Kidney & News

& Institute of Developments in A Physician Journal Glickman Urological Vol. 24 | Winter 2015 Vol. Urology and

CLEVELAND CLINIC Glickman Urological & Kidney Institute | Urology & News | Vol. 24 2015 2 Urology & Kidney Disease News Department Chairs Urology & Kidney

Edmund Sabanegh Jr., MD Chairman, Department Disease News of Urology Glickman Urological & Kidney Institute Chairman’s Report...... 4

News from the Glickman Urological & Kidney Institute New Staff...... 5 CME Upcoming Events — Save These Dates...... 5 2014 Glickman Urological & Kidney Institute Achievements...... 6 Robert J. Heyka, MD Chairman, Department of Nephrology and Best Practices We’re No. 1 ... by Putting Patients First...... 7 Glickman Urological Cleveland Clinic Urology, Las Vegas Expands Staff, & Kidney Institute Adds Services...... 8 From Inspiration to Commercialization: How a Test Gets to Market...... 9 Urology Residency Training at Cleveland Clinic: Striving for Excellence...... 10

Medical Editors Center for Robotics and Laparoscopic Surgery Intracorporeal Hypothermia During Robotic Partial Sankar Navaneethan, MD Nephrectomy Using Renal Ice Slush...... 11 Glickman Urological New Robotic System Designed for Single-Port Surgery: & Kidney Institute First Clinical Experience...... 13 Medical Editor, Nephrology Robotic Radical Perineal Prostatectomy: Urology & Kidney Disease News Potential Advantages of a New Approach...... 15 Partial Nephrectomy: Saving as Many as Possible...... 18 Robotic Radical Cystectomy with Intracorporeal Urinary Diversion: A New Horizon...... 20

Center for Urologic Oncology Daniel Shoskes, MD Emerging Technologies in Radiation Therapy May Improve Glickman Urological Tumor Control in ...... 22 & Kidney Institute Medical Editor, Urology Use of Salvage Therapies in the Treatment of Radioresistant Prostate Cancer...... 23 Urology & Kidney Disease News Determining Biochemical Success Following Primary Whole-Gland Prostate Cryoablation...... 24 Debunking the Myths of Chemotherapy in Prostate Cancer...... 25 A Progress Report on the Genomic Prostate Score and its Impact on Risk Stratification and Active Surveillance Decisions....28 Multiparametric Magnetic Resonance Imaging Ultrasound (MP-MRI-US) Fusion Targeted Prostate Biopsy...... 30 Brachytherapy Versus Other Radiotherapeutic Modalities for Prostate Cancer: Why the Bias?...... 32 On the Cover Advances in multiparametric magnetic resonance imaging and the fusion of that information with real-time transrectal Center for Blood Pressure Disorders ultrasound imaging (termed MP-MRI-US fusion biopsy; see ar- ticle on p. 30) have improved diagnostic accuracy for prostate Department of Nephrology and Hypertension Designated cancer. This image shows a prostate cancer lesion identified as a Comprehensive Hypertension Center...... 34 using diffusion-weighted imaging. Reprinted from Natarajan S, Marks LS, Margolis DJA, et al. Clinical application of a 3D ultrasound-guided prostate biopsy system. Urol Oncol 2011; 29(3):334-342. © 2011, used with permission from Elsevier. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 3

Center for Pulmonary Hypertension and Kidney Disease: A Deadly Duo...... 35 More News Articles Center for Genitourinary Reconstruction Available Online Erectile Dysfunction Is a Major Cause of Peyronie Disease: A Personal View...... 37 Staged Buccal Graft Urethroplasty for Difficult Strictures...... 39 Consult QD — Urology and Nephrology Center for Reproductive Medicine Proteomics and the Future of Sperm Testing...... 41 A blog featuring insights and perspectives from Cleveland Clinic Center for Endourology and Stone Disease experts. Visit today and join the Renal Access for Percutaneous Nephrolithotomy: Where Are We Today?...... 44 conversation.

Center for Female Pelvic Medicine and Reconstructive Surgery ConsultQD.clevelandclinic.org/ Predictors of Pelvic Organ Prolapse Progression...... 46 urology-nephrology Distribution and Homing of Marrow-Derived Mesenchymal Stem Cells Following Postpartum Intraperitoneal Injection into LOXL1 Knockout Mice...... 47

Center for Renal and Pancreas Transplantation at Cleveland Clinic: A Global Resource.....49 Impact of Low Testosterone in Renal Disease and Kidney Transplantation...... 51 A Surgical Approach to Patients with Intractable Nephrolithiasis...... 53

Center for Dialysis Therapies and Cleveland Clinic: Bringing Patients Back Home...... 55 Urgent-Start Peritoneal Dialysis at Cleveland Clinic: A Multidisciplinary Approach...... 56

Center for Pediatric Urology The Changing Paradigm of Management of Children with ...... 58 Transitional Urology Prepares Patients with Congenital Genitourinary Problems for Adult Care...... 60

Physician Resource Guide...... 62 4 Urology & Kidney Disease News

Chairman’s Report

• Surgical innovation, including intracorporeal hypo- thermia during robotic partial nephrectomy to pre- Eric A. Klein, MD serve long-term renal parenchymal function; renal autotransplantation and pyelovesicostomy to resolve Chairman, Cleveland Clinic Glickman in patients with intractable nephroli- Urological & Kidney Institute thiasis; and robotic radical perineal prostatectomy for localized prostate cancer.

• High-impact research that may lead to new treatment options, including tracking mesenchymal stem cells’ preferential homing to pelvic organs in a mouse model Dear Colleagues, of pelvic organ prolapse; using proteomic studies to Welcome to the Winter 2015 issue of Glickman Urological & identify novel biomarkers for sperm dysfunction; and Kidney Institute’s Urology & Kidney Disease News. As these examining the effect of low testosterone in renal dis- pages demonstrate, 2014 was a banner year for our institute ease and kidney transplantation, as a disease severity and its talented clinicians and researchers. indicator and a therapeutic target.

I am proud to report that our urology program was named • Clinical best practices, such as our efforts to educate the nation’s best and our nephrology program was No. 2 in patients about peritoneal dialysis and home hemo- U.S. News & World Report’s annual rankings of America’s top dialysis, and advice on how to transition adolescent hospitals. Our Urology Residency Program also was judged patients with congenital genitourinary problems to to be the country’s finest in an assessment by the online adult care. physician network Doximity in collaboration with U.S. News • Strategies to improve outcomes prediction in pelvic & World Report. And the American Society of Hypertension organ prolapse, after primary whole gland prostate accredited our Department of Nephrology and Hyperten- cryoablation, and in salvage therapies for radioresis- sion as the first Comprehensive Hypertension Center in tant prostate cancer. News from the Glickman Urological & Kidney Institute & Kidney Urological Glickman the from News Northeast Ohio, and one of only 12 nationally. This issue also brings you two thought-provoking prostate These achievements are the result of a relentless drive for cancer articles — on our increasing use of brachytherapy excellence by the programs’ directors and the Urological & (while other institutions are turning away), and on research Kidney Institute’s staff. I am pleased that their efforts have that’s overcoming the negative perceptions of systemic brought us recognition. Please be assured that we don’t take chemotherapy for castration-resistant cases. And we offer the honors for granted, and we don’t intend to rest on past progress reports on our kidney transplant program and our accomplishments. Continuously improving our patients’ medical and surgical care, conducting research that alters expansion of urology services in Las Vegas. disease outcomes, and providing superlative training for the I hope you find UKD News informative and helpful in your next generation of urologists and nephrologists will remain practice. If we can assist in any way, please let us know. our top priorities.

Urology & Kidney Disease News offers a rich digest of what we’ve done and learned in the past year, and where we’re headed. You’ll find comprehensive reports on:

• Leading-edge diagnostic technologies such as ul- Eric A. Klein, MD trasound/MRI fusion-guided biopsy to improve the Chairman localization and characterization of prostate tumors, and the Oncotype DX® Genomic Prostate Score assay to Glickman Urological & Kidney Institute accurately predict prostate cancer aggressiveness. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 5

New Glickman Urological & Kidney Institute Staff News from the Glickman Urological & Kidney Institute

Jeffrey Donohoe, MD, joined the Glickman Urological Jay Krishnan, DO, MBA, joined Cleveland Clinic Urology, & Kidney Institute as an associate staff member in the Las Vegas, in 2014. Dr. Krishnan received his medical de- Department of Urology in 2014. Dr. Donohoe received gree from the New York College of Osteopathic Medicine. his medical degree from New York Medical College. He He completed a general surgery internship at the National completed a urology residency at SUNY Downstate Medi- Naval Medical Center in Bethesda, Maryland, a urological cal Center, as well as a fellowship in pediatric urology surgery residency at the University of Medicine and Den- at Vanderbilt University Medical Center. Dr. Donohoe’s tistry of New Jersey in Stratford, and an advanced urologic specialty interests include urinary tract reconstruction for robotics and laparoscopy fellowship at Cleveland Clinic. Dr. congenital bladder defects; male and female genital recon- Krishnan served as a medical officer in the U.S. Navy with struction; and and obstructive uropathy. deployments to Japan, Kuwait, Iraq and Afghanistan. His specialty interests include reconstructive urologic surgery and minimally invasive robotic surgery for kidney, bladder and prostate cancer.

Upcoming Events — Save These Dates

April 24, 2015 Ambulatory Urology Symposium Course Co-Directors: Edmund Sabanegh Jr., MD, and J. Stephen Jones, MD, FACS May 14-16, 2015 2015 Nephrology Update Course Co-Directors: Brian R. Stephany, MD, and Sankar Navaneethan, MD October 23-24, 2015 Seventh Annual International Symposium on Robotic Kidney and Pelvic Urologic Surgery

Course Director: Jihad Kaouk, MD

Please visit ccfcme.org for more details about these events. 6 Urology & Kidney Disease News

2014 Glickman Urological & Kidney Institute Achievements

Appointments Eric A. Klein, MD — Presidential Citation from the American Urological Association for innovative research in molecular Stuart M. Flechner, MD, FACS — Board of Directors of the markers in prostate cancer, leadership of Society of Urologic United Network for Organ Sharing; representative of the Oncology and creating a center of excellence at Cleveland American Society of Transplant Surgeons on the American Clinic; received the Huggins Medal from the Society of Transplant Congress Program Committee Urologic Oncology for his distinguished and notable career Lawrence S. Hakim, MD — Sexual Medicine Society of North in urologic oncology, important contributions to the under- America’s representative to the 4th International Consulta- standing and treatment of prostate cancer, and mentorship tion on Sexual Medicine of many urologic oncologists J. Stephen Jones, MD, FACS — Associate Editor of the American Robert J. Heyka, MD — Kidney Foundation of Ohio 2014 Urological Association’s new Urology Practice journal Person of the Year for outstanding dedication and service to the foundation’s mission Manoj Monga, MD — Secretary-elect of the American Urologi- cal Association Department of Nephrology and Hypertension — accredited by American Society of Hypertension as the first Compre- Sankar Navaneethan, MD, FASN — American Society of hensive Hypertension Center in Northeast Ohio and one of Nephrology’s Chronic Kidney Disease Advisory Group; only 12 nationally Editorial Boards, Clinical Journal of the American Society of Nephrology, American Journal of Kidney and Ameri- Renal transplant team — received the National Kidney can Journal of Nephrology, Section Editor: Clinical Nephrology. Registry’s Excellence in Teamwork Award for its participa- tion in “Chain 221,” the second-longest paired donor kidney Emilio Poggio, MD, FASN — American Society of Nephrol- exchange in the history of renal transplantation ogy’s Transplant Advisory Group Ashok Agarwal, PhD, Rakesh Sharma, PhD, and Sajal Gupta, Edmund Sabanegh Jr., MD — President-elect, Society for MBBS — received Case Western Reserve University School of Study of Male Reproduction Medicine’s Scholarship in Teaching Award for making a posi- Daniel Shoskes, MD — American Urological Association’s tive impact on medical education and students’ careers, and representative to the United Network for Organ Sharing for being part of the School of Medicine’s legacy of educational excellence James Simon, MD — American Society of Nephrology’s Train- News from the Glickman Urological & Kidney Institute & Kidney Urological Glickman the from News ing Program Directors Executive Committee Hannah Kerr, MD — selected as the inaugural Andrew Novick Award recipient for best presentation at the 2014 George Thomas, MD — American Society of Nephrology’s Urologic Society for Transplantation and Renal Surgery Hypertension Advisory Group Annual Meeting Leslie P. Wong, MD, FASN — American Society of Nephrology’s Lawrence Hakim, MD — named 2014 Clinician of the Year Dialysis Advisory Committee by Cleveland Clinic Florida Hadley Wood, MD — Associate Editor of the new Urologic Nitin Yerram, MD, and co-authors — won the British Journal Congenitalism Section of Urology of Urology International’s 2014 Coffey-Krane Prize, awarded to authors of an outstanding paper published in the journal Honors and Awards who are trainees based in the Americas

Urology program — ranked No. 1 and nephrology program No. 2 in the nation in U.S. News & World Report’s 2014-2015 Best Hospitals survey Urology Residency Program — ranked No. 1 in America in an assessment by the online physician network Doximity in collaboration with U.S. News & World Report

Dr. Klein (left) receives the American Urological Association’s Presidential Citation from AUA President Pramod Sogani, MD. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 7

We’re No. 1 ... by Putting Patients First Best PracticesBest By Edmund Sabanegh Jr., MD Key Point In 2014, U.S. News & World Report Putting patients first in every aspect of medical care deliv- named Cleveland Clinic the No. 1 medi- ery — from employee hiring and training to treatment and cal center in the nation for urology care. research focus — is the key to Cleveland Clinic’s superior Of course, we are thrilled and humbled national ranking in urology. at the same time. This marks the third time since 1990 In light of our top rankings, some have asked what proven that we have received the honor, having practices we will carry forward. I tell them that, other than hovered near the top of the rankings most other years. With maintaining our Patients First focus, our one constant will be so many excellent organizations in the urology field, compe- driving change. Being named No. 1 is certainly not the time tition within the Top 10 is tight. Moving from second place to to settle for the status quo. first is a difficult feat. Pushing the envelope is in the DNA of all of us at Cleveland What helped Cleveland Clinic make the gain is our Patients Clinic. We will continue to develop new and better ways of First philosophy. Each of our nearly 150 team members in treating urologic disease and providing the highest level of the Department of Urology tries to keep a razor-sharp focus patient care. on outcomes, patient safety and patient satisfaction. Each of us acknowledges the pride that comes with taking superb Is it important for us to maintain our No. 1 ranking? I think it care of patients. is more important to maintain what the ranking represents: putting patients first so that Cleveland Clinic continues to be Putting patients first is the foremost discussion topic when the destination of choice for quality of care, urologic out- we interview potential new team members, not simply their comes and patient experience. national or international urological expertise. We listen to what candidates’ colleagues say about their demeanor and Dr. Sabanegh is Chairman of the Department of Urology in bedside manner. We spend extensive time talking about Pa- Cleveland Clinic’s Glickman Urological & Kidney Institute. tients First during our employee orientation process. We wear He can be reached at [email protected] or 216.445.4473. the motto on our lab coats. And we make sure our team mem- bers embody it, by regularly analyzing patient survey data. While we are honored by the recognition from U.S. News & World Report, the judging we ultimately value comes from our patients and their families. Keeping patients first for the longterm requires developing the next generation of urological treatments and training the next generation of urology caregivers. Cleveland Clinic’s Urology Residency Program has been among the most competitive in the , and in September 2014 it was ranked the nation’s No. 1 urology training program, in a physician survey conducted by Doximity and U.S. News & World Report. Led by Cleveland Clinic urologist Steven Campbell, MD, PhD, who has had a lifelong commitment to education, and a cadre of dedicated medical educators, our training program attracts smart, competitive trainees who engage in a partner- ship with their instructors. During their six-year residency, trainees dedicate one year to urology research. Cleveland Clinic is one of only a few programs to retain research as part of its urology training. We know research is vital to our suc- cess in caring for patients and to propelling the field. Best Practices 8 Urology &KidneyDiseaseNews geted biopsies rather than standard six- or 12-core biopsies. geted biopsiesratherthanstandard six-or12-corebiopsies. and characterizationofsuspicious lesionsbyenablingtar- imaging technologysignificantly improvesthelocalization sies fortheadvanceddetectionofprostatecancer. Thisnew We also offermultiparametricMRI/ultrasoundfusionbiop- ciplinary andoccurmonthly. urologic oncologycare.Thecancerconferencesaremultidis- campus, wewillprovideourpatientsthemostup-to-date conferences withourcolleaguesatClevelandClinic’smain By institutingregularcombinedcomprehensivecancer dures, includingneobladderimplantation. perform thecompleterangeofreconstructiveurologyproce- bladder, prostate,ureteralandkidneycancers.We willalso We plantoofferminimallyinvasivetreatmentoptionsfor and addresscomplexurologicreconstructivechallenges. care. We willnowbeabletotreatadvancedurologiccancers Vegas team,whichisdedicatedtoprovidingleading-edge I amexcitedaboutjoiningtheClevelandClinicUrology,Las at theUniversityofMedicineandDentistryNewJersey. military service,Icompletedmyresidencyinurologicsurgery ments toJapan,Kuwait,IraqandAfghanistan.Aftermy Medical Officerinthe U.S. Navyforfouryearswithdeploy- robotics atClevelandClinic.IpreviouslyservedasaGeneral after completingmyfellowshipinadvancedlaparoscopyand IjoinedClevelandClinicUrology,LasVegas inJuly2014 ogy withDr. Slavis since1994. the U.S. ArmyReserve MedicalCorpsandhaspracticedurol- Hospital &MedicalCenter. Dr. Larsenservedasacaptainin years anddevelopedtherenaltransplantprogramatSunrise Dr. Slavishaspracticed urologyintheLasVegas areafor25 Slavis, MD;LaurieLarsen,andJenniferUrena,PA-C. Our officeopenedinApril2013withthreeproviders:Scott expanded, andourservicesaregrowing. 2014-2015 “BestHospitals”survey. Ourstaffhasrecently are rankedNo.1inAmericaU.S. News&World Report ’s Cleveland Clinic’sDepartmentofUrology,whoseservices skills, technology,researchandtreatmentcapabilitiesof By Jay Krishnan, MBA DO, Cleveland Clinic Urology, Las Vegas Expands Staff, Adds Services provides patients with access to the provides patientswithaccesstothe Cleveland ClinicUrology,LasVegas the residentsofLasVegas. of thenation’stopurologyprogramto fering theexpertiseandinnovativecare Urological &KidneyInstitutebeganof- In 2013,ClevelandClinic’sGlickman at [email protected] or702.796.8669. at ClevelandClinicUrology, LasVegas. Hecan bereached &KidneyInstitute,practicing Clinic’s GlickmanUrological Dr. KrishnanisanassociatestaffmemberofCleveland ficult cases,”saysDr. Slavis. to assistthemedicalcommunityintakingcareofmoredif- Vegas, tooffertechnologiesnotcurrentlyavailablehereand “Our goalsaretoimprovethequalityofurologycareinLas locations. day appointmentsysteminuseatotherClevelandClinic ate accesstothehighestlevelofcare,modeledonsame- Cleveland ClinicUrology,LasVegas offerspatientsimmedi- overlapping neurologic/urologicconditions. which allowsustoprovideseamlesscareforpatientswith Our twocentersshareanelectronicmedicalrecordssystem, ongoing treatmentforpatientswithcognitivedisorders. Brain HealthinLasVegas. Thecenterprovidesdiagnosisand neurology colleaguesatClevelandClinicLouRuvoCenterfor land Clinic’smaincampus,wealsocollaboratewithour In additiontoourcloserelationshipwithcolleaguesatCleve- Las Vegas. Las available are program at Cleveland Clinicurology Urology, nation’s the and of innovative top care expertise the to cess and appointments ac options, same-day New treatment PointKey - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 9

From Inspiration to Commercialization: How a Prostate Cancer Test Gets to Market Best PracticesBest Mark Stovsky, MD, MBA Key Point In November 2013, Cleveland Clinic Commercialization of a medical product is a complex pro- announced a new spinoff company, cess that requires expert oversight, rigorous assessment and Cleveland Diagnostics (CDx), with the perseverance. objective of providing an institutional platform for increasing the accuracy of diagnostic tests for many types of negatives and approximately 80 percent specificity. Those cancer. results compare favorably with those of the traditional serum PSA test. As Chief Medical Officer of CDx, Science and Technology Innovations Officer of Cleveland Clinic’s commercialization Further analysis of data from serum appeared to show simi- arm, Cleveland Clinic Innovations, and a staff physician lar diagnostic accuracy for prostate cancer. Other preliminary within the Glickman Urological & Kidney Institute, I have results in breast and ovarian cancer detection demonstrated enjoyed a front-row seat for CDx’s journey from concept that SIA potentially could be used as a platform technology to to market and have learned several lessons along the way. diagnose a broad spectrum of . Above all: Trust in Cleveland Clinic Innovations (CCI) to lead the way. Strong Guidance and Rigorous Review

We knew we had a product that could have an immediate A New Approach to Diagnosis impact. But the research findings, as well as the intellectual The idea for CDx originated in 2013 and stemmed from the property implications of a multicenter discovery, required work of researchers at Cleveland-based AnalizaDx LLC, as significant commercialization guidance from experts. In fall well as physicians at Cleveland Clinic, Case Western Reserve 2013, Cleveland Clinic Innovations professionals assessed University School of Medicine and the VA Boston Healthcare the concept, and the framework for a spinoff company was System. born. The newly formed CDx would mesh the intellectual property and technology expertise of AnalizaDx LLC, the To diagnose or assess the risk of cancer, scientists for years clinical bandwidth of Cleveland Clinic, and the commercial- have focused narrowly on changes in the concentration of a ization capability and know-how of CCI to commercialize the single in biological fluids such as blood or or, novel cancer testing platform. alternatively, on genetic mutations. However, the diagnostic accuracy of single or multiple protein quantification tests With the strategy in place, CDx underwent a rigorous re- has suffered from relatively poor sensitivity, specificity and view to assess important factors including the company’s predictive values, which limit clinical utility, while tests that commercial potential, the funding necessary to support a identify multiple genetic mutations associated with cancer successful venture, the competitive and regulatory environ- are difficult to transform into actionable results. These short- ments, and the time frame for bringing products to market. comings result in poor clinical performance, an ineffective After formal approval by Cleveland Clinic and CCI leadership allocation of diagnostic resources, and substantial patient as well as CCI’s advisory board (which consists of outside anxiety and dissatisfaction. advisors), CDx received initial seed funding and became the 65th CCI portfolio company. Our idea was to build a breakthrough biomarker platform that focuses on changes in the structure of certain circulating in blood or other biological fluids to indicate the INVENT Nurtures Spinoffs presence or absence of cancer. Proprietary tests, based on the While CDx’s journey to commercialization has at times been novel Solvent Interaction Analysis (SIA) technology, would challenging — as is the case for most new medical compa- evaluate the structure of protein biomarkers and differentiate nies and products — CCI has helped minimize problems those produced by cancer in comparison with benign cells. through the use of its new INVENTSM process. We achieved the potential for commercial success with the INVENT stands for Idea submission, Need assessment, completion of an initial validation trial of the SIA technology Viability assessment, Enhancement, Negotiation and Trans- in the diagnosis of prostate cancer. In this multicenter trial, lation. The INVENT process guides an inventor from concep- the technology demonstrated favorable preliminary results. tion to commercialization. When compared with standard serum total prostate specific At Cleveland Clinic, each institute, including the Glickman antigen (PSA) testing, the proprietary PSA/SIA (today called Urological & Kidney Institute, is assigned an innovation IsoPSA) test showed 100 percent sensitivity with no false manager. The manager acts as the CCI point of contact as an Best Practices 10 Urology &KidneyDiseaseNews • • program’s strengthsinclude: in itseffortstoprovideanenrichedtrainingexperience.The The residencyhasastrongheritageanditsleaderstakepride with ourresidencyprogram. fied urologistsandrepresentsagreathonorforallinvolved This rankingisbasedinpartonnominationsbyboard-certi- and Kenneth W. Angermeier, MD K.Montague,MD; Steven C.Campbell,MD,PhD;Drogo market. to bring apotentiallygroundbreakingtechnologyfrombench ment andcommercializationprocess,developaplanto assess themyriadfactorsinvolvedintechnologydevelop- an opportunitywithbroadinstitutionalplatformappeal, CDx continuestobenefitgreatlyfromCCI’sabilityidentify company. dustry partnerortransitionedintoaClevelandClinicspinoff Technology andDeliverySolutions),islicensedtoanin- Devices, Therapeutics&Diagnostics,HealthInformation als, isfurtherdevelopedinoneoffourincubators(Medical invention isassessedbyinstitutepeersandCCIprofession- Urology Residency Training at Cleveland Clinic: Striving for Excellence novative, effective care. Institute’s international reputationasaprovider ofin- referral casesreflectingGlickman Urological&Kidney A widevarietyofchallengingmedical andsurgical cialty theychoose. and helptraineesbuildacareerin whateversubspe- leaders inallbranchesofurology whoserveasmentors Diverse subspecialtyrepresentation,withdedicated News &World Report. Doximity incollaborationwithU.S. ment bytheonlinephysiciannetwork training programinanationalassess- recently namedAmerica’sNo.1urology niversary ofits1954foundingandwas Program iscelebratingthe60than- Cleveland Clinic’sUrologyResidency or216.445.4096. org at land ClinicInnovations.Hecanbereached and ScienceTechnology InnovationsOfficerofCleve &KidneyInstitute in ClevelandClinic’sGlickmanUrological Dr. ofUrology StovskyisastaffmemberoftheDepartment As withCDx,itallstartsanidea. • • • • a supportive mentoring environment.a supportive in and challenging experience clinical, and research surgical adiverse residents by offering education asuperlative vide pro to seeks Program Cleveland Residency Clinic’s Urology PointKey that take place throughout the training experience. that takeplacethroughout thetrainingexperience. year, andoutpatientambulatory surgeryrotations Stokes ClevelandVA MedicalCenterduringthethird built intoourresidencythrough a rotationattheLouis Extensive exposureto“nutsand bolts” urologythatis the operatingroomsorclinicsevery day. activities. Thisallowsourresidentsatalllevelstobein who performroutinepreoperativeevaluationsandother urology-focused nursingteamsandphysicianextenders A healthyservice/educationbalancethatissupportedby require anopenapproach. Cleveland Clinicformajorsurgicalchallengesthatstill of Urology,andtheurologypatientswhoarereferredto plantation service,whichresideswithintheDepartment surgical casesremainsstrongduetoourrenaltrans- ing edgeofthefield.Exposuretovascularandopen more than1,000proceduresperyearandisatthelead- invasive. Ourminimallyinvasivesurgicalteamperforms urologic surgery:endourologic,openandminimally An appropriatebalanceamongthethreedomainsof system, whereverthatmightbe. cal andeducationalsettingswithinourhealthcare and ourphilosophyofplacingtraineesinthebestclini- main campusandthroughourcommunityhospitals, A largeclinicalvolumeavailableonClevelandClinic’s stovskm@ccf. - - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 11

• A dedicated research year that provides the opportunity Dr. Campbell is Vice Chair of the Department of Urology in to participate in a wide variety of well-established Na- Cleveland Clinic’s Glickman Urological & Kidney Institute, tional Institutes of Health-funded research. Residents Director of the Urology Residency Program, Associate Direc- learn the fundamentals of trial design, statistics, and tor of Graduate Medical Education, and Professor of Surgery writing and presenting research data during this year, at Cleveland Clinic Lerner College of Medicine. He holds Surgery Laparoscopic and Robotics for Center with opportunities to publish and to compete for the the Eric A. Klein Endowed Chair in Urologic Oncology and best urology fellowships. Education in the Glickman Urological & Kidney Institute. He can be reached at [email protected] or 216.444.5595. • Exposure to the Case Based Urology Learning Program (CBULP), a medical educational tool being developed by Dr. Montague is a staff member of the Center for Genitouri- the Department of Urology along with colleagues at Uni- nary Reconstruction in Cleveland Clinic’s Glickman Urologi- versity Hospitals’ Rainbow Babies & Children’s Hospital cal & Kidney Institute, Professor of Surgery at Cleveland (Cleveland). The CBULP provides cases representing the Clinic Lerner College of Medicine, and Associate Director of the Urology Residency Program. He can be reached at most common and important clinical scenarios a urolo- [email protected] or 216.444.5590. gist will encounter during routine practice. The goal is to illustrate the disease process and the fundamentals Dr. Angermeier is a staff member of the Department of of clinical evaluation and management. Each case can Urology in Cleveland Clinic’s Glickman Urological & Kidney be reviewed within 10 minutes via mobile electronic Institute, Director of the Center for Genitourinary Recon- platforms. More than 240 CBULP cases have been pro- struction, and Associate Director of the Urology Residency duced, and the portfolio will eventually be aligned with Program. He can be reached at [email protected] or the American Urological Association’s core curriculum. 216.444.0415.

More than 40 graduates of Cleveland Clinic’s Urology Resi- dency Program are currently active in academic medicine, almost all in top urology programs. Many serve in leadership roles within their institution or subspecialty. Many others have successful community practices.

Intracorporeal Hypothermia During Robotic Partial Nephrectomy Using Renal Ice Slush

Jihad H. Kaouk, MD; Homayoun Zargar Shostari, MD; and Key Points Jay Krishnan, DO, MBA An ice slush packed around the kidney can safely and ef- fectively cool the renal parenchyma during robotic partial nephrectomy (RPN), thereby preserving long-term renal parenchymal function.

The ice slush technique of renal hypothermia may be espe- cially advantageous when a prolonged clamp time is antici- pated during RPN.

Long-term functional outcomes assessment is needed to establish the utility of this approach to cool the renal paren- The application of robotic technology to partial nephrectomy chyma during RPN. has allowed surgeons to re-create the principles of open surgery via a minimally invasive approach. Even larger deeply infiltrative tumors, or hilar tumors, can be treated with Renal parenchymal cooling has been used in open partial ne- robotic partial nephrectomy (RPN). Excision of such tumors phrectomy (OPN) to protect against such detrimental effects. in a bloodless field requires that the renal hilum be clamped When renal parenchymal temperatures of 5 to 20 degrees as in open surgery. However, prolongation of clamp time in Celsius are achieved, renal metabolism is suspended and the such scenarios may be detrimental to long-term renal paren- chymal function. Center for Robotics and Laparoscopic Surgery 12 Urology &KidneyDiseaseNews temperatures of 20 degrees Celsius or less. At this point, the temperatures of20degreesCelsiusorless.Atthispoint,the and thekidneyisallowedtocoolfurtherparenchymal tored duringtheprocedure.Moreiceslushisintroduced introduced. Renal andcorebodytemperaturesaremoni- and renalveinaresequentiallyclampedmoreiceis abdomen andpackedaroundthekidney. Therenalartery and thepedicleisdissectedout,icedeliveredinto Once thekidneyandGerotafasciaarecompletelymobilized is measuredwithaneedletemperaturethermocouple. rectly abovethekidney. Therenalparenchymaltemperature ice isdeliveredviaalateral12mmaccessoryportplaceddi- multiple modifiedsyringesforsubsequenticedelivery. The slush iscreatedinanicemachineandprefilled After patientpositioningandplacementofports,sterileice pass renalhypothermiausingintracorporealiceslush. standardized techniqueofRPNhasbeenmodifiedtoencom- surgeon experiencedinRPNperformedallprocedures.Our our InstitutionalReview Board-approveddatabase.Asingle 20 minuteswereanticipatedcollectedprospectivelyin retroperitoneal) inwhichwarmischemiatimesofmorethan consecutive patientsundergoingRPN(transperitonealor to achieverenalhypothermiaduringRPN.Datafrom22 dium, wehavedevelopedaneasilyreproducibletechnique Based ontheprincipleofusingiceslushasacoolingme- Details oftheHypothermiaTechnique of surgicalproficiencyhaverestrictedtheirutility. surgery, technicaldifficulties,lackofreproducibilityand nal hypothermiaduringminimallyinvasivenephron-sparing Although varioustechniqueshavebeendevisedtoinducere- without permanentdamage. nephrons canwithstandasmuchthreehoursofischemia invasive technique. replicating coolingduringOPN,albeitwithaminimally peritoneal andtransperitonealRPNapproaches,essentially Our techniquewasreproducibleforadoptioninbothretro- clamp timeisanticipated. involving alargeorcomplexrenalmasswhenprolonged This techniqueislikelytohaveclinicalutilityinRPNcases term functionaloutcomesneedfurtherassessment. term renalfunctionaloutcomesarepromising,butlonger- intracorporeal renalcoolingissafeandreproducible.Short- From ourpreliminarystudyitappearsthattechniqueof Our patients’medianlengthofhospitalstaywastwodays. tion beyondtwodaysoranypostoperativecomplications. tantly, wedidnotobserveanydelayinreturnofbowelfunc- estimated glomerularfiltrationratewas81percent.Impor- Median short-term(one-monthfollow-up)preservationof tive complicationsoranincreaseinoursurgicalmarginrate. In ourinitialexperiencewedidnotobserveanyintraopera- achieve nadirrenalhypothermiawaseightminutes. body temperature(0.35degreesCelsius).Mediantimeto was 17degreesCelsiuswithminimalmedianchangeincore minutes. Themediannadirparenchymalrenaltemperature and themediantimeforintroductionoficeslushwasseven of 100cc.Themediancoldischemiatimewas28minutes, tive timewas220minuteswithmedianestimatedbloodloss Twenty patientswereincludedinouranalysis.Medianopera- Initial Patient ExperienceandConclusions entrapment sac. ice issuctionedorplacedalongwiththespecimenin is resected.Renorrhaphy isthenperformed.Theremaining ice slushoverlyingtherenaltumorisclearedand view of the port sites. view oftheport of thepatient,paralleltospine. (I) Postoperative (H)Therobotisdockeddirectlyoverthe head port. isplacedfourfinger-widths belowtherobotic port andtheassistant’s12 mm level oftheballoonport, isplacedatthe line,therobotic port anterior axillary Along the line slightlycephaladtothecamera port. isplacedalongtheposterioraxillary The roboticport isplacedatthetipof12thrib. mm cameraport nephrectomyusingrenaliceslush.The12 partial corporeal hypothermiaduringretroperitonealrobotic syringe, respectively(G)Port placementforintra (E) and(F)Ballooninflationwithpump dissector, 12mmblunt-tiptrocar, inflatingsyringe the plunger. toright:Inflationpump,balloon (D)Left slush container. (C)Iceslush isdeliveredbypushing intoanice syringe isfilledbysuccessiveinsertions rubber sealontheendofeachplunger. (B)The off thenozzleendsofbarrelsandremoving Figure 1.(A)20-ccsyringeismodifiedbycutting - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 13

Figure 2. (A) Ice delivery via our accessory port. (B) Intracorporeal view of ice being deposited around the kidney. The needle thermocouple can be seen inserted into renal parenchyma.

(C) Kidney covered by ice prior to tumor resec- Surgery Laparoscopic and Robotics for Center tion. (D) Tumor resection after pedicle clamping.

Dr. Kaouk is Director of Cleveland Clinic Glickman Urologi- Dr. Krishnan is an associate staff member of the Glickman cal & Kidney Institute’s Center for Robotics and Laparoscop- Urological & Kidney Institute, practicing at Cleveland Clinic ic Surgery and is the Urological & Kidney Institute’s Vice Urology, Las Vegas. He can be reached at [email protected] Chair for Surgical Innovations. He is Professor of Surgery or 702.796.8669. at Cleveland Clinic Lerner College of Medicine. He can be reached at [email protected] or 216.444.2976.

Dr. Zargar Shostari is a clinical fellow in the Glickman Uro- logical & Kidney Institute. He can be reached at zargarh@ ccf.org or 216.445.1172.

New Robotic System Designed for Single-Port Surgery: First Clinical Experience

Jihad H. Kaouk, MD Key Point Since the inception of minimally in- The single-port robotic system allows for a less invasive vasive surgery, physicians have been approach to single-site surgery, enabling intracorporeal inspired to push the limits of available triangulation while eliminating the challenge of instrument technology by devising new methods clashing as seen with other single-site techniques. and instruments.

The evolution of a single-site technique RLESS Is More in robotic surgery has resulted in the development of a device intended specifically for use during In 2009, Cleveland Clinic’s Glickman Urological & Kidney urologic procedures appropriate for a single-port approach, Institute reported the first series of successful robotic including laparoendoscopic single-site surgery (LESS). single-site surgeries.1 We found that combining LESS with the robotic platform (RLESS) greatly enhanced our surgical LESS has the primary goal of accelerating patient recovery capability by offering increased articulation and stability for and improving quality of life, but its role has yet to be deter- precise suturing and dissection. mined due to inherent challenges compared with standard laparoscopic techniques. Since the publication of our initial series, multiple institu- tions have adopted the technique and published series of Center for Robotics and Laparoscopic Surgery 14 Urology &KidneyDiseaseNews reached at reached at ClevelandClinicLernerCollegeofMedicine.Hecanbe Innovations.HeisProfessor ofSurgery Chair forSurgical &KidneyInstitute’sVice andistheUrological ic Surgery cal &KidneyInstitute’sCenterforRobotics- andLaparoscop Dr.- ofClevelandClinicGlickmanUrologi Kaouk isDirector surgery.single-site instrument clashingthatisobservedwithothermethodsof lows forintracorporealtriangulationwhileeliminatingthe forward inminimallyinvasivesurgery. Itisuniqueasital- This newsingle-portrobotictechnologyrepresentsastep standard techniques. three-year follow-upperiodwerecomparabletothoseusing or laparoscopictechnique.Functionaloutcomesduringa There werenoconversionstoopen,contemporaryrobotic nephrectomy.) nephrectomy. (Four ofthoseeightpatientsunderwentpartial prostatectomy andeightwhounderwentsingle-siterobotic patients, including11whounderwentsingle-siterobotic single-site roboticsurgeryusingthisnoveltechnologyin19 port roboticsysteminaclinicalseries. Our institutionwasoneofthefirsttoutilizenewsingle- Advancing MinimallyInvasiveSurgery Although thedaVinci their own. single porttointroducetheinstrumentsandcamera. the useofmultipleseparateports,SP999requiresonlya In contrasttotheoriginalroboticdesignthatnecessitated SP999). cally designedforRLESS(daVinciSpSurgicalSystem,Model manufacturer hasdevelopedaninnovativedevicespecifi- was notoriginallydesignedforthispurpose.Asaresult,its tially improvedourabilitytoperformsingle-sitesurgery,it surgery withouthavingtoreposition therobot. surgery Figure 2.Mainroboticarmcanbepositionedformulti-quadrant [email protected] or216.444.2976. ® roboticsurgicalsystemhassubstan- 2 We performed tectomy, showingrobotdockedtopatientumbilicus. radicalprosta Figure 3.Intraoperativeimageofroboticsingle-port that articulate atdifferentlevelsforextended rangeofmotion. that articulate cameras forstereoscopicvision,lightsource,andthreeinstruments arm.Commonsheathhousestwo Figure 1.Novelroboticsingle-port 2. Kaouk JH,HaberGP, AutorinoR,CrouzetS,OuzzaneA, 1. Kaouk JH,GoelRK,HaberGP, CrouzetS,SteinRJ.Robotic References In press. urologic surgery:firstclinicalinvestigation.EurUrol.2014. Flamand V,VillersA.Anovelroboticsystemforsingle-port BJU Int.2009;103:366-369. single-port transumbilicalsurgeryinhumans:initialreport. - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 15

Table 1. Perioperative outcomes after three- year follow-up. Center for Robotics and Laparoscopic Surgery Laparoscopic and Robotics for Center

Robotic Radical Perineal Prostatectomy: Potential Advantages of a New Approach

Jihad H. Kaouk, MD; Kenneth Angermeier, MD; and Oktay Key Points Akca, MD Robotic radical perineal prostatectomy (RPP) is feasible for patients with localized prostate cancer, and could shorten op- erative time and reduce blood loss compared with open RPP.

Robotic RPP may prove to be a minimally invasive solution for the treatment of localized prostate cancer, and may be especially advantageous in certain populations, such as those who have had previous abdominal surgery.

At Cleveland Clinic’s Glickman Urological & Kidney Institute, operating close to the rectum. Additionally, the perineum is a we have explored the feasibility of robot-assisted radical deep and narrow space compared with the retropubic route. perineal prostatectomy (RPP) with its inherent advantages of Millin initially described the retropubic technique in 1945.1 more direct access to the prostate and a small incision. Walsh et al. redefined the anatomical approach, applying Since Young first described it in 1905, open RPP remained the techniques of cavernous nerve sparing in the 1980s.2 For the most common surgical approach for the treatment of open surgery, the retropubic approach currently represents prostate cancer until the mid-1970s. the preferred technique of most urologic surgeons based on habit rather than on evidence-based medicine. Urologists discontinued common performance of RPP due to concerns about the perineal anatomy; urologists are not gen- Although the most widely used approach for open radi- erally familiar with the perineum since they routinely operate cal prostatectomy is the retropubic approach, there are no in the retropubic space and may be uncomfortable when randomized studies demonstrating its superiority over the Center for Robotics and Laparoscopic Surgery 16 Urology &KidneyDiseaseNews node positivity of not more than 4 percent. node positivityofnotmorethan4percent. diagnosed withlocalizedprostatecancerandariskforlymph botic RPP, weselectedforthefirstproceduresthosepatients After obtainingInstitutionalReview Boardapprovalforro- operative pain and analgesia requirements. operative painandanalgesiarequirements. traction. Minimizingtheincision couldalsodecreasepost- with anincisionjustlargeenough (4cm)forspecimenex- In ourinitialpatient,wewereable tocompletetheprocedure deep surgicalfield. difficulty ofperformingaprocedureinsuchnarrowand lated roboticinstruments,whichmayhelpminimizethe RPP includethemagnifiedviewaswelllong,articu- The potentialtechnicaladvantagesofroboticRPPoveropen after surgery(Figures1-4). continent whenhisurethralcatheterwasremovedoneweek discharged onpostoperativedayoneandwasimmediately tions, withanestimatedbloodlossof50cc.Thepatientwas Robotic RPPwascompletedsuccessfullywithout complica- multiple herniarepairs. He alsohadmeshontheanteriorabdominalwallowingto radiotherapy. Hewasthereforelivingwithanileostomy. of hisrectumtotreatrectalcancerandhadreceivedpelvic The initialpatientpreviouslyhadundergoneatotalresection First ExperienceandConclusions tomy operationusingfivecadavers. completed allstepsofthenerve-sparingradicalprostatec- plicability ofthedaVinciroboticsurgicalsystemforRPP. We We initiallydevelopedacadavermodeltoexaminetheap- RPP, suchasworkinginadeepandnarrowsurgicalarea. robotic instrumentscouldovercometrickypointsofopen using therobotspecificallyforRPP, withthehypothesisthat We wonderedwhethersimilaradvantagescouldexistwhen and theadvantageofitsarticulatingdesignoverlaparoscopy. increase inRALPcanbeattributedtoitsshortlearningcurve the treatmentofprostatecancerinUnitedStates.The sents themostcommonlyperformedsurgicalapproachfor was firstdescribedintheearly2000sandcurrentlyrepre- Robot-assisted laparoscopicradicalprostatectomy(RALP) Rethinking RPP lower rateoftransfusion. incision ofthedorsalvascularcomplex,lessbloodlossanda and inguinalhernia,owingtothelackofdissection lower ratesofpostoperativeurethralanastomosisstricture shorter operativetimeandhospitalstay,lowercost, rates. Reported advantagesoftheperinealapproachinclude perineal approachintermsofcancercontrolandcontinence 3

He can be reached [email protected] canbereached ofUrology.Dr. fellowintheDepartment Akcaisaresearch at He canbereached Reconstruction. oftheCenterforGenitourinary and Director ofUrology &KidneyInstitute’sDepartment man Urological Dr. AngermeierisastaffmemberofClevelandClinicGlick at reached at ClevelandClinicLernerCollegeofMedicine.Hecanbe Innovations.HeisProfessor ofSurgery Chair forSurgical &KidneyInstitute’sVice andistheUrological ic Surgery cal &KidneyInstitute’sCenterforRobotics- andLaparoscop Dr.- ofClevelandClinicGlickmanUrologi Kaouk isDirector tion forpatientsdiagnosedwithlocalizedprostatecancer. prostatectomy mightprovideanewminimallyinvasivesolu- system andanaturalanatomicapproachtoradicalperineal In conclusion,theintersectionofdaVinciroboticsurgical who areseverelyobese. abdominal operation,similartoourinitialpatientandthose be usefulinthosepatientswhohaveundergoneaprevious and vessels,givenitsextraperitonealnature.Itmightalso Robotic RPPeliminatesrisksofinjurytoabdominalorgans operative timeandlessbloodloss. dissection). Eliminationofthesestepscouldresultinshorter lization, endopelvicfasciaincisionanddorsalveincomplex the firstthreestepscommonlydoneinRALP(bladdermobi- the anteriorabdominalwall,whichallowsforeliminationof proach providesmoredirectaccesstotheprostatethandoes In comparingroboticRPPwithstandardRALP, aperinealap- 3. LaydnerH,AkcaO, AutorinoR,EyraudZargarH,Bran- 2. Walsh PC,MostwinJL.Radical prostatectomyandcysto- 1. MillinTJ.Retropubic prostatectomy. Lancet.1945;ii:693- References model. JEndourol.2014.[Epubaheadofprint] cal prostatectomy(P-RALP):feasibilitystudyinthecadaver Stein RJ,Kaouk J.Perineal robot-assistedlaparoscopicradi- dao LF, KhalifehA,Panumatrassamee K,LongJA,IsacW, new nerve-sparingtechnique.BrJUrol.1984;56(6):694-697. prostatectomy withpreservationofpotency. Results usinga 696. [email protected] or216.444.2976. [email protected] or216.444.0415. - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 17 Center for Robotics and Laparoscopic Surgery Laparoscopic and Robotics for Center

1 2

3 4

Figure 1. Exaggerated lithotomy position. Figure 2. Robot docking, approaching from head and passing between legs. Figure 3. Incision closure. Figure 4. Robotic RPP specimen. Center for Robotics and Laparoscopic Surgery 18 Urology &KidneyDiseaseNews 72). Forty-five patients(37percent)had asolitarykidney. of caseswithcoldischemia(N= 50) andwarmischemia(N= clamped PNsatourcenter,including arepresentativemix reconstruction inaseriesof122 patients withconventionally We recentlystudiedtheprecisionoftumor excisionand emia. Butisthisreallytrue? control assurgeons,longweavoidextendedwarmisch- functional outcomesafterPNwouldbemostlyoutofour by tumorsizeandlocation.Basedonthislineofreasoning, also anonmodifiablefactorbecauseitislargelyinfluenced struct thekidney. Somehavearguedthatthisprecisionis by theprecisionwithwhichweexcisetumorandrecon- The numberofnephronssavedduringPNisdetermined Outcomes Studying theImpactofSurgicalPrecision onPN number ofnephronssavedbytheprocedure? applied. Howcanweoptimizethequantityfactor— insult aslonglimitedwarmischemiaorhypothermiais preserved nephronsrecovercompletelyfromtheischemic Stated moresimply,thesestudieshaveshownthatalmostall significance unlessitiswarmandprolonged(>25minutes). this factorisincludedintheanalyses,ischemiatimelosesall volume ofnephronmasspreservedbytheprocedure.When ing factors,mostnotably,thequantityfactor,whichis failed toincorporateallthepotentiallyrelevantcontribut- However, thesestudieswereinherentlyflawedbecausethey sumed, expressedbythecatchphrase“everyminutecounts.” dence ofCKD,andacause-and-effectrelationshipwaspre- sociation betweenwarmischemiatimeandincreasedinci- is essentiallynonmodifiable.Earlystudiesreportedanas- age andthepresenceofcomorbiditiessuchasdiabetes, The qualityofthenephronsisdeterminedbypatient’s A FlawedView ofIschemiaTime’s Significance cold) anddurationofischemia. quantity ofnephronspreserved,andthetype(warmversus include thequalityofnephronspriortosurgery, Factors thatcaninfluenceultimaterenalfunctionafterPN Steven C.Campbell,MD,PhD Partial Nephrectomy: Saving as Many Nephrons as Possible kidney disease (CKD). kidney disease(CKD). solitary kidneyorpre-existingchronic with imperativeindicationssuchasa is particularlyimportantinpatients much renalfunctionaspossible.This nephrectomy (PN)istopreserveas One oftheprimarygoalspartial tion of ischemia, and other factors failed to correlate. tion ofischemia,andotherfactorsfailedtocorrelate. tary kidney,whiletumorsizeandcomplexity,typedura- correlated withsurgicalprecisionwasthepresenceofasoli- On univariateandmultivariateanalysis,theonlyfactorthat best-case scenariointermsofpreservationnephronmass. percent, demonstratingthatmostPNsapproximatedthe In ourseries,themedianvalueforsurgicalprecisionwas93 ideal PN. divided bytheamountthatwouldhavebeensavedwithan as theamountofvascularizedparenchymaactuallysaved defined precisionoftumorexcisionandreconstruction that wouldbelostwithanidealPNwasthenestimated.We tracting thevolumeoftumor,amountparenchyma tissue thatwouldbecompromisedinthissetting.Aftersub- located, intrinsictumor,andincludessomeradiallylocated ma andtumorthatwouldbelostduringPNforananteriorly Figure 1illustratesourestimateoftheamountparenchy- postoperative leakandbleeding). chyma (relatedtocapsularclosureminimizetheriskof well asdevascularizationofamodicumadjacentparen- removed alongwiththetumortoavoidapositivemargin)as parenchyma duetotumorexcision(someis ated withthelossofanapproximate5mmrimnormal described. We presumedthatan“idealPN”wouldbeassoci- before andfourto12monthsaftersurgeryaspreviously measure thevolumeofvascularizednormalparenchyma Volumetric computedtomography(CT)scanswereusedto determining ultimate renal function after PN. determining ultimate renalfunctionafterPN. able factor,and it appearstobethemostimportant factorfor kidney. Intheend, surgical precisionappearstobeamodifi- parenchyma aspossiblegiventhe absenceofacontralateral related totherecognizedneed preserveasmuchrenal a premium(i.e.,inpatientswith asolitarykidney),likely Our datasuggestthatprecisionwas highestwhenitwasat Surgical Precision IsModifiableandImportant lous surgical technique. surgical lous imaging and and meticu intraoperative quality preoperative high- of use the optimized through be and can important is critically possible much as as parenchyma vascularized save to tumor excision of and renal reconstruction Precision nephrectomy. partial after functional recovery with directly correlates nephrons preserved of quantity The and extended. warm only if but functional impact recovery, Ischemia can nonmodifiable. and is essentially function The quality the of nephrons determines the baseline renal Key Points - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 19 Center for Robotics and Laparoscopic Surgery Laparoscopic and Robotics for Center Our perspective is that high-quality preoperative imaging, in- Dr. Campbell is Vice Chair of Cleveland Clinic Glickman traoperative ultrasonography and operating within a blood- Urological & Kidney Institute’s Department of Urology, less field can all facilitate surgical precision. Director of the Urology Residency Program, Associate Direc- tor of Graduate Medical Education and Professor of Surgery Efforts to optimize surgical precision will be important mov- at Cleveland Clinic Lerner College of Medicine. He holds ing forward. They could include energy-based resection and the Eric A. Klein Endowed Chair in Urologic Oncology and hemostatic agents that might preclude the need for capsular Education. He can be reached at [email protected] or reconstruction; further improvements in perioperative imag- 216.444.5595. ing; and selective utilization of tumor enucleation.

ANTERIOR VIEW MEDIAL VIEW

Figure 1. Volumetric CT to measure the amount of parenchyma that would be lost during an ideal PN for an anteriorly located, intrinsic tumor. The kidney is viewed from anterior and medial aspects. Summation of areas at 3 mm intervals is utilized to obtain volume estimates as previously described. Center for Robotics and Laparoscopic Surgery 20 Urology &KidneyDiseaseNews though OR time and minor perioperative complications were though ORtime andminorperioperativecomplications were rates ofmajorcomplicationsand secondaryprocedures.Al- cost ismainlyduetoreductions in lengthofstayandthe despite thehigherdirectoperating room(OR)cost.Thelower all costisapproximately$2,000less fortheroboticgroup, In comparingtheoverallcostof our RRCs toORCs, theover- diet is5.5days,andmedianhospitalstaysevendays. a 90-daymortalityrateof2percent.Themediantimetofull percent rateofhigh-gradecomplications(ClavienIII/IV)and complication rateisapproximately50percent,witha20 dian bloodlossforourseriesis300cc.Theoverall90-day more than70RRCs withintracorporealdiversion.Theme- Since therefinementofourtechnique,wehaveperformed tive outcomes. allowed ustoimproveboththeintraoperativeandpostopera- corporeal ilealconduitandintracorporealneobladderhave Standardizing ourtechniqueanddefiningthestepsforintra- been encouraging. Our experiencewithRRC andintracorporealdiversionhas Improving RRCOutcomesThroughStandardization minimally invasivesurgery. ally throughanopenapproach,dilutingtheadvantagesof done robotically,thediversionwasperformedextracorpore- ated withincreasedcost.Eventhoughthecystectomywas superior toORC in termsofcomplicationsandwasassoci- However, recentprospectivedatashowedthatRRC wasnot with ORC. term oncologicoutcomeswithRRC areequivalenttothose momentum asanalternativetotheopenapproach.Long- prostatectomy, roboticradicalcystectomy(RRC) hasgained Expanding ontheexperiencegainedwithroboticradical a newhorizon. laparoscopic approach,therobot-assistedprocedureoffered clinicians. Afterarockystartwithtechnicallychallenging rate ofperioperativecomplicationsremainsachallengefor cal cystectomy(ORC) duringthepasttwodecades,high Despite thedeclineinmorbidityandmortalityofopenradi- BS; andGeorges-Pascal Haber, MD,PhD Shostari,MD;VishnuvardhanHomayoun Zargar Ganesan, Horizon New A Robotic Radical Cystectomy with Intracorporeal Urinary Diversion: Reducing Paralytic IleusIncidence stay andtherateofreadmissionsweresuperiorwithRRC. rate, therateofmajorperioperativecomplications,length comparable betweenRRC andORC, bloodloss,transfusion can be reached at can bereached ofUrology. &KidneyInstitute’sDepartment He Urological Dr. HaberisastaffmemberofClevelandClinicGlickman [email protected] ofMedicine.Hecanbereached . Mr. GanesanisamedicalstudentatClevelandClinic Lerner at [email protected] or216.445.1172. &KidneyInstitute. He canbereached Glickman Urological Dr. Shostariisa clinical fellowinClevelandClinic’s Zargar use wouldnotbeasurprisebutnaturalevolution. without compromisingoncologicoutcomes.Itswidespread decrease themorbidityassociatedwiththismajorprocedure RRC withintracorporeal urinarydiversionhasenabledusto standard forperformingRRC inthefuture. sparing multimodalanalgesiaislikelytobecomethegold of ERASsuchasearlyfeeding,mobilizationandopioid- radical cystectomyincombinationwithothercomponents of enhancedrecoveryaftersurgery(ERAS)forRRC. Robotic The minimallyinvasiveapproachisonlyonecomponent analgesia. minimize andinsomecaseseliminatetheneedfornarcotic aminophen andketorolactromethaminehasenabledusto traoperative injectableliposomalbupivacaine,regularacet- analgesia. Inourearlyexperience,thecombinationofin- a multimodalopioid-sparingapproachtopostoperative ther reducetheincidenceofparalyticileus,wehaveadopted pathways forpatientsundergoingRRC. Inanefforttofur- More recently,wehavemodifiedourperioperativecare analgesia is often possible. possible. analgesia is often postoperative lowing to RRC, approach an -sparing ileus fol paralytic of incidence the reduce to In an effort stay,of in resulting lower cost. and major and length complications morbidity of rates the in with reductions while associated cystectomy radical open with equivalent are those to diversion with intracorporeal (RRC) cystectomy radical with robotic outcomes Oncologic Key Points [email protected] or216.445.4781. - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 21

Figure 1. Intracorporeal reconstruction Surgery Laparoscopic and Robotics for Center of the neobladder.

Figure 2. Intracorporeal ureteroileal anastomosis. Center for Urologic Oncology 22 Urology &KidneyDiseaseNews have theoretical advantages over IMRT. over advantages theoretical have that radiation beam of external forms PBT are SBRT and techniques. older with compared rate control tumor and profile toxicity asuperior strating demon publications on numerous based of care standard current the as established been has of treatment, weeks several during delivered guidance, image daily (IMRT) with Dose-escalated, intensity-modulated radiation therapy tracking. tumor real-time with guidance image of incorporation the and organs, normal from away dose radiation shape to modulation of beam utilization the scan, tomography computed the of invention the celerator, ac linear development of the the of cobalt-60, discovery the including decades, ensuing the in made were radiation therapeutic in advancements technological Numerous in 1895. Roentgen Wilhelm by discovered first was radiation after adecade than 1904, less since cancer tate cancer since 1976. Protons are heavy charged particles with cancer since1976. Protonsareheavychargedparticles with PBT isatechnology thathasbeenusedtotreatprostate Theoretical Advantages,Barriers toPBTUse modalities. other SBRT with compare to conducted been have trials no randomized Unfortunately, cancer. prostate for early-stage treatments or other IMRT to efficacy similar and toxicities of late rate low a favorably suggest and emerging now are data outcomes long-term als, tri of clinical SBRT adoption recent in relatively the to Due patients. for convenient and cost-effective more be SBRT may addition, In used. are doses daily higher when ratio therapeutic enhanced an and ratio” “alpha/beta alow have cancers prostate most that suggest that studies on radiobiologic SBRT for based is using The rationale sessions. of daily weeks nine as many as require IMRT, can which conventional with compared time treatment overall the shortening significantly fractions, five in delivered typically is The therapy. treatment radiation of precise doses high deliver to target the and patient of the immobilization SBRT involves prostate, the to diotherapy ra hypofractionated deliver to technique alternate an As SBRT Reduces Treatment Time Tendulkar,Rahul MD Tumor Cancer in Prostate Control Emerging Technologies in Radiation Therapy May Improve been utilized in the treatment of pros treatment the in utilized been has therapy radiation beam External (PBT). therapy beam proton (SBRT) therapy and radiation body tic stereotac cancer: for prostate therapy radiation beam of external future the change may that emerged have gies technolo two decade, past the During ------reached at reached ofRadiationClinic’s Department Oncology. He canbe Dr. Tendulkar isanassociatestaff memberofCleveland technologies intheevolvinghealthcare economicclimate. important todeterminetherelative valueoftheseemerging delivery forprostatecancer. Ongoingclinicaltrialswillbe gies thatwilllikelyshapethefutureofradiationtreatment In summary,bothSBRTandPBTareencouragingtechnolo- to tumorcontrol,toxicity,qualityoflifeandcost. determining therelativeefficacyofeachmodalitywithregard are underway,andthesestudieswillbeextremelyvaluablein Fortunately, randomizedtrialscomparingPBTwithIMRT than forIMRT. ment ratetobeapproximately75percenthigherforPBT ers. OnestudyestimatedthemedianMedicarereimburse- the highercostofatreatmentcoursetopatientsandinsur- is thehighacquisitioncostofaprotonbeamunit,aswell Another potentialbarriertothewidespreadadoptionofPBT ing technologyitself. proton beam(“activescanning”),whichisyetanotheremerg- available methodstoactivelymodulatethedoseintensityofa excess ofGItoxicitymaybeexplainedinpartbythelack more gastrointestinal(GI)toxicitycomparedwithIMRT. This onstrated thatpatientstreatedwithPBTactuallyexperienced Surveillance, Epidemiology,andEndResults databasedem- One largestudyutilizingtheNationalCancerInstitute’s cancer. been clinicallyobservedtodateinthetreatmentofprostate Unfortunately, thetheoreticaladvantagesofPBThavenot reducing thetoxicitiestothoseorgans. dose tonormaltissuesbeyondtheBraggpeak,potentially cal propertyallowsfortherelativesparingofradiation burst ofenergyatthetailendaproton’srange.Thisphysi- Unique toPBTistheBraggpeak,whichdepositionofa X-ray photon-basedtherapy. a verydifferentradiationdosedistributioncomparedwith to healthytissuesurroundingtheprostate. PBT hasthetheoreticaladvantageofreducingdosedelivery intensity-modulated radiationtherapy. ease controlwhileloweringtreatmentcostscomparedwith sessions, ispossiblewithSBRT, whichmayenhancedis- A greaterbiologicdoseofradiation, deliveredinfewer therapy forthetreatmentofprostatecancer. therapy (PBT)areemergingformsofexternalbeamradiation Stereotactic bodyradiationtherapy(SBRT) andprotonbeam Key Points [email protected] or216.445.9869. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 23

Use of Salvage Therapies in the Treatment of Radioresistant Prostate Cancer Center for Urologic Oncology Urologic for Center By Nic Muruve, MD Key Points The treatment of locally recurrent There are minimal data on optimal treatment for locally prostate cancer after radiation therapy recurrent prostate cancer after radiation therapy. is difficult, as an ideal option remains A review of oncologic outcomes, toxicity and complications elusive. The current treatment options in Cleveland Clinic Florida patients who underwent either include surgical removal, additional salvage robotic prostatectomy or salvage cryotherapy identi- radiation therapy, ablative therapies fied some apparent advantages for prostatectomy. (cryoablation, high intensity focused Further analysis should clarify the choice of salvage proce- ultrasound) or observation with andro- dure for locally recurrent cancers. gen ablation. All these options carry significant morbidity that impacts patients’ quality of life. The only option that minimizes func- prostatectomy, with the most frequent complication after tional complications is observation and expectant androgen salvage cryotherapy being and after salvage ablation. This is not a curative choice, however, and if the prostatectomy being severe . patient is interested in eradication of the tumor, one of the There were no rectal injuries with salvage prostatectomy and other more invasive options must be undertaken. only one rectourethral fistula in the cohort after salvage cryo- Very little data exist on the optimal treatment. Most retro- therapy. Patients who underwent salvage cryotherapy were spective studies report a prostate specific antigen (PSA) con- statistically older and had a higher incidence of hypertension trol rate of approximately 50 percent at two years. As a result, than did the salvage prostatectomy cohort. most urologists tend to recommend what is perceived to be the least invasive treatment: ablative therapies. Review Identifies Advantages Salvage prostatectomy was always considered the most inva- Our outcomes review found that salvage procedures were sive option, but the advent of robotics in surgery has greatly generally safe and effective. Both salvage cryotherapy and diminished complications. salvage prostatectomy allow for adequate cancer control with minimal toxicity. Comparison of Prostatectomy and Cryotherapy The complication rates for salvage robotic prostatectomy ap- Outcomes peared no worse than for patients treated with salvage cryo- We reviewed oncologic outcomes and toxicity in patients ablation. Robotic salvage prostatectomy potentially has fewer who underwent either salvage prostatectomy or cryotherapy local complications (stricture disease) than does cryotherapy, treatments at Cleveland Clinic Florida to determine if ro- and urinary incontinence can be managed with new options botic salvage prostatectomy could offer similar outcomes to (e.g. artificial urinary sphincter implants), enabling us to cryoablation, a procedure that has been presumed to be less treat patients’ disease while preserving their quality of life. morbid than surgery. At Cleveland Clinic Florida we are further analyzing these We reviewed cases from January 2004 to June 2013 and iden- encouraging results to determine if a definitive advantage tified a total of 23 salvage procedures. Six of those patients of one procedure over the other exists. We believe this will underwent salvage robotic prostatectomy while 17 under- lead to better management of patients diagnosed with locally went salvage cryotherapy. recurrent prostate cancer after radiation therapy. Patients who were considered for salvage therapy had local- Dr. Muruve is a staff member of Cleveland Clinic Glickman ized disease at presentation, a PSA < 10 at recurrence, life Urological & Kidney Institute’s Department of Urology who expectancy > 10 years at recurrence and a negative metastatic practices at Cleveland Clinic Florida. He can be reached at workup. Patients were followed postoperatively to observe for [email protected] or 954.659.5188. cancer progression and any toxicity of treatment or compli- cations. The mean follow-up period for salvage cryotherapy patients was 14.1 months and for prostatectomy patients was 7.2 months. The incidence of disease progression was 23.5 percent and 16.7 percent after salvage cryotherapy and prostatectomy, respectively. The overall complication rate also was 23.5 percent after salvage cryotherapy versus 16.7 percent after Center for Urologic Oncology 24 Urology &KidneyDiseaseNews sents theculminationofoureffortstodate. patients who had a PSA nadir > 0.4 ng/mL were significant, patients whohad aPSAnadir>0.4ng/mLweresignificant, As showninTable 1, 24-monthbiochemicalfailure ratesin intermediate andhighrisk,respectively (Figure1). rates of90.4percent,81.1percent and73.6percentforlow, nadir PSA<0.4ng/mL,whichcorrelated withfive-yearBPFS A totalof891(74.25percent)1,111 patientsachieveda Impact Results andSurvival increments andanalyzedfailurerates. determined hazardratios(HR)basedon0.1ng/mLnadirPSA definition. Cohortdemographicsarelistedin Table 1. We Kaplan-Meier estimatesoffive-yearBPFSusing thePhoenix significant PSAendpointofbiochemicalsuccess. We plotted risk category(471men),aimingtoidentifyastatistically (BPFS) at0.1ng/mLPSAincrementsfortheintermediate teria. We studiedbiochemicalprogression-freesurvival Patients werestratifiedaccordingtotheD’Amico riskcri- clinical TstageandallpostoperativePSAvalues. cific antigen(PSA)levelattimeofdiagnosis,Gleasonscore, We studiedvariablesofinterestincludingage,prostatespe- ing thefollow-upperiod. None ofthecohortreceivedadjuvanttherapyanykinddur- all ofwhomhadaminimumfiveyearsfollow-updata. tients whounderwentprimarywhole-glandcryoablation, From theCOLDRegistry wereviewedhormone-naïvepa- Methodology forEvaluatingPSAEndpoint our goal.Arecentpublication as datafromClevelandClinicpatientpopulationstoachieve the nationalCryoOn-LineDatabase(COLD)Registry aswell treatment successforprostatecryoablation.We haveutilized years inanefforttoidentifyevidence-baseddefinitionof We haveconductednumerousstudiesduringthepastsix tectomy. treatment success,asexistforradiationtherapyandprosta- there arenoestablishedbiochemicalstandardsdefining localized prostatecancerisrecognizedasasafeprocedure, Although whole-glandcryosurgicalablationtotreatclinically Jones, MD,FACS David A.Levy, MD;AhmedEl-Shafei,andJ.Stephen Cryoablation Prostate Whole-Gland Primary Following Success Biochemical Determining 1 from theCOLDRegistry repre- percent confidenceinterval(CI)4.33-7.38],p<0.0001). endpoint comparedwiththe<0.4ng/mLvalue(HR5.649[95 Our analysisfailedtorevealastatisticallysuperiorPSAnadir ate- andhigh-riskpatients,respectively(Table 1). 92.2 percent,81percentand77forlow-,intermedi- who hadaPSAnadir<0.4ng/mL,withfive-yearBPFSratesof PSA <0.3ng/mLhadsimilaroutcomescomparedwiththose regardless ofriskgroup.Moreover,patientswhohadanadir [email protected] or216.986.4421. at reached be can in Oncology Urological Research. He andSamuelMillerDistinguishedChair Horvitz Leonard land ClinicLernerCollegeofMedicine andholdsthe atCleve and Family HealthCenters,Professor ofSurgery Dr. Cleveland ClinicRegional JonesisPresident, Hospitals at cation Institute.Hecanbereached Dr. fellowinClevelandClinic’sEdu El-Shafeiisaresearch at can bereached ofUrology. &KidneyInstitute’sDepartment He Urological Dr. LevyisastaffmemberofClevelandClinicGlickman local controlisconfirmed. salvage localtherapyorevaluationofpossiblemetastasisif to reachthatnadirmayhelpdirectmanagementeither eration ofpost-treatmentbiopsyinpatientswhosePSAfails which precludesusingahigher-nadirPSAendpoint.Consid- biochemical progressionat24monthsinallriskcategories, Patients withanadirPSA>0.4ng/mLshowedunacceptable of usingalowerPSAnadir. point forbiochemicalsuccess,withnostatisticaladvantage tion oftheprostate.AnadirPSA<0.4ng/mLisbestcutoff in patientswhounderwentprimarywhole-glandcryoabla- evidence-based studyfordefinitionofbiochemicalsuccess To thebestofourknowledge,resultsconveyfirst PSA NadirGuidesOngoingTreatment treatment decisions. decisions. treatment that nadirfollowingcryosurgery, inordertoinformongoing Biopsy shouldbeconsideredforpatientswhofailtoreach prostate specificantigenlevel<0.4ng/mL. evidence-based definitionofbiochemicalsuccess:nadir treatment datafromourinstitution, wedevelopedan andpatient On-LineDatabaseRegistry Utilizing theCryo standard thatdefinestreatmentsuccess. cancer, haslacked anestablishedbiochemical cryosurgery Unlike radiationtherapyandsurgicalextirpationforprostate Key Points [email protected] or216.692.8900. [email protected].

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More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 25 Center for Urologic Oncology Urologic for Center

Figure 1. Five-year biochemical progression-free survival (BPFS) comparing nadir PSA < 0.4 ng/mL and nadir PSA ≥ 0.4 ng/mL.

Table 1. D’Amico risk-stratified biochemical progression-free survival.

Reference

1. Levy DA, Ross AE, El-Shafei A, Krishnan N, Hatem A, Jones JS. Definition of biochemical success following primary whole gland prostate cryoablation. J Urol. 2014;192(5):1380-1384. Center for Urologic Oncology 26 Urology &KidneyDiseaseNews deprivation therapy (ADT). therapy deprivation androgen need who disease metastatic men with in therapy chemo role of upfront the evaluated Cancer (CHAARTED), Prostate in for Extensive Disease Trial Randomized tion Abla Androgen versus Therapy ChemoHormonal the as known 3805, also ECOG trial. intergroup American North alarge from results recent the with momentum gained has disease of this management the in role of chemotherapy approaches, the of some of these uniqueness the Despite domized phase 3 clinical trials (SWOG 9916 trials 3clinical phase domized ran well-conducted two when 2004, was PCa in years important most one of the Perhaps Cancer Prostate in Castration-Resistant Survival Overall Chemotherapy Improves benefit. survival show to failed disease chemotherapybased castration-resistant in mitoxantrone- evaluating 1990s late the in trials not help did that It certainly failed. has else everything choice after treatment last the as used it be should that perception the and PCa in activity questionable edly (QOL), of life suppos on its quality impact detrimental potential and side effects its to relate chemotherapy surrounding Myths oncology. medical by managed population patient a — castration-resistant become who disease advanced for men with reserved been traditionally has chemotherapy that fact the is debate the Fueling approach. treatment a from multidisciplinary efit ben PCa advanced men with that recognition now is there ways, many in answered be can questions these Although oncologist? amedical to apatient refer aurologist should When oncologists? or medical urologists by managed be disease advanced with one. patients Should biggest the been has oversight patient for responsibility have who should these, Among challenges. significant faced has PCa in of chemotherapy use the Historically, The Evolving View of Chemotherapy in PCa Garcia, A. Jorge MD, FACP Debunking the Myths of Chemotherapy in Prostate Cancer and the use of alpha emitters. of alpha use the and agents, targeted receptor androgen and adrenal novel immunotherapy, of introduction the with dramatically (PCa) changed cancer have prostate advanced with men for options ment treat years, five past the During 2

3,4

- - deprivation therapy D=docetaxel Medical School/Dana-Farberof Medicine,Harvard CancerInstitute.ADT=androgen study chairandpresentingauthorChristopher Sweeney, MBBS,AssociateProfessor American SocietyofClinicalOncology AnnualMeetingandreusedwithpermissionof resultsfromtheCHAARTEDtrial.Datapresentedat2014 Figure 1.Overallsurvival 1

- Primary endpoint:Overall survival Presented by:Christopher Sweeney,J. MBBS - Probability - - 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 ADT alone: 44.0 months 44.0 alone: ADT months 57.6 D:+ ADT Median OS: HR=0.61 (0.47-0.80) p=0.0003 mCRPC patients who have progressed on docetaxel. Men on docetaxel. progressed have who patients mCRPC in mitoxantrone against novel taxane this evaluated 3 trial phase This TROPIC trial. international the in demonstrated was docetaxel, to resistance with patients in activity for its developed derivative taxane asemisynthetic cabazitaxel, with chemotherapy second-line of utility the recently, More tumors. solid other treat to used agents chemotherapy of that to and similar manageable was profile side effect the men with symptomatic disease. symptomatic with men those in QOL in improvementand antigen (PSA) declines cific spe prostate reduction, burden tumor (OS) effective but led to survival overall improved not only docetaxel with Treatment for CRPC. regimen of this proval ap Administration’s Drug and Food (mCRPC) the led to cancer prostate castration-resistant metastatic with men in chemotherapy docetaxel-based TAX327)and evaluating those receiving mitoxantrone. receiving those 16.3 for versus months patients for docetaxel-treated months 19.2 is TAX327 trial for the analysis follow-up long-term the with advanceddisease. cer andbolsteredthecaseforupfrontuseinselectedmen systemic chemotherapyincastration-resistantprostatecan- Recent clinicaltrialresultshavechangedperceptions about untilothertherapiesareexhausted. be reserved in prostatecancer, andthebeliefthatchemotherapyshould impact onqualityoflife,itssupposedlyquestionableactivity by mythsregardingitssideeffectsandpotentialnegative useinprostatecancerhasbeenhampered Chemotherapy’s Key Points 12 24 OS (Months) OS 36 48 7 As important was the fact that that fact the was important As 5,6 In fact, the median OS in in OS median the fact, In 60 72 84 - - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 27

treated with cabazitaxel had an increased OS compared with The OS for the entire cohort was 57.6 months versus 44 those treated with mitoxantrone (hazard ratio [HR] 0.70, 95% months favoring the docetaxel + ADT arm (HR 0.61; p = 0.003). CI 0.59-0.83, median survival 15.1 versus 12.7 months).8 Similarly the OS in men with high-volume disease (defined as visceral disease and/or four or more bone metastases with

The results of these trials have clearly changed the thinking Oncology Urologic for Center at least one beyond pelvis and vertebral column) was 49.2 about systemic chemotherapy in CRPC and have debunked months versus 32.2 months in favor of the chemotherapy + some of the myths that discouraged this approach for many ADT arm (HR 0.60; p = 0.0006). Nearly twice as many patients years. achieved an undetectable PSA at six and 12 months in the Now the issues we face are of even greater magnitude. An chemotherapy arm (27.5 percent vs. 14 percent and 22.7 per- improved understanding of the biology of CRPC coupled cent vs. 11.7 percent, respectively; p < 0.0001), and the time with the availability of newer agents has challenged the to CRPC was also greater for those in the combination arm approach that one treatment fits all. As a result, questions (14.7 months vs. 20.7 months; p < 0.0001). about patient selection, the appropriate timing for treat- As one would expect, patients in the chemotherapy arm expe- ment, the mechanisms of resistance and the best treatment rienced more toxicities compared with those on ADT alone; sequence are the focus of additional research. however these toxicities were docetaxel-related and similar to those commonly observed when this agent is utilized in the Should Chemotherapy Be a Last Treatment Choice? CRPC setting. The simple answer to this complex question is NO. Some of These data continue to support the importance of chemo- the most dramatic findings ever published in PCa are the therapy in men with PCa. They debunk the myth that late recent results of ECOG 3805, a randomized phase 3 study of treatment is better and clearly establish the use of upfront androgen deprivation therapy (ADT) +/- 6 cycles of docetaxel chemotherapy for selected men with advanced disease (even chemotherapy in men with hormone-naïve metastatic PCa.2 prior to the development of castration-resistant disease) as a Cleveland Clinic participated in the ECOG 3805 trial. new standard of care. The rationale for the trial’s design was simple: Attack de novo testosterone-independent clones early, allowing ADT to keep Dr. Garcia is a staff member of Cleveland Clinic Glickman PCa in remission longer. Urological & Kidney Institute’s Department of Urology and of the Department of Hematology and Medical Oncology. He More than 790 men with metastatic PCa in need of ADT were can be reached at [email protected] or 216.444.7774. randomized to either ADT alone or chemotherapy and ADT. Patients were stratified based on extent of metastases (high References versus low volume), age, Eastern Cooperative Oncology Group 1. Garcia JA, Rini BI. Castration-resistant prostate cancer: performance status, use of agents to prevent skeletal-related many treatments, many options, many challenges ahead. events (SREs), use of anti-androgens and prior adjuvant ADT. Cancer. 2012;118(10):2583-2593. The primary endpoint of the study was OS. Standard second- ary endpoints included rate of PSA undetectability at six and 2. Sweeney C, Chen YH, Carducci MA, Liu G, Frasier DJ, Eisen- 12 months, time to CRPC, safety and QOL at 12 months berger MA, Wong YN, Hahn NM, Kohi M, Vogelzang NJ, Cooney MM, Dreicer R, Picus J, Shervin DH, Hussain M, Garcia JA, DiPaola RS. Impact OS by extent of metastatic disease at start of ADT on overall survival (OS) with chemohor- High volume Low volume monal therapy versus hormonal therapy for 1.0 1.0 0.9 0.9 hormone-sensitive newly metastatic pros- 0.8 0.8

0.7 0.7 tate cancer (mPrCa): An ECOG-led phase III 0.6 0.6 randomized trial. J Clin Oncol, 2014;32-5s, 0.5 0.5 p=0.0006 p=0.1398 0.4 0.4 (suppl; abstr LBA2). HR=0.60 (0.45-0.81) HR=0.63 (0.34-1.17) 0.3 0.3

Median OS: Probability Probability Median OS: 0.2 ADT + D: 49.2 months 0.2 ADT + D: Not reached 3. 3.Tannock Tannock IF, IF, Osoba Osoba D, D, Stockler Stockler MR, MR, Ernst Ernst 0.1 ADT alone: 32.2 months 0.1 ADT alone: Not reached 0.0 0.0 DS, Neville AJ, Moore MJ, Armitage GR, 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 OS (Months) OS (Months) Arm TOTAL DEAD ALIVE MEDIAN Wilson JJ, Venner PM, Coppin CM, Murphy In patients with high volume metastatic disease, there is a 17 month improvement in median overall survival from 32.2 months to 49.2 months KC. Chemotherapy with mitoxantrone We projected 33 months in ADT alone arm with collaboration of SWOG9346 team plusplus prednisoneprednisone oror prednisoneprednisone alonealone forfor Presented by: Christopher J. Sweeney, MBBS symptomaticsymptomatic hormone-resistanthormone-resistant prostateprostate cancer:cancer: aa CanadianCanadian randomizedrandomized trialtrial Figure 2. Overall survival results from the CHAARTED trial by the extent of metastatic with palliative end points. J Clin Oncol. disease at the start of androgen deprivation therapy. Data presented at the 2014 1996;14(6):1756.1996;14(6):1756 American Society of Clinical Oncology Annual Meeting and reused with permission of study chair and presenting author Christopher Sweeney, MBBS, Associate Professor of Medicine, Harvard Medical School/Dana-Farber Cancer Institute. Center for Urologic Oncology 28 Urology &KidneyDiseaseNews and, byextension, forincreasedconfidenceinAS. biopsy, havepersistedaschallenges foraccurateforecasting as wellthelimitsontumorsampling imposedbyneedle variations thatexistbetweenregions inindividualtumors, outcome inlocalizedPCa.However, thefrequentgenetic pression signatureshaveimproved thepotentialtopredict development ofvariousdiagnostic testsbasedongeneex- The adventofgenomicanalysisprostatetumorsandthe grade andstage. tests topredictindolentPCaandestimatetruetumor by theless-than-optimalabilityofconventionalpretreatment forecasting. Specifically,ASacceptancehasbeenhampered from alackofconfidenceinriskassessmentandoutcome The resistancetowidespreadadoptionofAShasstemmed overtreating biologicallyinsignificantdisease. course, therebyavoidingtheneedlesscostandmorbidityof vention onlyiftumorsprogress—wouldbetheappropriate testing, imagingandbiopsy,undertakingcurativeinter- toring withdigitalrectalexams,prostatespecificantigen Eric A.Klein,MD Risk Stratification and Active Surveillance Decisions A Progress Report on the Genomic Prostate Score and Its Impact on 6. 5. 4. 2004;351(15):1513. for advancedrefractoryprostatecancer. NEnglJMed. estramustine comparedwithmitoxantroneandprednisone MC, SmallEJ,Raghavan D,CrawfordED.Docetaxeland Taplin ME,BurchPA, BerryD,MoinpourC,Kohli M,Benson Petrylak DP, Tangen CM,HussainMH,LaraPNJr, JonesJA, prostate cancer. NEnglJMed.2004;351(15):1502. prednisone ormitoxantroneplusforadvanced MA, EisenbergerMA;TAX 327Investigators.Docetaxelplus KN, OudardS,ThéodoreC,JamesND,TuressonI,Rosenthal Tannock IF, deWitR,BerryWR,HortiJ,PluzanskaA,Chi 9182 study. JClinOncol.1999;17(8):2506. prostate cancer:resultsofthecancerandleukemiagroupB or withoutmitoxantroneinmenwithhormone-refractory V, TrumpD,WinerEP, Vogelzang NJ.Hydrocortisonewith Kantoff PW,HalabiS,ConawayM,PicusJ,KirshnerHars lance (AS)—employingserialmoni- In manyofthosecases,activesurveil- treatment withsurgeryorradiation. low-risk diseaseundergoimmediate than 90percentofmendiagnosedwith dying fromprostatecancer(PCa),more Despite thestatisticalimprobabilityof real-world setting. setting. real-world a to improverisk-stratificationandaiddecision-makingin type DX of theassay,marketedbyGenomicHealthInc.asOnco- California, SanFrancisco.Andourinitialclinicalevaluation test’s developersatClevelandClinicandtheUniversityof geneous tumor, could be identified. geneous tumor, could beidentified. PCa, regardlessofbiopsysampling locationwithinahetero- underlying biologythatreliablypredicts clinicallyaggressive opmental workintendedtodetermine whetheracommon The GPSistheresultofadecade ofinvestigativeanddevel- Development andValidation oftheTest mass withpublicationofasecondvalidationstudy to accuratelypredictPCaaggressivenessreachedcritical those challenges.Evidenceofanew17-geneassay’sability The year2014maymarkaturningpointinsurmounting 8. 7. 2010;376(9747):1147. docetaxel treatment:arandomisedopen-labeltrial.Lancet. static castration-resistantprostatecancerprogressingafter Prednisone pluscabazitaxelormitoxantroneformeta- Roessner M,GuptaS,SartorAO; TROPIC Investigators. JP, Kocak I, GravisG,BodrogiI,MackenzieMJ,ShenL, de BonoJS,OudardS,OzgurogluM,HansenMachiels in theTAX 327study. JClinOncol.2008;26(2):242. prednisone foradvancedprostatecancer:updatedsurvival Tannock IF.Docetaxelplusprednisoneormitoxantrone Berthold DR,Pond GR,SobanF, deWitR,EisenbergerM, Oncotype DX Key Points surveillance. logically indolentdiseasewhoaregoodcandidatesforactive menwithbio show thatGPShasthepotentialtoidentify Validation studyresultsandinitialtestinginaclinicalsetting accurately predictprostatecanceraggressiveness. onprostatebiopsies,hastheabilityto gene assayperformed ® Genomic Prostate Score (GPS), verified its capacity GenomicProstateScore(GPS),verifieditscapacity ® GenomicProstate Score(GPS),anew17- 1 by the bythe - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 29

The GPS’ 17-gene algorithm was derived from a progressively More research is needed to fully establish how GPS results narrowed pool of candidate genes identified by analyses of affect physician and patient confidence in choosing AS versus tumor specimens and confirmed to be associated with aggres- therapy. But these study outcomes show that the GPS clearly sive PCa. The GPS’ final set of 12 genes in four gene groups improves risk stratification at the time of PCa diagnosis, and representing four key PCa molecular pathways (plus five that it has the potential to help resolve perhaps the most Oncology Urologic for Center reference genes) is strongly linked with adverse pathology urgent and vexing issue in PCa — identifying men with bio- and, in an as-yet-unpublished third validation, with disease logically indolent disease who are good AS candidates — and recurrence. providing the reassurance to move forward. The latest validation study, published in European Urology in September 2014, used the GPS to assess biopsy tumor tissue Dr. Klein is Chairman of Cleveland Clinic’s Glickman Urologi- cal & Kidney Institute. He holds the Andrew C. Novick, MD, collected from a cohort of 395 men with low- to low-interme- Distinguished Chair in Urology and is a Professor of Surgery diate-risk PCa who were potential candidates for AS, but who at Cleveland Clinic Lerner College of Medicine. Dr. Klein is elected to undergo prostatectomy within six months of their the principal investigator for Cleveland Clinic’s GPS develop- initial diagnostic biopsy. The study evaluated the GPS’ ability ment studies. He is a paid consultant for Genomic Health to accurately predict the presence of adverse pathology (high- Inc. He can be reached at [email protected] or 216.444.5591. grade and/or non-organ-confined PCa) in the prostatectomy specimens. References

The study determined that the GPS was a significant predictor 1. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene of pathologic stage and grade at prostatectomy. Every 20-point assay to predict prostate cancer aggressiveness in the context rise in the GPS score (which ranges from 1 to 100) was associ- of Gleason grade heterogeneity, tumor multifocality, and ated with more than a doubling of the risk of high-grade PCa biopsy undersampling. Eur Urol. 2014;66(3):550-560. and a nearly doubled risk of malignancy beyond the prostate’s 2. Kartha GK, Nyame Y, Klein EA. Evaluation of the Oncotype confines. We and our UCSF coauthors concluded that the DX genomic prostate score for risk stratification in prostate independent molecular information the GPS results provide cancer patients considered candidates for active surveillance. correctly reflects a tumor’s underlying biology throughout the Presented at American Society of Clinical Oncology 2014 prostate, including the cancer’s potential to invade and dis- Genitourinary Cancers Symposium. tantly metastasize.

Assessment in Clinical Practice

In the latter half of 2013 we undertook an inception cohort study2 to evaluate the GPS assay’s performance in a clinical setting. One hundred fifteen patients at Glickman Urologi- cal & Kidney Institute with National Comprehensive Cancer Network (NCCN)-graded very low- to intermediate-risk PCa who were candidates for AS underwent GPS testing on pros- tate biopsy specimens obtained within six months of study entry. We sought to assess how often GPS testing altered patients’ NCCN risk stratification, the effect of GPS scores on physician recommendations for disease management and the impact of GPS results on patients’ decisions regarding disease management. GPS outcomes altered risk assignment in 21 percent of the study cohort, most often (in 18 patients) changing classifica- tion from NCCN low to GPS very low. Physicians recommend- ed AS to 100 percent of patients with very low-risk GPS results, and to 87 percent of patients with low GPS results. Physicians recommended treatment to 78 percent of patients who the GPS stratified as intermediate-risk. All but one patient chose treatment when assigned by GPS results to a higher risk cat- egory. All patients whose GPS outcomes reassigned them to a lower-risk category chose AS. Center for Urologic Oncology 30 Urology &KidneyDiseaseNews on T2WI. on T2WI. increases thespecificity oflow-signal-intensitylesions seen creased incancer) relativetocreatineandcitrate peaks,and in prostatecancers.MRSImeasures levelsofcholine(in- is restrictedinlesionswithincreased cellularity,asisseen prostate cancers.DWIquantifies freewatermotion,which washout inlesionsisassociated with angiogenesisseenin scanning. Evidenceofearlyand intense enhancementand lus injectionofgadoliniumcontrastduringrapidlyrepeated DCE allowsforthevisualizationofbloodperfusionviaabo- better diagnosticaccuracyforprostatecancer(Figure1). ment (DCE)andMRspectroscopicimaging(MRSI)enable fusion-weighted imaging(DWI),dynamiccontrastenhance- (3T) magnets,andfunctionalimagingsequencesusingdif- T1- andT2-weightedimages(T2WI)withtheuseof3Tesla Advances inMRIsuchasimprovedanatomicalresolutionon characterize individualprostatecancerlesions. potential toimproveourabilityaccuratelylocalizeand tal ultrasound(termedMP-MRI-USfusionbiopsy)havethe this informationtotargetedbiopsystrategiesusingtransrec- netic resonanceimaging(MP-MRI)andtheabilitytoapply Advances inprostateimagingusingmultiparametricmag- Imaging AdvancesImproveDiagnosticAccuracy reported despite50-to69-coresampling. biopsy (3D-TPMB),a20percentnegativeratehasbeen cer undergoingthree-dimensionaltransperinealmapping respectively. Amongmenwithknownlow-riskprostatecan- ported cancerdetectionratesof33percentand19percent, (≥ 20cores)afteroneortwopriornegativebiopsies,were- Likewise, amongmenundergoingrepeatsaturationbiopsy tate biopsy(10to14cores)onactivesurveillanceprotocols. low-risk menundergoingimmediaterepeatextendedpros- the consistent20to30percentreclassificationrateamong characterize andlocalizeprostatecancerarehighlightedby The limitationsoftransrectalbiopsystrategiestoaccurately ing deferredradicalprostatectomy. high as23percenthavebeenreportedamongmenundergo- sion, seminalvesicleinvasionorlymphnodemetastasis)as logical features(Gleasonscore≤4+3,extraprostaticexten- intervals havebeenreported,andratesofadvancedpatho- surveillance ashigh48percentovershort(<5years)time J.Stephenson,MD,FRCSC,By Andrew FACS (MP-MRI-US) Fusion Biopsy Targeted Prostate Multiparametric Magnetic Resonance Imaging Ultrasound Indeed, progression rates on active Indeed, progressionratesonactive lance andfocaltherapystrategies. is essentialforsuccessfulactivesurveil- erwise candidatesforcurativetherapy lesions amonghealthymen who areoth- of clinicallyimportantprostatecancer Accurate localization/characterization accuracy. (TRUS), orso-calledcognitiverecognition,hasquestionable of suspectedlesionsusingstandardtransrectalultrasound Likewise, theuseofMP-MRItoperformtargetedbiopsies ing biopsies underreal-timeMRIguidance in theMRIgantry. limited bythetime,expenseandimpracticalityofperform- The useofMP-MRIfortargetedprostatebiopsyhasbeen with 85percentdiagnosticaccuracy. cancer detectionof67percentand92percent,respectively, ing systemhasshownasensitivityandspecificityforprostate clinically significantcancer. MP-MRIusingthePI-RADSscor- gions ofinterestonascale1to5basedthelikelihood standardized gradingsystemcalledPI-RADSthatratesre- cancer detectionandcharacterizationhasbeenaidedbya sequences appearslimited.TheuseofMP-MRIforprostate However, theincrementalbenefitofMRSItoDWIandDCE added toastandard12-corebiopsy. are takenperpatientwhenatargeted biopsystrategyis significant cancers.Onaverage, 6to13additionalbiopsies appear tobeasaccurate3D-TPMBfordetectingclinically 12-core biopsyinonestudy).Targeted biopsystrategiesalso grade cancers(38percentofwhichweremissedbystandard Likewise, targetedbiopsiesaremorelikelytodetecthigh- a low,moderate,orhighprobabilityofcancer,respectively. cent havebeenreportedamonglesionsclassifiedashaving rates of15to20percent,2940and5071per- Using MP-MRI-USfusiontargetedbiopsy,cancerdetection tracking sensor. Thebestapproachhasyettobedetermined. pelvis withacustomUSprobeembeddedpassiveEM an electromagnetic(EM)fieldgeneratorplacedabovethe attached toamechanicalarm(Figure2),andonethatuses ing systemshavebeendescribed,includinga3-DUSprobe improve targetedbiopsyofsuspiciouslesions.Various track- be “fused”withTRUSusingspecializedcomputersoftwareto Technological developmentsnowenableMP-MRIimagesto Imaging Fusion Results inBetterBiopsy cancer. improve thelocalizationandcharacterizationofprostate and transrectalultrasoundhasthepotentialtosignificantly The fusionofmultiparametricmagneticresonanceimaging andtherapy.needed toguidefuturesurveillance Better meansofcharacterizingprostatecancerlesionsare Key Points More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 31

MP-MRI-US fusion targeted biopsy has the potential to sig- nificantly improve the localization and characterization of prostate cancer when added to a standard 12-core biopsy. It is anticipated that this strategy will enable better selection and monitoring of patients who choose active surveillance Oncology Urologic for Center and focal therapy as a management option. This technology may also be useful in patients with suspicion of prostate can- cer despite one or more negative biopsies. In 2014, Cleveland Clinic began offering MP-MRI-US fusion targeted prostate biopsy to patients. We also plan to investigate its utility in active surveillance and focal therapy protocols.

Dr. Stephenson is Director of the Center for Urologic On- cology at Cleveland Clinic’s Glickman Urological & Kidney Institute and a staff member of the Taussig Cancer Institute. He can be reached at [email protected] or 216.445.1062.

Figure 1. Prostate cancer lesion identified on (a) T2-weighted images, (b) diffusion-weighted sequences, (c) dynamic contrast enhancement sequences, and (d) whole-mount prostatectomy specimen. Reprinted from Natarajan S, Marks LS, Margolis DJA, et al. Clinical application of a 3D ultrasound-guided prostate biopsy system. Urol Oncol 2011;29(3):334-342. © 2011, used with permission from Elsevier.

Figure 2. Artemis™ 3D ultrasound biopsy tracking system (Eigen, Grass Valley, CA). Reprinted from: Natarajan S, Marks LS, Margolis DJA, et al. Clinical application of a 3D ultrasound-guided prostate biopsy system. Urol Oncol 2011;29(3): 334-342. © 2011, used with permission from Elsevier.

Figure 3. MP-MRI-US fusion guided image from biopsy procedure. Prostate is outlined in red, suspected tumor in green and biopsy needle in yellow. Center for Urologic Oncology 32 Urology &KidneyDiseaseNews this study. therapy, prostatectomyorexternal beamradiotherapyfor incidence ofgrade>3toxicityafter treatmentwithbrachy- Cancers Symposium.)Figure1demonstrates thecumulative American SocietyofClinicalOncology’s2012Genitourinary reinforced thisopinion.(We presentedourfindingsatthe lance, Epidemiology,andEndResults (SEER) databasehas groups. equal thatofbrachytherapyandprostatectomyacrossallrisk ity wasnotbalancedbyIMRT’sefficacy,whichcontinuesto long-term toxicityrateofIMRT. Asateam,wefeltthistoxic- Through thismechanismwecametoappreciatethehigher nual programreviewmeetings. prostatectomy throughourinceptioncohortstudyandbian- and comparedthemwiththeoutcomesofbrachytherapy cancer. Overthe yearswehavemonitoredIMRToutcomes ulated radiationtherapy(IMRT)forthetreatmentofprostate first medicalcentersinthecountrytoemployintensity-mod- cancer treatmentformanyyears.In1998wewereoneofthe Cleveland Clinichasbeenontheleadingedgeofprostate Long-term OutcomesMonitoring and discusswaystoimprovetheprostatecancerprogram. tion ontreatmenteffectiveness,toxicityandnewresearch, are invitedtoabiannualmeetinginwhichweshareinforma- ship, suchastheVeterans Administrationmedicalsystem, tion andthosewithwhomwehaveacloseworkingrelation- volved intreatingprostatecancerpatientswithintheinstitu- beam radiotherapyandbrachytherapy. Since1996,thosein- cohort studythatincludesradicalprostatectomy,external tate cancerhavebeenrecordedandfollowedinaninception All patientsdefinitivelytreatedatClevelandClinicforpros- toxicity. advantage forbrachytherapyintermsoflowerlong-term in 1996.Asexplainedbelow,thoseoutcomesshowaclear have continuouslyreviewedsincetheprogram’sinception The mostinfluentialareourpatientoutcomes,whichwe ing radiotherapeuticmodalitiesisduetoseveralfactors. Our preferenceforprostatebrachytherapyovercompet- By JayCiezki,MD Cancer: Why the Bias? Brachytherapy Versus Other Radiotherapeutic Modalities for Prostate 1 FurtherinvestigationbyourgroupusingtheSurveil- our utilization of this treatment. our utilizationofthistreatment. modalities, wehavebeenincreasing procedures theydoinfavorofother the numberofprostatebrachytherapy dure. Whilemostcentersarereducing 4,300th prostatebrachytherapyproce- Cleveland Clinicrecentlyperformedits patients notednoevidenceforlowertoxicitywithIMRT. but arecentmulti-institutionalstudyinwhichweenrolled termine iftheyhaveexperiencedbetteroutcomeswithIMRT, Not knowingtheirinternalreviewprocesses,onecannotde- centers havecontinuedtochooseIMRToverbrachytherapy. clear, givenourinternalreviewprocessresults,butother Our rationaleforpreferringbrachytherapyoverIMRTis Possible IncentivesforIMRT Use He can be reached at He canbereached ment ofRadiation ofCellBiology. Oncology andDepartment Dr.- Ciezkiisastaff member ofClevelandClinic’sDepart example ofthesuccessourmethod. prostate brachytherapyprogramatClevelandClinicisan and tailorourtreatmentrecommendationsforpatients.The ous evaluationofpatientoutcomeshasallowedustorefine permits ustooffertherapybasedonoutcomes.Thiscontinu- centive forphysicianstochooseonetreatmentoveranother, Cleveland Clinic’sstructure,inwhichthereisnofinancial- of IMRTasaradiotherapeuticmodalityforprostatecancer. between theseeconomicincentivesandthepreponderance to whichtheyreferpatients.Thereisclearlyanassociation an interestinexternalbeamradiationtreatmentcenter cer treatments.Thisexemptionenablesurologiststoown federal prohibitionofself-referralthatappliestoothercan- qualifies foranin-officeancillaryservicesexemptiontothe Moreover, externalbeamradiotherapyforprostatecancer brachytherapy. niques thatareabouttwiceasmuchforprostatectomyor payment forIMRTandotherexternalbeamradiationtech- ate theprocedures.Currentreimbursementstructuresallow treatments, therearefinancialconsiderationsthatdifferenti- Beyond themedicalevaluationofvariousprostatecancer rates at other institutions. rates atotherinstitutions. Economic incentivesmayexplainIMRT’s higher utilization terms ofreducedtoxicity. monitoring thatshowsanadvantageforbrachytherapyin isbasedonlong-terminstitutionaloutcomes This support utilization. (IMRT), ClevelandClinicisincreasingbrachytherapy’s intensity-modulatedradiationtherapy dalities, particularly medical centersinfavorofcompetingradiotherapeuticmo Though prostatebrachytherapyuseisdecliningatmany Key Points [email protected] or216.445.9465. 2

- 3 More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 33

1A Center for Urologic Oncology Urologic for Center

1B

Figure 1. A) Cumulative incidence of gastrointestinal toxicity after therapy with external beam radiation quickly outpaces brachyther- apy and prostatectomy. B) While prostatectomy has more initial genitourinary toxicity, external beam radiation again is seen to cause more toxicity with more follow-up. C) Despite the argument that the toxicity of modern external beam radiation (such as IMRT) is reduced because of its superior targeting, its toxicity exceeds standard, pre-IMRT radiotherapy.

1C

References

1. Hunter GK, Reddy CA, Klein EA, Kupelian P, Angermeier K, Ulchaker J, Chehade N, Altman A, Ciezki JP. Long-term (10-year) gastrointestinal and genitourinary toxicity after treatment with external beam radiotherapy, radical pros- tatectomy, or brachytherapy for prostate cancer. Prostate Cancer. 2012;2012:853487. Epub 2012 Apr 11.

2. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survi- vors. N Engl J Med. 2008;358(12):1250-1261.

3. Mitchell JM. Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N Engl J Med. 2013;369(17):1629-1637.

IMRT = intensity modulated radiation therapy sEBRT = standard external beam radiation therapy Center for Blood Pressure Disorders 34 Urology &KidneyDiseaseNews with internists, cardiologists, endocrinologists and vascular with internists,cardiologists,endocrinologists andvascular and monitoringofbloodpressure disorders.We workclosely The centerusesacollaborativeapproach todiagnosis,care A CollaborativeCareModel and renalarterystenosis. treatment ofprimaryaldosteronism,pheochromocytoma ary hypertension,specificallyrelatedtothediagnosisand The centeralsohasexpertiseinthemanagementofsecond- pulse wavevelocityandaugmentationindex. assess centralbloodpressureindices,includingmeasuresof blood pressuremeasurements,andwehavetheabilityto strongly withvasculardiseasethandoroutineperipheral Central bloodpressureshavebeenshowntocorrelatemore al profilesandhemodynamicparameters. ment decisionsandtailortherapybyassessing neurohumor- with difficult-to-controlhypertensiontohelpguidetreat- We utilizenoninvasiveimpedancecardiographyinpatients in additiontoassessmentoftherapyefficacy. of patientstohelp assessdifferentbloodpressurepatterns, ambulatory bloodpressuremeasurements foralargecohort sure devices inouroutpatientclinics,weprovide24-hour Along withthestandardizeduseofautomatedbloodpres- Monitoring Capabilities space andequipmentdevotedtoevaluationtesting. The centerhasadedicatedhypertensionlaboratorywith nurse practitioners. with medicalassistants,physicianassistantsandclinical specialists bytheAmericanSocietyofHypertension,and team ofexperiencednephrologistscertifiedashypertension Our CenterforBloodPressureDisordersisstaffedwitha hypertension cases. experience andexpertiseinthemanagementofdifficult designation recognizesinstitutionsthathavedemonstrated Center inNortheastOhio,andoneofonly12nationally. This Hypertension asthefirstComprehensive Thomas,MD Heyka,MD,andGeorge Robert Center Hypertension Comprehensive a as Designated Hypertension and Nephrology of Department Nephrology and Nephrology and Department of Cleveland Clinic’s recognized pertension has Society ofHy- The American [email protected] or216.636.5420. at Hecanbereached andHypertension. Nephrology Dr. of ThomasisastaffmemberoftheDepartment 216.444.6771. at Kidney Institute.Hecanbereached & in ClevelandClinic’sGlickmanUrological Hypertension Dr. and ofNephrology HeykaisChairmanoftheDepartment ing guidelines,lifestylechangesandnutrition. patients withinformationregardingbloodpressuremonitor- tween thepatientandcareproviders.Ourcentersupports An effectivetreatmentprogramrequirespartnershipbe- ment plantailoredtotheindividualpatient. medicine specialiststodevelopadiagnosticandmanage- in theircare. numerous specialties,andtoengagepatientsparticipate all formsofbloodpressuredisordersincollaborationwith has thecapabilityandexperiencetoevaluatemanage ofNephrologyandHypertension land Clinic’sDepartment Center,As adesignatedComprehensiveHypertension Cleve- Key Points [email protected] or

More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 35

Pulmonary Hypertension and Kidney Disease: A Deadly Duo Center for Chronic Kidney Disease Kidney Chronic for Center Sankar Navaneethan, MD Key Point Pulmonary hypertension (PH) is a The presence of chronic kidney disease is an independent progressive, fatal pulmonary circulatory risk factor for death in patients with pulmonary hyperten- disease that accompanies left or right sion. ventricular failure.

Several factors lead to the develop- In the multivariable adjusted Cox proportional hazards ment and worsening of PH, and kidney model, the presence of eGFR < 60 mL/min/1.73 m2 was inde- dysfunction and volume overload are pendently associated with mortality. When eGFR was exam- common occurrences in clinical practice that can lead to ined as a continuous variable, every 5 mL/min/1.73 m2 de- increased pulmonary artery (PA) pressure. This decline in crease in eGFR was associated with a greater hazard for death kidney function could be transiently related to hemody- (HR 1.05, 95% confidence interval [CI] 1.03-1.07). Presence of namic changes during the treatment of volume overload CKD did not seem to modify the associations between sever- associated with PH. These hemodynamic changes could lead ity of PH and death. to chronic kidney disease (CKD) if the insults are persistent or the underlying disease continues to worsen. Possible Explanations for CKD-PH-Associated Mortality Examining CKD-PH Relationships Pulmonary hypertension and CKD are disease states associ- Since kidney disease in itself is a significant risk factor for ated with poor outcomes. In this large cohort of patients with death, it is relevant to examine its effects in the population PH (based on right heart catheterization data), underlying with PH. Therefore, we attempted to determine if the pres- CKD was highly prevalent. The observed association between ence of pre-existing non-dialysis-dependent CKD is an inde- CKD and mortality in our study could be explained by the pendent risk factor for death in patients with PH of varying higher prevalence of diastolic dysfunction and volume over- etiology. load (resultant pulmonary congestion) in those with mild to We studied1 1,088 adult patients diagnosed with PH based on moderate CKD. mean PA pressure > 25 mm Hg at rest as measured by right In addition, other investigators have speculated on the po- heart catheterization performed at our institution between tential influence of uremic toxins, bone mineral disorder 1996 and January 2011. The primary outcome of interest was and endothelial dysfunction on outcomes among those PH all-cause mortality, which was ascertained from our elec- patients who are on dialysis. Particularly, these reports note tronic medical record and linkage of our data with the Social that nitric oxide levels are reduced and release of nitric oxide Security Death Index. is attenuated in patients on hemodialysis with PH. These Patients were followed from their date of right heart catheter- deficiencies in nitric oxide often lead to increased pulmonary ization until October 31, 2011. Mean age of the study cohort vascular tone, which in turn can promote arterial stiffness was 60 ± 15 years; 66 percent were females and 81 percent with resultant adverse consequences. were white. Mean serum and estimated glomerular filtration Whether such mechanistic pathways prevail in those with ± 2 rate (eGFR) was 72.2 29 mL/min/1.73 m . Mean PA pressure earlier stages of CKD, thereby causing higher mortality rates, ± of the entire cohort was 47 14 mm Hg. Among the 1,088 is unknown and could be explored in CKD cohorts with patients, 388 (36 percent) had evidence of CKD; 340 (31 per- longitudinal data relating to PH and left ventricular function. cent) had stage 3 CKD and 48 (4 percent) had stage 4 CKD. Our group is conducting these analyses, which might also During the median follow-up period of 3.2 years (interquar- help us identify novel risk stratification tools for our kidney tile range 1.5 to 5.6 years), 559 (51 percent) of the total cohort disease patients. died. Kaplan-Meier survival estimates at one year were 86 percent, 78 percent and 48 percent in those without CKD, Dr. Navaneethan is a staff member of Cleveland Clinic with stage 3 CKD and with stage 4 CKD, respectively (log-rank Glickman Urological & Kidney Institute’s Department of p < 0.001; see Figure 1). Nephrology and Hypertension. He can be reached at [email protected] or 216.636.9230. Center for Chronic Kidney Disease 36 Urology &KidneyDiseaseNews Figure 1. Survival based on eGFR in patients with pulmonary hypertension. basedoneGFRinpatientswithpulmonary Figure 1.Survival 1. NavaneethanSD,Wehbe E,HeresiGA,GaurV,MinaiOA, Reference nary hypertension.ClinJAmSocNephrol. ence andoutcomesofkidneydiseaseinpatientswithpulmo- Arrigain S,NallyJVJr, ScholdJD,Rahman M,DweikRA.Pres- 2014;9(5):855-863.

More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 3737

Erectile Dysfunction Is a Major Cause of Peyronie Disease: A Personal View Center for Genitourinary Reconstruction Reconstruction Genitourinary for Center Drogo K. Montague, MD Key Points Peyronie disease (PD) occurs in as many Mild erectile dysfunction (decreased erectile rigidity) is usu- as 9 percent of middle-aged and older ally a causal factor in the development of Peyronie disease. men. It is caused by plaque formation Peyronie disease can be prevented by advice to lessen the in the tunica albuginea, thought to possibility of penile injury during coitus. result from repeated minor injuries to Men with Peyronie disease who have difficulty with or are the penis during intercourse. The goal unable to perform coitus usually require surgical therapy. of treatment is to restore or maintain the ability to have intercourse. Surgery most often consists of either tunica albuginea plica- tion of the penis or inflatable penile prosthesis implantation, As a prelude to the following discussion of PD, penile frac- depending on baseline erectile rigidity. tures are uncommon, dramatic injuries that occur during coitus in young men with fully rigid erections. If a large force is applied to these erections during sexual activity, there Surgical Options is sharp pain followed by penile swelling and ecchymosis. Surgical exploration reveals a tear in the elastic covering To restore the ability to have sex safely without further injury, (tunica albuginea) of the erection chambers at the base of the the penis must be reasonably straight and erections must be penis. When the tear is surgically repaired, future erections reliably firm. If curvature is the problem and erections after remain straight. If surgical repair is not done, a palpable taking a PDE5 inhibitor are firm, then tunica albuginea plica- scar (plaque) develops at the base of the penis, and erections tion of the penis is advisable. In this procedure, the normal curve toward the side of this inelastic plaque. tunica albuginea is shortened at the point of maximal curva- ture to match the penile shortening due to the inelastic scar PD has some things in common with penile fracture. Typi- on the opposite side. The length of the resulting erection will cally, men with PD still have erections suitable to initiate be approximately equal to the preoperative stretched penile coitus; however, erectile rigidity is less than when they were length. With this procedure there should be no worsening of younger, and the penis may be subject to bending during co- the underlying ED. ital thrusting. The bending results in delaminating injuries to the tunica albuginea. In contrast to penile fracture, these If the patient does not respond to PDE5 inhibitor therapy, less dramatic injuries are often painless and occur farther we recommend inflatable penile prosthesis implantation. out on the shaft of the penis. Unlike penile fracture, there are If cylinders are used that expand only in girth, prosthesis no outward signs of injury. As healing takes place, scar tissue implantation usually results in satisfactory penile straighten- forms (Figure 1), causing loss of penile length and erectile ing. The prosthesis also provides a firm erection each time deformity (Figure 2). it is inflated. Men with PD invariably have lost penile length, and, as with tunica albuginea plication, the length of the Ways to Avoid PD erection after prosthesis surgery will be approximately equal to the stretched penile length prior to surgery. As men’s erectile rigidity declines with aging, they can avoid Penile plaque excision or incision with autologous tissue developing PD by regularly using a phosphodiesterase type grafts can be done to lengthen the scarred side of the penis 5 (PDE5) inhibitor (sildenafil, vardenafil or tadalafil) to treat (Figure 3). This extensive surgery straightens the penis and their mild erectile dysfunction (ED). Men should avoid excess restores some of the lost penile length. With these proce- bending of the penis during coitus, as well as sexual activity a. b. dures, however, there is a significant chance of worsening the when erections might be weaker than usual due to fatigue or underlying ED. If ED worsening occurs, a second procedure alcohol intake. If the penis slips out of the , the man or to implant an inflatable penile prosthesis is often necessary. his partner should use their hand to guide it back in. Avoid- ing coitus in which the partner is on top is also advisable In conclusion, PD is the result of an often silent injury or because of greater forces often applied to the penis in this recurrent injuries to the erect penis during sexual activity. position. Some degree of ED is usually an underlying factor. Occur- rence or worsening of PD is avoidable by following common- At Cleveland Clinic, when men present to us with PD, we sense advice. When PD makes coitus difficult or impossible, discuss this ED injury model and provide the above advice on surgical intervention is indicated. The goal in treatment, how to avoid recurring injury. If coitus is already impaired or provided erections are reliably firm, is correction of the de- impossible, we consider surgical treatment. formity. If the degree of ED precludes a straightening proce- dure alone, inflatable penile prosthesis implantation is often the surgical choice. Center for Genitourinary Reconstruction 38 Urology &KidneyDiseaseNews Daitch JA,AngermeierKW, MontagueDK.Modifiedcorporoplas- Mulhall JP, CreechSD,BoorjianSAetal.Subjectiveandobjec- Additional Reading [email protected] or216.444.5590. at Clinic LernerCollegeofMedicine.Hecanbereached atCleveland cal &KidneyInstituteandProfessor ofSurgery Reconstruction- atCleveland Clinic’sGlickmanUrologi nary Dr. MontagueisastaffmemberoftheCenterforGenitouri tion. JUrol.1999;162(6);2006-2009. ty forpenilecurvature:long-term resultsandpatientsatisfac- J Urol.2004;171(6Pt1);2250-2253. lation ofmenpresentingforprostatecancerscreening. tive analysisoftheprevalencePeyronie’s diseaseinapopu- Figure 3 Figure 1 - Flores S,ChoiJ,AlexBetal.Erectile dysfunctionafterplaque Montague DK,AngermeierKW,LakinMMetal.AMS3-piece predictors. JSexMed.2011;8(7);2031-2037. incision andgrafting:short-term assessment ofincidenceand comments]. JUrol.1996;156(5);1633-1635. ronie’s disease:comparisonofCXandUltrexcylinders[see inflatable penileprosthesisimplantationinmenwith Pey- an autologouspericardialgraft. Figure 3.Excision ofpenileplaqueandreplacementwith PD. ofthe erection inamanwith Figure 2.Dorsalcurvature is attachedcavernoussmoothmuscle. tunica albugineainapatientwithPD.Thetissueontop Figure 1.Onthebottomisadensescarreplacing Figure 2 More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 39

Staged Buccal Graft Urethroplasty for Difficult Strictures Center for Genitourinary Reconstruction Reconstruction Genitourinary for Center Kenneth Angermeier, MD; Hadley Wood, MD; and Key Point Ryan Mori, MD Staged buccal graft urethroplasty has emerged as a reli- able form of repair of difficult urethral strictures, especially in patients with a history of hypospadias surgery or lichen sclerosus.

At that site, a urethrostomy is created using adjacent penile or scrotal skin for part of the circumference when necessary. In the case of a particularly dense or obliterated area of stric- Although the majority of urethral strictures are repaired in a ture, which seems to occur most often within the glanular single operation, a two-stage approach is preferred in some and distal penile in men with LS, this segment may situations. For example: be completely excised. • Patients with recurrent stricture following hypospadias Dartos fascia may be mobilized to cover the tunica albuginea surgery often have insufficient genital skin for flap re- adjacent to the urethral plate if needed to provide a good construction, and may not have adequate dartos fascia graft bed. Buccal mucosa is then harvested, either unilater- to reliably support one-stage urethral reconstruction ally or bilaterally, and sutured and quilted into place along using a graft. In this setting, staged buccal graft urethro- either side of the urethral plate or across the midline in place plasty has emerged as a reliable form of repair. of the urethra. A bolster dressing is applied for five days to promote graft take, and a urethral catheter is left indwelling • A second group of patients who may benefit from this for two to three weeks. approach are those with anterior urethral strictures related to lichen sclerosus (LS), which are often long Second-stage tubularization is carried out when the graft and associated with significant spongiofibrosis. This has healed and softened, usually four to six months later. We group is known to have a higher stricture recurrence strive for a healed urethral plate of approximately 3 cm in rate following surgery compared with other stricture width to allow for adequate final diameter of the urethral lu- etiologies. Although success with a one-stage operation men and to minimize the chance of recurrent stricture. The has been reported, a staged technique has been shown patient is informed that additional oral mucosa (either lin- to be a reliable form of reconstruction, especially in the gual or buccal) may be harvested to complete the repair if the presence of inflammatory obliteration of the glanular plate is insufficient in a particular area. The urethra is closed and distal penile urethra. and additional tissue layers are mobilized and brought together as available, or a tunica vaginalis flap may be raised Previous reports of staged buccal graft urethroplasty have to cover the repair if the dartos is inadequate. The repair is occasionally described the need for three or more operations stented for three weeks, and the patient is then monitored in to complete the reconstruction, and in some series, relatively routine fashion. low rates of progression to urethral tubularization have been noted with patients retaining a proximal urethrostomy. Postoperative Complications and Conclusion These findings prompted us to review our experience with Postoperative results following staged buccal graft urethro- staged buccal graft urethroplasty during the past 10 years. plasty have been quite good. Recurrent stricture or urethro- Wea. identified 78 men who have undergoneb. the procedure, cutaneous fistula requiring intervention developed in 4 per- with hypospadias-related stricture present in 53 percent, LS cent and 5 percent of patients, respectively (one patient had in 40 percent and other conditions in 7 percent. Stricture was both). In five patients (6.4 percent), the glans closure opened limited to the penile urethra in 63 percent of patients, and to the level of the corona, and three requested a surgical revi- was multifocal or panurethral involving both the penile and sion as a result. bulbar urethra in 37 percent. More than 95 percent of our patients returned for second- Details of the Surgery stage tubularization. Ninety-six percent of repairs were completed in two operations, with those needing a planned The surgical procedure is initiated by opening the urethra additional procedure having had a history of obesity and from the distal end of the stricture (typically at the urethral buried penis. meatus) and continuing the urethrotomy incision into healthy wide-caliber urethra for a distance of 1 to 1.5 cm. Center for Genitourinary Reconstruction 40 Urology &KidneyDiseaseNews and acceptablemorbidity. local tissuesisquestionable,duetothehighrateofsuccess should nothesitatetouseastagedapproachifthestatusof be candidatesforreconstructioninasingleoperation,one or LS. Althoughsomepatientsinthesetwocategoriesmay tures, particularlythosewithahistoryofhypospadiasrepair procedure forpatientswithdifficultanteriorurethralstric- In summary,stagedbuccalgrafturethroplastyisaneffective 3A 1A 2 (B) Tubularization oftheurethra. (C)Immediatepostoperativeappearance. Figure 3.(A)Secondstage:Well-healed andurethralplateprior toprocedure. buccalgraft for fivedays. Figure 2.Bolstersecuredinplacetoimmobilizegraft suturedandquiltedontorecipientbed. (C)Buccalgraft buccal mucosaharvest. Figure 1.(A)First stage:Ventral urethrotomyandincisionofglanspenis.(B)Exposurefor 3B 1B struction. Recon- fellowintheCenterforGenitourinary thetic surgery - andpros Dr. reconstruction Moriisaformergenitourinary or 216.444.2146. at College ofMedicine.Shecanbereached atClevelandClinicLerner ofSurgery Assistant Professor Reconstruction andan Institute’s CenterforGenitourinary Dr. Wood &Kidney isastaffmemberoftheUrological at He canbereached Reconstruction. oftheCenterforGenitourinary and Director ofUrology &KidneyInstitute’sDepartment man Urological Dr. AngermeierisastaffmemberofClevelandClinic Glick 1C 3C [email protected] or216.444.0415. [email protected] - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 41

Proteomics and the Future of Sperm Testing Center for Reproductive Medicine Reproductive for Center Edmund Sabanegh Jr., MD, and Ashok Agarwal, PhD Key Points Up to 15 percent Examination of sperm function through proteomics has the of couples are potential to improve on conventional semen analysis in the infertile, with al- workup of male infertility. most 50 percent of Alterations in differentially expressed proteins (DEPs) are those having male present in infertile men with bilateral ; some of factor as a contrib- these proteins are involved in sperm function, sperm motility uting cause. For and other functions related to reproduction. the past 50 years, semen analysis has been the mainstay of DEPs may serve as novel biomarkers in the identification of the male fertility evaluation.1 bilateral varicocele and may help urologists identify better options for clinical management of infertile men. Although advances in semen testing have incorporated computer-assisted technologies, the test has remained fundamentally unchanged, with emphasis on the three main there are no proteomic studies comparing the etiology of parameters: sperm count, motility and morphology. The fertile men with that of infertile men with bilateral varicocele. most significant modifications have involved the redefinition of normal ranges of semen parameters as defined in five it- Examining Differential Expression of Key erations of the World Health Organization’s reference values, Spermatozoa Proteins most recently in 2010.2 Despite these updates, clinicians and patients remain In a recent study, we examined how the etiology of bilateral frustrated with the low sensitivity and specificity of the con- varicocele-related male infertility might be affected by the ventional semen analysis. Many men with abnormal semen differential expression of key proteins in spermatozoa that parameters will go on to achieve spontaneous pregnancies, results in testicular dysfunction and impairment of male and less than 50 percent of infertile men have a discernible fertility potential. We also validated two differentially ex- etiology. The remarkable day-to-day and geographic variabil- pressed proteins (DEPs) that have reproductive function. We ity in ejaculate quality further limits test utility. examined the DEPs extracted from spermatozoa cells from patients with bilateral varicocele (N = 17) and healthy donors Bringing Proteomics to Bear on Male Infertility (N = 10). Using genomewide profiling, we found more than 1,000 It is against this backdrop that our team has been working proteins in the fertile group and a similar number in the on new tests to assess sperm function. With the development group with bilateral varicocele. We identified 73 DEPs, of of tests including sperm DNA fragmentation3 and oxidative which seven were unique to the bilateral group and 58 were stress assessments,4 we have improved our ability to critically differentially expressed (overexpressed or underexpressed) in examine sperm function. New studies in sperm proteomics either group (Figure 1A). Proteins were further classified ac- show that proteomic analysis holds exciting promise that will cording to their abundance (high, medium, low and very low) allow targeted treatments for male infertility.5-9 (Figures 1B and C). The abundance (both high and medium) Proteomics involves careful analysis of proteins expressed of proteins observed in the group with bilateral varicocele by a cell or tissue. The study of protein expression has been again demonstrates their likely involvement in the etiology of the subject of intense research for many diseases during the disease. the past decade, with much interest devoted to reproductive We have demonstrated for the first time the presence of implications. At present, more than 6,000 discrete proteins DEPs and identified proteins with distinct reproductive have been identified in semen, which represents about three- functions that are affected in infertile men with bilateral quarters of the entire sperm proteome. varicocele. The majority of the DEPs were associated with Our work has demonstrated differential protein expression metabolic processes, stress responses, oxidoreductase activ- over controls in a variety of situations that include idio- ity, enzyme regulation and immune system processes. The pathic male infertility, varicocele, azoospermia and assisted topmost network with the core function of lipid metabolism reproductive technology failure. This early work allows the showed five overexpressed and seven underexpressed DEPs development of methods to study male infertility, which was in bilateral varicocele samples. Seven DEPs were involved in previously believed to be idiopathic, and ultimately to stratify sperm function such as capacitation, motility and zona-egg interventions based on laboratory results.10,11 binding. Two proteins, Tektin-3 (TEKT3) and T-complex pro- Although previous studies have examined altered protein pro- tein 11 homolog (TCP11), may serve as potential biomarkers files in varicocele patients compared with normal fertile men, for bilateral varicocele. Center for Reproductive Medicine 42 Urology &KidneyDiseaseNews He can be reached at He canbereached Center forReproductive Center. MedicineandtheAndrology ofUrology’s oftheDepartment Dr. isDirector Agarwal at can bereached ofUrology. &KidneyInstitute’sDepartment He Urological Dr. SabaneghisChairmanofClevelandClinicGlickman potentially helpinfertilecouples. and treatmentsforspermdysfunctionmaybedevelopedto novel biomarkersthroughproteomicstudies,clinicaltests tive medicinearmamentarium.Withtheidentificationof holds greatpromiseasadiagnostictoolinthereproduc- in theevaluationofsubfertilemale,proteomicanalysis While wecontinuetorelyonconventionalsemenparameters bilateral varicocele. better optionsforclinicalmanagementofinfertilemenwith tion ofbilateralvaricoceleandinhelpingurologistsidentify These DEPsmayserveasusefulbiomarkersintheidentifica- disease andspermdysfunctioninthesepatients. TOM22, whichmay beresponsiblefortheseverityof with bilateralvaricocelehadunderexpressionofCLGNand of DEPsODF2,TEKT3,TCP11 andTGM4. Inaddition,men also translateintosignificantalterationandoverexpression species inmenwithbilateralvaricocele.Theseabnormalities sperm morphologyandelevatedlevelsofreactiveoxygen For thefirsttime,wehavedemonstratedsignificantlypoorer compared withthefertilecontrolgroupareshowninTable 1. function oftheDEPsingroupwithbilateralvaricocele details ofthegenename,proteinnameandspermatogenic Apolipoprotein A1wasuniquetothefertilegrouponly. The were underexpressedinthegroupwithbilateralvaricocele. drial importreceptorsubunitTOM22 homolog(TOM22) tamyltransferase 4(TGM4). Calmegin(CLGN)andmitochon- (ODF2), TEKT3,TCP11 andprotein-glutaminegamma-glu- 2 varicocele group.Thesewereouterdensefibersprotein tions, fourproteinswereoverexpressedinthebilateral Of thesevenproteinsinvolvedinreproductive-relatedfunc- binding ofspermtozonapellucida. sperm tailfilaments,motility,functionand related toreproductionand/orspermatogenesis,including with distinctfunctionalcategories.Ofthese,sevenwere Additional proteomicanalysisidentified12DEPsannotated Potential BilateralVaricocele Biomarkers toIdentify [email protected] or216.445.4473. or216.444.9485. [email protected]

M = moderate L = low VL = very low M =moderateLlowVLvery the proteomicprofileandgeneontologyannotationsforDEPs. H=high bilateral varicocelebasedonthenormalizedspectralcountsobtainedfrom controlsandmenwith lowabundance ofDEPs infertile dium, loworvery control groupversusbilateralvaricocelegroup.(C)Comparisonofhigh, me that areoverexpressed, underexpressed oruniquelyexpressed inthefertile are commonlyexpressed inbothgroups.(B)Protein abundanceofDEPs are uniquelyexpressed inthebilateralvaricocelegroupand58 proteins controlgroup,sevenproteins proteins areuniquelyexpressed inthefertile Figure 1.(A)Venn diagramofdifferentiallyexpressed proteins(DEPs). Eight

Number of proteins Number of proteins - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 43 Center for Reproductive Medicine Reproductive for Center

Table 1. Gene name, protein name and spermatogenic function of the DEPs in the group with bilateral varicocele compared with the fertile control group.

References

1. Sabanegh E Jr, Agarwal A. Chapter 21: Male Infertility. In: 7. Hamada A, Sharma R, du Plessi, SS, Willard B, Yadav SP, Wein AJ, Kavoussi LR, Novick AC, et al., eds. Campbell- Sabanegh E, Agarwal A. Two-dimensional differential in-gel Walsh Urology. 10th ed. Philadelphia: Saunders Elsevier; electrophoresis-based proteomics of male gametes in rela- 2011. tion to oxidative stress. Fertil Steril. 2013;99:1216-1226.

2. Esteves SC, Zini A, Aziz N, Alvarez JG, Sabanegh ES Jr, Agar- 8. Sharma R, Agarwal A, Mohanty G, Hamada AJ, Gopalan B, wal A. Critical appraisal of World Health Organization’s Willard B, et al. Proteomic analysis of human spermatozoa new reference values for human semen characteristics and proteins with oxidative stress. Reprod Biol Endocrinol. effect on diagnosis and treatment of subfertile men. Urology. 2013;11:48. 2012;79:16-22. 9. Sharma R, Agarwal A, Mohanty G, Du Plessis SS, Gopalan 3. Sharma RK, Sabanegh E, Mahfouz R, Gupta S, Thiyagarajan B, Willard B, Yadav SP, Sabanegh E. Proteomic analysis of A, Agarwal A. TUNEL as a test for sperm DNA damage in the seminal fluid from men exhibiting oxidative stress. Reprod evaluation of male infertility. Urology. 2010;76:1380-1386. Biol Endocrinol. 2013;11:85.

4. Kashou AH, Sharma R, Agarwal A. Assessment of oxi- 10. Agarwal A, Durairajanayagam D, Halabi J, Peng J, Levin dative stress in sperm and semen. Methods Mol Biol. MV. Proteomics, oxidative stress and male infertility. Reprod 2013;927:351-361. Biomed Online. 2014:29:32-58.

5. du Plessis SS, Kashou AH, Benjamin DJ, Yadav SP, Agarwal A. 11. Barazani Y, Agarwal A, Sabanegh ES. Functional sperm Proteomics: a subcellular look at spermatozoa, Reprod Biol testing and the role of proteomics in the evaluation of male Endocrinol. 2011;9:36. infertility. Urology. 2014;84:255-261.

6. Thacker S, Yadav SP, Sharma RK, et al. Evaluation of sperm proteins in infertile men: a proteomic approach. Fertil Steril. 2011;95:2745. Center for Endourology and Stone Disease 44 Urology &KidneyDiseaseNews practice hadnoinfluence. obtained theirownaccess,whilenumberofyearsin ogy wasasignificantdeterminantofwhetherurologists dourologists, however,fellowshiptraininginendourol- within thesurveyedpopulations.Insurveyofen- This disparitymaybeattributabletoinherentbiases obtained theirownaccess. tion, whichreportedthatonly11percentofurologists Central SectionoftheAmericanUrologicalAssocia- contrast toaprevioussurvey mately 76percent)obtainedtheirownrenalaccess,in found thatthemajorityofendourologists(approxi- while the patient is in supine position; subsequently while thepatientisinsupineposition; subsequently of aureteralaccesscatheterinto theipsilateralureter The classicantegradeapproach begins withplacement (Figure 2). percent) ofendourologistsfavoring theproneposition Patient positioning alsovaried,withthemajority(85 12 percentutilizedacombinedapproach(Figure1). proach, 19percentutilizedaretrogradeapproachand established accessusingtheclassicantegradeap- According tothesurveyofendourologists,68percent and acombinedantegrade-retrogradeaccess. cluding pureantegradeaccess,retrogradeaccess expertise inthefullrangeofavailabletechniques,- niques havebeenrefined.AtClevelandClinic,we stone removal,andovertheyears,varioustech- Obtaining theidealaccessisparamounttosuccessful UseAntegradeApproach Majority inSurvey A recentsurvey and thetractplacementmaynotbeideal. the patientmustundergotwoseparateprocedures, this approachcanbecumbersomeandinefficient,as the initialaccesspriortodilatingtract.Practically, Often, interventionalradiologistsareaskedtoobtain endourologists whoroutinelyperformthisprocedure. The approachtoobtainingrenalaccessvariesamong impact thesafetyandefficacyofstoneremoval. Sri Sivalingam,MD,MSc,FRCSC We Today? Are Where Nephrolithotomy: Percutaneous for Renal Access 1 of Endourological Society members ofEndourologicalSocietymembers of the procedure and can directly of theprocedureandcandirectly often themostchallengingpart obtaining renalaccess,whichis initial stepinthisprocedureis large renalstones>2cm.The is thecurrentgoldstandardfor Percutaneous nephrolithotomy 2 of members of the North ofmemberstheNorth tion and nephrolithotomy are performed. tion andnephrolithotomyareperformed. repositioned inalateraldecubitusposition,andtractdilata- tive nephrostomytubeplacement.Thepatientisthengently double-J ureteralstentisplaced,whichobviatespostopera- placed antegradeforthrough-and-throughrenalaccess.A the puncturewireisremoved.Astiffguidecanthenbe the wireuntilcatheteremergesthroughskin,and skin attheflank.Anassistantthengraspsandgentlypulls the catheterunderfluoroscopyuntilitemergesthrough calyx. Apuncturewireisthenadvancedretrogradethrough a Lawson™steerablecatheterisadvancedintotheoptimal Cystoscopy andretrogradepyelographyisperformed, upward andprepped. fied lowlithotomypositionwiththeipsilateralflankwedged prone positioning.Itisperformedwiththepatientinamodi- useful inanondistendedcollectingsystemandprecludes retrograde accesstechnique. We recentlydemonstratedsafetyandefficacywithapurely nephrostomy tube. formed. Postoperative drainageistypicallymaintainedviaa calyx isenteredandaccesssecured,tractdilatationper- guidance (triangulation/bull’seyetechnique),andoncethe needle (CookMedical;Bloomington,IN)underfluoroscopic ous access.Renal accessisobtainedwitha21-gaugeChiba the patientisrepositionedinpronetoestablishpercutane- the calyx of choice. the calyxofchoice. forms ureteropyeloscopyandnavigates theureteroscopeinto sheath withthepatientinprone position.Anassistantper- proach. Thisbeginswithplacement ofaureteralaccess A thirdtechniqueisacombined antegrade-retrogradeap- Details oftheCombinedApproach surgeon experienceandcomfort. approaches, thechoiceofwhichtouseshouldbebasedon With outcomesdatashowingcomparablesafetyforallthree available atClevelandClinic. Society, inallthreeaccesstechniquesis whileexpertise monly usedapproachbyurologistsintheEndourological Antegrade accesswithpronepositioningisthemostcom- grade orcombinedtechniques. Renal accessmaybeobtainedsafelybyantegrade, retro trained surgeons. majority ofcasesmanagedbyendourologyfellowship- Percutaneous renalaccessisobtainedbyurologistsinthe Key Points 3 This technique is especially Thistechniqueisespecially - More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 4545

The primary surgeon then utilizes an antegrade approach to References obtain access, by which the 21-gauge Chiba needle is placed 1. Sivalingam S, Cannon ST, Nakada SY. Current practices into the preselected calyx with the tip of the ureteroscope as in percutaneous nephrolithotomy among endourologists. the target, and needle entry is confirmed by direct visualiza- J Endourol. 2014;28(5):524-527. Disease Stone and Endourology for Center tion. A guide wire is then placed though the needle, and once visualized with the ureteroscope, the guide wire is grasped 2. Bird VG, Fallon B, Winfield HN. Practice patterns in the and brought out through the external urethral meatus, es- treatment of large renal stones. J Endourol. 2003;17(6):355- tablishing a through-and-through access. The tract is dilated 363. and nephrolithotomy is completed with the patient in prone 3. Sivalingam S, Al-Essawi T, Hosking D. Percutaneous nephro- position. A ureteral stent is often placed, without a nephros- lithotomy with retrograde nephrostomy access: a forgotten tomy tube, at the end of the procedure. technique revisited. J Urol. 2013;189(5):1753-1756. While each of these techniques has inherent advantages and disadvantages, the approach of choice must be based on surgeon experience and comfort. Although some variability in operative time, radiation exposure, patient positioning and postoperative drainage may exist, outcomes data show that all these approaches are safe. Further comparative evalu- ation of these techniques will help determine which is most efficacious in different clinical scenarios.

Dr. Sivalingam is an associate staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Depart- ment of Urology. He can be reached at [email protected] or 440.461.6430.

Figure 1. Percutaneous renal access approach Figure 2. Patient positioning for percutaneous for nephrolithotomy among endourologists.1 nephrolithotomy among endourologists.1 Center for Female Pelvic Medicine and Reconstructive Surgery 46 Urology &KidneyDiseaseNews ated with a statistically higher risk of progression. ated withastatisticallyhigherrisk ofprogression. the hymenwereonlybaseline factorsthatwereassoci- prolapse. MoresevereanteriorPOP andleadingedgebeyond vs. 81.7percent).Therewerenodifferences intermsofapical the leadingedgeofprolapsebeyondhymen(72.8percent degree ofanteriorcompartmentdescentandthepresence statistically significantlydifferentatbaselineinregardtothe sion (N=206)andprogression186).Thegroupswere We performed abaselinecomparisonbetweennonprogres- apical compartment. compartment, 74percentoftheprogressionsinvolved ments, respectively. Whentheleadingedgewasanterior and 23percentintheanterior,posteriorapicalcompart- ment progressionwasobservedin29.4percent,7.1percent regressed and43.8percentdidnotchange.Same-compart- progressed (meaningprolapseworsened),8.7percent median follow-upofninemonths,47.5percentpatients A totalof392patientsmettheinclusioncriteria.Witha risk factorsforprogressionbothgroups. follow-up examinationsasclinicallysignificant. We analyzed rior, apicalorposteriorcompartments)betweeninitialand the POP-QmeasurementsofeitherpointsBa,CorBp(ante- surgery) wereincluded.We definedchangesof≥±2cmin prolapse) duringfollow-up(stillawaitingsurgeryorpriorto two ormorePOP-Qexaminations(ameasureofdegree tween 2008and2013.Women withsymptomaticPOPhaving We evaluatedaprospectivecohortofpatientstreatedbe- Evaluation Process andFindings tors forprogression. progression withthosewhodidnot,andevaluatingriskfac- group ofpatients,comparingthepatientswhodeveloped prospectively describethenaturalevolutionofPOPinthis for Female Pelvic MedicineandReconstructive Surgery,we those inClevelandClinicDepartmentofUrology’sCenter the Pontificia UniversidadCatolicaofSantiago,Chile,and Working withcolleaguesattheSoterodelRioHospitaland on progressionofPOPinsymptomaticwomenareminimal. atic womenmaketreatmentdecisions.Unfortunately,data Goldman,MD,andJavierPizarro-Berdichevksy,Howard MD Pelvic Prolapse Progression Organ of Predictors b. to helpsymptom- (POP) canbeused organ prolapse gression ofpelvic factors forpro- baseline risk Knowledge of ment ofUrology. at Hecanbe reached - Dr. isaclinicalfellowin theDepart Pizarro-Berdichevksy [email protected] or216.445.5121. at Clinic LernerCollegeofMedicine.Hecanbereached and Patient Safety, ofMedicineatCleveland andaProfessor &KidneyInstitute’sVicealso theUrological ChairforQuality ofUrology. &KidneyInstitute’sDepartment Heis Urological Dr. GoldmanisastaffmemberofClevelandClinicGlickman professionals. this populationwillrequireincreasedresourcesandtrained eration ages.Inthecomingdecades,treatmentofPOPin number ofwomenatriskforPOPasthebabyboomergen- It alsohaspublicpolicyimplications,giventheincreasing women regardingthechancethattheirPOPwillworsen. year. Thisinformation canbeusedtocounselsymptomatic seeking treatmentwillhaveprolapseprogressionwithina percent ofwomenwithsymptomaticPOPwhoareactively In summary,ourresearchhasdemonstratedthatalmost50 chance ofprogressionisdoubled. partment. Whentheleadingedgeisbeyondhymen, percent ofthepatients’progressioninvolvesapicalcom- When theleadingedgeisanteriorcompartment,74 symptomatic POPisprogressionin47.5percentofpatients. lapse inpatientsactivelyseekingtreatment.Theevolutionof We describeforthefirsttimenaturalevolutionofpro- Implications POP EvolutionHasTreatment andPolicy twofold increaseinriskofprogression. edge beyondthehymenatbaseline,whichdemonstrateda The onlyvariablethatwasstatisticallysignificantleading • • • ing thefollowingvariablesforPOPprogression: We performedamultiplelogisticregressionanalysisinclud- with atwofoldincreasedriskofprogression. A leadingedgeofprolapsebeyondthehymenisassociated seeking treatmentapproaches50percent. The riskofprogressionpelvicorganprolapseinwomen Points Key Leading edgebeyondthehymen Active tobaccouse History ofhysterectomy [email protected]. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 47 Center for Female Pelvic Medicine and Reconstructive Surgery

Figure 1. Pelvic organ prolapse progression in symptomatic and asymptomatic patients.

Distribution and Homing of Bone Marrow-Derived Mesenchymal Stem Cells Following Postpartum Intraperitoneal Injection into LOXL1 Knockout Mice

Howard Goldman, MD, and Javier Pizarro-Berdichevksy, MD Key Points Delivery of stem Intraperitoneally injected mesenchymal stem cells home to cells may someday pelvic organs in an animal model of pelvic organ prolapse represent a treat- after simulated childbirth delivery, confirming that tissue ment option for injury plays a role in the homing of these cells. childbirth injury A semilocal route of stem cell administration may take and related disor- advantage of the capability of these cells to enable recovery ders, such as pelvic in areas of injury not accessible by local delivery. organ prolapse (POP). First, it must be determined whether stem cells home preferentially to pelvic organs after injection. There is increasing agreement that the strongest risk fac- POP is the downward descent of the pelvic organs that results tor for lifetime development of POP is vaginal childbirth, in a protrusion of the , vagina or both. It is a problem which can injure the nerves, muscles and supportive tissues that affects adult women worldwide across different cultures responsible for maintaining pelvic support. Obesity, and races. mellitus and advanced age are other major risk factors for About 12.6 percent of women will undergo surgery for POP by development of POP. With obesity on the rise, the incidence the age of 80 in the United States. Although not life-threaten- of POP is expected to substantially increase. ing, POP can be devastating to one’s quality of life. Center for Female Pelvic Medicine and Reconstructive Surgery 48 Urology &KidneyDiseaseNews system (theIVIS in thisPOPmodelusinganvivoandexcelltracking delivery. We areconductingastudytoverifystemcellhoming other animalinjurymodelsbutnotinLOXL1KO miceafter floor disorders.Homingofstemcellshasbeendescribedin These miceserveasavaluableanimalmodeltostudypelvic tissues ofLOXL1KO femalemice. cells (MSCs),areupregulatedafterdeliveryinthepelvicfloor kines, particularlythosethatattractadultmesenchymalstem Our researchalsodemonstratesthatstemcellhomingcyto- that increaseswithparityandage,asinhumans. oxidase like-1(LOXL1)knockout(KO) mousedevelopsPOP man Urological&KidneyInstitute,haveshownthatalysyl ment ofBiomedicalEngineeringandClevelandClinic’sGlick- research groupledbyMargotS. Damaser,PhD,oftheDepart- vic Medicine,togetherwithHowardB.Goldman,MD,anda MD, andBrunaCouri,fromtheSectionofFemale Pel- Cleveland ClinicresearchfellowsJavierPizarro-Berdichevksy, in homing. times viathesamereceptor-mediatedmechanismsinvolved sites ofinjury,wheretheyfacilitatetherepairprocess,some- the injuredtissuesattractorhomecirculatingstemcellsto childbirth-related injuries.Cytokinegradientsproducedby fore havethepotentialtobeharnessedfacilitaterepairof Stem cellsparticipateinnormalrepairprocessesandthere- Delivery Stem CellUpregulationAfter luciferase. luciferase. MA) thatmeasuresradianceemittedbycellsexpress a. ® Luminasystem;PerkinElmer, Waltham, b. ment ofUrology. at Hecanbereached - Dr. isaclinicalfellowintheDepart Pizarro-Berdichevksy [email protected] or216.445.5121. at Clinic LernerCollegeofMedicine.Hecanbereached and Patient Safety, andaProfessor ofMedicineatCleveland &KidneyInstitute’sVicealso theUrological ChairforQuality ofUrology. &KidneyInstitute’sDepartment Heis Urological Dr. GoldmanisastaffmemberofClevelandClinicGlickman delivery-related disorders,suchasPOP. could berelevantforfuturestemcell-basedtherapies diffuse injuryprovokedbytheparturitionprocess,ourresults not accessiblebyalocaldeliverymechanism.Assuming tion mayenablearegenerativetherapytoreachareasofinjury A semilocalcelldeliveryroutesuchasintraperitonealinjec- related cytokines,aswehavepreviouslyconfirmed. gina andurethraareinjuredbyparturitionsecreteinjury- and urethra.Thispreferentialhomingsuggeststhattheva- delivered intraperitoneallyhomepreferentiallytothevagina After vaginaldelivery,bonemarrow-derivedMSCsthatwere after injection. with nulliparousanimals.Nodifferenceswerenotedoneday homing inotherorgansfourdaysafterinjectioncompared after thestemcellinjection.Therewerenodifferencesin ing ofcellsinthevaginaandurethra,respectively,fourdays Ex vivoimagingdemonstrated5.8and3.3timeshigherhom- the pelvicregionafterpupdeliveryinthesemice. tion, respectively,indicatingpreferentialstemcellhomingto radiance oneandfourdaysaftervaginaldeliveryinjec- In vivocelltrackingdemonstratedathree-and6.5-foldhigher Cell Tracking ShowsPreferential Homing [email protected]. delivery mice. delivery in nulliparousandvaginal- injection and fourdaysafter mesenchymal stemcellsone ing ofbonemarrow-derived comparing preferentialhom- Figure 1.Invivoimaging More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 49

Kidney Transplantation at Cleveland Clinic: A Global Resource Center for Renal and Pancreas Transplantation

By Eric A. Klein, MD Key Points Chronic kidney disease (CKD) remains Cleveland Clinic has a half-century of experience perform- a formidable health problem affecting ing kidney transplants and has treated more than 4,340 26 million American adults. Millions patients. more are at risk due to type 1 diabetes Graft and patient survival statistics show expected or better- mellitus or hypertension, the primary than-expected outcomes compared with similar transplant causes of CKD. patients nationwide. Hemodialysis, a therapeutic technol- Process improvements have resulted in significantly reduced ogy pioneered by Cleveland Clinic with the establishment of wait times to transplant and shortened post-transplant the nation’s first program in 1950, has extended the lives of hospital stays. many patients with end-stage renal disease (ESRD). The kidney transplant program’s reach and impact is na- tional and international, with affiliate sites in three states Kidney transplantation, which Cleveland Clinic surgeons and the United Arab Emirates. were among the first to perform beginning in 1963, has provided additional survival and quality-of-life benefits for ESRD patients. Cleveland Clinic transplant surgeons participated in the second-largest paired kidney exchange to date, involving 56 A Half-Century of Achievement donors and recipients and 19 hospitals. More than 4,340 patients have received kidney transplants More than 90 percent of our living donor nephrectomies during the program’s half-century of operation. We celebrat- were performed laparoscopically — a technique we have em- ed 50 years of success in October 2013. One of the attendees ployed in more than 1,000 patients since 1997, including the was a former patient who received a kidney as a teenager in first single-port kidney removal in 2007 and the first robotic 1968 from her mother, making her kidney 91 years old. transvaginal nephrectomy in 2012. Our most recent one-year and three-year graft and patient To further assist with the organ shortage, our transplant survival statistics show expected or better-than-expected program has extended the use of the deceased donor pool via outcomes compared with predictive statistical models repre- pediatric en bloc and dual adult kidney transplantation. We senting similar transplant patients nationwide. also are conducting research intended to improve pretrans- Though the availability of donor organs continues to be plant prediction of risk of rejection and acute and chronic a limiting factor for all transplant programs, our volume allograft injury. We have instituted a waitlist intravenous remains substantial. In 2013 our Center for Renal Trans- immunoglobulin desensitization program to enhance trans- plantation at Cleveland Clinic’s main campus performed a plant opportunities for highly sensitized patients. record 184 kidney transplants, a 12 percent increase from the previous year, making us the busiest program in Ohio for the Wait-Time Improvements calendar year. We have streamlined the assessment process for transplant This growth in transplantation is due, in part, to an increase candidates, resulting in a significant reduction in the time in the number of living donor procedures. In 2013, 44 per- from patient referral to evaluation and evaluation to listing cent of Cleveland Clinic’s kidney-only transplants involved in the United Network for Organ Sharing (UNOS) registry. living donors. The entire process is now completed in less than 80 days. We have refined the pretransplant monitoring and preparation The acquisition of these organs is largely the result of a regimens as well, contributing to our center’s 36.3-month relationship begun in 2011 with the National Kidney Registry median wait time to transplant, compared with the UNOS (NKR) to facilitate paired donations. In 2013 Cleveland Clinic Region 10 and national averages of 40.7 months and 54.3 was the seventh largest NKR participant by volume among months, respectively, for patients listed between 2007 and 75 hospitals. This collaboration has enabled us to perform 2012 (Figure 1). more than 20 living-donor transplants that otherwise would not have occurred. Through this program, an incompatible Analysis of post-transplant data had shown that delayed graft donor’s kidney is procured in Cleveland and shipped to a function was a major factor in determining length of stay in matching donor elsewhere in the United States. In return, prior years. Improved management of the transition from Cleveland Clinic has received organs from as far away as Los hospital to outpatient enabled us to decrease patients’ mean Angeles. Locally unmatched altruistic donors make it pos- length of stay in 2013 to less than six days, the shortest dura- sible for extended chains of transplants to occur; in 2013 tion in the past four years (Figure 2). Center for Renal and Pancreas Transplantation 50 Urology &KidneyDiseaseNews Figure 1. Time to kidney transplant for waitlist patients. waitlist for transplant kidney to 1. Time Figure resource. resource. in August2013.Ourtransplantprogramistrulyaglobal City inAbuDhabi2007,andatClevelandClinicFlorida began atClevelandClinic-managedSheikhKhalifaMedical in morethan200transplantstodate.Renal transplantation with St.VincentIndianapolisHospitalin2009hasresulted transplants havebeenperformed.Asimilarcollaboration Charleston AreaMedicalCenter,wheremorethan1,000 man Urological&KidneyInstituteandWest Virginia’s (Figure 3),beginningin1987withtheallianceofourGlick- renal transplantprogramwellbeyondourmaincampus Cleveland Clinichasextendedthereachandimpactof Expanding Transplant Services TRANSPLANT LOCA CLEVELAND CLINIC KIDNEY

INDIANAPOLIS INDIANAPOLIS HOSPITA ST . VINCENT INDIANA TIONS L, WESTO FLORID CLEVELAND CLINIC FLORI , A, DA OHIO CLEVELAND CLEVELAND CLINIC, M WEST VIRGINIA CHARLEST C N, HARLEST EDICAL CENTER, ON AREA

ON , Figure 2. Hospital mean length of stay for kidney transplant patients. transplant kidney for stay of length mean Hospital 2. Figure A M S HEIKH KHALIF EDICAL CITY, BU DHABI,UA A E 216.444.5591. [email protected] or lege ofMedicine.Hecanbe Cleveland ClinicLernerCol at ofSurgery and Professor &KidneyInstitute Urological Cleveland Clinic’sGlickman Dr. KleinisChairmanof - 51 Center for Renal and Pancreas Transplantation

± = 0.02) for low T (Figures 1 and = 0.003), three-year patient survival = 0.008), one-year graft survival (62.5 = 0.01) than those whose T had normalized. p Key Points Key reduced levels of serum testos- In men with renal disease, an increased mortalityterone are associated with risk com- levels. pared with higher testosterone level following kidney transplantA low serum testosterone of death and graftpredicts an increased risk loss. in these settings is a targetWhether low serum testosterone replacement therapy requiresfor treatment with testosterone study. More articlesMore at ConsultQD.clevelandclinic.org/urology-nephrology online 251.3) and was low (< 220 ng/dL) in 24 patients. in 24 251.3) and was low (< 220 ng/dL) Potential Low T’s Disease Marker patient sur- Low T transplant recipients had worse one-year vival (75 vs. 95 percent, p (62.5 vs. 86.1 percent, p vs. 92.4 percent) and three-year graft survival (50 vs. 76.3 per- cent, Survival curves showed significantly worse patient survival (p = 0.004) and graft survival (p 2). In multivariable analysis, low T was independently associ- ated with patient death (HR 2.27, 95% CI 1.19-4.32) and graft loss (HR 2.05, 95% CI 1.16-3.62). As we have shown in these two studies, there may be a unique opportunity to study low T and TRT in men with renal dys- function and renal transplantation, both as a marker for disease severity and as a target for TRT. Clinic Glickman Shoskes is a staff member of Cleveland Dr. Urological & Kidney Institute’s Department of Urology and of Surgery He is a Professor Center. at of the Transplant Cleveland Clinic Lerner College of Medicine. He can be reached at 216.445.4757. Given the negative impact of low T on survival in renal dis- Given the negative impact of low T on survival T on renalease, we next wished to study the effect of low utilized We transplant patient survival and graft survival. have seruma quick and convenient resource: All patients for use ifcollected and frozen on the day of their transplant needed in future immunologic testing. in male patients transplanted identified such samples We T and retro- six to 10 years ago, and were able to measure during thespectively correlate it with the clinical outcomes subsequent five years. with suf- There were 197 male renal transplant recipients Patients ranged in age from 14 ficient serum to run the assay. living and 97to 75 years (mean 48.9 years). There were 100 recipients weredeceased donors, and 53 (27 percent) of the (mean 477 diabetic. Serum T ranged from 48 to 2,013 ng/dL

). 2 The diagnosis of low testosterone (T)The diagnosis of low testosterone of testoster- and the risks and benefits (TRT) remainone replacement therapy controversial. for TRTWhile established guidelines years havedo exist, the past several forseen an explosion in prescriptions Examining Low T’s Effect on Survival The next obvious question is whether low T is a marker of other illness or disease burden or whether it is actually a mechanistic target that can be treated with TRT to improve survival. This is still an open question. transplant, men with low T com- successful kidney Following monly have their T levels normalize. Many do not, however, especially if they are diabetic. (but who are not yet on dialysis), we used the Cleveland Clinic(but who are not yet on dialysis), we used the focusing on men Chronic Kidney Disease (CKD) Registry, filtration ratewith CKD stages 3-4 (estimated glomerular [eGFR] 15 to 59 mL/min/1.73 m Few studies have looked at TRT in renal failure and disease. Few explore the impact of low T in men with renal disease To Querying Registry the Chronic Kidney Disease TRT, with the majority of men lacking the clinical and labora- the majority of men lacking the clinical with TRT, to guide safe and effective treatment.tory testing necessary physicians andThe surge in TRT has led to a backlash from agingpayers against TRT use, especially for the stereotypical male trying to regain lost youth. with low TBy contrast, there are at-risk patient populations and prolongin whom TRT has the potential to both improve HIV/AIDS, life. Low T is particularly common in men with and is associatedtype 2 diabetes and end-stage renal disease, with poor survival in those with these diseases. associat- Indeed, for men on dialysis, low T is independently TRT hased with death within three years. In type 2 diabetes, prolong life.been shown to improve glucose control and Daniel A. Shoskes, MD, MSc, FRCSC Daniel A. Shoskes, MD, Impact of Low Testosterone in Renal Disease and Kidney Transplantation Kidney and Disease Renal in Testosterone Low of Impact CI 1.12-2.19, respectively). We identified 2,633 such men in the database who had a We serum T measurement. Low T was identified in 54 percent and was more likely with lower eGFR, diabetes and a higher body mass index. In a multivariable Cox analysis, when com- the two ng/dL), pared with the highest quintile (T 512 to 7,469 lowest quintiles of T (100 to 225 ng/dL and 226 to 301 ng/dL) were associated with significantly higher mortality (HR 1.70, 95% confidence interval [CI] 1.21-2.39, and HR 1.56, 95% 52 Urology & Kidney Disease News

Figure 1. Renal transplant patient survival comparing low and normal T levels. Center for Renal and Pancreas Transplantation Pancreas and Renal for Center

Figure 2. Renal transplant graft survival in patients with low and normal T levels. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 53

A Surgical Approach to Patients with Intractable Nephrolithiasis Center for Robotics and Image Center for Renal and Pancreas Transplantation Stuart M. Flechner, MD, FACS, and Mark Noble, MD Key Points Kidney stone A proportion of patients with intractable nephrolithiasis disease or nephro- experience narcotic dependence. lithiasis is com- With careful patient selection, renal autotransplantation and mon, with nearly pyelovesicostomy may offer those with intractable nephro- 1 in 11 individu- lithiasis the opportunity for resolution of chronic pain and als in the United fewer subsequent stone treatment procedures. States experienc- ing a stone event at some point in their lives. In addition, at least 50 percent of individuals experience another stone Although this surgical approach alters the anatomy and abil- within 10 years of the first occurrence. ity to pass subsequent stones, it would not alter the meta- A small subset of these patients has identified metabolic bolic derangements that cause stone formation. abnormalities that cause a wide spectrum of stone events Candidates for this procedure undergo the following assess- ranging from the spontaneous passage of small stone debris ments (Figure 2): or gravel, causing minor symptoms, to frequent, painful –

• Rigorous evaluation of prior treatments and metabolic Guided Surgery calculi that do not pass easily, sometimes resulting in sepsis testing and loss of renal function. • Renal function testing The etiology of these metabolic stone diseases includes calcium oxalate, cystinuria, , calcium • Assessment of vascular and urologic anatomy oxalate and , and . The • Pain management evaluation with attempts to perform more severely afflicted patients require frequent radiologic nerve blocks and confirm the visceral localization of the imaging of the urinary tract plus a variety of urologic inter- chronic pain ventions including ureteral stents, nephrostomy tubes and percutaneous nephrostolithotomy, extracorporeal shock • Transplant psychiatric assessment to confirm any wave lithotripsy, ureteroscopy with lithotripsy, or open surgi- substance abuse, or psychiatric conditions, cal extraction of stones. Some patients report passing more and to quantify the degree of psychological disruption than 70 stones during their lives. caused by the intractable nephrolithiasis

For many of these patients, standard treatments will be Patients are selected for this approach only if there is a high inadequate to control the burden of their stone-related likelihood of successful rehabilitation and future medical symptoms. Such patients may become dependent on chronic compliance and follow-up. narcotics for pain relief, and for many, the metabolic stone burden becomes the driving force in their lives, interfering Autotransplantation Resolves Pain, Reduces with daily activities, family life and well-being. Treatment Rate

Surgery Alters Anatomy to Pass Stones During the past nine years, we have autotransplanted 28 kidneys in 22 patients (six bilateral), with resolution or im- To address the problem of intractable metabolic stone dis- provement in chronic pain in all. About half of these patients ease with narcotic dependence, we offer patients a surgical continue to pass stone gravel that is usually painless. About option of replacing their , which is the narrow point in one-third have had a subsequent procedure to remove a stone the urinary tract that causes most of the symptoms during during a five-year interval. However, the stone treatment rates, stone passage. We remove the kidney and all visible stones, even in those with cystinuria, were dramatically reduced from perform a renal autotransplantation, and create a bladder as many as 10 procedures a year to less than one every few tube, or modified pyelovesicostomy, to permit subsequent years. The preoperative mean estimated glomerular filtration passage of stone debris (Figure 1). rate was 77.2 cc/min; postoperatively it was 73.5, 71.9 and 79.2 It was anticipated that the procedure would result in (1) renal cc/min at 12, 36 and 60 months, respectively. denervation to reduce pain, (2) near complete removal of None of these procedures was performed for the sole pur- stone debris while the kidney was ex vivo, (3) replacement of pose of stone removal. This aggressive surgical approach the ureter with a wide channel for future stone passage and should be limited to carefully selected patients who meet (4) creation of an easier route to the kidney with endoscopic strict criteria and for whom success can be reasonably instruments if needed. In theory, vesicorenal reflux to wash predicted. Proper selection requires a team approach for out small stone granules would also likely occur over time. the evaluation of candidates, including urologic surgeons, 54 Urology & Kidney Disease News

physicians, nurses, pain management specialists and psy- Additional Reading chiatrists. Flechner SM, Noble M, Tiong HY, Coffman KL, Wee A. Re- Renal autotransplantation and pyelovesicostomy can offer nal autotransplantation and modified pyelovesicostomy patients with intractable metabolic stone disease the op- for intractable metabolic stone disease. J Urology. 2011; portunity to improve their quality of life and decrease daily 186:1910-1915. narcotic use. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical manage- Dr. Flechner is a staff member of Cleveland Clinic’s Glick- ment of kidney stones; AUA Guideline, 2014. Available at: man Urological & Kidney Institute and of the Transplantation http://www.auanet.org/common/pdf/education/clinical- Center. He is a Professor of Surgery at Cleveland Clinic guidance/Medical-Management-of-Kidney-Stones.pdf Lerner College of Medicine. He can be reached at [email protected] or 216.445.5772.

Dr. Noble is Surgical Director of Stone Disease at the Glickman Urological & Kidney Institute. He can be reached at [email protected] or 216.445.8501.

Pyelovesicostomy incorporating the and upper ureter Center for Renal and Pancreas Transplantation Pancreas and Renal for Center

Figure 1

Figure 1. Renal autotransplantation to the iliac Figure 2 fossa and creation of a modified pyelovesicostomy for subsequent stone passage. Figure 2. Evaluation of patients with intractable nephrolithiasis. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 55

Dialysis Therapies and Cleveland Clinic: Bringing Patients Back Home Center for Dialysis for Center for Robotics and Image Sheru Kansal, MD, and Leslie Wong, MD Key Points Home dialysis Misconceptions about home hemodialysis have hampered therapies, which its acceptance in the United States. include peritoneal Education about hemodialysis modalities and opportunities dialysis (PD) and to interact with patients on home therapies play a large role home hemodi- in facilitating home hemodialysis as a choice and optimizing alysis (HHD), have outcomes. traditionally been underutilized in the United States. The majority of American patients with end-stage renal disease (ESRD) — about 92 the Centers for Medicare & Medicaid Services has changed percent — are treated with center-based intermittent (thrice- reimbursement for dialysis providers to incentivize home weekly) hemodialysis (IHD), compared with 6 percent for PD therapies. and 2 percent for HHD. Through various educational programs and care coordina- Worldwide, PD utilization is almost twice that of the United tion, Cleveland Clinic has been able to increase its utiliza-

States. tion of home therapies significantly in the past few years. – Our HHD program, established in 2010, is the largest in Guided Surgery Myths and Realities of Renal Replacement Northeast Ohio and offers patients the options of short daily Therapies therapy or frequent extended hemodialysis. We have trained 18 patients during the past four years, of which 13 remain on Misconceptions are partially to blame for this underutilization therapy to date. of home therapies. Historically, PD has been viewed as the therapy of choice for the young and otherwise healthy, since Our PD program has also seen extraordinary growth during patients are responsible for performing the dialysis them- the past couple of years. Currently, Cleveland Clinic’s De- selves. Also, patients with diabetes have typically been advised partment of Nephrology and Hypertension provides care to to avoid PD since it involves increased glucose exposure. almost 60 patients on PD, spread across three units. One of these units, Ohio Home Dialysis, is the single largest PD unit Similar misconceptions have hampered the growth of HHD, in the region. particularly the notion that patients require a high level of intelligence to be successful on HHD, as well as the fear of Our successes are largely due to our commitment to patient catastrophic complications. Although observational studies education. Studies suggest that patients who undergo educa- lend credence to some of these notions, the reality of renal tion about the different hemodialysis modalities are more replacement therapy in the United States is that 80 percent likely to choose home therapies. Our department is well of patients who start on IHD use a central venous catheter. ahead of the curve in referring patients to dialysis modality These catheters are associated with numerous complications education — almost 50 percent of patients who begin dialy- and contribute markedly to morbidity and mortality. (On p. sis in our care have undergone modality education prior to 56 of this issue of Urology & Kidney Disease News, we outline starting, compared with about 20 percent nationally. an innovative new program being implemented at Cleveland Furthermore, when patients attend dialysis education, they Clinic to help decrease the use of central venous catheters are more likely to actually start on PD. In the first half of 2014, through increased utilization of PD.) 65 percent of patients who attended modality education actu- Another reality of renal replacement therapy is that the ally started on PD, compared with about 20 percent nationally. model of thrice-weekly hemodialysis is fraught with issues With a preponderance of evidence to suggest that dialysis that increase morbidity and mortality. Aggressive ultrafiltra- education is imperative to good outcomes, we have taken fur- tion (which is common for patients on IHD) is associated ther steps to educate our patients. We invite those who have with myocardial stunning and increased mortality. Also, the expressed interest in home therapies to a quarterly seminar. seven-day week necessitates a two-day skip every week, which During these seminars, patients meet the home therapy staff is associated with increased mortality compared with the rest and are exposed to aspects of home therapies that are un- of the week. available during educational classes. More important, they are able to talk to patients currently Bolstering the Utilization of Home Dialysis on home therapies. This discussion provides an invaluable Therapies opportunity for patients to ask questions and receive insight The realities described here underlie a growing movement from those with hands-on experience. to get more patients on home therapies for ESRD. In fact, 56 Urology & Kidney Disease News

Dr. Kansal is a staff member of Cleveland Clinic Glickman Dr. Wong is a staff member of the Department of Nephrology Urological & Kidney Institute’s Department of Nephrology and Hypertension. He can be reached at [email protected] or and Hypertension. He can be reached at [email protected] 216.445.0673. or 216.444.0026.

Urgent-Start Peritoneal Dialysis at Cleveland Clinic: A Multidisciplinary Approach

Leslie Wong, MD; Sheru Kansal, MD; and Dustin Thompson, MD Key Point Center for Dialysis A collaborative effort by nephrologists, interventional radi- ologists, surgeons, nurses and a national dialysis provider is leading the way to increased use of peritoneal dialysis for the treatment of . This effort has the potential to help patients avoid the complications associated with the use of central venous hemodialysis catheters.

Patients with end-stage renal disease (ESRD) who present to cycle of reliance on central venous hemodialysis catheters to the hospital and require urgent initiation of dialysis (defined treat ESRD patients who require unplanned dialysis initiation. as the need for dialysis within two weeks of presentation) almost always begin treatment with a central venous hemo- Urgent-start PD involves the timely placement of a PD cath- dialysis catheter. eter instead of a hemodialysis catheter, followed by supine, low-volume PD to reduce the risk of dialysis fluid leakage and Use of central venous hemodialysis catheters is strongly associ- complications. ated with bloodstream and reduced survival in ESRD. Despite these known risks, there is usually no alternative to a This approach has been employed in Europe for many years central venous catheter and hemodialysis in this setting. and has recently been successfully adopted by some U.S. centers. Widespread adoption of urgent-start PD is limited, PD Averts Infection Risk but Normally Requires however, by infrastructure barriers and lack of experience Wait with and knowledge about PD at many institutions. Led by nephrologists at Cleveland Clinic, a multidisciplinary Peritoneal dialysis (PD) is a viable but underutilized treat- task force was created that included interventional radiol- ment for patients who require urgent initiation of dialysis. ogy, surgery and nursing stakeholders interested in reducing Unlike hemodialysis, PD does not involve use of a central the use of central venous hemodialysis catheters for ESRD venous catheter and is largely free of risk for bloodstream patients. infection. Using established best practices in PD catheter placement PD is performed by inserting a silicone PD catheter into the and dialysis care as guidelines, the task force created a pro- abdominal cavity, where a sterile dialysis solution is instilled tocol to identify and educate patients and provide them with and drained to remove waste products and excess fluid via the option of urgent-start PD instead of default hemodialysis ultrafiltration across the peritoneal membrane. via a central venous catheter. Traditionally, a minimum wait period of two weeks after PD This protocol includes clear steps that outline the process catheter insertion is required to allow healing of the catheter of referral, patient selection and communication between exit site to avoid dialysis fluid leakage and infection. The different caregiver teams. Additionally, the protocol includes availability of operators skilled or interested in placing PD explicit roles and responsibilities for interventional radiolo- catheters is limited. gists and surgeons involved in PD catheter placement and The wait requirement to start dialysis and the lack of support care. Order sets and a visual urgent-start PD guide were devel- for timely PD catheter insertion at many hospitals have dis- oped to facilitate education and understanding by nursing couraged PD use despite its potential to avoid bloodstream staff and physicians about the desired process of care. infection. PD nurses from Fresenius Medical Care (FMC), a national dialysis provider affiliated with Cleveland Clinic, were given Urgent-Start PD Is Promising but Faces Barriers hospital vendor privileges to facilitate planning for tran- Recently, a modified technique known as urgent-start PD has sitioning patients from the hospital to the outpatient PD gained interest in the United States as a means to break the setting in a safe and appropriate manner. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 57

A Defined Protocol for Urgent-Start PD Care We recently implemented the Cleveland Clinic urgent-start PD program and created a PD research registry to track Instead of relying on central venous catheters, patients need- patient outcomes. Our experience suggests that through a ing urgent dialysis who meet defined selection criteria can dedicated multidisciplinary approach, efforts to promote PD now be offered urgent-start PD. in appropriate patients will help reduce use of central venous

Candidate patients are identified and referred to a core team hemodialysis catheters and their associated complications. Dialysis for Center of expert physicians and nurses for evaluation. If the patient has no contraindications, the core team approves initiation Dr. Wong is a staff member of Cleveland Clinic Glickman of the urgent-start PD protocol. Specialists in interventional Urological & Kidney Institute’s Department of Nephrology place the PD catheter, and a standard supine PD and Hypertension. He can be reached at [email protected] or prescription and exit site care pathway are implemented. 216.445.0673. Patients and their families receive additional education and Dr. Kansal is a staff member of the Department of Nephrology support to help them adjust to dialysis. and Hypertension. He can be reached at [email protected] If the PD catheter malfunctions, the surgical service is con- or 216.444.0026. sulted for timely revision. After patients have been stabilized, Dr. Thompson is an associate staff member of Cleveland they are discharged to an affiliated FMC dialysis unit to con- Clinic’s Department of Diagnostic Radiology. He can be tinue urgent-start PD treatment until the PD catheter site has reached at [email protected] or 216.444.2136. healed sufficiently for standard home dialysis training.

Figure 1. Diagram illustrating Cleveland Clinic’s urgent-start PD program process flow.

Figure 2. Interventional radiologist Dustin Thompson, MD, demonstrates PD catheter placement on a training model.

Figure 3. PD catheter prior to insertion into the abdominal cavity. Note the stenciled markings placed by the interventional radiologist to ensure proper catheter and exit site location. 5858 Urology & Kidney Disease News

The Changing Paradigm of Management of Children with Vesicoureteral Reflux

Jeffrey Donohoe, MD, and Audrey Rhee, MD Key Points The past 12 years An individualized approach to managing pediatric vesico- have seen several ureteral reflux (VUR) considers the history of renal scarring paradigm shifts in and risk of VUR to guide diagnostic study. The individual- the management ized strategy can reduce the number of unnecessary voiding of children with fe- cystourethrograms performed and may identify those who require continuous antibiotic prophylaxis and subsequent brile urinary tract definitive surgical treatment. (UTI) and vesicoureteral reflux (VUR), including but not limited to: Antibiotic prophylaxis for VUR should be reserved for chil- dren at increased risk of developing and renal • The use of continuous antibiotic prophylaxis (CAP) and scarring. the emergence of antimicrobial resistance (AMR). • The use of minimally invasive endoscopic techniques

Center for Urology Pediatric such as dextranomere/hyaluronic acid. This concern led to the 2011 American Academy of Pediatrics • The use of laparoscopy and robotic surgery. policy statement regarding VUR, which states that children with a first febrile UTI do not require VCUG and that a renal • Reconsideration of whether a voiding cystourethrogram ultrasound can be obtained instead. If further UTIs ensue, (VCUG) should be employed after a first febrile UTI in VCUG may then be warranted. Primary care practitioners an infant. were inclined to follow such guidelines because parents abhorred VCUGs, and they and the practitioners were con- Historically, children with febrile UTIs underwent a VCUG cerned about prophylaxis-related AMR. to determine if they had VUR. The purpose of this practice was to identify children who were at risk for progressive renal Without an early VCUG, urologists were concerned that they scarring, hypertension and, ultimately, renal demise from would not identify renal infections in a timely fashion, lead- . ing to progressive renal scarring, and thus reverting to a time when children presented with hypertension and chronic Children thus diagnosed were subsequently placed on CAP renal failure due to reflux nephropathy. to keep the urine sterile while the tincture of time deter- mined whether the VUR would resolve spontaneously during Meta-analysis of VUR studies further indicated that perhaps a defined period. not all VUR patients initially require antibiotic prophylaxis unless additional confounding factors, such as bladder and Many concerns have been raised regarding CAP, the most bowel dysfunction, abnormal renal sonograms, or pre-exist- pertinent of which pertains to its inappropriate use leading ing medical conditions are present. This is especially true for to AMR. lower grades of non-dilating VUR, which are at reduced risk The advent of endoscopic treatment with the copolymer dex- of causing progressive renal scarring and are more likely to ® tranomere/hyaluronic acid (Deflux ) provided a minimally resolve spontaneously. invasive outpatient procedure that could correct the reflux, A more recent study known as the Randomized Intervention thus avoiding reconstructive surgery and precluding the use for Children with Vesicoureteral Reflux (RIVUR) trial has of CAP. concluded that the use of antibiotic prophylaxis does prevent However, long-term success rates of Deflux do not consis- recurrent UTIs but does not necessarily prevent renal scarring. tently match those of open surgery. In addition, peculiar long-term sequelae are related to the Deflux implant, the Individualized VUR Treatment Plans significance of which has not been clearly determined (i.e., chronic intramural bladder calcifications). At Cleveland Clinic’s Glickman Urological & Kidney Institute, pediatric urologists employ a specific individualized treat- Should Low-Grade VUR Be Diagnosed? ment plan for each VUR patient. It is based on information gleaned from meticulous history-taking, including a detailed Also called into question is whether all children with VUR, bladder and bowel elimination history; specific information particularly low-grade VUR, should have been diagnosed about the urine culture results, including the actual organ- in the first place. Some believe that since low-grade VUR is ism and how the culture was obtained; and the clinical sce- more likely to resolve spontaneously, perhaps we should not nario regarding the first febrile UTI. treat or even diagnose low-grade VUR, considering the poten- tial for long-term antibiotic use to lead to AMR. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 59

We reserve the option to start CAP in infants and children Dr. Donohoe is an associate staff member in Cleveland younger than 2 if it is likely that they presented with pyelo- Clinic Glickman Urological & Kidney Institute’s Department . We believe that by employing this individualized of Urology. He can be reached at [email protected] clinical approach, we can exclude false positives, reduce the or 216.636.9483. Center for Pediatric Urology for Center number of unnecessary VCUG studies and perhaps correctly Dr. Rhee is an associate staff member of the Department identify those who do require CAP and subsequent definitive of Urology and of Cleveland Clinic Children’s and the Pe- surgical treatment as necessary. diatric Institute. She can be reached at [email protected] or We consider a top-down approach in which a VCUG is per- 216.636.9483. formed only if a prior dimercaptosuccinic acid (DMSA) study Additional Reading confirms renal scarring and only in subsets of patients who we believe are at reduced risk of having VUR but whose clini- Yankovic F, Swartz R, Cuckow P, et al. Incidence of Deflux® cal scenario compels us to perform a diagnostic study. calcification masquerading as distal ureteric calculi on We also believe that antibiotic prophylaxis should be re- ultrasound. J Pediatr Urol. 2013;9(6 Pt A):820-824. served for children at increased risk of developing pyelone- Smellie JM, Barratt TM, Chantler C, et al. Medical versus surgi- phritis and renal scarring: those with dilating grades of VUR cal treatment in children with severe bilateral vesicoureteric (grades 3-5) of those with low-grade reflux in children who reflux and bilateral nephropathy: a randomised trial. Lan- have bowel/bladder dysfunction or abnormal renal sono- cet. 2001;357:1329-1333. grams. Through judicious use of CAP, we aim to lower the potential for the development of AMR. We consider Deflux The RIVUR Trial Investigators. Antimicrobial prophylaxis for as a tool for children with low to moderate grades of VUR in children with vesicoureteral reflux. N Engl J Med. 2014; whom medical therapy with CAP has failed and who cannot 370:2367-2376. undergo definitive surgical repair. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, We advocate an open ureteral reimplant, either intra- or Walk ER. Imaging studies after a first febrile urinary tract in- extravesical, as the primary mode of treatment in patients fection in young children. N Engl J Med. 2003; 348:195-202. who have breakthrough UTIs despite medical therapy with Subcommittee on ; Roberts KB. CAP. By employing precise surgical techniques to achieve an 2009–2011; Urinary tract infection: clinical practice guide- obliquely traversing, sufficiently long, intramural ureter, us- line for the diagnosis and management of the initial UTI ing coaptation of the intramural ureter via a flap valve mech- in febrile infants and children 2 to 24 months. Pediatrics. anism, we can definitively prevent VUR and progressive renal 2011;128(3):595-610. scarring. Despite the considerable advances in laparoscopic robotic surgery, we adhere to the standard of a ureteral re- implant performed via an open extraperitoneal approach through a 5 cm Pfannenstiel incision, which significantly reduces potential morbidity.

Using a Tactical Approach

The treatment of VUR remains somewhat nebulous. Urolo- gists for the past 12 years have fluctuated on a treatment spectrum because they are not truly sure which patients are being helped, even with newly available treatment tech- niques. Although guidelines have been instituted by our governing bodies, these do not truly identify those patients who are at increased risk. We have carefully reviewed and considered present guide- lines and recommendations, which cannot be used to man- age unique patients, and we are mindful of the past, when reflux nephropathy presided. We believe that a tactical indi- vidualized approach brings Cleveland Clinic pediatric urolo- gists to the forefront in identifying patients at increased risk for long-term sequelae of VUR, and in providing definitive treatment. 6060 Urology & Kidney Disease News

Transitional Urology Prepares Patients with Congenital Genitourinary Problems for Adult Care

By Hadley Wood, MD Key Points Defects in the genitourinary tract are Improvements in pediatric treatment are enabling more among the most common congenital children with congenital genitourinary defects to survive problems. Affected children can have into adulthood, raising the need for an eventual transition to problems such as abnormal size, shape adult-centered medical care. or location of their genitals or lack of Transition can take several years and requires agreement of proper function. They may be missing all parties involved, coordination, and readiness and needs reproductive organs or have duplicates assessment. of an organ. Patients with neurological conditions such as The adult-centered urologist who assumes oversight of a cerebral palsy or spina bifida often have substantial urologi- young patient with congenital genitourinary anomalies must cal comorbidity. be prepared to deal with complex and wide-ranging medical issues. During youth and adolescence, these patients typically are treated by pediatric specialists, including pediatric urolo- Center for Urology Pediatric gists, who primarily focus on renal deterioration, inconti- After the patient has begun seeing the adult provider, pedi- nence and genital appearance. atric providers should follow up to confirm the transfer of Improvements in pediatric care have enabled more patients care has occurred, answer any questions and offer ongoing with genitourinary defects to survive into adulthood and have consultation services as needed. a higher quality of life. As they grow older, many patients are better served by being transitioned into adult-centered care. Forgoing Transition Can Be a Mistake Such a transition can allow physicians to focus on the medi- cal, psychosocial and educational aspects of these patients’ Simply transferring these patients into any adult urology unique maturation issues, such as sexuality, fertility or post- practice can be a mistake, as adult providers often do not pubertal genital function and appearance. have specialty expertise in congenital anomalies or the clini- cal resources to treat these very complex patients. Transi- Timing of the Transition tional urology and urological congenitalism often require an approach more akin to geriatrics or palliative medicine, Pediatric specialists have an integral role in deciding when since the patient has many competing medical issues that to begin transitioning patients and helping them make the must be considered to achieve optimal outcomes. change. In some cases, they remain an important part of the Diagnoses that fit into this category include: patient’s healthcare team even after transition has occurred. • Myelomeningocele (spina bifida) I am often asked when transition should begin. My typi- cal answer: “When everyone is ready.” Transition requires • Exstrophy agreement from all parties involved — the patient, his or her • Hypospadias personal caregivers and the providers. The process can take several years, so starting as early as age 12 allows ample time • Disorders of sexual differentiation (intersex) for full readiness by age 18 to 20. Many pediatric facilities do • Posterior urethral valves not permit patient admission beyond the age of 24 or 26, so • Pediatric cancer this often represents the upper age limit for transition. • Problems such as muscular dystrophies that affect the Transition typically involves a stepwise process in which urological system with progression of age pediatric providers regularly assess their patient’s readiness. Factors to consider include a patient’s cognitive level and These patients are not typical new consults. Initial examina- ability to assist in his or her care, as well as whether the pa- tions can be difficult and may need to be conducted under tient’s urological issues are of an adult nature, such as those anesthesia to define the anatomy thoroughly. These patients relating to sexual activity or pregnancy. often have been heavily dependent on family members for Pediatric providers should document their readiness assess- daily care, so taking a history may require two interviews: one ment findings and initiate conversations with all involved with the caregivers present and one with them outside the about the optimal timing for transition. They should help the exam room. As these patients begin to assume a decision- youth identify an appropriate adult provider and, after ob- making role after a lifetime of others being in charge of their taining consent, communicate with that provider about the care, be aware that the change may cause some tension for pending transfer of care and share medical records. patients and their caregivers. More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 61

Assessing Patients’ Needs, Goals CONDITIONS THAT TRANSITIONAL UROLOGISTS TREAT Patients often present with a single focus of interest, such as erection quality, whereas I may • Urinary incontinence be more concerned with other urological issues • Catheterization problems, including stomal stenosis or urethral Pediatric Urology for Center that seem more critical, such as worsening hy- strictures dronephrosis. Addressing both takes time and, • Penile curvature with erections sometimes, careful negotiation. • Abnormalities of penile appearance After gathering a full medical history, I perform a thorough baseline assessment of patients’ • Problems resulting from abnormal vaginal development urological health and ask about their goals and • Renal insufficiency due to kidney scarring how their urological issues affect their quality of life. Together, we begin to map out treatment • Kidney stones plans. • Increased risk These are a few highlights of what transitional urology offers and how it can be a valuable • Male and female infertility resource for pediatricians and pediatric urolo- • Hernias from prior surgeries gists with young adult patients whose needs have expanded beyond those of childhood. • Chronic from neurogenic bowel Pediatric providers are a key component in making the transition a success, by helping lay its groundwork, perceiving the patient’s readi- ness for the change, and connecting the patient with the right provider for the next phase of his or her life.

Dr. Wood is a staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Center for Genitourinary Re- construction and an Assistant Professor of Surgery at Cleve- land Clinic Lerner College of Medicine. She can be reached at [email protected] or 216.444.2146.

Figure 1. Relative importance of urologic and health issues throughout the life span of a patient with myelomeningocele.

6262 Urology & Kidney Disease News

Resources for Physicians Physician Directory 24/7 Referrals clevelandclinic.org/staff Referring Physician Center Same-Day Appointments and Hotline To help your patients get the care they need, right away, 855.REFER.123 (855.733.3712) have them call our same-day appointment line, clevelandclinic.org/refer123 216.444.CARE (2273) or 800.223.CARE (2273). Live help connecting with our specialists, Track Your Patients’ Care Online scheduling and confirming appointments, and resolving service-related issues. Establish a secure online DrConnect account at clevelandclinic.org/drconnect for real-time information Physician Referral App about your patients’ treatment. Download today at the Critical Care Transport Worldwide App Store or Google Play. To arrange for a critical care transfer, call 216.448.7000 or 866.547.1467. clevelandclinic.org/criticalcaretransport.

Outcomes Data View Outcomes books at clevelandclinic.org/outcomes.

CME Opportunities Stay Connected with Cleveland Visit ccfcme.org for convenient learning opportunities from Clinic’s Glickman Urological & Cleveland Clinic’s Center for Continuing Education. Kidney Institute Executive Education Consult QD — Urology and Nephrology Learn about our Executive Visitors’ Program and two-week A blog featuring insights and perspectives from Cleveland Samson Global Leadership Academy immersion program Clinic experts. Visit today and join the conversation. at clevelandclinic.org/executiveeducation. consultqd.clevelandclinic.org/urology-nephrology

The Cleveland Clinic Way Facebook for Medical Professionals By Toby Cosgrove, MD, CEO and President, Facebook.com/CMEClevelandClinic Cleveland Clinic Great things happen when a medical center Follow us on Twitter puts patients first. Visit clevelandclinic.org @CleClinicMD /ClevelandClinicWay for details or to order a copy. Connect with us on LinkedIn clevelandclinic.org/MDlinkedin About Cleveland Clinic Cleveland Clinic is an integrated healthcare delivery system with On the Web at clevelandclinic.org/Glickman local, national and international reach. At Cleveland Clinic, more than 3,000 physicians and researchers represent 120 medical specialties and subspecialties. We are a main campus, more than 75 northern Ohio outpatient locations (including 16 full-service family health centers), Cleveland Clinic Florida, Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, Sheikh Khalifa Medical City and Cleveland Clinic Abu Dhabi.

In 2014, Cleveland Clinic was ranked one of America’s top four hospitals in U.S. News & World Report’s “Best Hospitals” survey. The survey ranks Cleveland Clinic among the nation’s top 10 hospitals in 13 specialty areas, FSC LOGO HERE and the top hospital in heart care (for the 20th consecutive year) and urologic care.

More articles online at ConsultQD.clevelandclinic.org/urology-nephrology 63

INTRODUCING

UROLOGY & NEPHROLOGY

A blog featuring insights and perspectives from Cleveland Clinic experts in urology and kidney health. Visit today and join the conversation.

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Urology & Kidney Disease News Vol. 24 / Winter 2015

Urology & Kidney Disease News is a publication of Cleve- Daniel Shoskes, MD land Clinic’s Glickman Urological & Kidney Institute. Glickman Urological & Kidney Institute Medical Editor, Urology Urology & Kidney Disease News is written for physi- cians and should be relied on for medical education Sankar Navaneethan, MD

purposes only. It does not provide a complete overview Glickman Urological & Kidney Institute

of the topics covered and should not replace the inde- Medical Editor, Nephrology pendent judgment of a physician about the appropri- ateness or risks of a procedure for a given patient. John Mangels Managing Editor Eric A. Klein, MD [email protected] Chairman Glickman Urological & Kidney Institute Barbara Ludwig Coleman Graphic Designer

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