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Gleave, M. E., Liss, M., Martin, F., McKenney, J. K., Morgan, T. M., Wagner, A. A., Sokoll, L. J., Sanda, M. G., Chan, D. W., Lin, D. W. 2022: 101097JU0000000000002852


    OBJECTIVE: We assessed whether Prostate Health Index (phi) results improve prediction of grade reclassification for men on active surveillance.METHODS/MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group (GG) 1 cancer. Outcome was grade reclassification to GG2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+phi (R3). We considered an "or"-logic rule combining clinical score and phi (R4), and a "two-step" rule using clinical data followed by risk stratification based on phi (R2). Rules were applied to a validation set, where values of R2 - R4 vs R1 for specificity and sensitivity were evaluated.RESULTS: We included 1532 biopsies (n=610 discovery; n=922 validation) among 1142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In validation set, R3 had best performance vs R1 with Deltasensitivity = -4% and Deltaspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, DeltaAUC=0.021, 95%CI 0.002-0.041) but not for subsequent biopsies (DeltaAUC=-0.012, 95%CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (DeltaAUC=0.007, 95%CI -0.007-0.020).CONCLUSIONS: Among active surveillance patients, using phi with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

    View details for DOI 10.1097/JU.0000000000002852

    View details for PubMedID 35830553

  • Sialylated glycoproteins as biomarkers and drivers of progression in prostate cancer. Carbohydrate research Wen, R., Zhao, H., Zhang, D., Chiu, C., Brooks, J. D. 2022; 519: 108598


    Sialic acids have been implicated in cancer initiation, progression, and immune evasion in diverse human malignancies. Sialylation of terminal glycans on cell surface and secreted glycoproteins is a long-recognized feature of cancer cells. Recently, immune checkpoint inhibitor immunotherapy has tremendously improved the outcomes of patients with various cancers. However, available immunotherapy approaches have had limited efficacy in metastatic castration-resistant prostate cancer. Sialic acid modified glycoproteins in prostate cancers and their interaction with Siglec receptors on tumor infiltrating immune cells might underlie immunosuppressive signaling in prostate cancer. Here, we summarize the function of sialic acids and relevant glycosynthetic enzymes in cancer initiation and progression. We also discuss the possible uses of sialic acids as biomarkers in prostate cancer and the potential methods for targeting Siglec-sialic acid interactions for prostate cancer treatment.

    View details for DOI 10.1016/j.carres.2022.108598

    View details for PubMedID 35691122

  • Bridging the gap between prostate radiology and pathology through machine learning. Medical physics Bhattacharya, I., Lim, D. S., Aung, H. L., Liu, X., Seetharaman, A., Kunder, C. A., Shao, W., Soerensen, S. J., Fan, R. E., Ghanouni, P., To'o, K. J., Brooks, J. D., Sonn, G. A., Rusu, M. 2022


    Prostate cancer remains the second deadliest cancer for American men despite clinical advancements. Currently, Magnetic Resonance Imaging (MRI) is considered the most sensitive non-invasive imaging modality that enables visualization, detection and localization of prostate cancer, and is increasingly used to guide targeted biopsies for prostate cancer diagnosis. However, its utility remains limited due to high rates of false positives and false negatives as well as low inter-reader agreements.Machine learning methods to detect and localize cancer on prostate MRI can help standardize radiologist interpretations. However, existing machine learning methods vary not only in model architecture, but also in the ground truth labeling strategies used for model training. We compare different labeling strategies and the effects they have on the performance of different machine learning models for prostate cancer detection on MRI.Four different deep learning models (SPCNet, U-Net, branched U-Net, and DeepLabv3+) were trained to detect prostate cancer on MRI using 75 patients with radical prostatectomy, and evaluated using 40 patients with radical prostatectomy and 275 patients with targeted biopsy. Each deep learning model was trained with four different label types: pathology-confirmed radiologist labels, pathologist labels on whole-mount histopathology images, and lesion-level and pixel-level digital pathologist labels (previously validated deep learning algorithm on histopathology images to predict pixel-level Gleason patterns) on whole-mount histopathology images. The pathologist and digital pathologist labels (collectively referred to as pathology labels) were mapped onto pre-operative MRI using an automated MRI-histopathology registration platform.Radiologist labels missed cancers (ROC-AUC: 0.75 - 0.84), had lower lesion volumes (~68% of pathology lesions), and lower Dice overlaps (0.24 - 0.28) when compared with pathology labels. Consequently, machine learning models trained with radiologist labels also showed inferior performance compared to models trained with pathology labels. Digital pathologist labels showed high concordance with pathologist labels of cancer (lesion ROC-AUC: 0.97 - 1, lesion Dice: 0.75 - 0.93). Machine learning models trained with digital pathologist labels had the highest lesion detection rates in the radical prostatectomy cohort (aggressive lesion ROC-AUC: 0.91 - 0.94), and had generalizable and comparable performance to pathologist label trained-models in the targeted biopsy cohort (aggressive lesion ROC-AUC: 0.87 - 0.88), irrespective of the deep learning architecture. Moreover, machine learning models trained with pixel-level digital pathologist labels were able to selectively identify aggressive and indolent cancer components in mixed lesions on MRI, which is not possible with any human-annotated label type.Machine learning models for prostate MRI interpretation that are trained with digital pathologist labels showed higher or comparable performance with pathologist label-trained models in both radical prostatectomy and targeted biopsy cohort. Digital pathologist labels can reduce challenges associated with human annotations, including labor, time, inter- and intra-reader variability, and can help bridge the gap between prostate radiology and pathology by enabling the training of reliable machine learning models to detect and localize prostate cancer on MRI. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/mp.15777

    View details for PubMedID 35633505

  • Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance. Cancer medicine Brady, L., Newcomb, L. F., Zhu, K., Zheng, Y., Boyer, H., Sarkar, N. D., McKenney, J. K., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Filson, C. P., Gleave, M. E., Liss, M. A., Martin, F., Morgan, T. M., Thompson, I. M., Wagner, A. A., Pritchard, C. C., Lin, D. W., Nelson, P. S. 2022


    BACKGROUND: Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low-risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance.METHODS: Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively.RESULTS: Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2. The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR=0.87, 95% CI: 0.36-2.06, p=0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%).CONCLUSION: The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.

    View details for DOI 10.1002/cam4.4778

    View details for PubMedID 35467778

  • Cost-Effectiveness Analysis and Microsimulation of Serial Multiparametric Magnetic Resonance Imaging in Active Surveillance of Localized Prostate Cancer. The Journal of urology Magnani, C. J., Hernandez-Boussard, T., Baker, L. C., Goldhaber-Fiebert, J. D., Brooks, J. D. 2022: 101097JU0000000000002490


    PURPOSE: Many localized prostate cancers will follow an indolent course. Management has shifted towards active surveillance (AS), yet an optimal regimen remains controversial especially regarding expensive multiparametric magnetic resonance imaging (MRI). We aimed to assess cost-effectiveness of MRI in AS protocols.MATERIALS AND METHODS: A probabilistic microsimulation modeled individual patient trajectories for men diagnosed with low-risk cancer. We assessed no surveillance, up-front treatment (surgery or radiation), and scheduled AS protocols incorporating transrectal ultrasound-guided (TRUS) biopsy or MRI-based regimens at serial intervals. Lifetime quality-adjusted life years (QALYs) and costs adjusted to 2020-US$ were used to calculate expected net monetary benefit (NMB) at $50,000/QALY and incremental cost-effectiveness ratios (ICERs). Uncertainty was assessed with probabilistic sensitivity analysis and linear regression metamodeling.RESULTS: Conservative management with AS outperformed up-front definitive treatment in a modeled cohort reflecting characteristics from a multi-institutional trial. Biopsy decision conditional on positive imaging (MRI triage) at 2-year intervals provided the highest expected NMB (ICER $44,576). Biopsy after both positive and negative imaging (MRI pathway) and TRUS-based regimens were not cost-effective. MRI triage resulted in fewer biopsies while reducing metastatic disease or cancer death. Results were sensitive to test performance and cost. MRI triage was the most likely cost-effective strategy on probabilistic sensitivity analysis.CONCLUSIONS: For men with low-risk prostate cancer, our modeling demonstrated that AS with sequential MRI triage is more cost-effective than biopsy regardless of imaging, TRUS biopsy alone, or immediate treatment. AS-guidelines should specify the role of imaging, and prospective studies should be encouraged.

    View details for DOI 10.1097/JU.0000000000002490

    View details for PubMedID 35212570

  • SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer. Cell reports. Medicine Rice, M. A., Kumar, V., Tailor, D., Garcia-Marques, F. J., Hsu, E., Liu, S., Bermudez, A., Kanchustambham, V., Shankar, V., Inde, Z., Alabi, B. R., Muruganantham, A., Shen, M., Pandrala, M., Nolley, R., Aslan, M., Ghoochani, A., Agarwal, A., Buckup, M., Kumar, M., Going, C. C., Peehl, D. M., Dixon, S. J., Zare, R. N., Brooks, J. D., Pitteri, S. J., Malhotra, S. V., Stoyanova, T. 2022; 3 (2): 100502


    Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells invitro, cell-line and patient-derived xenografts invivo, and exvivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth invitro and invivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.

    View details for DOI 10.1016/j.xcrm.2021.100502

    View details for PubMedID 35243415

  • Development and Validation of a Quantitative Reactive Stroma Biomarker (qRS) for Prostate Cancer Prognosis. Human pathology Ruder, S., Gao, Y., Ding, Y., Bu, P., Miles, B., De Marzo, A., Wheeler, T., McKenney, J. K., Auman, H., Fazli, L., Simko, J., Coll, A. H., Troyer, D. A., Carroll, P. R., Gleave, M., Platz, E., Trock, B., Han, M., Sayeeduddin, M., True, L. D., Rowley, D., Lin, D. W., Nelson, P. S., Thompson, I. M., Feng, Z., Wei, W., Brooks, J. D., Ittmann, M., Lee, M., Ayala, G. 2022


    PURPOSE: To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor.MATERIALS AND METHODS: We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens.RESULTS: In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p=0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p=0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p=0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA.CONCLUSIONS: qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

    View details for DOI 10.1016/j.humpath.2022.01.009

    View details for PubMedID 35176252

  • Editorial Comment on Considerations in the Analysis of Clinical Trial Failure. I. The Journal of urology Brooks, J. D. 1800: 101097JU0000000000002428

    View details for DOI 10.1097/JU.0000000000002428

    View details for PubMedID 35000416

  • Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Chan, E., McKenney, J. K., Hawley, S., Corrigan, D., Auman, H., Newcomb, L. F., Boyer, H. D., Carroll, P. R., Cooperberg, M. R., Klein, E., Fazli, L., Gleave, M. E., Hurtado-Coll, A., Simko, J. P., Nelson, P. S., Thompson, I. M., Tretiakova, M. S., Troyer, D., True, L. D., Vakar-Lopez, F., Lin, D. W., Brooks, J. D., Feng, Z., Nguyen, J. K. 2022


    Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

    View details for DOI 10.1038/s41379-022-01009-7

    View details for PubMedID 35145197

  • Protein signatures to distinguish aggressive from indolent prostate cancer. The Prostate Garcia-Marques, F., Liu, S., Totten, S. M., Bermudez, A., Tanimoto, C., Hsu, E. C., Nolley, R., Hembree, A., Stoyanova, T., Brooks, J. D., Pitteri, S. J. 2022


    Distinguishing men with aggressive from indolent prostate cancer is critical to decisions in the management of clinically localized prostate cancer. Molecular signatures of aggressive disease could help men overcome this major clinical challenge by reducing unnecessary treatment and allowing more appropriate treatment of aggressive disease.We performed a mass spectrometry-based proteomic analysis of normal and malignant prostate tissues from 22 men who underwent surgery for prostate cancer. Prostate cancer samples included Grade Groups (3-5), with 8 patients experiencing recurrence and 14 without evidence of recurrence with a mean of 6.8 years of follow-up. To better understand the biological pathways underlying prostate cancer aggressiveness, we performed a systems biology analysis and gene enrichment analysis. Proteins that distinguished recurrent from nonrecurrent cancer were chosen for validation by immunohistochemical analysis on tissue microarrays containing samples from a larger cohort of patients with recurrent and nonrecurrent prostate cancer.In all, 24,037 unique peptides (false discovery rate < 1%) corresponding to 3,313 distinct proteins were identified with absolute abundance ranges spanning seven orders of magnitude. Of these proteins, 115 showed significantly (p < 0.01) different levels in tissues from recurrent versus nonrecurrent cancers. Analysis of all differentially expressed proteins in recurrent and nonrecurrent cases identified several protein networks, most prominently one in which approximately 24% of the proteins in the network were regulated by the YY1 transcription factor (adjusted p < 0.001). Strong immunohistochemical staining levels of three differentially expressed proteins, POSTN, CALR, and CTSD, on a tissue microarray validated their association with shorter patient survival.The protein signatures identified could improve understanding of the molecular drivers of aggressive prostate cancer and be used as candidate prognostic biomarkers.

    View details for DOI 10.1002/pros.24307

    View details for PubMedID 35098564

  • Expanding the Secondary Use of Prostate Cancer Real World Data: Automated Classifiers for Clinical and Pathological Stage. Frontiers in digital health Bozkurt, S., Magnani, C. J., Seneviratne, M. G., Brooks, J. D., Hernandez-Boussard, T. 2022; 4: 793316


    Background: Explicit documentation of stage is an endorsed quality metric by the National Quality Forum. Clinical and pathological cancer staging is inconsistently recorded within clinical narratives but can be derived from text in the Electronic Health Record (EHR). To address this need, we developed a Natural Language Processing (NLP) solution for extraction of clinical and pathological TNM stages from the clinical notes in prostate cancer patients.Methods: Data for patients diagnosed with prostate cancer between 2010 and 2018 were collected from a tertiary care academic healthcare system's EHR records in the United States. This system is linked to the California Cancer Registry, and contains data on diagnosis, histology, cancer stage, treatment and outcomes. A randomly selected sample of patients were manually annotated for stage to establish the ground truth for training and validating the NLP methods. For each patient, a vector representation of clinical text (written in English) was used to train a machine learning model alongside a rule-based model and compared with the ground truth.Results: A total of 5,461 prostate cancer patients were identified in the clinical data warehouse and over 30% were missing stage information. Thirty-three to thirty-six percent of patients were missing a clinical stage and the models accurately imputed the stage in 21-32% of cases. Twenty-one percent had a missing pathological stage and using NLP 71% of missing T stages and 56% of missing N stages were imputed. For both clinical and pathological T and N stages, the rule-based NLP approach out-performed the ML approach with a minimum F1 score of 0.71 and 0.40, respectively. For clinical M stage the ML approach out-performed the rule-based model with a minimum F1 score of 0.79 and 0.88, respectively.Conclusions: We developed an NLP pipeline to successfully extract clinical and pathological staging information from clinical narratives. Our results can serve as a proof of concept for using NLP to augment clinical and pathological stage reporting in cancer registries and EHRs to enhance the secondary use of these data.

    View details for DOI 10.3389/fdgth.2022.793316

    View details for PubMedID 35721793

  • Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results From the Canary PASS Cohort. The Journal of urology Waisman Malaret, A. J., Chang, P., Zhu, K., Zheng, Y., Newcomb, L. F., Liu, M., McKenney, J. K., Brooks, J. D., Carroll, P., Dash, A., Filson, C. P., Gleave, M. E., Liss, M., Martin, F. M., Morgan, T. M., Nelson, P. S., Lin, D. W., Wagner, A. A. 2021: 101097JU0000000000002354


    INTRODUCTION: Active Surveillance (AS) for grade group 2 (GG2) patients is not yet well-defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort.METHODS: Participants were prospectively enrolled in an AS study with protocol-directed follow up at 10 centers in the US and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology (AP) and recurrence were also analyzed.RESULTS: At diagnosis, 154 (9%) had GG2 and 1574 (91%) had GG1. Five-year reclassification rates were similar between GG2 or GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent RP after initial surveillance, the adjusted risk of AP was similar (HR=1.26; p=0.4). Biochemical recurrence (BCR) within 3 years of treatment for GG2 and GG1 patients was 6% for both groups.CONCLUSIONS: In patients on active surveillance, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after RP and short-term BCR after definitive treatment were similar between GG2 and GG1.

    View details for DOI 10.1097/JU.0000000000002354

    View details for PubMedID 34854745

  • Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer CANCER Kirk, P. S., Zhu, K., Zheng, Y., Newcomb, L. F., Schenk, J. M., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Filson, C. P., Gleave, M. E., Liss, M., Martin, F., McKenney, J. K., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Lin, D. W., Gore, J. L. 2021

    View details for DOI 10.1002/cncr.33911

    View details for Web of Science ID 000695224300001

  • Effect of Diagnostic Biopsy Practice Location on Grade/Volume Reclassification in Active Surveillance for Prostate Cancer: A Multicenter Analysis from the Canary PASS Cohort. Urology practice Waisman Malaret, A. J., Chang, P., Newcomb, L., Faino, A., Zheng, Y., Zhu, K., McKenney, J. K., Brooks, J. D., Dash, A., Ellis, W. J., Filson, C. P., Gleave, M., Liss, M., Martin, F. M., Morgan, T., Carroll, P., Nelson, P., Lin, D. W., Wagner, A. A. 2021; 8 (5): 576-582


    We analyzed the Canary Prostate Cancer Active Surveillance (PASS) cohort to determine if patients who had diagnostic biopsy at an off-site practice were at higher risk of reclassification than those having their diagnostic biopsy at a PASS site.Participants were prospectively enrolled at 10 academic institutions. We included patients with Gleason score 6 at diagnostic biopsy, <34% positive cores and a first surveillance biopsy in a PASS site <2 years after diagnosis. We dichotomized our population based on diagnostic biopsy location (on-PASS site vs off-PASS site) and used multivariable logistic regression to evaluate association with reclassification at first surveillance biopsy after controlling for possible confounders. We used Fisher's exact test to compare rates of definitive prostate cancer treatment by diagnostic biopsy location.Out of 1,648 participants in PASS, 906 met the eligibility criteria and were analyzed. Of 519 men who had off-site diagnostic biopsy, 102 (20%) had grade/volume reclassification compared to 72 (19%) of 399 patients who had on-site diagnostic biopsy. After controlling for potential confounders, location of diagnostic biopsy was not significantly associated with grade/volume reclassification (OR 1.32, IQR 0.91-1.92; p=0.141). Participants with an off-site diagnostic biopsy were more likely to elect definitive treatment than participants with an on-site diagnostic biopsy (17%, IQR 14-20 vs 14%, IQR 10-17 within 1 year after first surveillance biopsy; p <0.01).In this evaluation of a large multicenter active surveillance cohort, diagnostic biopsy location was not associated with significant differences in grade/volume reclassification on confirmatory biopsy at academic institutions.

    View details for DOI 10.1097/UPJ.0000000000000245

    View details for PubMedID 37145399

  • Effect of Diagnostic Biopsy Practice Location on Grade/Volume Reclassification in Active Surveillance for Prostate Cancer: A Multicenter Analysis from the Canary PASS Cohort UROLOGY PRACTICE Malaret, A., Chang, P., Newcomb, L., Faino, A., Zheng, Y., Zhu, K., McKenney, J. K., Brooks, J. D., Dash, A., Ellis, W. J., Filson, C. P., Gleave, M., Liss, M., Martin, F. M., Morgan, T., Carro, P., Nelson, P., Lin, D. W., Wagner, A. A. 2021; 8 (5): 576-582


    Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

    View details for Web of Science ID 000693688000420

    View details for PubMedID 34516660

  • Diverse patient trajectories during cytotoxic chemotherapy: Capturing longitudinal patient-reported outcomes. Cancer medicine Azad, A. D., Yilmaz, M., Bozkurt, S., Brooks, J. D., Blayney, D. W., Hernandez-Boussard, T. 2021


    BACKGROUND: High-value cancer care balances effective treatment with preservation of quality of life. Chemotherapy is known to affect patients' physical and psychological well-being negatively. Patient-reported outcomes (PROs) provide a means to monitor declines in a patients' well-being during treatment.METHODS: We identified 741 oncology patients undergoing chemotherapy in our electronic health record (EHR) system who completed Patient-Reported Outcomes Measurement Information System (PROMIS) surveys during treatment at a comprehensive cancer center, 2013-2018. PROMIS surveys were collected before, during, and after chemotherapy treatment. Linear mixed-effects models were performed to identify predictors of physical and mental health scores over time. A k-mean cluster analysis was used to group patient PROMIS score trajectories.RESULTS: Mean global physical health (GPH) scores were 48.7 (SD 9.3), 47.7 (8.8), and 48.6 (8.9) and global mental health (GMH) scores were 50.4 (8.6), 49.5 (8.8), and 50.6 (9.1) before, during, and after chemotherapy, respectively. Asian race, Hispanic ethnicity, public insurance, anxiety/depression, stage III cancer, and palliative care were predictors of GPH and GMH decline. The treatment time period was also a predictor of both GPH and GMH decline relative to pre-treatment. Trajectory clustering identified four distinct PRO clusters associated with chemotherapy treatment.CONCLUSIONS: Patient-reported outcomes are increasingly used to help monitor cancer treatment and are now a part of care reimbursement. This study leveraged routinely collected PROMIS surveys linked to EHRs to identify novel patient trajectories of physical and mental well-being in oncology patients undergoing chemotherapy and potential predictors. Supportive care interventions in high-risk populations identified by our study may optimize resource deployment.NOVELTY AND IMPACT: This study leveraged routinely collected patient-reported outcome (PROMIS) surveys linked to electronic health records to characterize oncology patients' quality of life during chemotherapy. Important clinical and demographic predictors of declines in quality of life were identified and four novel trajectories to guide personalized interventions and support. This work highlights the utility of monitoring patient-reported outcomes not only before and after, but during chemotherapy to help advert adverse patient outcomes and improve treatment adherence.

    View details for DOI 10.1002/cam4.4124

    View details for PubMedID 34254459

  • Identifying a novel glycolytic inhibitor for treatment of aggressive prostate cancer. Stoyanova, T., Rice, M. A., Kumar, V., Tailor, D., Garcia-Marques, F., Bermudez, A., Kanchustambham, V., Shankar, V., Inde, Z., Pandrala, M., Nolley, R., Ghoochani, A., Liu, S., Aslan, M., Agarwal, A., Buckup, M., Hsu, E., Going, C. C., Peehl, D. M., Dixon, S. J., Zare, R. N., Brooks, J. D., Pitteri, S. J., Malhotra, S. V., Stoyanova, T. AMER ASSOC CANCER RESEARCH. 2021
  • Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms. Stoyanova, T., Hsu, E., Liu, S., Marques, F., Bermudez, A., Aslan, M., Shen, M., Pitteri, S., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2021
  • 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

  • Identification of patients at high risk for preventable emergency department visits and inpatient admissions after starting chemotherapy: Machine learning applied to comprehensive electronic health record data. Peterson, D. J., Ostberg, N. P., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Automated Detection of Aggressive and Indolent Prostate Cancer on Magnetic Resonance Imaging. Medical physics Seetharaman, A., Bhattacharya, I., Chen, L. C., Kunder, C. A., Shao, W., Soerensen, S. J., Wang, J. B., Teslovich, N. C., Fan, R. E., Ghanouni, P., Brooks, J. D., To'o, K. J., Sonn, G. A., Rusu, M. 2021


    PURPOSE: While multi-parametric Magnetic Resonance Imaging (MRI) shows great promise in assisting with prostate cancer diagnosis and localization, subtle differences in appearance between cancer and normal tissue lead to many false positive and false negative interpretations by radiologists. We sought to automatically detect aggressive cancer (Gleason pattern ≥ 4) and indolent cancer (Gleason pattern 3) on a per-pixel basis on MRI to facilitate the targeting of aggressive cancer during biopsy.METHODS: We created the Stanford Prostate Cancer Network (SPCNet), a convolutional neural network model, trained to distinguish between aggressive cancer, indolent cancer, and normal tissue on MRI. Ground truth cancer labels were obtainedby registering MRI with whole-mount digital histopathology images from patients that underwent radical prostatectomy. Before registration, these histopathology images were automatically annotated to show Gleason patterns on a per-pixel basis. The model was trained on data from 78 patients that underwent radical prostatectomy and 24 patients without prostate cancer. The model was evaluated on a pixel and lesion level in 322 patients, including: 6 patients with normal MRI and no cancer, 23 patients that underwent radical prostatectomy, and 293 patients that underwent biopsy. Moreover, we assessed the ability of our model to detect clinically significant cancer (lesions with an aggressive component) and compared it to the performance of radiologists.RESULTS: Our model detected clinically significant lesions with an Area Under the Receiver Operator Characteristics Curve of 0.75 for radical prostatectomy patients and 0.80 for biopsy patients. Moreover, the model detected up to 18% of lesions missed by radiologists, and overall had a sensitivity and specificity that approached that of radiologists in detecting clinically significant cancer.CONCLUSIONS: Our SPCNet model accurately detected aggressive prostate cancer. Its performance approached that of radiologists, and it helped identify lesions otherwise missed by radiologists. Our model has the potential to assist physicians in specifically targeting the aggressive component of prostate cancers during biopsy or focal treatment.

    View details for DOI 10.1002/mp.14855

    View details for PubMedID 33760269

  • Prevalence of Postprostatectomy Incontinence Requiring Anti-incontinence Surgery After Radical Prostatectomy for Prostate Cancer: A Retrospective Population-Based Analysis. International neurourology journal Kim, J. H., Jeong, I. G., Khandwala, Y. S., Hernandez-Boussard, T., Brooks, J. D., Chung, B. I. 2021


    Purpose: The aim of this study was to examine the prevalence of surgery for post-prostatectomy incontinence (PI) following minimally invasive surgery compared to conventional open surgery for prostate cancer.Methods: This retrospective cohort study used the Florida State Ambulatory Surgery and State Inpatient Databases, 2008 to 2010, RP patients were identified using ICD-9/10 procedure codes and among this cohort PI was identified also using ICD-9/10 codes. Surgical approaches included Minimally invasive (robotic or laparoscopic) vs. open (retropubic or perineal) RP. The primary outcome was the overall prevalence of surgery for PI. The secondary outcome was the association of PI requiring anti-incontinence surgery with the surgical approach for RP.Results: Among the 13535 patients initially included in the study (mean age, 63.3 years), 6932 (51.2%) underwent open RP and 6603 (49.8%) underwent minimally invasive RP. The overall prevalence of surgical procedures for PI during the observation period among the all patients who had received RP was 3.3%. The rate of PI surgery for patients receiving minimally invasive surgery was higher than that for patients receiving open surgery (4.8% vs. 3.0%; risk difference, 1.8%; 95% CI, 0.3% to 3.4%). The adjusted prevalence of PI surgery for patients who had undergone laparoscopic RP was higher than that for those with retropubic RP (8.6% vs. 3.7%).Conclusions: Among patients undergoing RP for prostate cancer, the prevalence of PI surgery is not negligible. Patients undergoing minimally invasive RP had higher adjusted rates for PI surgery compared to open approaches, which was attributed to high rate of PI surgery following laparoscopic approach and low rate of PI surgery following perineal approach. More studies are needed to establish strategies to reduce the rate of PI surgery after RP.

    View details for DOI 10.5213/inj.2040296.148

    View details for PubMedID 33705635

  • Assessment of a Clinical Trial-Derived Survival Model in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA network open Coquet, J. n., Bievre, N. n., Billaut, V. n., Seneviratne, M. n., Magnani, C. J., Bozkurt, S. n., Brooks, J. D., Hernandez-Boussard, T. n. 2021; 4 (1): e2031730


    Randomized clinical trials (RCTs) are considered the criterion standard for clinical evidence. Despite their many benefits, RCTs have limitations, such as costliness, that may reduce the generalizability of their findings among diverse populations and routine care settings.To assess the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic castration-resistant prostate cancer (CRPC) when the model is applied to real-world data from electronic health records (EHRs).The RCT-trained model and patient data from the RCTs were obtained from the Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge for prostate cancer, which occurred from March 16 to July 27, 2015. This challenge included 4 phase 3 clinical trials of patients with metastatic CRPC. Real-world data were obtained from the EHRs of a tertiary care academic medical center that includes a comprehensive cancer center. In this study, the DREAM challenge RCT-trained model was applied to real-world data from January 1, 2008, to December 31, 2019; the model was then retrained using EHR data with optimized feature selection. Patients with metastatic CRPC were divided into RCT and EHR cohorts based on data source. Data were analyzed from March 23, 2018, to October 22, 2020.Patients who received treatment for metastatic CRPC.The primary outcome was the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic CRPC when the model is applied to real-world data. Model performance was compared using 10-fold cross-validation according to time-dependent integrated area under the curve (iAUC) statistics.Among 2113 participants with metastatic CRPC, 1600 participants were included in the RCT cohort, and 513 participants were included in the EHR cohort. The RCT cohort comprised a larger proportion of White participants (1390 patients [86.9%] vs 337 patients [65.7%]) and a smaller proportion of Hispanic participants (14 patients [0.9%] vs 42 patients [8.2%]), Asian participants (41 patients [2.6%] vs 88 patients [17.2%]), and participants older than 75 years (388 patients [24.3%] vs 191 patients [37.2%]) compared with the EHR cohort. Participants in the RCT cohort also had fewer comorbidities (mean [SD], 1.6 [1.8] comorbidities vs 2.5 [2.6] comorbidities, respectively) compared with those in the EHR cohort. Of the 101 variables used in the RCT-derived model, 10 were not available in the EHR data set, 3 of which were among the top 10 features in the DREAM challenge RCT model. The best-performing EHR-trained model included only 25 of the 101 variables included in the RCT-trained model. The performance of the RCT-trained and EHR-trained models was adequate in the EHR cohort (mean [SD] iAUC, 0.722 [0.118] and 0.762 [0.106], respectively); model optimization was associated with improved performance of the best-performing EHR model (mean [SD] iAUC, 0.792 [0.097]). The EHR-trained model classified 256 patients as having a high risk of mortality and 256 patients as having a low risk of mortality (hazard ratio, 2.7; 95% CI, 2.0-3.7; log-rank P < .001).In this study, although the RCT-trained models did not perform well when applied to real-world EHR data, retraining the models using real-world EHR data and optimizing variable selection was beneficial for model performance. As clinical evidence evolves to include more real-world data, both industry and academia will likely search for ways to balance model optimization with generalizability. This study provides a pragmatic approach to applying RCT-trained models to real-world data.

    View details for DOI 10.1001/jamanetworkopen.2020.31730

    View details for PubMedID 33481032

  • MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer. Scientific reports Hsu, E. C., Shen, M., Aslan, M., Liu, S., Kumar, M., Garcia-Marques, F., Nguyen, H. M., Nolley, R., Pitteri, S. J., Corey, E., Brooks, J. D., Stoyanova, T. 2021; 11 (1): 13305


    Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

    View details for DOI 10.1038/s41598-021-92552-x

    View details for PubMedID 34172788

  • Machine Learning Applied to Electronic Health Records: Identification of Chemotherapy Patients at High Risk for Preventable Emergency Department Visits and Hospital Admissions. JCO clinical cancer informatics Peterson, D. J., Ostberg, N. P., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. 2021; 5: 1106-1126


    Acute care use (ACU) is a major driver of oncologic costs and is penalized by a Centers for Medicare & Medicaid Services quality measure, OP-35. Targeted interventions reduce preventable ACU; however, identifying which patients might benefit remains challenging. Prior predictive models have made use of a limited subset of the data in the electronic health record (EHR). We aimed to predict risk of preventable ACU after starting chemotherapy using machine learning (ML) algorithms trained on comprehensive EHR data.Chemotherapy patients treated at an academic institution and affiliated community care sites between January 2013 and July 2019 who met inclusion criteria for OP-35 were identified. Preventable ACU was defined using OP-35 criteria. Structured EHR data generated before chemotherapy treatment were obtained. ML models were trained to predict risk for ACU after starting chemotherapy using 80% of the cohort. The remaining 20% were used to test model performance by the area under the receiver operator curve.Eight thousand four hundred thirty-nine patients were included, of whom 35% had preventable ACU within 180 days of starting chemotherapy. Our primary model classified patients at risk for preventable ACU with an area under the receiver operator curve of 0.783 (95% CI, 0.761 to 0.806). Performance was better for identifying admissions than emergency department visits. Key variables included prior hospitalizations, cancer stage, race, laboratory values, and a diagnosis of depression. Analyses showed limited benefit from including patient-reported outcome data and indicated inequities in outcomes and risk modeling for Black and Medicaid patients.Dense EHR data can identify patients at risk for ACU using ML with promising accuracy. These models have potential to improve cancer care outcomes, patient experience, and costs by allowing for targeted, preventative interventions.

    View details for DOI 10.1200/CCI.21.00116

    View details for PubMedID 34752139

  • Oncogene-mediated metabolic gene signature predicts breast cancer outcome. NPJ breast cancer Aslan, M., Hsu, E. C., Garcia-Marques, F. J., Bermudez, A., Liu, S., Shen, M., West, M., Zhang, C. A., Rice, M. A., Brooks, J. D., West, R., Pitteri, S. J., Győrffy, B., Stoyanova, T. 2021; 7 (1): 141


    Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

    View details for DOI 10.1038/s41523-021-00341-6

    View details for PubMedID 34711841

  • 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

  • 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

  • Real-world Evidence to Estimate Prostate Cancer Costs for First-line Treatment or Active Surveillance. European urology open science Magnani, C. J., Bievre, N., Baker, L. C., Brooks, J. D., Blayney, D. W., Hernandez-Boussard, T. 2021; 23: 20–29


    Background: Prostate cancer is the most common cancer in men and second leading cause of cancer-related deaths. Changes in screening guidelines, adoption of active surveillance (AS), and implementation of high-cost technologies have changed treatment costs. Traditional cost-effectiveness studies rely on clinical trial protocols unlikely to capture actual practice behavior, and existing studies use data predating new technologies. Real-world evidence reflecting these changes is lacking.Objective: To assess real-world costs of first-line prostate cancer management.Design setting and participants: We used clinical electronic health records for 2008-2018 linked with the California Cancer Registry and the Medicare Fee Schedule to assess costs over 24 or 60 mo following diagnosis. We identified surgery or radiation treatments with structured methods, while we used both structured data and natural language processing to identify AS.Outcome measurements and statistical analysis: Our results are risk-stratified calculated cost per day (CCPD) for first-line management, which are independent of treatment duration. We used the Kruskal-Wallis test to compare unadjusted CCPD while analysis of covariance log-linear models adjusted estimates for age and Charlson comorbidity.Results and limitations: In 3433 patients, surgery (54.6%) was more common than radiation (22.3%) or AS (23.0%). Two years following diagnosis, AS ($2.97/d) was cheaper than surgery ($5.67/d) or radiation ($9.34/d) in favorable disease, while surgery ($7.17/d) was cheaper than radiation ($16.34/d) for unfavorable disease. At 5 yr, AS ($2.71/d) remained slightly cheaper than surgery ($2.87/d) and radiation ($4.36/d) in favorable disease, while for unfavorable disease surgery ($4.15/d) remained cheaper than radiation ($10.32/d). Study limitations include information derived from a single healthcare system and costs based on benchmark Medicare estimates rather than actual payment exchanges.Patient summary: Active surveillance was cheaper than surgery (-47.6%) and radiation (-68.2%) at 2 yr for favorable-risk disease, which decreased by 5 yr (-5.6% and -37.8%, respectively). Surgery was less costly than radiation for unfavorable risk for both intervals (-56.1% and -59.8%, respectively).

    View details for DOI 10.1016/j.euros.2020.11.004

    View details for PubMedID 33367287

  • Ferroptosis inducers are a novel therapeutic approach for advanced prostate cancer. Cancer research Ghoochani, A. n., Hsu, E. C., Aslan, M. n., Rice, M. A., Nguyen, H. M., Brooks, J. D., Corey, E. n., Paulmurugan, R. n., Stoyanova, T. n. 2021


    Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species (ROS) in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of ferroptosis inducers in prostate cancer in pre-clinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis SLC7A11, SLC3A2 and GPX4 are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two ferroptosis inducers, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation anti-androgens for advanced prostate cancer halted prostate cancer cell growth and migration in vitro and tumor growth in vivo. These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation anti-androgens as novel therapeutic strategies for advanced prostate cancer.

    View details for DOI 10.1158/0008-5472.CAN-20-3477

    View details for PubMedID 33483372

  • Selective identification and localization of indolent and aggressive prostate cancers via CorrSigNIA: an MRI-pathology correlation and deep learning framework. Medical image analysis Bhattacharya, I., Seetharaman, A., Kunder, C., Shao, W., Chen, L. C., Soerensen, S. J., Wang, J. B., Teslovich, N. C., Fan, R. E., Ghanouni, P., Brooks, J. D., Sonn, G. A., Rusu, M. 2021; 75: 102288


    Automated methods for detecting prostate cancer and distinguishing indolent from aggressive disease on Magnetic Resonance Imaging (MRI) could assist in early diagnosis and treatment planning. Existing automated methods of prostate cancer detection mostly rely on ground truth labels with limited accuracy, ignore disease pathology characteristics observed on resected tissue, and cannot selectively identify aggressive (Gleason Pattern≥4) and indolent (Gleason Pattern=3) cancers when they co-exist in mixed lesions. In this paper, we present a radiology-pathology fusion approach, CorrSigNIA, for the selective identification and localization of indolent and aggressive prostate cancer on MRI. CorrSigNIA uses registered MRI and whole-mount histopathology images from radical prostatectomy patients to derive accurate ground truth labels and learn correlated features between radiology and pathology images. These correlated features are then used in a convolutional neural network architecture to detect and localize normal tissue, indolent cancer, and aggressive cancer on prostate MRI. CorrSigNIA was trained and validated on a dataset of 98 men, including 74 men that underwent radical prostatectomy and 24 men with normal prostate MRI. CorrSigNIA was tested on three independent test sets including 55 men that underwent radical prostatectomy, 275 men that underwent targeted biopsies, and 15 men with normal prostate MRI. CorrSigNIA achieved an accuracy of 80% in distinguishing between men with and without cancer, a lesion-level ROC-AUC of 0.81±0.31 in detecting cancers in both radical prostatectomy and biopsy cohort patients, and lesion-levels ROC-AUCs of 0.82±0.31 and 0.86±0.26 in detecting clinically significant cancers in radical prostatectomy and biopsy cohort patients respectively. CorrSigNIA consistently outperformed other methods across different evaluation metrics and cohorts. In clinical settings, CorrSigNIA may be used in prostate cancer detection as well as in selective identification of indolent and aggressive components of prostate cancer, thereby improving prostate cancer care by helping guide targeted biopsies, reducing unnecessary biopsies, and selecting and planning treatment.

    View details for DOI 10.1016/

    View details for PubMedID 34784540

  • Weakly Supervised Registration of Prostate MRI and Histopathology Images Shao, W., Bhattacharya, I., Soerensen, S. C., Kunder, C. A., Wang, J. B., Fan, R. E., Ghanouni, P., Brooks, J. D., Sonn, G. A., Rusu, M., DeBruijne, M., Cattin, P. C., Cotin, S., Padoy, N., Speidel, S., Zheng, Y., Essert, C. SPRINGER INTERNATIONAL PUBLISHING AG. 2021: 98-107
  • Consumption of cruciferous vegetables and the risk of bladder cancer in a prospective US cohort: data from the NIH-AARP diet and health study AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY Nguyen, T. P., Zhang, C. A., Sonn, G. A., Eisenberg, M. L., Brooks, J. D. 2021; 9 (3): 229-238
  • Discovery of CASP8 as a potential biomarker for high-risk prostate cancer through a high-multiplex immunoassay. Scientific reports Liu, S. n., Garcia-Marques, F. n., Zhang, C. A., Lee, J. J., Nolley, R. n., Shen, M. n., Hsu, E. C., Aslan, M. n., Koul, K. n., Pitteri, S. J., Brooks, J. D., Stoyanova, T. n. 2021; 11 (1): 7612


    Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.

    View details for DOI 10.1038/s41598-021-87155-5

    View details for PubMedID 33828176

  • 3D Registration of pre-surgical prostate MRI and histopathology images via super-resolution volume reconstruction. Medical image analysis Sood, R. R., Shao, W. n., Kunder, C. n., Teslovich, N. C., Wang, J. B., Soerensen, S. J., Madhuripan, N. n., Jawahar, A. n., Brooks, J. D., Ghanouni, P. n., Fan, R. E., Sonn, G. A., Rusu, M. n. 2021; 69: 101957


    The use of MRI for prostate cancer diagnosis and treatment is increasing rapidly. However, identifying the presence and extent of cancer on MRI remains challenging, leading to high variability in detection even among expert radiologists. Improvement in cancer detection on MRI is essential to reducing this variability and maximizing the clinical utility of MRI. To date, such improvement has been limited by the lack of accurately labeled MRI datasets. Data from patients who underwent radical prostatectomy enables the spatial alignment of digitized histopathology images of the resected prostate with corresponding pre-surgical MRI. This alignment facilitates the delineation of detailed cancer labels on MRI via the projection of cancer from histopathology images onto MRI. We introduce a framework that performs 3D registration of whole-mount histopathology images to pre-surgical MRI in three steps. First, we developed a novel multi-image super-resolution generative adversarial network (miSRGAN), which learns information useful for 3D registration by producing a reconstructed 3D MRI. Second, we trained the network to learn information between histopathology slices to facilitate the application of 3D registration methods. Third, we registered the reconstructed 3D histopathology volumes to the reconstructed 3D MRI, mapping the extent of cancer from histopathology images onto MRI without the need for slice-to-slice correspondence. When compared to interpolation methods, our super-resolution reconstruction resulted in the highest PSNR relative to clinical 3D MRI (32.15 dB vs 30.16 dB for BSpline interpolation). Moreover, the registration of 3D volumes reconstructed via super-resolution for both MRI and histopathology images showed the best alignment of cancer regions when compared to (1) the state-of-the-art RAPSODI approach, (2) volumes that were not reconstructed, or (3) volumes that were reconstructed using nearest neighbor, linear, or BSpline interpolations. The improved 3D alignment of histopathology images and MRI facilitates the projection of accurate cancer labels on MRI, allowing for the development of improved MRI interpretation schemes and machine learning models to automatically detect cancer on MRI.

    View details for DOI 10.1016/

    View details for PubMedID 33550008

  • In vivo imaging of methionine aminopeptidase II for prostate cancer risk stratification. Cancer research Xie, J. n., Rice, M. A., Chen, Z. n., Cheng, Y. n., Hsu, E. C., Chen, M. n., Song, G. n., Cui, L. n., Zhou, K. n., Castillo, J. B., Zhang, C. A., Shen, B. n., Chin, F. T., Kunder, C. A., Brooks, J. D., Stoyanova, T. n., Rao, J. n. 2021


    Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical for improving treatment decisions and patient survival. In this study, we analyzed radical prostatectomy specimens from 422 patients with localized disease to define the expression pattern of methionine aminopeptidase II (MetAP2), a cytosolic metalloprotease that has been identified as a druggable target in cancer. MetAP2 was highly expressed in 54% of low-grade and 59% of high-grade cancer. Elevated levels of MetAP2 at diagnosis were associated with shorter time to recurrence. Controlled self-assembly of a synthetic small molecule enabled design of the first MetAP2-activated positron emission tomography (PET) imaging tracer for monitoring MetAP2 activity in vivo. The nanoparticles assembled upon MetAP2 activation were imaged in single prostate cancer cells with post-click fluorescent labeling. The fluorine-18 labeled tracers successfully differentiated MetAP2 activity in both MetAP2 knockdown and inhibitor-treated human prostate cancer xenografts by micro-PET/CT scanning. This highly sensitive imaging technology may provide a new tool for non-invasive early risk stratification of prostate cancer and monitoring the therapeutic effect of MetAP2 inhibitors as anti-cancer drugs.

    View details for DOI 10.1158/0008-5472.CAN-20-2969

    View details for PubMedID 33637565

  • 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

  • Sprr2f protects against renal injury by decreasing the level of reactive oxygen species in female mice. American journal of physiology. Renal physiology Huynh, K. M., Wong, A., Wu, B., Horschman, M., Zhao, H., Brooks, J. D. 2020


    Renal injury leads to chronic kidney disease for which women are not only more likely to be diagnosed with than men but have poorer outcomes as well. We have previously shown that expression of Sprr2f, a member of the Small Proline Rich Region (Sprr) gene family, is increased several hundred-fold after renal injury using a unilateral ureteral obstruction (UUO) mouse model. To better understand the role of Sprr2f in renal injury, we generated a Sprr2f knockout (Sprr2f-KO) mouse model using CRISPR-Cas9 technology. Sprr2f-KO female mice showed greater renal damage after UUO compared to wild type (Sprr2f-WT) animals, evidenced by higher hydroxyproline levels and denser collagen staining, indicating a protective role of Sprr2f during renal injury. Gene expression profiling by RNA-seq identified 162 genes whose expression levels were significantly different between day 0 and day 5 after UUO in Sprr2f-KO mice. Out of the 162 genes, 121 were upregulated after UUO and enriched with those involved in oxidation-reduction, a phenomenon not observed in wild type animals, suggesting a protective role of Sprr2f in UUO through defense against oxidative damage. Consistently, bilateral ischemia reperfusion injury resulted in higher serum blood urea nitrogen level and higher tissue reactive oxygen species (ROS) in Sprr2f-KO compared to Sprr2f-WT female mice. Moreover, cultured renal epithelial cells from Sprr2f-KO female mice showed lower viability after oxidative damage induced by menadione compared to Sprr2f-WT cells that could be rescued by supplementation with reduced glutathione, suggesting that Sprr2f induction after renal damage acts as a defense against ROS.

    View details for DOI 10.1152/ajprenal.00318.2020

    View details for PubMedID 33017192

  • Phenotyping severity of patient-centered outcomes using clinical notes: A prostate cancer use case. Learning health systems Bozkurt, S., Paul, R., Coquet, J., Sun, R., Banerjee, I., Brooks, J. D., Hernandez-Boussard, T. 2020; 4 (4): e10237


    A learning health system (LHS) must improve care in ways that are meaningful to patients, integrating patient-centered outcomes (PCOs) into core infrastructure. PCOs are common following cancer treatment, such as urinary incontinence (UI) following prostatectomy. However, PCOs are not systematically recorded because they can only be described by the patient, are subjective and captured as unstructured text in the electronic health record (EHR). Therefore, PCOs pose significant challenges for phenotyping patients. Here, we present a natural language processing (NLP) approach for phenotyping patients with UI to classify their disease into severity subtypes, which can increase opportunities to provide precision-based therapy and promote a value-based delivery system.Patients undergoing prostate cancer treatment from 2008 to 2018 were identified at an academic medical center. Using a hybrid NLP pipeline that combines rule-based and deep learning methodologies, we classified positive UI cases as mild, moderate, and severe by mining clinical notes.The rule-based model accurately classified UI into disease severity categories (accuracy: 0.86), which outperformed the deep learning model (accuracy: 0.73). In the deep learning model, the recall rates for mild and moderate group were higher than the precision rate (0.78 and 0.79, respectively). A hybrid model that combined both methods did not improve the accuracy of the rule-based model but did outperform the deep learning model (accuracy: 0.75).Phenotyping patients based on indication and severity of PCOs is essential to advance a patient centered LHS. EHRs contain valuable information on PCOs and by using NLP methods, it is feasible to accurately and efficiently phenotype PCO severity. Phenotyping must extend beyond the identification of disease to provide classification of disease severity that can be used to guide treatment and inform shared decision-making. Our methods demonstrate a path to a patient centered LHS that could advance precision medicine.

    View details for DOI 10.1002/lrh2.10237

    View details for PubMedID 33083539

    View details for PubMedCentralID PMC7556418

  • Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability. JAMA oncology Cooperberg, M. R., Zheng, Y., Faino, A. V., Newcomb, L. F., Zhu, K., Cowan, J. E., Brooks, J. D., Dash, A., Gleave, M. E., Martin, F., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Carroll, P. R., Lin, D. W. 2020: e203187


    Importance: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost.Objective: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments.Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data.Exposures: Active surveillance for prostate cancer.Main Outcomes and Measures: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy.Results: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P=.004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P<.001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P<.001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P<.001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P<.001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P<.001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P=.003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P<.001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile.Conclusions and Relevance: In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.

    View details for DOI 10.1001/jamaoncol.2020.3187

    View details for PubMedID 32852532

  • AZGP1 Protein Expression in Hormone-Naive Advanced Prostate Cancer Treated with Primary Androgen Deprivation Therapy. Diagnostics (Basel, Switzerland) Winther, M. D., Kristensen, G., Stroomberg, H. V., Berg, K. D., Toft, B. G., Brooks, J. D., Brasso, K., Roder, M. A. 2020; 10 (8)


    Biomarkers for predicting the risk of castration-resistant prostate cancer (CRPC) in men treated with primary androgen deprivation therapy (ADT) are lacking. We investigated whether Zinc-alpha 2 glycoprotein (AZGP1) expression in the diagnostic biopsies of men with hormone-naive prostate cancer (PCa) undergoing primary ADT was predictive of the development of CRPC and PCa-specific mortality. The study included 191 patients who commenced ADT from 2000 to 2011. The AZGP1 expression was evaluated using immunohistochemistry and scored as high or low expression. The risks of CRPC and PCa-specific mortality were analyzed using stratified cumulative incidences and a cause-specific COX regression analysis for competing risk assessment. The median follow-up time was 9.8 (IQR: 6.1-12.7) years. In total, 94 and 97 patients presented with low and high AZGP1 expression, respectively. A low AZGP1 expression was found to be associated with a shorter time to CRPC when compared to patients with a high AZGP1 expression (HR: 1.5; 95% CI: 1.0-2.1; p = 0.03). However, the multivariable analysis demonstrated no added benefit by adding the AZGP1 expression to prediction models for CRPC. No differences for PCa-specific mortality between the AZGP1 groups were observed. In conclusion, a low AZGP1 expression was associated with a shorter time to CRPC for PCa patients treated with first-line ADT but did not add any predictive information besides well-established clinicopathological variables.

    View details for DOI 10.3390/diagnostics10080520

    View details for PubMedID 32726925

  • Phenotyping severity of patient-centered outcomes using clinical notes: A prostate cancer use case LEARNING HEALTH SYSTEMS Bozkurt, S., Paul, R., Coquet, J., Sun, R., Banerjee, I., Brooks, J. D., Hernandez-Boussard, T. 2020

    View details for DOI 10.1002/lrh2.10237

    View details for Web of Science ID 000548944700001

  • 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

  • Registration of pre-surgical MRI and histopathology images from radical prostatectomy via RAPSODI. Medical physics Rusu, M., Shao, W., Kunder, C. A., Wang, J. B., Soerensen, S. J., Teslovich, N. C., Sood, R. R., Chen, L. C., Fan, R. E., Ghanouni, P., Brooks, J. D., Sonn, G. A. 2020


    PURPOSE: Magnetic resonance imaging (MRI) has great potential to improve prostate cancer diagnosis, however, subtle differences between cancer and confounding conditions render prostate MRI interpretation challenging. The tissue collected from patients who undergo radical prostatectomy provides a unique opportunity to correlate histopathology images of the prostate with pre-operative MRI to accurately map the extent of cancer from histopathology images onto MRI. We seek to develop an open-source, easy-to-use platform to align pre-surgical MRI and histopathology images of resected prostates in patients who underwent radical prostatectomy to create accurate cancer labels on MRI.METHODS: Here, we introduce RAdiology Pathology Spatial Open-Source multi-Dimensional Integration (RAPSODI), the first open-source framework for the registration of radiology and pathology images. RAPSODI relies on three steps. First, it creates a 3D reconstruction of the histopathology specimen as a digital representation of the tissue before gross sectioning. Second, RAPSODI registers corresponding histopathology and MRI slices. Third, the optimized transforms are applied to the cancer regions outlined on the histopathology images to project those labels onto the pre-operative MRI.RESULTS: We tested RAPSODI in a phantom study where we simulated various conditions, e.g., tissue shrinkage during fixation. Our experiments showed that RAPSODI can reliably correct multiple artifacts. We also evaluated RAPSODI in 157 patients from three institutions that underwent radical prostatectomy and have very different pathology processing and scanning. RAPSODI was evaluated in 907 corresponding histpathology-MRI slices and achieved a Dice coefficient of 0.97±0.01 for the prostate, a Hausdorff distance of 1.99±0.70 mm for the prostate boundary, a urethra deviation of 3.09±1.45 mm, and a landmark deviation of 2.80±0.59 mm between registered histopathology images and MRI.CONCLUSION: Our robust framework successfully mapped the extent of cancer from histopathology slices onto MRI providing labels from training machine learning methods to detect cancer on MRI.

    View details for DOI 10.1002/mp.14337

    View details for PubMedID 32564359

  • 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

  • Determination of biologic and prognostic feature scores from whole slide histology images using deep learning. Eminaga, O., Abbas, M., Semjonow, A., Brooks, J. D., Rubin, D. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Four distinct patient-reported outcome (PRO) trajectories in longitudinal responses collected before, during, and after chemotherapy. Blayney, D. W., Azad, A., Yilmaz, M., Bozkurt, S., Brooks, J. D., Hernandez-Boussard, T. AMER SOC CLINICAL ONCOLOGY. 2020
  • Detection of prostate cancer and determination of its significance using explainable artificial intelligence. Eminaga, O., Loening, A., Lu, A., Brooks, J. D., Rubin, D. AMER SOC CLINICAL ONCOLOGY. 2020
  • The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution. Cell Rozenblatt-Rosen, O., Regev, A., Oberdoerffer, P., Nawy, T., Hupalowska, A., Rood, J. E., Ashenberg, O., Cerami, E., Coffey, R. J., Demir, E., Ding, L., Esplin, E. D., Ford, J. M., Goecks, J., Ghosh, S., Gray, J. W., Guinney, J., Hanlon, S. E., Hughes, S. K., Hwang, E. S., Iacobuzio-Donahue, C. A., Jane-Valbuena, J., Johnson, B. E., Lau, K. S., Lively, T., Mazzilli, S. A., Pe'er, D., Santagata, S., Shalek, A. K., Schapiro, D., Snyder, M. P., Sorger, P. K., Spira, A. E., Srivastava, S., Tan, K., West, R. B., Williams, E. H., Human Tumor Atlas Network, Aberle, D., Achilefu, S. I., Ademuyiwa, F. O., Adey, A. C., Aft, R. L., Agarwal, R., Aguilar, R. A., Alikarami, F., Allaj, V., Amos, C., Anders, R. A., Angelo, M. R., Anton, K., Ashenberg, O., Aster, J. C., Babur, O., Bahmani, A., Balsubramani, A., Barrett, D., Beane, J., Bender, D. E., Bernt, K., Berry, L., Betts, C. B., Bletz, J., Blise, K., Boire, A., Boland, G., Borowsky, A., Bosse, K., Bott, M., Boyden, E., Brooks, J., Bueno, R., Burlingame, E. A., Cai, Q., Campbell, J., Caravan, W., Cerami, E., Chaib, H., Chan, J. M., Chang, Y. H., Chatterjee, D., Chaudhary, O., Chen, A. A., Chen, B., Chen, C., Chen, C., Chen, F., Chen, Y., Chheda, M. G., Chin, K., Chiu, R., Chu, S., Chuaqui, R., Chun, J., Cisneros, L., Coffey, R. J., Colditz, G. A., Cole, K., Collins, N., Contrepois, K., Coussens, L. M., Creason, A. L., Crichton, D., Curtis, C., Davidsen, T., Davies, S. R., de Bruijn, I., Dellostritto, L., De Marzo, A., Demir, E., DeNardo, D. G., Diep, D., Ding, L., Diskin, S., Doan, X., Drewes, J., Dubinett, S., Dyer, M., Egger, J., Eng, J., Engelhardt, B., Erwin, G., Esplin, E. D., Esserman, L., Felmeister, A., Feiler, H. S., Fields, R. C., Fisher, S., Flaherty, K., Flournoy, J., Ford, J. M., Fortunato, A., Frangieh, A., Frye, J. L., Fulton, R. S., Galipeau, D., Gan, S., Gao, J., Gao, L., Gao, P., Gao, V. R., Geiger, T., George, A., Getz, G., Ghosh, S., Giannakis, M., Gibbs, D. L., Gillanders, W. E., Goecks, J., Goedegebuure, S. P., Gould, A., Gowers, K., Gray, J. W., Greenleaf, W., Gresham, J., Guerriero, J. L., Guha, T. K., Guimaraes, A. R., Guinney, J., Gutman, D., Hacohen, N., Hanlon, S., Hansen, C. R., Harismendy, O., Harris, K. A., Hata, A., Hayashi, A., Heiser, C., Helvie, K., Herndon, J. M., Hirst, G., Hodi, F., Hollmann, T., Horning, A., Hsieh, J. J., Hughes, S., Huh, W. J., Hunger, S., Hwang, S. E., Iacobuzio-Donahue, C. A., Ijaz, H., Izar, B., Jacobson, C. A., Janes, S., Jane-Valbuena, J., Jayasinghe, R. G., Jiang, L., Johnson, B. E., Johnson, B., Ju, T., Kadara, H., Kaestner, K., Kagan, J., Kalinke, L., Keith, R., Khan, A., Kibbe, W., Kim, A. H., Kim, E., Kim, J., Kolodzie, A., Kopytra, M., Kotler, E., Krueger, R., Krysan, K., Kundaje, A., Ladabaum, U., Lake, B. B., Lam, H., Laquindanum, R., Lau, K. S., Laughney, A. M., Lee, H., Lenburg, M., Leonard, C., Leshchiner, I., Levy, R., Li, J., Lian, C. G., Lim, K., Lin, J., Lin, Y., Liu, Q., Liu, R., Lively, T., Longabaugh, W. J., Longacre, T., Ma, C. X., Macedonia, M. C., Madison, T., Maher, C. A., Maitra, A., Makinen, N., Makowski, D., Maley, C., Maliga, Z., Mallo, D., Maris, J., Markham, N., Marks, J., Martinez, D., Mashl, R. J., Masilionais, I., Mason, J., Massague, J., Massion, P., Mattar, M., Mazurchuk, R., Mazutis, L., Mazzilli, S. A., McKinley, E. T., McMichael, J. F., Merrick, D., Meyerson, M., Miessner, J. R., Mills, G. B., Mills, M., Mondal, S. B., Mori, M., Mori, Y., Moses, E., Mosse, Y., Muhlich, J. L., Murphy, G. F., Navin, N. E., Nawy, T., Nederlof, M., Ness, R., Nevins, S., Nikolov, M., Nirmal, A. J., Nolan, G., Novikov, E., Oberdoerffer, P., O'Connell, B., Offin, M., Oh, S. T., Olson, A., Ooms, A., Ossandon, M., Owzar, K., Parmar, S., Patel, T., Patti, G. J., Pe'er, D., Pe'er, I., Peng, T., Persson, D., Petty, M., Pfister, H., Polyak, K., Pourfarhangi, K., Puram, S. V., Qiu, Q., Quintanal-Villalonga, A., Raj, A., Ramirez-Solano, M., Rashid, R., Reeb, A. N., Regev, A., Reid, M., Resnick, A., Reynolds, S. M., Riesterer, J. L., Rodig, S., Roland, J. T., Rosenfield, S., Rotem, A., Roy, S., Rozenblatt-Rosen, O., Rudin, C. M., Ryser, M. D., Santagata, S., Santi-Vicini, M., Sato, K., Schapiro, D., Schrag, D., Schultz, N., Sears, C. L., Sears, R. C., Sen, S., Sen, T., Shalek, A., Sheng, J., Sheng, Q., Shoghi, K. I., Shrubsole, M. J., Shyr, Y., Sibley, A. B., Siex, K., Simmons, A. J., Singer, D. S., Sivagnanam, S., Slyper, M., Snyder, M. P., Sokolov, A., Song, S., Sorger, P. K., Southard-Smith, A., Spira, A., Srivastava, S., Stein, J., Storm, P., Stover, E., Strand, S. H., Su, T., Sudar, D., Sullivan, R., Surrey, L., Suva, M., Tan, K., Terekhanova, N. V., Ternes, L., Thammavong, L., Thibault, G., Thomas, G. V., Thorsson, V., Todres, E., Tran, L., Tyler, M., Uzun, Y., Vachani, A., Van Allen, E., Vandekar, S., Veis, D. J., Vigneau, S., Vossough, A., Waanders, A., Wagle, N., Wang, L., Wendl, M. C., West, R., Williams, E. H., Wu, C., Wu, H., Wu, H., Wyczalkowski, M. A., Xie, Y., Yang, X., Yapp, C., Yu, W., Yuan, Y., Zhang, D., Zhang, K., Zhang, M., Zhang, N., Zhang, Y., Zhao, Y., Zhou, D. C., Zhou, Z., Zhu, H., Zhu, Q., Zhu, X., Zhu, Y., Zhuang, X. 2020; 181 (2): 236–49


    Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

    View details for DOI 10.1016/j.cell.2020.03.053

    View details for PubMedID 32302568

  • 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

  • Leveraging Digital Data to Inform and Improve Quality Cancer Care. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Hernandez-Boussard, T., Blayney, D. W., Brooks, J. D. 2020


    BACKGROUND: Efficient capture of routine clinical care and patient outcomes are needed at a population-level, as is evidence on important treatment-related side effects and their effect on well-being and clinical outcomes. The increasing availability of electronic health records (EHRs) offers new opportunities to generate population-level patient-centered evidence on oncological care that can better guide treatment decisions and patient-valued care.METHODS: This study includes patients seeking care at an academic medical center, 2008-2018. Digital data sources are combined to address missingness, inaccuracy, and noise common to EHR data. Clinical concepts were identified and extracted from EHR unstructured data using natural language processing (NLP) and machine/deep learning techniques. All models are trained, tested, and validated on independent data samples using standard metrics.RESULTS: We provide use cases for using EHR data to assess guideline adherence and quality measurements among cancer patients. Pretreatment assessment was evaluated by guideline adherence and quality metrics for cancer staging metrics. Patient outcomes included treatment-related side-effects and patient-reported outcomes.CONCLUSIONS: Advanced technologies applied to EHRs present opportunities to advance population-level quality assessment, to learn from routinely collected clinical data for personalized treatment, and to augment epidemiological and population health studies. The effective use of digital data can inform patient-valued care, quality initiatives and policy guidelines.IMPACT: A comprehensive set of health data analyzed with advanced technologies results in a unique resource that facilitates wide-ranging, innovative, and impactful research on prostate cancer. This work demonstrates novel use of EHRs and technology to advance epidemiological studies and benefit oncological care.

    View details for DOI 10.1158/1055-9965.EPI-19-0873

    View details for PubMedID 32066619

  • ProsRegNet: A deep learning framework for registration of MRI and histopathology images of the prostate. Medical image analysis Shao, W. n., Banh, L. n., Kunder, C. A., Fan, R. E., Soerensen, S. J., Wang, J. B., Teslovich, N. C., Madhuripan, N. n., Jawahar, A. n., Ghanouni, P. n., Brooks, J. D., Sonn, G. A., Rusu, M. n. 2020; 68: 101919


    Magnetic resonance imaging (MRI) is an increasingly important tool for the diagnosis and treatment of prostate cancer. However, interpretation of MRI suffers from high inter-observer variability across radiologists, thereby contributing to missed clinically significant cancers, overdiagnosed low-risk cancers, and frequent false positives. Interpretation of MRI could be greatly improved by providing radiologists with an answer key that clearly shows cancer locations on MRI. Registration of histopathology images from patients who had radical prostatectomy to pre-operative MRI allows such mapping of ground truth cancer labels onto MRI. However, traditional MRI-histopathology registration approaches are computationally expensive and require careful choices of the cost function and registration hyperparameters. This paper presents ProsRegNet, a deep learning-based pipeline to accelerate and simplify MRI-histopathology image registration in prostate cancer. Our pipeline consists of image preprocessing, estimation of affine and deformable transformations by deep neural networks, and mapping cancer labels from histopathology images onto MRI using estimated transformations. We trained our neural network using MR and histopathology images of 99 patients from our internal cohort (Cohort 1) and evaluated its performance using 53 patients from three different cohorts (an additional 12 from Cohort 1 and 41 from two public cohorts). Results show that our deep learning pipeline has achieved more accurate registration results and is at least 20 times faster than a state-of-the-art registration algorithm. This important advance will provide radiologists with highly accurate prostate MRI answer keys, thereby facilitating improvements in the detection of prostate cancer on MRI. Our code is freely available at

    View details for DOI 10.1016/

    View details for PubMedID 33385701

  • 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

  • Early-Life Cardiorespiratory Fitness and Long-Term Risk of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Crump, C. n., Stattin, P. n., Brooks, J. D., Stocks, T. n., Sundquist, J. n., Sieh, W. n., Sundquist, K. n. 2020


    Adolescence is a period of rapid prostatic growth, yet is understudied for susceptibility for future risk of prostate cancer (PC). We examined cardiorespiratory fitness (CRF) in late adolescence in relation to long-term PC risk.A population-based cohort study was conducted of all 699,125 Swedish military conscripts during 1972-1985 (97-98% of 18-year-old men) in relation to risk of PC overall, aggressive PC, and PC mortality during 1998-2017 (ages 50-65 years). CRF was measured by maximal aerobic workload, and PC was ascertained using the National Prostate Cancer Register. Muscle strength was examined as a secondary predictor.In 38.8 million person-years of follow-up, 10,782 (1.5%) men were diagnosed with PC. Adjusting for sociodemographic factors, height, weight, and family history of PC, high CRF was associated with a slightly increased risk of any PC (highest vs. lowest quintile: incidence rate ratio [IRR], 1.10; 95% CI, 1.03-1.19; P=0.008), but was not significantly associated with aggressive PC (1.01; 0.85-1.21; P=0.90) nor PC mortality (1.24; 0.73-2.13; P=0.42). High muscle strength also was associated with a modestly increased risk of any PC (highest vs. lowest quintile: IRR, 1.14; 95% CI, 1.07-1.23; P<0.001), but not aggressive PC (0.88; 0.74-1.04; P=0.14) nor PC mortality (0.81; 0.48-1.37; P=0.43).High CRF or muscle strength in late adolescence was associated with slightly increased future risk of PC, possibly related to increased screening, but not risk of aggressive PC nor PC mortality.These findings illustrate the importance of distinguishing aggressive from indolent PC and assessing for potential detection bias.

    View details for DOI 10.1158/1055-9965.EPI-20-0535

    View details for PubMedID 32856610

  • Magnetic Resonance Imaging for the Detection of High-Grade Cancer in the Canary Prostate Active Surveillance Study. The Journal of urology Liss, M. A., Newcomb, L. F., Zheng, Y. n., Garcia, M. P., Filson, C. P., Boyer, H. n., Brooks, J. D., Carroll, P. R., Cooperberg, M. R., Ellis, W. J., Gleave, M. E., Martin, F. M., Morgan, T. n., Nelson, P. S., Wagner, A. A., Thompson, I. M., Lin, D. W. 2020: 101097JU0000000000001088


    We investigated the ability of prostate MRI to detect Gleason Grade Group (GG) ≥2 cancer in a standardized, multi-institutional active surveillance cohort.We evaluated men enrolled in Canary Prostate Active Surveillance Study (PASS) with GG<2 and who underwent a biopsy within 12 months of a multiparametric MRI. Our primary outcome was biopsy reclassification to GG2 or greater. We evaluated the performance of MRI PIRADS score and clinical factors. Multivariable logistic regression models were fit with MRI and clinical factors and used to perform receiver operating curve analyses.There were 361 participants with 395 prostate MRIs with a median follow-up of 4.1 (IQR: 2.0-7.6) years. Overall, 108/395 (27%) biopsies showed reclassification. Defining positive MRI as PIRADS 3-5, the NPV and PPV for detecting GG ≥2 cancer was 83% (95% CI: 76-90%) and 31% (95% CI: 26-37%), respectively. PIRADS was significantly associated with reclassification (PIRADS 5 versus 1 and 2: OR = 2.71; 95% CI: 1.21-6.17, p = 0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 versus 0.762). In 194 fusion biopsies, higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer found in the systematic cores.This study adds the largest cohort data to the body of literature for MRI in active surveillance, recommending systematic biopsy in patients with a negative MRI and the inclusion of systematic biopsy in patients with a positive MRI.

    View details for DOI 10.1097/JU.0000000000001088

    View details for PubMedID 32343189

  • Clinical Trial Outcomes in Urology: Assessing Early Discontinuation, Results Reporting, and Publication in ClinicalTrials.Gov Registrations 2007-2019. The Journal of urology Magnani, C. J., Steinberg, J. R., Harmange, C. I., Zhang, X. n., Driscoll, C. n., Bell, A. n., Larson, J. n., You, J. G., Weeks, B. T., Turner, B. E., Brooks, J. D. 2020: 101097JU0000000000001432


    Clinical trials require significant resources, but benefits are only realized after trial completion and dissemination of results. We comprehensively assessed early discontinuation, registry results reporting, and publication by trial sponsor and subspecialty in urology trials.We assessed trial registrations from 2007-2019 on and publication data from PubMed/MEDLINE. Associations between sponsor or subspecialty with early discontinuation were assessed using Cox Proportional Hazards and results reporting or publication with logistic regression at three years after completion.Of 8,636 trials, 3,541 (41.0%) were completed while 999 (11.6%) were discontinued. 26.9% of completed trials reported results, and 21.6% were published. Sponsors included Academic institutions (53.1%), Industry (37.1%), or US Government (9.8%). Academic-sponsored (adjusted hazard ratio (aHR):0.81, 95% Confidence Interval (CI):0.69-0.96, p=0.012) and Government-sponsored trials (aHR:0.62, 95%CI:0.49-0.78, p <0.001) were less likely than Industry to discontinue early. Government-sponsored trials were more likely to report (adjusted odds ratio (aOR):1.72, 95%CI:1.17-2.54, p=0.006) and publish (aOR:1.89, 95%CI:1.23-2.89, p=0.004). Academic-sponsored were less likely to report (aOR:0.65, CI:0.48-0.88, p=0.006) but more likely to publish (aOR:1.72, 95%CI:1.25-2.37, p <0.001). These outcomes were similar across subspecialties; however, endourology was more likely to discontinue early (aHR:2.00, 95%CI:1.53-2.95, p <0.001), general urology more likely to report results (aOR:1.54, 95%CI:1.13-2.11, p=0.006), and andrology less likely to publish (aOR:0.53, 95%CI:0.35-0.81, p=0.003).Sponsor type is significantly associated with trial completion and dissemination; Government-sponsored trials had the best performance while Industry and Academic-sponsored lagged in trial completion and results reporting, respectively. Subspecialty played a lesser role. Lack of dissemination remains a problem for urology trials.

    View details for DOI 10.1097/JU.0000000000001432

    View details for PubMedID 33079618

  • 17-Gene Genomic Prostate Score Test Results in the Canary Prostate Active Surveillance Study (PASS) Cohort. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Lin, D. W., Zheng, Y. n., McKenney, J. K., Brown, M. D., Lu, R. n., Crager, M. n., Boyer, H. n., Tretiakova, M. n., Brooks, J. D., Dash, A. n., Fabrizio, M. D., Gleave, M. E., Kolb, S. n., Liss, M. n., Morgan, T. M., Thompson, I. M., Wagner, A. A., Tsiatis, A. n., Pingitore, A. n., Nelson, P. S., Newcomb, L. F. 2020: JCO1902267


    The 17-gene Oncotype DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort.Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models.GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade (P = .48).In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

    View details for DOI 10.1200/JCO.19.02267

    View details for PubMedID 32130059

  • 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

  • Sudden PSA rise to ≥20 ng/ml and prostate cancer diagnosis in the United States: A population-based study. The Prostate Vilson, F. L., Li, S. n., Brooks, J. D., Eisenberg, M. L. 2020


    While prostate-specific antigen (PSA) screening protocols vary, many clinicians have anecdotes of screened men with low PSA levels that rise significantly and are associated with high-risk prostate cancer (PC). We sought to better understand the frequency of high-risk cases that appear suddenly in a screened population.We utilized data from a Commercial and Medicare advantage claims database to identify all US men ages 50 and above undergoing PSA screening who then had a sudden interval rise in PSA (e.g., PSA ≥ 20) and diagnosis of PC. We determined associations with age, race, screening intensity, and baseline PSA levels.In all, 526,120 men met entry criteria with an average age of 60.7 and follow-up of 5.6 years. As the baseline PSA increased, the rate of high-risk PC increased from 2/10,000 persons among men with the lowest baseline PSA (<1 ng/ml) to 14/10,000 person-years among men with a baseline PSA < 5 ng/ml. Moreover, as a man's age at baseline PSA increased, the rate of high-risk PC also increased. In contrast, the incidence of high-risk PC did not vary significantly by race/ethnicity. More screening PSAs and shorter intervals between PSA screenings were associated with a lower incidence of high-risk PC.The incidence of high-risk PC in a screened population is low (<0.1%). Our findings suggest that systematic screening cannot eliminate all PC deaths and provide an estimate for the risk of the rapid development of high-risk cancers that is comparable to that observed in active surveillance populations.

    View details for DOI 10.1002/pros.24075

    View details for PubMedID 32956488

  • Association between patient-initiated emails and overall 2-year survival in cancer patients undergoing chemotherapy: Evidence from the real-world setting. Cancer medicine Coquet, J. n., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. n. 2020


    Prior studies suggest email communication between patients and providers may improve patient engagement and health outcomes. The purpose of this study was to determine whether patient-initiated emails are associated with overall survival benefits among cancer patients undergoing chemotherapy.We identified patient-initiated emails through the patient portal in electronic health records (EHR) among 9900 cancer patients receiving chemotherapy between 2013 and 2018. Email users were defined as patients who sent at least one email 12 months before to 2 months after chemotherapy started. A propensity score-matched cohort analysis was carried out to reduce bias due to confounding (age, primary cancer type, gender, insurance payor, ethnicity, race, stage, income, Charlson score, county of residence). The cohort included 3223 email users and 3223 non-email users. The primary outcome was overall 2-year survival stratified by email use. Secondary outcomes included number of face-to-face visits, prescriptions, and telephone calls. The healthcare teams' response to emails and other forms of communication was also investigated. Finally, a quality measure related to chemotherapy-related inpatient and emergency department visits was evaluated.Overall 2-year survival was higher in patients who were email users, with an adjusted hazard ratio of 0.80 (95 CI 0.72-0.90; p < 0.001). Email users had higher rates of healthcare utilization, including face-to-face visits (63 vs. 50; p < 0.001), drug prescriptions (28 vs. 21; p < 0.001), and phone calls (18 vs. 16; p < 0.001). Clinical quality outcome measure of inpatient use was better among email users (p = 0.015).Patient-initiated emails are associated with a survival benefit among cancer patients receiving chemotherapy and may be a proxy for patient engagement. As value-based payment models emphasize incorporating the patients' voice into their care, email communications could serve as a novel source of patient-generated data.

    View details for DOI 10.1002/cam4.3483

    View details for PubMedID 32986931

  • Reply by Authors. The Journal of urology Schenk, J. M., Newcomb, L. F., Zheng, Y. n., Faino, A. V., Zhu, K. n., Nyame, Y. A., Brooks, J. D., Carroll, P. R., Cooperberg, M. R., Dash, A. n., Filson, C. P., Gleave, M. E., Liss, M. n., Martin, F. M., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Lin, D. W. 2020: 101097JU000000000000062102

    View details for DOI 10.1097/JU.0000000000000621.02

    View details for PubMedID 31951502

  • Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer. British journal of cancer Liu, S. n., Shen, M. n., Hsu, E. C., Zhang, C. A., Garcia-Marques, F. n., Nolley, R. n., Koul, K. n., Rice, M. A., Aslan, M. n., Pitteri, S. J., Massie, C. n., George, A. n., Brooks, J. D., Gnanapragasam, V. J., Stoyanova, T. n. 2020


    Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

    View details for DOI 10.1038/s41416-020-01200-0

    View details for PubMedID 33288843

  • Clinical Documentation to Predict Factors Associated with Urinary Incontinence Following Prostatectomy for Prostate Cancer RESEARCH AND REPORTS IN UROLOGY Li, K., Banerjee, I., Magnani, C. J., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. 2020; 12: 7–14
  • Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proceedings of the National Academy of Sciences of the United States of America Hsu, E. C., Rice, M. A., Bermudez, A. n., Marques, F. J., Aslan, M. n., Liu, S. n., Ghoochani, A. n., Zhang, C. A., Chen, Y. S., Zlitni, A. n., Kumar, S. n., Nolley, R. n., Habte, F. n., Shen, M. n., Koul, K. n., Peehl, D. M., Zoubeidi, A. n., Gambhir, S. S., Kunder, C. A., Pitteri, S. J., Brooks, J. D., Stoyanova, T. n. 2020


    Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

    View details for DOI 10.1073/pnas.1905384117

    View details for PubMedID 31932422

  • Identification of Diagnostic Metabolic Signatures in Clear Cell Renal Cell Carcinoma Using Mass Spectrometry Imaging. International journal of cancer Vijayalakshmi, K., Shankar, V., Bain, R. M., Nolley, R., Sonn, G. A., Kao, C., Zhao, H., Tibshirani, R., Zare, R. N., Brooks, J. D. 2019


    Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy (PN). However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In this study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI-MSI was conducted on fresh-frozen 23 normal-tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal-tumor pairs were analyzed. DESI-MSI provides two-dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids, and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log-ratio Lasso analysis. Lasso analysis with leave-one-patient-out cross validation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI-MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94% and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI-MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ijc.32843

    View details for PubMedID 31863456

  • Editorial Comment. The Journal of urology Brooks, J. D. 2019: 10109701JU00006126127033813

    View details for DOI 10.1097/01.JU.0000612612.70338.13

    View details for PubMedID 31674872

  • African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study (PASS). The Journal of urology Schenk, J. M., Newcomb, L. F., Zheng, Y., Faino, A. V., Zhu, K., Nyame, Y. A., Brooks, J. D., Carroll, P. R., Cooperberg, M. R., Dash, A., Filson, C. P., Gleave, M. E., Liss, M., Martin, F. M., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Lin, D. W. 2019: 101097JU0000000000000621


    OBJECTIVE: To evaluate whether African American (AA) men are at higher risk of reclassification in a large, prospective multi-institutional active surveillance (AS) cohort.METHODS: The Canary Prostate Active Surveillance Study (PASS) is a protocol-driven active surveillance cohort with pre-specified prostate-specific antigen (PSA) and surveillance biopsies regimen. Men included in this study had Gleason Grade Group 1 or 2 at diagnosis, < 5 years between diagnosis and enrollment, and had undergone ≥ 1 surveillance biopsy. Risk of reclassification, defined as an increase in Gleason score on subsequent biopsy, was compared between AA and CA using cox proportional hazards models. For the subset of men undergoing delayed prostatectomy, rates of adverse pathology, defined as pT3a or greater or Gleason Grade Group 3 or greater, were compared for AA and CA.RESULTS: Of 1,315 men, there were 89 (7%) AA and 1,226 (93%) CA. There were no differences in the rate of treatment for AA and CA. In multivariate models, AA race was not associated with the risk of reclassification (HR=1.16, 95% CI: 0.78-1.72). Among 441 men who had a prostatectomy after a period of AS, rate of adverse pathology was similar for AA and CA (46% vs 47%, p=0.99).CONCLUSIONS: Among men on AS who follow a standardized protocol of regular PSA and biopsy, AA men were not at increased risk of pathologic reclassification on AS or adverse pathology at prostatectomy. AS appears to be an appropriate management strategy for AA men with favorable risk prostate cancer.

    View details for DOI 10.1097/JU.0000000000000621

    View details for PubMedID 31651227

  • 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

  • Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS) PROSTATE CANCER AND PROSTATIC DISEASES Newcomb, L. F., Zheng, Y., Faino, A., Bianchi-Frias, D., Cooperberg, M. R., Brown, M. D., Brooks, J. D., Dash, A., Fabrizio, M. D., Gleave, M. E., Liss, M., Morgan, T. M., Thompson, I. M., Wagner, A. A., Carroll, P. R., Nelson, P. S., Lin, D. W. 2019; 22 (3): 438–45
  • Simultaneous transrectal ultrasound and photoacoustic human prostate imaging. Science translational medicine Kothapalli, S., Sonn, G. A., Choe, J. W., Nikoozadeh, A., Bhuyan, A., Park, K. K., Cristman, P., Fan, R., Moini, A., Lee, B. C., Wu, J., Carver, T. E., Trivedi, D., Shiiba, L., Steinberg, I., Huland, D. M., Rasmussen, M. F., Liao, J. C., Brooks, J. D., Khuri-Yakub, P. T., Gambhir, S. S. 2019; 11 (507)


    Imaging technologies that simultaneously provide anatomical, functional, and molecular information are emerging as an attractive choice for disease screening and management. Since the 1980s, transrectal ultrasound (TRUS) has been routinely used to visualize prostatic anatomy and guide needle biopsy, despite limited specificity. Photoacoustic imaging (PAI) provides functional and molecular information at ultrasonic resolution based on optical absorption. Combining the strengths of TRUS and PAI approaches, we report the development and bench-to-bedside translation of an integrated TRUS and photoacoustic (TRUSPA) device. TRUSPA uses a miniaturized capacitive micromachined ultrasonic transducer array for simultaneous imaging of anatomical and molecular optical contrasts [intrinsic: hemoglobin; extrinsic: intravenous indocyanine green (ICG)] of the human prostate. Hemoglobin absorption mapped vascularity of the prostate and surroundings, whereas ICG absorption enhanced the intraprostatic photoacoustic contrast. Future work using the TRUSPA device for biomarker-specific molecular imaging may enable a fundamentally new approach to prostate cancer diagnosis, prognostication, and therapeutic monitoring.

    View details for DOI 10.1126/scitranslmed.aav2169

    View details for PubMedID 31462508

  • Extracting Patient-Centered Outcomes from Clinical Notes in Electronic Health Records: Assessment of Urinary Incontinence After Radical Prostatectomy. EGEMS (Washington, DC) Gori, D., Banerjee, I., Chung, B. I., Ferrari, M., Rucci, P., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. 2019; 7 (1): 43


    Objective: To assess documentation of urinary incontinence (UI) in prostatectomy patients using unstructured clinical notes from Electronic Health Records (EHRs).Methods: We developed a weakly-supervised natural language processing tool to extract assessments, as recorded in unstructured text notes, of UI before and after radical prostatectomy in a single academic practice across multiple clinicians. Validation was carried out using a subset of patients who completed EPIC-26 surveys before and after surgery. The prevalence of UI as assessed by EHR and EPIC-26 was compared using repeated-measures ANOVA. The agreement of reported UI between EHR and EPIC-26 was evaluated using Cohen's Kappa coefficient.Results: A total of 4870 patients and 716 surveys were included. Preoperative prevalence of UI was 12.7 percent. Postoperative prevalence was 71.8 percent at 3 months, 50.2 percent at 6 months and 34.4 and 41.8 at 12 and 24 months, respectively. Similar rates were recorded by physicians in the EHR, particularly for early follow-up. For all time points, the agreement between EPIC-26 and the EHR was moderate (all p < 0.001) and ranged from 86.7 percent agreement at baseline (Kappa = 0.48) to 76.4 percent agreement at 24 months postoperative (Kappa = 0.047).Conclusions: We have developed a tool to assess documentation of UI after prostatectomy using EHR clinical notes. Our results suggest such a tool can facilitate unbiased measurement of important PCOs using real-word data, which are routinely recorded in EHR unstructured clinician notes. Integrating PCO information into clinical decision support can help guide shared treatment decisions and promote patient-valued care.

    View details for DOI 10.5334/egems.297

    View details for PubMedID 31497615

  • miR-22 Regulates Invasion, Gene Expression and Predicts Overall Survival in Patients with Clear Cell Renal Cell Carcinoma. Kidney cancer Gong, X., Zhao, H., Saar, M., Peehl, D. M., Brooks, J. D. 2019; 3 (2): 119–32


    Background: Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC.Objective: Identify prognostic miRNAs and determine the role of miR-22 in ccRCC.Methods: Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary ccRCC cells and Matrigel invasion assay was performed to assess the effects of miR-22 overexpression on cell invasion.Results: Hierarchical clustering analysis using 2,621 prognostic genes previously identified by our group demonstrated that ccRCC patients with longer overall survival expressed lower levels of genes promoting proliferation or immune responses, while better maintaining gene expression associated with cortical differentiation and cell adhesion. Targets of 26 miRNAs were significantly enriched in the 2,621 prognostic genes and these miRNAs were prognostic by themselves. MiR-22 was associated with poor overall survival in the TCGA dataset. Overexpression of miR-22 promoted invasion of primary ccRCC cells in vitro and modulated transcriptional programs implicated in cancer progression including DNA repair, cell proliferation and invasion.Conclusions: Our results suggest that ccRCCs with differential clinical outcomes have distinct transcriptomes for which miRNAs could serve as master regulators. MiR-22, as a master regulator, promotes ccRCC progression at least in part by enhancing cell invasion.

    View details for DOI 10.3233/KCA-190051

    View details for PubMedID 31763513

  • Early detection of unilateral ureteral obstruction by desorption electrospray ionization mass spectrometry. Scientific reports Banerjee, S., Wong, A. C., Yan, X., Wu, B., Zhao, H., Tibshirani, R. J., Zare, R. N., Brooks, J. D. 2019; 9 (1): 11007


    Desorption electrospray ionization mass spectrometry (DESI-MS) is an emerging analytical tool for rapid in situ assessment of metabolomic profiles on tissue sections without tissue pretreatment or labeling. We applied DESI-MS to identify candidate metabolic biomarkers associated with kidney injury at the early stage. DESI-MS was performed on sections of kidneys from 80 mice over a time course following unilateral ureteral obstruction (UUO) and compared to sham controls. A predictive model of renal damage was constructed using the LASSO (least absolute shrinkage and selection operator) method. Levels of lipid and small metabolites were significantly altered and glycerophospholipids comprised a significant fraction of altered species. These changes correlate with altered expression of lipid metabolic genes, with most genes showing decreased expression. However, rapid upregulation of PG(22:6/22:6) level appeared to be a hitherto unknown feature of the metabolic shift observed in UUO. Using LASSO and SAM (significance analysis of microarrays), we identified a set of well-measured metabolites that accurately predicted UUO-induced renal damage that was detectable by 12h after UUO, prior to apparent histological changes. Thus, DESI-MS could serve as a useful adjunct to histology in identifying renal damage and demonstrates early and broad changes in membrane associated lipids.

    View details for DOI 10.1038/s41598-019-47396-x

    View details for PubMedID 31358807

  • Predictive value of AZGP1 following radical prostatectomy for prostate cancer: a cohort study and meta-analysis. Journal of clinical pathology Kristensen, G., Berg, K. D., Toft, B. G., Stroomberg, H. V., Nolley, R., Brooks, J. D., Brasso, K., Roder, M. A. 2019


    AIMS: Zinc-alpha 2-glycoprotein (AZGP1) is a promising tissue biomarker to predict outcomes in men undergoing treatment for localised prostate cancer (PCa). We aimed to examine the association between AZGP1 expression and the endpoints: risk of biochemical failure (BF), initiating castration-based treatment, developing castration-resistant PCa (CRPC) and PCa-specific mortality following radical prostatectomy (RP).METHODS: The study included a prospective cohort of 302 patients who underwent RP for PCa from 2002 to 2005. AZGP1 expression was analysed using immunohistochemistry on tissue microarray RP specimens and was scored semiquantitively as low or high expression. Risk of all endpoints was analysed using stratified cumulative incidences and cause-specific Cox regression, and validated with receiver operating curves, calibration and discrimination in competing-risk analyses. A meta-analysis was performed including previous studies investigating AZGP1 expression and risk of BF following RP.RESULTS: Median time of follow-up was 14.0 years. The cumulative incidence of all endpoints was significantly higher in patients with low AZGP1 expression compared with patients with high AZGP1 expression (p<0.001). In a multivariate analysis, low AZGP1 expression increases the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). Validation showed a low risk of prediction error and a high model performance for all endpoints. In a meta-analysis, low AZGP1 was associated with BF (HR 1.7; 95% CI 1.2 to 2.5).CONCLUSIONS: Low AZGP1 expression is associated with the risk of aggressive time-dependent outcomes in men undergoing RP for localised PCa.

    View details for DOI 10.1136/jclinpath-2019-205940

    View details for PubMedID 31331953

  • 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
  • Comparison of orthogonal NLP methods for clinical phenotyping and assessment of bone scan utilization among prostate cancer patients JOURNAL OF BIOMEDICAL INFORMATICS Coquet, J., Bozkurt, S., Kan, K. M., Ferrari, M. K., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. 2019; 94
  • Weakly supervised natural language processing for assessing patient-centered outcome following prostate cancer treatment JAMIA OPEN Banerjee, I., Li, K., Seneviratne, M., Ferrari, M., Seto, T., Brooks, J. D., Rubin, D. L., Hernandez-Boussard, T. 2019; 2 (1): 150-159
  • Distribution of Global Health Measures From Routinely Collected PROMIS Surveys in Patients With Breast Cancer or Prostate Cancer CANCER Seneviratne, M. G., Bozkurt, S., Patel, M., Seto, T., Brooks, J. D., Blayney, D. W., Kurian, A. W., Hernandez-Boussard, T. 2019; 125 (6): 943–51

    View details for DOI 10.1002/cncr.31895

    View details for Web of Science ID 000461693200015

  • Performance of the 17-gene genomic prostate score test in men with prostate cancer (PCa) managed with active surveillance (AS): Results from the Canary Prostate Active Surveillance Study (PASS). Lin, D. W., Zheng, Y., McKenney, J., Brown, M., Lu, R., Crager, M., Boyer, H., Brooks, J. D., Dash, A., Fabrizio, M., Gleave, M., Liss, M. A., Morgan, T., Thompson, I. M., Wagner, A., Tsiatis, A., Pingatore, A., Lawrence, H., Nelson, P. S., Newcomb, L. F. AMER SOC CLINICAL ONCOLOGY. 2019
  • Utilization of Prostate Cancer Quality Metrics for Research and Quality Improvement: A Structured Review JOINT COMMISSION JOURNAL ON QUALITY AND PATIENT SAFETY Gori, D., Dulal, R., Blayney, D. W., Brooks, J. D., Fantini, M. P., McDonald, K. M., Hernandez-Boussard, T. 2019; 45 (3): 217–26


    The shift toward value-based care in the United States emphasizes the role of quality measures in payment models. Many diseases, such as prostate cancer, have a proliferation of quality measures, resulting in resource burden and physician burnout. This study aimed to identify and summarize proposed prostate cancer quality measures and describe their frequency and use in peer-reviewed literature.The PubMed database was used to identify quality measures relevant to prostate cancer care, and included articles in English through April 2018. A gray literature search for other documents was also conducted. After the selection process of the pertinent articles, measure characteristics were abstracted, and uses were summarized for the 10 most frequently utilized measures in the literature.A total of 26 articles were identified for review. Of the 71 proposed prostate cancer quality measures, only 47 were used, and less than 10% of these were endorsed by the National Quality Forum. Process measures were most frequently reported (84.5%). Only 6 outcome measures (8.5%) were proposed-none of which were among the most frequently utilized.Although a high number of proposed prostate cancer quality measures are reported in the literature, few were assessed, and the majority of these were non-endorsed process measures. Process measures were most commonly assessed; outcome measures were rarely evaluated. In a step to close the quality chasm, a "top 5" core set of quality measures for prostate cancer care, including structure, process, and outcomes measures, is suggested. Future studies should consider this comprehensive set of quality measures.

    View details for DOI 10.1016/j.jcjq.2018.06.004

    View details for Web of Science ID 000461797400013

    View details for PubMedID 30236510

  • 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

  • Elevated urinary lipocalin-2, interleukin-6 and monocyte chemoattractant protein-1 levels in children with congenital ureteropelvic junction obstruction JOURNAL OF PEDIATRIC UROLOGY Yu, L., Zhou, L., Li, Q., Li, S., Luo, X., Zhang, C., Wu, B., Brooks, J. D., Sun, H. 2019; 15 (1)
  • 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

  • Is it possible to automatically assess pretreatment digital rectal examination documentation using natural language processing? A single-centre retrospective study. BMJ open Bozkurt, S. n., Kan, K. M., Ferrari, M. K., Rubin, D. L., Blayney, D. W., Hernandez-Boussard, T. n., Brooks, J. D. 2019; 9 (7): e027182


    To develop and test a method for automatic assessment of a quality metric, provider-documented pretreatment digital rectal examination (DRE), using the outputs of a natural language processing (NLP) framework.An electronic health records (EHR)-based prostate cancer data warehouse was used to identify patients and associated clinical notes from 1 January 2005 to 31 December 2017. Using a previously developed natural language processing pipeline, we classified DRE assessment as documented (currently or historically performed), deferred (or suggested as a future examination) and refused.We investigated the quality metric performance, documentation 6 months before treatment and identified patient and clinical factors associated with metric performance.The cohort included 7215 patients with prostate cancer and 426 227 unique clinical notes associated with pretreatment encounters. DREs of 5958 (82.6%) patients were documented and 1257 (17.4%) of patients did not have a DRE documented in the EHR. A total of 3742 (51.9%) patient DREs were documented within 6 months prior to treatment, meeting the quality metric. Patients with private insurance had a higher rate of DRE 6 months prior to starting treatment as compared with Medicaid-based or Medicare-based payors (77.3%vs69.5%, p=0.001). Patients undergoing chemotherapy, radiation therapy or surgery as the first line of treatment were more likely to have a documented DRE 6 months prior to treatment.EHRs contain valuable unstructured information and with NLP, it is feasible to accurately and efficiently identify quality metrics with current documentation clinician workflow.

    View details for DOI 10.1136/bmjopen-2018-027182

    View details for PubMedID 31324681

  • Continued 5 alpha-Reductase Inhibitor Use after Prostate Cancer Diagnosis and the Risk of Reclassification and Adverse Pathological Outcomes in the PASS JOURNAL OF UROLOGY Kearns, J. T., Faino, A., Schenk, J. M., Newcomb, L. F., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Fabrizio, M., Gleave, M. E., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A., Zheng, Y., Lin, D. W. 2019; 201 (1): 106–11


    Outcomes in patients who enroll in active surveillance programs for prostate cancer while receiving 5α-reductase inhibitors have not been well defined. We sought to determine the association of 5α-reductase inhibitor use with the risk of reclassification in the PASS (Canary Prostate Active Surveillance Study).Participants in the multicenter PASS were enrolled between 2008 and 2016. Study inclusion criteria were current or never 5α-reductase inhibitors use, Gleason score 3 + 4 or less prostate cancer at diagnosis, less than a 34% core involvement ratio at diagnosis and 1 or more surveillance biopsies. Included in study were 1,009 men, including 107 on 5α-reductase inhibitors and 902 who had never received 5α-reductase inhibitors. Reclassification was defined as increase in the Gleason score and/or an increase to 34% or greater in the ratio of biopsy cores positive for cancer. Adverse pathology at prostatectomy was defined as Gleason 4 + 3 or greater and/or nonorgan confined disease (pT3 or N1).On multivariable analysis there was no difference in reclassification between men who had received and those who had never received 5α-reductase inhibitors (HR 0.81, p = 0.31). Patients who had received 5α-reductase inhibitors were less likely to undergo radical prostatectomy (8% vs 18%, p = 0.01) or any definitive treatment (19% vs 24%, p = 0.04). In the 167 participants who underwent radical prostatectomy there was no suggestion of a difference in the rate of adverse pathology findings at prostatectomy between 5α-reductase inhibitor users and nonusers.Continued 5α-reductase inhibitor use after an initial diagnosis of prostate cancer was not associated with the risk of reclassification on active surveillance in men in the PASS cohort.

    View details for PubMedID 30076904

  • Framework for the co-registration of MRI and Histology Images in Prostate Cancer Patients with Radical Prostatectomy Rusu, M., Kunder, C., Fan, R., Ghanouni, P., West, R., Sonn, G., Brooks, J., Angelini, E. D., Landman, B. A. SPIE-INT SOC OPTICAL ENGINEERING. 2019

    View details for DOI 10.1117/12.2513099

    View details for Web of Science ID 000483012700057

  • Improved detection of prostate cancer using a magneto-nanosensor assay for serum circulating autoantibodies. PloS one Xu, L., Lee, J., Hao, S., Ling, X. B., Brooks, J. D., Wang, S. X., Gambhir, S. S. 2019; 14 (8): e0221051


    PURPOSE: To develop a magneto-nanosensor (MNS) based multiplex assay to measure protein and autoantibody biomarkers from human serum for prostate cancer (CaP) diagnosis.MATERIALS AND METHODS: A 4-panel MNS autoantibody assay and a MNS protein assay were developed and optimized in our labs. Using these assays, serum concentration of six biomarkers including prostate-specific antigen (PSA) protein, free/total PSA ratio, as well as four autoantibodies against Parkinson disease 7 (PARK7), TAR DNA-binding protein 43 (TARDBP), Talin 1 (TLN1), and Caldesmon 1 (CALD1) and were analyzed. Human serum samples from 99 patients (50 with non-cancer and 49 with clinically localized CaP) were evaluated.RESULTS: The MNS assay showed excellent performance characteristics and no cross-reactivity. All autoantibody assays showed a statistically significant difference between CaP and non-cancer samples except for PARK7. The most significant difference was the combination of the four autoantibodies as a panel in addition to the free/total PSA ratio. This combination had the highest area under the curve (AUC)- 0.916 in ROC analysis.CONCLUSIONS: Our results suggest that this autoantibody panel along with PSA and free PSA have potential to segregate patients without cancer from those with prostate cancer with higher sensitivity and specificity than PSA alone.

    View details for DOI 10.1371/journal.pone.0221051

    View details for PubMedID 31404106

  • Machine Learning Approaches for Extracting Stage from Pathology Reports in Prostate Cancer. Studies in health technology and informatics Lenain, R. n., Seneviratne, M. G., Bozkurt, S. n., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. n. 2019; 264: 1522–23


    Clinical and pathological stage are defining parameters in oncology, which direct a patient's treatment options and prognosis. Pathology reports contain a wealth of staging information that is not stored in structured form in most electronic health records (EHRs). Therefore, we evaluated three supervised machine learning methods (Support Vector Machine, Decision Trees, Gradient Boosting) to classify free-text pathology reports for prostate cancer into T, N and M stage groups.

    View details for DOI 10.3233/SHTI190515

    View details for PubMedID 31438212

  • Weakly supervised natural language processing for assessing patient-centered outcome following prostate cancer treatment. JAMIA open Banerjee, I. n., Li, K. n., Seneviratne, M. n., Ferrari, M. n., Seto, T. n., Brooks, J. D., Rubin, D. L., Hemandez-Boussard, T. n. 2019; 2 (1): 150–59


    The population-based assessment of patient-centered outcomes (PCOs) has been limited by the efficient and accurate collection of these data. Natural language processing (NLP) pipelines can determine whether a clinical note within an electronic medical record contains evidence on these data. We present and demonstrate the accuracy of an NLP pipeline that targets to assess the presence, absence, or risk discussion of two important PCOs following prostate cancer treatment: urinary incontinence (UI) and bowel dysfunction (BD).We propose a weakly supervised NLP approach which annotates electronic medical record clinical notes without requiring manual chart review. A weighted function of neural word embedding was used to create a sentence-level vector representation of relevant expressions extracted from the clinical notes. Sentence vectors were used as input for a multinomial logistic model, with output being either presence, absence or risk discussion of UI/BD. The classifier was trained based on automated sentence annotation depending only on domain-specific dictionaries (weak supervision).The model achieved an average F1 score of 0.86 for the sentence-level, three-tier classification task (presence/absence/risk) in both UI and BD. The model also outperformed a pre-existing rule-based model for note-level annotation of UI with significant margin.We demonstrate a machine learning method to categorize clinical notes based on important PCOs that trains a classifier on sentence vector representations labeled with a domain-specific dictionary, which eliminates the need for manual engineering of linguistic rules or manual chart review for extracting the PCOs. The weakly supervised NLP pipeline showed promising sensitivity and specificity for identifying important PCOs in unstructured clinical text notes compared to rule-based algorithms.

    View details for PubMedID 31032481

  • Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis. JCI insight Middleton, L. W., Shen, Z. n., Varma, S. n., Pollack, A. S., Gong, X. n., Zhu, S. n., Zhu, C. n., Foley, J. W., Vennam, S. n., Sweeney, R. T., Tu, K. n., Biscocho, J. n., Eminaga, O. n., Nolley, R. n., Tibshirani, R. n., Brooks, J. D., West, R. B., Pollack, J. R. 2019; 5


    Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain new insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules BMP5 and CXCL13 were enriched in BPH while estrogen regulated pathways were depleted. Notably, BMP5 addition to cultured prostatic myofibroblasts altered their expression profile towards a BPH profile that included the BPH stromal signature. RNAseq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, whilst depletion of neuroendocrine cells and an estrogen receptor (ESR1)-positive fibroblast cell type residing near epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants (SNVs) in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.

    View details for DOI 10.1172/jci.insight.129749

    View details for PubMedID 31094703

  • PSA Testing Use and Prostate Cancer Diagnostic Stage After the 2012 U.S. Preventive Services Task Force Guideline Changes. Journal of the National Comprehensive Cancer Network : JNCCN Magnani, C. J., Li, K. n., Seto, T. n., McDonald, K. M., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. n. 2019; 17 (7): 795–803


    Most patients with prostate cancer are diagnosed with low-grade, localized disease and may not require definitive treatment. In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against prostate cancer screening to address overdetection and overtreatment. This study sought to determine the effect of guideline changes on prostate-specific antigen (PSA) screening and initial diagnostic stage for prostate cancer.A difference-in-differences analysis was conducted to compare changes in PSA screening (exposure) relative to cholesterol testing (control) after the 2012 USPSTF guideline changes, and chi-square test was used to determine whether there was a subsequent decrease in early-stage, low-risk prostate cancer diagnoses. Data were derived from a tertiary academic medical center's electronic health records, a national commercial insurance database (OptumLabs), and the SEER database for men aged ≥35 years before (2008-2011) and after (2013-2016) the guideline changes.In both the academic center and insurance databases, PSA testing significantly decreased for all men compared with the control. The greatest decrease was among men aged 55 to 74 years at the academic center and among those aged ≥75 years in the commercial database. The proportion of early-stage prostate cancer diagnoses (

    View details for DOI 10.6004/jnccn.2018.7274

    View details for PubMedID 31319390

  • Analysis of Released N-Glycans and Glycopeptide Profiling of Prostate Cancer Tissue Totten, S. M., Bermudez, A., Guerrero, A., Yan, J., Jones, A., Brooks, J. D., Pitteri, S. J. OXFORD UNIV PRESS INC. 2018: 1056
  • 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

  • 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

  • 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

  • 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 2018; 74: 146-54 EUROPEAN UROLOGY Leppert, J. T., Brooks, J. D. 2018; 74 (5): E110-E111
  • Undertreatment of High-Risk Localized Prostate Cancer in the California Latino Population JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Lichtensztajn, D. Y., Leppert, J. T., Brooks, J. D., Shah, S. A., Sieh, W., Chung, B., Gomez, S. L., Cheng, I. 2018; 16 (11): 1353-1360
  • Elevated urinary lipocalin-2, interleukin-6 and monocyte chemoattractant protein-1 levels in children with congenital ureteropelvic junction obstruction. Journal of pediatric urology Yu, L., Zhou, L., Li, Q., Li, S., Luo, X., Zhang, C., Wu, B., Brooks, J. D., Sun, H. 2018


    INTRODUCTION: In children with congenital ureteropelvic junction obstruction (UPJO), urinary biomarkers could assist in the diagnosis of renal damage or kidneys at risk for damage. Urinary levels of interleukin-6 (IL6), neutrophil gelatinase-associated lipocalin (LCN2), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-beta1 (TGFB1) proteins have been correlated with renal damage in several contexts. Whether they might be useful non-invasive biomarkers of obstructive nephropathy due to unilateral and bilateral congenital UPJO was tested.PATIENTS AND METHODS: A cohort study was performed at People's Hospital of Xinjiang Uygur Autonomous Region in China. Bladder urine samples from 17 patients with UPJO were obtained before surgical intervention and from 17 healthy age-matched controls. Levels of IL6, LCN2, MCP1, and TGFB1 were determined by enzyme-linked immunosorbent assay and normalized to urinary creatinine levels.RESULTS: Levels of urinary LCN2, MCP1, and IL6 were significantly elevated in the urine from individuals with UPJO compared with controls (P=0.0003, P=0.0003, and P=0.0073, respectively). Children with bilateral UPJO (n=5) showed significantly higher levels of IL6, LCN2, and MCP1 protein in their urine compared with controls or those with unilateral UPJO (n=12; P=0.007, P<0.0001, and P=0.0002, respectively). Combining LCN2 and MCP1 slightly improved biomarker performance.DISCUSSION: Urinary biomarkers could be used in obstructed patients to monitor for renal damage and might find particular utility on patients with bilateral UPJO. Monitoring urinary biomarkers and imaging features in untreated patients could provide insights into the natural history of renal damage due to obstruction and will be necessary to test their performance characteristics as biomarkers.CONCLUSIONS: Urinary levels of LCN2 and MCP1 protein are promising biomarkers monitoring children with UPJO, particularly in those with bilateral disease.

    View details for PubMedID 30420258

  • James D. Brooks: prostate cancer screening awaits optimization to reduce inappropriate treatment TRANSLATIONAL ANDROLOGY AND UROLOGY Li, B., Brooks, J. D. 2018; 7 (5): 903–6
  • The Research Implications of Prostate Specific Antigen Registry Errors: Data from the Veterans Health Administration 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; 200 (3): 541–47
  • Methionine aminopeptidase II (MetAP2) activated in situ self-assembly of small-molecule probes for imaging prostate cancer. Xie, J., Rice, M., Cheng, Y., Song, G., Kunder, C., Brooks, J. D., Stoyanova, T., Rao, J. AMER ASSOC CANCER RESEARCH. 2018: 115–16
  • Defining new drivers of castration- resistant prostate cancer Hsu, E., Rice, M., Nolley, R., Bermudez, A., Huang, J., Peehl, D., Kunder, C., Pitteri, S., Brooks, J., Stoyanova, T. AMER ASSOC CANCER RESEARCH. 2018: 90
  • The Role of DNA Methylation in Renal Cell Carcinoma MOLECULAR DIAGNOSIS & THERAPY Lasseigne, B. N., Brooks, J. D. 2018; 22 (4): 431–42


    Renal cell carcinoma (RCC) is the most common kidney cancer and includes several molecular and histological subtypes with different clinical characteristics. While survival rates are high if RCC is diagnosed when still confined to the kidney and treated definitively, there are no specific diagnostic screening tests available and symptoms are rare in early stages of the disease. Management of advanced RCC has changed significantly with the advent of targeted therapies, yet survival is usually increased by months due to acquired resistance to these therapies. DNA methylation, the covalent addition of a methyl group to a cytosine, is essential for normal development and transcriptional regulation, but becomes altered commonly in cancer. These alterations result in broad transcriptional changes, including in tumor suppressor genes. Because DNA methylation is one of the earliest molecular changes in cancer and is both widespread and stable, its role in cancer biology, including RCC, has been extensively studied. In this review, we examine the role of DNA methylation in RCC disease etiology and progression, the preclinical use of DNA methylation alterations as diagnostic, prognostic and predictive biomarkers, and the potential for DNA methylation-directed therapies.

    View details for PubMedID 29777398

  • Refined Analysis of Prostate-specific Antigen Kinetics to Predict Prostate Cancer Active Surveillance Outcomes EUROPEAN UROLOGY Cooperberg, M. R., Brooks, J. D., Faino, A., Newcomb, L. F., Kearns, J. T., Carroll, P. R., Dash, A., Etzioni, R., Fabrizio, M. D., Gleave, M. E., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Lin, D. W., Zheng, Y. 2018; 74 (2): 211–17


    For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial.To develop prediction methods for utilizing serial PSA and evaluate frequency of collection.Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels.The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models.A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 [95% confidence interval 1.2-2.1, p<0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions.PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators.In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome.

    View details for PubMedID 29433975

  • Trends in Incidence and 5-Year Mortality in Men With Newly Diagnosed, Metastatic Prostate Cancer-A Population-Based Analysis of 2 National Cohorts CANCER Helgstrand, J. T., Roder, M. A., Klemann, N., Toft, B. G., Lichtensztajn, D. Y., Brooks, J. D., Brasso, K., Vainer, B., Iversen, P. 2018; 124 (14): 2931–38


    Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa.Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis.Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort.Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.

    View details for PubMedID 29723398

  • 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

  • N-linked glycosylation site mapping in prostate cancer and matched normal tissue: Defining glycan microheterogeneity Totten, S., Tanimoto, C., Bermudez, A., Hembree, A., Brooks, J. D., Pitteri, S. J. AMER ASSOC CANCER RESEARCH. 2018
  • Identification of transcripts associated with renal damage due to ureteral obstruction as candidate urinary biomarkers AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Wu, B., Gong, X., Kennedy, W. A., Brooks, J. D. 2018; 315 (1): F16-F26
  • Architecture and Implementation of a Clinical Research Data Warehouse for Prostate Cancer. EGEMS (Washington, DC) Seneviratne, M. G., Seto, T., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. 2018; 6 (1): 13


    Background: Electronic health record (EHR) based research in oncology can be limited by missing data and a lack of structured data elements. Clinical research data warehouses for specific cancer types can enable the creation of more robust research cohorts.Methods: We linked data from the Stanford University EHR with the Stanford Cancer Institute Research Database (SCIRDB) and the California Cancer Registry (CCR) to create a research data warehouse for prostate cancer. The database was supplemented with information from clinical trials, natural language processing of clinical notes and surveys on patient-reported outcomes.Results: 11,898 unique prostate cancer patients were identified in the Stanford EHR, of which 3,936 were matched to the Stanford cancer registry and 6153 in the CCR. 7158 patients with EHR data and at least one of SCIRDB and CCR data were initially included in the warehouse.Conclusions: A disease-specific clinical research data warehouse combining multiple data sources can facilitate secondary data use and enhance observational research in oncology.

    View details for PubMedID 30094285

  • Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study EUROPEAN UROLOGY Kearns, J. T., Faino, A. V., Newcomb, L. F., Brooks, J. D., Carroll, P. R., Dash, A., Ellis, W. J., Fabrizio, M., Gleave, M. E., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Zheng, Y., Lin, D. W. 2018; 73 (5): 706–12


    Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident.To define the association between negative surveillance PNBs and risk of reclassification on AS.All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3+4 prostate cancer and <34% core involvement ratio at diagnosis. Men were prescribed surveillance PNBs at 12 and 24 mo after diagnosis and then every 24 mo.Reclassification was defined as an increase in Gleason grade and/or an increase in the ratio of biopsy cores to cancer to ≥34%. PNB outcomes were defined as follows: (1) no cancer on biopsy, (2) cancer without reclassification, or (3) reclassification. Kaplan-Meier and Cox proportional hazard models were performed to assess the risk of reclassification.A total of 657 men met inclusion criteria. On first surveillance PNB, 214 (32%) had no cancer, 282 (43%) had cancer but no reclassification, and 161 (25%) reclassified. Among those who did not reclassify, 313 had a second PNB. On second PNB, 120 (38%) had no cancer, 139 (44%) had cancer but no reclassification, and 54 (17%) reclassified. In a multivariable analysis, significant predictors of decreased future reclassification after the first PNB were no cancer on PNB (hazard ratio [HR]=0.50, p=0.008), lower serum prostate-specific antigen, larger prostate size, and lower body mass index. A finding of no cancer on the second PNB was also associated with significantly decreased future reclassification in a multivariable analysis (HR=0.15, p=0.003), regardless of the first PNB result. The major limitation of this study is a relatively small number of patients with long-term follow-up.Men who have a surveillance PNB with no evidence of cancer are significantly less likely to reclassify on AS in the PASS cohort. These findings have implications for tailoring AS protocols.Men on active surveillance for prostate cancer who have a biopsy showing no cancer are at a decreased risk of having worse disease in the future. This may have an impact on how frequently biopsies are required to be performed in the future.

    View details for PubMedID 29433973

  • Male infertility is associated with altered treatment course of men with cancer ANDROLOGY Eminaga, O., Li, S., Baker, L. C., Brooks, J. D., Eisenberg, M. L. 2018; 6 (3): 408-413

    View details for DOI 10.1111/andr.12472

    View details for Web of Science ID 000434041100003

  • The CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy EUROPEAN UROLOGY FOCUS Roder, M., Berg, K., Loft, M., Thomsen, F., Ferrari, M., Kurbegovic, S., Rytgaard, H., Gruschy, L., Brasso, K., Gerds, T., Kjaer, A., Brooks, J. D., Iversen, P. 2018; 4 (3): 360-368
  • 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 CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy. European urology focus Roder, M. A., Berg, K. D., Loft, M. D., Thomsen, F. B., Ferrari, M., Kurbegovic, S., Rytgaard, H. C., Gruschy, L., Brasso, K., Gerds, T. A., Kjar, A., Brooks, J. D., Iversen, P. 2018; 4 (3): 360–68


    BACKGROUND: It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery.OBJECTIVE: To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death.DESIGN, SETTING, AND PARTICIPANTS: A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores.RESULTS AND LIMITATIONS: The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R-, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation.CONCLUSIONS: This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app.PATIENT SUMMARY: We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.

    View details for PubMedID 28753827

  • Identification of transcripts associated with renal damage due to ureteral obstruction as candidate urinary biomarkers. American journal of physiology. Renal physiology Wu, B., Gong, X., Kennedy, W. A., Brooks, J. D. 2018


    Renal obstruction is a common cause of renal failure in adults and children and is suspected when hydronephrosis is detected on imaging. Since not all cases of hydronephrosis are associated with renal damage, biomarkers are needed to guide intervention to relieve obstruction. We performed gene expression profiling on the kidneys from adult mice over a detailed time course after obstruction and compared these data to a neonatal model of bilateral high grade obstruction induced by conditional deletion of the calcineurin SS1 (Cnb1) gene. Having identified a set of 143 transcripts modulated in both adult and neonatal obstruction, we tested their expression in a model of short-term obstruction (1 day), where renal damage is transient and reversible, and long-term obstruction (5 days), where significant renal damage is permanent. A significantly number of transcripts increased early after obstruction, and later normalized, while 26 transcripts remained elevated 10 and 28 days after relief of 5 days of ureteral obstruction. Using QPCR, elevated levels of several of these candidate RNA biomarkers of renal damage were detected in urine from obstructed mice. In addition, several of these candidate RNA biomarkers of damage due to obstruction were detectable in catheterized urine samples from children undergoing surgery for ureteropelvic junction obstruction (UPJO). Measurement of urinary transcripts modulated in response to renal obstruction could serve as biomarkers of renal damage with important clinical applications.

    View details for PubMedID 29488389

  • Practice-based evidence for factors associated with urinary incontinence following prostate cancer care. Li, K., Magnani, C. J., Bozkurt, S., Seto, T., Blayney, D. W., Brooks, J. D., Hernandez-Boussard, T. AMER SOC CLINICAL ONCOLOGY. 2018
  • When can active surveillance be less active? Prediction of long-term nonreclassification for men with low-risk prostate cancer. Cooperberg, M. R., Faino, A. V., Newcomb, L. F., Carroll, P., Kearns, J. T., Brooks, J. D., Fabrizio, M., Gleave, M., Morgan, T., Dash, A., Nelson, P., Thompson, I., Wagner, A., Lin, D. W., Zheng, Y. AMER SOC CLINICAL ONCOLOGY. 2018
  • Male infertility is associated with altered treatment course of men with cancer. Andrology Eminaga, O., Li, S., Baker, L. C., Brooks, J. D., Eisenberg, M. L. 2018


    This study aims to evaluate whether cancer treatments differ in infertile men compared to men who have undergone vasectomy and age-matched controls. We analyzed subjects from the Truven Health MarketScan Claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups included vasectomized men and an age-matched cohort who were not infertile and had not undergone vasectomy. We considered cancer types previously associated with infertility that were diagnosed after the diagnosis of infertility. The treatment regimens were determined based on the presence of claims with CPT codes for chemotherapy (CTX), radiation (RTX) or surgical treatment (ST) for each entity in all study groups. Cases with multimodal treatments were also identified. As a result, CTX was similarly distributed among the infertile, vasectomized, and control groups. In contrast, RTX treatment length was shorter in infertile men. The frequency of multimodal treatment (i.e., radiation and chemotherapy) was twofold lower in men with infertility compared to other men. By focusing on treatment patterns for each cancer type among these groups, the duration of RTX and CTX was shorter in infertile men diagnosed with NHL compared to controls. We conclude that Infertile men diagnosed with cancer and specific cancer types experience different treatment courses, with shorter RTX and less combined RTX/CTX compared to fertile and vasectomized men. These differences could reflect differences in stage at presentation, biological behavior, or treatment responses in infertile men.

    View details for PubMedID 29457365

  • Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States CLINICAL GENITOURINARY CANCER Loft, M., Berg, K., Kjaer, A., Iversen, P., Ferrari, M., Zhang, C. A., Brasso, K., Brooks, J. D., Roder, M. 2018; 16 (1): E181-E192
  • Multi-lectin Affinity Chromatography and Quantitative Proteomic Analysis Reveal Differential Glycoform Levels between Prostate Cancer and Benign Prostatic Hyperplasia Sera. Scientific reports Totten, S. M., Adusumilli, R. n., Kullolli, M. n., Tanimoto, C. n., Brooks, J. D., Mallick, P. n., Pitteri, S. J. 2018; 8 (1): 6509


    Currently prostate-specific antigen is used for prostate cancer (PCa) screening, however it lacks the necessary specificity for differentiating PCa from other diseases of the prostate such as benign prostatic hyperplasia (BPH), presenting a clinical need to distinguish these cases at the molecular level. Protein glycosylation plays an important role in a number of cellular processes involved in neoplastic progression and is aberrant in PCa. In this study, we systematically interrogate the alterations in the circulating levels of hundreds of serum proteins and their glycoforms in PCa and BPH samples using multi-lectin affinity chromatography and quantitative mass spectrometry-based proteomics. Specific lectins (AAL, PHA-L and PHA-E) were used to target and chromatographically separate core-fucosylated and highly-branched protein glycoforms for analysis, as differential expression of these glycan types have been previously associated with PCa. Global levels of CD5L, CFP, C8A, BST1, and C7 were significantly increased in the PCa samples. Notable glycoform-specific alterations between BPH and PCa were identified among proteins CD163, C4A, and ATRN in the PHA-L/E fraction and among C4BPB and AZGP1 glycoforms in the AAL fraction. Despite these modest differences, substantial similarities in glycoproteomic profiles were observed between PCa and BPH sera.

    View details for PubMedID 29695737

  • Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer. Oncotarget Sahoo, D. n., Wei, W. n., Auman, H. n., Hurtado-Coll, A. n., Carroll, P. R., Fazli, L. n., Gleave, M. E., Lin, D. W., Nelson, P. S., Simko, J. n., Thompson, I. M., Leach, R. J., Troyer, D. A., True, L. D., McKenney, J. K., Feng, Z. n., Brooks, J. D. 2018; 9 (5): 6550–61


    The introduction of serum Prostate Specific Antigen (PSA) testing nearly 30 years ago has been associated with a significant shift towards localized disease and decreased deaths due to prostate cancer. Recognition that PSA testing has caused over diagnosis and over treatment of prostate cancer has generated considerable controversy over its value, and has spurred efforts to identify prognostic biomarkers to distinguish patients who need treatment from those that can be observed. Recent studies show that cancer is heterogeneous and forms a hierarchy of tumor cell populations. We developed a method of identifying prostate cancer differentiation states related to androgen signaling using Boolean logic. Using gene expression data, we identified two markers, CD38 and ARG2, that group prostate cancer into three differentiation states. Cancers with CD38-, ARG2- expression patterns, corresponding to an undifferentiated state, had significantly lower 10-year recurrence-free survival compared to the most differentiated group (CD38+ARG2+). We carried out immunohistochemical (IHC) staining for these two markers in a single institution (Stanford; n = 234) and multi-institution (Canary; n = 1326) cohorts. IHC staining for CD38 and ARG2 in the Stanford cohort demonstrated that combined expression of CD38 and ARG2 was prognostic. In the Canary cohort, low CD38 protein expression by IHC was significantly associated with recurrence-free survival (RFS), seminal vesicle invasion (SVI), extra-capsular extension (ECE) in univariable analysis. In multivariable analysis, ARG2 and CD38 IHC staining results were not independently associated with RFS, overall survival, or disease-specific survival after adjusting for other factors including SVI, ECE, Gleason score, pre-operative PSA, and surgical margins.

    View details for PubMedID 29464091

  • Distribution of global health measures from routinely collected PROMIS surveys in patients with breast cancer or prostate cancer. Cancer Seneviratne, M. G., Bozkurt, S. n., Patel, M. I., Seto, T. n., Brooks, J. D., Blayney, D. W., Kurian, A. W., Hernandez-Boussard, T. n. 2018


    The collection of patient-reported outcomes (PROs) is an emerging priority internationally, guiding clinical care, quality improvement projects and research studies. After the deployment of Patient-Reported Outcomes Measurement Information System (PROMIS) surveys in routine outpatient workflows at an academic cancer center, electronic health record data were used to evaluate survey completion rates and self-reported global health measures across 2 tumor types: breast and prostate cancer.This study retrospectively analyzed 11,657 PROMIS surveys from patients with breast cancer and 4411 surveys from patients with prostate cancer, and it calculated survey completion rates and global physical health (GPH) and global mental health (GMH) scores between 2013 and 2018.A total of 36.6% of eligible patients with breast cancer and 23.7% of patients with prostate cancer completed at least 1 survey, with completion rates lower among black patients for both tumor types (P < .05). The mean T scores (calibrated to a general population mean of 50) for GPH were 48.4 ± 9 for breast cancer and 50.6 ± 9 for prostate cancer, and the GMH scores were 52.7 ± 8 and 52.1 ± 9, respectively. GPH and GMH were frequently lower among ethnic minorities, patients without private health insurance, and those with advanced disease.This analysis provides important baseline data on patient-reported global health in breast and prostate cancer. Demonstrating that PROs can be integrated into clinical workflows, this study shows that supportive efforts may be needed to improve PRO collection and global health endpoints in vulnerable populations.

    View details for PubMedID 30512191

  • Identifying Cases of Metastatic Prostate Cancer Using Machine Learning on Electronic Health Records. AMIA ... Annual Symposium proceedings. AMIA Symposium Seneviratne, M. G., Banda, J. M., Brooks, J. D., Shah, N. H., Hernandez-Boussard, T. M. 2018; 2018: 1498–1504


    Cancer stage is rarely captured in structured form in the electronic health record (EHR). We evaluate the performance of a classifier, trained on structured EHR data, in identifying prostate cancer patients with metastatic disease. Using EHR data for a cohort of 5,861 prostate cancer patients mapped to the Observational Health Data Sciences and Informatics (OHDSI) data model, we constructed feature vectors containing frequency counts of conditions, procedures, medications, observations and laboratory values. Staging information from the California Cancer Registry was used as the ground-truth. For identifying patients with metastatic disease, a random forest model achieved precision and recall of 0.90, 0.40 using data within 12 months of diagnosis. This compared to precision 0.33, recall 0.54 for an ICD code-based query. High-precision classifiers using hundreds of structured data elements significantly outperform ICD queries, and may assist in identifying cohorts for observational research or clinical trial matching.

    View details for PubMedID 30815195

  • An Automated Feature Engineering for Digital Rectal Examination Documentation using Natural Language Processing. AMIA ... Annual Symposium proceedings. AMIA Symposium Bozkurt, S., Park, J. I., Kan, K. M., Ferrari, M., Rubin, D. L., Brooks, J. D., Hernandez-Boussard, T. 2018; 2018: 288–94


    Digital rectal examination (DRE) is considered a quality metric for prostate cancer care. However, much of the DRE related rich information is documented as free-text in clinical narratives. Therefore, we aimed to develop a natural language processing (NLP) pipeline for automatic documentation of DRE in clinical notes using a domain-specific dictionary created by clinical experts and an extended version of the same dictionary learned by clinical notes using distributional semantics algorithms. The proposed pipeline was compared to a baseline NLP algorithm and the results of the proposed pipeline were found superior in terms of precision (0.95) and recall (0.90) for documentation of DRE. We believe the rule-based NLP pipeline enriched with terms learned from the whole corpus can provide accurate and efficient identification of this quality metric.

    View details for PubMedID 30815067

  • Comparative rates of upstaging and upgrading in Caucasian and Korean prostate cancer patients eligible for active surveillance PLOS ONE Jeon, H., Yoo, J., Jeong, B., Seo, S., Jeon, S., Choi, H., Lee, H., Ferrari, M., Brooks, J. D., Chung, B. I. 2017; 12 (11)
  • Comparative rates of upstaging and upgrading in Caucasian and Korean prostate cancer patients eligible for active surveillance. PloS one Jeon, H. G., Yoo, J. H., Jeong, B. C., Seo, S. I., Jeon, S. S., Choi, H. Y., Lee, H. M., Ferrari, M., Brooks, J. D., Chung, B. I. 2017; 12 (11): e0186026


    To investigate the impact of race on the risk of pathological upgrading and upstaging at radical prostatectomy (RP) in an Asian (Korean) and Western (Caucasian) cohort eligible for active surveillance (AS).We performed a retrospective cohort study of 854 patients eligible for AS who underwent RP in United States (n = 261) and Korea (n = 593) between 2006 and 2015. After adjusting for age, PSA level, and prostate volume, we utilized multivariate logistic regression analysis to assess the effect of race on upgrading or upstaging.There were significant differences between Caucasian and Korean patients in terms of age at surgery (60.2 yr. vs. 64.1 yr.), PSA density (0.115 ng/mL/mL vs. 0.165 ng/mL/mL) and mean number of positive cores (3.5 vs. 2.4), but not in preoperative PSA values (5.11 ng/mL vs. 5.05 ng/mL). The rate of upstaging from cT1 or cT2 to pT3 or higher was not significantly different between the two cohorts (8.8% vs. 11.0%, P = 0.341). However, there were higher rates of upgrading to high-grade cancer (Gleason 4+3 or higher) in Korean patients (9.1%) when compared to Caucasian counterparts (2.7%) (P = 0.003). Multivariate logistic regression analysis showed that age (OR 1.07, P < 0.001) and smaller prostate volume (OR 0.97, P < 0.001), but not race, were significantly associated with upstaging or upgrading.There were no differences in rates of upgrading or upstaging between Caucasian and Korean men eligible for active surveillance.

    View details for DOI 10.1371/journal.pone.0186026

    View details for PubMedID 29136019

    View details for PubMedCentralID PMC5685613

  • Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States. Clinical genitourinary cancer Loft, M. D., Berg, K. D., Kjaer, A., Iversen, P., Ferrari, M., Zhang, C. A., Brasso, K., Brooks, J. D., Roder, M. A. 2017


    PURPOSE: To analyze how prostate-specific antigen (PSA) screening and practice patterns has affected trends in tumor characteristics in men undergoing radical prostatectomy (RP) in the United States and Denmark. Unlike in the United States, PSA screening has not been recommended in Denmark.PATIENTS AND METHODS: We performed an observational register study using pre- and postoperative data on 2168 Danish patients from Rigshospitalet, Copenhagen, Denmark, and 2236 patients from Stanford University Hospital, Stanford, CA, who underwent RP between 1995 and 2013. Patients were stratified according to Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) risk groups and D'Amico risk classification and were clustered into 4 time periods (1995-1999, 2000-2004, 2005-2009, and 2010-2013). Temporal trends in the proportions of patients of a given variable at the 2 institutions were evaluated with Cochran-Armitage test for trends and chi-square testing.RESULTS: A total of 4404 patients were included. Temporal changes in preoperative PSA, age, grade, and stage was found in both cohorts. Median preoperative PSA declined in both cohorts, while median age increased, with the Danish cohort showing the greatest changes in both PSA and age. In both cohorts, there was a trend for higher-risk preoperative features before RP over time. In 2010-2013, 27.7% and 21.8% of the patients were in the D'Amico high-risk group at Copenhagen and Stanford, respectively.CONCLUSION: Despite recommendation against PSA screening in Denmark, Danish men undergoing RP at Rigshospitalet to a considerable extent now resemble American men undergoing RP at Stanford. At both sites, there is continued trend to reduce the number of men undergoing RP for low-risk prostate cancer.

    View details for PubMedID 28988695

  • NUSAP1 promotes invasion and metastasis of prostate cancer ONCOTARGET Gordon, C. A., Gong, X., Ganesh, D., Brooks, J. D. 2017; 8 (18): 29935-29950


    We have previously identified nucleolar and spindle associated protein 1 (NUSAP1) as a prognostic biomarker in early stage prostate cancer. To better understand the role of NUSAP1 in prostate cancer progression, we tested the effects of increased and decreased NUSAP1 expression in cell lines, in vivo models, and patient samples. NUSAP1 promotes invasion, migration, and metastasis, possibly by modulating family with sequence similarity 101 member B (FAM101B), a transforming growth factor beta 1 (TGFβ1) signaling effector involved in the epithelial to mesenchymal transition. Our findings provide insights into the importance of NUSAP1 in prostate cancer progression and provide a rationale for further study of NUSAP1 function, regulation, and clinical utility.

    View details for DOI 10.18632/oncotarget.15604

    View details for Web of Science ID 000400456200032

    View details for PubMedID 28404898

  • Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns BMC CANCER Kirby, M. K., Ramaker, R. C., Roberts, B. S., Lasseigne, B. N., Gunther, D. S., Burwell, T. C., Davis, N. S., Gulzar, Z. G., Absher, D. M., Cooper, S. J., Brooks, J. D., Myers, R. M. 2017; 17


    Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer.We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models.We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues.DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.

    View details for DOI 10.1186/s12885-017-3252-2

    View details for Web of Science ID 000399668700002

    View details for PubMedID 28412973

    View details for PubMedCentralID PMC5392915

  • Mass spectrometric imaging of prostate biopsy samples: Cancer margin assessment from the distribution of small metabolites and lipids Banerjee, S., Zare, R. N., Tibshirani, R., Kunder, C., Nolley, R., Fan, R., Brooks, J. D., Sonn, G. AMER CHEMICAL SOC. 2017
  • Timing of Adverse Prostate Cancer Reclassification on First Surveillance Biopsy: Results from the Canary Prostate Cancer Active Surveillance Study JOURNAL OF UROLOGY Macleod, L. C., Ellis, W. J., Newcomb, L. F., Zheng, Y., Brooks, J. D., Carroll, P. R., Gleave, M. E., Lance, R. S., Nelson, P. S., Thompson, I. M., Wagner, A. A., Wei, J. T., Lin, D. W. 2017; 197 (4): 1026-1033
  • INTRA-TUMOR HETEROGENEITY IN RENAL CELL CARCINOMA: IMPLICATIONS FOR PROTEOMIC ANALYSIS OF RENAL MASS BIOPSIES Massoudi, R., Hoerner, C., Metzner, T., O'Rourke, J., Curtis, R., Stell, L., Sabatti, C., Brooks, J., Fan, A., Leppert, J. ELSEVIER SCIENCE INC. 2017: E496–E497
  • Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Banerjee, S., Zare, R. N., Tibshirani, R. J., Kunder, C. A., Nolley, R., Fan, R., Brooks, J. D., Sonn, G. A. 2017; 114 (13): 3334-3339


    Accurate identification of prostate cancer in frozen sections at the time of surgery can be challenging, limiting the surgeon's ability to best determine resection margins during prostatectomy. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on 54 banked human cancerous and normal prostate tissue specimens to investigate the spatial distribution of a wide variety of small metabolites, carbohydrates, and lipids. In contrast to several previous studies, our method included Krebs cycle intermediates (m/z <200), which we found to be highly informative in distinguishing cancer from benign tissue. Malignant prostate cells showed marked metabolic derangements compared with their benign counterparts. Using the "Least absolute shrinkage and selection operator" (Lasso), we analyzed all metabolites from the DESI-MS data and identified parsimonious sets of metabolic profiles for distinguishing between cancer and normal tissue. In an independent set of samples, we could use these models to classify prostate cancer from benign specimens with nearly 90% accuracy per patient. Based on previous work in prostate cancer showing that glucose levels are high while citrate is low, we found that measurement of the glucose/citrate ion signal ratio accurately predicted cancer when this ratio exceeds 1.0 and normal prostate when the ratio is less than 0.5. After brief tissue preparation, the glucose/citrate ratio can be recorded on a tissue sample in 1 min or less, which is in sharp contrast to the 20 min or more required by histopathological examination of frozen tissue specimens.

    View details for DOI 10.1073/pnas.1700677114

    View details for Web of Science ID 000397607300049

    View details for PubMedID 28292895

    View details for PubMedCentralID PMC5380053

  • Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer ONCOTARGET Gong, X., Siprashvili, Z., Eminaga, O., Shen, Z., Sato, Y., Kume, H., Homma, Y., Ogawa, S., Khavari, P. A., Pollack, J. R., Brooks, J. D. 2017; 8 (12): 18657-18669


    Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort (P=0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.5 (CI, 2.2-5.7), P < 0.001; Tokyo HR=8.4 (CI, 1.8-40.2), P = 0.007], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation.

    View details for PubMedID 28423633

  • A natural language processing algorithm to measure quality prostate cancer care. Hernandez-Boussard, T., Kourdis, P., Dulal, R., Ferrari, M., Henry, S., Seto, T., McDonald, K., Blayney, D. W., Brooks, J. D. AMER SOC CLINICAL ONCOLOGY. 2017
  • 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
  • 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

  • Trends in the incidence and survival of men diagnosed with denovo metastatic prostate cancer in the us and Denmark - a population-based analysis of two national cohorts Helgstrand, J. T., Klemann, N., Toft, B. G., Brasso, K., Vainer, B., Lichtensztajn, D., Iversen, P., Brooks, J. D., Roder, M. A. TAYLOR & FRANCIS LTD. 2017: 55-56
  • Mining Electronic Health Records to Extract Patient-Centered Outcomes Following Prostate Cancer Treatment. AMIA ... Annual Symposium proceedings. AMIA Symposium Hernandez-Boussard, T., Kourdis, P. D., Seto, T., Ferrari, M., Blayney, D. W., Rubin, D., Brooks, J. D. 2017; 2017: 876–82


    The clinical, granular data in electronic health record (EHR) systems provide opportunities to improve patient care using informatics retrieval methods. However, it is well known that many methodological obstacles exist in accessing data within EHRs. In particular, clinical notes routinely stored in EHR are composed from narrative, highly unstructured and heterogeneous biomedical text. This inherent complexity hinders the ability to perform automated large-scale medical knowledge extraction tasks without the use of computational linguistics methods. The aim of this work was to develop and validate a Natural Language Processing (NLP) pipeline to detect important patient-centered outcomes (PCOs) as interpreted and documented by clinicians in their dictated notes for male patients receiving treatment for localized prostate cancer at an academic medical center.

    View details for PubMedID 29854154

  • A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment PROSTATE CANCER AND PROSTATIC DISEASES Liss, M. A., Schenk, J. M., Faino, A. V., NEWCOMB, L. F., Boyer, H., Brooks, J. D., Carroll, P. R., Dash, A., Fabrizio, M. D., Gleave, M. E., Nelson, P. S., Neuhouser, M. L., Wei, J. T., Zheng, Y., Wright, J. L., Lin, D. W., THOMPSON, I. M. 2016; 19 (4): 390-394


    Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss.Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation.After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ(2) test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight.Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.

    View details for DOI 10.1038/pcan.2016.28

    View details for PubMedID 27431498

  • A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment PROSTATE CANCER AND PROSTATIC DISEASES Liss, M. A., Schenk, J. M., Faino, A. V., Newcomb, L. F., Boyer, H., Brooks, J. D., Carroll, P. R., Dash, A., Fabrizio, M. D., Gleave, M. E., Nelson, P. S., Neuhouser, M. L., Wei, J. T., Zheng, Y., Wright, J. L., Lin, D. W., Thompson, I. M. 2016; 19 (4): 390-394
  • Evaluating the Four Kallikrein Panel of the 4Kscore for Prediction of High-grade Prostate Cancer in Men in the Canary Prostate Active Surveillance Study. European urology Lin, D. W., Newcomb, L. F., Brown, M. D., Sjoberg, D. D., Dong, Y., Brooks, J. D., Carroll, P. R., Cooperberg, M., Dash, A., Ellis, W. J., Fabrizio, M., Gleave, M. E., Morgan, T. M., Nelson, P. S., Thompson, I. M., Wagner, A. A., Zheng, Y. 2016


    Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease.To evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance.Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA).The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit.Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies.Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.

    View details for DOI 10.1016/j.eururo.2016.11.017

    View details for PubMedID 27889277

  • MUC1 Expression by Immunohistochemistry Is Associated with Adverse Pathologic Features in Prostate Cancer: A Multi-Institutional Study PLOS ONE Eminaga, O., Wei, W., Hawley, S. J., Auman, H., Newcomb, L. F., Simko, J., Hurtado-Coll, A., Troyer, D. A., Carroll, P. R., Gleave, M. E., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., McKenney, J. K., Feng, Z., Fazli, L., Brooks, J. D. 2016; 11 (11)


    The uncertainties inherent in clinical measures of prostate cancer (CaP) aggressiveness endorse the investigation of clinically validated tissue biomarkers. MUC1 expression has been previously reported to independently predict aggressive localized prostate cancer. We used a large cohort to validate whether MUC1 protein levels measured by immunohistochemistry (IHC) predict aggressive cancer, recurrence and survival outcomes after radical prostatectomy independent of clinical and pathological parameters.MUC1 IHC was performed on a multi-institutional tissue microarray (TMA) resource including 1,326 men with a median follow-up of 5 years. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazard models and the Log-rank test.The presence of MUC1 expression was significantly associated with extracapsular extension and higher Gleason score, but not with seminal vesicle invasion, age, positive surgical margins or pre-operative serum PSA levels. In univariable analyses, positive MUC1 staining was significantly associated with a worse recurrence free survival (RFS) (HR: 1.24, CI 1.03-1.49, P = 0.02), although not with disease specific survival (DSS, P>0.5). On multivariable analyses, the presence of positive surgical margins, extracapsular extension, seminal vesicle invasion, as well as higher pre-operative PSA and increasing Gleason score were independently associated with RFS, while MUC1 expression was not. Positive MUC1 expression was not independently associated with disease specific survival (DSS), but was weakly associated with overall survival (OS).In our large, rigorously designed validation cohort, MUC1 protein expression was associated with adverse pathological features, although it was not an independent predictor of outcome after radical prostatectomy.

    View details for DOI 10.1371/journal.pone.0165236

    View details for PubMedID 27846218

  • Loss of Expression of AZGP1 Is Associated With Worse Clinical Outcomes in a Multi-Institutional Radical Prostatectomy Cohort. Prostate Brooks, J. D., Wei, W., Pollack, J. R., West, R. B., Shin, J. H., Sunwoo, J. B., Hawley, S. J., Auman, H., Newcomb, L. F., Simko, J., Hurtado-Coll, A., Troyer, D. A., Carroll, P. R., Gleave, M. E., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., McKenney, J. K., Feng, Z., Fazli, L. 2016; 76 (15): 1409-1419


    Given the uncertainties inherent in clinical measures of prostate cancer aggressiveness, clinically validated tissue biomarkers are needed. We tested whether Alpha-2-Glycoprotein 1, Zinc-Binding (AZGP1) protein levels, measured by immunohistochemistry, and RNA expression, by RNA in situ hybridization (RISH), predict recurrence after radical prostatectomy independent of clinical and pathological parameters.AZGP1 IHC and RISH were performed on a large multi-institutional tissue microarray resource including 1,275 men with 5 year median follow-up. The relationship between IHC and RISH expression levels was assessed using the Kappa analysis. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazards models and the Log-rank test.Absent or weak expression of AZGP1 protein was associated with worse recurrence free survival (RFS), disease specific survival, and overall survival after radical prostatectomy in univariable analysis. AZGP1 protein expression, along with pre-operative serum PSA levels, surgical margin status, seminal vesicle invasion, extracapsular extension, and Gleason score predicted RFS on multivariable analysis. Similarly, absent or low AZGP1 RNA expression by RISH predicted worse RFS after prostatectomy in univariable and multivariable analysis.In our large, rigorously designed validation cohort, loss of AZGP1 expression predicts RFS after radical prostatectomy independent of clinical and pathological variables. Prostate © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.23225

    View details for PubMedID 27325561

  • Timing of Adverse Prostate Cancer Reclassification on First Surveillance Biopsy: Results from the Canary Prostate Cancer Active Surveillance Study. journal of urology Macleod, L. C., Ellis, W. J., Newcomb, L. F., Zheng, Y., Brooks, J. D., Carroll, P. R., Gleave, M. E., Lance, R. S., Nelson, P. S., Thompson, I. M., Wagner, A. A., Wei, J. T., Lin, D. W. 2016


    During active surveillance for localized prostate cancer, the timing of the first surveillance biopsy varies. We analyzed the Canary PASS (Prostate Cancer Active Surveillance Study) to determine biopsy timing influence on rates of prostate cancer adverse reclassification at the first active surveillance biopsy.Of 1,085 participants in PASS, 421 had fewer than 34% of cores involved with cancer and Gleason sum 6 or less, and thereafter underwent on-study active surveillance biopsy. Reclassification was defined as an increase in Gleason sum and/or 34% or more of cores with prostate cancer. First active surveillance biopsy reclassification rates were categorized as less than 8, 8 to 13 and greater than 13 months after diagnosis. Multivariable logistic regression determined association between reclassification and first biopsy timing.Of 421 men, 89 (21.1%) experienced reclassification at the first active surveillance biopsy. Median time from prostate cancer diagnosis to first active surveillance biopsy was 11 months (IQR 7.8-13.8). Reclassification rates at less than 8, 8 to 13 and greater than 13 months were 24%, 19% and 22% (p = 0.65). On multivariable analysis, compared to men biopsied at less than 8 months the OR of reclassification at 8 to 13 and greater than 13 months were 0.88 (95% CI 0.5,1.6) and 0.95 (95% CI 0.5,1.9), respectively. Prostate specific antigen density 0.15 or greater (referent less than 0.15, OR 1.9, 95% CI 1.1, 4.1) and body mass index 35 kg/m(2) or greater (referent less than 25 kg/m(2), OR 2.4, 95% CI 1.1,5.7) were associated with increased odds of reclassification.Timing of the first active surveillance biopsy was not associated with increased adverse reclassification but prostate specific antigen density and body mass index were. In low risk patients on active surveillance, it may be reasonable to perform the first active surveillance biopsy at a later time, reducing the overall cost and morbidity of active surveillance.

    View details for DOI 10.1016/j.juro.2016.10.090

    View details for PubMedID 27810448

  • Histologic Grading of Prostatic Adenocarcinoma Can Be Further Optimized Analysis of the Relative Prognostic Strength of Individual Architectural Patterns in 1275 Patients From the Canary Retrospective Cohort AMERICAN JOURNAL OF SURGICAL PATHOLOGY McKenney, J. K., Wei, W., Hawley, S., Auman, H., Newcomb, L. F., Boyer, H. D., Fazli, L., Simko, J., Hurtado-Coll, A., Troyer, D. A., Tretiakova, M. S., Vakar-Lopez, F., Carroll, P. R., Cooperberg, M. R., Gleave, M. E., Lance, R. S., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., Feng, Z., Brooks, J. D. 2016; 40 (11): 1439-1456


    Histologic grading remains the gold standard for prognosis in prostate cancer, and assessment of Gleason score plays a critical role in active surveillance management. We sought to optimize the prognostic stratification of grading and developed a method of recording and studying individual architectural patterns by light microscopic evaluation that is independent of standard Gleason grade. Some of the evaluated patterns are not assessed by current Gleason grading (eg, reactive stromal response). Individual histologic patterns were correlated with recurrence-free survival in a retrospective postradical prostatectomy cohort of 1275 patients represented by the highest-grade foci of carcinoma in tissue microarrays. In univariable analysis, fibromucinous rupture with varied epithelial complexity had a significantly lower relative risk of recurrence-free survival in cases graded as 3+4=7. Cases having focal "poorly formed glands," which could be designated as pattern 3+4=7, had lower risk than cribriform patterns with either small cribriform glands or expansile cribriform growth. In separate multivariable Cox proportional hazard analyses of both Gleason score 3+3=6 and 3+4=7 carcinomas, reactive stromal patterns were associated with worse recurrence-free survival. Decision tree models demonstrate potential regrouping of architectural patterns into categories with similar risk. In summary, we argue that Gleason score assignment by current consensus guidelines are not entirely optimized for clinical use, including active surveillance. Our data suggest that focal poorly formed gland and cribriform patterns, currently classified as Gleason pattern 4, should be in separate prognostic groups, as the latter is associated with worse outcome. Patterns with extravasated mucin are likely overgraded in a subset of cases with more complex epithelial bridges, whereas stromogenic cancers have a worse outcome than conveyed by Gleason grade alone. These findings serve as a foundation to facilitate optimization of histologic grading and strongly support incorporating reactive stroma into routine assessment.

    View details for PubMedID 27635949

  • 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. 2016


    To assess whether patient factors, such as age and preoperative kidney function, were associated with receipt of partial nephrectomy in a national integrated healthcare system.We identified patients treated with a radical or partial nephrectomy from 2002 to 2014 in the Veterans Health Administration. We examined associations among patient age, sex, race or ethnicity, multimorbidity, baseline kidney function, tumor characteristics, and receipt of partial nephrectomy. We estimated the odds of receiving a partial nephrectomy and assessed interactions between covariates and the year of surgery to explore whether patient factors associated with partial nephrectomy changed over time.In our cohort of 14,186 patients, 4508 (31.2%) received a partial nephrectomy. Use of partial nephrectomy increased from 17% in 2002 to 32% in 2008 and to 38% in 2014. Patient race or ethnicity, age, tumor stage, and year of surgery were independently associated with receipt of partial nephrectomy. Black veterans had significantly increased odds of receipt of partial nephrectomy, whereas older patients had significantly reduced odds. Partial nephrectomy utilization increased for all groups over time, but older patients and patients with worse baseline kidney function showed the least increase in odds of partial nephrectomy.Although the utilization of partial nephrectomy increased for all groups, the greatest increase occurred in the youngest patients and those with the highest baseline kidney function. These trends warrant further investigation to ensure that patients at the highest risk of impaired kidney function are considered for partial nephrectomy whenever possible.

    View details for DOI 10.1016/j.urology.2016.08.044

    View details for PubMedID 27634733

  • Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of > 1000 prostatectomies PROSTATE CANCER AND PROSTATIC DISEASES Tretiakova, M. S., Wei, W., Boyer, H. D., NEWCOMB, L. F., Hawley, S., Auman, H., Vakar-Lopez, F., McKenney, J. K., Fazli, L., Simko, J., Troyer, D. A., Hurtado-Coll, A., Thompson, I. M., Carroll, P. R., Ellis, W. J., Gleave, M. E., Nelson, P. S., Lin, D. W., True, L. D., Feng, Z., Brooks, J. D. 2016; 19 (3): 264-270


    Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes.After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up).In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03).In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.Prostate Cancer and Prostatic Diseases advance online publication, 3 May 2016; doi:10.1038/pcan.2016.12.

    View details for DOI 10.1038/pcan.2016.12

    View details for PubMedID 27136741

  • 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

  • Analytic validation of a clinical-grade PTEN immunohistochemistry assay in prostate cancer by comparison with PTEN FISH MODERN PATHOLOGY Lotan, T. L., Wei, W., Ludkovski, O., Morais, C. L., Guedes, L. B., Jamaspishvili, T., Lopez, K., Hawley, S. T., Feng, Z., Fazli, L., Hurtado-Coll, A., McKenney, J. K., Simko, J., Carroll, P. R., Gleave, M., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., Brooks, J. D., Lance, R., Troyer, D., Squire, J. A. 2016; 29 (8): 904-914


    PTEN loss is a promising prognostic and predictive biomarker in prostate cancer. Because it occurs most commonly via PTEN gene deletion, we developed a clinical-grade, automated, and inexpensive immunohistochemical assay to detect PTEN loss. We studied the sensitivity and specificity of PTEN immunohistochemistry relative to four-color fluorescence in situ hybridization (FISH) for detection of PTEN gene deletion in a multi-institutional cohort of 731 primary prostate tumors. Intact PTEN immunostaining was 91% specific for the absence of PTEN gene deletion (549/602 tumors with two copies of the PTEN gene by FISH showed intact expression of PTEN by immunohistochemistry) and 97% sensitive for the presence of homozygous PTEN gene deletion (absent PTEN protein expression by immunohistochemistry in 65/67 tumors with homozygous deletion). PTEN immunohistochemistry was 65% sensitive for the presence of hemizygous PTEN gene deletion, with protein loss in 40/62 hemizygous tumors. We reviewed the 53 cases where immunohistochemistry showed PTEN protein loss and FISH showed two intact copies of the PTEN gene. On re-review, there was ambiguous immunohistochemistry loss in 6% (3/53) and failure to analyze the same tumor area by both methods in 34% (18/53). Of the remaining discordant cases, 41% (13/32) revealed hemizygous (n=8) or homozygous (n=5) PTEN gene deletion that was focal in most cases (11/13). The remaining 19 cases had two copies of the PTEN gene detected by FISH, representing truly discordant cases. Our automated PTEN immunohistochemistry assay is a sensitive method for detection of homozygous PTEN gene deletions. Immunohistochemistry screening is particularly useful to identify cases with heterogeneous PTEN gene deletion in a subset of tumor glands. Mutations, small insertions, or deletions and/or epigenetic or microRNA-mediated mechanisms may lead to PTEN protein loss in tumors with normal or hemizygous PTEN gene copy number.Modern Pathology advance online publication, 13 May 2016; doi:10.1038/modpathol.2016.88.

    View details for DOI 10.1038/modpathol.2016.88

    View details for Web of Science ID 000380821400012

    View details for PubMedID 27174589

  • The radiogenomic risk score stratifies outcomes in a renal cell cancer phase 2 clinical trial EUROPEAN RADIOLOGY Jamshidi, N., Jonasch, E., Zapala, M., Korn, R. L., Brooks, J. D., Ljungberg, B., Kuo, M. D. 2016; 26 (8): 2798-2807


    To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab.In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis.The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05).The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab.• The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.

    View details for DOI 10.1007/s00330-015-4082-8

    View details for Web of Science ID 000379192500043

    View details for PubMedID 26560727

  • Reply to being a widower may be an indication for routine prostate-specific antigen screening above age 69 years, which the American Urological Association recommends as a cutoff point. Cancer Gomez, S. L., Martínez, M. E., Brooks, J. D., Cheng, I., Lichtensztajn, D., Murphy, J. D. 2016

    View details for DOI 10.1002/cncr.30097

    View details for PubMedID 27286520

  • PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer. European urology focus Lotan, T. L., Wei, W., Morais, C. L., Hawley, S. T., Fazli, L., Hurtado-Coll, A., Troyer, D., McKenney, J. K., Simko, J., Carroll, P. R., Gleave, M., Lance, R., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., Feng, Z., Brooks, J. D. 2016; 2 (2): 180-188


    PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement.We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status.A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss. ERG status as determined by a genetically validated IHC assay was available for a subset of 938 tumors.Associations between PTEN and ERG status were assessed using Fisher's exact test. Kaplan-Meier and multivariate weighted Cox proportional models for RFS were constructed.When compared to intact PTEN, homogeneous (hazard ratio [HR] 1.66, p = 0.001) but not heterogeneous (HR 1.24, p = 0.14) PTEN loss was significantly associated with shorter RFS in multivariate models. Among ERG-positive tumors, homogeneous (HR 3.07, p < 0.0001) but not heterogeneous (HR 1.46, p = 0.10) PTEN loss was significantly associated with shorter RFS. Among ERG-negative tumors, PTEN did not reach significance for inclusion in the final multivariate models. The interaction term for PTEN and ERG status with respect to RFS did not reach statistical significance (p = 0.11) for the current sample size.These data suggest that PTEN is a useful prognostic biomarker and that there is no statistically significant interaction between PTEN and ERG status for RFS.We found that loss of the PTEN tumor suppressor gene in prostate tumors as assessed by tissue staining is correlated with shorter time to prostate cancer recurrence after radical prostatectomy.

    View details for PubMedID 27617307

  • Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016. Human genomics Srivastava, A. K., Wang, Y., Huang, R., Skinner, C., Thompson, T., Pollard, L., Wood, T., Luo, F., Stevenson, R., Polimanti, R., Gelernter, J., Lin, X., Lim, I. Y., Wu, Y., Teh, A. L., Chen, L., Aris, I. M., Soh, S. E., Tint, M. T., MacIsaac, J. L., Yap, F., Kwek, K., Saw, S. M., Kobor, M. S., Meaney, M. J., Godfrey, K. M., Chong, Y. S., Holbrook, J. D., Lee, Y. S., Gluckman, P. D., Karnani, N., Kapoor, A., Lee, D., Chakravarti, A., Maercker, C., Graf, F., Boutros, M., Stamoulis, G., Santoni, F., Makrythanasis, P., Letourneau, A., Guipponi, M., Panousis, N., Garieri, M., Ribaux, P., Falconnet, E., Borel, C., Antonarakis, S. E., Kumar, S., Curran, J., Blangero, J., Chatterjee, S., Kapoor, A., Akiyama, J., Auer, D., Berrios, C., Pennacchio, L., Chakravarti, A., Donti, T. 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    O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. 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Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. 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Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía P28 Genetic modifiers of Alström syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escareño, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar

    View details for DOI 10.1186/s40246-016-0063-5

    View details for PubMedID 27294413

    View details for PubMedCentralID PMC4896275

  • Targeted Methylation Sequencing of Prostate Cancer Jager, N., Chen, J., Haile, R., Hitchins, M., Brooks, J. D., Snyder, M. BMC. 2016
  • PROSTATE CANCER YIELD IN MRI LESIONS VARIES ACROSS RADIOLOGISTS Sonn, G., Fan, R., Li, S., Ghanouni, P., Loening, A., Daniel, B., To'o, K., Gill, H., Chung, B., Brooks, J. ELSEVIER SCIENCE INC. 2016: E42
  • GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress PROSTATE Mian, O. Y., Khattab, M. H., Hedayati, M., Coulter, J., Abubaker-Sharif, B., Schwaninger, J. M., Veeraswamy, R. K., Brooks, J. D., Hopkins, L., Shinohara, D. B., Cornblatt, B., Nelson, W. G., Yegnasubramanian, S., DeWeese, T. L. 2016; 76 (2): 199-206


    Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR).GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed.GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival.The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. Prostate © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.23111

    View details for Web of Science ID 000368810600007

    View details for PubMedID 26447830

  • Validation of Reactive Stroma as an Adverse Prognostic Factor for Gleason Grade 3+3=6 and 3+4=7 Prostatic Adenocarcinomas (PCA) In the Canary Retrospective Radical Prostatectomy (RP) Cohort McKenney, J. K., Wei, W., Hawley, S. J., Auman, H., Newcomb, L., Boyer, H., Fazli, L., Simko, J., Hurtado-Coll, A., Troyer, D., Tretiakova, M. S., Vakar-Lopez, F., Carroll, P. R., Cooperberg, M. R., Gleave, M. E., Lance, R., Lin, D., Nelson, P. S., Thompson, I., True, L., Feng, Z., Brooks, J. D. NATURE PUBLISHING GROUP. 2016: 249A
  • Validation of Reactive Stroma as an Adverse Prognostic Factor for Gleason Grade 3+3=6 and 3+4=7 Prostatic Adenocarcinomas (PCA) In the Canary Retrospective Radical Prostatectomy (RP) Cohort McKenney, J. K., Wei, W., Hawley, S. J., Auman, H., Newcomb, L., Boyer, H., Fazli, L., Simko, J., Hurtado-Coll, A., Troyer, D., Tretiakova, M. S., Vakar-Lopez, F., Carroll, P. R., Cooperberg, M. R., Gleave, M. E., Lance, R., Lin, D., Nelson, P. S., Thompson, I., True, L., Feng, Z., Brooks, J. D. NATURE PUBLISHING GROUP. 2016: 249A
  • Outcomes of Active Surveillance for Clinically Localized Prostate Cancer in the Prospective, Multi-Institutional Canary PASS Cohort JOURNAL OF UROLOGY Newcomb, L. F., Thompson, I. M., Boyer, H. D., Brooks, J. D., Carroll, P. R., Cooperberg, M. R., Dash, A., Ellis, W. J., Fazli, L., Feng, Z., Gleave, M. E., Kunju, P., Lance, R. S., McKenney, J. K., Meng, M. V., Nicolas, M. M., Sanda, M. G., Simko, J., So, A., Tretiakova, M. S., Troyer, D. A., True, L. D., Vakar-Lopez, F., Virgin, J., Wagner, A. A., Wei, J. T., Zheng, Y., Nelson, P. S., Lin, D. W. 2016; 195 (2): 313-320


    Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multi-center study of active surveillance.We studied 905 men in the prospective Canary Prostate cancer Active Surveillance Study (PASS) enrolled between 2008 to 2013. We collected clinical data at study entry and at pre-specified intervals and determined associations with adverse reclassification defined as increased Gleason grade or greater cancer volume on follow-up biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance.During a median follow-up of 28 months, 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued active surveillance. Overall, 19% of participants received treatment, 68% with adverse reclassification while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling, percent of biopsy cores with cancer, BMI, and PSA density were associated with adverse reclassification (P = 0.01, 0.04, 0.04). Of 103 participants subsequently treated by radical prostatectomy, 34% had adverse pathology, defined as primary pattern 4-5 or non-organ confined disease, including two with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (P = 0.76).Most men remain on active surveillance at five years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only modest association with disease reclassification, supporting the need for approaches that improve prediction of this outcome.

    View details for DOI 10.1016/j.juro.2015.08.087

    View details for Web of Science ID 000368054800023

  • 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

  • New Paradigms for Patient-Centered Outcomes Research in Electronic Medical Records: An Example of Detecting Urinary Incontinence Following Prostatectomy. EGEMS (Washington, DC) Hernandez-Boussard, T., Tamang, S., Blayney, D., Brooks, J., Shah, N. 2016; 4 (3): 1231-?


    National initiatives to develop quality metrics emphasize the need to include patient-centered outcomes. Patient-centered outcomes are complex, require documentation of patient communications, and have not been routinely collected by healthcare providers. The widespread implementation of electronic medical records (EHR) offers opportunities to assess patient-centered outcomes within the routine healthcare delivery system. The objective of this study was to test the feasibility and accuracy of identifying patient centered outcomes within the EHR.Data from patients with localized prostate cancer undergoing prostatectomy were used to develop and test algorithms to accurately identify patient-centered outcomes in post-operative EHRs - we used urinary incontinence as the use case. Standard data mining techniques were used to extract and annotate free text and structured data to assess urinary incontinence recorded within the EHRs.A total 5,349 prostate cancer patients were identified in our EHR-system between 1998-2013. Among these EHRs, 30.3% had a text mention of urinary incontinence within 90 days post-operative compared to less than 1.0% with a structured data field for urinary incontinence (i.e. ICD-9 code). Our workflow had good precision and recall for urinary incontinence (positive predictive value: 0.73 and sensitivity: 0.84).Our data indicate that important patient-centered outcomes, such as urinary incontinence, are being captured in EHRs as free text and highlight the long-standing importance of accurate clinician documentation. Standard data mining algorithms can accurately and efficiently identify these outcomes in existing EHRs; the complete assessment of these outcomes is essential to move practice into the patient-centered realm of healthcare.

    View details for DOI 10.13063/2327-9214.1231

    View details for PubMedID 27347492

  • Precision Medicine in Active Surveillance for Prostate Cancer: Development of the Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator EUROPEAN UROLOGY Ankerst, D. P., Xia, J., Thompson, I. M., Hoefler, J., Newcomb, L. F., Brooks, J. D., Carroll, P. R., Ellis, W. J., Gleave, M. E., Lance, R. S., Nelson, P. S., Wagner, A. A., Wei, J. T., Etzioni, R., Lin, D. W. 2015; 68 (6): 1083-1088


    Men on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly.To use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes.Biopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed.Logistic regression was used to predict progression, defined as an increase in Gleason score from ≤6 to ≥7 or increase in percentage of cores positive for cancer from <34% to ≥34%. Fivefold internal cross-validation was performed to evaluate the area under the receiver operating characteristic curve (AUC).Statistically significant risk factors for progression on biopsy were prostate-specific antigen (odds ratio [OR]: 1.045; 95% confidence interval [CI], 1.028-1.063), percentage of cores positive for cancer on most recent biopsy (OR: 1.401; 95% CI, 1.301-1.508), and history of at least one prior negative biopsy (OR: 0.524; 95% CI, 0.417-0.659). A multivariable predictive model incorporating these factors plus age and number of months since last biopsy achieved an AUC of 72.4%.A combination of readily available clinical measures can stratify patients considering AS prostate biopsy. Risk of progression or upgrade can be estimated and incorporated into clinical practice.The Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator, an online tool, can be used to guide patient decision making regarding follow-up prostate biopsy.

    View details for DOI 10.1016/j.eururo.2015.03.023

    View details for PubMedID 25819722

  • Klip1 lincRNA is a prognostic biomarker for clear cell renal cell carcinoma Gong, X., Pollack, J., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2015
  • The Radiogenomic Risk Score: Construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma RADIOLOGY Jamshidi, N., Jonasch, E., Zapala, M., Korn, R. L., Aganovic, L., Zhao, H., Sitaram, R. T., Tibshirani, R. J., Banerjee, S., Brooks, J. D., Ljungberg, B., Kuo, M. D. 2015; 277 (1): 114-123


    Purpose To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image. Materials and Methods In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis. Results Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001). Conclusion A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible. (©) RSNA, 2015 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on August 24, 2015.

    View details for DOI 10.1148/radiol.2015150800

    View details for Web of Science ID 000368434000014

  • A multicenter study shows PTEN deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer PROSTATE Troyer, D. A., Jamaspishvili, T., Wei, W., Feng, Z., Good, J., Hawley, S., Fazli, L., McKenney, J. K., Simko, J., Hurtado-Coll, A., Carroll, P. R., Gleave, M., Lance, R., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., Brooks, J. D., Squire, J. A. 2015; 75 (11): 1206-1215


    Loss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene is a promising marker of aggressive prostate cancer. Active surveillance and watchful waiting are increasingly recommended to patients with small tumors felt to be low risk, highlighting the difficulties of Gleason scoring in this setting. There is an urgent need for predictive biomarkers that can be rapidly deployed to aid in clinical decision-making. Our objectives were to assess the incidence and ability of PTEN alterations to predict aggressive disease in a multicenter study.We used recently developed probes optimized for sensitivity and specificity in a four-color FISH deletion assay to study the Canary Retrospective multicenter Prostate Cancer Tissue Microarray (TMA). This TMA was constructed specifically for biomarker validation from radical prostatectomy specimens, and is accompanied by detailed clinical information with long-term follow-up.In 612 prostate cancers, the overall rate of PTEN deletion was 112 (18.3%). Hemizygous PTEN losses were present in 55/612 (9.0%) of cancers, whereas homozygous PTEN deletion was observed in 57/612 (9.3%) of tumors. Significant associations were found between PTEN status and pathologic stage (P < 0.0001), seminal vesicle invasion (P = 0.0008), extracapsular extension (P < 0.0001), and Gleason score (P = 0.0002). In logistic regression analysis of clinical and pathological variables, PTEN deletion was significantly associated with extracapsular extension, seminal vesicle involvement, and higher Gleason score. In the 406 patients in which clinical information was available, PTEN homozygous (P = 0.009) deletion was associated with worse post-operative recurrence-free survival (number of events = 189), pre-operative prostate specific antigen (PSA) (P < 0.001), and pathologic stage (P = 0.03).PTEN status assessed by FISH is an independent predictor for recurrence-free survival in multivariate models, as were seminal vesicle invasion, extracapsular extension, and Gleason score, and preoperative PSA. Furthermore, these data demonstrate that the assay can be readily introduced at first diagnosis in a cost effective manner analogous to the use of FISH for analysis of HER2/neu status in breast cancer. Combined with published research beginning 17 years ago, both the data and tools now exist to implement a PTEN assay in the clinic. Prostate 75: 1206-1215, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.23003

    View details for PubMedID 25939393

  • In-depth quantitative analysis of protein glycoforms in human prostate cancer plasma Totten, S. M., Kulloli, M., Tanimoto, C., Brooks, J. D., Pitteri, S. J. AMER ASSOC CANCER RESEARCH. 2015
  • Evaluation of ERG and SPINK1 by Immunohistochemical Staining and Clinicopathological Outcomes in a Multi-Institutional Radical Prostatectomy Cohort of 1067 Patients PLOS ONE Brooks, J. D., Wei, W., Hawley, S., Auman, H., Newcomb, L., Boyer, H., Fazli, L., Simko, J., Hurtado-Coll, A., Troyer, D. A., Carroll, P. R., Gleave, M., Lance, R., Lin, D. W., Nelson, P. S., Thompson, I. M., True, L. D., Feng, Z., McKenney, J. K. 2015; 10 (7)


    Distinguishing between patients with early stage, screen detected prostate cancer who must be treated from those that can be safely watched has become a major issue in prostate cancer care. Identification of molecular subtypes of prostate cancer has opened the opportunity for testing whether biomarkers that characterize these subtypes can be used as biomarkers of prognosis. Two established molecular subtypes are identified by high expression of the ERG oncoprotein, due to structural DNA alterations that encode for fusion transcripts in approximately ½ of prostate cancers, and over-expression of SPINK1, which is purportedly found only in ERG-negative tumors. We used a multi-institutional prostate cancer tissue microarray constructed from radical prostatectomy samples with associated detailed clinical data and with rigorous selection of recurrent and non-recurrent cases to test the prognostic value of immunohistochemistry staining results for the ERG and SPINK1 proteins. In univariate analysis, ERG positive cases (419/1067; 39%) were associated with lower patient age, pre-operative serum PSA levels, lower Gleason scores (≤3+4=7) and improved recurrence free survival (RFS). On multivariate analysis, ERG status was not correlated with RFS, disease specific survival (DSS) or overall survival (OS). High-level SPINK1 protein expression (33/1067 cases; 3%) was associated with improved RFS on univariate and multivariate Cox regression analysis. Over-expression of either protein was not associated with clinical outcome. While expression of ERG and SPINK1 proteins was inversely correlated, it was not mutually exclusive since 3 (0.28%) cases showed high expression of both. While ERG and SPINK1 appear to identify discrete molecular subtypes of prostate cancer, only high expression of SPINK1 was associated with improved clinical outcome. However, by themselves, neither ERG nor SPINK1 appear to be useful biomarkers for prognostication of early stage prostate cancer.

    View details for DOI 10.1371/journal.pone.0132343

    View details for Web of Science ID 000358194900044

    View details for PubMedCentralID PMC4501723

  • The impact of robotic surgery on the surgical management of prostate cancer in the USA BJU INTERNATIONAL Chang, S. L., Kibel, A. S., Brooks, J. D., Chung, B. I. 2015; 115 (6): 929-936


    To describe the surgeon characteristics associated with RARP adoption and determine the possible impact of this adoption on practice patterns and cost.A retrospective cohort study with a weighted sample size of 489,369 men who underwent non-RARP (i.e., open or laparoscopic radical prostatectomy [RP]) or RARP in the United States from 2003 to 2010 was performed. We evaluated predictors for RARP adoption, defined as performing >50% of annual RP with the robotic approach. Additionally, we identified the resulting changes in prostate cancer surgery practice patterns and expenditures.From 2003 to 2010, RARP adoption increased from 0.7% to 42% of surgeons performing RP. High-volume surgeons, defined as performing >24 RP annually, had statically significantly higher odds of adopting RARP throughout the study period. From 2005 to 2007, adoption was more common among surgeons at teaching (OR: 2.4; 95% CI: 1.7-3.4), intermediate- (200-399 beds; OR: 5.96; 95% CI: 1.3-26.5) and large-sized hospitals (≥400 beds; OR: 6.1; 95% CI: 1.4-25.8); after 2007, adoption was more common among surgeons at urban hospitals (OR: 3.3; 95% CI: 1.7 to 6.4). RARP adoption was generally associated with increased RP volume, greatest for high-volume surgeons and least for low-volume surgeons (<5 RP annually). The annual number of surgeons performing RP decreased from approximately 10,000 to 8,200, with the proportion of cases performed by high-volume surgeons increasing from 10% to 45%. RARP was more costly, disproportionally contributing to the 40% increase in annual prostate cancer surgery expenditures. RARP costs generally decreased plateauing at over $10,000 while non-RARP costs increased to nearly $9,000 by the end of the study.There was widespread RARP adoption in the United States between 2003 and 2010, particularly among high-volume surgeons. The diffusion of RARP was associated with a centralization of care and an increased economic burden for prostate cancer surgery.

    View details for DOI 10.1111/bju.12850

    View details for Web of Science ID 000355275600019

    View details for PubMedID 24958338

  • Re: Nationwide prevalence of lymph node metastases in Gleason score 3+3=6 prostate cancer: authors' reply PATHOLOGY Sieh, W., Lichtensztajn, D. Y., Gomez, S., Liu, J., Chung, B. I., Cheng, I., Brooks, J. D. 2015; 47 (4): 394-395
  • Re: Nationwide prevalence of lymph node metastases in Gleason score 3?+?3?=?6 prostate cancer: authors' reply. Pathology Sieh, W., Lichtensztajn, D. Y., Gomez, S. L., Liu, J., Chung, B. I., Cheng, I., Brooks, J. D. 2015; 47 (4): 394-395

    View details for DOI 10.1097/PAT.0000000000000264

    View details for PubMedID 25938367

  • Increased Risk of Cancer in Infertile Men: Analysis of US Claims Data JOURNAL OF UROLOGY Eisenberg, M. L., Li, S., Brooks, J. D., Cullen, M. R., Baker, L. C. 2015; 193 (5): 1596-1601


    Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Data suggest a higher risk of testicular cancer in infertile men. However, the relationship between infertility and other cancers remains uncertain.We analyzed subjects from the Truven Health MarketScan® claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups were created of men who underwent vasectomy and a control cohort of men who were not infertile and had not undergone vasectomy. The incidence of cancer was compared to national U.S. estimates. Infertile men were also compared to men who underwent vasectomy and the control cohort using a Cox regression model.A total of 76,083 infertile men were identified with an average age of 35.1 years. Overall 112,655 men who underwent vasectomy and 760,830 control men were assembled. Compared to age adjusted national averages, infertile, vasectomy and control subjects in the study cohorts had higher rates of all cancers and many individual cancers. In time to event analysis, infertile men had a higher risk of cancer than those who underwent vasectomy or controls. Infertile men had a higher risk of testis cancer, nonHodgkin lymphoma and all cancers than the vasectomy and control groups.Consistent with prior reports, we identified an increased risk of testicular cancer in infertile men. The current data also suggest that infertile men are at a mildly increased risk of all cancers in the years after infertility evaluation. Future research should focus on confirming these associations and elucidating pathways between infertility and cancer.

    View details for DOI 10.1016/j.juro.2014.11.080

    View details for Web of Science ID 000353113200052

    View details for PubMedID 25463997

  • NUSAP1 expression is upregulated by loss of RB1 in prostate cancer cells. Prostate Gordon, C. A., Gulzar, Z. G., Brooks, J. D. 2015; 75 (5): 517-526


    Overexpression of NUSAP1 is associated with poor prognosis in prostate cancer, but little is known about what leads to its overexpression. Based on previous observations that NUSAP1 expression is enhanced by E2F1, we hypothesized that NUSAP1 expression is regulated, at least in part, by loss of RB1 via the RB1/E2F1 axis.Using Significance Analysis of Microarrays, we examined RB1, E2F1, and NUSAP1 transcript levels in prostate cancer gene expression datasets. We compared NUSAP1 expression levels in DU145, LNCaP, and PC-3 prostate cancer cell lines via use of cDNA microarray data, RT-qPCR, and Western blots. In addition, we used lentiviral expression constructs to knockdown RB1 in prostate cancer cell lines and transient transfections to knockdown E2F1, and investigated RB1, E2F1, and NUSAP1 expression levels with RT-qPCR and Western blots. Finally, in DU145 cells or PC-3 cells that stably underexpress RB1, we used proliferation and invasion assays to assess whether NUSAP1 knockdown affects proliferation or invasion.NUSAP1 transcript levels are positively correlated with E2F1 and negatively correlated with RB1 transcript levels in prostate cancer microarray datasets. NUSAP1 expression is elevated in the RB1-null DU145 prostate cancer cell line, as opposed to LNCaP and PC-3 cell lines. Furthermore, NUSAP1 expression increases upon knockdown of RB1 in prostate cancer cell lines (LNCaP and PC-3) and decreases after knockdown of E2F1. Lastly, knockdown of NUSAP1 in DU145 cells or PC-3 cells with stable knockdown of RB1 decreases proliferation and invasion of these cells.Our studies support the notion that NUSAP1 expression is upregulated by loss of RB1 via the RB1/E2F1 axis in prostate cancer cells. Such upregulation may promote prostate cancer progression by increasing proliferation and invasion of prostate cancer cells. NUSAP1 may thus represent a novel therapeutic target. Prostate 75: 517-526, 2015. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.22938

    View details for PubMedID 25585568

  • 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

  • PTEN Status Determination in Prostate Cancer: Comparison of IHC and FISH in a Large Multi-Center Cohort Lotan, T., Morais, C., Wei, W., Troyer, D., Jamaspishvili, T., Feng, Z., McKenney, J., Simko, J., Brooks, J., Squire, J. NATURE PUBLISHING GROUP. 2015: 241A
  • PTEN Status Determination in Prostate Cancer: Comparison of IHC and FISH in a Large Multi-Center Cohort Lotan, T., Moray, C., Wei, W., Troyer, D., Jamaspishvili, T., McKenney, J., Simko, J., Brooks, J., Squire, J. NATURE PUBLISHING GROUP. 2015: 241A
  • A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers. PloS one Jokerst, J. V., Chen, Z., Xu, L., Nolley, R., Chang, E., Mitchell, B., Brooks, J. D., Gambhir, S. S. 2015; 10 (9): e0139484


    Novel biomarker assays and upgraded analytical tools are urgently needed to accurately discriminate benign prostatic hypertrophy (BPH) from prostate cancer (CaP). To address this unmet clinical need, we report a piezeoelectric/magnetic bead-based assay to quantitate prostate specific antigen (PSA; free and total), prostatic acid phosphatase, carbonic anhydrase 1 (CA1), osteonectin, IL-6 soluble receptor (IL-6sr), and spondin-2. We used the sensor to measure these seven proteins in serum samples from 120 benign prostate hypertrophy patients and 100 Gleason score 6 and 7 CaP using serum samples previously collected and banked. The results were analyzed with receiver operator characteristic curve analysis. There were significant differences between BPH and CaP patients in the PSA, CA1, and spondin-2 assays. The highest AUC discrimination was achieved with a spondin-2 OR free/total PSA operation-the area under the curve was 0.84 with a p value below 10-6. Some of these data seem to contradict previous reports and highlight the importance of sample selection and proper assay building in the development of biomarker measurement schemes. This bead-based system offers important advantages in assay building including low cost, high throughput, and rapid identification of an optimal matched antibody pair.

    View details for DOI 10.1371/journal.pone.0139484

    View details for PubMedID 26421725

    View details for PubMedCentralID PMC4589536

  • DNA methylation profiling reveals novel diagnostic biomarkers in renal cell carcinoma. BMC medicine Lasseigne, B. N., Burwell, T. C., Patil, M. A., Absher, D. M., Brooks, J. D., Myers, R. M. 2014; 12 (1): 235


    BackgroundRenal cell carcinoma (RCC) is the tenth most commonly diagnosed cancer in the United States. While it is usually lethal when metastatic, RCC is successfully treated with surgery when tumors are confined to the kidney and have low tumor volume. Because most early stage renal tumors do not result in symptoms, there is a strong need for biomarkers that can be used to detect the presence of the cancer as well as to monitor patients during and after therapy.MethodsWe examined genome-wide DNA methylation alterations in renal cell carcinomas of diverse histologies and benign adjacent kidney tissues from 96 patients.ResultsWe observed widespread methylation differences between tumors and benign adjacent tissues, particularly in immune-, G-protein coupled receptor-, and metabolism-related genes. Additionally, we identified a single panel of DNA methylation biomarkers that reliably distinguishes tumor from benign adjacent tissue in all of the most common kidney cancer histologic subtypes, and a second panel does the same specifically for clear cell renal cell carcinoma tumors. This set of biomarkers were validated independently with excellent performance characteristics in more than 1,000 tissues in The Cancer Genome Atlas clear cell, papillary, and chromophobe renal cell carcinoma datasets.ConclusionsThese DNA methylation profiles provide insights into the etiology of renal cell carcinoma and, most importantly, demonstrate clinically applicable biomarkers for use in early detection of kidney cancer.

    View details for DOI 10.1186/s12916-014-0235-x

    View details for PubMedID 25472429

    View details for PubMedCentralID PMC4265327

  • Novel Fusion Transcripts Associate with Progressive Prostate Cancer AMERICAN JOURNAL OF PATHOLOGY Yu, Y. P., Ding, Y., Chen, Z., Liu, S., Michalopoulos, A., Chen, R., Gulzar, Z. G., Yang, B., Cieply, K. M., Luvison, A., Ren, B., Brooks, J. D., Jarrard, D., Nelson, J. B., Michalopoulos, G. K., Tseng, G. C., Luo, J. 2014; 184 (10): 2840-2849


    The mechanisms underlying the potential for aggressive behavior of prostate cancer (PCa) remain elusive. In this study, whole genome and/or transcriptome sequencing was performed on 19 specimens of PCa, matched adjacent benign prostate tissues, matched blood specimens, and organ donor prostates. A set of novel fusion transcripts was discovered in PCa. Eight of these fusion transcripts were validated through multiple approaches. The occurrence of these fusion transcripts was then analyzed in 289 prostate samples from three institutes, with clinical follow-up ranging from 1 to 15 years. The analyses indicated that most patients [69 (91%) of 76] positive for any of these fusion transcripts (TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, KDM4-AC011523.2, MAN2A1-FER, and CCNH-C5orf30) experienced PCa recurrence, metastases, and/or PCa-specific death after radical prostatectomy. These outcomes occurred in only 37% (58/157) of patients without carrying those fusion transcripts. Three fusion transcripts occurred exclusively in PCa samples from patients who experienced recurrence or PCa-related death. The formation of these fusion transcripts may be the result of genome recombination. A combination of these fusion transcripts in PCa with Gleason's grading or with nomogram significantly improves the prediction rate of PCa recurrence. Our analyses suggest that formation of these fusion transcripts may underlie the aggressive behavior of PCa.

    View details for DOI 10.1016/j.ajpath.2014.06.025

    View details for Web of Science ID 000342276800023

  • Higher rates of upgrading and upstaging in older patients undergoing radical prostatectomy and qualifying for active surveillance BJU INTERNATIONAL Busch, J., Magheli, A., Leva, N., Ferrari, M., Kramer, J., Klopf, C., Kempkensteffen, C., Miller, K., Brooks, J. D., Gonzalgo, M. L. 2014; 114 (4): 517-521

    View details for DOI 10.1111/bju.12466

    View details for Web of Science ID 000343007100012

  • The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magnetic resonance imaging Billingsley, K. L., Park, J. M., Josan, S., Hurd, R., Mayer, D., Spielman-Sun, E., Nishimura, D. G., Brooks, J. D., Spielman, D. 2014; 32 (7): 791-795


    Recent advancements in the field of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) have yielded powerful techniques capable of real-time analysis of metabolic pathways. These non-invasive methods have increasingly shown application in impacting disease diagnosis and have further been employed in mechanistic studies of disease onset and progression. Our goals were to investigate branched-chain aminotransferase (BCAT) activity in prostate cancer with a novel molecular probe, hyperpolarized [1-(13)C]-2-ketoisocaproate ([1-(13)C]-KIC), and explore the potential of branched-chain amino acid (BCAA) metabolism to serve as a biomarker. Using traditional spectrophotometric assays, BCAT enzymatic activities were determined in vitro for various sources of prostate cancer (human, transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse and human cell lines). These preliminary studies indicated that low levels of BCAT activity were present in all models of prostate cancer but enzymatic levels are altered significantly in prostate cancer relative to healthy tissue. The MR spectroscopic studies were conducted with two cellular models (PC-3 and DU-145) that exhibited levels of BCAA metabolism comparable to the human disease state. Hyperpolarized [1-(13)C]-KIC was administered to prostate cancer cell lines, and the conversion of [1-(13)C]-KIC to the metabolic product, [1-(13)C]-leucine ([1-(13)C]-Leu), could be monitored via hyperpolarized (13)C MRS.

    View details for DOI 10.1016/j.mri.2014.04.015

    View details for PubMedID 24907854

    View details for PubMedCentralID PMC4099288

  • The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-C-13]-ketoisocaproate MAGNETIC RESONANCE IMAGING Billingsley, K. L., Park, J., Josan, S., Hurd, R., Mayer, D., Spielman-Sun, E., Nishimura, D. G., Brooks, J. D., Spielman, D. 2014; 32 (7): 791–95
  • Increased Expression of GCNT1 is Associated With Altered O-glycosylation of PSA, PAP, and MUC1 in Human Prostate Cancers PROSTATE Chen, Z., Gulzar, Z. G., St Hill, C. A., Walcheck, B., Brooks, J. D. 2014; 74 (10): 1059-1067


    Protein glycosylation is a common posttranslational modification and glycan structural changes have been observed in several malignancies including prostate cancer. We hypothesized that altered glycosylation could be related to differences in gene expression levels of glycoprotein synthetic enzymes between normal and malignant prostate tissues.We interrogated prostate cancer gene expression data for reproducible changes in expression of glycoprotein synthetic enzymes. Over-expression of GCNT1 was validated in prostate samples using RT-PCR. ELISA was used to measure core 2 O-linked glycan sialyl Lewis X (sLe(x) ) of prostate specific antigen (PSA), Mucin1 (MUC1), and prostatic acidic phosphatase (PAP) proteins.A key glycosyltransferase, GCNT1, was consistently over-expressed in several prostate cancer gene expression datasets. RT-PCR confirmed increased transcript levels in cancer samples compared to normal prostate tissue in fresh-frozen prostate tissue samples. ELISA using PSA, PAP, and MUC1 capture antibodies and a specific core 2 O-linked sLe(x) detection antibody demonstrated elevation of this glycan structure in cancer compared to normal tissues for MUC1 (P = 0.01), PSA (P = 0.03) and near significant differences in PAP sLe(x) levels (P = 0.06). MUC1, PSA and PAP protein levels alone were not significantly different between paired normal and malignant prostate samples.GCNT1 is over-expressed in prostate cancer and is associated with higher levels of core 2 O-sLe(x) in PSA, PAP and MUC1 proteins. Alterations of O-linked glycosylation could be important in prostate cancer biology and could provide a new avenue for development of prostate cancer specific glycoprotein biomarkers. Prostate © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/pros.22826

    View details for Web of Science ID 000338039500007

    View details for PubMedID 24854630

  • Nationwide prevalence of lymph node metastases in Gleason score 3+3=6 prostate cancer PATHOLOGY Liu, J., Lichtensztajn, D. Y., Gomez, S., Sieh, W., Chung, B. I., Cheng, I., Brooks, J. D. 2014; 46 (4): 306-310
  • Measurement of urinary incontinence after prostate surgery from data-mining electronic health records (EHR). Hernandez-Boussard, T., Tamang, S., Brooks, J. D., Blayney, D. W., Shah, N. AMER SOC CLINICAL ONCOLOGY. 2014
  • Characterization of the mTOR autophosphorylation site, S2481, as a novel biomarker in renal cell carcinoma (RCC) Harshman, L., Muller, K., Lin, C., Brooks, J. D., Higgins, J., Berglin, J., Hunter, T., Copp, J. AMER SOC CLINICAL ONCOLOGY. 2014
  • 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

  • Prostate cancer risk profiles of asian-american men: disentangling the effects of immigration status and race/ethnicity. journal of urology Lichtensztajn, D. Y., Gomez, S. L., Sieh, W., Chung, B. I., Cheng, I., Brooks, J. D. 2014; 191 (4): 952-956


    Asian-American men with prostate cancer have been reported to present with higher grade and later stage disease than White Americans. However, Asian Americans comprise a heterogeneous population with distinct health outcomes. We compared prostate cancer risk profiles among the diverse racial and ethnic groups in California.We used data from the California Cancer Registry for 90,845 Non-Hispanic White, Non-Hispanic Black, and Asian-American men diagnosed with prostate cancer between 2004 and 2010. Patients were categorized into low, intermediate, or high-risk groups based on clinical stage, Gleason score, and PSA value at diagnosis. Using polytomous logistic regression, we estimated adjusted odds ratios for the association of race/ethnicity and nativity with risk group.In addition to Non-Hispanic Blacks, six Asian-American groups (US-born Chinese, foreign-born Chinese, US-born Japanese, foreign-born Japanese, foreign-born Filipino, and foreign-born Vietnamese) were more likely to have an unfavorable risk profile compared to Non-Hispanic Whites. The odds ratios for high vs. intermediate-risk disease ranged from 1.23 (95% CI, 1.02-1.49) for US-born Japanese to 1.45 (95% CI, 1.31-1.60) for foreign-born Filipinos. These associations appeared to be driven by higher grade and PSA values, rather than advanced clinical stage at diagnosis.In this large, ethnically diverse population-based cohort, we found that Asian-American men were more likely to have unfavorable risk profiles at diagnosis. This association varied by racial/ethnic group and nativity, and was not attributable to later stage at diagnosis, suggesting that Asian men may have biological differences that predispose to the development of more severe disease.

    View details for DOI 10.1016/j.juro.2013.10.075

    View details for PubMedID 24513166

  • Utilization of Renal Mass Biopsy in Patients With Renal Cell Carcinoma 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
  • 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

  • Nano-scale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC Leppert, J. T., Fan, A. C., Metzner, T., Liliental, J. E., Xu, L., Thong, A. E., Yost, C., Yaghi, A., Brooks, J. D., Harshman, L. C., Sabatti, C., Srinivas, S., Felsher, D. W. WILEY-BLACKWELL. 2013: 14
  • Identification and Characterization of 2 Testicular Germ Cell Markers, Glut3 and CyclinA2 APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Howitt, B. E., Brooks, J. D., Jones, S., Higgins, J. P. 2013; 21 (5): 401-407


    Testicular germ cell tumors (TGCT) are the most common type of testicular tumor and encompass different histologic types that greatly influence treatment and prognosis. Immunohistochemical studies may be required for accurate classification, particularly when these tumors present at extragonadal sites, and to aid in distinguishing histologic types. Traditional markers for identifying and distinguishing TGCT include PLAP, CD117, AFP, and CD30. More recently, the addition of OCT3/4 and SALL4 has increased sensitivity for immunohistochemical detection of germ cell tumors. We examined gene expression data from a previously published microarray study that compared normal testis mRNA expression to various TGCT. We also performed a search of the literature to identify less well-characterized markers. Glut3 and cyclinA2 showed promise as TGCT markers. Therefore, we evaluated expression of glut3 and cyclinA2 by immunohistochemistry using tissue microarrays (TMAs). Of 66 seminomas included in the TMA, 64 (97%) showed positive nuclear staining for cyclinA2 and 58 (88%) were strongly positive. Strong positive staining for cyclinA2 was also seen in the spermatocytic seminoma. All 20 of the embryonal carcinomas stained positively with cyclinA2, and 19 (95%) displayed strong nuclear staining for cyclinA2. Twenty of the 20 embryonal carcinomas stained for glut3 in a strong membranous pattern. Of 8 yolk sac tumors, 100% stained with glut3. We also evaluated glut3 and cyclinA2 staining on a general TMA containing 486 samples representing 156 different tumors. CyclinA2 stained a number of other tumor types, but the majority of these were weak or focal staining. Glut3 was rarely positive in other tumors; interestingly, most of these were of ovarian origin. We conclude that glut3 is a sensitive (96%) and specific (92%) marker for embryonal carcinomas and yolk sac tumors. Although cyclinA2 is a sensitive marker of seminomas and embryonal carcinomas (98%), its specificity is lower if focal and weak staining of nongerm cell tumors is considered positive. The sensitivity and specificity of glut3 are comparable with that seen for SALL4.

    View details for DOI 10.1097/PAI.0b013e31827b505f

    View details for Web of Science ID 000324837800004

    View details for PubMedID 23343953

  • NuSAP is regulated by RB1 and modulates prostate cancer progression Gordon, C. A., Gong, X., Gulzar, Z. G., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2013
  • Managing localized prostate cancer in the era of prostate-specific antigen screening. Cancer Brooks, J. D. 2013

    View details for DOI 10.1002/cncr.28301

    View details for PubMedID 24006273

    View details for PubMedCentralID PMC3875624

  • Smoking and adverse outcomes at radical prostatectomy UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Ngo, T. C., Lee, J. J., Brooks, J. D., Nolley, R., Ferrari, M., Presti, J. C. 2013; 31 (6): 749-754


    Multiple large epidemiologic studies have examined the relationship between smoking and prostate cancer incidence and mortality only to arrive at contradictory results. In this series, we studied the effect of smoking on pathologic outcomes and biochemical recurrence in a cohort of men undergoing radical prostatectomy.We identified 630 men who underwent radical prostatectomy between 1989 and 2005 who had detailed smoking histories. There were 321 smokers and 309 nonsmokers. Pathologic outcomes included prostate weight, volume of cancer, volume of high grade cancer, margin status, seminal vesicle involvement, extraprostatic extension, perineural invasion, angiolymphatic invasion, and the presence of nodal metastasis. Biochemical recurrence was defined as a postoperative PSA ≥ 0.1 ng/ml. Univariate analysis and multivariate linear and Cox regression were used to study the impact of smoking on these outcomes.The volume of cancer (2.54 vs. 2.16 ml, P = 0.016) and the volume of high grade cancer (0.58 vs. 0.28 ml, P = 0.004) were greater in smokers compared with nonsmokers. Smoking independently predicted greater volumes of cancer and high grade cancer in multivariate analysis. Heavy smokers (≥20 pack-year history) had a greater risk of biochemical recurrence on univariate survival analysis. Smoking also predicted a greater risk of biochemical recurrence on Cox regression, the magnitude of which was approximately 1% per pack-year smoked.Smoking is associated with adverse pathologic features and a higher risk of biochemical recurrence in men undergoing radical prostatectomy. If confirmed by additional studies, smoking history may need to be included into risk assessment models.

    View details for DOI 10.1016/j.urolonc.2011.06.013

    View details for Web of Science ID 000322681800006

    View details for PubMedID 21824793

  • Evaluation of SF-1 Expression in Testicular Germ Cell Tumors: A Tissue Microarray Study of 127 Cases. Applied immunohistochemistry & molecular morphology Sangoi, A. R., McKenney, J. K., Brooks, J. D., Higgins, J. P. 2013; 21 (4): 318-321


    Differentiating testicular germ cell tumors from sex-cord stromal tumors can be difficult in certain cases because of overlapping morphologic features and/or an absence of clinically apparent hormonal symptoms. Immunohistochemistry may be needed as an ancillary diagnostic tool in this differential diagnostic setting. Steroidogenic factor-1 (SF-1) is a nuclear transcription factor controlling steroidogenesis and is expressed in developing Sertoli and Leydig cells. Although 1 recent study has reported SF-1 nuclear immunoreactivity in testicular sex-cord stromal tumors, the specificity for this marker in germ cell tumors has not been evaluated. After encountering several problematic cases (including some on testicular biopsy), we sought to determine the diagnostic specificity of SF-1 in a large series of germ cell tumors. Nuclear immunohistochemical expression of SF-1 was evaluated in 127 germ cell tumors using tissue microarray technology with 23 non-germ cell tumor tissues as positive internal controls. No nuclear SF-1 expression was identified in any of the 127 germ cell tumors [including choriocarcinoma (3), embryonal carcinoma (25), epidermal inclusion cyst (1), intratubular germ cell neoplasia unclassified (4), seminoma (72), spermatocytic seminoma (2), teratoma (8), and yolk sac tumor (12)]. All 23 non-germ cell tumor tissues showed strong nuclear SF-1 expression in Sertoli and/or Leydig cells [including testicular atrophy (10), cryptorchidism (2), normal testis (4), hypospermatogenesis (1), immature testis (1), intratubular large cell calcifying Sertoli cell tumor (1), Leydig cell tumor (3), and Sertoli only (1)]. This study documents the absence of SF-1 expression in testicular germ cell tumors and supports its specificity for sex-cord stromal lesions in this diagnostic context.

    View details for DOI 10.1097/PAI.0b013e318277cf5a

    View details for PubMedID 23165333

  • Epigenetic changes in histologically normal prostate tissues. journal of urology Brooks, J. D. 2013; 189 (6): 2020-2021

    View details for DOI 10.1016/j.juro.2013.02.3193

    View details for PubMedID 23465550

  • Comprehensive Gene Expression Changes Associated with Mouse Postnatal Kidney Development JOURNAL OF UROLOGY Wu, B., Sahoo, D., Brooks, J. D. 2013; 189 (6): 2385-2390
  • Comprehensive gene expression changes associated with mouse postnatal kidney development. journal of urology Wu, B., Sahoo, D., Brooks, J. D. 2013; 189 (6): 2385-2390


    To provide a portrait of the molecular alterations in renal growth that occur in mice postnatally, we performed gene expression profiling at discrete time points during the first 5 weeks of life.Kidneys were harvested from C57BL/6 mice at embryonic day 19.5, and postnatal days 1, 3, 5, 7, 10, 14, 21, 28 and 35. Total RNA was extracted and gene expression profiling was done using microarrays (Agilent Technologies, Santa Clara, California). Transcripts whose expression levels changed during the study course were identified using StepMiner software ( Biological functions of the modulated genes were identified using IPA® software.Postnatal kidney growth and development are associated with widespread changes in gene expression with 6,949 transcripts significantly up-regulated and 6,696 down-regulated during the first 5 weeks of life. Pathway analysis showed progressive down-regulation of pathways associated with cell growth and embryonic development (postnatal days 5 to 7). This was followed by increased expression of transcripts associated with lipid/energy metabolism and molecular transport (postnatal days 10 to 14), and down-regulation of genes related to DNA replication, cell cycle, tissue development, protein trafficking and cell morphology (postnatal days 14 to 21).To our knowledge we report the most comprehensive temporal survey of postnatal kidney development to date. This data set provides a framework for interpreting nephropathy, such as that induced by congenital obstruction.

    View details for DOI 10.1016/j.juro.2012.12.002

    View details for PubMedID 23220383

  • Liquid biopsy-based assays to monitor residual disease in cancer. Mei, G., Sebisanovic, D., Mir, A., Gulzar, Z., Brooks, J. D., Jeffrey, S. S., Talasaz, A. AMER SOC CLINICAL ONCOLOGY. 2013
  • The impact of reducing the frequency of prostate specific antigen (PSA) testing among men on active surveillance for prostate cancer Cooperberg, M. R., Newcomb, L. F., Brown, E. C., Zhao, S., Feng, Z., Brooks, J. D., Lin, D. W., Canary PASS Investigators AMER SOC CLINICAL ONCOLOGY. 2013
  • Urinary TMPRSS2:ERG and PCA3 in an Active Surveillance Cohort: Results from a Baseline Analysis in the Canary Prostate Active Surveillance Study CLINICAL CANCER RESEARCH Lin, D. W., Newcomb, L. F., Brown, E. C., Brooks, J. D., Carroll, P. R., Feng, Z., Gleave, M. E., Lance, R. S., Sanda, M. G., Thompson, I. M., Wei, J. T., Nelson, P. S. 2013; 19 (9): 2442-2450


    Active surveillance is used to manage low-risk prostate cancer. Both PCA3 and TMPRSS2:ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.Urine was collected after digital rectal examination prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2:ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.In 387 men, both PCA3 and TMPRSS2:ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1% to 10%, 11% to 33%, 34% or more positive cores, median PCA3, and TMPRSS2:ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2:ERG scores were also significantly associated with the presence of high-grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3, and TMPRSS2:ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as continuous variables, the ORs for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI: 1.07-1.85), P = 0.01 for PCA3 and 1.28 (95% CI: 1.10-1.49), P = 0.001 for TMPRSS2:ERG.For men on active surveillance, both PCA3 and TMPRSS2:ERG seem to stratify the risk of having aggressive cancer as defined by tumor volume or Gleason score.

    View details for DOI 10.1158/1078-0432.CCR-12-3283

    View details for Web of Science ID 000318361900018

    View details for PubMedID 23515404

    View details for PubMedCentralID PMC3674574

  • NANO-SCALE PROTEOMIC PROFILING TO DEFINE DIAGNOSTIC SIGNATURES AND BIOMARKERS OF THERAPEUTIC ACTIVITY IN RCC Leppert, J., Fan, A., Liliental, J., Xu, L., Thong, A., Yost, C., Yaghi, A., Metzner, T., Brooks, J., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. ELSEVIER SCIENCE INC. 2013: E246–E247
  • Association of declining PSA values with a lower risk of progression in the Canary Prostate Cancer Active Surveillance Study (PASS) Brooks, J. D., Brown, E. C., Cooperberg, M. R., Newcomb, L. F., Carroll, P., Feng, Z., Gleave, M., Lance, R., Sanda, M. G., Thompson, I., Wei, J., Nelson, P., Lin, D. W. AMER SOC CLINICAL ONCOLOGY. 2013
  • Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC Fan, A. C., Leppert, J., Liliental, J. E., Xu, L., Thong, A. E., Yost, C., Yaghi, A., Brooks, J. D., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2013
  • Increased expression of NuSAP in recurrent prostate cancer is mediated by E2F1 ONCOGENE Gulzar, Z. G., McKenney, J. K., Brooks, J. D. 2013; 32 (1): 70-77


    Increasing evidence suggests that prostate cancer is overdiagnosed and overtreated, and prognostic biomarkers would aid in treatment selection. To define prognostic biomarkers for aggressive prostate cancer, we carried out gene-expression profiling of 98 prostate tumors and 52 benign adjacent prostate tissue samples with detailed clinical annotation. We identified 28 transcripts significantly associated with recurrence after radical prostatectomy including NuSAP, a protein that binds DNA to the mitotic spindle. Elevated NuSAP transcript levels were associated with poor outcome in two independent prostate cancer gene-expression datasets. To characterize the role and regulation of NuSAP in prostate cancer, we studied the expression of NuSAP in the LNCaP and PC3 human prostate cancer cell lines. Posttranscriptional silencing of the NuSAP gene severely hampered the ability of PC3 to invade and proliferate in vitro. The promoter region of the NuSAP gene contains two CCAAT boxes and binding sites for E2F. Transient transfection of an E2F1 cDNA and 431 bp of the NuSAP promoter demonstrated E2F1 as an important regulator of expression. Deletion of the E2F-binding site at nucleotide -246 negated the effects of E2F1 on NuSAP expression. Electrophoretic mobility shift assays demonstrated that nuclear extracts of cells overexpressing E2F1 bound directly to the E2F-binding site in the NuSAP promoter region. Finally, immunohistochemistry showed a strong correlation between E2F1 and NuSAP expression in human prostate cancer samples. NuSAP is a novel biomarker for prostate cancer recurrence after surgery and its overexpression appears to be driven in part by E2F1 activation.

    View details for DOI 10.1038/onc.2012.27

    View details for Web of Science ID 000313029500007

    View details for PubMedID 22349817

    View details for PubMedCentralID PMC3360134

  • Treatment and Mortality in Men with Localized Prostate Cancer: A Population-Based Study in California. The open prostate cancer journal Sieh, W., Lichtensztajn, D. Y., Nelson, D. O., Cockburn, M., West, D. W., Brooks, J. D., Chang, E. T. 2013; 6: 1-9


    To provide patients and physicians with population-based estimates of mortality from prostate cancer or other causes depending upon the primary treatment modality, stratified by patient age, tumor stage and grade.We conducted a 10-year competing-risk analysis of 45,440 men diagnosed with clinically localized (T1 or T2) prostate cancer in California during 1995-1998. Information on patient characteristics, primary treatment and cause of death was obtained from the California Cancer Registry.In this population-based cohort, the most common primary treatment was surgery (40.4%), followed by radiotherapy (29.1%), conservative management (20.8%), and androgen deprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p < 0.0001) across treatment groups among patients <80 years at diagnosis with moderately or poorly differentiated disease; the 10-year disease-specific mortality rates were generally highest for men treated with ADT monotherapy [range: 3.3% (95% CI=0.8-12.5%) to 53.8% (95% CI=34.4-72.2%)], intermediate for men treated with conservative management [range: 1.7% (95% CI=0.7-4.6%) to 30.0% (95% CI=16.2-48.8%] or radiotherapy [range: 3.2% (95% CI=1.8-5.5%) to 18.3% (95% CI=15.1-22.0%)], and lowest for men treated with surgery [range: 1.2% (95% CI=0.8-1.7%) to 11.0% (95% CI=8.4-14.2%)].The cause-specific mortality estimates provided by this observational study can help patients and physicians better understand the expected long-term outcomes of localized prostate cancer given the initial treatment choice and practice patterns in the general population.

    View details for PubMedID 23997838

  • Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape GENOME BIOLOGY Day, K., Waite, L. L., Thalacker-Mercer, A., West, A., Bamman, M. M., Brooks, J. D., Myers, R. M., Absher, D. 2013; 14 (9)


    DNA methylation is an epigenetic modification that changes with age in human tissues, although the mechanisms and specificity of this process are still poorly understood. We compared CpG methylation changes with age across 283 human blood, brain, kidney, and skeletal muscle samples using methylation arrays to identify tissue-specific age effects.We found age-associated CpGs (ageCGs) that are both tissue-specific and common across tissues. Tissue-specific ageCGs are frequently located outside CpG islands with decreased methylation, and common ageCGs show the opposite trend. AgeCGs are significantly associated with poorly expressed genes, but those with decreasing methylation are linked with higher tissue-specific expression levels compared with increasing methylation. Therefore, tissue-specific gene expression may protect against common age-dependent methylation. Distinguished from other tissues, skeletal muscle ageCGs are more associated with expression, enriched near genes related to myofiber contraction, and closer to muscle-specific CTCF binding sites. Kidney-specific ageCGs are more increasingly methylated compared to other tissues as measured by affiliation with kidney-specific expressed genes. Underlying chromatin features also mark common and tissue-specific age effects reflective of poised and active chromatin states, respectively. In contrast with decreasingly methylated ageCGs, increasingly methylated ageCGs are also generally further from CTCF binding sites and enriched within lamina associated domains.Our data identified common and tissue-specific DNA methylation changes with age that are reflective of CpG landscape and suggests both common and unique alterations within human tissues. Our findings also indicate that a simple epigenetic drift model is insufficient to explain all age-related changes in DNA methylation.

    View details for DOI 10.1186/gb-2013-14-9-r102

    View details for Web of Science ID 000328195700008

    View details for PubMedID 24034465

  • A Model for the Design and Construction of a Resource for the Validation of Prognostic Prostate Cancer Biomarkers: The Canary Prostate Cancer Tissue Microarray ADVANCES IN ANATOMIC PATHOLOGY Hawley, S., Fazli, L., McKenney, J. K., Simko, J., Troyer, D., Nicolas, M., Newcomb, L. F., Cowan, J. E., Crouch, L., Ferrari, M., Hernandez, J., Hurtado-Coll, A., Kuchinsky, K., Liew, J., Mendez-Meza, R., Smith, E., Tenggara, I., Zhang, X., Carroll, P. R., Chan, J. M., Gleave, M., Lance, R., Lin, D. W., Nelson, P. S., Thompson, I. M., Feng, Z., True, L. D., Brooks, J. D. 2013; 20 (1): 39-44


    Tissue microarrays (TMAs) provide unique resources for rapid evaluation and validation of tissue biomarkers. The Canary Foundation Retrospective Prostate Tissue Microarray Resource used a rigorous statistical design, quota sampling, a variation of the case-cohort study, to select patients for inclusion in a multicenter, retrospective prostate cancer TMA cohort. The study is designed to definitively validate tissue biomarkers of prostate cancer recurrence after radical prostatectomy. Tissue samples from over 1000 participants treated for prostate cancer with radical prostatectomy between 1995 and 2004 were selected at 6 participating institutions in the United States and Canada. This design captured the heterogeneity of screening and clinical practices in the contemporary North American population. Standardized clinical data were collected in a centralized database. The project has been informative in several respects. The scale and complexity of assembling TMAs with over 200 cases at each of 6 sites involved unanticipated levels of effort and time. Our statistical design promises to provide a model for outcome-based studies where tissue localization methods are applied to high-density TMAs.

    View details for DOI 10.1097/PAP.0b013e31827b665b

    View details for Web of Science ID 000312346800005

    View details for PubMedID 23232570

    View details for PubMedCentralID PMC3535290

  • mRNA-Seq of Single Prostate Cancer Circulating Tumor Cells Reveals Recapitulation of Gene Expression and Pathways Found in Prostate Cancer PLOS ONE Cann, G. M., Gulzar, Z. G., Cooper, S., Li, R., Luo, S., Tat, M., Stuart, S., Schroth, G., Srinivas, S., Ronaghi, M., Brooks, J. D., Talasaz, A. H. 2012; 7 (11)


    Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

    View details for DOI 10.1371/journal.pone.0049144

    View details for Web of Science ID 000311935800219

    View details for PubMedID 23145101

    View details for PubMedCentralID PMC3492322

  • Evaluation of Putative Renal Cell Carcinoma Markers PAX-2, PAX-8, and hKIM-1 in Germ Cell Tumors: A Tissue Microarray Study of 100 Cases APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Sangoi, A. R., McKenney, J. K., Brooks, J. D., Bonventre, J. V., Higgins, J. P. 2012; 20 (5): 451-453


    In a subset of cases, metastatic renal cell carcinoma can demonstrate significant morphologic overlap with germ cell neoplasms, making accurate diagnosis challenging. In such cases, immunohistochemistry is often used as an adjunct diagnostic tool. Expression of the putative renal cell carcinoma markers PAX-2, PAX-8, and hKIM-1 has been reported in a small series of certain germ cell tumors, raising doubt about their specificity for renal cell carcinoma. To further characterize these markers, we evaluated PAX-2, PAX-8, and hKIM-1 staining in 100 germ cell tumors using tissue microarrays. PAX-2 and PAX-8 staining was identified in 50% and 25% of yolk sac tumors (respectively), with hKIM-1 staining identified in 48% of embryonal carcinomas and 50% of yolk sac tumors. All other germ tumor cells (notably including 62 seminomas) were negative for all 3 markers, in contrast to prior reports of PAX-8 reactivity in seminoma. This study indicates that PAX-2, PAX-8, and hKIM-1 should be used cautiously in distinguishing renal cell carcinoma from nonseminomatous germ cell neoplasia and also adds to the growing list of nonrenal tumors that express these 3 markers.

    View details for DOI 10.1097/PAI.0b013e31824bb404

    View details for Web of Science ID 000309551700003

    View details for PubMedID 22495365

  • Gene Expression Changes Induced by Unilateral Ureteral Obstruction in Mice JOURNAL OF UROLOGY Wu, B., Brooks, J. D. 2012; 188 (3): 1033-1041


    Loss of renal function is often the impetus for operative intervention in renal obstruction cases. Obstructive nephropathy is characterized by discrete morphological and physiological changes, including tubular dilatation, apoptosis and atrophy as well as interstitial cellular infiltration and progressive interstitial fibrosis. We hypothesized that gene expression alterations correlate with obstructive nephropathy and could serve as biomarkers for early intervention.C57BL/6 mice were subjected to unilateral ureteral obstruction or sham surgery at postnatal day 21. Kidneys were harvested 1, 2, 5 and 9 days postoperatively. RNA was extracted from kidneys and comprehensive gene expression profiling was performed with microarrays. IPA® pathway analysis software was used to analyze the biological function and gene networks of gene expression data.Microarray analysis revealed more than 1,800 transcripts that were up-regulated or down-regulated during days 1 through 9 after obstruction, including many previously reported transcripts (FOS, CD44, CLU, SPP1 and EGF). Pathway analysis showed significant enrichment of transcripts in cell activation/differentiation, immune/inflammatory responses, cell cycle, metabolic process and transport. Network analysis using IPA showed that transcriptional regulatory pathways involving CEBPB and HNF4A are involved in obstructive nephropathy.This data set provides a foundation for development of biomarkers for obstructive nephropathy.

    View details for DOI 10.1016/j.juro.2012.05.004

    View details for Web of Science ID 000307551200115

    View details for PubMedID 22819101

  • PIVOT and the challenges of localized prostate cancer care. Translational andrology and urology Weinberg, A. E., Brooks, J. D. 2012; 1 (3): 141-3

    View details for DOI 10.3978/j.issn.2223-4683.2012.08.01

    View details for PubMedID 26816701

    View details for PubMedCentralID PMC4708249

  • Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness ONCOGENE Huang, S., Gulzar, Z. G., Salari, K., Lapointe, J., Brooks, J. D., Pollack, J. R. 2012; 31 (37): 4164-4170


    Though prostate cancer is often indolent, it is nonetheless a leading cause of cancer death. Defining the underlying molecular genetic alterations may lead to new strategies for prevention or treatment. Towards this goal, we performed array-based comparative genomic hybridization (CGH) on 86 primary prostate tumors. Among the most frequent alterations not associated with a known cancer gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Expression of CHD1 was significantly reduced in tumors with deletion (P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4) and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2 and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers, and indicate a possible novel role of altered chromatin remodeling in prostate tumorigenesis.

    View details for DOI 10.1038/onc.2011.590

    View details for Web of Science ID 000308688900008

    View details for PubMedID 22179824

  • Methods for registration of magnetic resonance images of ex vivo prostate specimens with histology JOURNAL OF MAGNETIC RESONANCE IMAGING Kimm, S. Y., Tarin, T. V., Lee, J. H., Hu, B., Jensen, K., Nishimura, D., Brooks, J. D. 2012; 36 (1): 206-212


    To evaluate two methods of scanning and tissue processing to achieve accurate magnetic resonance (MR)-histologic correlation in human prostate specimens.Two prostates had acrylic paint markers injected to define the plane of imaging and serve as internal fiducials. Each was placed on a polycarbonate plane-finder device (PFD), which was adjusted to align the imaging and cutting planes. Three prostates were aligned by use of a plane finder key (PFK), a polycarbonate plate that locks the specimen in a cylindrical carrier. Markers were injected for registration analysis. Prostates were imaged, then sectioned. Imaging software was used to create registration maps of the MR and histology images. Measurements between control points were made and compared.Accurate correlation was achieved between MR and histologic images. The mean displacement (MD) between the corresponding registration points using the PFD technique ranged from 1.11-1.38 mm for each section. The MD for all sections was 1.24 mm. The MD using the PFK technique ranged from 0.79-1.01 mm for each section, and the MD across all sections for the PFK was 0.92 mm.We describe two methods that can achieve accurate, reproducible correlation between MR imaging and histologic sections in human prostatectomy specimens.

    View details for DOI 10.1002/jmri.23614

    View details for PubMedID 22359365

  • Evaluation of SF-1 Expression in Testicular Germ Cell Tumors: A Tissue Microarray Study of 100 Cases Sangoi, A. R., McKenney, J. K., Brooks, J. D., Higgins, J. P. OXFORD UNIV PRESS INC. 2012: A355
  • Even-skipped homeobox 1 is frequently hypermethylated in prostate cancer and predicts PSA recurrence BRITISH JOURNAL OF CANCER Truong, M., Yang, B., Wagner, J., Kobayashi, Y., Rajamanickam, V., Brooks, J., Jarrard, D. F. 2012; 107 (1): 100-107


    DNA methylation is an important epigenetic mechanism in prostate cancer (PCa) progression. Given the role of even-skipped homeobox 1 (EVX1) in the regulation of multiple genes during embryogenesis, we postulated that EVX1 methylation is altered in PCa progression.Bisulphite sequencing and quantitative MethyLight were used to assess methylation in human prostate epithelial cells, four PCa cell lines, liver, lung, spleen, kidney, 35 paired tumour and tumour-associated benign tissues, and 11 normal prostate tissues. Prostate cancer cell lines were treated with 5-azacytidine (AzaC) or trichostatin A (TSA), and expression of EVX1 transcript and variants was assessed by qPCR. Hypermethylation was compared with clinicopathological features in a validation set of 58 patients using microarray.Even-skipped homeobox 1 hypermethylation was observed in all four PCa cell lines and 57% of tumours. High-grade tumours exhibited increased methylation compared with intermediate-grade tumours. Even-skipped homeobox 1 expression was induced in PCa cell lines after treatment with AzaC or TSA. In the validation set, 83% of tumours were hypermethylated and hypermethylation was associated with worse recurrence-free survival.In this first evaluation of EVX1 methylation in human cancer, EVX1 is one of the most commonly hypermethylated genes observed in PCa and predicted treatment failure in moderate risk patients.

    View details for DOI 10.1038/bjc.2012.216

    View details for Web of Science ID 000305888400015

    View details for PubMedID 22596233

    View details for PubMedCentralID PMC3389415

  • Performance Characteristics of Prostate-specific Antigen in Patients Undergoing Radical Prostatectomy UROLOGY Liu, J., Ferrari, M., Nolley, R., Brooks, J. D., Presti, J. C. 2012; 79 (6): 1336-1339


    To assess the performance characteristics of prostate-specific antigen (PSA) for predicting the volume of total or high-grade cancer in men undergoing radical prostatectomy. It is known that the performance characteristics of PSA are improved for predicting the presence of high-grade prostate cancer.We identified 1459 patients from the Stanford Radical Prostatectomy Database with clinical Stage T1c (n = 783) and T2 (n = 676) disease who underwent surgery from 1988 to 2003 with detailed morphometric mapping. We generated receiver operating characteristic curves for PSA levels according to the total and high-grade (Gleason score 4 or 5) cancer volume and compared the areas under the curve (AUC) for the various total and high-grade cancer volumes.For patients with Stage T1c disease, the AUC for the PSA ROC curve increased in a stepwise fashion as both the total cancer volume and the high-grade cancer volume increased. Significant differences between the AUCs for low and high volumes of total and high-grade disease were observed. For T2 disease, the AUCs for predicting high-grade cancer volume were generally greater than the corresponding AUCs for T1c disease, although no incremental increase was observed.In patients with Stage T1c disease, in whom the PSA level was the driving force for biopsy, the PSA performance improved in a stepwise fashion with greater total and high-grade cancer volumes as evidenced by improved ROC. Previous studies have shown that PSA performs better for detecting the presence of high-grade disease. We have shown that PSA performs better in predicting greater volumes of high-grade disease in radical prostatectomy specimens.

    View details for DOI 10.1016/j.urology.2012.02.036

    View details for Web of Science ID 000304720600046

    View details for PubMedID 22516358

  • Use of nano-immuno assay to generate rapid, quantitative nanoscale proteomic profiling of the hypoxia pathway in renal cell carcinoma clinical specimens. Fan, A. C., Banerjee, P., Leppert, J., Harshman, L., Sabatti, C., Brooks, J. D., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2012
  • Deficiency in Mammalian Histone H2B Ubiquitin Ligase Bre1 (Rnf20/Rnf40) Leads to Replication Stress and Chromosomal Instability CANCER RESEARCH Chernikova, S. B., Razorenova, O. V., Higgins, J. P., Sishc, B. J., Nicolau, M., Dorth, J. A., Chernikova, D. A., Kwok, S., Brooks, J. D., Bailey, S. M., Game, J. C., Brown, J. M. 2012; 72 (8): 2111-2119


    Mammalian Bre1 complexes (BRE1A/B (RNF20/40) in humans and Bre1a/b (Rnf20/40) in mice) function similarly to their yeast homolog Bre1 as ubiquitin ligases in monoubiquitination of histone H2B. This ubiquitination facilitates methylation of histone H3 at K4 and K79, and accounts for the roles of Bre1 and its homologs in transcriptional regulation. Recent studies by others suggested that Bre1 acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. In this study, we present an additional mechanism of tumor suppression by Bre1 through maintenance of genomic stability. We track the evolution of genomic instability in Bre1-deficient cells from replication-associated double-strand breaks (DSB) to specific genomic rearrangements that explain a rapid increase in DNA content and trigger breakage-fusion-bridge cycles. We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells. Combined with a previously reported defect in homologous recombination, generation of R-loops is a likely initiator of replication stress and genomic instability in Bre1-deficient cells. We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma.

    View details for DOI 10.1158/0008-5472.CAN-11-2209

    View details for Web of Science ID 000302905700022

    View details for PubMedID 22354749

    View details for PubMedCentralID PMC3328627

  • Treatment and mortality in men with localized prostate cancer: A population-based study in California Sieh, W., Lichtensztajn, D. Y., Nelson, D. O., Cockburn, M., West, D. W., Brooks, J. D., Chang, E. T. AMER ASSOC CANCER RESEARCH. 2012
  • Urinary TMPRSS2: Use of ERG and PCA3 to predict tumor volume and Gleason grade in an active surveillance cohort-Results from the Canary/EDRN Prostate Active Surveillance Study Lin, D. W., Newcomb, L. F., Brown, E. C., Brooks, J. D., Carroll, P., Feng, Z., Gleave, M. E., Lance, R., Sanda, M. G., Thompson, I., Wei, J., Nelson, P. AMER SOC CLINICAL ONCOLOGY. 2012
  • Performance characteristics of PSA in patients undergoing radical prostatectomy. Liu, J., Brooks, J. D., Ferrari, M., Nolley, R., Presti, J. C. AMER SOC CLINICAL ONCOLOGY. 2012
  • LONG-TERM OUTCOMES FROM A PROSPECTIVE TRIAL OF STEREOTACTIC BODY RADIOTHERAPY FOR LOW-RISK PROSTATE CANCER 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) King, C. R., Brooks, J. D., Gill, H., Presti, J. C. ELSEVIER SCIENCE INC. 2012: 877–82


    Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented.From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG).Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%).Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.

    View details for DOI 10.1016/j.ijrobp.2010.11.054

    View details for Web of Science ID 000299239900063

    View details for PubMedID 21300474

  • Translational genomics: The challenge of developing cancer biomarkers GENOME RESEARCH Brooks, J. D. 2012; 22 (2): 183-187


    Early detection and definitive treatment of cancer have been shown to decrease death and suffering in epidemiologic and intervention studies. Application of genomic approaches to many malignancies has produced thousands of candidate biomarkers for detection and prognostication, yet very few have become established in clinical practice. Fundamental issues related to tumor heterogeneity, cancer progression, natural history, and biomarker performance have provided challenges to biomarker development. Technical issues in biomarker assay detection limits, specificity, clinical deployment, and regulation have also slowed progress. The recent emergence of biomarkers and molecular imaging strategies for treatment selection and monitoring demonstrates the promise of cancer biomarkers. Organized efforts by interdisciplinary teams will spur progress in cancer diagnostics.

    View details for DOI 10.1101/gr.124347.111

    View details for Web of Science ID 000299606400002

    View details for PubMedID 22301132

    View details for PubMedCentralID PMC3266026

  • The Potential Impact of Reproducibility of Gleason Grading in Men With Early Stage Prostate Cancer Managed by Active Surveillance: A Multi-Institutional Study JOURNAL OF UROLOGY McKenney, J. K., Simko, J., Bonham, M., True, L. D., Troyer, D., Hawley, S., Newcomb, L. F., Fazli, L., Kunju, L. P., Nicolas, M. M., Vakar-Lopez, F., Zhang, X., Carroll, P. R., Brooks, J. D. 2011; 186 (2): 465-469


    We evaluated the reproducibility of Gleason grading as relevant to the clinical treatment of men on active surveillance.Three sets of digital images of prostatic adenocarcinoma in biopsies were reviewed and assigned Gleason scores by a total of 11 pathologists from 7 institutions. Interobserver and intra-observer reproducibility were assessed for assignment of the highest Gleason pattern (3 vs 4 or higher). We also identified 97 consecutive patients on active surveillance. Prostate biopsy glass slides from 82 of the patients were available for re-review and the frequency of carcinoma requiring the distinction of tangentially sectioned Gleason pattern 3 from 4 was determined.Interobserver reproducibility for classic Gleason patterns was substantial (Light's κ 0.76). Interobserver reproducibility for the histological distinction of tangentially sectioned Gleason pattern 3 from Gleason pattern 4 was only fair (Light's κ 0.27). Intra-observer reproducibility ranged from 65% to 100% (mean 81.5%). Of the 82 patients on active surveillance 61 had carcinoma and 15 (24.5%) had a set of biopsies with at least 1 focus in which the distinction between tangentially sectioned Gleason pattern 3 and poorly formed pattern 4 glands had to be considered.The reproducibility of grading classic Gleason patterns is high. However, variability in grading occurred when distinguishing between tangentially sectioned pattern 3 glands and the poorly formed gland subset of pattern 4. Developing universally accepted histological and/or molecular criteria to distinguish these patterns and subsequently characterizing their natural history would be useful when treating patients on active surveillance.

    View details for DOI 10.1016/j.juro.2011.03.115

    View details for Web of Science ID 000292545100030

    View details for PubMedID 21679996

  • DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer GENOME RESEARCH Kobayashi, Y., Absher, D. M., Gulzar, Z. G., Young, S. R., McKenney, J. K., Peehl, D. M., Brooks, J. D., Myers, R. M., Sherlock, G. 2011; 21 (7): 1017-1027


    Candidate gene-based studies have identified a handful of aberrant CpG DNA methylation events in prostate cancer. However, DNA methylation profiles have not been compared on a large scale between prostate tumor and normal prostate, and the mechanisms behind these alterations are unknown. In this study, we quantitatively profiled 95 primary prostate tumors and 86 benign adjacent prostate tissue samples for their DNA methylation levels at 26,333 CpGs representing 14,104 gene promoters by using the Illumina HumanMethylation27 platform. A 2-class Significance Analysis of this data set revealed 5912 CpG sites with increased DNA methylation and 2151 CpG sites with decreased DNA methylation in tumors (FDR < 0.8%). Prediction Analysis of this data set identified 87 CpGs that are the most predictive diagnostic methylation biomarkers of prostate cancer. By integrating available clinical follow-up data, we also identified 69 prognostic DNA methylation alterations that correlate with biochemical recurrence of the tumor. To identify the mechanisms responsible for these genome-wide DNA methylation alterations, we measured the gene expression levels of several DNA methyltransferases (DNMTs) and their interacting proteins by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in tumors. Subsequent transient transfection assays in cultured primary prostate cells revealed that DNMT3B1 and DNMT3B2 overexpression resulted in increased methylation of a substantial subset of CpG sites that showed tumor-specific increased methylation.

    View details for DOI 10.1101/gr.119487.110

    View details for Web of Science ID 000292298000003

    View details for PubMedID 21521786

    View details for PubMedCentralID PMC3129245

  • Integrated genomic analyses of ovarian carcinoma NATURE Bell, D., Berchuck, A., Birrer, M., Chien, J., Cramer, D. W., Dao, F., Dhir, R., Disaia, P., Gabra, H., Glenn, P., Godwin, A. K., GROSS, J., Hartmann, L., Huang, M., Huntsman, D. G., Iacocca, M., Imielinski, M., Kalloger, S., Karlan, B. Y., Levine, D. A., Mills, G. B., Morrison, C., Mutch, D., Olvera, N., Orsulic, S., Park, K., Petrelli, N., Rabeno, B., Rader, J. S., Sikic, B. I., Smith-McCune, K., Sood, A. K., Bowtell, D., PENNY, R., Testa, J. R., Chang, K., Dinh, H. H., Drummond, J. A., Fowler, G., Gunaratne, P., Hawes, A. C., Kovar, C. L., Lewis, L. R., Morgan, M. B., Newsham, I. F., Santibanez, J., Reid, J. G., Trevino, L. R., Wu, Y., Wang, M., Muzny, D. M., Wheeler, D. A., Gibbs, R. A., Getz, G., Lawrence, M. S., Cibulskis, K., Sivachenko, A. Y., Sougnez, C., VOET, D., Wilkinson, J., Bloom, T., Ardlie, K., Fennell, T., Baldwin, J., Gabriel, S., Lander, E. S., Ding, L., Fulton, R. S., Koboldt, D. C., McLellan, M. D., Wylie, T., Walker, J., O'Laughlin, M., Dooling, D. J., Fulton, L., Abbott, R., Dees, N. D., Zhang, Q., Kandoth, C., Wendl, M., Schierding, W., Shen, D., Harris, C. C., Schmidt, H., Kalicki, J., Delehaunty, K. D., Fronick, C. C., Demeter, R., Cook, L., Wallis, J. W., Lin, L., Magrini, V. J., Hodges, J. S., ELDRED, J. M., Smith, S. M., Pohl, C. S., Vandin, F., Raphael, B. J., Weinstock, G. M., Mardis, R., Wilson, R. K., Meyerson, M., Winckler, W., Getz, G., Verhaak, R. G., Carter, S. L., Mermel, C. H., Saksena, G., Nguyen, H., Onofrio, R. C., Lawrence, M. S., Hubbard, D., Gupta, S., Crenshaw, A., RAMOS, A. H., Ardlie, K., Chin, L., Protopopov, A., Zhang, J., Kim, T. M., Perna, I., Xiao, Y., Zhang, H., Ren, G., Sathiamoorthy, N., Park, R. W., Lee, E., Park, P. J., Kucherlapati, R., Absher, D. M., Waite, L., Sherlock, G., Brooks, J. D., Li, J. Z., Xu, J., Myers, R. M., Laird, P. W., Cope, L., Herman, J. G., Shen, H., Weisenberger, D. J., Noushmehr, H., Pan, F., Triche, T., Berman, B. P., Van den Berg, D. J., Buckley, J., BAYLIN, S. B., Spellman, P. T., Purdom, E., Neuvial, P., Bengtsson, H., Jakkula, L. R., Durinck, S., Han, J., Dorton, S., Marr, H., Choi, Y. G., Wang, V., Wang, N. J., Ngai, J., Conboy, J. G., Parvin, B., Feiler, H. S., Speed, T. P., Gray, J. W., Levine, D. A., Socci, N. D., Liang, Y., Taylor, B. S., Schultz, N., Borsu, L., Lash, A. E., Brennan, C., Viale, A., Sander, C., Ladanyi, M., Hoadley, K. A., Meng, S., Du, Y., Shi, Y., Li, L., Turman, Y. J., Zang, D., Helms, E. B., Balu, S., Zhou, X., Wu, J., Topal, M. D., Hayes, D. N., Perou, C. M., Getz, G., VOET, D., Saksena, G., Zhang, J., Zhang, H., Wu, C. J., Shukla, S., Cibulskis, K., Lawrence, M. S., Sivachenko, A., Jing, R., Park, R. W., Liu, Y., Park, P. J., Noble, M., Chin, L., Carter, H., Kim, D., Karchin, R., Spellman, P. T., Purdom, E., Neuvial, P., Bengtsson, H., Durinck, S., Han, J., Korkola, J. E., Heiser, L. M., Cho, R. J., Hu, Z., Parvin, B., Speed, T. P., Gray, J. W., Schultz, N., Cerami, E., Taylor, B. S., Olshen, A., Reva, B., Antipin, Y., Shen, R., Mankoo, P., Sheridan, R., Ciriello, G., Chang, W. K., Bernanke, J. A., Borsu, L., Levine, D. A., Ladanyi, M., Sander, C., Haussler, D., Benz, C. C., Stuart, J. M., Benz, S. C., Sanborn, J. Z., Vaske, C. J., Zhu, J., Szeto, C., Scott, G. K., Yau, C., Hoadley, K. A., Du, Y., Balu, S., Hayes, D. N., Perou, C. M., Wilkerson, M. D., Zhang, N., Akbani, R., Baggerly, K. A., YUNG, W. K., Mills, G. B., Weinstein, J. N., PENNY, R., Shelton, T., Grimm, D., Hatfield, M., Morris, S., Yena, P., Rhodes, P., Sherman, M., Paulauskis, J., Millis, S., Kahn, A., Greene, J. M., Sfeir, R., Jensen, M. A., Chen, J., Whitmore, J., Alonso, S., Jordan, J., Chu, A., Zhang, J., Barker, A., Compton, C., Eley, G., Ferguson, M., Fielding, P., Gerhard, D. S., Myles, R., Schaefer, C., Shaw, K. R., Vaught, J., Vockley, J. B., Good, P. J., Guyer, M. S., Ozenberger, B., Peterson, J., Thomson, E. 2011; 474 (7353): 609-615


    A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

    View details for DOI 10.1038/nature10166

    View details for Web of Science ID 000292204300032

    View details for PubMedID 21720365

    View details for PubMedCentralID PMC3163504

  • Small Prostate Size and High Grade Disease-Biology or Artifact? JOURNAL OF UROLOGY Liu, J., Brooks, J. D., Ferrari, M., Nolley, R., Presti, J. C. 2011; 185 (6): 2108-2111


    Prior radical prostatectomy series have shown an inverse association between prostate size and high grade cancer. It has been suggested that smaller size prostates arise in a low androgen environment, enabling development of more aggressive cancer. We propose that this observation is the result of ascertainment bias driven by prostate specific antigen performance.We identified 1,404 patients from the Stanford Radical Prostatectomy Database with clinical stage T1c (723) and T2 (681) disease who underwent surgery between 1988 and 2002, and underwent detailed morphometric mapping by a single pathologist. Multivariate linear regression was performed to assess for the effects of age, prostate weight and prostate specific antigen on total and high grade (Gleason grade 4/5) cancer volume and percentage of high grade disease.In patients who underwent biopsy due to abnormal prostate specific antigen (stage T1c), prostate weight was negatively associated (p = 0.0002) with total cancer volume, volume of high grade disease and percentage of high grade disease. For patients who underwent biopsy based on abnormal digital rectal examination (stage T2) these associations were not observed.Improved prostate specific antigen performance for high grade disease results in ascertainment bias in patients with T1c disease. Thus, the association between prostate size and high grade disease may be a consequence of grade dependent performance of prostate specific antigen rather than true tumor biology.

    View details for DOI 10.1016/j.juro.2011.02.053

    View details for Web of Science ID 000290389600027

    View details for PubMedID 21496855

  • A Tri-Marker Proliferation Index Predicts Biochemical Recurrence after Surgery for Prostate Cancer PLOS ONE Malhotra, S., Lapointe, J., Salari, K., Higgins, J. P., Ferrari, M., Montgomery, K., van de Rijn, M., Brooks, J. D., Pollack, J. R. 2011; 6 (5)


    Prostate cancer exhibits tremendous variability in clinical behavior, ranging from indolent to lethal disease. Better prognostic markers are needed to stratify patients for appropriately aggressive therapy. By expression profiling, we can identify a proliferation signature variably expressed in prostate cancers. Here, we asked whether one or more tissue biomarkers might capture that information, and provide prognostic utility. We assayed three proliferation signature genes: MKI67 (Ki-67; also a classic proliferation biomarker), TOP2A (DNA topoisomerase II, alpha), and E2F1 (E2F transcription factor 1). Immunohistochemical staining was evaluable on 139 radical prostatectomy cases (in tissue microarray format), with a median clinical follow-up of eight years. Each of the three proliferation markers was by itself prognostic. Notably, combining the three markers together as a "proliferation index" (0 or 1, vs. 2 or 3 positive markers) provided superior prognostic performance (hazard ratio = 2.6 (95% CI: 1.4-4.9); P = 0.001). In a multivariate analysis that included preoperative serum prostate specific antigen (PSA) levels, Gleason grade and pathologic tumor stage, the composite proliferation index remained a significant predictor (P = 0.005). Analysis of receiver-operating characteristic (ROC) curves confirmed the improved prognostication afforded by incorporating the proliferation index (compared to the clinicopathologic data alone). Our findings highlight the potential value of a multi-gene signature-based diagnostic, and define a tri-marker proliferation index with possible utility for improved prognostication and treatment stratification in prostate cancer.

    View details for DOI 10.1371/journal.pone.0020293

    View details for PubMedID 21629784

  • Comparison of prostate cancer tumor volume and percent cancer in prediction of biochemical recurrence and cancer specific survival 103rd Annual Meeting of the American-Urological-Association Chung, B. I., Tarin, T. V., Ferrari, M., Brooks, J. D. ELSEVIER SCIENCE INC. 2011: 314–18


    Tumor volume and percent cancer (ratio of tumor volume/prostate volume) have been proposed as predictors of biochemical recurrence and cancer specific survival after radical prostatectomy. However, their relative merits as prognosticators have not been tested. We therefore evaluated and compared tumor volume and percent cancer as independent predictors of biochemical recurrence and prostate cancer specific death after radical prostatectomy.A retrospective review of 739 patients who underwent radical prostatectomy for prostate cancer between 1984 and 2004 was conducted. Median follow-up was 91.7 months, and 22 patients died of prostate cancer. Univariate and multivariate analysis evaluated the following factors in predicting biochemical recurrence and prostate cancer specific death: tumor volume, prostate volume, percent cancer, Gleason score, percentage of Gleason grade 4/5, margin status, capsular invasion status, seminal vesicle invasion status, preoperative PSA, and lymph node status.In univariate analysis, both tumor volume (P<0.001) and percent cancer (P<0.001) significantly correlated with biochemical recurrence. Since they are highly correlated, they did not predict outcome independently when included in the same model; however, both were highly predictive for biochemical recurrence in separate multivariate models (P=0.01 for both). Both also correlated with cancer specific survival as single variables; however, in separate multivariate models, only tumor volume (P=0.03) predicted death, while percent cancer did not (P=0.09).Tumor volume and percent cancer are independent predictors of recurrence after radical prostatectomy. However, in our series, tumor volume predicted cancer specific death better than percent cancer. Therefore, accurate determination of tumor volume, along with other accepted pathologic indices, is sufficient and preferred over percent cancer for prognostication after radical prostatectomy.

    View details for DOI 10.1016/j.urolonc.2009.06.017

    View details for Web of Science ID 000290779400016

    View details for PubMedID 19837617

  • Transcriptome sequencing of circulating tumor cells reveals their heterogeneity Cann, G., Gulzar, Z., Tat, M., Li, R., Stuart, S., Khrebtukova, I., Luo, S., Bentley, D., Ronaghi, M., Brooks, J. D., Talasaz, A. H. AMER ASSOC CANCER RESEARCH. 2011
  • Increased expression of NuSAP gene in recurrent prostate cancer is mediated by E2F Gulzar, Z. G., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2011
  • Length of site-specific positive surgical margins as a risk factor for biochemical recurrence following radical prostatectomy INTERNATIONAL JOURNAL OF UROLOGY Hsu, M., Chang, S. L., Ferrari, M., Nolley, R., Presti, J. C., Brooks, J. D. 2011; 18 (4): 272-279
  • SMOKING AND ADVERSE OUTCOMES AT RADICAL PROSTATECTOMY Ngo, T., Lee, J., Brooks, J., Nolley, R., Ferrari, M., Presti, J. ELSEVIER SCIENCE INC. 2011: E187
  • Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases MODERN PATHOLOGY Sangoi, A. R., Karamchandani, J., Lane, B., Higgins, J. P., Rouse, R. V., Brooks, J. D., McKenney, J. K. 2011; 24 (3): 425-429


    Brachyury is recognized as a specific marker for notochord-derived tissues and neoplasms, and has become a defining immunohistochemical feature of chordoma. The main differential diagnostic consideration for chordoma is chondrosarcoma, which is known to lack brachyury expression. However, within the spectrum of genitourinary neoplasia, metastatic germ cell tumors and clear cell renal cell carcinoma may also be close morphological mimics of chordoma, particularly given the increasing prevalence of small tissue samples from image-guided biopsies. Although immunoreactivity for brachyury has been reported in a few germ cell tumors, a thorough characterization of staining by specific subtype has not been performed in a large series. Additionally, brachyury expression in clear cell renal cell carcinoma has not been well studied. In this study, immunohistochemical expression with the brachyury antibody was evaluated in 111 germ cell tumors, 30 non-neoplastic and neoplastic (non-germ cell) testicular tissues, and 184 metastatic clear cell renal cell carcinomas using tissue microarray technology. In addition, immunoreactivity for PAX-8 and SALL-4 was evaluated in 12 chordomas on whole section. No nuclear brachyury expression was identified in any of the 101 germ cell tumors within the tissue microarray (including choriocarcinoma (1), embryonal carcinoma (20), intratubular germ cell neoplasia unclassified (2), seminoma (64), spermatocytic seminoma (1), teratoma (5) and yolk sac tumor (8)), in any of the 30 non-neoplastic and neoplastic (non-germ cell) testicular tissues, or in any of the 10 whole-section seminomas. All 184 metastatic clear cell renal cell carcinomas were also non-reactive for brachyury. All 12 chordomas showed strong nuclear immunoreactivity for brachyury, but no expression of SALL-4. In all, 1 of 12 chordoma cases showed patchy, 1+ nuclear immunoreactivity for PAX-8. This study confirms the specificity of brachyury for chordoma in the differential diagnostic distinction from the potential genitourinary mimics, germ cell tumors and metastatic clear cell renal cell carcinoma.

    View details for DOI 10.1038/modpathol.2010.196

    View details for Web of Science ID 000287986600010

    View details for PubMedID 21102418

  • Evaluation of Putative Renal Cell Carcinoma Markers PAX-2, PAX-8, and hKIM-1 in Germ Cell Tumors (GCT): A Tissue Microarray Study of 100 Cases Sangoi, A., Higgins, J., Brooks, J., Bonventre, J., McKenney, I. NATURE PUBLISHING GROUP. 2011: 222A
  • Evaluation of Putative Renal Cell Carcinoma Markers PAX-2, PAX-8, and hKIM-1 in Germ Cell Tumors (GCT): A Tissue Microarray Study of 100 Cases Sangoi, A., Higgins, J., Brooks, J., Bonventre, J., McKenney, J. NATURE PUBLISHING GROUP. 2011: 222A
  • The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis HUMAN PATHOLOGY Quick, C. M., Gokden, N., Sangoi, A. R., Brooks, J. D., McKenney, J. K. 2010; 41 (8): 1145-1149


    PAX-2 is a homeogene strongly expressed during development of the genitourinary tract, including the kidney and both wolffian- and müllerian-derived tissues. Expression of PAX-2 by immunohistochemistry has been studied mainly in renal epithelial neoplasms with little attention to the lower male genitourinary tract. We studied PAX-2 expression in epithelium of normal seminal vesicle, normal ejaculatory duct, normal prostatic secretory epithelium, and prostatic adenocarcinoma to define its immunoreactivity pattern throughout the prostate gland and to evaluate its potential diagnostic role in the discrimination of seminal vesicle/ejaculatory duct epithelium from prostatic adenocarcinoma. In addition, given that PAX-2 is highly expressed in tissues of wolffian duct embryologic origin, we also sought to confirm the divergent embryogenesis of the central zone, seminal vesicle, and ejaculatory duct from other regions of the prostate. Prostatectomy specimens from 12 patients were reviewed to identify blocks containing seminal vesicle, ejaculatory duct, periurethral glands, benign prostatic glands, and prostatic acinar adenocarcinoma. A total of 35 blocks from the 12 patients were evaluated. In addition, 2 tissue microarrays representing 15 additional seminal vesicles and 45 prostatic adenocarcinomas, 7 whole sections from prostatic adenocarcinomas of the central zone, and 5 core needle biopsies of seminal vesicle were also evaluated with anti-PAX-2 antibody. In the 12 radical prostatectomy whole sections, nuclear reactivity for PAX-2 was identified in 12 (100%) of 12 of the seminal vesicle epithelium, 9 (90%) of 10 of the ejaculatory duct epithelium, 0 of 12 of the prostatic adenocarcinoma, and 0 of 6 of the high-grade prostatic intraepithelial neoplasia. All 20 total additional seminal vesicles were positive for PAX-2 in the tissue microarray and biopsies; and all 52 additional prostatic adenocarcinomas were negative, including 7 of central zone origin. The staining intensity and percentage of immunoreactive cells in seminal vesicle were both 3+ in all cases. Although the ejaculatory ducts also showed diffuse staining, their staining intensity was less (2+) than that in the seminal vesicles, particularly in the ejaculatory ducts in the periurethral area (1-2+intensity). The smaller glands surrounding the main seminal vesicle duct also showed less intense staining than the luminal cells of the main duct. Of the 19 total cases with evaluable central zone glands, 2 (10.5%) had focal nuclear reactivity in normal, benign prostatic secretory cells. All other benign prostatic secretory epithelia from the peripheral and transition zones were negative for PAX-2. In conclusion, nuclear PAX-2 immunoreactivity is typical in epithelium of the seminal vesicle and ejaculatory duct; but the intensity of staining is less in the ejaculatory duct. No reactivity for PAX-2 was seen in prostatic adenocarcinoma or high-grade prostatic intraepithelial neoplasia. PAX-2 has diagnostic utility as a positive immunohistochemical marker of seminal vesicle and ejaculatory duct epithelium. In addition, these data add further support to the proposed embryogenesis of the prostatic central zone, seminal vesicle, and ejaculatory ducts from the wolffian system.

    View details for DOI 10.1016/j.humpath.2010.01.010

    View details for Web of Science ID 000280128300011

    View details for PubMedID 20413145

  • Canary Prostate Active Surveillance Study: Design of a Multi-institutional Active Surveillance Cohort and Biorepository UROLOGY Newcomb, L. F., Brooks, J. D., Carroll, P. R., Feng, Z., Gleave, M. E., Nelson, P. S., Thompson, I. M., Lin, D. W. 2010; 75 (2): 407-413


    Active surveillance is a management plan for localized prostate cancer that offers selective delayed intervention on indication of disease progression, allowing patients to delay or avoid treatment and associated side-effects. Outcomes from centers that promote active surveillance are favorable, with high rates of disease-specific survival. However, there remains a need for prognostic variables or biomarkers that distinguish with high specificity the aggressive cancers that progress on surveillance from the indolent cancers. The Canary Prostate Active Surveillance Study is a multicenter study and a biorepository that will discover and confirm biomarkers of aggressive disease as defined by histologic, prostate-specific antigen, or clinical criteria.

    View details for DOI 10.1016/j.urology.2009.05.050

    View details for Web of Science ID 000274393300051

    View details for PubMedID 19758683

  • Evaluation of Brachyury Expression in Germ Cell Tumors (GCT) and Clear Cell Renal Cell Carcinomas (CC-RCC): A Tissue Microarray Study of 295 Cases Sangoi, A. R., Higgins, J. P., Brooks, J. D., McKenney, J. K. NATURE PUBLISHING GROUP. 2010: 216A
  • Evaluation of Brachyury Expression in Germ Cell Tumors (GCT) and Clear Cell Renal Cell Carcinomas (CC-RCC): A Tissue Microarray Study of 295 Cases Sangoi, A. R., Higgins, J. P., Brooks, J. D., McKenney, J. M. NATURE PUBLISHING GROUP. 2010: 216A
  • Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns. Genes & cancer Brannon, A. R., Reddy, A., Seiler, M., Arreola, A., Moore, D. T., Pruthi, R. S., Wallen, E. M., Nielsen, M. E., Liu, H., Nathanson, K. L., Ljungberg, B., Zhao, H., Brooks, J. D., Ganesan, S., Bhanot, G., Rathmell, W. K. 2010; 1 (2): 152-163


    Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.

    View details for DOI 10.1177/1947601909359929

    View details for PubMedID 20871783

    View details for PubMedCentralID PMC2943630

  • Adjuvant docetaxel and abbreviated androgen deprivation therapy in patients with high risk prostate cancer The Open Prostate Cancer Journal Bazan JG, King CR, Brooks JD, Srinivas S 2010; 3: 99-104
  • Patient-Reported Long-term Outcomes after Hypofractionated Stereotactic Radiotherapy for Low-risk Prostate Cancer: Evidence from a Prospective Trial King, C. R., Brooks, J. D., Gill, H., Presti, J. C. ELSEVIER SCIENCE INC. 2010: S336
  • Gene expression changes induced by genistein in the prostate cancer cell line LNCaP The Open Prostate Cancer Journal Bhamre S, Sahoo D, Tibshirani R, Dill DL, Brooks JD 2010; 3: 86-98
  • Prognostic significance of prostate cancer originating from the transition zone UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS King, C. R., Ferrari, M., Brooks, J. D. 2009; 27 (6): 592-597


    Transition zone (TZ) cancers are reported to have better biochemical relapse-free survival (bRFS) after radical prostatectomy (RP) than cancers from the peripheral zone (PZ). To understand the influence of tumor location, we compared bRFS for TZ and PZ cancers stratified for risk using known clinical and pathological prognostic factors.The surgical pathology and outcomes of 494 patients were reviewed. Cancers originating from the TZ and PZ were identified from step sectioning of surgical specimens and tumor mapping. Univariate and multivariate analyses of bRFS after RP were compared.TZ cancers were present in 89 (18%) patients. On univariate analysis, most factors predicted bRFS, although cancer location did not: 5-year bRFS was 85% for TZ vs. 77% for PZ (P = 0.12). However, on multivariate analysis, all factors except SV involvement were significant, including TZ cancer location (P = 0.04, HR = 1.88 [1.02-3.47]). Interestingly, TZ location was correlated with improved 5-year bRFS for cancers > 2 cc (81% for TZ vs. 65% for PZ, P = 0.017), for preop PSA >10 (80% for TZ vs. 59% for PZ, P = 0.027), and for PSAV > 2 (85% for TZ vs. 66% for PZ, P = 0.08). However, TZ cancers showed no difference in outcome for small volumes, low preop PSA, low PSAV, or high Gleason grade.TZ cancers that are large, with high preop PSA, low Gleason scores, and high PSAV show better outcomes than their PZ counterparts. However, high-grade cancer tumor location had no apparent influence on outcome. Tumor location could be considered in subsets for optimal prognostication.

    View details for DOI 10.1016/j.urolonc.2008.05.009

    View details for Web of Science ID 000271801200003

    View details for PubMedID 18799332

  • Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes BMC GENOMICS Holterhus, P., Bebermeier, J., Werner, R., Demeter, J., Richter-Unruh, A., Cario, G., Appari, M., Siebert, R., Riepe, F., Brooks, J. D., Hiort, O. 2009; 10


    Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females.A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures.A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.

    View details for DOI 10.1186/1471-2164-10-292

    View details for Web of Science ID 000268754800001

    View details for PubMedID 19570224

    View details for PubMedCentralID PMC2713997

  • Alteration of Gene Expression Signatures of Cortical Differentiation and Wound Response in Lethal Clear Cell Renal Cell Carcinomas PLOS ONE Zhao, H., Ma, Z., Tibshirani, R., Higgins, J. P., Ljungberg, B., Brooks, J. D. 2009; 4 (6)


    Clear cell renal cell carcinoma (ccRCC) is the most common malignancy of the adult kidney and displays heterogeneity in clinical outcomes. Through comprehensive gene expression profiling, we have identified previously a set of transcripts that predict survival following nephrectomy independent of tumor stage, grade, and performance status. These transcripts, designated as the SPC (supervised principal components) gene set, show no apparent biological or genetic features that provide insight into renal carcinogenesis or tumor progression. We explored the relationship of this gene list to a set of genes expressed in different anatomical segments of the normal kidney including the cortex (cortex gene set) and the glomerulus (glomerulus gene set), and a gene set expressed after serum stimulation of quiescent fibroblasts (the core serum response or CSR gene set). Interestingly, the normal cortex, glomerulus (part of the normal renal cortex), and CSR gene sets captured more than 1/5 of the genes in the highly prognostic SPC gene set. Based on gene expression patterns alone, the SPC gene set could be used to sort samples from normal adult kidneys by the anatomical regions from which they were dissected. Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival. While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list. Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

    View details for DOI 10.1371/journal.pone.0006039

    View details for Web of Science ID 000267356900003

    View details for PubMedID 19557179

    View details for PubMedCentralID PMC2698218

  • Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome JOURNAL OF MOLECULAR MEDICINE-JMM Appari, M., Werner, R., Wuensch, L., Cario, G., Demeter, J., Hiort, O., Riepe, F., Brooks, J. D., Holterhus, P. 2009; 87 (6): 623-632


    Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development usually caused by mutations in the androgen receptor (AR) gene. AIS is characterized by a poor genotype-phenotype correlation, and many patients with clinically presumed AIS do not seem to have mutations in the AR gene. We therefore aimed at identifying a biomarker enabling the assessment of the cellular function of the AR as a transcriptional activator. In the first step, we used complementary DNA (cDNA) microarrays for a genome-wide screen for androgen-regulated genes in two normal male primary scrotal skin fibroblast strains compared to two labia majora fibroblast strains from 46,XY females with complete AIS (CAIS). Apolipoprotein D (APOD) and two further transcripts were significantly upregulated by dihydrotestosterone (DHT) in scrotum fibroblasts, while CAIS labia majora cells were unresponsive. Microarray data were well correlated with quantitative real-time polymerase chain reaction (qRT-PCR; R = 0.93). Subsequently, we used qRT-PCR in independent new cell cultures and confirmed the significant DHT-dependent upregulation of APOD in five normal scrotum strains [13.5 +/- 8.2 (SD)-fold] compared with three CAIS strains (1.2 +/- 0.7-fold, p = 0.028; t test) and six partial androgen insensitivity syndrome strains (2 +/- 1.3-fold, p = 0.034; t test). Moreover, two different 17ss-hydroxysteroid dehydrogenase III deficiency labia majora strains showed APOD induction in the range of normal scrotum (9.96 +/- 1.4-fold), supporting AR specificity. Therefore, qRT-PCR of APOD messenger RNA transcription in primary cultures of labioscrotal skin fibroblasts is a promising tool for assessing AR function, potentially allowing a function-based diagnostic evaluation of AIS in the future.

    View details for DOI 10.1007/s00109-009-0462-3

    View details for Web of Science ID 000266475800009

    View details for PubMedID 19330472

  • Prostatic Soy Isoflavone Concentrations Exceed Serum Levels After Dietary Supplementation PROSTATE Gardner, C. D., Oelrich, B., Liu, J. P., Feldman, D., Franke, A. A., Brooks, J. D. 2009; 69 (7): 719-726


    The effects of soy isoflavones on prostate cancer may be concentration-dependent. The impact of soy supplementation on isoflavone concentrations in prostate tissues and serum remain unclear.To assess and compare concentrations of soy isoflavones in prostate tissue and serum among 19 men with prostate cancer who had elected to undergo radical prostatectomy.Participants were randomized to receive either daily soy supplements (82 mg/day aglycone equivalents) or placebos for 2 weeks (14 days) prior to surgery. Serum samples were obtained at the time of the surgery. Isoflavone concentrations were measured by HPLC/ESI-MS-MS.The median (25th, 75th percentile) total isoflavone concentration in the isoflavone-supplemented group was 2.3 micromol/L (1.2, 6.9) in the prostate tissue and 0.7 micromol/L (0.2, 1.2) in the serum. Total isoflavone concentrations in this group were an average of approximately 6-fold higher in prostate tissue compared to serum; the tissue versus serum ratio was significantly lower for genistein than daidzein, 4-fold versus 10-fold, P = 0.003. Tissue and serum levels of isoflavones among the placebo group were negligible with a few exceptions.The findings from the present study suggest that prostate tissue may have the ability to concentrate dietary soy isoflavones to potentially anti-carcinogenic levels.

    View details for DOI 10.1002/pros.20922

    View details for Web of Science ID 000265727700004

    View details for PubMedID 19180569

    View details for PubMedCentralID PMC2734961

  • Recommendations for the Reporting of Surgically Resected Specimens of Renal Cell Carcinoma AMERICAN JOURNAL OF CLINICAL PATHOLOGY Higgins, J. P., McKenney, J. K., Brooks, J. D., Argani, P., Epstein, J. I. 2009; 131 (5): 623-?

    View details for DOI 10.1309/AJCP84ESGXKXYNRA

    View details for Web of Science ID 000265264200003

    View details for PubMedID 19369620

  • Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients INTERNATIONAL JOURNAL OF CANCER Swami, S., Krishnan, A. V., Moreno, J., Bhattacharya, R. S., Gardner, C., Brooks, J. D., Peehl, D. M., Feldman, D. 2009; 124 (9): 2050-2059


    Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE(2) by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment.

    View details for DOI 10.1002/ijc.24161

    View details for Web of Science ID 000264647600007

    View details for PubMedID 19127598

  • Recommendations for the reporting of surgically resected specimens of renal cell carcinoma The Association of Directors of Anatomic and Surgical Pathology HUMAN PATHOLOGY Higgins, J. P., McKenney, J. K., Brooksd, J. D., Argani, P., Epstein, J. I. 2009; 40 (4): 456-463


    A checklist based approach to reporting the relevant pathologic details of renal cell carcinoma resection specimens improves the completeness of the report. Karyotypic evaluation of renal neoplasms has refined but also complicated their classification. The number of diagnostic possibilities has increased and the importance of distinguishing different tumor types has been underscored by dramatic variation in prognosis and the development of targeted therapies for specific subtypes. The increasing number of recognized renal neoplasms has implications for handling renal resection specimens. Furthermore, the prognostic significance of other features of renal neoplasms related to grade and stage has been demonstrated. This guideline for the handling of renal resection specimens will focus on problem areas in the evolving practice of diagnosis, grading, and staging of renal neoplasms. The accompanying checklist will serve to ensure that all necessary details of the renal resection specimen are included in the surgical pathology report.

    View details for DOI 10.1016/j.humpath.2008.12.004

    View details for Web of Science ID 000264990200002

    View details for PubMedID 19289184



    The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report results of a prospective Phase II clinical trial of stereotactic body radiotherapy (SBRT) for localized prostate cancer.Forty-one low-risk prostate cancer patients with 6 months' minimum follow-up received 36.25 Gy in five fractions of 7.25 Gy with image-guided SBRT alone using the CyberKnife. The early (<3 months) and late (>6 months) urinary and rectal toxicities were assessed using validated quality of life questionnaires (International Prostate Symptom Score, Expanded Prostate Cancer Index Composite) and the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Patterns of prostate-specific antigen (PSA) response are analyzed.The median follow-up was 33 months. There were no RTOG Grade 4 acute or late rectal/urinary complications. There were 2 patients with RTOG Grade 3 late urinary toxicity and none with RTOG Grade 3 rectal complications. A reduced rate of severe rectal toxicities was observed with every-other-day vs. 5 consecutive days treatment regimen (0% vs. 38%, p = 0.0035). A benign PSA bounce (median, 0.4 ng/mL) was observed in 12 patients (29%) occurring at 18 months (median) after treatment. At last follow-up, no patient has had a PSA failure regardless of biochemical failure definition. Of 32 patients with 12 months minimum follow-up, 25 patients (78%) achieved a PSA nadir

    View details for DOI 10.1016/j.ijrobp.2008.05.059

    View details for Web of Science ID 000264257400013

    View details for PubMedID 18755555

  • Temporal Changes in Gene Expression Induced by Sulforaphane in Human Prostate Cancer Cells PROSTATE Bhamre, S., Sahoo, D., Tibshirani, R., Dill, D. L., Brooks, J. D. 2009; 69 (2): 181-190


    Prostate cancer is thought to arise as a result of oxidative stresses and induction of antioxidant electrophile defense (phase 2) enzymes has been proposed as a prostate cancer prevention strategy. The isothiocyanate sulforaphane, derived from cruciferous vegetables like broccoli, potently induces surrogate markers of phase 2 enzyme activity in prostate cells in vitro and in vivo. To better understand the temporal effects of sulforaphane and broccoli sprouts on gene expression in prostate cells, we carried out comprehensive transcriptome analysis using cDNA microarrays.Transcripts significantly modulated by sulforaphane over time were identified using StepMiner analysis. Ingenuity Pathway Analysis (IPA) was used to identify biological pathways, networks, and functions significantly altered by sulforaphane treatment.StepMiner and IPA revealed significant changes in many transcripts associated with cell growth and cell cycle, as well as a significant number associated with cellular response to oxidative damage and stress. Comparison to an existing dataset suggested that sulforaphane blocked cell growth by inducing G2/M arrest. Cell growth assays and flow cytometry analysis confirmed that sulforaphane inhibited cell growth and induced cell cycle arrest.Our data suggest that in prostate cells sulforaphane primarily induces cellular defenses and inhibits cell growth by causing G2/M phase arrest. Furthermore, based on the striking similarities in the gene expression patterns induced across experiments in these cells, sulforaphane appears to be the primary bioactive compound present in broccoli sprouts, suggesting that broccoli sprouts can serve as a suitable source for sulforaphane in intervention trials.

    View details for DOI 10.1002/pros.20869

    View details for Web of Science ID 000262701200008

    View details for PubMedID 18973173

    View details for PubMedCentralID PMC2612096

  • CD 9 and vimentin distinguish clear cell from chromophobe renal cell carcinoma. BMC clinical pathology Williams, A. A., Higgins, J. P., Zhao, H., Ljunberg, B., Brooks, J. D. 2009; 9: 9-?


    Clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma (chRCC) can usually be distinguished by histologic characteristics. Occasionally, diagnosis proves challenging and diagnostic difficulty will likely increase as needle biopsies of renal lesions become more common.To identify markers that aid in differentiating ccRCC from chRCC, we used gene expression profiles to identify candidate markers that correlate with histology. 39 antisera and antibodies, including 35 for transcripts identified from gene expression profiling, were evaluated. Promising markers were tested on a tissue microarray (TMA) containing 428 renal neoplasms. Strength of staining of each core on the TMA was formally scored and the distribution of staining across different types of renal neoplasms was analyzed.Based on results from initial immunohistochemical staining of multitissue titer arrays, 23 of the antisera and antibodies were selected for staining of the TMA. For 7 of these markers, strength of staining of each core on the TMA was formally scored. Vimentin (positive in ccRCC) and CD9 (positive in chRCC) best distinguished ccRCC from chRCC. The combination of vimentin negativity and CD9 positivity was found to distinguish chRCC from ccRCC with a sensitivity of 100.0% and a specificity of 95.2%.Based on gene expression analysis, we identify CD9 and vimentin as candidate markers for distinguishing between ccRCC and chRCC. In difficult cases and particularly when the amount of diagnostic tissue is limited, vimentin and CD9 staining could serve as a useful adjunct in the differential diagnosis of ccRCC and chRCC.

    View details for DOI 10.1186/1472-6890-9-9

    View details for PubMedID 19922654

    View details for PubMedCentralID PMC2788570

  • CD 9 and vimentin distinguish clear cell from chromophobe renal cell carcinoma BMC CLINICAL PATHOLOGY Williams, A. A., Higgins, J. T., Zhao, H., Ljungberg, B., Brooks, J. D. 2009; 9
  • Comprehensive genomic characterization defines human glioblastoma genes and core pathways NATURE Chin, L., Meyerson, M., Aldape, K., Bigner, D., Mikkelsen, T., VandenBerg, S., Kahn, A., PENNY, R., Ferguson, M. L., Gerhard, D. S., Getz, G., Brennan, C., Taylor, B. S., Winckler, W., Park, P., Ladanyi, M., Hoadley, K. A., Verhaak, R. G., Hayes, D. N., Spellman, P. T., Absher, D., Weir, B. A., Ding, L., Wheeler, D., Lawrence, M. S., Cibulskis, K., Mardis, E., Zhang, J., Wilson, R. K., Donehower, L., Wheeler, D. A., Purdom, E., Wallis, J., Laird, P. W., Herman, J. G., Schuebel, K. E., Weisenberger, D. J., BAYLIN, S. B., Schultz, N., Yao, J., Wiedemeyer, R., WEINSTEIN, J., Sander, C., Gibbs, R. A., Gray, J., Kucherlapati, R., Lander, E. S., Myers, R. M., Perou, C. M., McLendon, R., Friedman, A., Van Meir, E. G., Brat, D. J., Mastrogianakis, G. M., Olson, J. J., Lehman, N., Yung, W. K., Bogler, O., Berger, M., Prados, M., Muzny, D., Morgan, M., Scherer, S., Sabo, A., Nazareth, L., Lewis, L., Hall, O., Zhu, Y., Ren, Y., Alvi, O., Yao, J., Hawes, A., Jhangiani, S., Fowler, G., San Lucas, A., Kovar, C., Cree, A., Dinh, H., Santibanez, J., Joshi, V., Gonzalez-Garay, M. L., Miller, C. A., Milosavljevic, A., Sougnez, C., Fennell, T., Mahan, S., Wilkinson, J., Ziaugra, L., Onofrio, R., Bloom, T., Nicol, R., Ardlie, K., Baldwin, J., Gabriel, S., Fulton, R. S., McLellan, M. D., Larson, D. E., Shi, X., Abbott, R., Fulton, L., Chen, K., Koboldt, D. C., Wendl, M. C., Meyer, R., Tang, Y., Lin, L., Osborne, J. R., Dunford-Shore, B. H., Miner, T. L., Delehaunty, K., Markovic, C., Swift, G., Courtney, W., Pohl, C., Abbott, S., Hawkins, A., Leong, S., Haipek, C., Schmidt, H., Wiechert, M., Vickery, T., Scott, S., Dooling, D. J., Chinwalla, A., Weinstock, G. M., O'Kelly, M., Robinson, J., Alexe, G., Beroukhim, R., Carter, S., Chiang, D., Gould, J., Gupta, S., Korn, J., Mermel, C., Mesirov, J., Monti, S., Nguyen, H., Parkin, M., Reich, M., Stransky, N., Garraway, L., Golub, T., Protopopov, A., Perna, I., Aronson, S., Sathiamoorthy, N., Ren, G., Kim, H., Kong, S. W., Xiao, Y., Kohane, I. S., Seidman, J., Cope, L., Pan, F., Van Den Berg, D., van Neste, L., Yi, J. M., Li, J. Z., Southwick, A., Brady, S., Aggarwal, A., Chung, T., Sherlock, G., Brooks, J. D., Jakkula, L. R., Lapuk, A. V., Marr, H., Dorton, S., Choi, Y. G., Han, J., Ray, A., Wang, V., Durinck, S., Robinson, M., Wang, N. J., Vranizan, K., Peng, V., Van Name, E., Fontenay, G. V., Ngai, J., Conboy, J. G., Parvin, B., Feiler, H. S., Speed, T. P., Socci, N. D., Olshen, A., Lash, A., Reva, B., Antipin, Y., Stukalov, A., Gross, B., Cerami, E., Wang, W. Q., Qin, L., Seshan, V. E., Villafania, L., Cavatore, M., Borsu, L., Viale, A., Gerald, W., Topal, M. D., Qi, Y., Balu, S., Shi, Y., Wu, G., Bittner, M., Shelton, T., Lenkiewicz, E., Morris, S., Beasley, D., Sanders, S., Sfeir, R., Chen, J., Nassau, D., Feng, L., Hickey, E., Schaefer, C., Madhavan, S., Buetow, K., Barker, A., Vockley, J., Compton, C., Vaught, J., Fielding, P., Collins, F., Good, P., Guyer, M., Ozenberger, B., Peterson, J., Thomson, E. 2008; 455 (7216): 1061-1068


    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

    View details for DOI 10.1038/nature07385

    View details for Web of Science ID 000260252600035

    View details for PubMedID 18772890

  • Identification of candidate prostate cancer genes through comparative expression-profiling of seminal vesicle PROSTATE Thompson, M., Lapointe, J., Choi, Y., Ong, D. E., Higgins, J. P., Brooks, J. D., Pollack, J. R. 2008; 68 (11): 1248-1256


    Prostate cancer is the most frequently diagnosed cancer among men in the United States. In contrast, cancer of the seminal vesicle is exceedingly rare, despite that the prostate and seminal vesicle share similar histology, secretory function, androgen dependency, blood supply, and (in part) embryonic origin. We hypothesized that gene-expression differences between prostate and seminal vesicle might inform mechanisms underlying the higher incidence of prostate cancer.Whole-genome DNA microarrays were used to profile gene expression of 11 normal prostate and 7 seminal vesicle specimens (including six matched pairs) obtained from radical prostatectomy. Supervised analysis was used to identify genes differentially expressed between normal prostate and seminal vesicle, and this list was then cross-referenced to genes differentially expressed between normal and cancerous prostate. Expression patterns of selected genes were confirmed by immunohistochemistry using a tissue microarray.We identified 32 genes that displayed a highly statistically significant expression pattern with highest levels in seminal vesicle, lower levels in normal prostate, and lowest levels in prostate cancer. Among these genes was the known candidate prostate tumor suppressor GSTP1 (involved in xenobiotic detoxification). The expression pattern of GSTP1 and four other genes, ABCG2 (xenobiotic transport), CRABP2 (retinoic acid signaling), GATA3 (lineage-specific transcription), and SLPI (immune response), was confirmed by immunohistochemistry.Our findings identify candidate prostate cancer genes whose reduced expression in prostate (compared to seminal vesicle) may be permissive to prostate cancer initiation. Such genes and their pathways may inform mechanisms of prostate carcinogenesis, and suggest new opportunities for prostate cancer prevention.

    View details for DOI 10.1002/pros.20792

    View details for Web of Science ID 000258021300012

    View details for PubMedID 18500686

    View details for PubMedCentralID PMC2516917

  • Postoperative prostate-specific antigen velocity independently predicts for failure of salvage radiotherapy after prostatectomy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, C. R., Presti, J. C., Brooks, J. D., Gill, H., Spiotto, M. T. 2008; 70 (5): 1472-1477


    Identification of patients most likely to benefit from salvage radiotherapy (RT) using postoperative (postop) prostate-specific antigen (PSA) kinetics.From 1984 to 2004, 81 patients who fit the following criteria formed the study population: undetectable PSA after radical prostatectomy (RP); pathologically negative nodes; biochemical relapse defined as a persistently detectable PSA; salvage RT; and two or more postop PSAs available before salvage RT. Salvage RT included the whole pelvic nodes in 55 patients and 4 months of total androgen suppression in 56 patients. The median follow-up was >5 years. All relapses were defined as a persistently detectable PSA. Kaplan-Meier and Cox proportional hazards multivariable analysis were performed for all clinical, pathological, and treatment factors predicting for biochemical relapse-free survival (bRFS).There were 37 biochemical relapses observed after salvage RT. The 5-year bRFS after salvage RT for patients with postop prostate-specific antigen velocity < or = 1 vs. >1 ng/ml/yr was 59% vs. 29%, p = 0.002. In multivariate analysis, only postop PSAV (p = 0.0036), pre-RT PSA level < or = 1 (p = 0.037) and interval-to-relapse >10 months (p = 0.012) remained significant, whereas pelvic RT, hormone therapy, and RT dose showed a trend (p = approximately 0.06). PSAV, but not prostate-specific antigen doubling time, predicted successful salvage RT, suggesting an association of zero-order kinetics with locally recurrent disease.Postoperative PSA velocity independently predicts for the failure of salvage RT and can be considered in addition to high-risk features when selecting patients in need of systemic therapy following biochemical failure after RP. For well-selected patients, salvage RT can achieve high cure rates.

    View details for DOI 10.1016/j.ijrobp.2007.08.014

    View details for Web of Science ID 000254660800028

    View details for PubMedID 17935902

  • Do cancer index and tumor volume predict prostate cancer specific death? Tarin, T. V., Chung, B. I., Brooks, J. D. ELSEVIER SCIENCE INC. 2008: 115
  • hCAP-D3 expression marks a prostate cancer subtype with favorable clinical behavior and androgen signaling signature AMERICAN JOURNAL OF SURGICAL PATHOLOGY Lapointe, J., Malhotra, S., Higgins, J. P., Bair, E., Thompson, M., Salari, K., Giacomini, C. P., Ferrari, M., Montgomery, K., Tibshirani, R., van de Rijn, M., Brooks, J. D., Pollack, J. R. 2008; 32 (2): 205-209


    Growing evidence suggests that only a fraction of prostate cancers detected clinically are potentially lethal. An important clinical issue is identifying men with indolent cancer who might be spared aggressive therapies with associated morbidities. Previously, using microarray analysis we defined 3 molecular subtypes of prostate cancer with different gene-expression patterns. One, subtype-1, displayed features consistent with more indolent behavior, where an immunohistochemical marker (AZGP1) for subtype-1 predicted favorable outcome after radical prostatectomy. Here we characterize a second candidate tissue biomarker, hCAP-D3, expressed in subtype-1 prostate tumors. hCAP-D3 expression, assayed by RNA in situ hybridization on a tissue microarray comprising 225 cases, was associated with decreased tumor recurrence after radical prostatectomy (P=0.004), independent of pathologic tumor stage, Gleason grade, and preoperative prostate-specific antigen levels. Simultaneous assessment of hCAP-D3 and AZGP1 expression in this tumor set improved outcome prediction. We have previously demonstrated that hCAP-D3 is induced by androgen in prostate cells. Extending this finding, Gene Set Enrichment Analysis revealed enrichment of androgen-responsive genes in subtype-1 tumors (P=0.019). Our findings identify hCAP-D3 as a new biomarker for subtype-1 tumors that improves prognostication, and reveal androgen signaling as an important biologic feature of this potentially clinically favorable molecular subtype.

    View details for PubMedID 18223322

  • The impact of tumor volume on outcomes after radical prostatectomy: Implications for prostate cancer screening. The Open Prostate Cancer Journal James D. Brooks, Robert Tibshirani, Michelle Ferrari, Joseph C. Presti, Jr., Harcharan Gill, Christopher R. King 2008; 1: 1-8
  • Editorial comments JOURNAL OF UROLOGY Brooks, J. D. 2007; 178 (6): 2400
  • Intrinsic androgen-dependent gene expression patterns revealed by comparison of genital fibroblasts from normal males and individuals with complete and partial androgen insensitivity syndrome BMC GENOMICS Holterhus, P., Deppe, U., Werner, R., Richter-Unruh, A., Bebermeier, J., Wuensch, L., Krege, S., Schweikert, H., Demeter, J., Riepe, F., Hiort, O., Brooks, J. D. 2007; 8


    To better understand the molecular programs of normal and abnormal genital development, clear-cut definition of androgen-dependent gene expression patterns, without the influence of genotype (46, XX vs. 46, XY), is warranted. Previously, we have identified global gene expression profiles in genital-derived fibroblasts that differ between 46, XY males and 46, XY females with complete androgen insensitivity syndrome (CAIS) due to inactivating mutations of the androgen receptor (AR). While these differences could be due to cell autonomous changes in gene expression induced by androgen programming, recent work suggests they could also be influenced by the location from which the fibroblasts were harvested (topology). To minimize the influence of topology, we compared gene expression patterns of fibroblasts derived from identical urogenital anlagen: the scrotum in normally virilized 46, XY males and the labia majora from completely feminized 46, XY individuals with CAIS.612 transcripts representing 440 unique genes differed significantly in expression levels between scrotum and CAIS labia majora, suggesting the effects of androgen programming. While some genes coincided with those we had identified previously (TBX3, IGFBP5, EGFR, CSPG2), a significant number did not, implying that topology had influenced gene expression in our previous experiments. Supervised clustering of gene expression data derived from a large set of fibroblast cultures from individuals with partial AIS revealed that the new, topology controlled data set better classified the specimens.Inactivating mutations of the AR, in themselves, appear to induce lasting changes in gene expression in cultured fibroblasts, independent of topology and genotype. Genes identified are likely to be relevant candidates to decipher androgen-dependent normal and abnormal genital development.

    View details for DOI 10.1186/1471-2164-8-376

    View details for Web of Science ID 000252779600001

    View details for PubMedID 17945006

    View details for PubMedCentralID PMC2212662

  • Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis CANCER RESEARCH Lapointe, J., Li, C., Giacomini, C. P., Salari, K., Huang, S., Wang, P., Ferrari, M., Hernandez-Boussard, T., Brooks, J. D., Pollack, J. R. 2007; 67 (18): 8504-8510


    Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.

    View details for DOI 10.1158/0008-5472.CAN-07-0673

    View details for Web of Science ID 000249679500013

    View details for PubMedID 17875689

  • Adjuvant docetaxel chemotherapy with abbreviated hormonal therapy in patients with high-risk prostate cancer Colocci, N., King, C. R., Brooks, J. D., Gill, H. S., Presti, J. C., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2007
  • Placental S100 (S100P) and GATA3: Markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray AMERICAN JOURNAL OF SURGICAL PATHOLOGY Higgins, J. P., Kaygusuz, G., Wang, L., Montgomery, K., Mason, V., Zhu, S. X., Marinelli, R. J., Presti, J. C., van de Rijn, M., Brooks, J. D. 2007; 31 (5): 673-680


    The morphologic distinction between prostate and urothelial carcinoma can be difficult. To identify novel diagnostic markers that may aid in the differential diagnosis of prostate versus urothelial carcinoma, we analyzed expression patterns in prostate and bladder cancer tissues using complementary DNA microarrays. Together with our prior studies on renal neoplasms and normal kidney, these studies suggested that the gene for placental S100 (S100P) is specifically expressed in benign and malignant urothelial cells. Using tissue microarrays, a polyclonal antiserum against S100P protein stained 86% of 295 urothelial carcinomas while only 3% of 260 prostatic adenocarcinomas and 1% of 133 renal cell carcinomas stained. A commercially available monoclonal antibody against S100P stained 78% of 300 urothelial carcinomas while only 2% of 256 prostatic adenocarcinomas and none of 137 renal cell carcinomas stained. A second gene, GATA3, also showed high level expression in urothelial tumors by cDNA array. A commercially available monoclonal antibody against GATA3 stained 67% of 308 urothelial carcinomas, but none of the prostate or renal carcinomas. For comparison, staining was also performed for p63 and cytokeratin 5/6. p63 stained 87% of urothelial carcinomas whereas CK5/6 stained 54%. Importantly, when S100P and p63 were combined 95% of urothelial carcinomas were labeled by one or both markers. We conclude that the detection of S100P and GATA3 protein expression may help distinguish urothelial carcinomas from other genitourinary neoplasms that enter into the differential diagnosis.

    View details for PubMedID 17460449

  • A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells NUCLEIC ACIDS RESEARCH Li, T., Zhao, H., Peng, Y., Beliakoff, J., Brooks, J. D., Sun, Z. 2007; 35 (8): 2767-2776


    Although the vital role of the androgen receptor (AR) has been well demonstrated in primary prostate cancers, its role in the androgen-insensitive prostate cancers still remains unclear. Here, we used a small hairpin RNA approach to directly assess AR activity in prostate cancer cells. Reduction of AR expression in the two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC4, significantly decreased AR-mediated transcription and cell growth. Intriguingly, in two androgen-insensitive prostate cell lines, LNCaP-C42B4 and CWR22Rv1, knockdown of AR expression showed a more pronounced effect on AR-induced transcription and cell growth than androgen depletion. Using cDNA microarrays, we also compared the transcriptional profiles induced by either androgen depletion or AR knockdown. Although a significant number of transcripts appear to be regulated by both androgen depletion and AR knockdown, we observed a subset of transcripts affected only by androgen depletion but not by AR knockdown, and vice versa. Finally, we demonstrated a direct role for AR in promoting tumor formation and growth in a xenograft model. Taken together, our results elucidate an important role for the AR in androgen-insensitive prostate cancer cells, and suggest that AR can be used as a therapeutic target for androgen-insensitive prostate cancers.

    View details for DOI 10.1093/nar/gkm198

    View details for Web of Science ID 000247239600029

    View details for PubMedID 17426117

    View details for PubMedCentralID PMC1885678

  • A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis MODERN PATHOLOGY Lapointe, J., Kim, Y. H., Miller, M. A., Li, C., Kaygusuz, G., van de Rijn, M., Huntsman, D. G., Brooks, J. D., Pollack, J. R. 2007; 20 (4): 467-473


    Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform fusion. In this specimen set, the presence of a TMPRSS2-ERG fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS fusions.

    View details for DOI 10.1038/modpathol.3800759

    View details for PubMedID 17334351

  • Endothelin-1 promotes cell survival in renal cell carcinoma through the ETA receptor CANCER LETTERS Pflug, B. R., Zheng, H., Udan, M. S., D'Antonio, J. M., Marshall, F. F., Brooks, J. D., Nelson, J. B. 2007; 246 (1-2): 139-148


    Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to significantly impact many benign and malignant tissues by signaling through its two cognate receptors: ET(A) and ET(B). As ET-1 has a role in both normal and diseased kidney, we initiated studies to investigate endothelin axis expression and function in renal cell carcinoma (RCC). In this study, relatively high levels of ET-1 were detected in all six human RCC cell lines investigated. RT-PCR and Southern analyses revealed that all six RCC cell lines expressed ET(A) receptor mRNA, while 3/6 cell lines also expressed ET(B) mRNA. High affinity ET-1 binding occurred in all but one RCC cell line and quantitative RT-PCR demonstrated ET(A) mRNA expression in all six cell lines. Methylation of the ET(B) promoter (EDNRB) in 4/6 RCC cell lines was observed, suggesting a mechanism for repressed ET(B) expression. Moreover, methylation occurred in 32/48 of renal tumors and in 27/55 of histologically normal adjacent tissue samples studied, while no methylation was evident in any normal tissue isolated from nephrectomy or at autopsy. Functionally, ET-1 significantly inhibited paclitaxel-induced apoptosis in RCC cells through binding ET(A) with the ET-1 signaling mediated via the PI3-kinase/Akt pathway. Collectively, these data support the therapeutic targeting of the ET(A) receptor as a novel treatment strategy for RCC.

    View details for DOI 10.1016/j.canlet.2006.02.007

    View details for Web of Science ID 000244154900017

    View details for PubMedID 16581180

  • Selenomethionine induced transcriptional programs in human prostate cancer cells JOURNAL OF UROLOGY Zhao, H., Brooks, J. D. 2007; 177 (2): 743-750


    We determined the effects of selenomethionine, the major organic selenium containing compound found in the diet and the form of selenium being used in the Selenium and Vitamin E Cancer Prevention Trial, on prostate cancer cells.We assessed global transcript profiles of selenomethionine treated LNCaP using cDNA microarrays and compared them to those of cells treated with methylselenic acid, a direct precursor of methylselenol, which is the active form of selenium in vivo.After treatment with selenomethionine 2,336 unique genes showed expression changes of at least 1.5-fold in at least 3 time points during 48 hours and 366 unique transcripts differed significantly between selenomethionine and methylselenic acid treated LNCaP. Approximately half of the 76 cell cycle regulated genes affected by selenomethionine were down-regulated and enriched for genes associated with the G2/M phase. Flow cytometry analysis showed that selenomethionine induced G2/M arrest in LNCaP at low concentrations. Selenomethionine also affected expression levels of 35 known androgen responsive genes and 18 of these transcripts showed changes that were the inverse of those seen after androgen stimulation. At high concentrations selenomethionine decreased prostate specific antigen promoter driven luciferase expression.Selenomethionine modulates transcript levels of genes involved in a number of biological processes, including cell cycle/apoptosis androgen signaling, signal transduction and transcriptional regulation. Although the pathways affected paralleled in many ways those that are modulated by methylselenic acid, distinct differences in transcript patterns and effects on cell cycle regulation suggest that different selenium compounds could exert unique effects in prostate cells.

    View details for DOI 10.1016/j.juro.2006.09.071

    View details for Web of Science ID 000243453900074

    View details for PubMedID 17222674

    View details for PubMedCentralID PMC2729366

  • Distinctive gene expression of prostatic stromal cells cultured from diseased versus normal tissues JOURNAL OF CELLULAR PHYSIOLOGY Zhao, H., Ramos, C. F., Brooks, J. D., Peehl, D. M. 2007; 210 (1): 111-121


    To obtain a comprehensive view of the transcriptional programs in prostatic stromal cells of different histological/pathological origin, we profiled 18 adult human stromal cell cultures from normal transition zone (TZ), normal peripheral zone (PZ), benign prostatic hyperplasia (BPH), and prostate cancer (CA) using cDNA microarrays. A hierarchical clustering analysis of 714 named unique genes whose expression varied at least threefold from the overall mean abundance in at least three samples in all 18 samples demonstrated that cells of different origin displayed distinct gene expression profiles. Many of the differentially expressed genes are involved in biological processes known to be important in the development of prostatic diseases including cell proliferation and apoptosis, cell adhesion, and immune response. Significance Analysis of Microarrays (SAM) analysis identified genes that showed differential expression with statistical significance including 24 genes between cells from TZ versus BPH, 34 between BPH versus CA, and 101 between PZ versus CA. S100A4 and SULF1, the most up- and downregulated genes in BPH versus TZ, respectively, showed expression at the protein level consistent with microarray analysis. In addition, sulfatase assay showed that BPH cells have lower SULF1 activity compared to TZ cells. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression of ENPP2/autotoxin and six other genes between PZ versus CA, as well as differential expression of six genes between BPH versus CA. Our results support the hypothesis that prostatic stromal cells of different origin have unique transcriptional programs and point towards genes involved in actions of stromal cells in BPH and CA.

    View details for DOI 10.1002/jcp.20828

    View details for Web of Science ID 000242568200012

    View details for PubMedID 17044071

    View details for PubMedCentralID PMC2732006

  • Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription JOURNAL OF MOLECULAR MEDICINE-JMM Bebermeier, J., Brooks, J. D., DePrimo, S. E., Werner, R., Deppe, U., Demeter, J., Hiort, O., Holterhus, P. 2006; 84 (11): 919-931


    Normal genital skin fibroblasts (GSF) and the human prostate carcinoma cell line LNCaP have been used widely as cell culture models of genital origin to study androgen receptor (AR) signaling. We demonstrate that LNCaP shows a reproducible response to androgens as assessed using cDNA-microarrays representing approximately 32,000 unique human genes, whereas several independent GSF strains are virtually unresponsive. We show that LNCaP cells express markedly higher AR protein levels likely contributing to the observed differences of androgen responsiveness. However, previous data suggested that AR-expression levels alone do not determine androgen responsiveness of human GSF compared to LNCaP. We hypothesized that cell-specific differences in expression levels of AR coregulators might contribute to differences in androgen responsiveness and might be found by comparing LNCaP and GSFs. Using the Canadian McGill-database of AR coregulators ( ), we identified 61 AR-coregulator genes represented by 282 transcripts on our microarray platform that was used to measure transcript profiles of LNCaP and GSF cells. Baseline expression levels of 48 AR-coregulator transcripts representing 33 distinct genes showed significant differences between GSF and LNCaP, four of which we confirmed by reverse transcriptase polymerase chain reaction. Compared to LNCaP, GSFs displayed significant upregulation of AR coregulators that can function as repressors of AR-transactivation, such as caveolin 1. Analysis of a recently published comprehensive dataset of 115 microarrays representing 35 different human tissues revealed tissue-specific signatures of AR coregulators that segregated with ontogenetically related groups of tissues (e.g., lymphatic system and genital tissues, brain). Our data demonstrate the existence of cell-line and tissue-specific expression patterns of molecules with documented AR coregulatory functions. Therefore, differential expression patterns of AR coregulators could modify tissue-specificity and diversity of androgen actions in development, physiology, and disease.

    View details for DOI 10.1007/s00109-006-0081-1

    View details for Web of Science ID 000241589100005

    View details for PubMedID 16932916

  • Natural history of positive urinary cytology after radical cystectomy - Editorial comment JOURNAL OF UROLOGY Brooks, J. D. 2006; 176 (5): 2005
  • Application of genomic technologies to human prostate cancer OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY Li, S., Bhamre, S., Lapointe, J., Pollack, J. R., Brooks, J. D. 2006; 10 (3): 261-275


    Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in U.S. males and has a broad spectrum of clinical behavior ranging from indolent to lethal. Microarray technology has provided unprecedented opportunity to explore the genetic processes underlying prostate cancer by providing a comprehensive survey of a cell's transcriptional landscape. Prostate cancer, however, has posed significant challenges that have contributed to inconsistent results between studies and difficulty replicating findings. Despite these challenges, several important insights have been gained along with new clinical biomarkers of diagnosis and prognosis. Continued improvements in methods of tissue preparation, microarray technology and data analysis will overcome existing challenges and fuel future discoveries.

    View details for Web of Science ID 000241666200002

    View details for PubMedID 17069507

  • Reliability of small amounts of cancer in prostate biopsies to reveal pathologic grade UROLOGY King, C. R., McNeal, J. E., Gill, H., Brooks, J. D., Srinivas, S., Presti, J. C. 2006; 67 (6): 1229-1234


    To examine grade reliability when biopsies contain very small amounts of prostate cancer. Prostate biopsy findings are known to undergrade prostate cancer compared with the pathologic specimens yet remain the only grade guiding disease management.The presence of a clinically significant grade change from biopsy cores to matched prostatectomy specimens was examined in 371 patients. The biopsies were characterized for primary and secondary Gleason grade, number of positive cores, and total linear length of cancer. The pathologic specimens were characterized for cancer volume and relative percentage by grade. The rates of upgrading or downgrading were tested against all clinical and biopsy information for any significant predictive value.The overall rate of upgrading was 40.7% and downgrading was 16.1%. Upgrading was constant and independent of any clinical or biopsy tumor volume indexes. Specifically, when cancer was present in only one biopsy core and measured 2 mm or less (n = 48), it was just as predictive of the pathologic grade as that from any greater number of positive cores and any greater extent of cancer length present. Downgrading was less frequent for biopsies with small amounts of cancer.Histologic grading from small amounts of cancer in prostate biopsies is reliable and not more prone to grading errors. A repeat biopsy for these patients may not be indicated.

    View details for DOI 10.1016/j.urology.2005.12.031

    View details for PubMedID 16765184

  • Refractory hematuria from amyloidosis successfully treated by splenectomy UROLOGY Ma, J. F., Coutre, S. E., Curet, M. J., Brooks, J. D. 2006; 67 (5)


    Systemic amyloidosis can result in a coagulopathy that is associated with low levels of factor X. We present a case of intractable, life-threatening hematuria that was successfully managed with activated recombinant human factor VII and splenectomy.

    View details for DOI 10.1016/j.urology.2005.11.048

    View details for Web of Science ID 000238390800059

    View details for PubMedID 16698382

  • The application of genomic and proteomic approaches to human prostate cancer in developing diagnostic and prognostic markers UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Brooks, J. D. 2006; 24 (3): 222–23
  • Modest induction of phase 2 enzyme activity in the F-344 rat prostate BMC CANCER Jones, S. B., Brooks, J. D. 2006; 6


    Prostate cancer is the most commonly diagnosed malignancy in men and is thought to arise as a result of endogenous oxidative stress in the face of compromised carcinogen defenses. We tested whether carcinogen defense (phase 2) enzymes could be induced in the prostate tissues of rats after oral feeding of candidate phase 2 enzyme inducing compounds.Male F344 rats were gavage fed sulforaphane, beta-naphthoflavone, curcumin, dimethyl fumarate or vehicle control over five days, and on the sixth day, prostate, liver, kidney and bladder tissues were harvested. Cytosolic enzyme activities of nicotinamide quinone oxidoreductase (NQO1), total glutathione transferase (using DCNB) and mu-class glutathione transferase (using CDNB) were determined in the treated and control animals and compared.In prostatic tissues, sulforaphane produced modest but significant increases in the enzymatic activities of NQO1, total GST and GST-mu compared to control animals. beta-naphthoflavone significantly increased NQO1 and GST-mu activities and curcumin increased total GST and GST-mu enzymatic activities. Dimethyl fumarate did not significantly increase prostatic phase 2 enzyme activity. Compared to control animals, sulforaphane also significantly induced NQO1 or total GST enzyme activity in the liver, kidney and, most significantly, in the bladder tissues. All compounds were well tolerated over the course of the gavage feedings.Orally administered compounds will induce modestly phase 2 enzyme activity in the prostate although the significance of this degree of induction is unknown. The 4 different compounds also altered phase 2 enzyme activity to different degrees in different tissue types. Orally administered sulforaphane potently induces phase 2 enzymes in bladder tissues and should be investigated as a bladder cancer preventive agent.

    View details for DOI 10.1186/1471-2407-6-62

    View details for Web of Science ID 000236547000001

    View details for PubMedID 16539699

    View details for PubMedCentralID PMC1421427

  • Gene expression profiling predicts survival in conventional renal cell carcinoma PLOS MEDICINE Zhao, H. J., Ljungberg, B., Grankvist, K., Rasmuson, T., Tibshirani, R., Brooks, J. D. 2006; 3 (1): 115-124


    Conventional renal cell carcinoma (cRCC) accounts for most of the deaths due to kidney cancer. Tumor stage, grade, and patient performance status are used currently to predict survival after surgery. Our goal was to identify gene expression features, using comprehensive gene expression profiling, that correlate with survival.Gene expression profiles were determined in 177 primary cRCCs using DNA microarrays. Unsupervised hierarchical clustering analysis segregated cRCC into five gene expression subgroups. Expression subgroup was correlated with survival in long-term follow-up and was independent of grade, stage, and performance status. The tumors were then divided evenly into training and test sets that were balanced for grade, stage, performance status, and length of follow-up. A semisupervised learning algorithm (supervised principal components analysis) was applied to identify transcripts whose expression was associated with survival in the training set, and the performance of this gene expression-based survival predictor was assessed using the test set. With this method, we identified 259 genes that accurately predicted disease-specific survival among patients in the independent validation group (p < 0.001). In multivariate analysis, the gene expression predictor was a strong predictor of survival independent of tumor stage, grade, and performance status (p < 0.001).cRCC displays molecular heterogeneity and can be separated into gene expression subgroups that correlate with survival after surgery. We have identified a set of 259 genes that predict survival after surgery independent of clinical prognostic factors.

    View details for DOI 10.1371/journal.pmed.0030013

    View details for Web of Science ID 000236342700020

    View details for PubMedID 16318415

    View details for PubMedCentralID PMC1298943

  • S100p: A marker for transitional epithelium and urothelial carcinoma Higgins, J. P., Kaygusuz, G., Wang, L., Montgomery, K., Mason, Brooks, J. D., van de Rijn, M. NATURE PUBLISHING GROUP. 2006: 142A
  • The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer CANCER RESEARCH Kim, H., Lapointe, J., Kaygusuz, G., Ong, D. E., Li, C. D., van de Rijn, M., Brooks, J. D., Pollack, J. R. 2005; 65 (18): 8118-8124


    Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1a2), was also associated with shorter recurrence-free survival. ALDH1a2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1a2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1a2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1a2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1a2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer.

    View details for DOI 10.1158/0008-5472.CAN-04-4562

    View details for PubMedID 16166285

  • Preoperative PSA velocity is an independent prognostic factor for relapse after radical prostatectomy JOURNAL OF CLINICAL ONCOLOGY Patel, D. A., Presti, J. C., McNeal, J. E., Gill, H., Brooks, J. D., King, C. R. 2005; 23 (25): 6157-6162


    Preoperative prostate-specific antigen (PSA) velocity (PSAV), or the rate of PSA rise before diagnosis, predicts for risk of cancer death after radical prostatectomy (RP). We evaluated the relative merit of established preoperative factors, including biopsy indices and preoperative PSAV, for their impact on relapse after RP.The outcomes of 202 men who underwent RP were reviewed. Biopsies were characterized for grade, percentage positive cores, and total linear tumor length. Surgical specimens were characterized for cancer volume, relative percentage by grade, extracapsular extension, and margin status. Univariate and multivariate analyses were performed with respect to relapse-free survival after RP.Thirty-one patients relapsed after RP (defined as PSA > or = 0.2 ng/mL), with a median time to failure of 16 months. Median follow-up was 48 months. Kaplan-Meier relapse-free survival at 5 years was 89%, compared with 73% for PSAV < or = 2 v > 2 ng/mL/year (P = .003). On multivariate analysis, only the biopsy Gleason sum (P < .008; relative risk, > 4.8) and the preoperative PSAV (P < .04; relative risk, 3.0 to 4.7) remained significant. Patients with a PSAV of > 2 ng/mL/year were more likely to be pT3 (P = .007), have positive margins (P = .01), have tumors > 1 mL (P = .05), and possess > 10% grade 4/5 tumors (P = .04).The preoperative PSAV is a significant independent clinical factor predicting for relapse after RP and also predicts for larger, more aggressive, and more locally advanced tumors. Its inclusion will be useful in risk stratification, evaluation for alternatives to surgery, and patient selection for neoadjuvant or adjuvant therapies as part of randomized clinical trials.

    View details for DOI 10.1200/JCO.2005.01.2336

    View details for Web of Science ID 000231606300041

    View details for PubMedID 16135482

  • Genome-wide characterization of gene expression variations and DNA copy number changes in prostate cancer cell lines PROSTATE Zhao, H. J., Kim, Y., Wang, P., Lapointe, J., Tibshirani, R., Pollack, J. R., Brooks, J. D. 2005; 63 (2): 187-197


    The aim of this study was to characterize gene expression and DNA copy number profiles in androgen sensitive (AS) and androgen insensitive (AI) prostate cancer cell lines on a genome-wide scale.Gene expression profiles and DNA copy number changes were examined using DNA microarrays in eight commonly used prostate cancer cell lines. Chromosomal regions with DNA copy number changes were identified using cluster along chromosome (CLAC).There were discrete differences in gene expression patterns between AS and AI cells that were not limited to androgen-responsive genes. AI cells displayed more DNA copy number changes, especially amplifications, than AS cells. The gene expression profiles of cell lines showed limited similarities to prostate tumors harvested at surgery.AS and AI cell lines are different in their transcriptional programs and degree of DNA copy number alterations. This dataset provides a context for the use of prostate cancer cell lines as models for clinical cancers.

    View details for DOI 10.1002/pros.20158

    View details for PubMedID 15486987

  • Microarray Data Mining for Potential Selenium Targets in Chemoprevention of Prostate Cancer. Cancer genomics & proteomics Zhang, H., Dong, Y., Zhao, H., Brooks, J. D., Hawthorn, L., Nowak, N., Marshall, J. R., Gao, A. C., Ip, C. 2005; 2 (2): 97-114


    BACKGROUND: A previous clinical trial showed that selenium supplementation significantly reduced the incidence of prostate cancer. We report here a bioinformatics approach to gain new insights into selenium molecular targets that might be relevant to prostate cancer chemoprevention. MATERIALS AND METHODS: We first performed data mining analysis to identify genes which are consistently dysregulated in prostate cancer using published datasets from gene expression profiling of clinical prostate specimens. We then devised a method to systematically analyze three selenium microarray datasets from the LNCaP human prostate cancer cells, and to match the analysis to the cohort of genes implicated in prostate carcinogenesis. Moreover, we compared the selenium datasets with two datasets obtained from expression profiling of androgen-stimulated LNCaP cells. RESULTS: We found that selenium reverses the expression of genes implicated in prostate carcinogenesis. In addition, we found that selenium could counteract the effect of androgen on the expression of a subset obtained from androgen-regulated genes. CONCLUSIONS: The above information provides us with a treasure of new clues to investigate the mechanism of selenium chemoprevention of prostate cancer. Furthermore, these selenium target genes could also serve as biomarkers in future clinical trials to gauge the efficacy of selenium intervention.

    View details for PubMedID 18548127

    View details for PubMedCentralID PMC2424238

  • Juvenile posttraumatic high-flow priapism: current management dilemmas JOURNAL OF PEDIATRIC SURGERY Marotte, J. B., Brooks, J. D., Sze, D., Kennedy, W. A. 2005; 40 (4)


    High-flow priapism results from disruption of the intercavernosal artery resulting in an arteriocavernosal fistula and is rarely encountered in the pediatric and adolescent population. Clinically it manifests as a painless, prolonged erection after perineal trauma. Treatment has ranged from expectant management to open surgical exploration with vessel ligation. Internal pudendal arteriogram and superselective embolization with autologous blood clot has emerged as a safe and effective treatment modality in the young male population. Here the authors present 3 patients with high-flow priapism and discuss management of this rare clinical entity.

    View details for DOI 10.1016/j.jpedsurg.2005.01.023

    View details for Web of Science ID 000229359300042

    View details for PubMedID 15852259

  • Reg IV: A promising marker of hormone refractory metastatic prostate cancer CLINICAL CANCER RESEARCH Gu, Z. N., Rubin, M. A., Yang, Y., DePrimo, S. E., Zhao, H. J., Horvath, S., Brooks, J. D., Loda, M., Reiter, R. E. 2005; 11 (6): 2237-2243


    The diagnosis and management of prostate cancer is hampered by the absence of markers capable of identifying patients with metastatic disease. In order to identify potential new markers for prostate cancer, we compared gene expression signatures of matched androgen-dependent and hormone refractory prostate cancer xenografts. One candidate gene overexpressed in a hormone refractory xenograft was homologous to the regenerating protein gene family, a group of secreted proteins expressed in the gastrointestinal tract and overexpressed in inflammatory bowel disease and cancer. This gene, Reg IV, was confirmed to be differentially expressed in the LAPC-9 hormone refractory xenograft. Consistent with its up-regulation in a hormone refractory xenograft, it is expressed in several prostate tumors after neoadjuvant hormone ablation therapy. As predicted by its sequence homology, it is secreted from transiently transfected cells. It is also expressed strongly in a majority of hormone refractory metastases represented on two high-density tissue microarrays. In comparison, it is not expressed by any normal prostate specimens and only at low levels in approximately 40% of primary tumors. These data support Reg IV as a candidate marker for hormone refractory metastatic prostate cancer.

    View details for Web of Science ID 000227770000019

    View details for PubMedID 15788672

  • Resveratrol-induced gene expression profiles in human prostate cancer cells CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Jones, S. B., DePrimo, S. E., Whitfield, M. L., Brooks, J. D. 2005; 14 (3): 596-604


    The transhydroxystilbene resveratrol is found at high levels in red wine and grapes, and red wine consumption may be inversely associated with prostate cancer risk. To gain insights into the possible mechanisms of action of resveratrol in human prostate cancer, we did DNA microarray analysis of the temporal transcriptional program induced by treatment of the human prostate cancer cell line LNCaP with resveratrol.Spotted DNA microarrays containing over 42,000 elements were used to obtain a global view of the effects of resveratrol on gene expression. Prostate-specific antigen (PSA) and androgen receptor (AR) expression were determined by Northern blot and immunoblot analyses. Cell proliferation was determined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay and cell cycle analysis by flow cytometry.We observed time-dependent expression changes in >1,600 transcripts as early as 6 hours after treatment with resveratrol. Most striking was the modulation of a number of important genes in the androgen pathway including PSA and AR. Resveratrol also down-regulated expression of cell cycle and proliferation-specific genes involved in all phases of the cell cycle, induced negative regulators of proliferation, caused accumulation of cells at the sub-G1 and S phases of the cell cycle, and inhibited cell proliferation in a time- and dose-dependent manner.Resveratrol produces gene expression changes in the androgen axis and cell cycle regulators that may underlie its putative anticancer activities in prostate cancer.

    View details for Web of Science ID 000227545900011

    View details for PubMedID 15767336

  • Molecular targets of Doxazosin in human prostatic stromal cells PROSTATE Zhao, H. J., Lai, F., Nonn, L., Brooks, J. D., Peehl, D. M. 2005; 62 (4): 400-410


    We used cDNA microarray analysis to obtain insights into the mechanisms of action of doxazosin, an alpha(1)-adrenergic receptor antagonist used to treat benign prostatic hyperplasia (BPH).Hierarchical clustering analysis and significance analysis of microarray (SAM) were performed to identify genes differentially expressed between untreated stromal cells cultured from normal tissue and BPH, and changes in gene expression induced by doxazosin. Transcript levels of selected genes were validated by real-time reverse-transcription polymerase chain reaction (RT-PCR).Hierarchical clustering analyses separated untreated normal and BPH cells. Sixty-seven genes whose expression varied at least twofold after doxazosin treatment in both normal and BPH cells were identified, as were 93 genes differentially regulated in normal versus BPH cells. Molecular targets consistent with tumor necrosis factor (TNF)-alpha-related activity were identified.Normal versus BPH stromal cells differ in global gene transcription. Doxazosin induced gene expression changes relevant to proliferation/apoptosis, immune defense, cell-cell signaling/signal transduction, and transcriptional regulation.

    View details for DOI 10.1002/pros.20161

    View details for Web of Science ID 000226991500011

    View details for PubMedID 15378519

  • Positive family history of prostate cancer not associated with worse outcomes after radical prostatectomy UROLOGY Lee, K. L., Marotte, J. B., Ferrari, M. K., McNeal, J. E., Brooks, J. D., Presti, J. C. 2005; 65 (2): 311-315


    To determine the clinical outcomes in men with (FH) and without (NFH) a family history of prostate cancer after radical prostatectomy.We performed a retrospective analysis of 557 men with localized prostate cancer treated by radical prostatectomy between 1989 and 2000. We defined a positive FH as having one or more first-degree relatives such as a father or brother with prostate cancer. The clinical and pathologic features, as well as biochemical disease-free survival, defined as an undetectable prostate-specific antigen level (less than 0.2 ng/mL), were compared between the FH and NFH groups.Compared with the NFH group, the FH men were younger at surgery (median 62 years versus 64 years, P = 0.01), had a lower median preoperative prostate-specific antigen level (7.2 ng/mL versus 7.8 ng/mL, P = 0.05), and were more likely to have only low-grade disease at the final pathologic evaluation (26.2% versus 17.8%, P = 0.05). At a median follow-up of 7.5 years (mean 7.6 +/- 2.9 years), 17% of the FH group had biochemical disease recurrence compared with 30% in the NFH group. The actuarial disease-free survival rate at 5 and 10 years for the two groups was 86% and 80% compared with 73% and 66%, respectively (P = 0.01). When controlled for pathologic variables in a multivariate analysis, FH was not an independent predictor of disease-free survival.The association of improved disease-free survival in the FH patients may have been driven by an earlier age at diagnosis and more favorable pathologic features.

    View details for DOI 10.1016/j.urology.2004.09.005

    View details for Web of Science ID 000227307000021

    View details for PubMedID 15708044

  • A transcriptional profile of aging in the human kidney PLOS BIOLOGY Rodwell, G. E., Sonu, R., Zahn, J. M., Lund, J., Wilhelmy, J., Wang, L. L., Xiao, W. Z., Mindrinos, M., Crane, E., Segal, E., Myers, B. D., Brooks, J. D., Davis, R. W., Higgins, J., Owen, A. B., Kim, S. K. 2004; 2 (12): 2191-2201


    In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.

    View details for DOI 10.1371/journal.pbio.0020427

    View details for PubMedID 15562319

  • Induction of phase 2 enzymes in the F-344 rat prostate. Jones, S. B., Bhamre, S., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2004: 1942S
  • Molecular activity of 1,25-dihydroxyvitamin D-3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY Peehl, D. M., Shinghal, R., Nonn, L., Seto, E., Krishnan, A. V., Brooks, J. D., Feldman, D. 2004; 92 (3): 131-141


    1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] exerts anti-proliferative, differentiating and apoptotic effects on prostatic cells. These activities, in addition to epidemiologic findings that link Vitamin D to prostate cancer risk, support the use of 1,25(OH)(2)D(3) for prevention or therapy of prostate cancer. The molecular mechanisms by which 1,25(OH)(2)D(3) exerts antitumor effects on prostatic cells are not well-defined. In addition, there is heterogeneity among the responses of various prostate cell lines and primary cultures to 1,25(OH)(2)D(3) with regard to growth inhibition, differentiation and apoptosis. To understand the basis of these differential responses and to develop a better model of Vitamin D action in the prostate, we performed cDNA microarray analyses of primary cultures of normal and malignant human prostatic epithelial cells, treated with 50 nM of 1,25(OH)(2)D(3) for 6 and 24 h. CYP24 (25-hydroxyvitamin D(3)-24-hydroxylase) was the most highly upregulated gene. Significant and early upregulation of dual specificity phosphatase 10 (DUSP10), validated in five additional primary cultures, points to inhibition of members of the mitogen-activated protein kinase (MAPK) superfamily as a key event mediating activity of 1,25(OH)(2)D(3) in prostatic epithelial cells. The functions of other regulated genes suggest protection by 1,25(OH)(2)D(3) from oxidative stress. Overall, these results provide new insights into the molecular basis of antitumor activities of Vitamin D in prostate cells.

    View details for DOI 10.1016/j.jsbmb.2004.07.003

    View details for Web of Science ID 000226009000003

    View details for PubMedID 15555907

  • Vascular invasion predicts recurrence after radical prostatectomy: Stratification of risk based on pathologic variables UROLOGY Ferrari, M. K., McNeal, J. E., Malhotra, S. M., Brooks, J. D. 2004; 64 (4): 749-753


    To determine whether vascular invasion (VI) is an independent predictor of prostate cancer recurrence and/or survival and to stratify risk of recurrence in patients with VI.Vascular invasion status was documented in 620 radical prostatectomy specimens with an average of 7.5 years of follow-up. The relationship between VI and other clinical and pathologic features was tested. Vascular invasion as an independent predictor of recurrence was investigated by logistic regression analysis. Survival analyses and stratification of VI patients was developed with Kaplan-Meier survival curves.Vascular invasion was identified in 110 patients (18%) and correlated significantly (P <0.0001) with high Gleason grade, extracapsular extension (EPE), seminal vesicle invasion, increasing cancer volumes, positive margins, and elevated preoperative prostate-specific antigen (PSA) levels. Logistic regression analysis demonstrated that VI was a strong and independent predictor for disease recurrence, when considered with grade, EPE, seminal vesicle invasion, lymph node involvement, cancer volume, preoperative PSA levels, and positive margins. At 12 years after radical prostatectomy, patients with VI demonstrated significantly lower disease-specific survival (P = 0.0005). Among patients with VI, stratification of grade, EPE, and the number of VI foci identified three significantly different prognostic groups.In long-term follow-up, VI was a significant predictor of prostate cancer recurrence and death after radical prostatectomy. In patients with VI, high Gleason grade, EPE, and more than five foci of VI are associated with poor prognosis.

    View details for DOI 10.1016/j.urology.2004.04.070

    View details for Web of Science ID 000224680300030

    View details for PubMedID 15491714

  • Lower body mass index is associated with a higher prostate cancer detection rate and less favorable pathological features in a biopsy population JOURNAL OF UROLOGY Presti, J. C., Lee, U., Brooks, J. D., Terris, M. K. 2004; 171 (6): 2199-2202


    Body mass index (BMI), calculated as weight in kg divided by the square of height in m, is used as an indicator of obesity. We assessed the relationship between BMI, and prostate cancer detection rates and biopsy features in a referral based biopsy population.A total of 787 consecutive patients referred for abnormal digital rectal examination and/or prostate specific antigen (PSA) greater than 4 ng/ml underwent systematic prostate biopsy. Three standard categories of BMI were considered, namely normal-less than 25, overweight-25 to 29.9 and obese-30 or greater kg/m. The presence or absence of cancer, percent of core involvement and tumor grade were correlated with BMI. Additional analyses controlled for patient age, PSA and prostate volume.For the entire population detection rates were highest in the normal BMI group compared to the overweight or obese group (52% vs 37% vs 42%, p = 0.0026). When stratified by age, this observation was true for men younger than 70 years (49% vs 32% vs 37%, p = 0.0042) but not for men 70 years or older. When only patients with PSA 10 ng/ml or less were considered, detection rates were highest in the normal BMI group (44% vs 28% vs 36%, p = 0.0061). This observation also persisted in patients younger than 70 years with PSA 10 ng/ml or less, or when only patients younger than 70 years with a total prostate volume of less than 50 cc were included. Of patients with cancer those with a normal BMI had a greater length of needle core involvement on biopsy.Normal BMI correlates with a higher cancer detection rate and larger cancers in men undergoing prostate biopsy.

    View details for DOI 10.1097/01.ju.0000124847.82541.60

    View details for Web of Science ID 000221510300018

    View details for PubMedID 15126785

  • Radiotherapy after radical prostatectomy: Does transient androgen suppression improve outcomes? 44th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology King, C. R., Presti, J. C., Gill, H., Brooks, J., Hancock, S. L. ELSEVIER SCIENCE INC. 2004: 341–47


    The long-term biochemical relapse-free survival and overall survival were compared for patients receiving either radiotherapy (RT) alone or radiotherapy combined with a short-course of total androgen suppression for failure after radical prostatectomy.Between 1985 and 2001, a total of 122 patients received RT after radical prostatectomy at our institution. Fifty-three of these patients received a short-course of total androgen suppression (TAS) 2 months before and 2 months concurrent with RT with a nonsteroidal antiandrogen and an luteinizing hormone-releasing hormone (LHRH) agonist (combined therapy group); the remaining 69 patients received RT alone. Treatment failure was defined after postoperative RT as a detectable PSA >0.05 ng/mL. Clinical and treatment variables examined included: presurgical PSA, clinical T stage, pathologic Gleason sum (pGS), seminal vesicle (SV) involvement, lymph node involvement, surgical margins, pre-RT PSA, prostate dose, pelvic irradiation, indication for postoperative RT (salvage or adjuvant), and time interval between surgery and RT. Minimum follow-up after postoperative RT was 1 year and median follow-up was 5.9 years (maximum, 14 years) for patients receiving RT alone, and 3.9 years (maximum, 11 years) for patients receiving RT with TAS (combined therapy group). Kaplan-Meier analysis was performed for PSA failure-free survival (bNED) and for overall survival (OS). Cox proportional hazards multivariable analysis examined the influence all clinical and treatment variables predicting for bNED and OS.The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p = 0.19), with no failures beyond 5 years. At 5 years, the actuarial bNED rates were 57% for the combined therapy group compared with 31% for the RT alone group (p = 0.0012). Overall survival rates at 5 years were 100% for the combined therapy group compared with 87% for the RT alone group (p = 0.0008). For pGS or=8 the 5-year bNED rates were 65% for combined therapy and 17% for RT alone (p = 0.075). The 5-year OS rates for pGS or=8 was 100% for combined therapy and 54% for RT alone (p = 0.04). On multivariable analysis, only SV involvement (p = 0.0145) and the addition of short-course TAS to postoperative RT (p = 0.0019) were significant covariates predicting for bNED and, similarly, approached significance for overall survival (p = 0.0594 and p = 0.0856, respectively).Radiotherapy combined with a short-course TAS after radical prostatectomy appears to confer a PSA relapse-free survival advantage and possibly an overall survival advantage when compared with RT alone. The hypothesis that a transient course of androgen suppression with salvage or adjuvant RT after prostatectomy improves outcomes will need to be tested in a randomized trial.

    View details for DOI 10.1016/j.ijribp.2003.10.015

    View details for Web of Science ID 000221440800002

    View details for PubMedID 15145146

  • Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays PROSTATE Krishnan, A. V., Shinghal, R., Raghavachari, N., Brooks, J. D., Peehl, D. M., Feldman, D. 2004; 59 (3): 243-251


    1,25-dihydroxyvitamin D(3) [1,25(OH)2D3] exerts growth inhibitory, pro-differentiating, and pro-apoptotic effects on prostate cells. To better understand the molecular mechanisms underlying these actions, we employed cDNA microarrays to study 1,25(OH)2D3-regulated gene expression in the LNCaP human prostate cancer cells.mRNA isolated from LNCaP cells treated with vehicle or 50 nM 1,25(OH)2D3 for various lengths of time were hybridized to microarrays carrying approximately 23,000 genes. Some of the putative target genes revealed by the microarray analysis were verified by real-time PCR assays.1,25(OH)2D3 most substantially increased the expression of the insulin-like growth factor binding protein-3 (IGFBP-3) gene. Our analysis also revealed several novel 1,25(OH)2D3-responsive genes. Interestingly, some of the key genes regulated by 1,25(OH)2D3 are also androgen-responsive genes. 1,25(OH)2D3 also down-regulated genes that mediate androgen catabolism.The putative 1,25(OH)2D3 target genes appear to be involved in a variety of cellular functions including growth regulation, differentiation, membrane transport, cell-cell and cell-matrix interactions, DNA repair, and inhibition of metastasis. The up-regulation of IGFBP-3 gene has been shown to be crucial in 1,25(OH)2D3-mediated inhibition of LNCaP cell growth. 1,25(OH)2D3 regulation of androgen-responsive genes as well as genes involved in androgen catabolism suggests that there are interactions between 1,25(OH)2D3 and androgen signaling pathways in LNCaP cells. Further studies on the role of these genes and others in mediating the anti-cancer effects of 1,25(OH)2D3 may lead to better approaches to the prevention and treatment of prostate cancer.

    View details for DOI 10.1002/pros.20006

    View details for Web of Science ID 000220910600003

    View details for PubMedID 15042599

  • Time trends in pathologic features of radical prostatectomy - impact of family history UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Marotte, J. B., Ferrari, M. K., McNeal, J. E., Brooks, J. D., Presti, J. C. 2004; 22 (3): 169-173


    We investigated whether the clinical or pathological features of patients with a family history of prostate cancer treated by radical prostatectomy differ from patients without a family history. A retrospective analysis of patients treated by radical prostatectomy between 1989 through 2000 was performed. The clinical and pathologic features of patients with a family history (defined as at least one first-degree relative with prostate cancer, N = 103) were compared with those with no family history (N = 456). In addition, the patients were stratified into two groups, those treated from 1989 through 1992 and those treated after 1992. In the entire cohort from 1989 through 2000, patients with a family history had a greater proportion of well-differentiated tumors than the NFH group (26.2% vs. 17.8%; P = 0.05). From 1989 to 1992 there was no statistical difference between patients with a family history (FH) and those without a family history (NFH) with respect to age, prostate specific antigen (PSA), PSA density, clinical or pathologic stage, Gleason grade, or total tumor volume. However, after 1992 the FH group tended to be younger than the NFH group (61.1 vs. 63.4; P = 0.02) and have a lower PSA (6.8 vs. 7.9; P = 0.01) at the time of diagnosis. We believe these differences are predominantly driven by more aggressive screening in patients with a family history of prostate cancer rather than any true genetic differences.

    View details for DOI 10.1016/j.urolonc.2004.04.003

    View details for Web of Science ID 000223195600002

    View details for PubMedID 15271309

  • Prognostic significance of vascular invasion: A long-term follow-up of 621 radical prostatectomy patients Ferrari, M. K., Malhotra, S. M., McNeal, J. E., Brooks, J. D. LIPPINCOTT WILLIAMS & WILKINS. 2004: 222
  • Normal body mass index is associated with a higher prostate cancer detection rate and less favorable pathologic features in a biopsy population Presti, J. C., Lee, U., Brooks, J. D., Terris, M. K. LIPPINCOTT WILLIAMS & WILKINS. 2004: 122
  • Biochemical remission after resection of prostate cancer lung metastasis UROLOGY Chao, D. H., Higgins, J. P., Brooks, J. D. 2004; 63 (3)


    Once metastatic, prostate cancer was regarded as a systemic disease that is not amenable to surgical therapy. We present a case of a solitary pulmonary recurrence of prostate cancer after radical prostatectomy that was resected, resulting in 12 years of biochemical remission without additional therapy.

    View details for DOI 10.1016/j.urology.2003.10.069

    View details for Web of Science ID 000220223500041

    View details for PubMedID 15028469

  • Gene expression in the normal adult human kidney assessed by complementary DNA microarray MOLECULAR BIOLOGY OF THE CELL Higgins, J. P., Wang, L. L., Kambham, N., Montgomery, K., Mason, V., Vogelmann, S. U., Lemley, K. V., Brown, P. O., Brooks, J. D., van de Rijn, M. 2004; 15 (2): 649-656


    The kidney is a highly specialized organ with a complex, stereotyped architecture and a great diversity of functions and cell types. Because the microscopic organization of the nephron, the functional unit of the kidney, has a consistent relationship to the macroscopic anatomy of the kidney, knowledge of the characteristic patterns of gene expression in different compartments of the kidney could provide insight into the functions and functional organization of the normal nephron. We studied gene expression in dissected renal lobes of five adult human kidneys using cDNA microarrays representing approximately 30,000 different human genes. Total RNA was isolated from sections of the inner and outer cortex, inner and outer medulla, papillary tips, and renal pelvis and from glomeruli isolated by sieving. The results revealed unique and highly distinctive patterns of gene expression for glomeruli, cortex, medulla, papillary tips, and pelvic samples. Immunohistochemical staining using selected antisera confirmed differential expression of several cognate proteins and provided histological localization of expression within the nephron. The distinctive patterns of gene expression in discrete portions of the kidney may serve as a resource for further understanding of renal physiology and the molecular and cellular organization of the nephron.

    View details for DOI 10.1091/mbc.E03-06-0432

    View details for PubMedID 14657249

  • Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells MOLECULAR BIOLOGY OF THE CELL Zhao, H. J., Whitfield, M. L., Xu, T., Botstein, D., Brooks, J. D. 2004; 15 (2): 506-519


    Methylseleninic acid (MSA) has been shown to have potent anticancer activity and is an excellent compound for studying the anticancer effects of selenium in vitro. To gain insights into the effects of MSA in prostate cancer, we characterized the global transcriptional response of LNCaP, an androgen-sensitive human prostate cancer cell line, to MSA by using high-density cDNA microarrays. We identified 951 genes whose expression shows striking dose- and time-dependent changes in response to 3-30 microM MSA over the time course of 48 h. Transcript levels of many cell cycle-regulated genes change in response to MSA, suggesting that MSA inhibits proliferation. Consistent with these gene expression changes, cell proliferation, monitored by carboxyfluoroscein succinimidyl ester staining, was decreased after MSA treatment, and an accumulation of cells at G0/G1 phase was detected by flow cytometry. Surprisingly, MSA also modulated expression of many androgen-regulated genes, suppressed androgen receptor (AR) expression at both mRNA and protein level, and decreased levels of prostate specific antigen secreted into the medium. Low concentrations of MSA also induced significant increases in transcript levels of phase 2 detoxification enzymes and induced NADPH dehydrogenase, quinone 1 enzymatic activity, a surrogate marker of global phase 2 enzyme activity. Our results suggest that MSA may protect against prostate cancer by inhibiting cell proliferation, by modulating the expression of AR and AR-regulated genes and by inducing carcinogen defenses.

    View details for DOI 10.1091/mbc.E03-07-0501

    View details for Web of Science ID 000188718900012

    View details for PubMedID 14617803

    View details for PubMedCentralID PMC329225

  • Gene expression profiling identifies clinically relevant subtypes of prostate cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lapointe, J., Li, C., Higgins, J. P., van de Rijn, M., Bair, E., Montgomery, K., Ferrari, M., Egevad, L., Rayford, W., Bergerheim, U., Ekman, P., DeMarzo, A. M., Tibshirani, R., Botstein, D., Brown, P. O., Brooks, J. D., Pollack, J. R. 2004; 101 (3): 811-816


    Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

    View details for DOI 10.1073/pnas.0304146101

    View details for PubMedID 14711987

  • Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sperger, J. M., Chen, X., Draper, J. S., Antosiewicz, J. E., Chon, C. H., Jones, S. B., Brooks, J. D., Andrews, P. W., Brown, P. O., Thomson, J. A. 2003; 100 (23): 13350-13355


    Remarkably little is known about the transcriptional profiles of human embryonic stem (ES) cells or the molecular mechanisms that underlie their pluripotency. To identify commonalties among the transcriptional profiles of different human pluripotent cells and to search for clues into the genesis of human germ cell tumors, we compared the expression profiles of human ES cell lines, human germ cell tumor cell lines and tumor samples, somatic cell lines, and testicular tissue samples by using cDNA microarray analysis. Hierarchical cluster analysis of gene expression profiles showed that the five independent human ES cell lines clustered tightly together, reflecting highly similar expression profiles. The gene expression patterns of human ES cell lines showed many similarities with the human embryonal carcinoma cell samples and more distantly with the seminoma samples. We identified 895 genes that were expressed at significantly greater levels in human ES and embryonal carcinoma cell lines than in control samples. These genes are candidates for involvement in the maintenance of a pluripotent, undifferentiated phenotype.

    View details for DOI 10.1073/pnas.2235735100

    View details for Web of Science ID 000186573700044

    View details for PubMedID 14595015

    View details for PubMedCentralID PMC263817

  • Resveratrol-induced gene expression profiles in human prostate cancer cells. Jones, S. B., DePrimo, S. E., Brooks, J. D. AMER ASSOC CANCER RESEARCH. 2003: 1353S-1354S
  • Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray AMERICAN JOURNAL OF PATHOLOGY Higgins, J. P., Shinghal, R., Gill, H., Reese, J. H., Terris, M., Cohen, R. J., Fero, M., Pollack, J. R., van de Rijn, M., Brooks, J. D. 2003; 162 (3): 925-932


    Renal cell carcinoma comprises several histological types with different clinical behavior. Accurate pathological characterization is important in the clinical management of these tumors. We describe gene expression profiles in 41 renal tumors determined by using DNA microarrays containing 22,648 unique cDNAs representing 17,083 different UniGene Clusters, including 7230 characterized human genes. Differences in the patterns of gene expression among the different tumor types were readily apparent; hierarchical cluster analysis of the tumor samples segregated histologically distinct tumor types solely based on their gene expression patterns. Conventional renal cell carcinomas with clear cells showed a highly distinctive pattern of gene expression. Papillary carcinomas formed a tightly clustered group, as did tumors arising from the distal nephron and the normal kidney samples. Surprisingly, conventional renal cell carcinomas with granular cytoplasm were heterogeneous, and did not resemble any of the conventional carcinomas with clear cytoplasm in their pattern of gene expression. Characterization of renal cell carcinomas based on gene expression patterns provides a revised classification of these tumors and has the potential to supply significant biological and clinical insights.

    View details for PubMedID 12598325

  • Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy UROLOGY Shinghal, R., Yemoto, C., McNeal, J. E., Brooks, J. D. 2003; 61 (2): 380-385
  • Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor GENOME BIOLOGY Holterhus, P. M., Hiort, O., Demeter, J., Brown, P. O., Brooks, J. D. 2003; 4 (6)


    Androgen insensitivity syndrome (AIS) comprises a range of phenotypes from male infertility to complete feminization. Most individuals with AIS carry germline mutations of the androgen receptor (AR) that interfere with or ablate its function. As genital fibroblasts retain expression of the AR in vitro, we used genital skin fibroblasts from normal males and 46,XY females with complete AIS due to known AR mutations to gain insights into the role of the AR in human genital differentiation.Using DNA microarrays representing 32,968 different genes, we identified 404 transcripts with significant differences in transcription levels between genital skin fibroblasts cultured from normal and AIS-affected individuals. Gene-cluster analyses uncovered coordinated expression of genes involved in key processes of morphogenesis. On the basis of animal studies and human genetic syndromes, several of these genes are known to have specific roles in genital differentiation. Remarkably, genital fibroblasts from both normal and AIS-affected individuals showed no transcriptional response to dihydrotestosterone treatment despite expression of the AR.The results suggest that in addition to differences in the anatomic origin of the cells, androgen signaling during prenatal development contributes to setting long-lasting, androgen-independent transcriptional programs in genital fibroblasts. Our findings have broad implications in understanding the establishment and the stability of sexual dimorphism in human genital development.

    View details for Web of Science ID 000183720100007

    View details for PubMedID 12801411

  • Gene expression in the normal adult human kidney assessed by complementary DNA microarray Higgins, J. P., Wang, L., Kambham, N., Montgomery, K., Vogelmann, S., Lemley, K., Pollack, van de Rijn, M., Brooks, J. D. LIPPINCOTT WILLIAMS & WILKINS. 2003: 266A
  • Expression of FKBP12 in benign and malignant vascular endothelium - An immunohistochemical study on conventional sections and tissue microarrays AMERICAN JOURNAL OF SURGICAL PATHOLOGY Higgins, J. P., Montgomery, K., Wang, L. L., Domanay, E., Warnke, R. A., Brooks, J. D., van de Rijn, M. 2003; 27 (1): 58-64


    FKBP12 is a cytosolic FK506 binding protein that interacts with calcineurin and thereby mediates the immunosuppressive effects of FK506. Because initial immunohistochemical staining showed abundant expression of FKBP12 in vascular endothelial cells, we evaluated whether it could serve as a marker for vascular neoplasms. We performed immunohistochemical staining of conventional sections from formalin-fixed, paraffin-embedded tissue from 59 benign and malignant vascular neoplasms using a polyclonal rabbit antiserum against FKBP12. Western blot analysis of tissue from 6 angiosarcomas showed a single band at 12 kD, consistent with the published molecular weight for the FKBP12 protein. Together, CD31, CD34, and FKBP12 identified all 59 vascular neoplasms in this study. Specificity of immunohistochemical staining was assessed on 1,321 tissues represented on 7 tissue microarrays. All proteins were occasionally expressed in non-vascular tissue. Six of 8 vascular neoplasms represented on the arrays stained for FKBP12, as did normal vessels in numerous cores. The polyclonal antiserum shows comparable sensitivity (94.9%) and specificity (96.5%) to CD34 and CD31 and may be a useful additional marker for vascular differentiation. Because we have evaluated a large number of tissues by tissue microarray, we anticipate that our estimate of the specificity of immunostaining for FKBP12 as a marker for vascular endothelium will be accurate. In addition, our findings may explain the toxic effects of FK506 on vascular endothelium of the kidney.

    View details for PubMedID 12502928

  • Identification of potential prostate cancer preventive agents through induction of quinone reductase in vitro CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., Goldberg, M. F., Nelson, L. A., Wu, D., Nelson, W. G. 2002; 11 (9): 868-875


    Human prostate cancer is characterized by an early and near-universal loss of expression of the phase 2 enzyme glutathione S-transferase-pi (GSTP1). We hypothesize that a mechanism-based prostate cancer preventive strategy could involve induction of phase 2 enzymes within the prostate to compensate for the loss of GSTP1 expression. NAD[P]H:(quinone-acceptor) oxidoreductase (quinone reductase or QR) enzymatic activity, a surrogate of phase 2 enzyme response, was measured after treating the human prostate cancer cell line LNCaP with known phase 2 enzyme-inducing agents from 10 distinct chemical classes. QR enzymatic activity was assayed in microtiter plates using the menadione-coupled reduction of tetrazolium dye. Degree of induction was expressed as fold-increase over control and corrected for toxicity. Compounds were also tested in LNCaP-5-aza-C, an LNCaP subline selected in 5-aza-cytidine that expresses GSTP1, and in the human liver cell line HepG2. LNCaP showed robust induction of QR enzymatic activity after treatment with a subset of the phase 2 enzyme-inducing agents. All Michael acceptors were effective at inducing QR activity in LNCaP. Some phenolic antioxidants, heavy metal salts, and quinones also significantly increased QR activity, although inducer potency varied widely within these classes of compounds. Some of the isothiocyanates, mercaptans, bifunctional inducers, and trivalent arsenicals also produced modest QR induction, but peroxides and dithiolethiones were inactive. LNCaP-5-aza-C and LNCaP responded similarly to all compounds, but the pattern of response for HepG2 differed significantly. The differences in QR responsiveness between the prostate cell lines and HepG2 suggest that prostate tissues may have a unique pattern of response to phase 2-inducing agents distinct from other tissue types. Our data suggest that measurement of QR induction in prostate cancer cell lines may help identify potential cancer chemopreventive agents effective in the prostate.

    View details for PubMedID 12223431

  • Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis PROSTATE Shibata, A., Garcia, M. I., Cheng, I., Stamey, T. A., McNeal, J. E., Brooks, J. D., Henderson, S., Yemoto, C. E., Peehl, D. M. 2002; 52 (4): 269-278


    Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer.We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5.In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables.We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established.

    View details for DOI 10.1002/pros.10119

    View details for Web of Science ID 000177541200003

    View details for PubMedID 12210487

  • Microarray analysis in prostate cancer research. Current opinion in urology Brooks, J. D. 2002; 12 (5): 395-399


    Microarray technologies are now being used to analyse prostate tumors and to gain insights into prostate cancer biology. This review provides a background on microarray technology, reviews recent applications of these techniques in prostate cancer research, and discusses the potential application of this technology to patient care.An analysis of genome-wide changes in expression has identified several hundred genes differentially expressed by normal and malignant prostate tissues. Some, such as hepsin, not only show increased expression in cancer, but can also provide prognostic information on prostate tumors based on their level of expression. Microarrays have also been used to characterize gene expression changes associated with androgen stimulation, the activation of EGR1 pathways, and prostate epithelial cellular senescence.Microarray analysis of gene expression in prostate cancer is in its infancy. Future work will probably yield new diagnostic and prognostic markers, provide insight into prostate cancer biology, and aid in identifying new therapeutic strategies.

    View details for PubMedID 12172426

  • Silencing of pi-class glutathione S-transferase in MDA PCa 2a and MDA PCa 2b cells PROSTATE Vidanes, G. M., Paton, V., Wallen, E., Peehl, D. M., Navone, N., Brooks, J. D. 2002; 51 (4): 225-230


    Loss of expression of the glutathione S-transferase-pi (GSTP1) is the most common genetic alteration described in human prostate cancer, occurring in virtually all tumors regardless of grade or stage. Of the available human prostate cancer cell lines, only LNCaP mirrors this phenotype. We investigated whether the prostate cancer cell lines MDA PCa 2a and MDA PCa 2b share this phenotype.GSTP1 protein and mRNA levels were assessed in the MDA PCa 2a and MDA PCa 2b cell lines by Western and Northern blot. DNA methylation was evaluated by Southern blot analysis of genomic DNA digested with the methylation-sensitive restriction enzymes BssHII, NotI, and SacII. Re-expression of GSTP1 was determined by RT-PCR following treatment with 5-azacytidine, a DNA methyltransferase inhibitor, and/or the histone deacetylase inhibitor trichostatin A (TSA).Like all human prostatic carcinomas in vivo, both the MDA PCa 2a and 2b cell lines lack protein and mRNA expression of GSTP1. This lack of expression is associated with methylation in the GSTP1 gene promoter. Treatment with the methyltransferase inhibitor 5-azacytidine resulted in re-expression of GSTP1. By itself, TSA did not result in re-expression of GSTP1, nor did it augment expression induced by 5-azacytidine.MDA PCa 2a and 2b appear to be useful models of human prostatic carcinoma in that they lack expression of GSTP1 due to gene silencing via promoter methylation. Inhibition of histone acetylation does not appear to affect GSTP1 expression.

    View details for DOI 10.1002/pros.10093

    View details for Web of Science ID 000175909900001

    View details for PubMedID 11987150

  • Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells JOURNAL OF BIOLOGICAL CHEMISTRY Schwarze, S. R., DePrimo, S. E., Grabert, L. M., Fu, V. X., Brooks, J. D., Jarrard, D. F. 2002; 277 (17): 14877-14883


    Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype, a critical feature in tumorigenesis. The inactivation of multiple pathways that positively regulate senescence are required for immortalization. To identify these pathways in an unbiased manner, we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells (HPECs) passaged to senescence. These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein. Senescent cells display gene expression patterns that reflect their nonproliferative, differentiated phenotype and express secretory proteases and extracellular matrix components. A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes: the chemokine BRAK, DOC1, and a member of the insulin-like growth factor axis, IGFBP-3. Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts, and previously, their inactivation was documented in tumor samples. Thus, these genes may function in novel pathways that regulate senescence and are inactivated during immortalization. These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo.

    View details for DOI 10.1074/jbc.M200373200

    View details for Web of Science ID 000175203000068

    View details for PubMedID 11836256

  • Ten-core systematic biopsy results are the most powerful predictors of cancer volume at radical prostatectomy Presti, J. C., Brooks, J. D., Gill, H., Nolley, R., McNeal, J. E. LIPPINCOTT WILLIAMS & WILKINS. 2002: 226
  • Transcriptional programs activated by exposure of human prostate cancer cells to androgen GENOME BIOLOGY DePrimo, S. E., Diehn, M., Nelson, J. B., Reiter, R. E., Matese, J., Fero, M., Tibshirani, R., Brown, P. O., Brooks, J. D. 2002; 3 (7)


    Androgens are required for both normal prostate development and prostate carcinogenesis. We used DNA microarrays, representing approximately 18,000 genes, to examine the temporal program of gene expression following treatment of the human prostate cancer cell line LNCaP with a synthetic androgen.We observed statistically significant changes in levels of transcripts of more than 500 genes. Many of these genes were previously reported androgen targets, but most were not previously known to be regulated by androgens. The androgen-induced expression programs in three additional androgen-responsive human prostate cancer cell lines, and in four androgen-independent subclones derived from LNCaP, shared many features with those observed in LNCaP, but some differences were observed. A remarkable fraction of the genes induced by androgen appeared to be related to production of seminal fluid and these genes included many with roles in protein folding, trafficking, and secretion.Prostate cancer cell lines retain features of androgen responsiveness that reflect normal prostatic physiology. These results provide a broad view of the effect of androgen signaling on the transcriptional program in these cancer cells, and a foundation for further studies of androgen action.

    View details for Web of Science ID 000207581200008

    View details for PubMedID 12184806

  • Gene expression profiles in renal cell carcinoma assessed by complementary DNA microarray Higgins, J. P., Shinghal, R., Reese, J. H., Terris, M., Cohen, R. J., Tibshirani, R., Sherlock, G., Fero, M., Pollack, Brown, P. O., Botstein, D., van de Rijn, M., Brooks, J. D. NATURE PUBLISHING GROUP. 2002: 164A
  • Gene expression profiles in renal cell carcinoma assessed by complementary DNA microarray Higgins, J. P., Shinghal, R., Reese, J. H., Terris, M., Cohen, R. J., Tibshirani, R., Sherlock, G., Fero, M., Pollack, Brown, P. O., Botstein, D., van de Rijn, M., Brooks, J. D. NATURE PUBLISHING GROUP. 2002: 164A
  • Anatomy of the rectourethralis muscle EUROPEAN UROLOGY Brooks, J. D., Eggener, S. E., Chao, W. M. 2002; 41 (1): 94-100


    To define the true anatomic structure of the rectourethralis muscle.Cross-sectional images of fresh tissues from the Visible Human Data set were reviewed. Three-dimensional computer reconstructions of the rectourethralis and surrounding structures were generated from these data using a high speed computer and imaging software. The structure of rectourethralis was confirmed by dissection of fresh cadavers.The rectourethralis arises deep within the substance of the smooth muscle of the rectal wall as two limbs of muscle which face posterolaterally. These limbs fuse into a single thick muscle which inserts into the perineal body.In contrast to all previous descriptions in the literature, the rectourethralis is a Y-shaped muscle which arises within the substance of the rectal wall deep to the outer longitudinal smooth muscle. This shape is consistent with the muscle's embryologic origin. Knowledge of the structure of the rectourethralis muscle will help urologists avoid rectal injuries during perineal approaches to the prostate.

    View details for Web of Science ID 000174457200021

    View details for PubMedID 11999473

  • Plasma selenium level before diagnosis and the risk of prostate cancer development JOURNAL OF UROLOGY Brooks, J. D., Metter, E. J., Chan, D. W., Sokoll, L. J., Landis, P., Nelson, W. G., Muller, D., Andres, R., Carter, H. B. 2001; 166 (6): 2034-2038


    Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer.A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression.After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001).Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men.

    View details for PubMedID 11696701

  • GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells AMERICAN JOURNAL OF PATHOLOGY Lin, X. H., Tascilar, M., Lee, W. H., Vles, W. J., Lee, B. H., Veeraswamy, R., Asgari, K., Freije, D., Van Rees, B., Gage, W. R., Bova, G. S., Isaacs, W. B., Brooks, J. D., DeWeese, T. L., De Marzo, A. M., Nelson, W. G. 2001; 159 (5): 1815-1826


    GSTP1 CpG island hypermethylation is the most common somatic genome alteration described for human prostate cancer (PCA); lack of GSTP1 expression is characteristic of human PCA cells in vivo. We report here that loss of GSTP1 function may have been selected during the pathogenesis of human PCA. Using a variety of techniques to detect GSTP1 CpG island DNA hypermethylation in PCA DNA, we found only hypermethylated GSTP1 alleles in each PCA cell in all but two PCA cases studied. In these two cases, CpG island hypermethylation was present at only one of two GSTP1 alleles in PCA DNA. In one of the cases, DNA hypermethylation at one GSTP1 allele and deletion of the other GSTP1 allele were evident. In the other case, an unmethylated GSTP1 allele was detected, accompanied by abundant GSTP1 expression. GSTP1 CpG island DNA hypermethylation was responsible for lack of GSTP1 expression by LNCaP PCA cells: treatment of the cells with 5-azacytidine (5-aza-C), an inhibitor of DNA methyltransferases, reversed the GSTP1 promoter DNA hypermethylation, activated GSTP1 transcription, and restored GSTP1 expression. GSTP1 promoter activity, assessed via transfection of GSTP1 promoter-CAT reporter constructs in LNCaP cells, was inhibited by SssI-catalyzed CpG dinucleotide methylation. Remarkably, although selection for loss of GSTP1 function may be inferred for human PCA, GSTP1 did not act like a tumor suppressor gene, as LNCaP cells expressing GSTP1, either after 5-aza-C treatment or as a consequence of transfection with GSTP1 cDNA, grew well in vitro and in vivo. Perhaps, GSTP1 inactivation may render prostatic cells susceptible to additional genome alterations, caused by electrophilic or oxidant carcinogens, that provide a selective growth advantage.

    View details for Web of Science ID 000171988000024

    View details for PubMedID 11696442

  • Potent induction of phase 2 enzymes in human prostate cells by sulforaphane CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., Paton, V. G., Vidanes, G. 2001; 10 (9): 949-954


    Two population-based, case-control studies have documented reduced risk of prostate cancer in men who consume cruciferous vegetables. Cruciferae contain high levels of the isothiocyanate sulforaphane. Sulforaphane is known to bolster the defenses of cells against carcinogens through up-regulation of enzymes of carcinogen defense (phase 2 enzymes). Prostate cancer is characterized by an early and near universal loss of expression of the phase 2 enzyme glutathione S-transferase (GST)-pi. We tested whether sulforaphane may act in prostatic cells by increasing phase 2 enzyme expression. The human prostate cancer cell lines LNCaP, MDA PCa 2a, MDA PCa 2b, PC-3, and TSU-Pr1 were treated with 0.1-15 microM sulforaphane in vitro. LNCaP was also treated with an aqueous extract of broccoli sprouts. Quinone reductase enzymatic activity, a surrogate of global phase 2 enzyme activity, was assayed by the menadione-coupled reduction of tetrazolium dye. Expression of NQO-1, GST-alpha, gamma-glutamylcysteine synthetase-heavy and -light chains, and microsomal GST was assessed by Northern blot analysis. Sulforaphane and broccoli sprout extract potently induce quinone reductase activity in cultured prostate cells, and this induction appears to be mediated by increased transcription of the NQO-1 gene. Sulforaphane also induces expression of gamma-glutamylcysteine synthetase light subunit but not the heavy subunit, and this induction is associated with moderate increases in intracellular glutathione levels. Microsomal and alpha-class glutathione transferases were also induced transcriptionally. Sulforaphane induces phase 2 enzyme expression and activity significantly in human prostatic cells. This induction is accompanied by, but not because of, increased intracellular glutathione synthesis. Our findings may help explain the observed inverse correlation between consumption of cruciferae and prostate cancer risk.

    View details for Web of Science ID 000170899000006

    View details for PubMedID 11535546

  • Prevention of prostate cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA DePrimo, S. E., Shinghal, R., Vidanes, G., Brooks, J. D. 2001; 15 (3): 445-?


    Strategies for reducing the occurrence of prostate cancers will be critical in limiting the morbidity and mortality of this disease. The long latency period of prostate tumors and improved understanding of prostate carcinogenesis suggest opportunities for effective preventive measures. Because androgen is integral to prostatic carcinogenesis, several preventive strategies under investigation target the androgen axis. Epidemiologic and basic studies implicate dietary factors in prostate cancer development and suggest that altering diet may influence prostate cancer risk and progression. Many of the micronutrients with preventive potential have antioxidant properties; cellular defenses against oxidative stresses are likely to be crucial in reducing prostate carcinogenesis. This article summarizes the current status and opportunities in prostate cancer prevention.

    View details for Web of Science ID 000170718000004

    View details for PubMedID 11525290

  • New molecular approaches for identifying novel targets, mechanisms, and biomarkers for prostate cancer chemopreventive agents National-Cancer-Institute Workshop Williams, E. D., Brooks, J. D. ELSEVIER SCIENCE INC. 2001: 100–102


    Recently developed complementary DNA (cDNA) microarray technology allows simultaneous assessment of expression on many hundreds or thousands of genes simultaneously. This technology holds great promise for providing new insights into prostate carcinogenesis that will reveal new targets for preventive intervention strategies. In addition, this technology will deepen understanding of the means by which putative preventive compounds exert their effects, generating molecular genetic biomarkers of treatment efficacy. Several putative preventive agents are currently under investigation, and development of novel preventive strategies poses significant challenges. High throughput approaches, such as cDNA microarrays, will speed discovery and progress in prostate cancer chemoprevention.

    View details for Web of Science ID 000168170400018

  • Role of cytologic criteria in the histologic diagnosis of gleason grade 1 prostatic adenocarcinoma HUMAN PATHOLOGY McNeal, J. E., Cohen, R. J., Brooks, J. D. 2001; 32 (4): 441-446


    Gleason grade 1 prostatic adenocarcinoma is defined by its gland architecture, which resembles that of benign prostate more than any other grade. It is characterized by closely spaced glands and expansile tumor border. Cytoplasm is clear to pale, superficially identical to benign nodular hyperplasia (BPH). However, there is recent evidence that prostatic "clear-cell carcinoma," including grade 1, has cytoplasm whose composition is distinctively different from BPH, being filled with lipid rather than with the protein-rich granules that characterize benign secretory cells or the nongranular protein matrix of other prostate cancers. We reasoned that grade 1 cancer might also have additional distinctive cellular features; we tested this hypothesis by observations on 17 grade 1 carcinoma foci found as components of transition zone clear-cell cancers. Unlike BPH secretory cells, cells of grade 1 cancer were uniformly large with even, straight borders laterally and luminally. Nuclei appeared sometimes benign but were fixed in a basal row dissimilar to the uneven distribution in BPH. Nuclear pyknotic foci, blue-tinged cytoplasm, and abundant dense luminal secretion were distinctively common. Immunostain for glutathione-S transferase was negative in grade 1 cancer but lightly positive in BPH secretory cells. These cytologic findings were proposed to be useful as diagnostic clues, especially in small-needle biopsy samples, in which architecture may be difficult to interpret. HUM PATHOL 32:441-446.

    View details for PubMedID 11331962

  • Preneoplastic prostate lesions - An opportunity for prostate cancer prevention 4th Strang International Cancer Prevention Conference Nelson, W. G., De Marzo, A. M., DeWeese, T. L., Lin, X. H., Brooks, J. D., Putzi, M. J., Nelson, C. P., Groopman, J. D., Kensler, T. W. NEW YORK ACAD SCIENCES. 2001: 135–144


    Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.

    View details for Web of Science ID 000173778200012

    View details for PubMedID 11795433

  • GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas INTERNATIONAL JOURNAL OF ONCOLOGY Tchou, J. C., Lin, X. H., Freije, D., Isaacs, W. B., Brooks, J. D., Rashid, A., De Marzo, A. M., Kanai, Y., Hirohashi, S., Nelson, W. G. 2000; 16 (4): 663-676


    Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. We report here that the pathogenesis of hepatocellular carcinoma (HCC), one of the most common cancers in the world, frequently involves an accumulation of somatic DNA methylation changes at GSTP1, the gene encoding the pi-class glutathione S-transferase. For our study, Hep3B HCC cells and a cohort of 20 HCC tissue specimens were subjected to analysis for GSTP1 expression and for somatic GSTP1 alterations. GSTP1 DNA hypermethylation in HCC DNA was assessed by Southern blot analysis, via a polymerase chain reaction (PCR) assay, and by using a genomic sequencing approach. Hep3B HCC cells failed to express GSTP1 mRNA or GSTP1 polypeptides. Similarly, HCC cells in 19 of 20 HCC cases were devoid of GSTP1 polypeptides. By Southern blot analysis, DNA from Hep3B HCC cells displayed abnormal GSTP1 hypermethylation. Treatment of Hep3B HCC cells in vitro with the DNA methyltransferase inhibitor 5-aza-deoxycytidine both reversed GSTP1 DNA hypermethylation and restored GSTP1 expression. Using a PCR assay, somatic GSTP1 DNA hypermethylation was also detected in HCC DNA from 17 of 20 HCC cases. Genomic sequencing analyses, undertaken to map 5-methyldeoxycytidine nucleotides located at the GSTP1 transcriptional regulatory region, frequently detected somatic DNA hypermethylation near the gene promoter in HCC DNA. The data indicate that GSTP1 DNA hypermethylation changes appear frequently in human HCC. In addition, the data raise the possibility that somatic GSTP1 inactivation, via hypermethylation, may contribute to the pathogenesis of HCC.

    View details for Web of Science ID 000085926100003

    View details for PubMedID 10717233

  • Potent induction of carcinogen defence enzymes with sulforaphane, a putative prostate cancer chemopreventive agent. Prostate cancer and prostatic diseases Brooks, J. D., Paton, V. 1999; 2 (S3): S8

    View details for DOI 10.1038/sj.pcan.4500334

    View details for PubMedID 12496788

  • Absence of HinfI restriction abnormalities in renal oncocytoma mitochondrial DNA MOLECULAR UROLOGY Brooks, J. D., Marshall, F. F., Isaacs, W. B., Johns, D. R. 1999; 3 (1): 1-3


    Renal oncocytomas are characterized by bland-appearing eosinophilic cells with a profusion of mitochondria. Previous work has suggested that these tumors possess a mutation in the 16.5-kbp circular mitochondrial DNA (mtDNA) manifested by an abnormal restriction fragment pattern after digestion with HinfI (Welter et al, Genes Chromosomes Cancer 1989;1:7-82). To better characterize this mtDNA abnormality in renal oncocytomas, we amplified the entire mitochondrial genome from five paired normal and oncocytoma specimens and subjected the amplified fragments to digestion with the restriction enzyme HinfI. No somatically acquired alterations were detected in the mtDNA from any of the five renal oncocytomas. One specimen displayed a known HinfI polymorphism in the mtDNA from both the normal and oncocytoma tissues. Our data do not support the existence of somatically acquired mitochondrial genome abnormalities in renal oncocytomas.

    View details for Web of Science ID 000079433600001

  • Partial nephrectomy and caval thrombectomy for renal cell carcinoma in a solitary kidney with an accessory renal vein BJU INTERNATIONAL Pruthi, R. S., Angell, S. K., Brooks, J. D., Gill, H. 1999; 83 (1): 142-143

    View details for Web of Science ID 000079775000026

    View details for PubMedID 10233469

  • CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., WEINSTEIN, M., Lin, X. H., Sun, Y. H., Pin, S. S., Bova, G. S., Epstein, J. I., Isaacs, W. B., Nelson, W. G. 1998; 7 (6): 531-536


    Prostate intraepithelial neoplasia (PIN) is a purported prostate cancer precursor lesion and a candidate biomarker for efficacy assessment in prostate cancer chemoprevention trials. Loss of expression of the pi-class glutathione S-transferase enzyme GSTP1, which is associated with the hypermethylation of deoxycytidine residues in the 5'-regulatory CG island region of the GSTP1 gene, is a near-universal finding in human prostate cancer. GSTP1 expression was assessed by immunohistochemistry in 60 high-grade PIN samples adjacent to and distant from prostate adenocarcinoma. Whereas abundant enzyme polypeptide expression was evident in all normal prostatic tissues, all samples of high-grade PIN and adenocarcinoma were completely devoid of GSTP1. DNA from 10 high-grade PIN lesions was analyzed for GSTP1 CG island methylation changes using a PCR technique targeting a polymorphic (ATAAA)n repeat sequence in the promoter region of the GSTP1 gene. Somatic GSTP1 CG island methylation changes were detected in DNA from 7 of the 10 PIN lesions. Allele discrimination was possible for 5 of the 10 DNA samples: 2 of the 5 samples exhibited DNA methylation changes at both alleles; whereas 3 samples displayed no DNA methylation changes at either allele. GSTP1 CG island methylation changes were present in each of the five homozygous samples. Hypermethylation of the 5'-regulatory region of the GSTP1 gene may serve as an important molecular genetic biomarker for both prostate cancer and PIN. The finding of frequent GSTP1 methylation changes in PIN and prostate cancer supports a role for PIN lesions as a prostate cancer precursor and may provide insight to the molecular pathogenesis of prostate cancer.

    View details for Web of Science ID 000074029000013

    View details for PubMedID 9641498

  • Male pelvic anatomy reconstructed from the visible human data set Brooks, J. D., Chao, W. M., Kerr, J. LIPPINCOTT WILLIAMS & WILKINS. 1998: 14
  • Male pelvic anatomy reconstructed from the visible human data set JOURNAL OF UROLOGY Brooks, J. D., Chao, W. M., Kerr, J. 1998; 159 (3): 868-872


    To improve understanding of the male pelvic anatomy pertinent to urological surgery we performed computer generated, 3-dimensional reconstruction of the male pelvis from the Visible Human data set.A total of 18 discrete anatomical structures, including the prostate, bladder, urethra, rectum and pelvic musculature, was segmented from the Visible Human cross-sectional data obtained from the National Library of Medicine. Using high speed computing and rendering software, 3-dimensional models of each structure were generated and assembled into composite figures.These reconstructions offer a revised view of pelvic anatomy as it has been traditionally depicted. The lateral surfaces of the levator ani muscle are oriented vertically in the pelvis and directly applied to the entire lateral surface of the prostate. The bladder rests primarily anterior to the prostate rather than directly above it, as has been commonly depicted. In the cross-sectional data and reconstructions the trigone and anterior fibromuscular stroma of the prostate appear as a single unit in continuity, which may have functional implications for understanding the mechanisms of continence at the bladder neck. The striated urethral sphincter appears circular with abundant tissue posteriorly. This sphincteric muscle has greater length anteriorly than posteriorly.These 3-dimensional reconstructions provide unique insights into male pelvic anatomy. They are a useful teaching tool for investigation and virtual reality modeling of the male pelvis.

    View details for Web of Science ID 000071913700068

    View details for PubMedID 9474171

  • Differentiation of colonic metaplasia from adenocarcinoma of urinary bladder HUMAN PATHOLOGY JACOBS, L. B., Brooks, J. D., Epstein, J. I. 1997; 28 (10): 1152-1157


    Colonic metaplasia and primary bladder adenocarcinoma are relatively uncommon entities that can have similar gross clinical appearances. Examples of colonic metaplasia histologically mimicking cancer have only rarely been reported. We retrospectively analyzed 38 cases of cystitis glandularis (18 cases of colonic metaplasia), 12 cases of adenocarcinoma of urinary bladder (two well-differentiated, WDA), and one in situ adenocarcinoma from the surgical pathology files of Johns Hopkins Hospital. Nine patients with colonic metaplasia had widespread lesions. Two showed superficial muscularis propria involvement, mimicking adenocarcinoma; one of these cases had been diagnosed as infiltrating WDA at both an academic center and a community hospital. Dissecting mucin pools were focally seen in four cases of widespread colonic metaplasia, also mimicking cancer. One of the nine cases showed minimal cytological atypia, but no cases showed mitoses or signet ring cells. Distinguishing WDA from colonic metaplasia was the finding in WDA of infiltrative architectural pattern (two of two), extensive muscle invasion (two of two), moderate anaplasia (one of two), mitotic figures (two of two), and extensive mucinous pools (one of two). The diagnosis of adenocarcinoma in situ was based on anaplasia. Clinically, colonic metaplasia may resemble cancer. Histologically, colonic metaplasia may mimic cancer based on extensive involvement of the lamina propria, focal mucinous pools, focal muscularis propria involvement, focal mild cytological atypia, and rare mitoses. Despite overlapping features with colonic metaplasia, the diagnosis of WDA is based on the greater degree and extent of these atypical findings in cancer.

    View details for Web of Science ID A1997YD80100007

    View details for PubMedID 9343322

  • The Swedish prostate cancer paradox JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Walsh, P. C., Brooks, J. D. 1997; 277 (6): 497-498

    View details for Web of Science ID A1997WG05400039

    View details for PubMedID 9020276

  • Methylation of the 5' CpG island of the endothelin B receptor gene is common in human prostate cancer CANCER RESEARCH Nelson, J. B., Lee, W. H., Nguyen, S. H., Jarrard, D. F., Brooks, J. D., Magnuson, S. R., Opgenorth, T. J., Nelson, W. G., Bova, G. S. 1997; 57 (1): 35-37


    Production of the potent vasoconstrictor endothelin-1 (ET-1) by human prostate cancer cells accompanies prostate cancer progression in vivo. The predominant endothelin receptor expressed by normal prostate epithelium, ETB, is not expressed by any of the established human prostate cancer cell lines, and ETB binding is decreased on prostate cancer tissues. ETB, which may mediate ET-1 clearance and may inhibit ET-1 secretion, is encoded by a gene that contains a 5' CpG island encompassing the transcriptional regulatory region. We examined this regulatory region of the ETB receptor gene (EDNRB) to determine whether hypermethylation of cytidine nucleotides accompanies decreased ETB expression in human prostate cancer. We found somatic methylation of CpG island sequences in EDNRB in 5 of 5 human prostate cancer cell lines, 15 of 21 primary prostate cancer tissues, and 8 of 14 prostate cancer metastases (70% of samples overall). Normal tissues contained only unmethylated EDNRB. Treatment of human prostatic carcinoma cell line cultures with 5-azacytidine induced ETB mRNA expression, suggesting that CpG island methylation changes might accompany the apparent transcriptional silencing of EDNRB in vivo.

    View details for Web of Science ID A1997WA69100009

    View details for PubMedID 8988036

  • An uncertain role for p53 gene alterations in human prostate cancers CANCER RESEARCH Brooks, J. D., Bova, G. S., Ewing, C. M., PIANTADOSI, S., Carter, B. S., Robinson, J. C., Epstein, J. I., Isaacs, W. B. 1996; 56 (16): 3814-3822


    Inactivation of the p53 gene has been implicated in prostate cancer progression. To determine the role of p53 inactivation in the progression of clinical prostatic carcinomas, we assessed 67 tumors derived from patients with clinically localized disease for chromosome 17p and p53 gene allelic loss, p53 gene mutations using single-strand conformational polymorphism and direct sequencing, and p53 protein expression using immunohistochemical staining. Of 55 informative tumors, 10 demonstrated loss of 17p or the p53 gene; however, only a single tumor had a mutation in its remaining p53 allele. Significant p53 overexpression was observed in 2 of 38 tumors, and 9 others had faint staining of a few nuclei ( < 1%). p53 overexpression occurred in no informative tumor with allelic loss or mutation. In a 1-7-year follow-up, positive immunohistochemical staining did not confer an increased risk of recurrence (risk of recurrence, 0.86, P = 0.78), whereas allelic loss of chromosome 17p appeared to be highly correlated with recurrence (risk of recurrence, 3.7, P = 0.003). In an unrelated group of 42 patients with metastatic prostate cancer, p53 overexpression was found in 26 tumors (62%), and 15(36%) had high grade staining. Neither the presence nor the degree of expression correlated with time to progression or time to death. This series suggests that p53 gene inactivation is rare in primary prostatic tumors, not essential to the development of prostate cancer metastases, and of limited use as a prognostic marker in patients with primary or metastatic disease. Another gene or genes on chromosome 17p may be involved in prostate cancer progression.

    View details for Web of Science ID A1996VB98600038

    View details for PubMedID 8706029

  • Epidemiologic and molecular features of prostate carcinogenesis as clues for new prostate cancer prevention strategies Canadian Journal of Urology Brooks JD, Lee WH, Nelson WG 1996; 3 (Supplement): 30-36
  • Molecular staging of prostate cancer Canadian Journal of Urology Lee WH, Brooks JD, Nelson WG 1996; 3 (Supplement): 80-88
  • UPJ obstruction: assessing minimally invasive therapies. Contemporary urology Moore, R. G., Brooks, J. D. 1995; 7 (12): 47-?

    View details for PubMedID 10172648

  • COMPARISON OF OPEN AND ENDOUROLOGICAL APPROACHES TO THE OBSTRUCTED URETEROPELVIC JUNCTION UROLOGY Brooks, J. D., Kavoussi, L. R., Preminger, G. M., Schuessler, W. W., Moore, R. G. 1995; 46 (6): 791-795


    To compare open pyeloplasty with three minimally invasive modalities: antegrade endopyelotomy, Acucise endopyelotomy (Applied Medical, Laguna Hills, Calif), and laparoscopic pyeloplasty.Forty-five adult patients with ureteropelvic junction obstruction were managed by one of the above four techniques. Success rates, analgesic use, length of hospital stay, recovery time, and complications were compared between each of the four groups.Successful relief of obstruction was achieved in 100% of patients undergoing open and laparoscopic dismembered pyeloplasty, 78% undergoing Acucise endopyelotomy, and 77% undergoing antegrade percutaneous endopyelotomy. Acucise endopyelotomy results in shorter convalescence (1 week) than antegrade endopyelotomy (4.7 weeks), laparoscopic pyeloplasty (2.3 weeks) or open pyeloplasty (10.3 weeks). Complication rates appear to be similar among all groups.Our limited data imply that Acucise endopyelotomy offers low morbidity with success rates comparable to antegrade pyeloplasty, whereas laparoscopic pyeloplasty is as effective as open pyeloplasty with diminished morbidity.

    View details for Web of Science ID A1995TJ34700007

    View details for PubMedID 7502417

  • MOLECULAR-GENETICS AND CHROMOSOMAL ALTERATIONS IN PROSTATE-CANCER National Conference on Prostate Cancer Isaacs, W. B., Bova, G. S., Morton, R. A., Bussemakers, M. J., Brooks, J. D., Ewing, C. M. WILEY-LISS. 1995: 2004–12


    Inactivation of the retinoblastoma (Rb) gene has been implicated in the genesis and progression of a number of tumor types, including prostatic adenocarcinomas. We have analyzed a series of 46 surgically-resected human prostatic adenocarcinomas for allelic loss of the Rb gene with PCR amplification of a highly polymorphic region of the gene. 41 of 46 tumors (89%) were informative and 11 of these (27%) had lost one Rb allele. The relative frequency of this occurrence suggests that inactivation of the retinoblastoma gene may be an important event in prostate carcinogenesis.

    View details for Web of Science ID A1995QE72800007

    View details for PubMedID 7845865

  • FREQUENT LOSS OF CHROMOSOME ARMS 8P AND 13Q IN COLLECTING DUCT CARCINOMA (CDC) OF THE KIDNEY GENES CHROMOSOMES & CANCER Schoenberg, M., Cairns, P., Brooks, J. D., Marshall, F. F., Epstein, J. I., Isaacs, W. B., Sidransky, D. 1995; 12 (1): 76-80


    Collecting duct carcinoma (CDC) is a malignant renal neoplasm that is believed to arise from the epithelium of the ducts of Bellini in the distal nephron. These tumors are clinically aggressive and more often occur in a younger population than is typical of the more common clear cell renal carcinoma (RCC). Using highly informative polymorphic microsatellite markers on chromosome arms 3p, 5q, 6q, 9p, 9q, 11p, 13q, 17p, and 18q, we analyzed DNA from nonmalignant and tumor tissue in 6 cases of CDC. We found no evidence of 3p loss of heterozygosity (LOH) in these renal tumors by using multiple markers, a finding that distinguishes CDC from RCC in which 3p LOH has frequently been observed. We found LOH of 8p in 50% of the tumors examined; in addition, we observed LOH of 13q in 50% of the tumors studied. Interestingly, 8p LOH may be associated with high stage and poor clinical prognosis. These data suggest that the molecular events responsible for the development of CDC differ from those associated with the origin of RCC, and that tumor suppressor genes on 8p and 13q may be involved in the pathogenesis of CDC.

    View details for Web of Science ID A1995QU21600014

    View details for PubMedID 7534117

  • MOLECULAR-BIOLOGY OF PROSTATE-CANCER PROGRESSION CANCER SURVEYS Isaacs, W. B., Bova, G. S., Morton, R. A., Bussemakers, M. J., Brooks, J. D., Ewing, C. M. 1995; 23: 19-32


    A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). The most consistent changes seen are those of allelic loss events, with the majority of tumours examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, seem to be the most frequent regions of loss, suggesting the presence of novel tumour suppressor genes. Deletions of one copy of the RB and TP53 genes are less frequent as are mutations of the TP53 gene, and accumulating evidence suggests the presence of an additional tumour suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation modulated gene expression. The presence of multiple changes in these tumours is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way, which may elucidate critical early events in prostatic carcinogenesis.

    View details for Web of Science ID A1995RH96200003

    View details for PubMedID 7621457

  • Embryonal adenoma of the kidney: case report Journal of Urology Perlman EJ, Brooks J, Gordon AH, Griffin CA, Schoenberg M 1995; 154: 1473-1474


    Hypermethylation of regulatory sequences at the locus of the pi-class glutathione S-transferase gene GSTP1 was detected in 20 of 20 human prostatic carcinoma tissue specimens studied but not in normal tissues or prostatic tissues exhibiting benign hyperplasia. In addition, a striking decrease in GSTP1 expression was found to accompany human prostatic carcinogenesis. Immunohistochemical staining with anti-GSTP1 antibodies failed to detect the enzyme in 88 of 91 prostatic carcinomas analyzed. In vitro, GSTP1 expression was limited to human prostatic cancer cell lines containing GSTP1 alleles with hypomethylated promoter sequences; a human prostatic cancer cell line containing only hypermethylated GSTP1 promoter sequences did not express GSTP1 mRNA or polypeptides. Methylation of cytidine nucleotides in GSTP1 regulatory sequences constitutes the most common genomic alteration yet described for human prostate cancer.

    View details for Web of Science ID A1994PU28500092

    View details for PubMedID 7972132

  • MOLECULAR-BIOLOGY OF PROSTATE-CANCER SEMINARS IN ONCOLOGY Isaacs, W. B., Bova, G. S., Morton, R. A., Bussemakers, M. J., Brooks, J. D., Ewing, C. M. 1994; 21 (5): 514-521


    A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16 appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers, and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are underway and will hopefully elucidate critical early events in prostatic carcinogenesis.

    View details for Web of Science ID A1994PM94000002

    View details for PubMedID 7939745



    We report a patient who underwent embolization of a varicocele for chronic testicular pain with Gianturco coils and developed increased bilateral pain. Complete pain relief was achieved by laparoscopic resection of both spermatic cords. The case provides insights into the pathophysiology of testicular pain and may suggest alternative therapies for chronic orchialgia.

    View details for Web of Science ID A1994PQ01200010

    View details for PubMedID 7858624

  • Mutations of the VHL tumour suppressor gene in renal carcinoma Nature Genetics Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, Lubensky I, Duan DR, Florence C, Pozzatti R, Walther MM, Bander NH, Grossman HB, Braunch H, Pomer S, Brooks JD, Isaacs WB, Lerman MI, Zbar B, Linehan WM 1994; 7: 85-90
  • GENETIC ALTERATIONS IN PROSTATE-CANCER 59th Cold Spring Harbor Symposium on Quantitative Biology - The Molecular Genetics of Cancer Isaacs, W. B., Bova, G. S., Morton, R. A., Bussemakers, M. J., Brooks, J. D., Ewing, C. M. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. 1994: 653–659


    A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent, as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha-catenin-mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way and may elucidate critical early events in prostatic carcinogenesis.

    View details for Web of Science ID A1994RH96600074

    View details for PubMedID 7587126

  • TUMOR-SUPPRESSOR GENE ALLELIC LOSS IN HUMAN RENAL CANCERS JOURNAL OF UROLOGY Brooks, J. D., Bova, G. S., Marshall, F. F., Isaacs, W. B. 1993; 150 (4): 1278-1283


    It is now apparent that multiple genetic alterations, including oncogene activation and tumor suppressor gene inactivation, are necessary steps in carcinogenesis. We have studied this concept in renal cancers by looking at specific tumor suppressor genes implicated in several allelotyping studies. Primary, predominantly low stage renal tumors of varying grades and histologic subtypes were investigated for allelic loss of 3p, 17p and the p53 gene, the DCC gene and the Rb gene and its product. 3p loss occurred in 47% of tumors studied and was much more common in clear cell cancers (85%). 17p and p53 gene loss were relatively uncommon events with only 6 of 42 tumors demonstrating loss. None of the tumors with typical histologies had allelic loss of the DCC gene, though loss did occur in leiomyosarcoma and a collecting duct tumor. Allelic loss of the Rb gene occurred in one clear cell tumor, the leiomyosarcoma, and, interestingly, in both collecting duct tumors in this series. Allelic loss of the Rb gene was correlated with little or no RB protein expression as judged by immunohistochemistry. At all loci studied, allelic loss did not appear to correlate with tumor grade or stage. These results suggest that inactivation of the p53, Rb, and DCC genes by allelic loss are uncommon events in the early stages of renal carcinogenesis.

    View details for Web of Science ID A1993LX76200066

    View details for PubMedID 8371415

  • TUBULARIZED NEOURETHRA FOLLOWING RADICAL RETROPUBIC PROSTATECTOMY JOURNAL OF UROLOGY Steiner, M. S., Burnett, A. L., Brooks, J. D., Brendler, C. B., STUTZMAN, R. E., Carter, H. B. 1993; 150 (2): 407-409


    A 1.5 cm. tubularized neourethra was formed using an anterior bladder flap as part of bladder neck reconstruction after radical retropubic prostatectomy in 69 consecutive patients with clinically localized prostate cancer (study group). Postoperative continence (defined as requiring no protection for any activity) was assessed by history at 3 months (all men) and 6 months (45 of 69 men). Continence in the study group was compared to that of 45 men with 6 months of followup who underwent radical retropubic prostatectomy without tubularization of the anterior bladder (control group). At 3 months 38 of 69 men (55%) were continent in the study group and 14 of 45 (31%) were continent in the control group (p < 0.03). At 6 months 39 of 45 men (87%) were continent in the study group compared to 21 of 45 (47%) in the control group (p < 0.01). Upright cystograms performed on men with and without the tubularized neourethra after radical retropubic prostatectomy suggest that a neourethra proximal to the external sphincter may increase resistance in this area and result in early return of urinary control in men undergoing radical retropubic prostatectomy.

    View details for Web of Science ID A1993LM76500032

    View details for PubMedID 8326564

  • Regional DNA Hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors Cancer Research Makos M, Nelkin BD, Reiter RE, Gnarra JR, Brooks J, Isaacs W, Linehan M, Baylin SB 1993; 53: 2719-2722
  • Genetic alterations in prostate cancer - prognostic implications? Akteulle Onkologie Isaacs WB, Bova GS, Brooks JD, Ewing CM, Morton RA, Robinson JC 1993; 78: 84-92


    1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a recently described neurotoxin, produces a marked dopamine (DA) depletion in the mouse striatum. In this study, a series of DA uptake blockers was tested for their ability to prevent this effect of MPTP. The agents tested (amfonelic acid, benztropine, bupropion and mazindol) completely protected against DA depletion in the mouse striatum when given before DA-depleting doses of MPTP were administered, whereas atropine and trihexyphenidyl (which were employed for comparative purposes) did not. DA uptake blocking agents appear to represent a second general class of compounds, monoamine oxidase inhibitors being the first, which protect against the biologic effects of MPTP in the mouse.

    View details for Web of Science ID A1985ASY5800005

    View details for PubMedID 3932903