The James Buchanan Brady Urological Institute

Baltimore, MD, United States

The James Buchanan Brady Urological Institute

Baltimore, MD, United States

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News Article | April 19, 2017
Site: www.eurekalert.org

The latest in a series of studies led by researchers at Johns Hopkins Medicine shows that addition of a widely available, noninvasive imaging test called 99mTc-sestamibi SPECT/CT to CT or MRI increases the accuracy of kidney tumor classification. The research team reports that the potential improvement in diagnostic accuracy will spare thousands of patients each year in the United States alone from having to undergo unnecessary surgery. In a recent report on ongoing work to improve kidney tumor classification, published in the April issue of the journal Clinical Nuclear Medicine, the team reports that the sestamibi SPECT/CT test--short for 99mTc-sestamibi single-photon emission computed tomography/computed tomography(CT) -- adds additional diagnostic information in conjunction with conventional CTs and MRI and improves physicians' ability to differentiate between benign and malignant kidney tumors. "Sestamibi SPECT/CT lets radiologists and urologists 'see' the most common benign kidney tumor, something CT and MRI have not succeeded in doing alone," says Mohamad E. Allaf, M.D., MEA Endowed Professor of Urology at the Johns Hopkins University School of Medicine. "This noninvasive scan may prevent patients with a potentially benign kidney tumor from having to undergo a surgery to remove the tumor or potentially the entire kidney, along with its associated risks and high costs. At Johns Hopkins, use of this test has already spared a number of our patients from unnecessary surgery and unnecessary removal of a kidney that would require them to be on dialysis. These results are hugely encouraging, but we need to do more studies." For this study, 48 patients who were diagnosed with a kidney tumor on conventional CT or MRI were imaged with sestamibi SPECT/CT at Johns Hopkins prior to surgery. Radiologists, who were not allowed to talk to each other or know the results of the surgeries, graded the conventional and sestamibi SPECT/CT images benign or malignant using a 5-point scale (1 = definitely benign, 5 = definitely cancerous). Following surgery, similarly 'blinded' pathologists analyzed the tumors without knowing the radiologists' imaging results. Pathology results of surgically removed tumors showed that 8 of the 48 were benign. The remaining 40 were classified as a variety of other tumor types, including malignant renal cell carcinomas. Reviewing sestamibi SPECT/CT scan results in conjunction with CT or MRI changed the initial rating levels from cancerous (score 3, 4, 5) toward benign (score 1 and 2) in 9 cases, and changed reviewers' score from likely cancerous (score 4) to definitely cancerous (score 5) in 5 cases, or about 10 percent of all cases. The addition of sestamibi SPECT/CT increased the reviewers' diagnostic certainty in 14 of the 48 patients, or in nearly 30 percent of all cases. Overall, the investigators said, adding sestamibi SPECT/CT helped identify 7 of 9 benign tumors, and conventional imaging with added sestamibi SPECT/CT outperformed conventional imaging alone, as measured by a statistical analysis that measures tradeoffs between sensitivity and specificity. On this measure, a value of 0.50 indicates that a diagnostic test is no better than chance. Conventional imaging combined with sestamibi SPECT/CT had a value of 0.85, while conventional imaging alone had a value of 0.60. Even for patients whose tumors were not reclassified, the addition of sestamibi SPECT/CT increased physicians' ability to more confidently classify malignant tumors, which reduces the risk of misdiagnosis and unnecessary surgery for all patients, the researchers say. Radiologists and urologists have been frustrated for decades by the inability of conventional imaging tests, such as CT and MRI, to distinguish benign from malignant kidney tumors. At Johns Hopkins, multispecialty teams work together to determine the best care for patients and as partners on research innovations and quality improvement initiatives. "This collaborative venue enabled two then-residents [Drs. Michael Gorin and Steven Rowe] from different departments and specialties to design a clinical trial based on a few reports in the literature suggesting a potential role for sestamibi SPECT/CT in this diagnostic conundrum, and their hypothesis proved correct," says Mehrbod Som Javadi, MD, assistant professor of radiology at Johns Hopkins University School of Medicine and the senior author on the paper. Pamela T. Johnson, MD, associate professor of radiology at the Johns Hopkins University School of Medicine notes, "these types of advances are critical to our precision medicine initiative, Hopkins inHealth, designed for individualized patient management, and to our mission of high-value health care, where the highest quality care is safely delivered at the lowest personal and financial cost to the patient." "As radiologists, we have struggled to find noninvasive ways to better classify patients and spare unnecessary surgery, but this has not been easy," says Steven P. Rowe, M.D., Ph.D., one of the two former residents who developed this approach, and now assistant professor of radiology and radiological science at the Johns Hopkins University School of Medicine. "Sestamibi SPECT/CT offers an inexpensive and widely available means of better characterizing kidney tumors, and the identical test is now being performed as part of a large trial in Sweden, for which the first results have just recently been published and appear to confirm our conclusions." Although further study is needed to validate the accuracy of sestamibi SPECT/CT, this test appears to be a less expensive, faster, noninvasive alternative to surgery, says Michael A. Gorin, M.D., the other resident involved in developing this approach and now chief resident with The James Buchanan Brady Urological Institute of the Johns Hopkins University School of Medicine. "In the absence of diagnostic certainty, surgeons tend to remove kidney tumors in an abundance of caution, leading to an estimated 5,600 surgically removed benign kidney tumors each year in the United States." Other authors on this paper include, Sara Sheikhbahaei, Christopher S. Jones, Kristin K. Porter, Alex S. Baras, Phillip M. Pierorazio, Mark W. Ball, Lilja B. Solnes, Jonathan I. Epstein, and Mehrbod S. Javadi, all of the Johns Hopkins University School of Medicine, and Takahiro Higuchi of Wurzburg University in Germany.


Axelrod H.,The Cellular and Molecular Medicine Program | Axelrod H.,The James Buchanan Brady Urological Institute | Pienta K.J.,The Cellular and Molecular Medicine Program | Pienta K.J.,The James Buchanan Brady Urological Institute
Oncotarget | Year: 2014

The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context.


Meldrum D.R.,University of California at Los Angeles | Burnett A.L.,The James Buchanan Brady Urological Institute | Dorey G.,University of the West of England | Esposito K.,The Second University of Naples | Ignarro L.J.,University of California at Los Angeles
Journal of Sexual Medicine | Year: 2014

Introduction: Penile rigidity depends on maximizing inflow while minimizing outflow. Aim: The aim of this review is to describe the principal factors and mechanisms involved. Main Outcome Measure: Erectile quality is the main outcome measure. Methods: Data from the pertinent literature were examined to inform our conclusions. Results: Nitric oxide (NO) is the principal factor increasing blood flow into the penis. Penile engorgement and the pelvic floor muscles maintain an adequate erection by impeding outflow of blood by exerting pressure on the penile veins from within and from outside of the penile tunica. Extrinsic pressure by the pelvic floor muscles further raises intracavernosal pressure above maximum inflow pressure to achieve full penile rigidity. Aging and poor lifestyle choices are associated with metabolic impediments to NO production. Aging is also associated with fewer smooth muscle cells and increased fibrosis within the corpora cavernosa, preventing adequate penile engorgement and pressure on the penile veins. Those same penile structural changes occur rapidly following the penile nerve injury that accompanies even "nerve-sparing" radical prostatectomy and are largely prevented in animal models by early chronic use of a phosphodiesterase type 5 (PDE5) inhibitor. Pelvic floor muscles may also decrease in tone and bulk with age, and pelvic floor muscle exercises have been shown to improve erectile function to a similar degree compared with a PDE5 inhibitor in men with erectile dysfunction (ED). Conclusions: Because NO is critical for vascular health and ED is strongly associated with cardiovascular disease, maximal attention should be focused on measures known to increase vascular NO production, including the use of PDE5 inhibitors. Attention should also be paid to early, regular use of PDE5 inhibition to reduce the incidence of ED following penile nerve injury and to assuring normal function of the pelvic floor muscles. These approaches to maximizing erectile function are complementary rather than competitive, as they operate on entirely different aspects of erectile hydraulics. © 2014 International Society for Sexual Medicine.


Inoue L.Y.T.,University of Washington | Trock B.J.,The James Buchanan Brady Urological Institute | Partin A.W.,The James Buchanan Brady Urological Institute | Carter H.B.,The James Buchanan Brady Urological Institute | Etzioni R.,Fred Hutchinson Cancer Research Center
Statistics in Medicine | Year: 2014

Prostate cancer grade, assessed with the Gleason score, describes how abnormal the tumor tissue and cells appear, and it is an important prognostic indicator of disease progression. Whether prostate tumors change grade is a question that has implications for screening and treatment. Empirical data on tumor grade over time have become available from men biopsied regularly as part of active surveillance (AS). However, biopsy (BX) grade is subject to misclassification. In this article, we develop a model that allows for estimation of the time of grade change while accounting for the misclassification error from BX grade. We use misclassification rates from studies of prostate cancer BXs followed by radical prostatectomy. Estimation of the transition times from true low-grade to high-grade disease is conducted within a Bayesian framework. We apply our model to serial observations on BX grade among 627 cases enrolled in a cohort of AS patients at Johns Hopkins University who were biopsied annually and referred to treatment if there was any evidence of disease progression on BX. We consider different prior distributions for the time to true grade progression. The estimated likelihood of grade progression within 10years of study entry ranges from 12% to 24% depending on the prior. We conclude that knowledge of rates of grade misclassification allows for determination of true grade progression rates among men with serial BXs on AS. Although our results are sensitive to prior specifications, they indicate that in a nontrivial fraction of the patient population, tumor grade can progress. © 2013 John Wiley & Sons, Ltd.


Musicki B.,The James Buchanan Brady Urological Institute | Bivalacqua T.J.,The James Buchanan Brady Urological Institute | Champion H.C.,University of Pittsburgh | Burnett A.L.,The James Buchanan Brady Urological Institute
Journal of Sexual Medicine | Year: 2014

Introduction: Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. Aims: We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. Methods: SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Main Outcome Measures: Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Results: Continuous treatment with sildenafil reversed (P<0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters. Conclusion: Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. Musicki B, Bivalacqua TJ, Champion HC, and Burnett AL. Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis. © 2013 International Society for Sexual Medicine.


Mulhall J.P.,Sloan Kettering Cancer Center | Bivalacqua T.J.,The James Buchanan Brady Urological Institute | Becher E.F.,University of Buenos Aires
Journal of Sexual Medicine | Year: 2013

Introduction. Prostate cancer is common, and, thus, more men are being treated surgically. Long-term functional outcomes are of significant importance to the patient and their partners. Erectile function (EF) preservation (rehabilitation) has gained significant traction worldwide, despite the absence of definitive evidence supporting its use. Aim. To review the effectiveness of specific pharmacological therapies and other erectogenic aids in the treatment of post-radical prostatectomy (RP) erectile dysfunction. Methods. A systematic literature review of original peer-reviewed manuscripts and clinical trials reported in Medline. Main Outcome Measure. This review focused on the evaluation of interventions that aimed to improve EF recovery following RP. Results. Although well documented in animal models, studies supporting the rehabilitation with phosphodiesterase type 5 inhibitors in humans are scarce. Daily sildenafil has been used in trials (only one randomized placebo-controlled trial) with a significant improvement in erection recovery when compared to placebo or no rehabilitation but with a low return to baseline rates (27% vs. 4% placebo). Nightly vardenafil vs. on demand vs. placebo has been studied in the Recovery of Erections: INtervention with Vardenafil Early Nightly Therapy trial with no difference in erection recovery following RP. Intracavernosal injections, although widely used and attractive from a rehabilitation standpoint, does not yet have definitive supporting its role in rehabilitation. Vacuum erection devices use following RP has been reported, but there are no data to support its role as monotherapy. Intraurethral alprostadil was also studied vs. sildenafil in a multicenter, randomized, open-label trial, and no superiority was found. Conclusions. At this time, we are unable to define what represents the optimal rehabilitation program in regard to strategies utilized, timing of intervention, or duration of treatment. © 2012 International Society for Sexual Medicine.


Rubio-Aurioles E.,Clinical Research | Bivalacqua T.J.,The James Buchanan Brady Urological Institute
Journal of Sexual Medicine | Year: 2013

Introduction. Low sexual desire in men is a condition that has received little attention; nevertheless it occurs with high frequency. Clinicians are in need of clear guidelines to address this problem. Aim. To develop standardized operational procedures to be implemented with men presenting low sexual desire/interest (LSD/I). Methods. Review of relevant evidence-based literature and published guidelines, integrated with expert opinion. Main Outcome. Operational procedures for LSD/I that are recommended for clinical practice with various degrees of support from published evidence. Results. A new classification scheme is proposed; LSD/I is proposed as an umbrella term for which hypoactive sexual desire disorder (HSDD) is only a subtype. The following standard operational procedures are described: (i) Detection of LSD/I: screening for LSD/I, screening for LSD/I in patients with other sexual dysfunctions; (ii) Diagnosis and assessment of etiology: diagnostic criteria for LSD/I, assessment of depression status, assessment of relationship status, assessment of endocrinologic status, diagnostic criteria for HSDD in men; (iii) Treatment: treatment of LSD/I secondary to low testosterone, treatment of LSD/I secondary to elevated prolactin, treatment of LSD/I secondary to other endocrinologic disorders, treatment of LSD/I secondary to depressive illness and or anxiety disorders, treatment of LSD/I secondary to relationship conflict and treatment of HSDD. A diagnostic and treatment algorithm is presented. Conclusions. LSD/I is a common condition that should be identified in patients; it is recommended that this condition be actively investigated by the clinician. Once the diagnosis of LSD/I in men is confirmed, a thorough search for possible causes needs to include both biological and psychological causes. Treatment should be etiologically oriented. © 2012 International Society for Sexual Medicine.


Bivalacqua T.J.,The James Buchanan Brady Urological Institute | Musicki B.,The James Buchanan Brady Urological Institute | Kutlu O.,The James Buchanan Brady Urological Institute | Burnett A.L.,The James Buchanan Brady Urological Institute
Journal of Sexual Medicine | Year: 2012

Introduction. Priapism is defined as an erectile disorder, in which erection persists uncontrollably without sexual purpose. The precise mechanisms involved in the development of sickle cell disease-associated priapism are ill defined. Aim. To summarize the recent developments that increase our understanding of the molecular mechanisms of priapism. Methods. This article reviews the literature (Medline search 2000-2010) that relates the key molecular signaling pathways that contribute to the development of priapism associated with sickle-cell disease. It focuses on basic science investigations using multiple animal models. Main Outcome Measures. The reader will be informed of the most current research regarding the role of endothelial nitric oxide synthase, phosphodiesterase type 5 (PDE5), adenosine, RhoA/Rho-kinase (ROCK), and opiorphins in the pathophysiology of priapism. Results. New concepts in the field of priapism research suggest that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection control mechanisms on a molecular level. A leading proposal in this regard is the notion of aberrant signaling of the endothelium-derived nitric oxide and PDE5 signal transduction pathway in the penis. Additionally, dysfunctional regulatory control of signal transduction systems which interact with this pathway such as adenosine and RhoA/Rho-kinase may contribute to the development of priapism. Recent investigations of opiorphins also demonstrate a role in regulating corporal smooth muscle tone and thereby dysregulation of erection physiology in priapism. These advances have paved the way for understanding this disorder as having a molecular pathogenesis. Conclusions. As the science underlying priapism further emerges, increasingly effective therapeutics for sickle cell disease-associated priapism is certain to follow. © 2011 International Society for Sexual Medicine.


Di Carlo H.N.,The James Buchanan Brady Urological Institute | Darras F.S.,The James Buchanan Brady Urological Institute
Advances in Chronic Kidney Disease | Year: 2015

Urologic considerations during the kidney transplantation process, starting with initial recipient evaluation and continuing through the post-transplant, long-term follow-up, are critical for minimizing urologic complications and improving graft survival. Appropriate, targeted, preoperative urologic evaluation of the recipient allows for an optimized urinary tract to accept the graft, whereas post-transplant urologic follow-up and monitoring decrease the risk of graft lost secondary to a urologic cause, particularly in patients with a urologic reason for their kidney failure and in those patients with concomitant urologic diagnoses. Urologic complications comprise the second most common adverse post-transplant event, occurring in 2.5% to 14% of patients and are associated with high morbidity, graft loss, and mortality. Early and late urologic complications, including hematuria, hematoma, lymphocele, urine leak, ureteral stricture, nephrolithiasis, and vesicoureteral reflux, and their causes and treatment options are explored. A multidisciplinary team approach to kidney transplantation, including transplant surgery, urology, and nephrology, optimizes outcomes and graft survival. Although the current role of the urologist in kidney transplantation varies greatly by institution, appropriate consultation, participation, and monitoring in select patients is essential. © 2015 National Kidney Foundation, Inc.


Lu C.,The James Buchanan Brady Urological Institute | Luo J.,The James Buchanan Brady Urological Institute
Translational Andrology and Urology | Year: 2013

In the past five years, multiple structurally and functionally distinct androgen receptor (AR) splice variants have been decoded and characterized. The mature transcripts for the majority of the fully decoded AR splice variants contain a transcribed "intronic" sequence, capable of encoding a short variant-specific peptide to replace the AR ligand-binding domain (LBD). Functionally, AR splice variants represent a diverse group of molecules often demonstrating cell context-specific genomic functions that may or may not be coupled with the functions of the canonical full-length AR (AR-FL). However, the full spectrum of their functional diversity and the underlying mechanistic basis remains very poorly characterized. In clinical specimens derived from men treated with a variety of hormone therapy regimens, AR splice variants are almost always expressed at detectable, yet lower levels when compared to that of AR-FL. In spite of the collective in vitro data supporting the putative role of AR splice variants in therapeutic resistance to hormone therapies, the extent to which AR splice variants mediate resistance to each individual regimen is not known and awaits thorough investigations in a clinically relevant setting using specimens from men undergoing treatments. Among the AR splice variants, AR-V7 is more abundantly and frequently expressed in castration-resistant prostate cancer (CRPC) and remains the most important variant identified so far. The relative importance of different AR molecules, including AR-FL, should be functionally dissected in the setting of castration-resistant prostate cancer, particularly in tumors resistant to more potent inhibitors of AR-FL recently approved by the FDA. In this review, we will focus on the discovery and characterization of AR splice variants, their putative functions and roles in mediating constitutively active AR signaling, and key areas of investigation that are necessary to establish their clinical relevance. © AME Publishing Company.

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