European Urology - Volume 82, Issue 6

EDITOR EMERITUS (1975–2005) EDITOR EMERITUS (2006–2013)
Claude Schulman, Belgium Francesco Montorsi, Italy
EDITOR-IN-CHIEF
James Catto, UK
ASSOCIATE EDITORS
Maarten Albersen, Belgium Jean-Nicolas Cornu, France Todd Morgan, USA
Giacomo Novara, Italy Sarah Psutka, USA
STATISTICAL EDITOR STATISTICAL ASSOCIATE EDITOR STATISTICAL ASSOCIATE EDITOR

Andrew Vickers, USA Melissa Assel, USA Rodney Dunn, USA
DIGITAL MEDIA EDITOR DIGITAL MEDIA ASSOCIATE EDITOR DIGITAL MEDIA ASSOCIATE EDITOR
Zachary Klaassen, USA Alessandro Larcher, Italy Christopher Wallis, Canada
SURGERY IN MOTION EDITOR IMAGING EDITOR WORDS OF WISDOM EDITOR

Alexander Mottrie, Belgium Jelle Barentsz, The Netherlands George Thalmann, Switzerland
MEDICAL ONCOLOGY EDITOR RADIATION ONCOLOGY EDITOR

Elizabeth Plimack, USA Piet Ost, Belgium
MANAGING EDITOR EDITORIAL OFFICE ASSISTANT COPY EDITOR

Cathy Pierce, USA Kirsten Marshall, UK Compuscript Ltd
EDITORIAL INTERNS
Carissa Chu, USA
Satoshi Funada, Japan
Lisa Moris, Belgium
CONSULTING EDITORS
Ardalan Ahmad, Canada Lars Dyskjot, Denmark Giorgio Ivan Russo, Italy
Neeraj Agarwal, USA Giorgio Gandaglia, Italy Gottfrid Sjodahl, Sweden
Riccardo Campi, Italy Stephanie Gazdovich, Canada Jeremy Y. Teoh, Hong Kong
Samantha Conroy, UK Veeru Kasivisvanathan, UK Roderick Van den Bergh,
Sigrid Carlsson, USA Fumitake Koga, Japan Netherlands
Jozefina Casuscelli, Germany Caroline Moore, UK Christopher Wallis, USA
Douglas Cheung, USA Alessandra Mosca, Italy Mary Elizabeth Westerman, USA
Edmund Chiong, Singapore Declan Murphy, Australia
Timothy Clinton, USA Andrea Necchi, Italy
EUROPEAN UROLOGY
James Catto, Editor-in-Chief
Academic Urology Unit, University of Sheffield
The Medical School
Beech Hill Road, Sheffield S10 2RX, UK
Official Journal of E-mail: platinum@europeanurology.com
Tel: +31 26 389 0680; Fax: +44 114 271 2268
EDITORIAL BOARD
Hashim Ahmed, UK Jack Elder, USA Valeria Panebianco, Italy

Peter Albers, Germany Matthew Galsky, USA Benoit Peyronnet, France
Peter Albertsen, USA John Gearhart, USA Tom Powles, UK
Andrea Apolo, USA Matthew Gettman, USA Benjamin Pradere, Austria
Apostolos Apostolidos, Greece Inderbir Gill, USA Ranjith Ramasamy, USA
Riccardo Autorino, Italy Francesco Greco, Germany Jens Rassweiler, Germany
Marko Babjuk, Czech Republic Jüergen Gschwend, Germany Maria J. Ribal, Spain
Christopher Barbieri, USA Ari Hakimi, USA Jennifer R. Rider, USA
Ricarda Bauer, Germany Noburu Hara, Japan Monique J. Roobol,
Joaquim Bellmunt, Spain Michael S. Hofman, Australia The Netherlands
Karim Bensalah, France Brent Hollenbeck, USA Morgan Roupret, France
Bimal Bhindi, USA Syed Hussain, UK Kazutaka Saito, Japan
Trinity J. Bivalacqua, USA Maha Hussain, USA Andrea Salonia, Italy
Anders Bjartell, Sweden Brant Inman, USA Guiseppe Simone, Italy
Peter Black, USA Kazuto Ito, Japan Guru Sonpavde, USA
Marco Borghesi, Italy R. Jeffrey Karnes, USA Gary Steinberg, USA
Alberto Bossi, France Max Kates, USA Arnulf Stenzl, Germany
Paul Boutros, USA M. Pilar Laguna, Christian Stief, Germany
Alberto Breda, Spain The Netherlands Nazareno Suardi, Italy
Laura Bukavina, USA Alastair Lamb, UK George Thalmann, Switzerland
Steve Campbell, USA Richard S. Lee, USA Houston Thompson, USA
Abdullah Canda, Turkey Seth Lerner, USA Bertrand Tombal, Belgium
Umberto Capitanio, Italy Evangelos Liatsikos, Greece Scott Tomlins, USA
Christopher Chapple, UK Stacy Loeb, USA Quoc-Dien Trinh, Canada
Joseph Chin, Canada Yair Lotan, USA Roderick van den Bergh,
Renzo Colombo, Italy Stephan Madersbacher, Austria The Netherlands
Elisabetta Costantini, Italy Luis Martı́nez-Piñeiro, Spain Theo van der Kwast, Canada
Francisco Cruz, Portugal Surena Matin, USA Bas van Rhijn, The Netherlands
Cosimo De Nunzio, Italy Joshua Meeks, USA Jochen Walz, France
Giuseppe Di Lorenzo, Italy Rodolfo Montironi, Italy Stephen Williams, USA
Jason Efstathiou, USA Alicia Morgans, USA Johannes Witjes, The Netherlands
Shin Egawa, Japan Alicia K. Morgans, USA Christopher Wood, USA
Scott Eggener, USA Nicolas Mottet, France Alex Zlotta, Canada
Behfar Ehdaie, USA James N’dow, UK
The Platinum Hall of Fame is online only at http://www.sciencedirect.com/science/journal/03022838/82/6
EUROPEAN UROLOGY
James Catto, Editor-in-Chief
Academic Urology Unit, University of Sheffield
The Medical School
Beech Hill Road, Sheffield S10 2RX, UK
Official Journal of E-mail: platinum@europeanurology.com
Società Italiana di Urologia (SIU) Tel: +31 26 389 0680; Fax: +44 114 271 2268
The Platinum
Hall of Fame
European Urology would like to recognize the award-winning authors and exceptional reviewers who ensure
that ‘your’ platinum journal remains a cut above the rest.
Best Scientific Paper Prizes 2000 to the Present 2006

Prevalence of Asymptomatic Coronary Artery Disease
2000 in Men with Vasculogenic Erectile Dysfunction:
Laparoscopic Radical Prostatectomy: Technical and
A Prospective Angiographic Study
Early Oncological Assessment of 40 Operations C. Vlachopoulos, K. Rokkas, N. Ioakeimidis, C. Aggeli, A. Michaelides,
B. Guillonneau, X. Cathelineau, E. Barret, F. Rozet, G. Vallancien G. Roussakis, C. Fassoulakis, A. Askitis, C. Stefanadis
European Urology 1999;36:14–20 European Urology 2005;48:996–1002
2001 2007
RPLND or Primary Chemotherapy in Clinical Stage Excellent Long-Term Cancer Control with Elective
IIA/B Nonseminomatous Germ Cell Tumors? Results Nephron-Sparing Surgery for Selected Renal Cell
of a Prospective Multicenter Trial Including Quality of Carcinomas Measuring More Than 4 cm
Life Assessment F. Becker, S. Siemer, M. Hack, U. Humke, M. Ziegler, M. Stöckle
L. Weissbach, R. Bussar-Maatz, H. Flechtner, U. Pichlmeier, European Urology 2006;49:1058–1064
M. Hartmann, L. Keller &
European Urology 2000;37:582–594 Elective Nephron-Sparing Surgery Should Become
Standard Treatment for Small Unilateral Renal Cell
2002 Carcinoma: Long-term Survival Data of 216 Patients
Nonrandomized Comparison of Open Flank versus F. Becker, S. Siemer, U. Humke, M. Hack, M. Ziegler, M. Stöckle
Laparoscopic Nephrectomy in 249 Patients with Benign European Urology 2006;49:308–313
Renal Disease
2008
P. Fornara, C. Doehn, H.-J. Friedrich, D. Jocham
European Urology 2001;40:24–31
Morbidity and Clinical Outcome of Nephron-Sparing
Surgery in Relation to Tumour Size and Indication
J.-J. Patard, A.J. Pantuck, M. Crepel, J.S. Lam, L. Bellec, B. Albouy,
2003
D. Lopes, J.-C. Bernhard, F. Guillé, B. Lacroix, A. De La Taille, L. Salomon,
Laparoscopic Dismembered Pyeloplasty – The Method C. Pfister, M. Soulié, J. Tostain, J.-M. Ferriere, C.C. Abbou, M. Colombel,
of Choice in the Presence of an Enlarged Renal Pelvis A.S. Belldegrun
and Crossing Vessels European Urology 2007;52:148–154
I.A. Türk, J.W. Davis, B. Winkelmann, S. Deger, F. Richter,
M.D. Fabrizio, B. Schönberger, G.H. Jordan, S.A. Loening 2009
European Urology 2002;42:268–275 The Template of the Primary Lymphatic Landing
Sites of the Prostate Should Be Revisited: Results of a
2004 Multimodality Mapping Study
A. Mattei , F.G. Fuechsel, N. Bhatta Dhar, S.H. Warncke,G.N. Thalmann,
The Side Effects of Bacillus Calmette-Guérin in the
T. Krause, U.E. Studer
Treatment of Ta T1 Bladder Cancer do not Predict its
Efficacy: Results from a European Organisation for
Research and Treatment of Cancer Genito-Urinary 2010
Group Phase III Trial Preoperative Aspects and Dimensions Used for an
R.J. Sylvester, A.P.M. Van Der Meijden, W. Oosterlinck, W. Hoeltl, Anatomical (PADUA) Classification of Renal Tumours in
A.V. Bono Patients who are Candidates for Nephron-Sparing
European Urology 2003;44:423–428 Surgery
& V. Ficarra, G. Novara, S. Secco, V. Macchi, A. Porzionato, R. De Caro,
Maintenance Bacillus Calmette-Guérin for Ta T1 Bladder W. Artibani
Tumors is not Associated with Increased Toxicity: Results European Urology 2009;56:786–793
from a European Organisation for Research and Treatment Sponsored By Elsevier
of Cancer Genito-Urinary Group Phase III Trial
2011
A.P.M. Van Der Meijden, R.J. Sylvester, W. Oosterlinck, W. Hoeltl,
A.V. Bono
Positive Surgical Margin Appears to Have Negligible
European Urology 2003;44:429–434 Impact on Survival of Renal Cell Carcinomas Treated
by Nephron-Sparing Surgery
K. Bensalah, A.J. Pantuck, N. Rioux-Leclercq, R. Thuret, F. Montorsi,
2005 P. Karakiewicz, N. Mottet, L. Zini, R. Bertini, L. Salomon, A. Villers,
DD3A3 RNA Analysis in Urine – A New Perspective for M. Soulie, L. Bellec, P. Rischmann, A. De La Taille, R. Avakian, M. Crepel,
Detecting Prostate Cancer J. Ferriere, J. Bernhard, T. Dujardin, et al.
M. Tinzl, M. Marberger, S. Horvath, C. Chypre European Urology 2010;57:466–473
European Urology 2004;46:182–186 Sponsored By Elsevier
http://dx.doi.org/10.1016/j.eururo.2022.10.015
The Platinum
Hall of Fame
2012 F. Porpigalia, M. Manfredi, F. Mele, M. Cossu, E. Bollito, A. Veltri,

Pentafecta: A New Concept for Reporting Outcomes of S. Cirillo, D. Regge, R. Faletti, R. Passera, C. Fiori, S. De Luca
Robot-Assisted Laparoscopic Radical Prostatectomy
V. Patel, A. Sivaraman, R. Coelho, S. Chauhan, K. Palmer, M. Orvieto,
I. Camacho, G. Coughlin, B. Rocco
2019
Value of an Immediate Intravesical Instillation of
2013 Mitomycin C in Patients with Non–muscle-invasive
Pathologic Downstaging Is a Surrogate Marker for Bladder Cancer: A Prospective Multicentre Randomised
Efficacy and Increased Survival Following Neoadjuvant Study in 2243 patients
Chemotherapy and Radical Cystectomy for Muscle- J. Bosschieter, J.A. Nieuwenhuijzen, T. van Ginkel, A.N. Vis, B. Witte,
Invasive Urothelial Bladder Cancer D. Newling, G.M.A. Beckers, R.J.A. van Moorselaar
R. Rosenblatt, A. Sherif, E. Rintala, R. Wahlqvist, A. Ullén, European Urology, Vol. 73, Issue 2, p226–232
M. Nilsson, P.-U. Malmström, the Nordic Urothelial Cancer Group
European Urology 2012;61:1229–1238 2020
2014 Genomic Drivers of Poor Prognosis and Enzalutamide
Final Results of an EORTC-GU Cancers Group Resistance in Metastatic Castration-resistant Prostate
Randomized Study of Maintenance Bacillus Calmette- Cancer
William S. Chen, Rahul Aggarwal, Li Zhang, Shuang G. Zhao,
Guérin in Intermediate- and High-risk Ta, T1 Papillary
George V. Thomas, Tomasz M. Beer, David A. Quigley, Adam Foyea,
Carcinoma of the Urinary Bladder: One-third Dose Denise Playdlea,, Jiaoti Huang, Paul Lloyd, Eric Lu, Duanchen Sun,
Versus Full Dose and 1 Year Versus 3 Years of Xiangnan Guan, Matthew Rettig, Martin Gleave, Christopher P.
Maintenance Evans, Jack Youngren, Lawrence True, Primo Lara, Vishal Kothari,
J. Oddens, M. Brausi, R. Sylvester, A. Bono, C. van de Beek, Zheng Xia, Kim N. Chj, Robert E. Reiter, Christopher A. Maher, Felix
G. van Andel, P. Gontero, W. Hoeltl, L. Turkeri, S. Marreaud, Y. Feng, Eric J. Small, Joshi J. Alumkal on behalf of the West Coast
S. Collette, W. Oosterlinck Prostate Cancer Dream Team
European Urology 2013;63:462–472 European Urology, Vol 76, Issue 5, p562–571
2015 2021
Bacillus Calmette-Guérin Strain Differences Have an Impact
The DaBlaCa-13 Study: Short-term, Intensive
on Clinical Outcome in Bladder Cancer Immunotherapy
Chemoresection Versus Standard Adjuvant Intravesical
C.A. Rentsch, F.D. Birkhðuser, C. Biot, J.R. Gsponer, A. Bisiaux,
C. Wetterauer, M. Lagranderie, G. Marchal, M. Orgeur, C. Bouchier,
Instillations in Non–muscle-invasive Bladder Cancer
A. Bachmann, M.A. Ingersoll, R. Brosch, M.L. Albert, G.N. Thalmann A Randomised Controlled Trial
European Urology 2014;66:677–688 Maria S. Lindgren, Peter Bue, Nessn Azawi, Linea Blichert-Refsgaard,
Maria O. Sundelin, Lars Dyrskjø, Jørgen B. Jensen
2016 European Urology, Vol 78, Issue 6, p856–862
Survival with Newly Diagnosed Metastatic Prostate Cancer
in the ‘‘Docetaxel Era’’: Data from 917 Patients in the Control 2022
Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019) The Additive Diagnostic Value of Prostate-specific
N.D. James, M.R. Spears, N.W. Clarke, D.P. Dearnaley, J.S. De Bono, Membrane Antigen Positron Emission Tomography
J. Gale, J. Hetherington, P.J. Hoskin, R.J. Jones, R. Laing, J.F. Lester, Computed Tomography to Multiparametric Magnetic
D. McLaren, C.C. Parker, M.K.B. Parmar, A.W.S. Ritchie, J.M. Russell, Resonance Imaging Triage in the Diagnosis of Prostate
R.T. Strebel, G.N. Thalmann, M.D. Mason, M.R. Sydes
Cancer (PRIMARY): A Prospective Multicentre Study
Louise Emmett, James Buteau, Nathan Papa, Daniel Moon, James
2017 Thompson, Matthew J.Roberts, Kris Rasiah, David A. Pattison,
John Yaxley, Paul Thomas, Anthony C. Hutton, Shikha Agrawal,
A Randomized Controlled Trial To Assess and Compare
Amer Amin, Alexandar Blazevski, Venu Chalasani, Bao Ho,
the Outcomes of Two-core Prostate Biopsy Guided by Andrew Nguyen, Victor Liu, Phillip Stricker
Fused Magnetic Resonance and Transrectal Ultrasound European Urology, Vol 80, Issue 6, p690–692
Images and Traditional 12-core Systematic Biopsy
E. Baco, E. Rud, L.M. Eri, G. Moen, L. Vlatkovic, A. Svindland, Best Scientific Paper on Fundamental Research
H.B. Eggesbø, O. Ukimura
Frozen Section for the Management of Intraoperatively
2018 Detected Palpable Tumor Lesions During Nerve-Sparing
Diagnostic Pathway with Multiparametric Magnetic Scheduled Radical Prostatectomy
Resonance Imaging Versus Standard Pathway: Results C. Eichelberg, A. Erbersdobler, A. Haese, T. Schlomm, F.K.H. Chun,
from a Randomized Prospective Study in Biopsy-naı̈ve E. Currlin, J. Walz, T. Steuber, M. Graefen, H. Huland
Patients with Suspected Prostate Cancer European Urology 2006;49:1011–1018
The Platinum
Hall of Fame
2008 2015
Use of Haemostatic Agents and Glues during Targeted Prostate Cancer Screening in BRCA1 and
Laparoscopic Partial Nephrectomy: A Multi-Institutional BRCA2 Mutation Carriers: Results from the Initial
Survey from the United States and Europe of 1347 Cases Screening Round of the IMPACT Study
A. Breda, S.V. Stepanian, J.S. Lam, J.C. Liao, I.S. Gill, J.R. Colombo, E.K. Bancroft, E.C. Page, E. Castro, H. Lilja, A. Vickers, D. Sjoberg,
G. Guazzoni, M.D. Stifelman, K.T. Perry, A. Celia, G. Breda, P. Fornara, M. Assel, C.S. Foster, G. Mitche, K. Drew, L. MÌhle, K. Axcrona,
S.V. Jackman, A. Rosales, J. Palou, M. Grasso, V. Pansadoro, V. Disanto, D.G. Evans, B. Bulman, D. Eles, D. McBride, C. van Asperen,
F. Porpiglia, C. Milani, C.C. Abbou, R. Gaston, G. Janetschek, N.A. H. Vasen, L.A. Kiemeney, J. Ringelberg, C. Cybulski, D. Wokolorczyk,
Soomro, J.J. De la Rosette, P.M. Laguna, P.G. Schulam C. Selkirk, P.J. Hulick, A. Bojesen, A.-B. Skytte, Jiy Lam, L. Taylor,
European Urology 2007;52:798–803 R. Oldenburg, R. Cremers, G. Verhaegh, W.A. van Zelst-Stams,
J.C. Oosterwijk, I. Blanco, M. Salinas, Jackie Ck, D.J. Rosario, S. Buys,
2009 T. Conner, M.G. Ausems, K.-r. Ong, J. Homan, S. Domchek,
Predictive Factors for Progression in Patients with J. Powers, M.R. Teixeira, S. Maia, W.D. Foulkes, N. Taherian, M. Ruijs,
Clinical Stage T1a Prostate Cancer in the PSA Era A.T. Helderman-van den Enden, L. Izatt, R. Davidson, M.A. Adank,
A. Descazeaud, M. Peyromaure, A. Salin, D. Amsellem-Ouazana, L. Walker, R. Schmutzler, K. Tucker, J. Kirk, S. Hodgson, M. Harris,
T. Flam, A. Viellefond, B. Debré, M. Zerbib F. Douglas, G.J. Lindeman, J. Zgajnar, M. Tischkowitz, V.E. Clowes,
European Urology 2008;53:355–362 R. Susman, T. Ramœn y Cajal, N. Patcher, N. Gadea, A. Spigelman,
T. van Os, A. Liljegren, L. Side, C. Brewer, A.F. Brady, A. Donaldson,
2010
V. Stefansdottir, E. Friedman, R. Chen-Shtoyerman, D.J. Amor,
Should All Patients with Non–Muscle-Invasive Bladder L. Copakova, J. Barwell, V.N. Giri, V. Murthy, N. Nicolai, S.-H. Teo,
Cancer Receive Early Intravesical Chemotherapy after L. Grnhalgh, S. Strom, A. Henderson, J. McGrath, D. Gallagher,
Transurethral Resection? The Results of a Prospective N. Aaronson, A. Ardern-Jones, C. Bangma, D. Dearnaley, P. Costello,
Randomised Multicentre Study J. Eyfjord, J. Rothwell, A. Falconer, H. Gronberg, F.C. Hamdy,
S. Gudjœnsson, L. Adell, F. Merdasa, R. Olsson, B. Larsson, T. Davidsson, O. Johannsson, V. Kh, Z. Kote-Jarai, J. Lubinski, U. Axcrona, J. Melia,
J. Richthoff, G. Hagberg, M. Grabe, P.O. Bendahl, W. MÍnsson, F. Liedberg J. McKinley, A.V. Mitra, C. Moynihan, G. Rennert, M. Suri, P. Wilson,
European Urology 2009;55:773–780 E. Killick, The IMPACT Collaborators, S. Moss, R.A. Eeles
Sponsored By Eli Lilly European Urology 2014;66:489–499
2011 2016
Complications in 2200 Consecutive Laparoscopic Molecular Characterization of Enzalutamide-treated
Radical Prostatectomies: Standardized Evaluation and Bone Metastatic Castration-resistant Prostate Cancer
Analysis of Learning Curves E. Efstathiou, M. Titus, S. Wen, A. Hoang, M. Karlou, R. Ashe,
M. Hruza, H. Weiß, G. Pini, A. Goezen, M. Schulze, D. Teber, J. Rassweiler S.M. Tu, A. Aparicio, P. Troncoso, J. Mohler, C.J. Logothetis
Sponsored by Elsevier
2012 2017
Salvage Radical Prostatectomy for Radiation-recurrent Tissue-based Genomics Augments Post-prostatectomy
Prostate Cancer: A Multi-institutional Collaboration Risk Stratification in a Natural History Cohort of
D. Chade, S. Shariat, A. Cronin, C. Savage, J. Karnes, M. Blute, Intermediate- and High-Risk Men
A. Briganti, F. Montorsi, H. van der Poel, H. Van Poppel, S. Joniau, A.E. Ross, M.H. Johnson, K. Yousefi, E. Davicioni, G.J. Netto,
G. Godoy, A. Hurtado-Coll, M. Gleave, M. Dall’Oglio, M. Srougi, L. Marchionni, H.L. Fedor, S. Glavaris, V. Choeurng, C. Buerki,
P. Scardino, J. Eastham N. Erho, L.L. Lam, E.B. Humphreys, S. Faraj, S.M. Bezerra, M. Han,
European Urology 2011;60:205–210 A.W. Partin, B.J. Trock, E.M. Schaeffer
2013
Stage-Specific Impact of Tumor Location on Oncologic 2018
Outcomes in Patients With Upper and Lower Tract SRRM4 Drives Neuroendocrine Transdifferentiation of
Urothelial Carcinoma Following Radical Surgery Prostate Adenocarcinoma Under Androgen Receptor
M. Rink, B. Ehdaie, E.K. Cha, D.A. Green, P.I. Karakiewicz, Pathway Inhibition
M. Babjuk, V. Margulis, J.D. Raman, R.S. Svatek, H. Fajkovic, R.K. Lee, Y. Li, N. Donme, C. Sahinalp, N. Xie, Y. Wang, H. Xue, F. Mo,
G. Novara, J. Hansen, S. Daneshmand, Y. Lotan, W. Kassouf, H. Beltran, M. Gleave, Y. Wang, C. Collins, X. Dong
H.-M. Fritsche, A. Pycham, M. Fisch, D.S. Scherr, S.F. Shariat, for the European Urology 2017;71:68–78
Bladder Cancer Research Consortium (BCRC) and for the Upper Tract
Urothelial Carcinoma Collaboration (UTUCC) 2019
Intravesical Activation of the Cation Channel TRPV4
2014 Improves Bladder Function in a Rat Model for Detrusor
Natural History of Early, Localized Prostate Cancer: Underactivity
A Final Report from Three Decades of Follow-up Y. Deruyver, E. Weyne, K. Dewulf, R. Rietjens, S. Pinto, N. Van Ranst,
M. Popiolek, J.R. Rider, O. Andrén, S.-O. Andersson, L. Holmberg, J. Franken, M. Vanneste, M. Albersen, T. Gevaert, R. Vennekens,
H.-O. Adami, J.-E. Johansson D. De Ridder, T. Voets, W. Everaerts
European Urology 2013;63:428–435 European Urology, Vol. 74, Issue 3, p336–345
The Platinum
Hall of Fame
2020 2010
Antifibrotic Synergy Between Phosphodiesterase Type 5 Characteristics of Spontaneous Activity in the Bladder
Inhibitors and Selective Oestrogen Receptor Modulatorso Trigone
in Peyronie’s Disease Models A. Roosen, C. Wu, G. Sui, R.A. Chowdhury, P.M. Patel, C.H. Fry
Marcus M. Ilg , Marta Mateus , William J. Stebbeds , Uros Milenkovic, European Urology 2009;56:346–354
Nim Christopher, Asif Muneer, Maarten Albersen, David J. Ralph, Sponsored By Elsevier
Selim Cellek
European Urology, Vol. 75, Issue 2, Pages p329–340 2011
Stem Cell Characteristics in Prostate Cancer Cell Lines
M.J. Pfeiffer, J.A. Schalken
2021 European Urology 2010;57:246–255
Gut Bacteria Composition Drives Primary Resistance to Sponsored By Elsevier
Cancer Immunotherapy in Renal Cell Carcinoma Patients
Lisa Derosa, Bertrand Routy, Marine Fidelle, Valerio Iebba, Laurie
2012
Alla, Edoardo Pasolli, Nicola Segata, Aude Desnoyer, Filippo Transplantation of Autologous Differentiated Urothelium
Pietrantonio, Gladys Ferrere, Jean-Eudes Fahrner, Emmanuelle Le in an Experimental Model of Composite Cystoplasty
Chatellier, Nicolas Pons, Nathalie Galleron, Hugo Roume, Connie A. Turner, R. Subramanian, D. Thomas, J. Hinley, S. Abbas,
P.M. Duong, Laura Mondragœn, Kristina Iribarren, Mélodie Bonvalet, J. Stahlschmidt, J. Southgate
Safae Terrisse, Conrad Rauber, Anne-Gaëlle Goubet, Romain Daillère, European Urology 2011;59:447–454
Fabien Lemaitre, Anna Reni, Beatrice Casu, Maryam Tidjani Alou,
Carolina Alves Costa Silva, Didier Raoult, Karim Fizazi, Bernard 2013
Escudier, Guido Kroemer, Laurence Albiges, Laurence Zitvogel Genome-wide Analysis of CpG Island Methylation in
European Urology, Vol 78, Issue 2, p195-206 Bladder Cancer Identified TBX2, TBX3, GATA2, and ZIC4
as pTa-Specific Prognostic Markers
2022 R. Kandimalla, A.A.G. van Tilborg, L.C. Kompier, D.J.P.M. Stumpel, R.W.
Integrated Expression of Circulating miR375 and Stam, C.H. Bangma, E.C. Zwarthoff
miR371 to Identify Teratoma and Active Germ Cell European Urology 2012;61:1245–1256
Malignancy Components in Malignant Germ Cell
Tumors 2014
Lucia Nappi, Marisa Thi, Nabil Adra, Robert J. Hamilton, Indium-111- labeled Girentuximab ImmunoSPECT as
Ricardo Leao, Jean-Michel Lavoie, Maryam Soleimani, a Diagnostic Tool in Clear Cell Renal Cell Carcinoma
Bernhard J. Eigl, Kim Chi, Martin Gleave, Alan So, Peter C. Black, C.H.J. Muselaers, O.C. Boerman, E. Oosterwijk, J.F. Langenhuijsen,
Robert Bell, Siamak Daneshmand, Clint Cary, Timothy Masterson, W.J.G. Oyen, P.F.A. Mulders
Lawrence Einhorn, Craig Nichols, Christian Kollmannsberger European Urology 2013;63:1101–1106
European Urology, Vol 79, Issue 1, p16–19
2015
Best Scientific Paper on Clinical Research Renal Function After Nephron-sparing Surgery
2007 Versus Radical Nephrectomy: Results from EORTC
Randomized Trial 30904
Depressed Contractile Responses to Neurokinin A
E. Scosyrev, E.M. Messing, R. Sylvester, S. Campbell, H. Van Poppel
in Idiopathic but not Neurogenic Overactive Human European Urology 2014;65:372–377
Detrusor Muscle
D.J. Sellers, C.R. Chapple, D.P.W. Hay, R. Chess-Williams
2016
Combination Treatment with Mirabegron and Solifenacin in
Patients with Overactive Bladder: Efficacy and Safety Results
2008 from a Randomised, Double-blind, Dose-ranging, Phase 2
Effects of the M3 Receptor Selective Muscarinic Study (Symphony)
Antagonist Darifenacin on Bladder Afferent Activity of P. Abrams, C. Kelleher, D. Staskin, T. Rechberger, R. Kay,
R. Martina, D. Newgreen, A. Paireddy, R. van Maanen, A. Ridder
the Rat Pelvic Nerve
European Urology 2015:67:577–588
K. Iijima, S. De Wachter, J.-J. Wyndaele
2017
2009 PI-RADS Prostate Imaging – Reporting and Data System:
Marked Gene Transcript Level Alterations Occur Early 2015, Version 2
During Radical Prostatectomy J.C. Weinreb*, J.O. Barentsz*, P.L. Choyk, F. Cornu, M.A. Haider,
T. Schlomm, E. Nðkel, A. Lübke, A. Buness, F.K.-H. Chun, T. Steuber, K.J. Macur, D. Margolis, M.D. Schnall, F. Shtern, C.M. Tempany, H.C.
M. Graefen, R. Simon, G. Sauter, A. Poustka, H. Huland, Thoeny, S. Verma
A. Erbersdobler, H. Sültmann, O.J.C. Hellwinkel European Urology 2016;69:16–40
European Urology 2008;53:333–346 * These authors share first authorship.
The Platinum
Hall of Fame
2018 F.K.-H. Chun, M. Graefen, A. Briganti, A. Gallina, J. Hopp,

CheckMate 025 Randomized Phase 3 Study: Outcomes by M.W. Kattan, H. Huland, P.I. Karakiewicz
Key Baseline Factors and Prior Therapy for Nivolumab
&
Versus Everolimus in Advanced Renal Cell Carcinoma
B. Escudier, P. Sharma, D.F. McDermott, S. George, H.J. Hammers,
hK2 and Free PSA, a Prognostic Combination in Predicting
S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, Minimal Prostate Cancer in Screen-Detected Men within
D. Castellano, H. Gurney, F. Donskov, K. Peltola, J. Wagstaff, the PSA Range 4–10 ng/ml
T.C. Gauler, T. Ueda, H. Zhao, I.M. Waxman, R.J. Motzer, on behalf of R. Raaijmakers, S.H. de Vries, B.G. Blijenberg, M.F. Wildhagen,
the CheckMate 025 investigators R. Postma, C.H. Bangma, C. Darte, F.H. Schröder
2019 2009
Metabolic Biosynthesis Pathways Identified from Fecal Evaluation of Prostate Cancer Detection with Ultrasound
Microbiome Associated with Prostate Cancer Real-Time Elastography: A Comparison with Step Section
M.A. Liss, J.R. White, M. Goros, J. Gelfond, R. Leach, T. Johnson-Pais, Pathological Analysis after Radical Prostatectomy
Z. Lai, E. Rourke, J. Basler, D. Ankerst, D.P. Shah G. Salomon, J. Köllerman, I. Thederan, F.K.H. Chun, L. Budðus,
European Urology, Vol. 74, Issue 5, p575–582 T. Schlomm, H. Isbarn, H. Heinzer, H. Huland, M. Graefen
2020 &
Extended Versus Limited Lymph Node Dissection in Bladder Radical Prostatectomy for Incidental (Stage T1a–T1b)
Cancer Patients Undergoing Radical Cystectomy: Survival Prostate Cancer: Analysis of Predictors for Residual
Results from a Prospective, Randomized Trial Disease and Biochemical Recurrence
Jürgen E. Gschwend, Matthias M. Heck, Jan Lehmann, Herbert Rübben, U. Capitanio, V. Scattoni, M. Freschi, A. Briganti, A. Salonia, A. Gallina,
Peter Albers, Johannes M. Wolff, Detlef Frohneberg, Patrick de Geeter, R. Colombo, P.I. Karakiewicz, P. Rigatti, F. Montorsi
Axel Heidenreich, Tilman Kðlble, Michael Stöckle, Thomas Schnöller, European Urology 2008;54:118–125
Arnulf Stenzl,, Markus Müller, Michael Truss, Stephan Roth, Uwe-
Bernd Liehr, Joachim LeiÔner, Thomas Bregenzer, Margitta Retz
European Urology, Vol 75, Issue 4, p604–611
2010
Influence of Nerve Transsections and Combined
2021 Bladder Filling on Intravesical Electrostimulation-
Treatment of High-grade Non–muscle-invasive Induced Bladder Contraction in the Rat
L. De Bock, S. De Wachter, J.J. Wyndaele
Bladder Carcinoma by Standard Number and Dose
of BCG Instillations Versus Reduced Number and Sponsored By Eli Lilly
Standard Dose of BCG Instillations: Results of the &
European Association of Urology Research Foundation The Role of Biopsy Core Number in Selecting Prostate
Randomised Phase III Clinical Trial NIMBUS Cancer Patients for Active Surveillance
Marc-Oliver Grimm, Antoine G. van der Heijden, Marc Colombel, M. Ploussard, E. Xylinas, L. Salomon, Y. Allory, D. Vordos, A. Hoznek,
Tim Muilwijk, Luis MartÚnez-Piþeiro, Marko M. Babjuk, Levent C.-C. Abbou, A. de la Taille
N. Türkeri, Joan Palou, Anup Patel, Anders S. Bjartell, Christien European Urology 2009;56:891–898
Caris, Raymond G. Schipper, Wim P.J. Witjes for the EAU Research Sponsored By Eli Lilly
Foundation NIMBUS Study Group
European Urology, Vol 78, Issue 5, p690-698 2011
Midterm Prospective Evaluation of TVT-Secur Reveals
2022 High Failure Rate
Shockwave Lithotripsy Versus Ureteroscopic Treatment J.N. Cornu, P. Sèbe, L. Peyrat, C. Ciofu, O. Cussenot, F. Haab
as Therapeutic Interventions for Stones of the Ureter European Urology 2010;58:157–161
(TISU): A Multicentre Randomised Controlled Non- &
inferiority Trial HYAL-1 Hyaluronidase: A Potential Prognostic Indicator
Ranan Dasgupta, Sarah Cameron, Lorna Aucott, Graeme MacLen- for Progression to Muscle Invasion and Recurrence in
nan, Ruth E. Thomas, Mary M. Kilonzo, Thomas B.L. Lam, James Bladder Cancer
N Dow, John Norrie, Ken Anson, Neil Burgess, Charles T. Clark, M.W. Kramer, R. Golshani, A.S. Merseburger, J. Knapp, A. Garcia,
Francis X. Keeley, Sara J. MacLennan, Kath Starr, Sam McClinton J. Hennenlotter, R.C. Duncan, M.S. Soloway, M. Jorda, M.A. Kuczyk,
European Urology, Vol 80, Issue 1, p46–54 A. Stenzl, V.B. Lokeshwar
Residents’ Corner
2008 2012
Initial Biopsy Outcome Prediction—Head-to-Head Exosomes as Biomarker Treasure Chests for Prostate
Comparison of a Logistic Regression-Based Nomogram Cancer
versus Artificial Neural Network D. Duijvesz, T. Luider, C. Bangma, G. Jenster
The Platinum
Hall of Fame

& Efficacy of enzalutamide following abiraterone acetate
Cancer-Specific and Other-Cause Mortality After Radical in chemotherapy-naive metastatic castration-resistant
Prostatectomy Versus Observation in Patients with prostate cancer patients
Prostate Cancer: Competing-Risks Analysis of a Large A.A. Azad, B.J. Eigl, R.N. Murray, C. Kollmannsberger, K.N. Chi
North American Population-Based Cohort European Urology 2015;67:23–29
F. Abdollah, M. Sun, J. Schmitges, Z. Tian, C. Jeldres, A. Briganti, &
L. Shariat, P. Perrotte, F. Montorsi, P. Karakiewicz Preoperative Prostate-specific Antigen Isoform p2PSA
European Urology 2011;60:920–930 and Its Derivatives, %p2PSA and Prostate Health Index,
Predict Pathologic Outcomes in Patients Undergoing
2013 Radical Prostatectomy for Prostate Cancer: Results
Prospective Assessment of Prostate Cancer Aggressiveness from a Multicentric European Prospective Study
Using 3-T Diffusion-Weighted Magnetic Resonance N. Fossati, N.M. Buffi, A. Haese, C. Stephan, A. Larcher,
Imaging–Guided Biopsies Versus a Systematic 10-Core T. McNicholas, A. de la Taille, M. Freschi, G. Lughezzani,
Transrectal Ultrasound Prostate Biopsy Cohort A. Abrate, V. Bini, J. Palou Redorta, M. Graefen, G. Guazzoni,
T. Hambrock, C. Hoeks, C. Hulsbergen-van de Kaa, T. Scheenen, M. Lazzeri
J. Fütterer, S. Bouwense, I. van Oort, F. Schröder, H. Huisman, J. Barentsz European Urology 2015;68:132–138
& 2017
Immunocytology Is a Strong Predictor of Bladder Renal Cell Carcinoma Programmed Death-ligand 1,
Cancer Presence in Patients With Painless Hematuria: a New Direct Target of Hypoxia-inducible Factor-2
A Multicentre Study Alpha, is Regulated by von Hippel–Lindau Gene
E.K. Cha, L.-A. Tirsar, C. Schwentner, P.J. Christos, C. Mian, Mutation Status
J. Hennenlotter, T. Martini, A. Stenzl, A. Pycha, S.F. Shariat, Y. Messai, S. Gad, M.Z. Noman, G. Le Teuff, S. Couve, B. Janji,
B.J. Schmitz-Drðger S.F. Kammerer, N. Rioux-Leclerc, M. Hasmim, S. Ferlicot, V. Baud,
European Urology 2012;61:185–192 A. Mejean, D.R. Mole, S. Richard, A.M.M. Eggermont, L. Albiges,
F. Mami-Chouaib, B. Escudier, S. Chouaib
2014 &
Prostate-specific Antigen (PSA) Testing Is Prevalent and Results of a Randomised Controlled Trial Comparing
Increasing in Stockholm County, Sweden, Despite No Intravesical Chemohyperthermia with Mitomycin C
Recommendations for PSA Screening: Results from a Versus Bacillus Calmette-Guérin for Adjuvant Treatment
Population-based Study, 2003 –2011 of Patients with Intermediate- and High-risk Non–
T. Nordström, M. Aly, M.S. Clements, C.E. Weibull, J. Adolfsson, Muscleinvasive Bladder Cancer
H. Grönberg
T.J.H. Arends, O. Nativ, M. Maffezzini, O. de Cobelli, G. Canepa,
F. Verweij, B. Moskovitz, A.G. van der Heijden, J.A. Witjes
& European Urology 2016;69:1046–1052
Metformin and Prostate Cancer: Reduced Development of
Castration-resistant Disease and Prostate Cancer Mortality 2018
D.E. Spratt, C. Zhang, Z.S. Zumsteg, X. Pei, Z. Zhang, M.J. Zelefsky Ex Vivo Model of Human Penile Transplantation and
Rejection: Implications for Erectile Tissue Physiology
N.A. Sopko, H. Matsui, D.M. Lough, D. Miller, K. Harris, M. Kates,
2015 X. Liu, K. Billups, R. Redett, A.L. Burnett, G. Brandacher,
Propensity-Matched Comparison of Morbidity and T.J. Bivalacqua
Costs of Open and Robot-Assisted Radical Cystectomies: European Urology 2017;71:584–93
A Contemporary Population-Based Analysis in the &
United States Racial Variation in Patient-Reported Outcomes Following
J.J. Leow, S.W. Reese, W. Jiang, S.R. Lipsitz, J. Bellmunt, Q.-D. Trinh, Treatment for Localized Prostate Cancer: Results from
B.I. Chung, A.S. Kibel, Steven L. Chang the CEASAR Study
European Urology 2014;66:569–576 M.D. Tyson, J. Alvarez, T. Koyama, K.E. Hoffman, M.J. Resnick,
& X.-C. Wu, M.R. Cooperberg, M. Goodman, S. Greenfield,
Survival Outcome and Treatment Response of Patients A.S. Hamilton, M. Hashibe, L.E. Paddock, A. Stroup, V.W. Chen,
with Late Relapse from Renal Cell Carcinoma in the D.F. Penson, D.A. Barocas
Era of Targeted Therapy European Urology 2017;72:307–14
N. Kroeger, T.K. Choueiri, J.-L. Lee, G.A. Bjarnason, J.J. Knox,
M.J. MacKenzie, L. Wood, S. Srinivas, U.N. Vaishamayan, 2019
S.-Y. Rha, S.K. Pal, T. Yuasa, F. Donskov, N. Agarwal, M.-H. Tan, Prospective Implementation of Enhanced Recovery After
A. Bamias, C.K. Kollmannsberger, S.A. North, B.I. Rini, D.Y.C. Heng Surgery Protocols to Radical Cystectomy
European Urology 2014;65:1086–1092 K.H. Pang, R. Groves, S. Venugopal, A.P. Noon, J.W.F. Catto
The Platinum
Hall of Fame
European Urology, Vol. 73, Issue 3, p363–371 Zhu W., Zeng G., Sfakianos J.P., Gupta M., Tewari A., Gozen A.S.,
& Rassweiler J., Skolarikos A., Kunit T., Knoll T., Moltzahn F.,
Substitution Urethroplasty with Closure Versus Thalmann G.N., Lantz Powers A.G., Chew B.H., Sarica K., Shamim
Nonclosure of the Buccal Mucosa Graft Harvest Site: A Khan M., Dasgupta P.
Randomized Controlled Trial with a Detailed Analysis of European Urology, Vol 80, Issue 4, p385–393
Oral Pain and Morbidity
A. Soave, R. Dahlem, H.O. Pinnschmidt, M. Rink, J. Langetepe, Best Paper in Robotic Surgery
O. Engel, L.A. Kluth, B. Loechelt, P. Reiss, S.A. Ahyai, M. Fisch
European Urology, Vol. 73, Issue 6, p910–922 2016
Pilot Validation Study of the European Association of
2020 Urology Robotic Training Curriculum
Prediction of High-grade Prostate Cancer Following A. Volpe, K. Ahmed, P. Dasgupta, V. Ficarra, G. Novara, H. van der Poel,
Multiparametric Magnetic Resonance Imaging: Improving A. Mottrie
the Rotterdam European Randomized Study of Screening European Urology 2015;68:292–299
for Prostate Cancer Risk Calculators
Arnout R. Alberts, Monique J. Roobol, Jan F.M. Verbeek, Ivo G. 2017
Schoots, Peter K. Chiu, Daniël F. Osses, Jasper D. Tijsterman, Harrie
Measuring to Improve: Peer and Crowd-sourced
P. Beerlage, Christophe K. Mannaerts, Lars Schimmöller, Peter
Assessments of Technical Skill with Robot-assisted
Albers, Christian Arsov
European Urology, Vol 75, Issue 2, p310–318 Radical Prostatectomy
K.R. Ghani, D.C. Miller, S. Linsell, A. Brachulis, B. Lane, R. Sarle,
&
D. Dalela, M. Menon, B. Comstock, T.S. Lendvay, J. Montie, J.O. Peabody,
Metastasis-directed Therapy in Treating Nodal
for the Michigan Urological Surgery Improvement Collaborative
Oligorecurrent Prostate Cancer: A Multi-institutional European Urology 2016;69:547–550
Analysis Comparing the Outcome and Toxicity of
Stereotactic Body Radiotherapy and Elective Nodal
Radiotherapy 2018
Elise De Bleser, Barbara Alicja Jereczek-Fossab, David Pasquierd, Multispectral Fluorescence Imaging During
Thomas Zillif,, Nicholas Van Ash, Shankar Siva, Andrei Fodor, Robotassisted Laparoscopic Sentinel Node Biopsy: A
Piet Dirixl, Alfonso Gomez-Iturriaga, Fabio Trippa, Beatrice Dettip First Step Towards a Fluorescence-based Anatomic
Gianluca Ingrosso, Luca Triggiani, Alessio Bruni, Filippo Along, Roadmap
Dries Reynders, Gert De Meerleer, Alessia Surgo, Kaoutar Loukili, N.S. van den Berg, T. Buckle, G.H. KleinJan, H.G. van der Poel,
Raymond Miralbellf, Pedro Silvah, Sarat Chander, Nadia Gisella Di F.W.B. van Leeuwen
Muzio, Ernesto Maranzano, Giulio Francolini, Andrea Lancia, Alison European Urology 2017;72:110–17
Treeh,i, Chiara Lucrezia Deantoni, Elisabetta Ponti, Giulia Marvaso,
Els Goetghebeur, Piet Ost
European Urology, Vol 76, Issue 6, p732–739 2019
Randomized Trial Comparing Open Radical Cystectomy
2021 and Robot-assisted Laparoscopic Radical Cystectomy:
The Clinicopathologic and Molecular Landscape of Clear Oncologic Outcomes
Cell Papillary Renal Cell Carcinoma: Implications in B.H. Bochner, G. Dalbagni, K.H. Marzouk, D.D. Sjoberg, J. Lee,
S.M. Donat, J.A. Coleman, A. Vickers, H.W. Herr, V.P. Laudone
Diagnosis and Management
European Urology, Vol. 74, Issue 4, p465–471
Stanley Weng, Renzo G. DiNatale, Andrew Silagy, Roy Mano,
Kyrollis Attalla, Mahyar Kashani, Kate Weiss, Nicole E. Benfante, 2020
Andrew G. Winer, Jonathan A. Coleman, Victor E. Reuter, Paul Russo,
Robot-assisted AMS-800 Artificial Urinary Sphincter
Ed Reznik, Satish K. Tickoo, A. Ari Hakimi,
European Urology, Vol 79, Issue 4, p468-477 Bladder Neck Implantation in Female Patients with
Stress Urinary Incontinence
2022 Benoit Peyronnet, Gregoire Capon, Olivier Belas, Andrea Manunta,
Is There a Detrimental Effect of Antibiotic Therapy in Clement Allenet, Juliette Hascoet, Jehanne Calves, Michel Belas,
Patients with Muscle-invasive Bladder Cancer Treated Pierre Callerot, Gregoire Robert, Aurelien Descazeaud, Georges
with Neoadjuvant Pembrolizumab? Fournier
Pederzoli F., Bandini M., Raggi D., Marandino L., Basile G., Alfano M., European Urology, Vol 75, Issue 1, p169–175
Colombo R., Salonia A., Briganti A., Gallina A., Montorsi F., Necchi A.
European Urology, Vol 80, Issue 3, p319–322 2021
& Outcomes of Gender Affirming Peritoneal Flap
Effect of Simulation-based Training on Surgical Vaginoplasty Using the Da Vinci Single Port Versus Xi
Proficiency and Patient Outcomes: A Randomised Robotic Systems
Controlled Clinical and Educational Trial Geolani W. Dy, Min Suk Jun, Gaines Blasdel, Rachel Bluebond-
Aydin A., Ahmed K., Abe T., Raison N., Van Hemelrijck M., Garmo H., Langner, Lee C. Zhao
Ahmed H.U., Mukhtar F., Al-Jabir A., Brunckhorst O., Shinohara N., European Urology, Vol 79, Issue 5, p676-683
The Platinum
Hall of Fame
2022 Platinum Award Winners 2018

A DROP-IN Gamma Probe for Robot-assisted 1. Peter Black
2. Christopher Evans
Radioguided Surgery of Lymph Nodes During Radical
3. Joan Palou-Redorta
Prostatectomy
4. Monique Roobol
Paolo Dell’Oglio, Philippa Meershoek, Tobias Maurer,
5. Shahrokh Shariat
Esther M.K. Wit, Pim J. van Leeuwen, Henk G. van der Poel,
Fijs W.B. van Leeuwen, Matthias N. van Oosterom Platinum Award Winners 2019
European Urology, Vol 79, Issue 1, p124–132 1. Stephen Boorjian
2. Fiona Burkhard
Platinum Award Winners 2009 3. Pierre Karakiewicz
1. Fritz Schröder 4. Luis Martinez-Piþeiro
2. Urs Studer 5. Peter Mulders
6. Maria Ribal
Platinum Award Winners 2010
1. Christopher Chapple
1. Prokar Dasgupta
2. Oliver Hakenberg
2. Karim Fizazi
3. Rodolfo Montironi
3. Silke Gillessen
4. Caroline Moore
Platinum Award Winners 2011 5. Declan Murphy
1. Guido Dalbagni 6. Karin Plass
2. Monique J. Roobol
Platinum Award Winners 2012 1. Matthew Cooperberg
1. Anders Bjartell 2. Anthony D’Amico
2. Markus Graefen 3. Emily Zabor
3. Mani Menon
4. Christian Stief Platinum Award Winners 2022
5. Tullio Sulser 1. Morgan Roupre ^t
6. Alexandre Zlotta 2. Stacy Loeb
3. Maria de Santis
Platinum Award Winners 2013 4. Fred Witjes
1. Per-Anders Abrahamsson 5. Borje Ljungberg
2. Walter Artibani
3. Jacqueline Roelofswaard 2007 Reviewers of the Month
4. Maurice Schlief January: Massimo Maezzini (Italy)
5. Claude Schulman February: Hiten R. H. Patel (UK)
6. Pierre Teillac March: Pierre Karakiewicz (Canada)
7. Manfred Wirth April: Christian Gratzke (Germany)
8. Hendrik van Poppel May: Fred Witjes (The Netherlands)
June: Ziya Kirkali (Turkey)
Platinum Award Winners 2014 July: Bertrand Guillonneau (USA)
1. Inderbir Gill August: Chris Chapple (UK)
2. Richard Sylvester September: Axel Heidenreich (Germany)
3. Henk van der Poel October: Jean-Jacques Patard (France)
November: Oliver Reich (Germany)
1. Stephen Freedland Reviewer of the Year 2007
2. Axel Heidenreich Vincenzo Ficarra (Italy)
3. Francesco Montorsi
4. Keith Parsons 2008 Reviewers of the Month
January: Shahrokh Shariat (USA)
February: Alberto Briganti (Italy)
March: Alexander Bachmann (Switzerland)
1. Matthew Gettman
April: Scott Eggener (USA)
2. George Thalmann
May: Roger Dmochowski (USA)
June: Felix K.-H. Chun (Germany)
Platinum Award Winners 2017 July: Giacomo Novara (Italy)
1. Peter Albertsen August: Michael Blute (USA)
2. Axel Bex September: Patrick Bastian (Germany)
3. James N’Dow October: Rafael Badalyan (Armenia)
4. Daniel Sjoberg November: Henk van der Poel (The Netherlands)
The Platinum
Hall of Fame
Reviewer of the Year 2008 September: Sabine Brookman-May (Germany)

Pierre Karakiewicz (Canada) October: Nicolas Mottet (France)
November: Hendrik Isbarn (Germany)
2009 Reviewers of the Month
January: Matthew Gettman (USA) Reviewers of the Year 2012
February: Oliver Hakenberg (Germany) Peter Albertsen (USA)
March: Riccardo Autorino (Italy) Jean-Nicolas Cornu (France)
April: Urs Studer (Switzerland) Gianluca Giannarini (Switzerland)
May: Fritz Schröder (The Netherlands)
June: Petrisor Geavlete (Romania) 2013 Reviewers of the Month
July: Clare Fowler (UK) January: Massimo Lazzeri (Italy)
August: Francisco Cruz (Portugal) February: Guillaume Ploussard (France)
September: John Denstedt (Canada) March: Derya Tilki (Germany)
October: Jacques Irani (France) April: Giuseppe Simone (Italy)
November: Apostolos Apostolidis (Greece) May: Evanguelos Xylinas (USA)
June: Joseph Chin (Canada)
Reviewer of the Year 2009 July: Rodolfo Montironi (Italy)
Henk van der Poel (The Netherlands) August: Matthew Galsky (USA)
September: Hashim Ahmed (UK)
October: Peter Black (Canada)
November: Tobias Klatte (Germany)
January: Ricarda Bauer (Germany)
February: Declan Murphy (Australia) Reviewers of the Year 2013
March: Harry Herr (USA) Francesco Greco (Germany)
April: Marko Babjuk (Czech Republic) Stephen Boorjian (USA)
May: Umberto Capitanio (Italy) Matthew Galsky (USA)
June: Stephen Freedland (USA)
July: Richard Sylvester (Belgium) 2014 Reviewers of the Month
August: Rufus Cartwright (UK) January: Morgan Rouprõt (France)
September: Jens Rassweiler (Germany) February: Malte Rieken (Switzerland)
October: Mike Kattan (USA) March: Jochen Walz (France)
November: George Thalmann (Switzerland) April: Noburo Hara (Japan)
May: Aidan Noon (UK)
Reviewers of the Year 2010 June: Stacy Loeb (USA)
Michael Kattan (USA) July: Dan Sjoberg (USA)
Matthew Gettman (USA) August: Cosimo De Nunzio (Italy)
Giacomo Novara (Italy) September: Michael Abern (USA)
October: Fumitaka Koga (Japan)
2011 Reviewers of the Month November: Christopher Barbieri (USA)
January: Ofer Yossepowitch (Israel)
February: Theo de Reijke (The Netherlands) Reviewers of the Year 2014
March: Evangelos Liatsikos (Greece) Noboru Hara (Japan)
April: Christopher Eden (UK) Aidan Noon (UK)
May: Ofer Gofrit (Israel) Christopher Barbieri (USA)
June: James Catto (UK)
July: R. Houston Thompson (USA) 2015 Reviewers of the Month
August: Karim Bensalah (France) January: Bertram Yuh (USA)
September: Gianluca Giannarini (Italy) February: Francesco Porpiglia (Italy)
October: Mesut Remzi (Austria) March: Henry Woo (Australia)
November: Peter Albertsen (USA) April: Umberto Anceschi (Italy)
Reviewer of the Year 2011 May: Kazutaka Saito (Japan)
Alexander Bachmann (Switzerland) June: Alessandra Mosca (Italy)
July: Giorgio Gandaglia (Italy)
2012 Reviewers of the Month August: Sarah Psutka (USA)
January: Francesco Greco (Germany) September: Daniel Moreira (USA)
February: Stephen Boorjian (USA) October: Boris Gershman (USA)
March: Jean-Nicolas Cornu (France) November: Roderick van den Bergh (The Netherlands)
April: Mark Emberton (UK)
May: Firas Abdollah (Italy) Reviewers of the Year 2015
June: Stephan Madersbacher (Austria) Giorgio Gandaglia (Italy)
July: Michael Rink (Germany) Joseph Chin (Canada)
August: Rik Bryan (UK) Boris Gershman (USA)
The Platinum
Hall of Fame
2016 Reviewers of the Month October: Jacob Patterson (UK)

January: Paolo Verze (Italy) November: Ryan Hutchinson (USA)
February: Liam Bourke (UK)
March: Brant Inman (USA) Reviewers of the Year 2019
April: Maurizio Serati (Italy) Jacob Patterson (UK)
May: William Parker (USA) Daniel Spratt (USA)
June: Homayoun Zargar (Australia) Stephen Williams (USA)
July: Ola Bratt (UK)
August: Riccardo Bartoletti (Italy) 2020 Reviewers of the Month
September: Zachary Klaassen (Canada) January: Mikkel Fode (DK)
October: Francesco Sanguedolce (Italy) February: Marco Borghesi (Italy)
November: Antonio Galfano (Italy) March: Fumitaka Koga (JP)
April: Camilio Porta (Italy)
Reviewers of the Year 2016 May: Jeery Tosoian (USA)
Ola Bratt (Sweden) June: Douglas Cheung (CAN)
Riccardo Bartoletti (Italy) July: Xavier Deeux (France)
Zachary Klassen (Canada) August: Yair Lotan (USA)
September: Daniel Geynisman (USA)
2017 Reviewers of the Month October: Andrea Cocci (Italy)
January: Steeve Doizi (France) November: Riccardo Campi (Italy)
February: Kazuto Ito (Japan)
March: Harras Zaid (USA) Reviewers of the Year 2020
April: Alberto Bossi (France) Riccardo Campi (Italy)
May: Joshua Meeks (USA) Jozefina Casuscelli (Germany)
June: Zoran Culig (Austria) Douglas Cheung (Canada)
July: Nicola Fossati (Italy) Fumitaka Koga (Japan)
August: Alexander Kutikov (USA)
September: Melissa Assel (USA) 2021 Reviewers of the Month
October: Maximilien Gilles-André Baron (France) January: Max Kates (USA)
November: Bimal Bhindi (Canada) February: Mario Álvarez-Maestro (ES)
March: David D’Andrea (Austria)
Reviewers of the Year 2017
April: Christian Meyer (Germany)
Alexander Kutikov (USA)
May: Abdullah Erdem Canda (Turkey)
Melissa Assel (USA)
June: Hendrik Borgmann (Germany)
Nicola Fossati (Italy)
July: Imad Bentellis (FR)
Kazuto Ito (Japan)
August: Laura Marandino (CH)
2018 Reviewers of the Month September: Hanan Goldberg (CAN)
January: Andrea Necchi (USA) October: Neeraj Agarwal (USA)
February: Christopher Wallis (Canada) November: Mary Elizabeth Westerman (USA)
March: Ross Mason (Canada)
April: Joseph Clark (USA) Reviewers of the Year 2021
May: Giorgio Russo (Italy) Mario Álvarez-Maestro (Spain)
June: Benoit Peyronnet (France) Hendrik Borgmann (Germany)
July: Timothy Lyon (USA) Laura Marandino (Switzerland)
August: Ardalan Ahmad (Canada) Mary Elizabeth Westerman (USA)
September: Alastair Lamb (UK)
October: Paul Boutros (Canada)
January: Stephanie Gazdovich (CAN)
November: Paras Shah (USA)
February: Sarah Markt (USA)
Reviewers of the Year 2018 March: Zine-Eddine Khene (FR)
Andrea Necchi (USA) April: Sumanta Pal (USA)
Christopher Wallis (Canada) May: Laura Bukavina (USA)
Alastair Lamb (UK) June: Michiel van der Heijden (NL)
July: Riccardo Bertolo (IT)
August: Roger Li (USA)
January: Keith Lawson (Canada)
September: Carissa Chu (USA)
February: Alessandro Antonelli (Italy)
October: Timothy Clinton (USA)
March: Christopher Filson (USA)
November: Samantha Conroy (UK)
April: Scott Eggener (USA)
May: Sumanta Pal (USA) Reviewers of the Year 2022
June: Panagiotis Kallidonis (Greece) Laura Bukavina (USA)
July: Adam Weiner (USA) Timothy Clinton (USA)
August: Stephen Williams (USA) Stephanie Gazdovich (CAN)
September: Daniel Spratt (USA) Zine-Eddine Khene (FR)
european urology, vol. 82, no vi, December 2022
CONTENTS
The Platinum Hall of Fame e155
10.1016/j.eururo.2022.10.015
Platinum Opinion Methods Modernizing Statistical Reporting in Medical Journals: Challenges and Future 575
Directions
A.J. Vickers, D.D. Sjoberg
Despite the advent of enormous computing power and the switch to the web as the primary
means of reporting empirical research results, papers available online present data on a
screen exactly as if it was a printed page. It is now straightforward to program analyses to
create interactive figures that allow readers to hover the cursor over a graph and see
numerical estimates and tables that allow presentation of data according to user-defined
inputs. We recommend that interactive apps for statistical results be routinely included in
the HTML versions of medical research papers or as supplementary material.
How Advanced Imaging Will Guide Therapeutic Strategies for Patients with Newly 578
Diagnosed Prostate Cancer in the Years to Come
M.G.M. Schilham, M. Rijpkema, T. Scheenen, R. Hermsen, J.O. Barentsz, J.P. Michiel Sedelaar,
H. Kusters-Vandevelde, L.G.W. Kerkmeijer, D.M. Somford, M. Gotthardt
In recent years, clinical use of novel advanced imaging modalities in prostate cancer
detection, staging, and therapy has intensified and is currently reforming clinical guidelines.
In the future, advanced imaging technologies will continue to develop and become even
more accurate, which will offer new opportunities for improving patient selection, surgical
treatment, and radiotherapy, with the potential to guide prostate cancer therapy.
Shaping the Undergraduate Curriculum in Europe: Consensus Statement from the 581
European School of Urology
J. Gómez Rivas, B. Somani, M. Rodriguez Socarrás, G. Marra, I. Pearce, L. Henningsohn, P. Zondervan,
H. Van Poppel, J. N’Dow, E. Liatsikos, J. Palou
The European School of Urology has created a taskforce to develop a comprehensive,
structured urology curriculum with clinical exposure, practical skills, and hands-on training.
The curriculum proposal includes cognitive teaching by symptoms and practical aspects to
guarantee uniform access to undergraduate medical education in urology among all
European countries, regardless of location, local urology exposure, or bias in national
curricula.
Platinum Priority Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with 584
Papers Androgen Deprivation Therapy for Metastatic Hormone-sensitive
Prostate Cancer: A Systematic Review and Meta-analysis
Original Articles, together with T. Yanagisawa, P. Rajwa, C. Thibault, G. Gandaglia, K. Mori, T. Kawada, W. Fukuokaya, S.R. Shim,
the Full Length Editorials H. Mostafaei, R.S. Motlagh, F. Quhal, E. Laukhtina, M. Pallauf, B. Pradere, T. Kimura, S. Egawa, S.F. Shariat
Triplet therapy with androgen receptor signaling inhibitors, docetaxel, and androgen
Prostate Cancer deprivation therapy improved survival endpoints in patients with metastatic hormone-
sensitive prostate cancer (mHSPC) compared with currently available doublet regimens. The
benefit seems to be more reliable in high-volume mHSPC patients.
Triplet Therapy: Entering the Metaverse of Metastatic Hormone-sensitive Prostate 599
Cancer Treatment
H.E. Dzimitrowicz, A.J. Armstrong
Bladder Cancer First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune 602

Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin
K. Meghani, L.F. Cooley, B. Choy, M. Kocherginsky, S. Swaminathan, S.S. Munir, R.S. Svatek, T. Kuzel,
J.J. Meeks
We conducted a phase 1 clinical trial of intravesical pembrolizumab and bacillus Calmette-
Guérin. The trial found both local and systemic toxicity, and identified a subset of patients
who had a longer response with decreased immune exhaustion.
The Evolving Role of Locally Delivered Checkpoint Inhibitors in Non–muscle-invasive 611
Bladder Cancer
D. Hayne, A. Redfern
Kidney Cancer The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell Carcinoma 613
M. Ali, J. Mooi, N. Lawrentschuk, R.R. McKay, R. Hannan, S.S. Lo, W.A. Hall, S. Siva
Stereotactic ablative body radiotherapy (SABR) is associated with good oncological
outcomes and a favourable toxicity profile in patients with localised renal cell carcinoma
(RCC). Intriguing multimodality approaches, which include SABR in the operable setting, are
emerging. In the context of metastatic RCC, SABR alone or in combination with systemic
treatment has shown promising clinical outcomes with minimal toxicity. Other
investigational applications of SABR, including cytoreduction and neoadjuvant SABR, for
primary RCC, oligometastatic RCC in deferring systemic therapy, and oligoprogressive RCC
concurrent with systemic therapy are evolving and should be tested in clinical trials.
Stereotactic Ablative Body Radiotherapy: An Emerging Weapon in the Treatment 623
Armamentarium for Renal Cell Carcinoma or a Potential Avenue for Overtreatment?
D.E. Magee, J.K. Wong, A.F. Correa
Infections Genitourinary Lesions Due to Monkeypox 625
M. Gomez-Garberi, P. Sarrio-Sanz, L. Martinez-Cayuelas, E. Delgado-Sanchez, S. Bernabeu-Cabezas,
J. Peris-Garcia, L. Sanchez-Caballero, B. Nakdali-Kassab, C. Egea-Sancho, E.H. Olarte-Barragan,
M.A. Ortiz-Gorraiz
In our series of 14 patients, 43% sought a consultation for a genitourinary area lesion as the
initial symptom. Hence, urologists have a fundamental role in the differential diagnosis of
monkeypox disease, as it can be confused with sexually transmitted diseases.
Monkeypox and the Urologist: Playing an Important Role in This Emerging Global 631
Outbreak
J.W.F. Catto
Education Optimal Dissemination of Scientific Manuscripts via Social Media: 633
A Prospective Trial Comparing Visual Abstracts Versus Key Figures
in Consecutive Original Manuscripts Published in European Urology
Z. Klaassen, E. Vertosick, A.J. Vickers, M.J. Assel, G. Novara, C. Pierce, C.J.D. Wallis, A. Larcher,
M.R. Cooperberg, J.W.F. Catto, A. Kutikov
Visual abstracts increase the social media reach of new urology literature compared to
manuscript key figures, but were associated with a significantly lower article click-through
rate. In the increasingly virtual world of academic medicine, these findings may assist
authors, editors, and publishers with new research dissemination.
Can We Measure the Academic Impact of Social Media? 637
J.G. Rivas, J.Y.-C. Teoh, G. Cacciamani
Surgery in Motion Robotic Radical Prostatectomy for Prostate Cancer in Renal Transplant Recipients: 639
Results from a Multicenter Series
G. Marra, M. Agnello, A. Giordano, F. Soria, M. Oderda, C. Dariane, M.-O. Timsit, J. Branchereau, O. Hedli,
B. Mesnard, D. Tilki, J. Olsburgh, M. Kulkarni, V. Kasivisvanathan, A. Breda, L. Biancone, P. Gontero,
collaborators
Robotic prostatectomy is safe and feasible in patients with a renal transplant. Oncological
and functional results and complications seem to be similar to those for patients without a
renal transplant, with no cases of graft injury being described.
Full Length Article Elevated T-cell Exhaustion and Urinary Tumor DNA Levels Are Associated with Bacillus 646
Bladder Cancer Calmette-Guérin Failure in Patients with Non–muscle-invasive Bladder Cancer
T. Strandgaard, S.V. Lindskrog, I. Nordentoft, E. Christensen, K. Birkenkamp-Demtröder, T.G. Andreasen,
P. Lamy, A. Kjær, D. Ranti, Y.A. Wang, C. Bieber, F. Prip, J. Rasmussen, T. Steiniche, N. Birkbak,
J. Sfakianos, A. Horowitz, J.B. Jensen, L. Dyrskjøt
High-grade (HG) recurrence of non–muscle-invasive bladder cancer after bacillus Calmette-
Guérin (BCG) may be caused by T-cell exhaustion. Pre-BCG tumor characteristics and tumor
subtype may identify patients at high risk of post-BCG HG recurrence. Urinary
measurements have potential for real-time assessment of treatment response.
Words of Wisdom Re: Tranexamic Acid in Patients Undergoing Noncardiac Surgery 657
M. Stöckle
Re: Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis 658
F.M.E. Wagenlehner, F. Dittmar
Re: Sequential Intravesical Gemcitabine and Docetaxel for Bacillus Calmette-Guérin- 659
naı̈ve High-risk Nonmuscle-invasive Bladder Cancer
M. Kavoussi, A.A. Nasrallah, S.B. Williams
Re: Sperm Count is Increased by Diet-induced Weight Loss and Maintained by Exercise 659
or GLP-1 Analogue Treatment: A Randomized Controlled Trial
S.D. Lokeshwar, A.M. Geada, R. Ramasamy
Re: A Randomized, Single-blind Clinical Trial Comparing Robotic-assisted Fluoroscopic- 660

guided with Ultrasound-guided Renal Access for Percutaneous Nephrolithotomy
E. Ventimiglia, C. Corsini, F. Montorsi, A. Salonia, I.K. Goumas
Re: MRI-guided Focused Ultrasound Focal Therapy for Patients with Intermediate-risk 661
Prostate Cancer: A Phase 2b, Multicentre Study
W.A. Hall, J. Shoag, D.E. Spratt
Research Letter BlaDimiR: A Urine-based miRNA Score for Accurate Bladder Cancer Diagnosis and 663
Follow-up
C. Suarez-Cabrera, L. Estudillo, E. Ramón-Gil, M. Martı́nez-Fernández, J. Peral, C. Rubio, I. Lodewijk,
Á. Martı́n de Bernardo, R. Garcı́a-Escudero, F. Villacampa, J. Duarte, F. de la Rosa, D. Castellano,
F. Guerrero-Ramos, F.X. Real, N. Malats, J.M. Paramio, M. Dueñas
Letters to the Re: James W.F. Catto, Pramit Khetrapal, Federico Ricciardi, et al. Effect of Robot- e165
Editor assisted Radical Cystectomy with Intracorporeal Urinary Diversion vs Open Radical
Cystectomy on 90-Day Morbidity and Mortality Among Patients with Bladder Cancer:
A Randomized Clinical Trial. JAMA 2022;327:2092–103
B. Rocco, M.C. Sighinolfi
Reply to Bernardo Rocco and Maria Chiara SighinolfiÕs Letter to the Editor re: James e167
W.F. Catto, Pramit Khetrapal, Federico Ricciardi, et al. Effect of Robot-assisted Radical
Cystectomy with Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-
Day Morbidity and Mortality Among Patients with Bladder Cancer: A Randomized
Clinical Trial. JAMA 2022;327:2092–103. Lacking the Evidence for Neobladder Use After
Radical Cystectomy
J.W.F. Catto, P. Khetrapal, G. Ambler, N.R. Williams, C. Brew-Graves, J.D. Kelly, iROC Study Team
Re: Daniel J. Lee, Ryan Hausler, Anh N. Le, et al. Association of Inherited Mutations in e169
DNA Repair Genes with Localized Prostate Cancer. Eur Urol 2022;81:559–67
J.L. Dickinson, G.R. Foley, L.M. FitzGerald
Reply to Joanne L. Dickinson, Georgea R. Foley, and Liesel M. FitzGeraldÕs Letter to the e170
Editor re: Daniel J. Lee, Ryan Hausler, Anh N. Le, et al. Association of Inherited
Mutations in DNA Repair Genes with Localized Prostate Cancer. Eur Urol 2022;81:559–
67. Red Flags in Association Analyses for Rare Variants
D.J. Lee, R. Hausler, K.N. Maxwell
Re: Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, et al. Inherited TP53 e172
Variants and Risk of Prostate Cancer. Eur Urol 2022;81:243–50. Off-core Li-Fraumeni
Syndrome Spectrum Cancers: Increasing Interest for Prostate Cancer?
H. Sassi, O. Caron, E. Rouleau
Re: Jens Bedke, Brian I. Rini, Elizabeth R. Plimack, et al. Health-related Quality of Life e174
Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for
Advanced Renal Cell Carcinoma. Eur Urol. 2022;82:427–39
B. Zhao
Re: Bernadett Szabados, Mark Kockx, Zoe June Assaf, et al. Final Results of e176
Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive
Urothelial Cancer of the Bladder. Eur Urol 2022;82:212–22
Z. Zhao, H. Guo, R. Yang
Reply to Leonard P. Bokhorst and Berdine L. HeestermanÕs Words of Wisdom re: High- e177
dose Radiotherapy and Risk-adapted Androgen Deprivation in Localised Prostate
Cancer (DART 01/05): 10-Year Results of a Phase 3 Randomised, Controlled Trial. Eur
Urol. 2022;82:441
A. Zapatero, F.A. Calvo, C. Gonzalez San-Segundo, A. Alvarez
Erratum Erratum to ‘‘Effect of Simulation-based Training on Surgical Proficiency and Patient e179
Outcomes: A Randomised Controlled Clinical and Educational Trial’’ [Eur Urol
2022;81:385–393]
A. Aydın, K. Ahmed, T. Abe, N. Raison, M. Van Hemelrijck, H. Garmo, H.U. Ahmed, F. Mukhtar, A. Al-Jabir,
O. Brunckhorst, N. Shinohara, W. Zhu, G. Zeng, J.P. Sfakianos, M. Gupta, A. Tewari, A. Serdar Gözen,
J. Rassweiler, A. Skolarikos, T. Kunit, T. Knoll, F. Moltzahn, G.N. Thalmann, A.G. Lantz Powers, B.H. Chew,
K. Sarica, M. Shamim Khan, P. Dasgupta
Congress Calendar Congress Calendar e180
Acknowledgement to Reviewers e182

The illustration on the cover of this issue is taken from the article by
M. Gomez-Garberi, P. Sarrio-Sanz, L. Martinez-Cayuelas, et al –
Genitourinary Lesions Due to Monkeypox, which is published
on pp. 625–630 of this issue.
EUROPEAN UROLOGY 82 (2022) 575–577
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Opinion
Methods Modernizing Statistical Reporting in Medical Journals:

Challenges and Future Directions
Andrew J. Vickers *, Daniel D. Sjoberg

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Statisticians today live in a quite different world to our pre- Reporting of biostatistics should, instead, take advantage
decessors. In place of hand calculators and look-up tables, of the interactive nature of the Web. It is now straightfor-
we have laptop computers that can run thousands of com- ward to program analyses that allow statisticians to create
plex calculations in a fraction of a second. Instead of visiting interactive figures and tables, for instance, using plotly [1]
a library to read a journal, we can call up papers on screen for R [2] and Python [3], or Data Tips in SAS. Instead of a sta-
without leaving home. Given such fundamental changes in tic graph, HTML graphs created with plotly or Data Tips pro-
statistical practice, it is somewhat odd that the end product vide additional information when the user hovers the cursor
of our analyses—publication of statistical findings in a scien- over part of the graph, such as percentage survival at a given
tific paper—has barely changed since the time of the hand follow-up time for a survival curve. The user can also hide
calculator. The papers available online present data on a certain lines, highlight others, zoom in and out, and save
screen exactly as if it was a printed page in a hardbound images. Interactive HTML graphs can be incorporated
journal, with graphs and tables not appreciably different directly into HTML documents and websites. Using the
from those published by Fisher or Bradford-Hill. shiny app [4] (for R or Python) or the SAS Visual Analytics
Consider a simple graph such as a survival curve, a application, tables and figures can be created that give users
regression line plotting risk against a biomarker, or an age a variety of display options.
distribution. Such graphs give readers a rapid visual impres- An example shiny app, incorporating interactive plotly
sion of study findings. However, they are limited if a reader graphs and a table, is available at https://sjobergd.shi-
wants to dig deeper and obtain estimates such as the prob- nyapps.io/modernize_reporting_shiny/, with illustrative
ability of 1-, 2-, or 5-yr survival, the risk of positive lymph screenshots shown in Figure 1 and 2. Such an approach
nodes for a prostate-specific antigen (PSA) level of 4 ng/ml allows readers to choose the information they see, and to
versus 10 ng/ml, or the distribution of age. The reader is left dig deeper if they choose. They are not restricted to a set
to do things such as trying to trace up from the x-axis to a of analyses constrained by journal limits. For instance, the
point on the graph and then tracing across to the y-axis, survival curve and table of baseline characteristics reported
and estimating by eye a value between two tick marks. in the shiny app are similar in form to those provided in
Similarly, consider a table of baseline demographic char- many prostate cancer studies, such as the report by Neal
acteristics, which is routine in almost all clinical studies. A et al. [5] published in European Urology in 2020. This paper
statistician might choose to report median and quartile val- cites mortality estimates at 10 yr and gives prostate cancer
ues for, say, the year of enrollment. This would not help a risk in various groups, such as the proportion with PSA >10
reader who wanted to know the number of patients entered ng/ml, and age in median and quartiles. Interactive tables
before a particular year in which adjunctive treatment and graphics would allow a reader to obtain mortality esti-
changed, or one interested in a particular subgroup who mates for any time point, examine the extremes of the dis-
wanted to know about the baseline characteristics of that tribution (rather than just percentage with PSA >10 ng/ml),
subgroup. and other categories that might be of interest (eg, men aged
* Corresponding author. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, New York, NY
10017, USA. Tel. +1 646 8888233.
E-mail address: vickersa@mskcc.org (A.J. Vickers).
https://doi.org/10.1016/j.eururo.2022.09.014
0302-2838/Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
576 EUROPEAN UROLOGY 82 (2022) 575–577
Fig. 1 – Screenshot of shiny applications for presenting data and figures interactively (https://sjobergd.shinyapps.io/modernize_reporting_shiny/): (table of
cohort characteristics and a survival curve. The interactive plotly figure on the right gives the user the ability to hover over the survival curve to obtain
estimates, such as the 5-yr probability of being free of progression along with the number at risk. The panel on the top, implemented in the shiny application,
allows the user to select a subcohort of patients to report the survival curve, in this case, patients with high-grade cancer treated in 2013–2016.
Fig. 2 – Screenshotof shiny applications for presenting data and figures interactively (https://sjobergd.shinyapps.io/modernize_reporting_shiny/): risk curve
and distribution plot. In this case, the user is particularly interested in the risk of lymph node involvement (LNI) at the widely used PSA cutpoint of 10 ng/ml
and in the proportion of patients aged >70 yr. CI = confidence interval; IQR = interquartile range; PSA = prostate-specific antigen.
>70 yr). The shiny app also shows a prostate cancer risk It is notable that interactive statistics are now common-
curve comparable to that reported in European Urology by place in the news media, with recent coverage of the
Canter et al. [6] for a 2019 study on use of a cell cycle score COVID-19 pandemic being an obvious example. It is hard
to predict the risk of metastasis. The shiny app allows read- to understand why science journalism in newspapers such
ers to obtain the central estimate and 95% confidence inter- as the New York Times and the Financial Times, and websites
val for any particular value of interest on the x-axis (eg, a such as Statnews.com and fivethirtyeight.com use interactive
score of 1) rather than trying to guess by eye. statistical reporting, while reporting of scientific data in
Simple interactive graphics, such as plotly figures that medical journals sticks to static graphs and tables. European
show survival probabilities when the mouse hovers over a Urology has now pioneered the interactive approach, pub-
time point, can often require no more than addition of a sin- lishing a paper on a prostate cancer biomarker with a link
gle line of code when used with ggplot2 [7]. More complex to an interactive graphical interface that allows the user
apps, such as a shiny app reporting subgroup analyses, can to specify different criteria for the population of interest [8].
naturally be more cumbersome to build, yet this would rep- That said, incorporation of interactive statistics into
resent only a small investment of time compared to that biomedical publishing presents a number of challenges.
required for data analysis. These are summarized in Table 1 and described in more
EUROPEAN UROLOGY 82 (2022) 575–577 577
Table 1 – Challenges regarding interactive tables and graphics in the by print production. We recommend that interactive apps
biomedical literaturea
for statistical results be routinely included in the HTML ver-
Problem Possible solution sions of medical research papers or as supplementary
Scientific papers are written to A primary set of analyses, graphs, material.
address specific questions and and tables that support the authors’
draw precise conclusions: conclusions should be reported in
interactive statistical results the main text of the paper Conflicts of interest: The authors have nothing to disclose.
could invite p hacking and
similar problems
An app might allow an author to Interactive apps will need to be
modify data after publication or subject to archiving and version
Acknowledgments: This work was supported in part by the National
have results modified by a third control in order to protect the Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer
party integrity of the analyses. Apps Center Support Grant to Memorial Sloan Kettering Cancer Center (P30
would need to be stored either on
CA008748).
the journal’s website or in an
independent repository
Interactive statistics would Peer review would initially focus Supplementary data
constitute an additional burden on the main text of a study report,
of peer review with statistical apps considered
similar to supplementary material Supplementary data to this article can be found online at
in terms of the degree of peer https://doi.org/10.1016/j.eururo.2022.09.014.
review scrutiny
Harm from the possibility of Unclear at the current time
References
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themselves from the self- computing. https://www.r-project.org/.
imposed straightjacket of [3] Python Core Team. Python: a dynamic, open source programming
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A fuller discussion is given in the Supplementary material.
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Ten-year mortality, disease progression, and treatment-related side
effects in men with localised prostate cancer from the ProtecT
randomised controlled trial according to treatment received. Eur
detail in the Supplementary material. In particular, journal Urol 2020;77:320–30.
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a medium, with the stuttering progress towards open access African American and non-African American men with localized
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of medical research data to the static displays necessitated
Platinum Opinion
How Advanced Imaging Will Guide Therapeutic Strategies for

Patients with Newly Diagnosed Prostate Cancer in the Years to Come
Melline G.M. Schilham a,b,c,*, Mark Rijpkema a, Tom Scheenen a, Rick Hermsen d, Jelle O. Barentsz a,
J.P. Michiel Sedelaar b,c, Heidi Kusters-Vandevelde e, Linda G.W. Kerkmeijer f, Diederik M. Somford b,g,
Martin Gotthardt a
a
Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, The Netherlands; b Prosper Prostate Cancer Clinics, Nijmegen/Eindhoven, The
Netherlands; c Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands; d Department of Nuclear Medicine, Canisius Wilhelmina
Hospital, Nijmegen, The Netherlands; e Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; f Department of Radiation
Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands; g Department of Urology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
1. Introduction 2. Patient stratification
Recent developments in (molecular) imaging technologies We expect that the greatest imaging impact will be in
have led to significant changes in diagnostic, staging, and improving risk group stratification for newly diagnosed
therapeutic processes in prostate cancer (PCa). The recent PCa cases in order to separate patients eligible for deferred
inclusion of prebiopsy multiparametric magnetic resonance or active treatment. At present, a shift towards more con-
imaging (mpMRI) in guidelines on the routine clinical work- servative management is evident and increasingly applied
up for primary diagnosis of PCa is a prime example of how for patients with low-risk characteristics and patients in
image guidance can transform PCa management. Another the ‘‘favourable’’ intermediate-risk group (International
example is the rapid worldwide adoption of prostate- Society of Urological Pathology grade group 2) [1]. The cur-
specific membrane antigen (PSMA) positron emission rent challenge is to reliably select patients who benefit from
tomography (PET) imaging to detect locoregional and dis- active surveillance (AS) and those who benefit from active
tant PCa metastases even before the currently growing sci- treatment. Advanced imaging such as mpMRI and PSMA
entific evidence because of its clinical usefulness. PET/CT provides more reliable identification of the true
Advanced imaging is rapidly expanding detection, stag- aggressiveness of a lesion. More precise imaging will facilitate
ing, determination of aggression, and subsequent risk strat- more reliable selection of patients who are fit for AS than is
ification possibilities that directly influence treatment possible with conventional imaging, which is limited by
decisions. In addition, real-time image guidance during sur- underclassification [2]. Furthermore, in the future we will
gery and radiotherapy (RT) has great potential to improve increasingly rely on imaging findings during surveillance pro-
oncological outcomes while reducing side effects. Here we grammes. However, to prevent overtreatment, careful inter-
share our multidisciplinary view of how current and emerg- pretation of results obtained with novel imaging is
ing advanced imaging modalities will influence PCa man- warranted, as the goal should be to enlarge the population
agement over the next years by solving current diagnostic of patients for whom AS is desirable and safe while not incor-
and therapeutic challenges. rectly excluding patients fit for AS on the basis of imaging.
* Corresponding author. Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA
Nijmegen, The Netherlands. Tel. +31 2 43690031.
E-mail address: melline.schilham@radboudumc.nl (M.G.M. Schilham).
3. Lesion localisation and treatment planning 4.1. Image-guided intraoperative surgery
While metastatic disease was considered an incurable con- Although the direct oncological benefit of PLND has not
dition until recently, this position gradually changed with been proven, PLND can still cure patients with limited
the recognition that low-volume metastatic (oligometa- lymph node metastases (LNMs). Furthermore, meticulous
static) disease is potentially curable with local therapy, PLND can indirectly improve survival by identifying
whether combined or not with (neo-)adjuvant systemic patients who need adjuvant treatment. However, the proce-
therapy. However, for oligometastatic disease to be curable dure is widely underutilised and often insufficient, missing
through surgery or RT, two important conditions must be approximately one-third of nodes in the template, including
met: (1) all metastatic sites must be localised, and (2) effec- 13% of LNMs [5]. Image-guided surgery (IGS) has the poten-
tive and definitive therapy must be applied to all metastatic tial to achieve individualised precision surgery in terms of
lesions. Advanced imaging has the potential to meet these both resection accuracy and detailed balancing between
two needs and serve as a guide to improving treatment radicality and side effects. We are still far from the intro-
results. duction of IGS as standard practice, but many promising
Advanced molecular functional imaging modalities such pioneering IGS studies are being conducted [6–8].
as PSMA PET/CT, whole-body diffusion-weighted MRI, and The concept of IGS can be divided into three categories.
ultrasmall superparamagnetic iron oxide (USPIO) particle- First, advances in augmented and virtual reality can allow
enhanced MRI are increasingly used for pretreatment TNM the use of preoperative imaging as a roadmap for surgical
staging. Owing to the limitations for scientific validation, navigation and replace the cognitive roadmaps of urologists
such as the impossibility of obtaining tissue for reference, by providing an overlay of preoperative scans on the laparo-
there is a lack of standards for interpreting imaging results. scopic video feed of the robot console with mechanical or
This prevents assessment of the additional value of these propriosensory information from the robotic system for
new imaging techniques and therefore limits optimal visual registration. The second category is intraoperative
patient management strategies. Although the sensitivity of (molecular) tumour-targeting tracers. Owing to its highly
these novel imaging techniques is not sufficient to com- tumour-specific overexpression on >95% of PCa cells, the
pletely replace pelvic lymph node dissection (PLND), their PSMA receptor is the ideal target for IGS [6]. Using PSMA
negative predictive value for men with a lower risk of nodal targeting molecules (ligands) labelled with low- to mid-
involvement seems sufficient to safely omit this invasive energy gamma-emitting radionuclides (eg, 99mTc and
111
procedure [3,4]. The use of these imaging tools is highly In), PSMA-expressing LNMs can be detected with a
advantageous, considering the low prevalence of N+ disease gamma probe. Combinations of different PSMA ligand labels
on final pathology and the potential significant morbidity of (radionuclides with fluorophores) will improve detection of
PLND. Expected improvements in these technologies will LNMs. Real-time visualisation of metastasis results in an
lead to higher sensitivity and specificity. This will allow optimal surgical balance between radicality and damage
more reliable selection of patients for whom PLND omission to vital structures. The third IGS category is surgical (back
is justified on the one hand, while on the other hand iden- table) ex vivo imaging for verification. Imaging of resected
tifying patients with oligometastatic PCa who are candi- structures (eg, ultra-fast confocal laser imaging or fluores-
dates for therapy with curative intent. cence imaging) allows direct confirmation of complete
In summary, in future PCa guidelines we expect an removal of target lesions [7]. Furthermore, high-resolution
increasing role for advanced imaging in TNM staging and ex vivo imaging of resected specimens (eg, via l single-
treatment planning, particularly in terms of guiding cura- photon emission CT/CT) can optimise histopathological
tive strategies for locoregional nodal or oligometastatic evaluation by directing the pathologist to suspicious tissue
disease. [8].
4.2. Image-guided RT
4. Image-guided therapy
In radiation oncology, imaging has always been a crucial
In patients with locally advanced and locoregional nodal component of treatment planning (CT, MRI, PSMA PET)
disease, novel imaging can provide guidance during both and delivery (cone-beam CT, fiducial markers). However,
lymph node dissection and RT by effectively identifying all recent advances in imaging have led to significant improve-
metastatic lesions. Using image-guided real-time ‘‘precision ments in efficacy and toxicity, and this development is
therapy’’, all lesions can be accurately removed or likely to continue. In RT, the balance between a very high
destroyed, minimising the damage to healthy surrounding radiation dose to the target volumes and minimising the
tissue. It is also possible to combine advanced image- dose to the surrounding tissues is crucial. As imaging
guided oligometastasis therapy (metastases-directed ther- becomes increasingly sensitive and image resolution
apy, MDT) with treatment of the primary tumour. In the improves, opportunities will arise to shift this balance
past, the limited accuracy of conventional imaging is the towards more accurate dose delivery, with an increase in
most likely explanation for failed attempts to prove the tumour control and further reductions in toxicity [9].
benefit of MDT. Therefore, highly sensitive advanced imag- Currently, MRI-guided online adaptive RT (MRgART) sys-
ing techniques could be the key to successful MDT in the tems are being implemented in numerous early adopter
future. centres worldwide and show promising results regarding
efficacy, toxicity, and feasibility. MRgART uses a linear ous disciplines involved in PCa care to determine the best
accelerator with an on-board MRI system to adapt the RT future treatment strategy for individual patients.
contours according to the daily anatomy of the target vol-
umes (intraprostatic lesion, prostate, seminal vesicles, Conflicts of interest: Jelle O. Barentsz is a scientific advisor for SPL Med-
lymph nodes) and surrounding tissues (bladder, rectum, ical B.V. The remaining authors have nothing to disclose.
urethra, penile bulb, anal canal, bowel) and allows active
monitoring of motion during treatment delivery. This online References
MRI guidance and adaptation limits RT-related toxicity to
surrounding and vital organs, while the dose to the tumour [1] Lam TBL, MacLennan S, Willemse P-P-M, et al. EAU-EANM-ESTRO-
ESUR-SIOG prostate cancer guideline panel consensus statements
(dose escalation) and the dose per fraction (hypofractiona- for deferred treatment with curative intent for localised prostate
tion) can be increased [10]. Ultrahypofractionation is cancer from an international collaborative study (DETECTIVE
already widely used for intermediate-risk PCa and could study). Eur Urol 2019;76:790–813.
[2] Sundahl N, Gillessen S, Sweeney C, Ost P. When what you see is not
be used in the future for high-risk and locally advanced
always what you get: raising the bar of evidence for new diagnostic
PCa. Studies on high-risk PCa that combine ultrahypofrac- imaging modalities. Eur Urol 2021;79:565–7.
tionation with a focal RT boost to intraprostatic lesions [3] Baas DJH, Schilham M, Hermsen R, et al. Preoperative PSMA-PET/CT
and/or regional lymph node RT are ongoing [11]. as a predictor of biochemical persistence and early recurrence
following radical prostatectomy with lymph node dissection.
Prostate Cancer Prostat Dis 2022;25:65–70.
[4] Stabile A, Pellegrino A, Mazzone E, et al. Can negative prostate-
5. Conclusions specific membrane antigen positron emission
tomography/computed tomography avoid the need for pelvic
lymph node dissection in newly diagnosed prostate cancer
Owing to technological innovations in imaging modalities, patients? A systematic review and meta-analysis with backup
advanced imaging will undoubtedly affect clinical guideli- histology as reference standard. Eur Urol Oncol 2022;5:1–17.
nes and become increasingly important in guiding the man- [5] Joniau S, Van den Bergh L, Lerut E, et al. Mapping of pelvic lymph
agement of patients with newly diagnosed PCa in the next node metastases in prostate cancer. Eur Urol 2013;63:450–8.
[6] Hensbergen AW, van Willigen DM, van Beurden F, et al. Image-
decade. As advanced imaging has the potential to overcome guided surgery: are we getting the most out of small-molecule
challenges in the diagnostic and therapeutic workflows for prostate-specific-membrane-antigen-targeted tracers? Bioconjug
PCa care, these developments require a reconsideration of Chem 2020;31:375–95.
[7] Vonk J, de Wit JG, Voskuil FJ, et al. Epidermal growth factor receptor
current clinical practice. Increased reliance on imaging for
targeted fluorescence molecular imaging for postoperative lymph
patient stratification will provide for adequate treatment node assessment in patients with oral cancer. J Nucl Med
strategies, including confident AS. Furthermore, advanced 2021;63:672–8.
imaging will provide increasingly sensitive information [8] Schilham MGM, Küsters-Vandevelde H, Somford DM, Rijpkema M,
Gotthardt M. How image-guided pathology can improve the
regarding disease stage, location, and aggressiveness, and detection of lymph node metastases in prostate cancer. Clin Nucl
will subsequently steer effective and definitive treatment Med 2022;47:559–61.
strategies in the future. Lastly, real-time image guidance [9] Tocco BR, Kishan AU, Ma TM, Kerkmeijer LGW, Tree AC. MR-guided
radiotherapy for prostate cancer. Front Oncol 2020;10:616291.
could deliver ‘‘precision therapy’’ in both surgery and RT.
[10] Kerkmeijer LGW, Kishan AU, Tree AC. Magnetic resonance imaging-
Although it may seem appealing to directly implement guided adaptive radiotherapy for urological cancers: what
technological innovations in clinical practice, utilisation of urologists should know. Eur Urol 2022;82:149–51.
the full potential of advanced imaging requires large [11] Brand DH, Tree AC, Ostler P, et al. Intensity-modulated fractionated
radiotherapy versus stereotactic body radiotherapy for prostate
(long-term) prospective studies to validate and properly cancer (PACE-B): acute toxicity findings from an international,
interpret imaging results and to accurately determine their randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol
benefits. This requires close cooperation between the vari- 2019;20:1531–43.
Platinum Opinion
Shaping the Undergraduate Curriculum in Europe: Consensus

Statement from the European School of Urology
Juan Gómez Rivas a,*, Bhaskar Somani b, Moises Rodriguez Socarrás c, Giancarlo Marra d,
Ian Pearce e, Lars Henningsohn f, Patricia Zondervan g, Hendrik Van Poppel h, James N’Dow i,
Evangelos Liatsikos j, Joan Palou k
a
Department of Urology, Hospital Clínico San Carlos, Madrid, Spain; b University Hospital Southampton NHS Trust, Southampton, UK; c Instituto de Cirugía
Urológica Avanzada, Madrid, Spain; d Department of Urology, San Giovanni Battista Hospital, Città della Salute e della Scienza, University of Turin, Turin, Italy;
e
Manchester University NHS Foundation Trust, Manchester, UK; f Department of Urology, Karolinska Institutet, Karolinska University Hospital, Stockholm,
Sweden; g Amsterdam University Medical Centers, Department of Urology, Amsterdam, The Netherlands; h Department of Urology, Katholieke Universiteit,
Leuven, Belgium; i Academic Urology Unit, University of Aberdeen, Aberdeen, UK; j Department of Urology, University Hospital of Patras, Patras, Greece;
k
Department of Urology, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain
1. Introduction addition, it has been recorded that undergraduate exposure

to different specialties correlates with future chosen career
Regardless of their ultimate career intention, all doctors will pathways.
face patients with urological conditions on wards, in the In light of the above, the European School of Urology
emergency department, and in primary care. At least 5– (ESU) created a taskforce to develop a comprehensive,
10% of general practitioner visits and 20% of acute hospital structured urology curriculum comprising clinical exposure,
surgical referrals involve patients with urological problems, practical skills, and hands-on training (HOT).
highlighting the need for robust urological teaching and
training for all medical undergraduates.
To date, there is no standardised pan-European under- 2. Step 1: assessment of the current state of
graduate medical education (UME) curriculum for urology European UME in urology
[1] and data on undergraduate education in Europe are
sparse. In the UK, previous surveys revealed that teaching To assess the current state of urology UME in Europe, we
and training in urology among medical students were performed a pan-European survey [3]. Beyond assessing
highly variable across many different medical schools, trends in UME, we evaluated the relationship between vari-
prompting calls for an undergraduate urological curriculum ables such as the timing of initial urology exposure in med-
to ensure a minimum level of exposure, knowledge, and ical school, theoretical and practical activities, and medical
practical experience [2]. Other surveys of undergraduate student perceptions regarding urology career aspirations.
medical students and newly qualified doctors suggested We found that current exposure to urology at undergradu-
that UME in urology was insufficient to equip individuals ate level in Europe is heterogeneous, with various factors
with the knowledge and skills required for safe functioning influencing future decisions regarding training and special-
as newly qualified junior doctors. The respondents felt that isation. We concluded that a uniform undergraduate cur-
experience in core practical skills such as catheterisation riculum was required to mitigate such heterogeneous
was lacking and many newly qualified doctors were not exposure and produce a workforce capable of catering for
confident in managing basic urological problems [1]. In future urological demand.
* Corresponding author. Department of Urology, Hospital Clínico San Carlos, Calle Profesor Martín Lagos s/n, 28040 Madrid, Spain. Tel. +34 91 3303760.
E-mail address: juangomezr@gmail.com (J. Gómez Rivas).
3. Step 2: deeper evaluation of UME culture and eral factors, often mapped to meet the health care needs of
ways to improve the future patient population and subsequent workforce
requirements [5]. This implies that undergraduate urology
Many questions arose from the aforementioned study, teaching and training should only be aimed at those with
including how to create such a curriculum, and how it could urology career aspirations; however, the urology commu-
be most effectively implemented. To answer these ques- nity must accept that most students will not choose urology
tions, an advisory panel was set up consisting of key opinion as a career, so any proposed urology undergraduate curricu-
leaders with a special interest in UME and training in urol- lum should emphasise aspects pertinent to surgically
ogy, and a survey was designed using Delphi methodology. minded students and also the requirement of a primary care
This survey assessed educational and training gaps, such as physician.
urology programme introduction and duration in UME, dis- The majority of European universities teach urology as a
tribution in universities, and various practical aspects [4]. subspecialty or as part of an organ-specific teaching pro-
Participants agreed on the following points (Table 1): gramme rather than by symptoms, which has previously
been suggested as the ideal curriculum framework and
1. Urological teaching should be introduced before the fifth forms the basis of the British Association of Urological Sur-
year of medical school. geons undergraduate curriculum [6,7]. Surgically minded
2. Urological exposure should consist of at least 20 h of the- students may respond better to a practical-based curricu-
oretical activities. lum. Surprisingly, only 14% of European universities seem
3. Urological exposure should consist of at least 30 h of to adopt this approach, while the majority favour an almost
practical activities.
equal distribution between theory and practical teaching
4. Urology should be taught as a stand-alone subject, rather
[3]. Any urology curriculum should also reinforce basic sur-
than combined with another surgical specialty or a
gical training, including gowning and gloving, aseptic non-
nephrology programme.
touch technique principles, recognition of the
5. Urology should be taught by symptom.
characteristics of surgical instruments, identification and
6. Teaching should include the anatomy and physiology of
the urinary tract. utilisation of the correct techniques for laying safe surgical
7. Students should know how to perform a clinical assess- knots, and being able to explain and practice safe local
ment of a urological patient. anaesthetic techniques. As a part of the curriculum, non-
technical skills should also be addressed [7,8], including sit-
uational awareness, decision-making, communication,
4. Step 3: implications and challenges for
leadership, and teamwork. A safe curriculum should include
implementing change in urology UME
these topics to improve interpersonal, cognitive, and per-
sonal resource skills to help individuals cope with stress
The most challenging aspect for the development of future
and fatigue and enhance their resilience.
curricula is how to change the culture around UME. In Eur-
Here we describe the stepwise approach used by the ESU
ope, undergraduate urology teaching is mandatory in only
looked to address undergraduate urology in Europe. The
76% of universities [3] and the curricula in individual med-
curriculum proposal includes cognitive teaching by symp-
ical schools nationally and internationally are based on sev-
toms and practical aspects that will be delivered via online
tutorials, prerecorded instructional videos on practical
Table 1 – Overview of consensus statements on undergraduate medical skills, and counselling on intimate examination. Wider
education in Europe with a final decision
uptake and use of simulation training models for digital rec-
Urology programme introduction and duration in the undergraduate tal examination and scrotal examination will help in the
curriculum
1 Urology must be introduced in the 5th year of medical school
acquisition of skills and in improving trainee confidence.
2 Urology programmes should have at least 20 h of theoretical Within the current and future digital world, UME should
activities (lectures, classes, etc.) also evolve and embrace technology-based virtual training
3 Urology programmes should have at least 30 h of practical activities
(patients, clinical cases, training models)
[9]. In this way, we can guarantee uniform access to UME
4 The use of training models should be part of the undergraduate in urology in all European countries (Fig. 1). This will stan-
curriculum dardise urology teaching and training at undergraduate
Urology curriculum distribution in universities
5 Urology should be taught as a stand-alone subject
level and will equip all medical graduates with basic knowl-
6 Urology should be mandatory in undergraduate education edge and skills in urology. UME across Europe is likely to
7 Urology has to be taught by symptoms (haematuria, lower urinary improve and the curriculum will ensure that all students
tract symptoms, etc.)
Practical curriculum
have balanced exposure to theory, HOT, and practical uro-
8 Students should perform digital rectal examination logical skills. The model may not only inform and stimulate
9 Students should perform abdominogenital examination the future workforce but is also likely to be adopted and
10 Students should perform urethral catheterisation
11 It is mandatory for students to know how to perform a clinical
implemented by medical schools throughout the rest of
assessment of a urological patient the world.
12 Urology programmes should include a recap of the anatomy, The development and evolution of ‘‘checkpoints’’ for
physiology, and semiology of the urinary tract
13 Medical students should rate urology and give feedback
implementation will also be required and remain work in
14 Students are attracted by urology as a specialty progress, with several challenges to overcome. There are
15 By the time that students choose their training, urology makes a high very few incentives to engage in education; unlike research,
impact in residency choice
there is little dedicated time, sparse funding, and very few
Fig. 1 – Undergraduate urology curriculum proposal from the European School of Urology.
hybrid job opportunities for those with a keen interest in [2] Yap C, Rosen S, Sinclair AM, Pearce I. What undergraduate factors
influence medical students when making their choice of
education. If we are able to build a system with a greater
postgraduate career? Br J Med Surg Urol 2012;5:11–5. 10.1016/j.
number of highly skilled and trained educators, we can bjmsu.2011.10.004.
hopefully create future generations of urologists actively [3] Gómez Rivas J, Rodriguez Socarrás M, Somani B, et al. Undergraduate
involved in undergraduate education with the dual aim of education for urology in Europe. Where do we stand? Eur Urol
2020;78:381–4. 10.1016/j.eururo.2020.05.037.
ensuring that all medical graduates are urologically compe-
[4] Gómez Rivas J, Somani B, Rodriguez Socarrás M, et al. Essentials for
tent at a defined level and attracting high-quality colleagues standardising the undergraduate urology curriculum in Europe:
to pursue a career in urology. outcomes of a Delphi consensus from the European School of
This final aim, of course, starts at the beginning of a med- Urology. Eur Urol Open Sci 2021;33:72–80. 10.1016/J.
EUROS.2021.09.003.
ical career: all current experts were once first-year medical [5] Sharma M, Murphy R, Doody GA. Do we need a core curriculum for
undergraduates and we need to stimulate and fascinate medical students? A scoping review. BMJ Open 2019;9:e027369.
medical students to enable them to make an informed [6] Scott R, Sinclair AM, Pearce I. Is there a need for an undergraduate
urological curriculum? Br J Med Surg Urol 2012;5:16–9. 10.1016/j.
career choice and aspire to a future in urology.
bjmsu.2011.11.001.
[7] Agha RA, Fowler AJ, Sevdalis N. The role of non-technical skills in
surgery. Ann Med Surg 2015;4:422–7. 10.1016/j.amsu.2015.10.006.
Conflicts of interest: The authors have nothing to disclose. [8] Yule S, Flin R, Paterson-Brown S, Maran N, Rowley D. Development of
a rating system for surgeons’ non-technical skills. Med Educ
References 2006;40:1098–104. 10.1111/j.1365-2929.2006.02610.x.
[9] Pang KH, Carrion DM, Gomez Rivas J, et al. The impact of COVID-19
[1] Jones P, Rai BP, Qazi HAR, Somani BK, Nabi G. Perception, career on European health care and urology trainees. Eur Urol 2020;78.
choice and self-efficacy of UK medical students and junior doctors in 10.1016/j.eururo.2020.04.042.
urology. Can Urol Assoc J 2015;9:E573–8. 10.5489/cuaj.2919.
Platinum Priority – Review – Prostate Cancer

Editorial by Hannah E. Dzimitrowicz, Andrew J. Armstrong on pp. 599–601 of this issue
Androgen Receptor Signaling Inhibitors in Addition to Docetaxel

with Androgen Deprivation Therapy for Metastatic Hormone-
sensitive Prostate Cancer: A Systematic Review and Meta-analysis
Takafumi Yanagisawa a,b, Pawel Rajwa a,c, Constance Thibault d, Giorgio Gandaglia e,
Keiichiro Mori b, Tatsushi Kawada a,f, Wataru Fukuokaya b, Sung Ryul Shim g, Hadi Mostafaei a,h,
Reza Sari Motlagh a,i, Fahad Quhal a,j, Ekaterina Laukhtina a,k, Maximilian Pallauf a,l,
Benjamin Pradere a,m, Takahiro Kimura b, Shin Egawa b, Shahrokh F. Shariat a,k,n,o,p,q,r,*
a
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; b Department of Urology, The Jikei University School of
Medicine, Tokyo, Japan; c Department of Urology, Medical University of Silesia, Zabrze, Poland; d Department of Medical Oncology, Hopital Européen Georges
Pompidou, Institut du Cancer Paris CARPEM, AP-HP Centre, Paris, France; e Unit of Urology/Division of Oncology, IRCCS San Raffaele, San Raffaele Hospital,
Milan, Italy; f Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;
g
Department of Health and Medical Informatics, Kyungnam University College of Health Sciences, Changwon, Republic of Korea; h Research Center for Evidence
Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; i Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of
Medical Sciences, Tehran, Iran; j Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia; k Institute for Urology and Reproductive
Health, Sechenov University, Moscow, Russia; l Department of Urology, Paracelsus Medical University Salzburg, University Hospital Salzburg, Salzburg, Austria;
m
Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France; n Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University,
Amman, Jordan; o Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; p Department of Urology, Second Faculty of
Medicine, Charles University, Prague, Czech Republic; q Department of Urology, Weill Cornell Medical College, New York, NY, USA; r Karl Landsteiner Institute of
Urology and Andrology, Vienna, Austria
Article info Abstract
Article history: Context: Recent randomized controlled trials (RCTs) examined the role of adding andro-
Accepted August 3, 2022 gen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalu-
tamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and
Associate Editor: androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive
Todd M. Morgan prostate cancer (mHSPC).
Objective: To analyze the oncologic benefit of triplet combination therapies using ARSI +
Statistical Editor: DOC + ADT, and comparing them with available treatment regimens in patients with
mHSPC.
Andrew Vickers Evidence acquisition: Three databases and meetings abstracts were queried in April
2022 for RCTs analyzing patients treated with first-line combination systemic therapy
for mHSPC. The primary interests of measure were overall survival (OS) and
Keywords: progression-free survival (PFS). Subgroup analyses were conducted to assess the differ-
Androgen receptor signaling ential outcomes in patients with low- and high-volume disease as well as de novo and
inhibitor metachronous metastasis.
* Corresponding author. Department of Urology, Medical University of Vienna, Wahringer Gurtel 43

18-20, 1090 Vienna, Austria. Tel. +4314040026150; Fax: +4314040023320.
E-mail address: shahrokh.shariat@meduniwien.ac.at (S.F. Shariat).
0302-2838/Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Docetaxel Evidence synthesis: Overall, 11 RCTs were included for meta-analyses and network meta-
Metastatic hormone-sensitive analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in
prostate cancer terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65–0.84) and
PFS (pooled HR: 0.49, 95% CI: 0.42–0.58). There was no statistically significant difference
between patients with low- and high-volume disease in terms of an OS benefit from adding
an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outper-
formed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55–
Please visit www.eu-acme.org/europeanurology 0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51–0.91, and ENZ + DOC + ADT: HR:
to answer questions on-line. The EU-ACME cred- 0.70, 95% CI: 0.53–0.93). An analysis of treatment ranking among de novo mHSPC patients
its will then be attributed automatically. showed that triplet therapy had the highest likelihood of improved OS in patients with
high-volume disease; however, doublet therapy using ARSI + ADT had the highest likeli-
hood of improved OS in patients with low-volume disease.
Conclusions: We found that the triplet combination therapy improves survival endpoints
in mHSPC patients compared with currently available doublet treatment regimens. Our
findings need to be confirmed in further head-to-head trials with longer follow-up and
among various patient populations.
Patient summary: Our study suggests that triplet therapy with androgen receptor signal-
ing inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with
metastatic hormone-sensitive prostate cancer compared with the current standard dou-
blet therapy.
Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
1. Introduction 2. Evidence acquisition
The management of metastatic hormone-sensitive prostate The protocol has been registered in the International
cancer (mHSPC) is rapidly evolving [1–7]. The current stan- Prospective Register of Systematic Reviews database (PROS-
dard of care combines androgen deprivation therapy (ADT) PERO: CRD42022298107).
with other systemic therapies, either docetaxel (DOC) or an
androgen receptor signaling inhibitor (ARSI) [1–7]. Today, 2.1. Search strategy
there is no clear consensus on their comparative efficacy
This meta-analysis and NMA was conducted based on the
[8–11]. Although limited evidence of the STAMPEDE trial
guidelines of the Preferred Reporting Items for Meta-
did not show a superior benefit of any combination [12],
analyses of Observational Studies in Epidemiology State-
network meta-analyses (NMAs) have reported that ARSIs
ment (Supplementary Fig. 1) [17]. In April 2022, a literature
might be the best treatment option regarding overall sur-
search was performed in the PubMed, Web of Science, and
vival (OS) [8–11]. ARSIs, DOC, and ADT have different mech-
Scopus databases to identify studies investigating the onco-
anisms of targeting androgen receptors and prostate cancer
logic outcomes of systemic therapy for mHSPC. The detailed
cells, thus potentiating the effect of combination therapy
search strategy is shown in the Supplementary material.
[13]. Some evidence could also be derived from the recent
Furthermore, we also reviewed abstracts presented at
trials that aimed to assess the impact of ARSI + ADT versus
recent major conferences, such as the American Society of
ADT for mHSPC, which allowed the use of DOC before or at
Clinical Oncology and the European Society for Medical
the time of randomization [1,3,14]. In addition, recent ran-
Oncology, to include unpublished RCTs and trial updates.
domized controlled trials (RCTs), such as the PEACE-1 or
The primary outcome of interest was OS; secondary out-
ARASENS trials, aiming directly at analyzing the impact of
comes were progression-free survival (PFS) and adverse
triplet combination therapies showed a significant OS ben-
events (AEs). Two investigators performed initial screening
efit with ARSI + DOC + ADT compared with DOC + ADT
based on the titles and abstracts to identify eligible studies.
[15,16]. However, as most of these data are preliminary,
Potentially relevant studies were subjected to a full-text
the clinical impact of the triplet treatment for mHSPC
review. Additionally, manual searches of the reference lists
remains unproven. Furthermore, there are no head-to-
of relevant articles were performed to identify additional
head comparisons regarding triplet therapy versus
studies of interest. Disagreements were resolved by consen-
ARSI + ADT, and little is known regarding the true treatment
sus with coauthors.
benefit of DOC in these combinations. We believe that clar-
ification of these controversies may provide an immense
2.2. Inclusion and exclusion criteria
impact on future trials. Therefore, we conducted this sys-
tematic review, meta-analysis, and NMA to analyze the Studies were deemed eligible if those analyzed patients
oncologic outcomes of combination therapy with ARSI + D with mHSPC (patients), who were treated with triplet com-
OC + ADT and to compare its efficacy with currently avail- bination therapy using ARSI + DOC + ADT (interventions),
able treatments. and compared them with patients treated with other
currently available treatment strategies (comparisons), to column or pelvic bone [7,21]. Odds ratios (ORs) were
assess the differential effects of treatment on OS, PFS, and calculated to compare AEs of the triplet treatment arms
AEs (outcome) only in RCTs (study design). Studies with those of the DOC + ADT arms. A fixed-effect model
lacking original patient data, reviews, letters, editorial was used for calculations of HRs and ORs [22]. Heterogene-
comments, replies from authors, case reports, and articles ity among the outcomes of included studies in this
not written in English were excluded. In cases of duplicate meta-analysis was assessed using Cochrane’s Q test. When
cohorts, the higher-quality or most recent publication was significant heterogeneity (p < 0.05 in the Cochrane’s Q test)
selected. Thus, we solely selected the arm C versus arm G was observed, we attempted to investigate the cause of
of the STAMPEDE trial, reported by Sydes et al [12], to avert heterogeneity [23]. All analyses were conducted using R
the cohort’s duplication. However, this study did not version 4.0.3 (R Foundation for Statistical Computing,
provide subgroup analyses based on disease volume Vienna, Austria), and the statistical significance level was
(high- vs low-volume); thus, we selected the other two set at p < 0.05.
studies from the STAMPEDE trial for subgroup analyses
[6,18,19]. Regarding the ARSI + ADT arm, we included only 2.5.2. Network meta-analysis
abiraterone acetate (ABI) + ADT from the LATITUDE trial, For OS and PFS, an NMA using random-effect models with a
as none of the patients received DOC [4]. References of all frequentist approach was performed for direct and indirect
included papers were scanned for additional studies of treatment comparisons [24,25]. In the assessment of OS and
interest. PFS, contrast-based analyses were applied with estimated
differences in the log HR, and the standard error was calcu-
2.3. Data extraction
lated from the published HR and CI [26]. The relative effects
Data were extracted independently by two authors. The were presented as HRs and 95% CIs [24]. For OS and PFS,
first author’s name, publication year, inclusion criteria, subgroup analyses for high- versus low-volume disease
agents, agent dosage, number of patients, age, de novo dis- and de novo versus metachronous metastasis were con-
ease, disease volume, number of patients treated with DOC, ducted. For comparing AEs, arm-based analyses were per-
and follow-up periods were extracted. Subsequently, the formed to estimate the ORs of the AEs (and 95% CIs) from
hazard ratios (HRs) and 95% confidence intervals (CIs) form the available data presented in the included articles. We
Cox regression models for OS and PFS, and the number of also estimated the relative ranking of the different treat-
any AEs, severe AEs (Common Terminology Criteria for ments for each outcome using the surface under the cumu-
Adverse Events [CTCAE] grade 3–5), and other drug- lative ranking (SUCRA) [24]. Network plots were utilized to
specific events were retrieved. For a fair comparison of AE illustrate the connectivity of the treatment networks in
rates between different treatment exposure durations, in terms of OS, PFS, and AEs. Heterogeneity was assessed using
severe AEs, we calculated the exposure-adjusted incidence Cochrane’s Q test when more than one trial was available
rates (EAIRs); an EAIR is defined as the number of patients for a given comparison. All statistical analyses were per-
with a given event divided by the total treatment duration formed using R version 4.0.3 (R Foundation for Statistical
of all patients in years, if treatment duration data were Computing).
available. All discrepancies were resolved by consensus
with coauthors. 3. Evidence synthesis
2.4. Risk of bias assessment

3.1. Study selection and characteristics
An assessment of study quality and risk of bias was carried
Our initial search identified 671 records. After removing
out using the Cochrane Handbook for Systematic Reviews of
duplicates, 554 records remained for screening of titles
Interventions risk-of-bias tool (version 2; Supplementary
and abstracts (Fig. 1). After screening, 526 articles were
Fig. 2) [20]. The risk-of-bias figure was created using Review
excluded and a full-text review of 28 articles/abstracts
Manager 5.3 software (RevMan; The Cochrane Collabora-
was performed. According to our inclusion criteria, we
tion, Oxford, UK). The risk-of-bias assessment of each study
finally identified 11 RCTs comprising 7679 patients eligible
was performed independently by two authors.
for meta-analyses and NMAs [1–7,12,14–16,18,19,27–30].
The demographics of each included study are shown in
2.5. Statistical analyses
Table 1. Of 11 RCTs, only the ARASENS trial assessed the
2.5.1. Meta-analysis OS difference between darolutamide (DAR) + DOC + ADT
Forest plots with HRs were used to analyze the relation- and DOC + ADT as a primary endpoint [16]. The patients
ships between combination therapy and survival outcomes. treated with DOC in addition to ARSI + ADT in the PEACE-
PFS was defined as the time from treatment initiation to 1, ARCHES, ENZAMET, and TITAN trials were extracted from
radiological progression, clinical progression, or death. For their subgroup analyses [14,27,31,32]. The percentage of
OS and PFS, subgroup analyses were conducted among high-volume disease patients was the highest at 82% in
patients with high- versus low-volume disease and de novo the LATITUDE trial, owing to the inclusion of high-risk
versus metachronous metastasis. High-volume disease was patients only [4]. The percentages of patients with high-
defined following the CHARRTED trial as the presence of volume disease included in the other trials ranged from
visceral metastases, or four or more bone metastases, of 48% to 66%. The median follow-up duration ranged from
which at least one must be located outside the vertebral 34 to 83.9 mo.
Idenficaon of studies via databases and registers
Records idenfied through PUBMED, Web of Science,

Idenficaon Scopus:
Search Query:
prostate cancer AND (metastac OR advanced) AND
(castraon sensive OR castraon naïve OR hormone
sensive OR hormone naïve) AND randomized
(n = 671)
Screening
Records excluded aer tle and abstract

removed review (n = 526)
・Nonrelevant according to inclusion
criteria (n = 412)
・Review arcle (n = 101)
・Leer/Editorial comment (n = 8)
・Other than English (n = 5)
eligibility
Eligibility
Records excluded aer evaluaon

(n = 11)
・Nonclear data regarding associaon
between the systemic therapy and
oncologic outcomes
Included
Studies included in meta-analysis

(n = 17: 11RCTs)
Fig. 1 – The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart, detailing the article selection process.
RCT = randomized controlled trial.
3.2. Risk of bias assessment Among de novo mHSPC patients, addition of an ARSI to
DOC + ADT also reduced the risk of death (pooled HR:
The risk of bias judgments of each domain for each included
0.72, 95% CI: 0.62–0.84, p < 0.001; Supplementary Fig. 2).
study is summarized in Supplementary Figure 1. All
There were no statistical differences in HRs for OS and PFS
included studies had a low risk of bias owing to the nature
between the concomitant and sequential use of DOC
of the selected studies, that is, prospective randomized
(p = 0.4; Supplementary Fig. 3). The Cochrane’s Q tests
phase 3 trials.
revealed no significant heterogeneity among all analyses
of OS and PFS.
3.3. Meta analysis of ARSIs with DOC plus ADT versus DOC plus
ADT
3.3.2. Differences of OS and PFS between patients with high-
The results of the meta-analysis are described and summa- and low-volume disease
rized in Figure 2 and Table 2. Two studies comprising 1213 patients provided data on OS
and PFS in mHSPC patients separately for high- and low-
3.3.1. OS and PFS volume disease. Addition of an ARSI to DOC + ADT reduced
Five studies comprising 2837 patients provided data on OS the risk of death in patients with high-volume disease
and PFS in mHSPC patients treated with systemic therapy, (pooled HR: 0.79, 95% CI: 0.63–0.99, p = 0.039); it did not
ARSI + DOC + ADT versus DOC + ADT. As shown in Table 2, reach statistical significance in terms of OS in patients with
addition of an ARSI to DOC + ADT reduced the risk of death low-volume disease (pooled HR: 0.79, 95% CI: 0.50–1.23,
(pooled HR: 0.74, 95% CI: 0.65–0.84, p < 0.001) and progres- p = 0.3; Supplementary Fig. 4). However, there was no
sion (pooled HR: 0.49, 95% CI: 0.42–0.58, p < 0.001; Fig. 2). statistically significant difference between patients with
Table 1 – Study demographics of included studies
588
PEACE-1 ARASENS ARCHES ENZAMET TITAN LATITUDE STAMPEDE STAMPEDE STAMPEDE CHAARTED GETUG-
(arm G) (arms C, G) (arm B, C, E) AFU15
Author Fizazi [15] Smith [16] Armstrong Davis [3] Chi [14]] Fizazi [4] James [19]/ Sydes [12] Clarke [18] Kyriakopoulos Gravis [29]/
[1]/Azad [28] Hoyle [6] [7] Gravis [5]
Year 2022 2022 2019/2022 2019 2021 2019 2017/2019 2018 2019 2018 2013/2016
Treatment arm Abiraterone Darolutamide Enzalutamide Enzalutamide Apalutamide Abiraterone Abiraterone Abiraterone Docetaxel Docetaxel Docetaxel
+ SOC (±RT） + docetaxel + ADT + ADT + ADT + ADT + ADT + ADT + ADT + ADT + ADT + ADT
Dosage 1000 mg Darolutamide: 160 mg 160 mg 240 mg 1000 mg 1000 mg 1000 mg 75 mg/m2 75 mg/m2 75 mg/m2
600 mg
Docetaxel:
75 mg/m2
Control arm SOC (±RT） Placebo Placebo + ADT NSAA + ADT Placebo Placebo ADT Docetaxel ADT ADT ADT
+ docetaxel + ADT + ADT + ADT + ADT
b
Inclusion criteria De novo mHSPC mHSPC mHSPC mHSPC High-risk mHSPC mHSPC b mHSPC mHSPC mHSPC
mHSPC de novo
mHSPC a
Number of patients 1172 1306 1150 1125 1152 1199 1917 (990 b) 566 (392 b) 1086 790 385
Treatment 583 651 574 563 525 597 960 (493 b) 377 (277 b) 362 397 192

Control 589 655 576 562 527 602 957 (497 b) 189 (115 b) 724 393 193
Age (yr), median
Treatment 66 (IQR: 60– 67 (range: 41–89) 70 (range: 46– 69.2 (IQR: 69 (range: 67.3 ± 8.5 67 (IQR: 63– 66 (IQR: 61– 65 (IQR: 60–70) 64 (range: 36– 63 (IQR: 57–
70) 92) 63.2–74.5) 45–94) (mean ± SD) 72) 70) 88) 68)
Control 66 (IQR: 59– 67 (range: 42–86) 70 (range: 42– 69 (IQR: 63.6– 68 (range: 66.8 ± 8.7 67 (IQR: 63– 66 (IQR: 62– 65 (IQR: 60–71) 63 (range: 39– 64 (IQR: 58–
70) 92) 74.5) 43–90) (mean ± SD) 72) 71) 91) 70)
De novo disease (%)
Treatment 100 86 73 58 82 100 94 93 96 73 68
Control 100 87 72 58 85 100 96 97 95 73 66
Disease volume
(high/low c; %)
Treatment 63/37 NA 62/38 52/48 62/38 82/18 54/46 NA 54/46 66/34 48/52
Control 65/35 NA 65/35 53/47 64/36 78/22 51/49 NA 57/43 64/36 47/53
No. of docetaxel patients
Treatment 355 All 103 254 58 No use No use NA NA NA NA
Control 355 102 249 55
HR for OS (95% CI)
All 0.82 0.68 0.66 0.6 0.67 0.66 0.61 1.13 0.81 0.72 0.88
(0.69–0.98) (0.57–0.80) (0.53–0.81) (0.52–0.86) (0.51–0.89) (0.56–0.78) (0.49–0.75) (0.77–1.66) (0.69–0.95) (0.59–0.89) (0.68–1.14)
De novo metastasis 0.71 NA 0.65 0.68 0.59 NA NA 0.68 0.93
(0.59–0,85) (0.47–0.89) (0.55–0.85) (0.47–0.74) (0.54–0.85) (0.69–1.25)
Prior local treatment NA 0.65 NA 0.7 0.39 NA NA NA NA 0.97 0.83
(0.35–1.05) (0.47–1.09) (0.22–0.69) (0.58–1.62) (0.47–1.47)
Docetaxel cohort 0.75 (0.59– 0.68 (0.57–0.80) 0.74 (0.46– 0.9 (0.62– 1.12 (0.59– NA NA NA NA NA NA
0.95) 1.2) 1.31) 2.12)
HR for PFS (95% CI) rPFS Time to CRPC rPFS cPFS rPFS rPFS PFS rPFS rPFS cPFS rPFS
All 0.54 0.36 0.39 0.40 0.48 0.47 0.45 0.69 0.69 0.62 0.69
(0.44–0.67) (0.30–0.42) (0.3–0.5) (0.33–0.49) (0.39–0.60) (0.39–0.55) (0.37–0.54) (0.50–0.95) (0.59–0.81) (0.51–0.75) (0.55–0.87)
Docetaxel cohort 0.5 0.36 0.52 0.48 0.47 NA NA NA NA NA NA
(0.4–0.62) (0.30–0.42) (0.3–0.89) (0.37–0.62) (0.22–1.01)
Follow-up (mo), median 45.7 (46.2/ 43 (43.7/42.4) 44.6 34 44 51.8 40 48 78.2 53.7 83.9
(treatment/control arm) 45.0)
ADT = androgen deprivation therapy, APA = apalutamide; CI = confidential interval; cPFS = clinical PFS; CRPC = castration-resistant prostate cancer; DOC = docetaxel; HR = hazard ratio; IQR = interquartile range;
mHSPC = metastatic hormone-sensitive prostate cancer; NA = not applicable; NSAA = nonsteroidal antiandrogen; OS = overall survival; PFS = progression-free survival; rPFS = radiographic PFS; RT = radiotherapy; SD = s-
tandard deviation; SOC = standard of care.
a
High risk was defined with at least two of the following risk factors: (1) Gleason score 8, (2) at least three bone metastases, and (3) visceral metastasis.
b
HR was included only for mHSPC patients in this meta-analysis.
c
High volume was defined with one of the two following risk factors: (1) at least four bone metastases (with one or more beyond the vertebral bodies and pelvis) and (2) visceral metastasis.
Fig. 2 – Forest plots showing association of ARSI + DOC + ADT versus DOC + ADT with (A) OS and (B) PFS in mHSPC patients. ADT = androgen deprivation
therapy; ARSI = androgen receptor signaling inhibitor; CI = confidence interval; DOC = docetaxel; HR = hazard ratio; mHSPC = metastatic hormone-sensitive
prostate cancer; OS = overall survival; PFS = progression-free survival.
Table 2 – Summary of oncologic impact of triplet therapy and its differential outcomes stratified by clinical settings
Meta-analysis of ARSI + DOC + ADT vs Network meta-analysis

DOC + ADT
OS, pooled HR (95% PFS, pooled HR (95% Best treatment probability ranking for OS
CI) CI)
All patients 0.74 (0.65–0.84) 0.49 (0.42–0.84) DAR + DOC: 88% > ABI + DOC: 79% > ENZ + DOC: 66% > ABI: 50% >
DOC: 41%
High-volume 0.79 (0.63–0.99) 0.49 (0.40–0.59) ABI + DOC: 91% > ABI: 74% > ENZ + DOC: 47% > DOC: 36%
Low-volume 0.79 (0.50–1.23) 0.50 (0.36–0.70) ENZ + DOC: 84% > ABI: 67% > ABI + DOC: 49% > DOC: 28%
Patients with de novo metastasis 0.72 (0.62–0.84) NA DAR + DOC: 84% > ABI + DOC: 76% > ABI: 61% > DOC: 29%
High-volume NA ABI + DOC: 97%> ABI: 56% > DOC: 48%
Low-volume ABI: 83% > ABI + DOC: 59% > DOC: 43%
Patients with metachronous NA APA: 91% > DAR + DOC: 74% > ENZ: 55% > DOC: 40% > ABI: 22% a
metastasis
ABI = abiraterone acetate; ADT = androgen deprivation therapy; APA = apalutamide; ARSI = androgen receptor signaling inhibitor; CI = confidence interval;
DAR = darolutamide; DOC = docetaxel; ENZ = enzalutamide; HR = hazard ratio; NA = not applicable; OS = overall survival; PFS = progression-free survival.
a
Analysis included docetaxel cohort in the ARCHES, TITAN, and ENZAMET trials.
low- and high-volume disease in terms of an OS benefit all cohorts from the TITAN and ARCHES trials for an AE anal-
from adding an ARSI to DOC +ADT (p = 1). In addition, addi- ysis owing to the use of DOC before randomization.
tion of an ARSI to DOC + ADT reduced the risk of progression
irrespective of tumor burden (Supplementary Fig. 5). The 3.4.2. All patients
Cochrane’s Q tests revealed no significant heterogeneity 3.4.2.1. Overall survival. Nine studies were included in
among all analyzed endpoints. this NMA to assess the primary outcome of OS. As shown
in Table 2 and Figure 3, addition of an ARSI to DOC + ADT
3.3.3. Adverse events reduced the risk of death (DAR + DOC + ADT: HR: 0.68,
The AE profiles, including the EAIRs of severe AEs (CTCAE 95% CI: 0.56–0.82, and ABI + DOC + ADT: HR: 0.75, 95% CI:
grade 3) are shown in Table 3. Three studies comprising 0.58–0.97; Fig. 3B). Furthermore, addition of DOC to
2498 patients with concomitant use of ARSIs and DOC pro- ARSI + ADT also reduced the risk of death (DAR + DOC +
vided data on the incidence of clinically relevant AE profiles ADT: HR: 0.74, 95% CI: 0.55–0.99; Fig. 3C). Based on the
(Supplementary Fig. 6). Addition of an ARSI to DOC + ADT SUCRA analysis of treatment rankings for OS, triplet therapy
increased the incidence of severe AEs (pooled OR: 1.28, had a high likelihood of providing the maximal OS benefit
95% CI: 1.06–1.54, p = 0.009; Supplementary Fig. 6B). On (DAR + DOC + ADT: 88%, ABI + DOC + ADT: 79%; Supplemen-
the contrary, pooled EAIRs of severe AEs were comparable tary Fig. 8A). We did not find any significant heterogeneity
between ARSI + DOC + ADT (25%) and DOC + ADT (33%). for all results.
Regarding hematologic AEs, addition of an ARSI to
DOC + ADT did not increase the incidence of febrile neu- 3.4.2.2. Progression-free survival. Eight studies were
tropenia (FN) and severe neutropenia (Supplementary included in this NMA to assess the PFS. The results are
Fig. 6C and 6D). On the contrary, for nonhematologic AEs, shown in Table 2 and Figure 4. Addition of an ARSI to
addition of an ARSI to DOC + ADT increased the incidence DOC + ADT reduced the risk of progression (enzalutamide
of severe hypertension (CTCAE grade 3; pooled OR: 1.96, [ENZ] + DOC + ADT: HR: 0.49, 95% CI: 0.39–0.61, and
95% CI: 1.42–2.70, p < 0.001; Supplementary Fig. 6I). There ABI + DOC + ADT: HR: 0.50, 95% CI: 0.40–0.62; Fig. 4B). Fur-
were no differences in the rates of the other AEs. The thermore, addition of DOC to ARSI + ADT also reduced the
Cochrane’s Q tests revealed no significant heterogeneity risk of progression (ENZ + DOC + ADT: HR: 0.68, 95% CI:
among the endpoints analyzed, except for the rate of 0.51–0.91, and ABI + DOC + ADT: HR: 0.70, 95% CI: 0.53–
peripheral neuropathy. 0.93; Fig. 4C). Based on the SUCRA analysis of treatment
rankings for OS, triplet therapy had a high likelihood of pro-
3.4. NMA of differential oncologic and safety outcomes viding the maximal PFS benefit (apalutamide [APA] + DOC +
between DOC with/without ARSI plus ADT ADT: 85%, ENZ + DOC + ADT: 74%, ABI + DOC + ADT: 72%;
Supplementary Fig. 8B). We did not find any significant
3.4.1. Study selection
heterogeneity for all results.
All 11 included studies were eligible for this NMA to com-
pare the OS of available systemic combination treatment 3.4.3. Patients with de novo or metachronous metastasis
regimens. However, the ARASENS trial was ineligible for All six studies were included in this NMA to assess the out-
the analyses of PFS, lacking data for this endpoint [16]. In come of OS in de novo and metachronous mHSPC patients.
the ENZAMET, ARCHES, and TITAN trials, only patients trea- In patients with de novo mHSPC patinets, addition of an
ted with DOC were extracted and analyzed for the NMAs ARSI to DOC + ADT reduced the risk of death (DAR + DOC +
[14,27,32]. As previously mentioned, arm C versus arm G ADT: HR: 0.71, 95% CI: 0.55–0.92; Supplementary Fig. 9B).
of the STAMPEDE trial, reported by Sydes et al [12], was Based on the SUCRA analysis of treatment rankings for OS,
selected to analyze OS and PFS of all cohorts to avoid data triplet therapies had a high likelihood of providing the max-
duplication. As for a subgroup analysis of high- and low- imal OS benefit (DAR + DOC + ADT: 84% and ABI + DOC +
volume disease patients, the PEACE-1, ENZAMET, GETUG- ADT: 76%; Supplementary Fig. 9C). The outcomes of OS in
15, CHARRTED, and LATITUDE trials, and two studies from metachronous mHSPC patients are depicted in Supplemen-
the STAMPEDE trial assessing the differential effect tary Figure 10. Treatment rankings revealed that ARSI
between oncologic outcomes and tumor burden were (APA) + ADT had the highest likelihood of providing the
selected for NMAs [3–7,18,31]. For a subgroup analysis of maximal benefit on OS (91%); however, these findings are
patients with de novo or metachronous metastasis, the limited due to a low number of available studies and
PEACE-1, ARASENS, ARCHES, TITAN, ENZAMET, GETUG-15, patients, resulting in a wide range of 95% CIs of HRs for
CHARRTED, and LATITUDE trials, and one study from the OS. We did not find any significant heterogeneity for all
STAMPEDE trial were selected for NMAs [3–7,14–16,27]. results.
The networks of eligible comparisons are graphically
described as network plots addressing all survival end- 3.4.4. Patients with high-volume disease
points (Supplementary Fig. 7). Results of NMAs comparing Seven and four studies were included in this NMA to assess
the combinations and currently available regimens are the OS and PFS stratified by tumor burden in all and de novo
depicted in Table 2. mHSPC patients, respectively.
For analyses of AEs, ten RCTs reporting any and severe
(CTCAE grade 3) AEs, and clinically relevant AEs were eli- 3.4.4.1. Overall survival. Among patients with high-
gible for NMAs [1–4,12,15,16,19,29,30]. We extracted the volume mHSPC, addition of an ARSI to DOC + ADT reduced
data of DOC cohort from the ENZAMET trial and included the risk of death (ABI + DOC + ADT: HR: 0.72, 95% CI:
0.55–0.95; Supplementary Fig. 11). As shown in Table 2, tri- combination. Third, our NMAs revealed that triplet therapy
plet therapy had the highest likelihood of providing the (eg, DAR + DOC + ADT) was associated with better OS than
maximal OS benefit in both all and de novo mHSPC patients ARSI-based doublet therapy. Third, based on treatment
based on treatment rankings for OS (ABI + DOC + ADT: 91% ranking analysis, triplet therapy demonstrated the highest
and 97%, respectively; Supplementary Fig. 11C and 12C). likelihood of an OS benefit in patients with high-volume
We did not find any significant heterogeneity for all results. disease; this was not true for patients with de novo low-
volume disease who were most likely to benefit from
3.4.4.2. Progression-free survival. Addition of an ARSI to ARSI-based doublet therapy.
DOC + ADT reduced the risk of progression (ABI + DOC + A Our analysis showed that the triplet therapy outper-
DT: HR: 0.47, 95% CI: 0.37–0.60, and ENZ + DOC + ADT: formed DOC + ADT in terms of OS and PFS in mHSPC
HR: 0.51, 95% CI: 0.38–0.69; Supplementary Fig. 13). In patients. In recent years, combination treatment with DOC
addition, addition of DOC to ARSI +ADT also reduced the risk or ARSIs plus ADT has become the first treatment option
of progression (ABI + DOC + ADT: HR: 0.62, 95% CI: 0.45– for mHSPC patients [33]. Despite limited direct compar-
0.85, and ENZ + DOC + ADT: HR: 0.67, 95% CI: 0.47–0.97; isons, data from separate RCTs showed that DOC + ADT
Supplementary Fig. 13). Treatment rankings showed that and ARSI + ADT decreased the risk of death by 12–28%
triplet therapies had a high likelihood of providing the max- [5,7,18] and 33–39% [1,3,4,6,14,19,28], respectively, when
imal PFS benefit (ABI + DOC + ADT: 92% and ENZ + DOC + compared with ADT alone. Four NMAs, assessing the com-
ADT: 83%; Supplementary Fig. 13). We did not find any sig- parative effectiveness of the currently available treatment
nificant heterogeneity for all results. options, concluded that the oncologic benefit of
DOC + ADT was likely inferior to all ARSI + ADT combina-
3.4.5. Patients with low-volume disease tions [8–11]. Moreover, cost effectiveness and quality-
3.4.5.1. Overall survival. As shown in Table 2 and Supple- adjusted life-year assessments suggested more favorable
mentary Figure 14, addition of an ARSI to DOC + ADT did not results for ARSI combination therapies than DOC + ADT
improve OS significantly (ENZ + DOC + ADT: HR: 0.65, 95% [34–36]. On the contrary, initial data from the STAMPEDE
CI: 0.25–1.71, and ABI + DOC + ADT: 0.83, 95% CI 0.50– trial directly comparing ABI + ADT (n = 377) to DOC + ADT
1.38). This was also seen in patients with de novo mHSPC. (n = 189) showed no clear advantage of any specific treat-
Treatment rankings revealed that ARSI + ADT had the high- ment strategy with comparable OS; however, better PFS
est likelihood of providing the maximal OS benefit in was provided with ABI + ADT [12]. Considering their mech-
patients with de novo metastasis (ABI + ADT: 86%; Supple- anisms of action and the differences in treatment applica-
mentary Fig. 15). We did not find any significant hetero- tions, the hypothesis has arisen that triplet combination of
geneity for all results. ARSI + DOC + ADT might lead to even better survival than
any doublet combination.
3.4.5.2. Progression-free survival. Addition of an ARSI to Our NMAs revealed that triplet therapy was the best
DOC + ADT reduced the risk of progression (ENZ + DOC + treatment combination among the currently available com-
ADT: HR: 0.37, 95% CI: 0.20–0.68, and ABI + DOC +ADT: binations with regard to an OS benefit. The PEACE-1 study,
HR: 0.58, 95% CI: 0.38–0.89); however, addition of DOC to which assessed the efficacy of adding ABI to ADT ± DOC,
ARSI +ADT did not reduce the risk of progression (Supple- revealed that the combination treatment with ABI + DOC +
mentary Fig. 16). Triplet therapies had a high likelihood of ADT was associated with better radiographic PFS and OS
providing the maximal benefit for PFS based on treatment [31]. More recently, the ARASENS study, which assessed
rankings (ENZ + DOC + ADT: 96%, followed by ABI + DOC + the impact of adding DAR to DOC + ADT, demonstrated an
ADT: 73%; Supplementary Fig. 16). We did not find any sig- OS benefit for DAR + DOC + ADT compared with
nificant heterogeneity for all results. DOC + ADT [16]. Based on these trials and our NMAs, one
can conclude that DAR + DOC + ADT and ABI + DOC + ADT
3.4.6. Adverse events
significantly improve OS compared with DOC + ADT. Fur-
The available results from eight studies were included in
thermore, triplet therapy using DAR + DOC + ADT was asso-
this NMA. Compared with ADT alone, combination thera-
ciated with better OS than ARSI-based doublet therapy, the
pies with DOC, such as DOC + ADT and ARSI + DOC + ADT,
current standard treatment. The population selection of the
had a higher likelihood of any and severe AEs (Fig. 5). Based
LATITUDE trial, which assessed the impact of ABI + ADT ver-
on the SUCRA analyses, triplet therapy had the lowest like-
sus ADT alone in high-risk mHSPC patients, was the strictest
lihood of safety concerning any and severe AEs (Supplemen-
among included studies, including 100% de novo patients
tary Fig. 17). Other relevant AE profiles are summarized in
and the highest number of high-volume disease patients
Supplementary Figure 18.
[4]. These aspects need to be considered in the interpreta-
tion of our analyses; nevertheless, triplet therapy demon-
3.5. Discussion
strated improved OS compared with ABI + ADT
This is the first meta-analysis and NMA to analyze and com- (ARSI + ADT arm); these findings could change clinical prac-
pare the novel promising triplet combination therapies in tice and stimulate the future clinical trials. Furthermore, tri-
patients with mHSPC. There are several key findings to plet combination regimens outperformed ARSI + ADT in
our study. First, triplet therapy, addition of an ARSI to terms of PFS. Indeed, our results suggest that the addition
DOC + ADT, improved both OS and PFS. Second, triplet ther- of DOC to ARSI + ADT improves PFS in mHSPC patients. It
apy improved PFS compared with any available doublet has to be acknowledged that PFS has not been found to be
Table 3 – Profile of adverse events in included studies
592
Study name Year Treatment duration (mo) Adverse events, number of patients (%)
Any Grade 3–5 Details and drug-specific events
Treatment arm Control arm Treatment arm Control arm Treatment arm Control arm Treatment arm Control arm
PEACE-1 2022 32.0 21.3 346/347 (99.7%) 349/350 (99.7%) 217/347 (63%) 181/350 (52%) FN: 18/346 (5.2%) FN: 19/350 (5.4%)
EAIR: 23% EAIR: 29% Neutropenia (G3): 34/346 (9.8%) Neutropenia (G3): 32/350 (9.1%)
Hepatotoxicity (G3): 20/347 (5.8%) Hepatotoxicity (G3): 2/350 (0.6%)
Fatigue (any): 146/347 (42%) Fatigue (any): 134/350 (38%)
Neuropathy (any): 140/347 (40%) Neuropathy (any): 125/350 (36%)
ARASENS 2022 31.8 22.2 649/652 (99.5%) 643/650 (98.9%) 458/652 (70%) 439/650 (68%) FN: 51/652 (7.8%) FN: 48/650 (7.4%)
EAIR: 27% EAIR: 37% Neutropenia (G3): 220/652 (34%) Neutropenia (G3): 222/650 (34%)
Anemia (any): 181/652 (28%) Anemia (any): 163/650 (25%)
Cardiovascular (any): 71/652 (11%) Cardiovascular (any): 76/650 (12%)
Neuropathy (any): 76/652 (12%) Neuropathy (any): 67/650 (10%)
ARCHES 2019 40.2 13.8 487/572 (85%) 493/574 (86%) 139/572 (24%) 147/574 (26%) Cardiovascular (any): 23/572 (4.0%) Cardiovascular (any): 17/574 (3.0%)
EAIR: 7.2% EAIR: 22% Fatigue (any): 112/572 (20%) Fatigue (any): 88/574 (15%)
Hot flush (any): 155/572 (27%) Hot flush (any): 128/574 (22%)

a a a
ENZAMET 2019 NA NA 563/563 (100%) 548/558 (98%) 321/563 (57%) 241/558 a (43%) FN: 35/254 (14%) b FN: 32/246 (13%) b
Fatigue (any): 199/254 (78%) b Fatigue (any): 166/246 (67%) b
Neuropathy (any): 117/254 (46%) b Neuropathy (any): 172/246 (29%) b
TITAN 2021 39.3 20.2 507/524 a (96.8%) 509/527 a (96.6%) 221/524 a (42%) 215/527 a (41%) Cardiovascular (any):31/524(5.9%) a Cardiovascular (any): 11/527 (2.1%) a
EAIR: 13% EAIR: 24% Fatigue (any): 103/524 (20%) a Fatigue (any): 88/527 (17%) a
Rash (any): 142/ 524 (27%) a Rash (any): 45/ 527 (8.5%) a
LATITUDE 2019 25.8 14.4 558/597 (93.5%) 557/602 (92.5%) 374/597 (63%) 287/602 (48%) Cardiovascular (any): 74/597 (12%) Cardiovascular (any): 47/602 (7.8%)
EAIR: 29% EAIR: 40% Hypertension (G3): 121/597 (20%) Hypertension (G3): 60/602 (10%)
AST increase (G3): 26/597 (4.4%) AST increase (G3): 9/602 (1.5%)
STAMPEDE (arm G) 2017 33.2 NA 943/948 a (99.4%) 950/960 a
(99.0%) 443/948 a (47%) 315/960 a (33%) Cardiovascular (any): 168/948 (18%) a Cardiovascular (any): 105/960 (11%) a
EAIR: 17% Hypertension (G3): 44/948 (4.6%) a Hypertension (G3): 13/960 (1.4%) a
Hepatotoxicity (G3): 70/948 (7.4%) a Hepatotoxicity (G3): 12/960 (1.3%) a
Fatigue (any): 551/948 (58%) a Fatigue (any): 648/960 (68%) a
STAMPEDE c 2018 NA NA 370/373 (99.1%) 172/172 (100%) 180/373 (48%) 86/172 (50%) FN: 3/373 (0.8%) FN: 29/172 (17%)
(arms C, G) Cardiovascular (any): 32/373 (8.6%) Cardiovascular (any): 6/172 (3.5%)
Fatigue (G3): 8/373 (2.1%) Fatigue (G3): 7/172 (4.1%)
STAMPEDE 2019 NA NA 362/362 (100%) 703/724 (97%) 141/362 (39%) 179/724 (25%) Neutropenia (G3): 65/362 (18%) Neutropenia (G3): 8/724 (1.1%)
(arms B, C, E) Cardiovascular (any): 27/331 (8.2%) Cardiovascular (any): 64/735 (8.7%)
CHARRTED 2015 NA NA ND ND 114/390 (29%) ND FN: 24/390 (6.2%) ND
Neutropenia (G3): 47/390 (12%)
Fatigue (G3): 16/390 (4.1%)
GETUG-AFU15 2013 NA NA ND FN: 15/189 (8%) FN: 0/186 (0%)
Neuropathy: 54/189 (29%) Neuropathy: 7/186 (3.8%)
AST = aspartate aminotransferase; EAIR = exposure-adjusted incidence rates; FN = febrile neutropenia; NA = not applicable; ND = no data.
EAIR was defined as the number of patients with a given event divided by the total treatment duration of all patients in years; the rate is expressed in 100 patient-years.
a
Described as entire cohort.
b
Described as docetaxel cohort.
c
Defined treatment arm as abiraterone.
Fig. 3 – Forest plots showing the association of systemic therapy for mHSPC with OS: (A) comparison with ADT alone, (B) comparison with DOC + ADT, and (C)
comparison with ARSI (ABI) + ADT. ABI = abiraterone; ADT = androgen deprivation therapy; APA = apalutamide; ARSI = androgen receptor signaling inhibitors;
CI = confidence interval; DAR = darolutamide; DOC = docetaxel; ENZ = enzalutamide; HR = hazard ratio; mHSPC = metastatic hormone-sensitive prostate
cancer; OS = overall survival.
a surrogate endpoint for OS in mHSPC [37]. Nevertheless, therapy could improve distant oncologic outcomes in
PFS is an important endpoint itself, as it leads to a change patients with mHSPC with a significant impact on long-
of therapy. Thus, taken together, our data signal that triplet term oncologic outcomes.
Fig. 4 – Forest plots showing the association of systemic therapy for mHSPC with PFS: (A) comparison with ADT alone, (B) comparison with DOC + ADT, and (C)
comparison with ARSI (ABI) + ADT. ABI = abiraterone; ADT = androgen deprivation therapy; APA = apalutamide; ARSI = androgen receptor signaling inhibitors;
CI = confidence interval; DOC = docetaxel; ENZ = enzalutamide; mHSPC = metastatic hormone-sensitive prostate cancer; PFS = progression-free survival.
Fig. 5 – Forest plots showing the association of systemic therapy for mHSPC with AE: (A) any AE and (B) severe AE (CTCAE grade 3). ABI = abiraterone;
ADT = androgen deprivation therapy; AE = adverse event; APA = apalutamide; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse
Events; DAR = darolutamide; DOC = docetaxel; ENZ = enzalutamide; mHSPC = metastatic hormone-sensitive prostate cancer; OR = odds ratio.
Based on our NMAs, our sensitivity analysis among de GETUG-15, CHARRTED, and STAMPEDE trials with a median
novo metastasis patients suggested the limited utility of 6 yr of follow-up showed that an OS benefit from DOC + ADT
adding DOC to ARSI (ABI) + ADT for low-volume disease was seen in patients with both high-volume (HR: 0.60, 95%
(Table 2). High-volume disease generally represents an CI: 0.52–0.68) and low-volume (HR: 0.78, 95% CI: 0.64–
aggressive feature of disease with a higher likelihood of 0.94) disease [39]. However, the authors concluded that
involving androgen receptor–independent cells [38]. In line patients with low-volume and metachronous disease
with this scenario, the CHARRTED trial showed that the OS should be managed differently based on less survival bene-
benefit of DOC + ADT was most prominent in mHSPC fit than those with high-volume and/or de novo disease
patients with high-volume disease [21]. Hence, it seems [39]. Therefore, longer follow-ups are needed to clarify a
rational that addition of DOC to ARSI + ADT in patients with survival benefit from adding DOC to ARSI + ADT in patients
high-volume disease might lead to better outcomes. with low-volume disease; notably, a head-to-head compar-
By contrast, low-volume disease generally has longer ison of DOC + ARSI + ADT versus ARSI + ADT are awaited.
survival and less heterogeneous tumor biology. The results On the contrary, our meta-analyses showed no statisti-
from the STAMPEDE trial with long-term follow-ups (78 cally significant difference between patients with low-
mo) demonstrated comparable impact of DOC + ADT combi- and high-volume disease in terms of an OS benefit from
nation therapy on OS between patients with low-volume adding an ARSI to DOC +ADT. Indeed, the ARASENS trial
(HR: 0.76, 95% CI: 0.54–1.07) and high-volume (HR: 0.81, lacks data of differential OS stratified by tumor burden.
95% CI: 0.64–1.02) disease [18]. In addition, a recent Therefore, limited available data and insufficient statistical
meta-analysis using individual participant data from the power make drawing conclusions uncertain. In the
PEACE-1 trial, 5-yr OS was 60% for DOC + ADT and 68% for regimens is the best for each clinical setting due to the lim-
ARSI + DOC + ADT in low-volume disease compared with ited number of studies assessing the outcomes stratified by
31% for DOC + ADT and 50% for ARSI + DOC + ADT in de novo/metachronous or tumor burden. In addition, we
high-volume disease [15]. These differences in absolute need to wait for the results of the ARANOTE trial (Clini-
estimates might suggest that the addition of an ARSI to calTrials.gov identifier: NCT04736199) assessing
DOC + ADT actually work better in high-volume disease. DAR + ADT versus ADT alone in mHSPC patients, in order
The potential OS benefit from triplet therapy in mHSPC to conclude the comparative efficacy of DAR with other
patients with low-volume disease remains controversial. ARSIs. Fourth, as mentioned above, for the ARSI
However, together with our results from NMAs, the benefit (ABI) + ADT arm, we included only the LATITUDE trial as
seems to be reliable in those with high-volume disease. no patient received DOC in the control arm. To prevent a
Finally, regarding AEs, our findings indicate that DOC- serious selection bias, we did not include the control
related hematologic AEs such as FN and severe neutropenia cohorts from the ENZAMET, ARCHES, and TITAN trials, as a
do not increase when adding an ARSI to DOC + ADT. How- significant proportion of patients in the arms either
ever, ARSI + DOC + ADT was associated with a higher inci- received or did not receive DOC. Finally, the ENZAMET trial
dence of severe AEs compared with DOC + ADT. included the use of nonsteroidal antiandrogen therapy with
Furthermore, our NMAs revealed that triplet therapy had ADT in the control arm. This might provide a differential
the lowest likelihood of safety concerning AEs compared survival benefit in the control arm, therefore weighing
with doublet therapy. By contrast, treatment duration of against the survival outcomes of ENZ.
the treatment arm was obviously longer than that of the
control arm (Table 1). Therefore, for a fair comparison of
AE rates between different treatment exposure duration, 4. Conclusions
recent RCTs proposed the evaluation of EAIRs [15,16]. Our
results showed that the pooled EAIRs of severe AEs were We found that the triplet therapy reduces the risk of death
higher for DOC-based combination therapy than for ARSI- and progression endpoints in patients with mHSPC com-
based combination therapy (29 vs 17 per 100 patient- pared with currently available doublet treatment regimens.
year), while those were comparable between triplet therapy The efficacy of triplet therapy appears to be reliable in
and DOC + ADT. A recent published meta-analysis assessing patients with high-volume disease, while the potential ben-
the benefit-harm balance in mHSPC treatment showed that efit in patients with low-volume disease is still controver-
ARSI-based doublet therapy had high probabilities for a net sial. However, triplet therapy had the highest likelihood of
clinical benefit; however, DOC-based doublet as well as tri- increased rates of AEs. Based on efficacy and AEs, further
plet therapy appeared unlikely to be beneficial [40]. The studies with long-term follow-up are needed to select
authors also highlighted that any combination systemic mHSPC patient populations, which are most likely to benefit
therapy did not show a clear benefit of health-related qual- from triplet therapy in terms of quality-adjusted survival.
ity of life compared with to ADT alone [40]. Although our
analyses showed a survival benefit of triplet therapy, pre-
cise comprehension of AE rates (ie, using EAIRs) and weigh- Author contributions: Takafumi Yanagisawa had full access to all the
ing up the risks and benefits are mandatory to provide a data in the study and takes responsibility for the integrity of the data
personalized treatment approach and guide clinical and the accuracy of the data analysis.
decision-making.
The present study has several limitations that need to be Study concept and design: Yanagisawa, Rajwa, Shariat.
considered. First, this meta-analysis and NMA included Acquisition of data: Yanagisawa, Rajwa.
RCTs that differed in patient populations, such as the pro- Analysis and interpretation of data: Yanagisawa, Rajwa.
portion with de novo disease, disease burden, and rate Drafting of the manuscript: Yanagisawa, Rajwa.
and type of sequential therapies. Therefore, we conducted Critical revision of the manuscript for important intellectual content:
sensitivity analyses of de novo/metachronous metastasis Thibault, Gandaglia, Mori, Kawada, Mostafaei, Motlagh, Quhal,
and tumor burden. However, results need to be interpreted Laukhtina, Pallauf, Pradere.
with caution due to the limited number of patients, events, Statistical analysis: Yanagisawa, Rajwa, Fukuokaya, Shim.
and included studies, thus decreasing statistical power. In Obtaining funding: None.
addition, NMAs have a limited role in facilitating proper Administrative, technical, or material support: None.
patient selection for current treatment options. Thus, this Supervision: Kimura, Egawa, Shariat.
approach cannot substitute for a direct comparison of each Other: None.
treatment and is mostly hypothesis generating; our findings
need to be validated in head-to-head, well-designed RCTs. Financial disclosures: Takafumi Yanagisawa certifies that all conflicts of
Second, the follow-up duration of each included study was interest, including specific financial interests and relationships and affili-
somewhat different, thus affecting the number of survival ations relevant to the subject matter or materials discussed in the manu-
events. Further follow-ups of recently published RCTs are script (eg, employment/affiliation, grants or funding, consultancies,
warranted to clarify the potential benefit of triplet therapy honoraria, stock ownership or options, expert testimony, royalties, or
for low-volume disease. Third, despite showing an OS ben- patents filed, received, or pending), are the following: Shin Egawa is a
efit of triplet therapy compared with ARSI + ADT, our anal- paid consultant/advisor of Takeda, Astellas, AstraZeneca, Sanofi, Janssen,
yses have a limited role for assessing which combination and Pfizer. Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer,
Janssen, and Sanofi. Shahrokh F. Shariat reports receiving honoraria from analysis of the randomized, double-blind, phase III TITAN study. J
Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Clin Oncol 2021;39:2294–303.
[15] Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added
Roche, and Takeda; having a consulting or advisory role in Astellas, Astra-
to androgen deprivation therapy and docetaxel in de novo
Zeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Pierre Fabre, metastatic castration-sensitive prostate cancer (PEACE-1): a
Roche, and Takeda; and being in the speakers’ bureau of Astellas, Astra multicentre, open-label, randomised, phase 3 study with a 2 2
Zeneca, Bayer, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Richard factorial design. Lancet 2022;399:1695–707.
Wolf, Roche, and Takeda. The other authors declare no conflicts of interest [16] Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in
metastatic, hormone-sensitive prostate cancer. N Engl J Med
associated with this manuscript.
2022;386:1132–42.
[17] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that
Funding/Support and role of the sponsor: This work was supported by evaluate health care interventions: explanation and elaboration.
the EUSP Scholarship of the European Association of Urology (Pawel PLoS Med 2009;6:e1000100.
Rajwa). [18] Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to
hormonal therapy in low- and high-burden metastatic hormone
sensitive prostate cancer: long-term survival results from the
Peer Review Summary STAMPEDE trial. Ann Oncol 2019;30:1992–2003.
[19] James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate
cancer not previously treated with hormone therapy. N Engl J Med
Peer Review Summary and Supplementary data to this arti- 2017;377:338–51.
cle can be found online at https://doi.org/10.1016/j.eururo. [20] Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane
2022.08.002. Collaboration’s tool for assessing risk of bias in randomised trials.
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Platinum Priority – Editorial

Referring to the article published on pp. 584–598 of this issue
Triplet Therapy: Entering the Metaverse of Metastatic

Hormone-sensitive Prostate Cancer Treatment
Hannah E. Dzimitrowicz, Andrew J. Armstrong *

Department of Medicine, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA
Systemic treatment options for patients with metastatic feasibility of sequential use of these ARSIs after docetaxel
hormone-sensitive prostate cancer (mHSPC) have evolved in combination with ADT, and clearly showing significant
dramatically in recent years on the basis of clear evidence delays in PFS in this subgroup of docetaxel-pretreated
that treatment intensification at an early stage improves men with mHSPC, although an OS benefit was not clear
survival and delays progression over androgen deprivation and the trials were not designed or adequately powered
therapy (ADT) alone. Initially, evidence supported the use to address this question of triple therapy [1–3].
of doublet therapy, with the addition of either docetaxel Identification of patient subgroups most likely to benefit
chemotherapy or one of multiple approved androgen recep- from treatment intensification, specifically the incorpora-
tor signaling inhibitors (ARSIs), including abiraterone acet- tion of docetaxel, is important to individualize treatment
ate, apalutamide, and enzalutamide, to ADT, each of which decisions and optimize treatment intensification for those
provided similar and meaningful clinical benefits in specific men most likely to benefit while minimizing the harms
trials [1–5]. Two randomized control trials (RCTs), PEACE-1 and added costs for those men who do not clearly benefit.
and ARASENS, recently compared triplet therapy (docetaxel In the phase 3 CHAARTED trial evaluating docetaxel + ADT
+ ARSI + ADT) to docetaxel + ADT and clearly demonstrated compared to ADT in mHSPC, patients were stratified by dis-
better overall survival (OS) with triplet therapy, making tri- ease volume, with high-volume disease defined as visceral
plet therapy a new standard of care for patients with metastases and/or four or more bone metastases, with at
mHSPC, particularly in high-volume and de novo mHSPC least one outside the vertebral column and pelvis [5]. An
[6,7]. Still, outstanding questions remain as to which OS benefit was observed for patients with high-volume dis-
patients might benefit most from this further intensification ease, whereas no OS benefit was seen for patients with low-
of systemic therapy given the added toxicity and temporary volume disease [5]. By contrast, a benefit of ARSI addition to
quality-of-life impact of docetaxel, as well as how to apply ADT was seen across subgroups stratified by disease volume
these results to clinical practice. or risk [1–3,8]. In PEACE-1, patients with high-volume dis-
In PEACE-1, addition of abiraterone to docetaxel plus ease according to CHAARTED criteria had significantly bet-
ADT significantly improved progression-free survival (PFS) ter OS, while OS data for patients with low-volume
and OS in comparison to docetaxel + ADT alone [6]. In ARA- disease were immature and thus any potential OS benefit
SENS, addition of darolutamide to docetaxel plus ADT sig- in this population is not yet clear owing to lower event rates
nificantly improved OS [7]. On the basis of these results, over time [6]. Patients were not stratified and the data have
darolutamide was recently approved by the US Food and not yet been reported by disease volume in ARASENS for
Drug Administration for use in combination with docetaxel darolutamide outcomes [7].
and ADT for patients with mHSPC. In addition to these stud- In this issue of European Urology, Yanagisawa et al. [9]
ies of concurrent ARSI + docetaxel, the registrational trials of report results of a systematic review, meta-analysis, and
enzalutamide and apalutamide allowed some patients to network meta-analysis (NMA) undertaken to evaluate the
receive prior docetaxel, demonstrating the safety and outcomes of triplet therapy involving docetaxel + ARSI + ADT
DOI of original articles: https://doi.org/10.1016/j.eururo.2022.08.002

* Corresponding author. Department of Medicine, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Box 103861,
Durham, NC 27710, USA. Tel. +1 919 6684667.
E-mail address: andrew.armstrong@duke.edu (A.J. Armstrong).
and to compare its efficacy with currently available doublet alone and thus are generally not necessarily practice- or
therapies in mHSPC. They identified 11 RCTs comprising guideline-changing by themselves.
7679 patients, including the previously mentioned trials, Triplet therapy with docetaxel + ARSI + ADT has clearly
for inclusion in their meta-analyses and NMAs. Not surpris- become a standard of care for patients with mHSPC, partic-
ingly, they found that triplet therapy resulted in better OS ularly for patients with high-volume de novo metastatic
and PFS for patients with mHSPC in comparison to doc- disease, but should be considered for all patients in settings
etaxel + ADT or ARSI + ADT. They used NMAs to rank all in which these treatments are available and affordable
treatments and found that for patients with de novo high- (Table 1). It remains incumbent on our collective societies
volume mHSPC, triplet therapy had the highest likelihood to now make these therapies more available and affordable
of better OS, while doublet therapy with ARSI + ADT had given that many men with mHSPC remain undertreated in
the highest likelihood of better OS for patients with low- the community and often receive ADT alone [11,12].
volume disease. This study is a timely and comprehensive Patients with high-volume de novo metastatic disease are
evaluation of triplet therapy in mHSPC and provides sup- a subgroup of the mHSPC population who generally have
port to conclusions that can be drawn from the individual aggressive disease at presentation and lower survival
RCTs. Still, as the authors note, caution is needed to avoid reported across trials, warranting aggressive upfront sys-
overinterpreting results from an NMA or making statements temic options such as triplet therapy. In contrast, patients
of individual agent superiority on the basis of the results, with low-volume mHSPC, particularly those with metachro-
particularly given the lack of power for patients with low- nous metastatic disease, generally have more indolent,
volume disease and the heterogeneity of patient eligibility potentially hormone-responsive disease, and thus the bene-
in each trial, as well as the lack of prospective head-to-head fit of adding chemotherapy is less clear for this group. Radi-
pairwise comparisons of individual ARSIs in this setting. ation to the prostate is another form of treatment
NMAs extend the principles of meta-analyses to allow intensification reserved at present for patients with de novo
for comparison of more than two treatments in a single low-volume disease on conventional imaging [13]. Ulti-
analysis using both direct comparisons of interventions mately, for all patients with mHSPC, these treatment deci-
within RCTs and indirect comparisons across RCTs obtained sions are multifaceted and need to factor in quality of life,
via a common reference comparator [10]. The potential of financial costs, and individual patient factors and prefer-
NMAs to allow comparison of treatments across trials is ences in addition to survival differences [14].
appealing in oncology, with multiple available therapies Questions remain as to how best to apply these findings
for a given disease never compared directly to each other in clinical practice. Whether triplet therapy is superior to an
in RCTs but often evaluated in RCTs with a common control ARSI + ADT doublet has not been addressed in an RCT; how-
comparator. Still, the results from this and other NMAs ever, given the comparable efficacy of docetaxel and ARSIs
should be interpreted with caution given the heterogeneity in the STAMPEDE trial, this is generally assumed [15]. Is
of even similar-appearing trial populations and compara- concurrent administration of an ARSI such as abiraterone
tors (eg, lumping all ARSIs together as one treatment) and or darolutamide with docetaxel superior to sequential
the potential biases that may impact these results [10]. administration with these same agents or enzalutamide or
For example, the proportion of patients in each trial may apalutamide? Concurrent enzalutamide with docetaxel is
differ by disease volume, prior local therapy, geographic not recommended owing to potential drug interactions
region, post-treatment therapy availability, study time peri- and added toxicity, as observed in ENZAMET, but sequential
ods, the method for efficacy measurement over time, and use of triplet therapy in all patients or in risk-adapted set-
tumor or germline genetic alterations, and even the control tings on the basis of early responses to docetaxel/ADT has
groups may differ widely in outcomes, including toxicities. not been adequately addressed in any trials. How do we
Results from NMAs can be hypothesis-generating and help incorporate more sensitive imaging modalities such as
in supporting conclusions from well-designed RCTs, as can prostate-specific membrane antigen positron emission
be done with the report by Yanagisawa et al, but should tomography/computed tomography into decision-making
not be used to declare the superiority of a specific regimen in the context of these studies that used conventional imag-
Table 1 – Recommended treatment approach for metastatic hormone-sensitive prostate cancer according to disease volume on conventional imaging and the
timing of metastatic disease developmenta
Disease De novo/synchronous metastases Relapsed/metachronous metastases

volume
High volume Better OS with TTx Rare population with unclear role of TTx
Recommend TTx with DOC + ARSI + ADT as the standard of careb Consider TTx with DOC + ARSI + ADT vs doublet of ADT + ARSI or DOCb
Low volume OS data for TTx not yet available No clear benefit of TTx
Consider TTx with DOC + ARSI + ADT vs doublet of ADT + ARSIb Recommend doublet therapy with ARSI + ADTb
Recommend RT to the primary tumor (±pelvis)
A DT = androgen deprivation therapy; ARSI = androgen receptor signaling inhibitor; DOC = docetaxel; OS = overall survival; RT = radiation therapy; TTx = triplet
therapy.
a
High-volume disease is defined as visceral metastases and/or four or more bone metastases, with at least one outside of the vertebral column and pelvis
according to the CHAARTED criteria. De novo metastasis is defined as metastatic disease at the time of initial prostate cancer diagnosis. Relapsed/meta-
chronous metastasis is defined as metastatic disease identified after initial diagnosis and treatment for localized prostate cancer. Assessments are made
using conventional imaging (computed tomography and bone scan).
b
Consider a clinical trial to further optimize and improve outcomes.
ing alone? Ultimately, identification of better predictive and [5] Kyriakopoulos CE, Chen Y, Carducci MA, et al. Chemohormonal
prognostic biomarkers, whether imaging-based, genotypic, therapy in metastatic hormone-sensitive prostate cancer: long-
term survival analysis of the randomized phase III E3805
or other patient-specific factors, to help identify patients CHAARTED trial. J Clin Oncol 2018;36:1080–7.
most in need of and most likely to benefit from aggressive [6] Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added
triplet or even potentially quadruplet future therapy are to androgen deprivation therapy and docetaxel in de novo
essential to ensure that patients are receiving the best indi- metastatic castration-sensitive prostate cancer (PEACE-1): a
multicentre, open-label, randomised, phase 3 study with a 2 2
vidualized treatments in the context of ever-evolving ther-
factorial design. Lancet 2022;399:1695–707.
apeutic options. [7] Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in
metastatic hormone-sensitive prostate cancer. N Engl J Med
2022;386:1132–42.
Conflicts of interest: Andrew J. Armstrong has received institutional [8] Hoyle AP, Ali A, James ND, et al. Abiraterone in ‘‘high-’’ and ‘‘low-
research support from the National Institutes of Health/National Cancer risk’’ metastatic hormone-sensitive prostate cancer. Eur Urol
Institute, Prostate Cancer Foundation/Movember, US Department of 2019;76:719–28.
[9] Yanagisawa T, Rajwa P, Thibault C, et al. Androgen receptor
Defense, Astellas, Pfizer, Bayer, Janssen, Dendreon, Genentech/Roche,
signaling inhibitors in addition to docetaxel with androgen
BMS, AstraZeneca, Merck, Constellation, Beigene, Forma, Celgene, and deprivation therapy for metastatic hormone-sensitive prostate
Amgen; and has a consulting or advisory relationship with Astellas, Epic cancer: a systematic review and meta-analysis. Eur Urol.
Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, 2022;82:584–98. https://doi.org/10.1016/j.eururo.2022.08.002.
Forma, Celgene, Clovis, and Exact Sciences. Hannah E. Dzimitrowicz has [10] Rouse B, Chaimani A, Li T. Network meta-analysis: an introduction
for clinicians. Intern Emerg Med 2017;12:103–11.
nothing to disclose.
[11] George DJ, Agarwal N, Ramaswamy K, et al. Real-world utilization
of advanced therapies by metastatic site and age among patients
References with metastatic castration-sensitive prostate cancer (mCSPC): a
Medicare database analysis. Ann Oncol 2021;32(Suppl 5):S655–6.
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enzalutamide in patients with metastatic hormone-sensitive treatment patterns in patients (pts) with metastatic castration-
prostate cancer. J Clin Oncol 2022;40:1616–22. sensitive prostate cancer (mCSPC) in a U.S. health insurance
[2] Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with database. J Clin Oncol 2021;39(15 Suppl):5072.
metastatic castration sensitive prostate cancer: final survival [13] Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary
analysis of the randomized, double-blind, phase III TITAN study. J tumour for newly diagnosed, metastatic prostate cancer
Clin Oncol 2021;39:2294–303. (STAMPEDE): a randomised controlled phase 3 trial. Lancet
[3] Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard 2018;392:2353–66.
first-line therapy in metastatic prostate cancer. N Engl J Med [14] Dzimitrowicz HE, Armstrong AJ. Elevating the patient voice in
2019;381:121–31. metastatic hormone-sensitive prostate cancer clinical trials. J Clin
[4] Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in Oncol 2022;40:807–10.
patients with newly diagnosed high-risk metastatic castration- [15] Sydes MR, Spears MR, Mason MD, et al. Adding abiraterone or
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Platinum Priority – Bladder Cancer

Editorial by Dickon Hayne, Andrew Redfern on pp. 611–612 of this issue
First-in-human Intravesical Delivery of Pembrolizumab Identifies

Immune Activation in Bladder Cancer Unresponsive to Bacillus
Calmette-Guérin
Khyati Meghani a,b, Lauren Folgosa Cooley a,b, Bonnie Choy c, Masha Kocherginsky d,
Suchitra Swaminathan e, Sabah S. Munir d, Robert S. Svatek f, Timothy Kuzel g, Joshua J. Meeks a,b,h,*
a
Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; b Department of Biochemistry and Molecular Genetics,
Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; c Department of Pathology, Northwestern University, Feinberg School of
Medicine, Chicago, IL, USA; d Division of Biostatistics, Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago,
IL, USA; e Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; f Department of Urology, UT Health San
Antonio, San Antonio, TX, USA; g Division of Hematology and Oncology, Department of Medicine, Rush Medical College, Chicago, IL, USA; h Jesse Brown
VA Medical Center, Chicago, IL, USA
Article history: Background: Intravenous immune checkpoint inhibition is an effective anticancer strat-
Accepted August 3, 2022 egy for bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder can-
cer (NMIBC) but may be associated with greater systemic toxicity compared with
Associate Editor: localized therapies.
James Catto Objective: We assessed the safety and antitumor activity of intravesical pembrolizumab
combined with BCG.
Statistical Editor: Design, setting, and participants: A 3 + 3 phase 1 trial of pembrolizumab + BCG was con-
Andrew Vickers ducted in patients with BCG-unresponsive NMIBC (NCT02808143).
Intervention: Pembrolizumab was given intravesically (1–5 mg/kg for 2 h) beginning
Keywords: 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and
Clinical trial spatial transcriptomic profiling of pre- and post-treatment tumors were conducted to
Bacillus Calmette-Guérin identify biomarkers that correlated with response.
Digital spatial profiling Outcome measurements and statistical analysis: Safety and tolerability of immune
Bladder cancer checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed.
Intravesical pembrolizumab Results and limitations: Nine patients completed therapy. Median follow-up was 35
months for five patients still alive at the end of the trial. The trial was closed due to
the COVID-19 pandemic. Grade 1–2 urinary symptoms were common. The maximum
tolerated dose was not reached; however, one dose-limiting toxicity was reported (grade
2 diarrhea) in the only patient who reached 52 weeks without recurrence. One death
occurred from myasthenia gravis that was deemed potentially related to treatment.
Please visit www.eu-acme.org/europeanurology The 6-mo and 1-yr recurrence-free rates were 67% (95% confidence interval [CI]: 42–
to answer questions on-line. The EU-ACME cred-
100%) and 22% (95% CI: 6.5–75%), respectively. Pembrolizumab was detected in the urine
its will then be attributed automatically.
* Corresponding author. Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Tel. +1 (312)363-8959.
E-mail address: joshua.meeks@northwestern.edu (J.J. Meeks).
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
and not in blood. CD4+ T cells were significantly increased in the urine after treatment,
and a transcriptomic analysis identified decreased expression of T-cell exhaustion mark-
ers in late recurrences.
Conclusions: We demonstrate that intravesical pembrolizumab is safe, feasible, and cap-
able of eliciting strong immune responses in a clinical setting and should be investigated
further.
Patient summary: Direct application of pembrolizumab to the bladder is a promising
alternative for non–muscle-invasive bladder cancer unresponsive to Bacillus Calmette-
Guérin and should be investigated further.
Urology. This is an open access article under the CC BY-NC-ND license (http://creative-
commons.org/licenses/by-nc-nd/4.0/).
1. Introduction pants had to have a Eastern Cooperative Oncology Group performance of

0 or 1. The inclusion and exclusion criteria are listed in the protocol
available on request.
Treatment for non–muscle-invasive bladder cancer
(NMIBC) is endoscopic resection followed by intravesical
adjuvant chemotherapy or bacillus Calmette-Guérin (BCG)
2.2. Study procedures and dose-escalation scheme
[1]. Non-responders to BCG have limited options. In 2021,
the first intravenous anti-PD1 checkpoint immunotherapy After enrollment, patients received a single intravesical dose of pem-
(CPI) was approved for patients with BCG-unresponsive brolizumab at the specified dose level (1 or 2 mg/kg) at week –2 prior
NMIBC with carcinoma in situ [2]. Although the 3-mo to induction (Fig. 1B). Participants were then treated with BCG (TICE;
response was 41% (39/96), the median duration of a com- 50 mg, weeks 0–5) and intravesical pembrolizumab (weeks 0, 2, and
plete response (CR) was 16 mo (95% confidence interval 4). After induction, participants received only intravesical pem-
[CI]: 7–36), with 19% (18/96) CR at 12 mo. While pembrolizumab during maintenance, first every 2 weeks until week 17 and
brolizumab was well tolerated, 66% of patients reported then every 4 weeks for the remainder of the year. Dose-limiting toxici-
an adverse event (AE), with a total of 11 serious AEs (SAEs) ties (DLTs) were defined as SAEs from week –2 through week 5 and
in eight patients. Hence, even though some patients defined by Common Terminology Criteria for Adverse Events v4.03.
Additional details can be found in the Supplementary material.
responded to pembrolizumab, >80% did not respond and
two of three reported AEs.
We hypothesized that changing the route of delivery
2.3. Outcome measures
could limit toxicity. For >40 years, urologists have adminis-
tered medication into the bladder to treat bladder cancer At each visit, patients underwent an evaluation and physical examina-
[3,4]. Recently, several trials have focused on intravesical tion to identify any AEs with endoscopic evaluation at week 17 and
administration of immune-modulating agents to generate every 8 weeks until the completion of the trial at week 52 (last cys-
a localized immune response [5]. To date, activity and safety toscopy on week 49). Urine was analyzed for cytopathology and any con-
profile of CPIs administered as an intravesical therapy have cerning lesion was biopsied. Any high-grade recurrence, whether in the
not been investigated. Recent preclinical studies in mice bladder or throughout the urinary tract, was considered a recurrence
suggest an increase in lymphocytes in the bladder after and treatment was halted. After the last dose of trial therapy, patients
intravesical CPI antibodies [6]. Herein, we report safety, tox- were followed clinically for disease recurrence and survival every 3
icity, and clinical response from the first-in-human clinical mo (±30 d) during years 1 and 2.
trial of intravesical administration of an immune check-

point inhibitor.
2.4. Statistics
This is a phase 1 dose-escalation study using the 3 + 3 design with four

2. Patients and methods
doses. All analyses were conducted using R version 4.0.3 or GraphPad
2.1. Study design and participants Prism version 9.3.1. Wilcoxon signed rank test was used for paired sam-
ple comparisons (eg, from before to after comparison). For comparing
NCT02808143 was a phase 1 dose-escalation trial with a 3 + 3 design independent groups, the Kruskal-Wallis test was used to generate p val-
using increasing doses of intravesical pembrolizumab with BCG in ues. For repeated measures across different time points, a mixed-effect
patients unresponsive to BCG. All patients were recruited from one insti- model was used to generate p values. Recurrence-free survival (RFS),
tution. The trial was approved by Northwestern University IRB progression-free survival (PFS), and overall survival (OS) were defined
(STU00202754) and the Robert H. Lurie Comprehensive Cancer Center as time from the start of pre-induction until the corresponding event.
Scientific Review Committee and Data Safety and Monitoring Commit- Patients were censored for PFS and OS on the date of last cystoscopy
tee. Patients had a history of high-grade bladder cancer (Ta, T1, or Tis) or imaging without observed progression or the date the patient was last
and were treated with at least seven doses of BCG (five during induction known to be alive. Survival estimates were obtained using the method of
and two during maintenance). Patients were also eligible if they were Kaplan-Meier, and groups were compared using the log-rank test.
BCG unresponsive and had been treated with at least three doses of a sal- Detailed methods for urine pK, urine flow cytometry, serum pK, urine
vage regimen (such as gemcitabine and/or docetaxel). Any patient with cytokine analysis, GeoMx digital spatial profiling, and PD-L1 immunohis-
an invasion (T1) must have had imaging within 60 days, and all partici- tochemistry are included in the Supplementary material.
Fig. 1 – Clinical trial design. (A) Treatment schema with dosing schedule of pembrolizumab (MK-3475) and BCG at each stage of the clinical trial. Kaplan-Meier
curves showing (B) Recurrence-free survival for the entire cohort (n = 9), (C) Recurrence-free survival by dose cohort (cohort 1 at 1 mg/kg and cohort 2 at 2
mg/kg), (D) Progression-free survival, and (E) Overall survival for the entire cohort. AOI = Area Of Interest; BCG = Bacillus Calmette-Guérin; FFPE = Formalin-
Fixed Paraffin Embedded; ROI = Region Of Interest; TME = Tumor Microenvironment; Tx = Treatment.
3. Results weeks until week 17 (first cystoscopy), and then every 4

weeks for the remainder of the year.
3.1. Clinical trial design
3.2. Toxicity
Eleven patients were screened, and nine were enrolled
between June 2016 and May 2020 when the trial was closed There were 21 grade 1–2 AEs related to BCG and/or pem-
due to the coronavirus disease 2019 (COVID-19) pandemic brolizumab and one grade 5 AE related to pembrolizumab
(Supplementary Fig. 1A). Patients were followed up through (Table 2). Nearly all BCG-related AEs were bladder related,
May 2021. Patient demographics are described in Table 1. with the most common being gross hematuria (five cases;
All patients received a preinduction dose at week –2 Table 2). AEs are described in Table 2. The trial was closed
(Fig. 1A) followed by BCG at weeks 0–5 along with intraves- early due to the COVID-19 outbreak. Three patients were
ical pembrolizumab at weeks 0, 2, and 4. After induction, treated at a starting dose of pembrolizumab 1 mg/kg (co-
participants received intravesical pembrolizumab every 2 hort 1), and six were treated at 2 mg/kg (cohort 2). One
Table 1 – Baseline demographics patient presented with vision changes and an elevated
Treatment group anti-ACHR antibody level. This was originally reported 117
d after the last dose of pembrolizumab. The patient was
Cohort 1 Cohort 2
(N = 3) (N = 6) treated with pyridostigmine, prednisone, and intravenous
Age (yr), median 76 82
immunoglobulin and expired 10 mo after symptom onset.
Sex (no.) All patients in both dose cohorts experienced grade 1–2
Male 3 5 events (3/3 and 6/6 patients) related to BCG.
ECOG performance status score
0 3 6
Tumor stage (no.) 3.3. Clinical response data
Tis 1 2
TaHG 0 2
The response to pembrolizumab and BCG was evaluated by
TaHG + CIS 1 1
T1 1 0 cystoscopy, urine cytology, and bladder biopsy when indi-
T1HG 0 1 cated. The median follow-up time among five patients
PD-L1 status
who were alive at the end of the study was 35 months (in-
Combined positive score 10 2 4
Adverse events attributed to BCG terquartile range: 26–36). All patients recurred with RFS
Maximum event grade rates of 100%, 67% (95% CI: 42–100%), and 22% (95% CI: 7–
Grade 1–2 3 6
75%) at 3, 6, and 12 months, respectively (Fig. 1B and Sup-
Adverse events attributed to pembrolizumab
Maximum event grade plementary Fig. 1B). The median RFS was 6.2 months (95%
Grade 1–2 3 4 CI: 5–not available [NA]). No differences in RFS rates was
Grade 5 0 1
observed between the two cohorts (log-rank test, p = 0.6;
Number of doses of BCG Overall (N = 9)
Median (range) 12 (6–27) Fig. 1C). The patient with the longest time to recurrence of
Other BCG-unresponsive therapies (no.) 31 months was also the only participant who experienced
Docetaxel 3
a DLT.
Gemcitabine 1
Nadofaragene firadenovec 1 Progression occurred in five patients with median PFS of
BCG = Bacillus Calmette-Guérin; CIS = Carcinoma In Situ; ECOG = Eastern 36 months (95% CI: 10–not reached). The PFS rates at 6 and
Cooperative Oncology Group. 12 months were 100% and 56%, respectively (95% CI: 31–
100%; Fig. 1D and Supplementary Fig. 1B). There were no
significant differences in recurrence and progression rates
DLT of grade 2, diarrhea lasting 21 d, was observed during when the cohort was stratified by carcinoma in situ (CIS;
treatment in cohort 2. One patient died due to treatment- Supplementary Fig. 1B and 1C). Progression to locally
related myasthenia gravis, an autoimmune disorder. The advanced cancer (T2+Nany, TxN+, or M+) occurred in four
Table 2 – Adverse events attributed to BCG or pembrolizumab
Event, no. (%) Grade 1 or 2 Grade 3 Grade 4 Grade 5

Adverse events attributed to BCG
Any 21 (100) 0 0 0
Hematuria 5 (55.6) 0 0 0
Diarrhea 2 (22.2) 0 0 0
Fatigue 2 (22.2) 0 0 0
Renal and urinary disorders—other, specify 2 (22.2) 0 0 0
Urinary tract infection 2 (22.2) 0 0 0
Abdominal pain 1 (11.1) 0 0 0
Anemia 1 (11.1) 0 0 0
Cystitis noninfective 1 (11.1) 0 0 0
Flatulence 1 (11.1) 0 0 0
Nausea 1 (11.1) 0 0 0
Pain 1 (11.1) 0 0 0
Urinary frequency 1 (11.1) 0 0 0
Urinary urgency 1 (11.1) 0 0 0
Adverse events attributed to pembrolizumab
Any 21 (88.9) 0 0 1 (11.1)
Hematuria 4 (44.4) 0 0 0
Diarrhea 2 (22.2) 0 0 0
Fatigue 2 (22.2) 0 0 0
Renal and urinary disorders—other, specify 2 (22.2) 0 0 0
Abdominal pain 1 (11.1) 0 0 0
Anemia 1 (11.1) 0 0 0
Autoimmune disorder 0 0 0 1 (11.1)
Cystitis noninfective 1 (11.1) 0 0 0
Flatulence 1 (11.1) 0 0 0
Nausea 1 (11.1) 0 0 0
Pain 1 (11.1) 0 0 0
Pruritus 1 (11.1) 0 0 0
Urinary urgency 1 (11.1) 0 0 0
BCG = Bacillus Calmette-Guérin.
of nine patients, with recurrence in six of nine patients out- By urine cytokine profiling, we detect increased levels of
side of the treated bladder—upper tract urothelial (two), BCG-regulated inflammatory cytokines (tumor necrosis fac-
lung (one), prostate (two), and pelvis (one) (Supplementary tor [TNF]-alpha and interleukin [IL]-8) [8,9]; chemokines
Table 5). Death occurred in four of nine patients (Fig. 1E and such as MIP-1 beta and monocyte chemoattractant (MCP-
Supplementary Fig. 1D). Major cancer surgeries after enroll- 1) increased from week –2 to 5 during induction treatment
ment included radical cystectomy (two patients), (Supplementary Fig. 2B).
nephroureterectomy (one), and distal ureterectomy with Collectively, a multiomic urine analysis identified
partial cystectomy (one). immune recruitment to the bladder following exposure to
intravesical BCG and pembrolizumab.
3.4. Response during therapy: urine analytes 3.5. Spatial transcriptomic analysis
To determine whether pembrolizumab was confined to the We sought to understand how intravesical pembrolizumab
bladder, we evaluated plasma and urine levels of pem- and BCG affected bladder tumors and investigate the mech-
brolizumab for cohort 1, and serum levels in the patient anisms of resistance. Given the technical limitations in pro-
with a DLT and a grade 5 SAE. We found no detectable levels filing CIS by bulk RNA-seq or macrodissection, we
of pembrolizumab in the blood (serum or plasma) in any performed transcriptomic analysis of pre- and post-
patient. We were able to detect pembrolizumab in the urine treatment tumors using NanoString’s digital spatial profil-
samples collected at weeks –2 and 4. No detectable levels of ing technology (GeoMx DSP, NanoString, Seattle, WA, USA)
pembrolizumab were found in the urine sample collected (Fig. 1A) [10]. Using DNA, pan-cytokeratin, and CD68 and
prior to treatment at week 4 (Supplementary Fig. 2A). CD3 as protein markers for the tumor and tumor microenvi-
To understand local immune changes that occurred after ronment (TME), we evaluated 151 areas of interest (AOIs)
intravesical pembrolizumab administration, we prospec- collectively from eight patients, 86 from post-treatment
tively evaluated the urine of patients collected during the and 65 from pre-treatment tumors. A principal component
trial (Fig. 1A) [7]. To identify the potential mechanisms of analysis confirmed discrete clustering of PanCK+ (tumor)
a response, we compared patients with early recurrence and PanCK– (TME) AOIs (Fig. 3A). We first evaluated bladder
(n = 5, median months to recurrence: 5.3, 95% CI: 4.9–NA) cancer subtypes in PanCK+ AOIs. While one tumor had fea-
to late recurrence (n = 4, median: 12 months, 95% CI: 10– tures of a basal/squamous tumor, the rest expressed only
NA). luminal markers [11]. We compared AOIs from multiple
At baseline, the patient who developed myasthenia regions, and found little intratumoral spatial heterogeneity
gravis had the highest level of CD45+ immune cells with in tumor subtype and no changes in subtype after treatment
an increase of 8.7-fold over the median of other patients (Fig. 3B).
at baseline (before treatment, week –2; Fig. 2A). Next, we compared the transcriptomic profile of pre- and
Next, we investigated whether a single dose of pem- post-treatment tumor epithelium (PanCK+) using a gene-set
brolizumab could alter local immune environment by com- enrichment analysis and found significant enrichment of
paring the urine collected at baseline (before treatment, inflammatory pathways in PanCK+ post-treatment tumor
week –2) with that collected 2 weeks after the first dose AOIs (Fig. 3C). Pretreatment tumor AOIs expressed minimal
of intravesical pembrolizumab (before treatment, week 0). inflammatory gene expression programs, with the excep-
Although most of the pretreatment urine collected at base- tion of proinflammatory TNF signaling, suggestive of prior
line had a large concentration of granulocytes, we observed BCG treatment. Post-treatment tumors depicted an
a significant decrease in granulocytes (median: 41%, 95% CI: inflamed phenotype with enrichment of pathways involved
0–60%, Wilcoxon signed rank test, p = 0.023), and a signifi- in immune regulation (inflammation and antigen presenta-
cant increase in CD4+ (median: 18%, 95% CI: 0.2–33%, tion, and TGF-b signaling) and cytokine signaling (IL-6, IL-2,
p = 0.023) and CD8+ T cells (median: 12%, 95% CI: 0–14.2, IFNA, CXCR4, TLR, and IL signaling).
p = 0.015) after a single dose of pembrolizumab (Fig. 2B). Next, we evaluated changes in the TME (PanCK–), com-
Since this measurement was performed 2 weeks later, alter- paring AOIs of the same patient before and after therapy.
ations in immune cell populations reflect at least transient We found a significant increase in ImmuneScore (median
changes to the microenvironment after a single intravesical increase: 48, 95% CI: 12–104, Wilcoxon signed rank test,
dose of pembrolizumab. p = 0.031; Fig. 3D) in post-treatment TMEs. In particular,
To identify immune changes that occurred with BCG and we found a significant increase in plasma (median differ-
pembrolizumab, we compared urinary immune profiles ence: 6.5, 95% CI: 4.3–9.2), natural killer (NK; median differ-
between early and late recurrences at each week during ence: 3, 95% CI: 1.4–4.2), CD8+ T (median difference: 6.9,
the 6 weeks of induction. The most striking differences in 95% CI: 4.5–9.9), and Treg (median difference: 7.0, 95% CI:
immune populations were observed for time points when 2.2–8.1) cells in post-treatment samples relative to pre-
the patients received BCG and pembrolizumab (weeks 0, treatment samples (Fig. 3E). This increase was most pro-
2, and 4) relative to BCG alone (weeks 1, 3, and 5). Relative nounced in the patient who developed myasthenia gravis
to early recurrences, late recurring populations had signifi- (patient 104; Supplementary Fig. 3A and 3B).
cantly lower fractions of granulocytes and a higher fraction To identify the mechanisms of resistance or response to
of lymphocytes, in particular higher CD4+ and CD8+ T cells, intravesical pembrolizumab and BCG, we compared spatial
at weeks 0 and 2 (Fig. 2C and Supplementary Table 6). profiling of pretreatment tumor and TME from early and
Fig. 2 – Progressive remodeling of local immune contents over the course of treatment by urine analysis of immune cells and cytokines. (A) CD45+ cell number
in the urine at baseline prior to the start of treatment. (B) Composition of immune cells in the urine at baseline and 2 weeks after administration of a single
dose of pembrolizumab. (C) Changes in immune cell population in the urine during the induction period (weeks 0–5). Each bar represents the mean of
indicated immune cells for each group (n = 4 for late responders and n = 5 for early responders). NK = Natural Killer; NKT = Natural Killer T; Tx = Treatment.
late recurrences. Tumor epithelium AOIs from early recur- Overall, this is the first direct comparison of the hetero-
rences showed an inflamed phenotype with upregulation geneity of tumor and TME in NMIBC and BCG-unresponsive
of TNF-mediated inflammatory signaling and MHC class II NMIBC by spatial profiling. Our data indicate that differ-
signaling. In contrast, late recurrences were enriched for ences in clinical endpoints of BCG-unresponsive tumors
pathways involved in cell cycle regulation, DNA damage may be secondary to distinct pathways of the tumor/TME,
response, and innate immune pathways (Fig. 4A). with responsive tumors showing greater T-cell infiltration
Next, we evaluated the pretreatment TME of early and with less exhaustion, while resistant tumors have increased
late recurrent tumors. Early recurrent TME was enriched neutrophils and a stroma-rich microenvironment (Supple-
in stress response pathways, stromal signatures, and angio- mentary Fig. 3E).
genesis with a higher stromal score and significantly ele-
vated levels of PDGFRB (Fig. 4B and Supplementary 4. Discussion
Fig. 3C). In contrast, late recurring TME had an enrichment
of pathways associated with adaptive immune system pro-
Although CPI has revolutionized the treatment of solid
cesses (T-cell receptor and B-cell receptor signaling), cyto-
tumors, toxicity of CPI and its efficacy in early-stage NMIBC
kine signaling (IL-2 and NF-KB pathways; Fig. 4B) along
require further investigation for broader use. In this trial, we
with a significantly higher ImmuneScore (median differ-
attempted to mitigate the toxicity of CPI by direct applica-
ence: 26, 95% CI: 12–95; Supplementary Fig. 3D).
tion of pembrolizumab into the bladder, potentially avoid-
In particular, we find elevated CD8+ T (median differ-
ing systemic toxicity. We combined pembrolizumab with
ence: 12, 95% CI: 6–19), Treg (median difference: 9.2, 95%
BCG with the intent to both increase immune recruitment
CI: 2.3–11), B (median difference: 9.9, 95% CI: 3.5–36),
and decrease exhaustion. We had initially hoped to deliver
plasma (median difference: 4.8, 95% CI: 1–5.5), and NK (me-
higher doses of pembrolizumab; however, our trial was dis-
dian difference: 2.2, 95% CI: 0.18–5.2) cells in late recurring
continued at the start of the COVID-19 pandemic.
tumors relative to early recurrences (before treatment;
We did not detect pembrolizumab in the serum or
Fig. 4C). To characterize the activation state of an immune
plasma in all five patients tested; however, two patients
response, we compared immune cell counts and exhaustion
experienced toxicity during treatment, and both AEs
score. Late recurrent tumors had a large significant increase
occurred at the higher dose of pembrolizumab tested—2
in immune cells in the TME, and a significant reduction in
mg/kg. While we cannot conclude that lower dosing of
exhaustion markers from before to after treatment (Fig. 4D).
pembrolizumab is safe, higher doses may not be needed
Fig. 3 – Changes in the tumor microenvironment as a consequence of therapy. (A) PCA plot showing individual region of interest (ROI) profiled from pre- and
post-Tx tumor sections. (B) Heatmap showing transcriptomic subtypes identified for each PanCK+ ROI within the cohort. (C) Gene expression programs
identified in PanCK+ segments before and after treatment (Tx). (D) ImmuneScore values calculated from PanCK– segments for each analyzed sample. Bars
represent mean ± SEM. (E) Immune cell counts within the tumor microenvironment derived by deconvolution of PanCK– RNA expression profiles of pre- and
post-Tx ROIs (top). Bars represent Mean ± SEM. Representative images are shown for pre- and post-Tx groups (bottom). EMT = Epithelial Mesenchymal
Transition; IFNA = Interferon A; IL = Interleukin; PCA = Principal Component Analysis; SEM = Standard Error of the Mean.
to modulate the immune response. We observed increased This patient had the highest number of CD45+ cells in the
lymphocyte recruitment, suggestive of immune modulation urine prior to treatment initiation, and this number
2 weeks after a single dose of intravesical pembrolizumab. increased further during the course of treatment. Although
Similar to other immunotherapies, we find a correlation this resulted in a longer delay to recurrence, the enhanced
between an inflammatory response and the durability of a immune activation from intravesical therapy may have has-
clinical response. The patient who had the longest response tened progression of myasthenia gravis. While BCG and
to therapy, >12 months without high grade recurrence, was advanced age have been associated with myasthenia gravis,
also the patient who experienced a DLT during induction. only a few case reports have described myasthenia gravis
Except for two patients, intravesical pembrolizumab was associated with intravenous checkpoint therapy [12,13].
well tolerated with only grade 1–2 AEs that were mostly There are several limitations of our study. Our sample
urinary related. Thus, intravesical delivery of CPI is a viable size was limited to nine patients due to premature closure
strategy for patients with BCG-unresponsive NMIBC, merit- of the trial. Although we attempt to describe our findings
ing further investigation of dose, delivery, and patient for pre- and post-treatment therapy samples, validation in
selection. larger cohorts is necessary. The rate of extravesical recur-
Evaluation of tissue and blood from the one patient with rence was greater than expected and may reflect the limited
a grade 5 autoimmune AE identified possible mechanisms number of treatment options available for patients
of systemic immune activation from intravesical therapy. recruited in this study.
Fig. 4 – Differences in transcriptional programs in tumor and TME from early and late responders. (A) Gene expression programs identified in pretreatment
PanCK+ ROIs from early and late recurrences. (B) Gene expression programs identified in pretreatment PanCK– ROIs from early and late recurrences. (C) Radar
plot of immune cell distribution in PanCK– pre-Tx ROIs from early and late responding tumors. Each point represents mean values (p values from comparing
immune cell populations in early vs late recurrences were generated using the Kruskal-Wallis test). (D) Changes in ImmuneScore and exhaustion score for
each PanCK– ROI from before to after treatment segregated by early and late responders. BCR = B-cell receptor; IL = Iinterleukin; NK = Natural Killer;
ROI = Region Of Interest; TCR = T-cell receptor; TME = Tumor Microenvironment; TNF = Tumor Necrosis Factor; Tx = Treatment.
5. Conclusions Analysis and interpretation of data: All authors.

Drafting of the manuscript: Meghani, Meeks, Cooley, Choy.
Critical revision of the manuscript for important intellectual content: All
Here, we demonstrate that intravesical pembrolizumab is a
authors.
safe and feasible alternative in patients with BCG-
Statistical analysis: Meghani, Munir, Kocherginsky.
unresponsive NMIBC. We attempted to decrease the toxicity
Obtaining funding: Meeks.
of anti-PD1 therapy by intravesical delivery; however, two Administrative, technical, or material support: Meghani, Choy, Swami-
of nine patients had a DLT or an SAE. nathan, Munir.
We are encouraged by the broad range of immune Supervision: Meeks, Kocherginsky.
responses observed in the urine collected during trial and Other: None.
in the tumor tissue at the end of the trial. Changes in the
immune niche are detectable in the urine as early as after
one dose of pembrolizumab. Nevertheless, as evident by Financial disclosures: Joshua J. Meeks certifies that all conflicts of inter-
est, including specific financial interests and relationships and affiliations
analysis of recurrences observed in our trial, duration of
relevant to the subject matter or materials discussed in the manuscript
antitumor immunity is dependent on pretreatment tumor
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
composition, and future trials should explore combination
stock ownership or options, expert testimony, royalties, or patents filed,
therapies and careful patient selection to improve efficacy.
received, or pending), are the following: Khyati Meghani, Lauren Folgosa
Overall, intravesical administration of pembrolizumab is
Cooley, Bonnie Choy, Masha Kocherginsky, Suchitra Swaminathan, and
a promising therapeutic modality, capable of generating
Sabah S. Munir have nothing to disclose. Robert S. Svatek is the PI of
long-lasting antitumor immunity, and should be investi- S1602, which utilizes TICE BCG provided by Merck. Timothy Kuzel serves
gated further. on DSMC for Merck trials, but has no conflict of interest. Joshua J. Meeks
received funding from Merck for the described clinical trial through the
Author contributions: Joshua J. Meeks had full access to all the data in the Merck Investigator Studies Program (MISP), received funding from Lurie
study and takes responsibility for the integrity of the data and the accu- Cancer Center, and participated in advisory boards for Merck.
racy of the data analysis.
Funding/Support and role of the sponsor: This study was supported by

Study concept and design: Meeks, Kuzel, Svatek. funding from MISP and the Robert H. Lurie Cancer Center. Joshua J. Meeks
Acquisition of data: Meghani, Cooley, Choy. is supported by grants from the VHA BX005599 and BX003692. This work
was supported by the Northwestern University RHLCCC Flow Cytometry [4] Herr HW, Morales A. History of bacillus Calmette-Guerin and
Facility and the Quantitative Data Sciences Core (Masha Kocherginsky bladder cancer: an immunotherapy success story. J Urol
2008;179:53–6.
and Sabah S. Munir) under the Cancer Center Support grant (NCI
[5] Giannarini G, Agarwal N, Apolo AB, et al. Urologists, you’ll never
CA060553). walk alone! How novel immunotherapy and modern imaging may
change the management of non-muscle-invasive bladder cancer.
Eur Urol Oncol 2022;5:268–72.
Acknowledgments: We thank Arighno Das for technical assistance. [6] Kirschner AN, Wang J, Rajkumar-Calkins A, Neuzil KE, Chang SS.
Intravesical anti-PD-1 immune checkpoint inhibition treats
urothelial bladder cancer in a mouse model. J Urol
2021;205:1336–43.
Peer Review Summary
[7] Wong YNS, Joshi K, Khetrapal P, et al. Urine-derived lymphocytes as
a non-invasive measure of the bladder tumor immune
Peer Review Summary and Supplementary data to this arti- microenvironment. J Exp Med 2018;215:2748–59.
[8] de Boer EC, Somogyi L, de Ruiter GJ, de Reijke TM, Kurth KH,
cle can be found online at https://doi.org/10.1016/j.eururo. Schamhart DH. Role of interleukin-8 in onset of the immune
2022.08.004. response in intravesical BCG therapy for superficial bladder cancer.
Urol Res 1997;25:31–4.
[9] Kamat AM, Briggman J, Urbauer DL, et al. Cytokine Panel for
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The Evolving Role of Locally Delivered Checkpoint Inhibitors in

Non–muscle-invasive Bladder Cancer
Dickon Hayne a,b,c,*, Andrew Redfern a,b,d

a
Medical School, The University of Western Australia, Perth, Australia; b Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney,
Australia; c Department of Urology, Fiona Stanley Hospital, Murdoch, Australia; d Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Australia
Urologists have been successfully using intravesical tration, as has diarrhoea, providing an alternative aetiology
immunotherapy to treat non–muscle-invasive bladder can- [4]. Pembrolizumab was, perhaps predictably, detected in
cer (NMIBC) since the 1970s. Almost half a century later, the urine but was notably not detected in the blood, sug-
bacillus Calmette-Guérin (BCG) remains the contemporary gesting low systemic absorption of this large molecule via
standard of care for high-risk disease according to level 1 the urothelium. Exploratory analyses of urinary immune
evidence [1]. However, approximately one-third of patients cell populations after CPI but before BCG commencement
with high-risk disease will experience either recurrence or suggested an immune effect. The significantly lower granu-
progression, often then necessitating radical cystectomy. locyte and higher lymphocyte counts seen in late compared
Recognising that more efficacious management options to early relapsers is of interest. Certainly, there is evidence
are required, the US Food and Drug Administration (FDA) of improved survival, with lower neutrophil (predominant
has classified BCG-unresponsive NMIBC (BU-NMIBC) as an cell in the granulocyte population)-to-lymphocyte ratios
area of unmet clinical need. across melanoma, non–small-cell lung cancer, and geni-
In this issue of European Urology, Meghani and colleagues tourinary cancer with CPI treatment [5]. The spatial tran-
[2] report the first use of intravesical pembrolizumab with scriptomic analysis elements of the study represent the
concurrent intravesical BCG administration. The authors application of cutting-edge technology to these tumours
are to be congratulated on this inaugural intravesical check- across treatment, combining the advantages of bulk
point inhibitor (CPI) study incorporating extensive and sequencing with assay of multiple gene products and reten-
highly contemporary translational work. This dose escalation of information on the spatial relationships between cell
tion trial reports on nine patients with median follow up types. A range of potentially biologically important differ-
of 35 mo and a 1-yr recurrence-free rate of 22%, having ences were observed between early and late relapsers.
unfortunately closed early because of the COVID-19 pan- Higher stress responses, activation of angiogenesis, and T-
demic. Longer-term outcomes were disappointing, with cell exhaustion were seen in relapsing patients. By contrast,
progression in 5/9 patients, recurrence outside of the blad- innate immune activity was higher, accompanied by greater
der in 6/9, and death of 4/9 during follow-up. The single epi- infiltration of plasma cells, T cells and NK cells, in late relap-
sode of grade 2 diarrhoea, lasting for 21 d, is consistent with sers. Although these studies do not distinguish between the
the known toxicity profile of CPIs. A fatal episode of myas- impact of CPI and BCG exposure, they provide a wealth of
thenia gravis was also attributed to treatment. Although hypothesis-generating information for the design of future
myasthenia gravis is a recognised side effect of CPI treat- randomised controlled trials and their accompanying trans-
ment, reported episodes tend to manifest relatively early lational programmes.
on during treatment, whereas this event was approximately The emergence of systemically administered CPIs has
4 mo after treatment completion [3]. Cases of myasthenia transformed many aspects of urological cancer treatment.
gravis have been occasionally reported after BCG adminis- In the BU-NMIBC setting, the Keynote 57 trial broke new
DOI of original article: https://doi.org/10.1016/j.eururo.2022.08.004
* Corresponding author. The University of Western Australia, 35 Stirling Highway, Perth, WA, Australia. Tel. +61 8 61511130.
E-mail address: dickon.hayne@uwa.edu.au (D. Hayne).
ground by using systemic administration of the PD-1 inhibi- The changes observed for immune infiltrates in the atten-
tor pembrolizumab [6]. While activity was demonstrated, dant translational studies do suggest that intravesically
with a 39% complete response (CR) rate at 3 mo, long-term instilled CPIs have the ability to modulate the local immune
results were perhaps underwhelming, with a CR rate at 12 environment. Whether this translates into useful clinical
mo of 19%. However, in considering data for this indication, efficacy and whether local or systemic CPI administration
the FDA defined a clinically useful CR rate as one for which emerges as the preferable option remain to be seen.
the lower 95% confidence interval bound does not reach
20%, taken from a meta-analysis of currently available ther-
Conflicts of interest: Dickon Hayne has served on advisory boards for
apies. This target was met by the Keynote 57 trial, which led
Merck/Pfizer, BMS, Urogen, and Pacific Edge; given talks for Telix; and
to rapid approval of pembrolizumab for this indication.
provided drug or other support for clinical trials for Medical Develop-
While pembrolizumab was reasonably tolerated, 66% of ments International and AstraZeneca. Andrew Redfern has served on
patients reported an adverse event, with a total of 11 seri- advisory boards for Roche, AstraZeneca, Pfizer, and Novartis; and given
ous adverse events in eight patients, an event rate that con- talks for Eisai, Eli Lily, and Novartis.
tributed to the rationale for the study by Meghani et al [2].
Using a similar design to Keynote 57, the single-arm SWOG References
S1605 study delivered the CPI atezolizumab systemically to
patients with BU-NMIBC who were unfit for or declined rad- [1] Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus
Calmette-Guerin in Ta and Tbladder cancer. Cochrane Database
ical cystectomy. The overall 18-mo event-free survival rate Syst Rev 2000;2000:CD001986.
was a more encouraging 29%, 17% for patients with carci- [2] Meghani K, Cooley LF, Choy B, et al. First-in-human intravesical
noma in situ and 47% for those with Ta/T1 disease [7]. CR delivery of pembrolizumab identifies immune activation in bladder
cancer unresponsive to bacillus Calmette-Guérin. Eur Urol
rates also met the predefined FDA threshold for utility.
2022;82:602–10.
There are numerous ongoing studies currently investigating [3] Shi J, Tan Y, Huang Y, et al. Association between clinical factors and
the roles of various systemic CPIs in the NMIBC and BU- result of immune checkpoint inhibitor related myasthenia gravis: a
NMIBC settings [8]. Two of these trials include randomisa- single center experience and systematic review. Front Neurol
2022;13:858628.
tion to CPI as a single agent. [4] Davalos L, Kushlaf H. New onset of seropositive generalized
The potential role of locally administered CPI therapy via myasthenia gravis following intravesical bacille Calmette-Guerin
suburothelial injection is also under study [9]. This treatment for bladder cancer: a case study. Muscle Nerve 2019;59:
approach may be an appealing alternative, with better E1–2.
[5] Sacdalan DB, Lucero JA, Sacdalan DL. Prognostic utility of baseline
urothelial penetration in comparison to intravesical instilla- neutrophil-to-lymphocyte ratio in patients receiving immune
tion and the possibility of better safety and a lower rate of checkpoint inhibitors: a review and meta-analysis. Onco Targets
immunological side effects in comparison to systemic CPI. Ther 2018;11:955–65.
[6] Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab
Furthermore, novel immune-modulating agents such as
monotherapy for the treatment of high-risk non-muscle-invasive
nadofaragene firadenovec and the IL-15 superagonist bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label,
N803 administered intravesically (with coadministration single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:
of BCG in the case of N803) have already demonstrated 919–30.
[7] Black PC, Tangen C, Singh P, et al. Phase II trial of atezolizumab in
potentially superior responses in the BU-NMIBC to those BCG-unresponsive non-muscle invasive bladder cancer: SWOG
with systemic CPI [10,11]. S1605. J Clin Oncol 2021;39(15 Suppl):4541.
Local administration leaves the delivery of these agents [8] García-Perdomo HA, Sánchez AL, Spiess PE. Immune checkpoints
inhibitors in the management of high-risk non-muscle-invasive
under the auspices of the urologists who manage this space
bladder cancer. A scoping review. Urol Oncol 2022. 10.1016/j.
and who can also offer the gold-standard definitive treat- urolonc.2022.02.003, In press.
ment of cystectomy. It remains to be seen if urologists, or [9] Hayne D, Swarbrick N, McCombie S, et al. SUB-urothelial
even the wider uro-oncology community, will embrace durvalumab injection: 1 (SUBDUE-1)—results from the first nine
urothelial cancer patients using a dose-escalation schedule. J Clin
the use of systemic CPIs with all the attendant risks for Oncol 2022;40(6 Suppl):483.
the treatment of BU-NMIBC, which is, by definition, a loca- [10] Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical
lised disease. nadofaragene firadenovec gene therapy for BCG-unresponsive
What can we learn from the study by Meghani and col- non-muscle-invasive bladder cancer: a single-arm, open-label,
repeat-dose clinical trial. Lancet Oncol 2021;22:107–17.
leagues? Certainly, coadministration of BCG and CPI has a [11] Chamie K, Chang SS, Gonzalgo M, et al. Final clinical results of
logical scientific rationale and has been shown to be feasi- pivotal trial of IL-15RaFc superagonist N-803 with BCG in BCG-
ble. The occurrence of two significant adverse events, even unresponsive CIS and papillary nonmuscle-invasive bladder cancer
(NMIBC). J Clin Oncol 2022;40(16 Suppl):4508.
accepting that potential alternative causes exist, leaves
safety unconfirmed, with further work required in this area.
Platinum Priority – Review – Kidney Cancer – Editor’s Choice

Editorial by Diana E. Magee, Jessica Karen Wong, Andres F. Correa on pp. 623–624 of this issue
The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell

Carcinoma
Muhammad Ali a,b,*, Jennifer Mooi c, Nathan Lawrentschuk d,e,f, Rana R. McKay g,
Raquibul Hannan h, Simon S. Lo i, William A. Hall j, Shankar Siva a,b
a
Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; b Sir Peter MacCallum Department of Oncology,
The University of Melbourne, Melbourne, Victoria, Australia; c Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia; d Department
of Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; e Department of Surgery, Peter MacCallum cancer Centre, Melbourne, Victoria, Australia;
f
Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia; g University of California, San Diego, CA, USA; h Department of Radiation
Oncology, UT Southwestern Medical Centre, Dallas, TX, USA; i Department of Radiation Oncology, University of Washington, Seattle, WA, USA; j Department of
Radiation Oncology, Medical College of Wisconsin, WI, USA
Article history: Context: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment
Accepted June 21, 2022 modality for primary and metastatic renal cell carcinoma (RCC).
Objective: To review and summarise the evidence on the use of SABR in RCC in a narra-
Associate Editor: tive review.
Sarah P. Psutka Evidence acquisition: We performed an online search of the PubMed database from
January 2000 through December 2021. Studies of SABR/stereotactic radiosurgery (SRS)
Keywords: targeting primary, extracranial, or intracranial metastatic RCC were included.
Stereotactic ablative Evidence synthesis: Two meta-analyses (including 54 studies), and 13 prospective and
radiotherapy 20 retrospective studies were included in this review. In aggregate, SABR for 589 primary
Stereotactic ablative body RCCs in 575 patients resulted in a local control rate of above 90% with grade 3–4 toxicity
radiotherapy of 0–9%. Similarly, the local control rate ranged between 90% and 97% with SRS in 1225
Renal cell carcinoma patients with intracranial metastatic RCC. SABR was able to delay systemic therapy for at
least 1 yr in 70–90% of oligometastatic RCC patients with grade 3–4 toxicity of <10%. As
per the early data, the combination of SABR with systemic therapy for metastatic RCC,
such as targeted therapy or immunotherapy, appears safe, feasible, and tolerable.
Conclusions: We outlined data supporting SABR in the key clinical scenarios of primary
Please visit www.eu-acme.org/europeanurology and metastatic, including oligometastatic, RCC in lieu of systemic therapy, in combina-
to answer questions on-line. The EU-ACME cred-
tion with systemic therapy, and palliation of brain and spinal metastases.
its will then be attributed automatically.
Patient summary: Stereotactic ablative body radiotherapy (SABR) is a relatively new
treatment option in kidney cancer. Here, we review the published literature on the expe-
rience of using SABR in kidney cancer. The accumulated evidence demonstrates that
SABR can be used safely and effectively to treat selected cases of primary or secondary
kidney cancer.
Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. 305 Grattan Street, Melbourne, Victoria 3000, Australia. Tel. +6138 5597
749.
E-mail address: muhammad.ali@petermac.org (M. Ali).
1. Introduction and abstracts included renal cell carcinoma, RCC, kidney

cancer, advanced RCC, metastatic RCC, radiotherapy, SBRT,
Renal cell carcinoma (RCC) was historically considered one SABR, and stereotactic radiosurgery (SRS). After consensus,
of the most radioresistant tumours when treated with con- two meta-analyses (including 54 studies), and 13 prospec-
ventional fractionation (<5 Gy per fraction). The basis of this tive and 20 retrospective studies published in English lan-
historic radioresistant description of RCC is unclear. How- guage were included for this narrative review.
ever, in vitro cell culture studies revealed that ablative
doses of radiation could eradicate RCC cells when higher 3. Evidence synthesis
doses per fraction are used [1]. Biological mechanisms
underlying this dichotomy are not clearly understood but Clinical outcomes, safety, and key indications of SABR in
may be related to translocation of acid sphingomyelinase RCC are summarised in Fig. 1.
and production of proapoptotic ceramide, resulting in rapid
endothelial cell death within 1 h of radiotherapy [2,3]. 3.1. SABR for primary RCC
Furthermore, there is evidence that radiotherapy also
has immunomodulatory effects, orchestrating a spectrum SABR is emerging as an alternative noninvasive treatment
of cellular and molecular alterations culminating in the option in the paradigm of localised RCC management. In
potentiation of systemic immune response. Chow et al. [4] 2019, Correa et al. [5] reported a systematic review and
analysed samples of patients treated with 15 Gy stereotac- meta-analysis of 26 studies involving 372 patients with
tic ablative body radiotherapy (SABR) for primary RCC fol- 383 primary tumours (included studies are summarised in
lowed 4 wk later by nephrectomy. The authors found Supplementary Table 2). The LC and grade 3–4 toxicity were
broad transcriptional immune activation and increased 97.2% and 1.5%, respectively. The estimated glomerular fil-
clonality of immune cells within the tumour microenviron- tration rate (eGFR) mean difference before and after SABR
ment. An analysis of peripheral blood samples revealed a was –7.7 ml/min. Dialysis was required in six patients, all
dynamic reshaping of the peripheral T-cell repertoire within of whom had pre-existing renal dysfunction. None of the
the first 2 wk following radiation. 35 solitary kidney patients required dialysis.
With the advent of SABR also known as stereotactic body Multiple prospective and retrospective studies have
radiotherapy (SBRT), high local control (LC) rates have been reported the outcomes for SABR in localised RCC, sum-
reported for primary and metastatic RCC (mRCC), contrary marised in Table 1 and discussed in subsequent sections.
to the historical belief that RCC is radioresistant [5,6]. The
changing perception brought on by the demonstrated effi- 3.2. SABR for large renal masses (T1b)
cacy with an excellent safety profile in clinical practice
Nephron-sparing partial nephrectomy, if technically feasi-
has resulted in the increased use of SABR for patients with
ble, is recommended for T1b tumours [8–10]. The evidence
RCC [7]. The review aims to summarise the key contempo-
for partial nephrectomy in T2 tumours is contradictory and
rary evidence of SABR in localised RCC and mRCC.
of low quality [8,9]. The treatment options are limited for
We present the following article as per the Narrative
patients with T1b disease who are not surgical candidates.
Review reporting checklist (Supplementary Table 1).
TA is not suitable for patients with T1b RCC due to an
increased risk of local recurrence and complications [11].
1.1. SABR in RCC: current guidelines
In this subset of patients, SABR can be an attractive
Current European Association of Urology and European approach.
Society of Medical Oncology guidelines consider SABR as In a retrospective report from the International Radio-
an alternative treatment for patients with localised RCC in surgery Oncology Consortium for Kidney (IROCK), Siva
whom surgery cannot be carried out due to poor perfor- et al. [12] reported outcomes for 95 patients with T1b pri-
mance status or unsuitable clinical condition, and other mary RCC receiving SABR. The median age was 76 yr and
local therapies such as thermal ablation (TA) are not consid- tumour diameter 4.9 cm. One-third of the cohort had a
ered appropriate [8,9]. The 2022 National Comprehensive baseline eGFR of <45 ml/min. At a median follow-up of
Cancer Network version 1.0 kidney cancer guidelines state 2.7 yr, local failure rate was 2.9%. Cancer-specific survival
that ‘‘SABR may be considered for medically inoperable (CSS), overall survival (OS), and progression-free survival
patients with stage I kidney cancer (category 2B) and stage (PFS) were, respectively, 91.4%, 69.2%, and 64.9% at 4 yr.
II/III kidney cancer (category 3)’’ [10]. These guidelines also After treatment, the mean eGFR decreased by 7.9 ml/min.
recommend SABR as a treatment option for metastatic sites No grade 3–5 toxicities were reported. Similarly, another
including the lung, bone, and brain for selected patients retrospective review of 36 patients treated with stereotactic
with oligometastatic (OM) RCC or oligoprogression, or in magnetic resonance guided radiotherapy reported 1-yr LC
cases treated with immunotherapy (IO) or targeted therapy of 95.2% [13]. This study included patients with a median
(TT) [8–10]. tumour size of 5.6 cm, with 31 patients having T1b or T2
disease.
2. Evidence acquisition
3.3. SABR for elderly or comorbid patients with primary RCC
PubMed was used to conduct literature search from January In contrast to surgical approaches or TA, SABR is noninva-
2000 to December 31, 2021. Keywords used to search titles sive and does not require anaesthesia or sedation.
Fig. 1 – Safety and efficacy of SABR in renal cell carcinoma. FFST = freedom from systemic therapy; G-3/4 = grade 3 and 4; IO = immunotherapy; IVC = inferior
vena cava; LC = local control; NSS = nephron-sparing surgery; RCC = renal cell carcinoma; SABR = stereotactic ablative body radiotherapy; TA = thermal
ablation.
Therefore, it may be a more suitable option for frail patients, was 81 yr. All the patients were medically unfit for surgery
those on long-term anticoagulation, or those with multiple due to multiple comorbidities and older age. They were
competing comorbidities that render them high risk from poor candidates for TA due to tumour size of >4 cm or a
anaesthesia, surgery, or TA. close approximation to renal pelvic structures. After a med-
In one study, Grelier et al. [14] reported outcomes for 23 ian follow-up of 22 mo, local recurrence-free survival, CSS,
frail patients with SABR for primary RCC. The median age and OS were 96%, 96%, and 83%, respectively. There were
Table 1 – SABR for primary RCC (inclusive of, and since the Correa et al. [5] meta-analyses)
Author (year) Study Patients Tumour Follow-up Dose (Gy)/ Toxicity LC (%)
type (n) sizea (mo) fraction (grade 3/4)
Grelier et al. (2021) [14] R 23 4.0 cm 22 35/5–7 0 96
Grubb et al. (2021) [17] P 11 3.7 cm 34.3 48/3 9.1% 90
54/3
60/3
Swaminath et al. (2021) [16] P 28 13 patients with 4 cm NA 30–42/3–5 NA NA
and 19 with >4 cm
Margulis et al. (2021) [21]b P 6 NA 24 40/5 0 NA
Tetar et al. (2020) [13] R 36 5.6 cm 16.4 40/5 0 95.2
Siva et al. (2020) [12] R 95 4.9 cm 32.4 – 0 97.1
Senger et al. (2019) [15] R 10 7 patients with T1a disease 27 24–25/1 0 92.3
(size range 1.0–3.9 cm) 36/3
and 3 patients with T3a disease
(size range 0.9–7.0 cm)
Correa et al. (2019) [5] MA 372 4.6 cm 28 26/1 1.5% 97.2
30-40/3-5
IVC-TT = tumour thrombus in the renal vein that can invade the inferior vena cava; LC = local control; MA = meta-analyses; NA = not available; P = prospective;
R = retrospective; SABR = stereotactic ablative body radiotherapy.
a
Median or mean.
b
Neoadjuvant SABR for patients with IVC-TT (tumour thrombus).
no grade 3–4 side effects. The authors concluded that SABR 3.5. Response evaluation after SABR for primary RCC
appeared to be a promising alternative to treat primary RCC
LC after SABR is measured using the Response Evaluation Cri-
in frail patients. Another study investigated ten RCC
teria in Solid Tumors (RECIST). However, this assessment tool
patients with moderate to severe chronic kidney disease
has some limitations as it does not explicitly reflect the treat-
and reported LC of 92.3% with no grade 3 or 4 toxicity [15].
ment modality. Owing to the different mechanisms involved
In one prospective cohort study of 28 patients, of whom
in cell kill, a complete response following SABR is a rare event,
the majority were over 80 yr of age, treated with 30–42 Gy
as there typically is a tumour carcass that remains after treat-
SABR in three to five fractions [16], the authors reported
ment. Persistent post-SABR stable masses are common find-
minimal impact on quality of life (QOL) after SABR. Using
ings immediately after treatment. Furthermore, RCC is a
the minimal clinically important difference, the global
slow-growing tumour, and it can be expected to show a slow
QOL score reached a 10-point reduction at 1 wk but
radiographic response. Currently, arrest of radiological
reverted to baseline at subsequent follow-up.
growth and subsequent slow regression on size criteria is con-
sidered a successful response to treatment [5,19].
3.4. Optimal SABR dose fractionation for localised RCC Future research should focus on novel imaging modali-
ties, including multiparametric magnetic resonance imag-
A variety of dose-fractionation schedules were used in stud-
ing (MRI) and positron emission tomography, for a better
ies included in the systematic review and meta-analyses
response assessment after SABR. Functional MRI sequences
reported by Correa et al. [5]. The most common schedules
show promise in detecting early response to therapy. The
were 26 Gy in a single fraction and 30–45 Gy in three to five
early changes in diffusion and perfusion following renal
fractions. Reported local failures tended to occur in low-
SABR appear to be an early imaging biomarker that corre-
dose groups or where the tumour was underdosed to min-
lates with subsequent computed tomography–based
imise toxicity due to nearby structures. Grubb et al. [17]
tumour response [5].
reported a prospective study of dose escalation for SABR
Postprocedure biopsy is utilised to assess the success of
in 11 patients with localised RCC. Groups of four, four, and
TA for primary RCC. However, post-SABR biopsy is not rec-
three patients received, respectively, 48, 54, and 60 Gy in
ommended in routine clinical practice and should be con-
three fractions. There was no dose-limiting toxicity. One
sidered experimental [5]. In the study reported by Grubb
patient in the 60 Gy cohort had local progression of the dis-
et al. [17], five patients consented to undergo biopsy after
ease. The TransTasman Radiation Oncology Group (TROG)
6 mo of SABR. Interestingly, all five biopsy results were pos-
15.03 FASTRACK II is evaluating 26 Gy in one fraction for
itive for residual tumour cells. However, there was no radio-
tumours 4 cm and 42 Gy in three fractions for tumours
graphic evidence of local or distant disease progression in
>4 cm in size [18].
the three patients where follow-up scans were available
A dose-response relationship may exist in RCC, but there
after biopsy. Furthermore, Ki-67 staining was negative in
are no data to guide the maximum safe dose level to opti-
the postbiopsy samples, confirming that presence of cells
mise LC rates while minimising toxicity. In clinical practice
does not necessarily indicate tumour viability.
outside of clinical trials, optimal dose fractionation depends
on the tumour size and its proximity to the adjacent normal
3.6. SABR for locally advanced RCC: novel applications and
tissues. Until longer follow-up and more prospective stud-
future perspectives
ies, we recommend following the IROCK consensus state-
ment, which suggested 25–26, 35–45, and 40–50 Gy in RCC forms tumour thrombus in the renal vein that can
single, three, and five fractions, respectively [19]. invade the inferior vena cava (IVC-TT) in approximately
4–10% of patients and sometimes reach the right atrium 3.8. Stereotactic radiotherapy for brain and spinal metastatic
[20]. IVC-TT can lead to multiple serious complications such disease
as pulmonary embolism or Budd-Chiari syndrome. The only
Brain metastases (BMs) occur in approximately 3–20% of
effective treatment option for IVC-TT is nephrectomy, patients with RCC [23–26]. Although patients with active
which is associated with significant operative morbidity
RCC BMs were excluded from clinical trials using TT and
and mortality, and a high risk of tumour recurrence [20].
IO, the recently reported results of the NIVOREN study
Neoadjuvant SABR has been tested with the goal of
have shown overall intracranial response rate of 12% with
improved disease control for patients with RCC IVC-TT.
nivolumab [27]. Another study has reported considerable
Margulis et al. [21] reported initial results on six patients
intracranial activity (response rate 55%) with cabozantinib
in the safety lead-in phase of a phase II trial
[28]. However, local treatment in the form of surgery, SRS,
(NCT02473536), which is on-going. All patients underwent
and/or whole-brain radiotherapy (WBRT) remains the
SABR (40 Gy in five fractions) to the IVC-TT, followed by sur-
mainstay of treatment. Recently, SRS has been preferred
gery. In total, 81 adverse events were reported within 90 d
to WBRT for patients with limited BMs due to minimal
of surgery: 4% were grade 3 with no grade 4 or 5 events.
toxicity and improved LC without compromising survival.
Based on the immunomodulatory effects of RCC SABR, it Published literature on patients receiving SRS for RCC
may be hypothesised that immunomodulation with IO and
BM is mainly limited to retrospective studies (Table 2)
SABR in the neoadjuvant setting before nephrectomy might
[23–26,29].
elicit a more potent antitumour immune response due to
Klausner et al. [23] reported the largest series involving
the presentation of a large repertoire of tumour-associated
120 patients with 362 BMs from RCC. The median number
antigens prior to the removal of the antigen depot. One trial
(range) and volume (range) of BMs were 2 (1–35) and 13
(NCT05024318) is assessing this approach in patients with
mm (1–50), respectively. The median (range) prescription
T1B-T3, N0 or N1, or M0 or low-volume M1 RCC before
doses were 18 Gy (14–22) and 16 Gy (10–26) by gamma-
nephrectomy.
knife and LINAC, respectively. The authors reported 94%
and 92% LC at 1 and 3 yr, respectively. In multivariate anal-
3.7. SABR for stage IV RCC
yses, a minimum dose of >17 Gy and concomitant use of TT
Approximately one-third of patients with RCC present with were associated with higher rates of LC. Seventeen patients
metastatic disease, and up to 30% treated for localised dis- had grade 3 or 4 adverse effects. As outlined in Table 2, the
ease develop metachronous metastases [22]. RCC can results of other retrospective series also showed good LC
metastasise to almost all soft tissues in the body, but most rates with SRS [24–26,29].
commonly to the lung followed by bone, liver, and brain. The spine is the most common bone site to be involved
While systemic treatment with TT and IO alone or in com- by mRCC [30]. Local treatment modalities (surgical resec-
bination is the standard of care for stage IV RCC, there is a tion, spinal fixation, radiotherapy, or a combination of
key role for metastasis-directed therapy (MDT) with sur- these) play an integral part in the management of spinal
gery, TA, or SABR in selected patients with mRCC [8–10]. mRCC [30]. SABR showed LC rates of 70–90% with good pain
As SABR is noninvasive, this approach is increasingly used control and acceptable toxicity [30]. A recent randomised
in the management paradigm for mRCC [7]. phase III trial confirmed superiority of SABR over conven-
In a meta- analysis (SABR ORCA) of 28 studies including tional radiotherapy for complete pain response and
1602 patients, Zaorsky et al. [6] evaluated the use of SABR/ included patients with RCC [31]. The control rates after
SRS in mRCC (included studies are summarised in Supple- spinal SABR are relatively lower than those for SABR to
mentary Table 3). The 1-yr LC was 89.1% for extracranial other bone sites, which can be explained by dose limitations
and 90.1% for intracranial disease. The incidence of any near the spinal cord to avoid myelopathy. There is increas-
grade 3–4 toxicity was 0.7% for extracranial disease and ing interest in a hybrid approach of separation surgery with
1.1% for intracranial disease. Multiple other studies have adjuvant radiotherapy in cases with epidural disease
reported the safety and efficacy of SABR in mRCC (Fig. 1). extension.
Table 2 – Single fraction radiosurgery for intracranial metastatic RCC (inclusive of, and since the Zaorsky et al. [6] meta-analyses)
Author (year) Study Patients Total lesions Median size/ Median radiation % On systemic Toxicity (grade LC
type (n) (n) volume dose treatment 3/4) (%)
Stenman et al. (2021) R 43 194 0.1 cm3 22 Gy 88 7 97
[24]
Uezono et al. (2021) R 48 372 0.6 cm 20 Gy 92 5 89.6
[25]
Kroeze et al. (2021) R 53 77 0.84 ml 20 Gy 100 3 NR
[29]
Klausner et al. (2019) R 120 362 1.3 cm 18 Gy (GK) 31 17 94
[23] 16 Gy (LINAC)
Wardak et al. (2019) R 38 243 0.6 cm 18 Gy 100 2 91.8
[26]
3
Zaorsky et al. (2019) MA 923 2733 2.3 cm – NR 1.1% 90.1
[6]
GK = gamma knife; LC = local control; MA = meta-analyses; NR = not reported; R = retrospective; RCC = renal cell carcinoma.
Hussain et al. [32] reported outcomes for 90 RCC patients therapy by >1 yr in >60% of patients. The study met its pri-
with high-grade epidural spinal cord compression who mary endpoint of 1-yr freedom from systemic therapy in
underwent separation surgery with adjuvant SABR. The 91.3%. When compared with baseline, there was no signifi-
authors reported a 2-yr LC rate of 92%. Only seven patients cant decline in QOL. In a multicentre prospective registry
experienced local progression requiring repeated treatment. trial of various primary tumour types, Chalkidou et al.
The 2-yr incidence of significant complications was 7.7% for [37] reported the OS outcomes of 145 OM RCC patients to
hardware failure, 3.3% for wound infection, and 1.1% for be 94% at 1 yr and 85% at 2 yr, which is consistent with
oesophageal perforation. These findings suggest the need the reported 1-yr OS rates of 100% and 95.5% in the studies
for a multimodality approach in managing spinal mRCC. of Tang et al. [35] and Hannan et al. [34], respectively.
These results suggest that SABR might facilitate deferral
of systemic treatment in carefully selected OM RCC patients
3.9. SABR for OM RCC and deferral of systemic therapy without compromising OS and maintaining QOL. Before
OM disease is described as an intermediate condition in implementing this approach outside clinical trials, clini-
which the number of metastatic lesions is limited (one to cians need to acknowledge the limitations of short follow-
five lesions), involving either single or multiple organs up, single-arm noncomparative design, and relatively novel
[33]. The clinical behaviour of OM RCC varies from rapidly nature of freedom from systemic treatment as an endpoint.
progressive to indolent, with some patients experiencing Future areas of investigation should focus on long-term
long-term survival with local therapies alone [33]. In care- safety/outcomes of this approach, appropriate clinical/
fully selected OM RCC patients, MDT may delay the need biomarkers for better selection of patients, and dose frac-
for systemic treatment without compromising survival tionation schedules for SABR.
and maintaining QOL. At least three prospective and two
retrospective studies have reported favourable outcomes
3.10. SABR in combination with systemic treatment for
with SABR in this setting (summarised in Table 3) [33–36].
extracranial metastatic disease
In a prospective phase II clinical trial, Tang et al. [35]
evaluated the feasibility and efficacy of definitive intent Systemic treatment (TT and IO) has improved outcomes for
radiotherapy in 30 mRCC patients with fewer than six patients with mRCC and is considered the frontline treat-
lesions. Feasibility was defined as completion of SABR with ment [8–10]. New combinations of systemic therapies
<7 day of unplanned break. Patients received SABR for all (TT + IO and IO + IO) have further improved outcomes in
lesions and were maintained off systemic therapy. patients with high-risk disease based on the International
At median follow-up of 17.5 mo, the trial demonstrated Metastatic Renal Cell Carcinoma Database Consortium
impressive 1-yr PFS and systemic therapy–free survival of (IMDC) risk criteria [8]. However, complete response (CR)
64% and 82%, respectively, with two grade 3 and one grade rates remains low (<10%), and at present, resistance to sys-
4 (hyperglycaemia) adverse events. temic treatment is inevitable [38]. In a multidisciplinary
Similarly, in another phase II clinical trial, Hannan et al. approach to mRCC treatment, combining SABR with sys-
[34] reported outcomes of 57 metastatic sites in 23 patients temic treatment may exploit potential additive or synergis-
with SABR in mRCC (three or fewer extracranial disease). tic interactions between the modalities to increase
The primary objective was to delay the start of systemic responses [39].
Table 3 – SABR in lieu of systemic treatment for oligometastatic RCC (since the Zaorsky et al. [6] meta-analyses)
Author (year) Study Patients Site of Radiation dose Toxicity 1-yr 1-yr
type (n) disease (%) (grade 3/4) FFST (%) OS (%)
Tang et al. (2021) [35] P 30 Lung (57) Most common 50 Gy in 6%/3% 82 100
Bone (17) 4 fractions
Nodes (11)
Other (15)
Hannan et al, (2021) [34] P 23 Total 57 sites 25 Gy 1 fraction, 12 Gy 0 91.3 95
3 fractions, or 8 Gy
5 fractions
Chalkidou et al. (2021) [37] P 143a Most common NR <5%b NR 95.3
site lung
Marvaso et al. (2021) [36] R 61 Bone (43) Median 25 Gy in 5–10 0 70 78
Lung (15) fractions
Liver (9)
Soft tissue (9)
Other (24)
Zhang et al. (2019) [33] R 47 Bone (34) 18–26 Gy/1 fraction 0 Median 15.2 mo 93.1
Lung (30) 36–42 Gy/3–5 fractions
Brain (12)
Nodes (8)
Other (16)
FFST = freedom from systemic therapy; NR = not reported; OS = overall survival; P = prospective; R = retrospective; RCC = renal cell carcinoma;
SABR = stereotactic ablative body radiotherapy.
a
A total of 143 renal cell carcinoma patients (total 1422 patients with different tumour histologies).
b
Toxicity for all 1422 patients.
In a prospective phase Ib trial, Dengina et al. [40] treated mRCC patients were treated with single-agent nivolumab
17 patients on systemic treatment (single-agent TT or IO with SABR (30 Gy in three fractions) to a single lesion
with sunitinib was most common) with SABR for one lesion [43]. The primary objective was to induce an objective
while leaving other lesions within the same organ as an response rate (ORR) of 40%. However, the study could not
internal control. The response in treated lesions was 76%, meet its primary objective (ORR of only 17%). Similarly,
with a CR of 29%. SABR-related toxicity was reported as another phase II study (30 patients) of interleukin-2 and
grade 1 in 12% of patients. The authors concluded that SABR SABR by Hannan et al. [42] reported an ORR of 16%.
in patients with mRCC treated with systemic treatment is safe In contrast, RADVAX RCC, investigating the combination
and possibly efficacious. Multiple prospective and retrospec- of SABR to one to two metastatic sites with dual IO therapy
tive studies have reported the combination of SABR with TT using nivolumab and ipilimumab, reported a more encour-
or IO in patients with mRCC (Table 4) [29,38,41–47]. aging ORR of 56% [44]. However, the median PFS of 8.2 mo
The largest retrospective study included 190 mRCC was similar to the historic reported PFS of the combination
patients treated with front-line TT between December of IOs.
2007 and June 2019 [38]. In this cohort, 85 (45%) patients While the trials mentioned above tried to exploit the
received SABR (most common dose 35–45 Gy in five frac- abscopal effect of SABR by targeting some metastatic sites,
tions). A total of 149 patients (78.4%) had IMDC a more effective approach may be to target all disease sites
intermediate- or poor-risk disease. Sunitinib was the most using SABR with IO. Recently, Siva et al. [46] reported the
common (57.9%) TT. The median OS in the TT + SABR group RAPPORT single-arm phase I/II study of total metastatic
was significantly longer than that of TT alone (63.2 vs 29.8 irradiation followed by eight cycles of pembrolizumab in
mo, p < 0.001). Patients with OM disease and those with 30 patients with one to five OM RCCs. The most common
IMDC favourable or intermediate risk had significantly site of metastatic disease was the lung (52%), and SABR
longer OS with combination treatment. SABR-related grade (20 Gy single fraction) was delivered in 77% of patients
3 toxicity was only 5.9%. (23% received 30 Gy in ten fractions with conformal radio-
Considering radiation-induced dynamic changes to the therapy). After a median follow-up of 28 mo, 2-yr OS and
T-cell repertoire and immune system in RCC [4], there was PFS were 74% and 45%, respectively. The freedom from local
interest in combining SABR with IO to enhance antitumour progression at 2 yr was 92%, with an ORR of 63%. Four
effects. In a single-arm multicentre phase II NIVES trial, 69 patients (13%) experienced grade 3 toxicity.
Table 4 – SABR in combination with systemic treatment for extracranial metastatic RCC (since the Zaorsky et al. [6] meta-analyses)
Author (year) Study Patients Systemic treatment IMDC Toxicity (grade 3– Outcomes
type (n) risk, 4) %
%
Siva et al. (2022) [46] P 30 Pembrolizumab F 56 13 2-yr FFLP 92%
I 44 2-yr PFS 45%
2-yr OS 74%
Hannan et al. (2022) [42] P 30 IL-2 NA 73 ORR 16%
Median PFS 2 mo
Median OS 37 mo
Masini et al. (2022) [43] P 69 Nivolumab F 26 26 ORR 17%
I 65 Median PFS 5.6 mo
Po 09 Median OS 20 mo
Liu et al. (2021) [38] R 190 TKIs F 21 5.9 2-yr LC 92.8%
I 58 Median OS 63.2 mo (in TKI + SABR
Po 21 group)
Liu et al. (2021) [47] R 74 TKIs F 16 54.8 1-yr LC 98.2%
mTOR inhibitors I 66 Median PFS 13.2 mo
IO Po 18 Median OS 38.5 mo
Kroeze et al. (2021) [29] R 53 TKIs NA 0 1-yr LC 75%
mTOR inhibitors
IO
Hammers et al. (2020) [44] P 25 Nivolumab and F 08 0 ORR 56%
(abs) ipilimumab I 80
Po 12
He et al. (2020) [41] R 56 TKIs F 18 0 2-yr LC 94%
I 57 Median PFS 11.5 mo
Po 21
U 04
Buti et al. (2020) [45] R 48 NA F 38 0 1-yr LC 87.7%
I 54 Median PFS not reached
Po 08
Dengina et al. (2019) [40] P 17 TKIs NA 0 ORR in target lesions 76% with CR in
mTOR inhibitors 29%
IO
abs = abstract; CR = complete response; F = favourable; FFLP = freedom from local progression; I = intermediate; IL-2 = interleukin-2; IMDC = International
Metastatic RCC Database Consortium; IO = immunotherapy; LC = local control; NA = not available; ORR = overall response rate; OS = overall survival;
P = prospective; PFS = progression free survival; Po = poor; R = retrospective; RCC = renal cell carcinoma; SABR = stereotactic ablative body radiotherapy;
TKI = tyrosine kinase inhibitor; U = unknown.
The evidence suggests that SABR in combination with 93% and 92%, respectively. Post hoc exploratory analyses
systemic treatment is safe. However, these studies have showed that a cumulative incidence of changing systemic
inherent limitations of being single-arm prospective or ret- therapy was 47% at 1 yr, with a median time to change in
rospective in nature, small sample size, and shorter follow- systemic therapy of 12.6 mo. There was no reported
up. Studies on the optimal dose have been limited, and SABR-related grade 3 toxicity.
whether low or ablative doses should be utilised is not spec- In another prospective phase II trial with the primary
ified. We urge caution to clinicians considering the use of objective to extend on-going systemic treatment by >6 mo
this strategy off protocol. Before deployment in routine clin- in >40% of patients, Hannan et al. [49] treated 37 oligopro-
ical practice, further prospective randomised trials are gressive sites with SABR in 20 patients who progressed at
needed to elucidate the benefit and utility of this approach. three or more sites while on systemic treatment. At a med-
Moreover, combinatorial strategies would benefit from a ian follow-up of 10.4 mo, the study met its primary objec-
supportive mechanistic rationale. tive by extending systemic treatment by >6 mo in 70% of
patients. The median time to change in systemic treatment
after SABR was 11.1 mo. Owing to the previously mentioned
3.11. SABR for oligoprogressive RCC immunogenic properties of SABR, an improved benefit of
Oligoprogression is a term used to describe the clinical sit- this strategy for patients on IO compared with TT has also
uation where a solitary or a few metastatic lesions progress, been reported in a retrospective study [53].
while all other metastases are stable or responding to the These studies highlight the role of SABR in extending on-
on-going systemic therapy. The standard approach for going systemic therapy in carefully selected oligoprogressive
oligoprogressive mRCC is to change systemic treatment mRCC patients and provide a strong rationale for evaluating
[8,10], but an alternative approach can be MDT to oligopro- this paradigm in prospective randomised trials. Patients
gressive site(s) while continuing the same systemic treat- who are tolerating systemic treatment well, with control of
ment. Multiple prospective and retrospective studies have most of the systemic disease and limited future treatment
shown that SABR for oligoprogressive disease can delay options, may benefit from this approach. Further questions
the switching of systemic treatment in mRCC (Table 5) that need to be evaluated in prospective trials include the
[48–53]. optimal number of lesions to be treated, radiation dose, and
In a prospective phase II trial, Cheung et al. [48] reported timing of administration to achieve immunomodulation.
outcomes for 37 mRCC patients (12 patients with IMDC
favourable and 25 with intermediate risk) with 57 oligopro-
3.12. Future perspectives
gressive tumours while on TT. All oligoprogressive sites
were treated with SABR while continuing the same TT. In the era of newer systemic treatments with TT and IO,
One-year LC rates of the irradiated tumours and OS were cytoreductive nephrectomy (CN) is less commonly
Table 5 – SABR for oligoprogressive RCC (since the Zaorsky et al. [6] meta-analyses)
Author Study Patients Sites of Radiation dose Toxicity (grade 3–4), % Outcomes
(year) type (n) progression (%)
Hannan et al. P 20 Lung (27) Different schedules based on 5 1-yr LC 100%
(2022) Bone (30) treatment sites. Median BED10, Median time to change
[49] Liver (16) 72 Gy systemic treatment
Adrenal (8) 11.1 mo
Kidney (8)
Other (11)
Cheung et al. P 37 Lung (37) 25 Gy/1# 0 1-yr LC 93%
(2021) Bone (26) 36 Gy/3# Median time to change
[48] Nodes (12) 40 Gy/5# systemic treatment
Adrenal (7) 12.6 mo
Liver (7) 1-yr OS 92%
Other (11)
Franzese R 116 Most common site Variable, most common 48 Gy/ 0 1-yr LC 83%
et al. bone (32.7) 4# 25 Gy/5# Median time to change
(2021) systemic treatment
[51] 13.9 mo
Schoenhals R 36 Bone (46) Median None (1 patient died due to 1-yr LC 93%
et al. Lung (14) 36 Gy/3# haemoptysis? SABR related or Median PFS 9.2 mo
(2021) Liver (12) progressive disease) Median OS from SABR
[53] Soft tissue (12) 43.4 mo
Other (16)
De et al. R 72 Lung/mediastinum Median 50 Gy/4# 0 1-yr LC 96%
(2022) (49) 1-yr PFS 52%
[50] Bone (49) 1-yr OS 91%
Other (2)
Gebbia et al. R 28 Most common site Median 30 Gy/10# 0 Median PFS after
(2020) bone followed by radiotherapy 4.55 mo
[52] lung
LC = local control; OS = overall survival; P = prospective; PFS = progression-free survival; R = retrospective; RCC = renal cell carcinoma; SABR = stereotactic
ablative body radiotherapy; # = fractions.
performed, given the data from the CARMENA and SURTIME References
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Analysis and interpretation of data: Ali.
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Drafting of the manuscript: Ali. from the International Radiosurgery Oncology Consortium for
Critical revision of the manuscript for important intellectual content: Mooi, Kidney (IROCK). Int J Radiat Oncol Biol Phys 2020;108:941–9.
Lawrentschuk, McKay, Hannan, Lo, Hall, Siva. [13] Tetar SU, Bohoudi O, Senan S, et al. The role of daily adaptive
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Statistical analysis: None.
(Basel) 2020;12:2763.
Obtaining funding: None. [14] Grelier L, Baboudjian M, Gondran-Tellier B, et al. Stereotactic body
Administrative, technical, or material support: None. radiotherapy for frail patients with primary renal cell carcinoma:
Supervision: Siva. preliminary results after 4 years of experience. Cancers (Basel)
Other: None. 2021;13:3129.
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Financial disclosures: Muhammad Ali certifies that all conflicts of inter-
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est, including specific financial interests and relationships and affiliations quality of life following stereotactic body radiation therapy for
relevant to the subject matter or materials discussed in the manuscript primary kidney cancer—results from a prospective cohort study.
(eg, employment/affiliation, grants or funding, consultancies, honoraria, Clin Oncol (R Coll Radiol) 2021;33:468–75.
stock ownership or options, expert testimony, royalties, or patents filed, [17] Grubb WR, Ponsky L, Lo SS, et al. Final results of a dose escalation
protocol of stereotactic body radiotherapy for poor surgical
received, or pending), are the following: Muhammad Ali is a PhD candi-
candidates with localized renal cell carcinoma. Radiother Oncol
date who is supported through an ‘‘Australian Government Research 2021;155:138–43.
Training Program (RTP) scholarship’’. Shankar Siva is funded by the Can- [18] Siva S, Chesson B, Bressel M, et al. TROG 15.03 phase II clinical trial
cer Council Victoria Colebatch fellowship. of focal ablative stereotactic radiosurgery for cancers of the
kidney—FASTRACK II. BMC Cancer 2018;18:1030.
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International Radiosurgery Oncology Consortium for Kidney for
Funding/Support and role of the sponsor: None.
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Editorial
Stereotactic Ablative Body Radiotherapy: An Emerging Weapon in

the Treatment Armamentarium for Renal Cell Carcinoma or a
Potential Avenue for Overtreatment?
Diana E. Magee a, Jessica Karen Wong b, Andres F. Correa a,*

a
Division of Urology, Department of Surgical Oncology, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA; b Department
of Radiation Oncology, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA
The incidence of renal cell carcinoma (RCC) continues to able. To date, these patients have been managed very safely
increase, a trend attributed to the greater utilization of with active surveillance: the progression risk is
cross-sectional imaging whereby the majority of patients approximately 2% [5], even for those with larger masses
are diagnosed with an incidental localized renal lesion [1]. (cT1 and cT2) [6], and any treatment, even a noninvasive
This increase is most notable for patients older than 75 yr option, would constitute overtreatment. Moreover, an
[1], for whom a greater burden of comorbidities muddies assessment of outcomes in these patients has yet to be
the treatment waters and a noninvasive treatment option established, and follow-up protocols remain poorly defined.
would be beneficial. Use of radiation therapy in the RCC set- As the authors mention, a residual, measurable tumor per-
ting has historically been avoided owing to widespread sists following SABR, with slow regression being a marker
belief in its radioresistance. The emergence of stereotactic of success. However, anticipated timelines for regression
ablative radiotherapy (SABR), which delivers a high dose are unclear and post-treatment biopsy does not yield mean-
of radiation to the target tissue, has changed this paradigm ingful data owing to the consistent persistence of tumor
in the management of patients with localized and meta- cells. Severe toxicity is limited, occurring in 0–9.1% of
static disease [2]. patients receiving treatment, but the long-term impact on
In their narrative review in this issue of European Urol- renal function remains unclear. Although a small risk, any
ogy, Ali et al. [3] summarize the key contemporary evidence chance of a need to initiate dialysis must be taken seriously
on the use of SABR in both localized and metastatic RCC. when weighing the benefits and risks of treatment.
Using a comprehensive search strategy, they included two The authors discuss the unique use of SABR in the neoad-
meta-analyses, 13 prospective studies, and 20 retrospective juvant setting for patients presenting with a concomitant
studies. tumor thrombus. Building on the success of SABR in the
Evidence for the use of SABR for primary RCC is largely management of hepatocellular carcinoma invading the por-
retrospective in nature and with short-term follow-up. tal vein or inferior vena cava [7], several institutions have
Results from the studies available demonstrate excellent adopted the technique for patients who are deemed poor
local control rates of 90–97.2%: the 5-yr overall survival candidates for surgery, reporting a radiographic response
(OS) for patients with cT1 disease is approximately 89%, rate of 58% and significant relief from venous obstruction
with larger tumor size and receipt of multiple fractions as symptoms [8]. In a novel clinical trial by Margulis and col-
factors associated with treatment failure [4]. As we think leagues [9], SABR is being applied in the neoadjuvant setting
about the role of SABR in the treatment of localized RCC, to decrease the morbidity of surgery and possibly aid in
the ideal candidate would be a significantly comorbid oncological outcomes by eliciting an abscopal response
patient for whom surgical removal or ablation is not suit- [9]. At median follow-up of 24 months, all patients were

* Corresponding author. Division of Urology, Department of Surgical Oncology, Fox Chase Cancer Center, Temple University Health System, 333
Cottman Avenue, Philadelphia, PA 19111, USA.
E-mail address: andres.correa@fccc.edu (A.F. Correa).
0302-2838/Ó 2022 Published by Elsevier B.V. on behalf of European Association of Urology.
alive and, interestingly, the use of neoadjuvant SABR was ensure that SABR use does not become a source of unneces-
associated with higher PD-L1 expression. This elevated sary treatment in localized disease and that this therapy is
PD-L1 expression may be harnessed moving forward, deployed in a maximally efficacious manner for those with
considering the thrombus susceptibility to PD-L1-targeting locally advanced and metastatic RCC.
agents in RCC [10].
In the oligometastatic setting, small clinical trials
Conflicts of interest: The authors have nothing to disclose.
demonstrated that SABR to all lesions resulted in deferral
of systemic therapies in 82% [11] and 87% [12] of patients
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localized and widely metastatic settings. Care is needed to
Platinum Priority – Infections – Editor’s Choice

Editorial by James W.F. Catto on pp. 631–632
Genitourinary Lesions Due to Monkeypox
Miguel Gomez-Garberi a, Pau Sarrio-Sanz a,*, Laura Martinez-Cayuelas a, Elisabet Delgado-Sanchez b,

Sara Bernabeu-Cabezas c, Jorge Peris-Garcia b, Laura Sanchez-Caballero a, Baraa Nakdali-Kassab a,
Cristina Egea-Sancho a, Edgar Humberto Olarte-Barragan a, Manuel Angel Ortiz-Gorraiz a
a
Urology Service, University Hospital of San Juan de Alicante, San Juan de Alicante, Spain; b Internal Medicine Service, University Hospital of San Juan de
Alicante, San Juan de Alicante, Spain; c Centre d’Informació i Prevenció del Sida, Alicante, Spain
Article history: Background: Since May 2022, 31 000 cases of monkeypox infection have been reported
Accepted August 29, 2022 in nonendemic areas.
Objective: To describe a series of cases of monkeypox with genitourinary involvement.
Associate Editor: Design, setting, and participants: This was a prospective observational study of men
James Catto diagnosed with monkeypox disease with genitourinary involvement.
Results and limitations: A total of 14 patients were recruited. The median age was 42 yr.
Keywords: Of these patients, 43% sought a consultation for genitourinary symptomatology, and 71%
Monkeypox disease had engaged in sex with other men. Eight patients (57%) were positive for human
Genitourinary lesions immunodeficiency virus, one diagnosed synchronously; the remainder had a median
Penile oedema CD4 count of 663/ll. Six patients (43%) had a different sexually transmitted disease.
Penile oedema was present in 43% of patients and two patients required surgical
exploration.
Conclusions: Genitourinary involvement is frequent in monkeypox disease and is often
the reason for the consultation visit.
Patients summary: In this report we looked at how monkeypox disease can affect the
genitourinary area, causing swelling of the penis or skin lesions.
1. Introduction research. Two different genetic clades of the virus can be

distinguished, the Central African (Congo Basin) and the
Monkeypox is a zoonosis caused by monkeypox virus West African clade, with the latter usually giving rise to
(MPXV), an orthopoxvirus. The disease is the most prevalent milder disease with more limited human-to-human trans-
orthopoxvirus zoonosis since the eradication of smallpox in mission [2,3]. MPXV is endemic in Central and West African
1980 [1]. MPXV was first isolated from humans in 1970, and areas [4]. One of the most severe disease outbreaks was
was previously isolated in 1958 from macaques used in reported in 2017 in Nigeria, with more than 200 confirmed
* Corresponding author. University Hospital of San Juan de Alicante, Ctra Alicante-Valencia, km 87,
Sant Joan d’Alacant 03550, Alicante, Spain. Tel. +34 6 6448 7934.
E-mail address: pausarrio@gmail.com (P. Sarrio-Sanz).
cases and a reported mortality rate of between 3% and 12.5% (n = 8) were HIV-positive; one patient was diagnosed at
[2,3,5]. an STD screening clinic and the rest were HIV-positive
Since May 2022, more than 40 000 cases have been patients on antiretroviral treatment with good control, with
reported in 87 countries not previously considered MPXV normal CD4 T-cell counts (median 663/ll). 43% of the
endemic areas [6]. In the current situation, transmission is patients (n = 6) presented synchronously with other STDs.
mainly human-to-human. Transmission can occur through
close contact with skin lesions, droplets, or fomites [7]. 3.3. Clinical findings
The virus has also been isolated from blood, urine, seminal
In six patients (43%) the initial symptom was related to the
fluid, and the nasopharynx [4,8]. The typical clinical picture
genitourinary area. In the remaining patients, the median
includes fever, headache, palpable lymphadenopathy, and
time from first symptoms to the onset of genitourinary
worsening general condition associated with a macular skin
symptoms was 5 days. All patients presented with cuta-
rash progressing to vesiculopustular lesions. The most
neous or mucosal involvement with vesicles and pustules,
recent series describes genital area involvement showing
which evolved into scabs and were resolved in all cases.
vesiculopustular lesions and associated penile oedema
Penile oedema was present in 43% of cases (n = 6) and
[4,9,10].
57% (n = 8) had palpable lymphadenopathy in the groin
The aim of this study was to describe a series of cases of
area. All the patients had systemic symptoms such as
monkeypox with genitourinary involvement.
malaise (n = 4, 28.5%), fever (n = 5, 35.7%), and different skin
lesions such as papules, vesicles, pustules, and scabs (n = 14,
2. Patients and methods 100%; Table 1).
This was a prospective observational descriptive study of male patients
3.4. Treatments used
with confirmed MPXV infection and genital area involvement. All the
patients with confirmed MPXV disease at our hospital and genitourinary Two patients (14.2%) required surgical intervention for
symptoms between May and August 2022 were invited to participate in abscess drainage (patient 2) and penile surgical exploration
the study. Genital area involvement was defined as any skin lesions, skin (patient 1). Treatment for uncomplicated cases was for
changes, or oedema in the penile and scrotal areas. symptom relief with antihistamines, analgesics, and nons-
All patients were diagnosed using polymerase chain reaction (PCR).
teroidal anti-inflammatory drugs, with addition of amoxi-
For the PCR test, three swabs were taken from different skin lesions
cillin/clavulanic acid when bacterial superinfection of the
(vesicles/pustules were punctured and scabs were removed). When the
skin lesions was detected.
patient did not present with lesions, a rectal swab was performed.
Real-time PCR for qualitative detection of MPXV-specific DNA test was
3.5. Atypical presentation
performed (FlexStar PCR, altona Diagnostics, Hamburg, Germany).
Screening for sexually transmitted diseases (STDs) was carried out Patient 1 had an atypical presentation; he attended for con-
systematically for human immunodeficiency virus (HIV), chlamydia, sultation because of symptoms compatible with sepsis. He
syphilis, Neisseria gonorrhoeae, Epstein-Barr virus, and cytomegalovirus. presented with fever (42 °C), hypotension (blood pressure
Blood cultures were taken in cases with fever. STD screening was carried 94/54 mm Hg), and tachycardia (140 beats/min) accompa-
out during the hospital stay or when the patient’s isolation had ended. nied by headache and poor general condition; a test for
Genitourinary symptoms and other systemic symptoms are described SARS-CoV-2 infection was negative.
separately. The patient presented with oedema of the penis with
The patients provided informed consent to publication of their case
inflammatory changes on the surface, showing erythema-
details. Data collection and management were conducted according to
tous penile lesions, and the penis was warm on palpation.
ethical practice and basic ethical principles.
No rash, ulcers, or other skin lesions were observed at the
time. Bilateral inguinal lymph nodes were palpable and a
3. Results purulent discharge from the anus was observed.
Penile ultrasound and a computed tomography scan
3.1. Patients showed inflammatory changes in the skin and subcuta-
neous cellular tissue, proctitis without collections or
We present 14 cases of males with genitourinary involve-
abscesses, and prominent bilateral mesorectal and inguinal
ment (Fig. 1) due to MPXV infection, with no history of tra-
lymphadenopathies (Fig. 2A, C). The study was completed
vel to endemic areas. The sociodemographic and clinical
with pelvic magnetic resonance imaging, which revealed
characteristics are summarised in Table 1. The median age
penile cellulitis, proctitis, and inflammatory pelvic lym-
of the patients was 42 yr (range 20–56). All the patients
phadenopathy (Fig. 2B).
(100%) were recruited from the same urban area.
Given the patient’s haemodynamic instability, an anus-
copy examination was performed under anaesthesia, which
3.2. Transmission
revealed intense anal inflammation, granuloma 3 cm from
The median time between exposure (when known) and the sphincter (pathological anatomy of nonspecific proctitis);
symptom onset was 13 days (range 3–30). Of the patients, examination of the penis showed no abscesses or collections.
71% (n = 10) were men who had sex with other men and The patient had negative urine and blood cultures. Serol-
14.2% (n = 2) had heterosexual intercourse. Two patients ogy was positive for HIV-1 (viral load 7820 copies/ml and
(14.5%) maintained that they had had no sexual intercourse 265/mm3 CD4 T-lymphocytes) and Chlamydia trachomatis
in the weeks before symptom onset. 57% of the patients (serovar L1–L3).
Fig. 1 – Genitourinary lesions and penile oedema.
Skin lesions appeared 21 days after this first episode, pubis, penis (glans penis and skin), all four extremities,
with fever and nonpainful papular lesions affecting the and the oral and ocular mucosa. Lymphoedema persisted
Table 1 – Clinical and sociodemographic characteristics of the patients
Case Age TES TSO-GU MSM HIV Dx Other STDs Genitourinary symptoms Other symptoms
(yr) (d) (d)
1 26 5 0 Yes Yes (synchronous Dx, Chlamydia Penile oedema Malaise, fever
CD4 265) Proctalgia and RD Bilateral IA
2 20 30 7 Yes No Gonococcus Penile oedema
3 30 7 2 Yes No No Penile oedema Malaise, fever
Perianal vesicle Arthromyalgia
Odynophagia
4 27 30 5 No No Syphilis Inguinoscrotal abscess Malaise, fever,
asthenia
IA left
5 40 ? 7 Yes Yes (Dx in 2011, CD4 589) No Pustular lesions on DP Arthralgia,
asthenia
6 30 14 0 Yes Yes (Dx in 2016, CD4 811) ? Pustular lesions on DP Bilateral IA
Rectal itching and RD
7 55 21 14 Yes Yes (Dx in 2021, CD4 769) No Scab lesions on the penis Fever and malaise
8 42 3 0 Yes No No Whitish lesion on the GP Right IA
Penile oedema
Pain in the perineal area
9 56 ? 0 ? Yes (Dx in 2018, CD4 663) No Vesicles on the DP Bilateral IA
Penile oedema
10 55 21 0 No No Herpes type 2 Penile oedema Bilateral IA
VP lesions on GP and foreskin 4–5 mm
11 47 7–14 3 Yes Yes (Dx in 2010, CD4 Chlamydia VP lesion on the right scrotum,
>500) trachomatis excessively raised
12 38 10 5 ? ? ? VP lesions on the DP Malaise and
arthralgia
13 51 13 0 Yes Yes (Dx in 2005, CD4 660) No VP lesions on pubis and GP Low fever
Bilateral IA
14 59 10 5 Yes Yes (Dx in 2004 Mycoplasma 2 scrotal lesions with purulent exudate Fever
CD4 682) genitalium Right IA
TES = time from exposure to symptoms; TSO-GU = time from symptom onset to genitourinary symptoms; MSM = men who have sex with men; HIV = human
immunodeficiency virus; STD = sexually transmitted disease; Dx = diagnosis; CD4 = count of T cells positive for CD4 (in cells/ll); AI = inguinal adenopathy;
RD = rectal discharge; DP = dorsum of the penis; GP = glans penis; VP = vesicopustular.
on the penis with a 1.5-cm scabbed lesion in the dorsal absence of skin lesions should not in itself exclude MPXV
region of the foreskin, while the surgical wound remained disease.
clean. A bladder catheter was used because of voiding diffi- Urologists should know that MPXV infection may pre-
culties. A PCR diagnosis of MPXV was made at this time. PCR sent as penile oedema and they should therefore maintain
determination of the virus was performed on a sample a high level of suspicion for such cases, making an early
taken from the rectum, in which no amplification of the diagnosis of the infection and screening for other STDs.
virus genome was observed, although the sample had to The urologist should also know that the normal incubation
be deparaffinised to perform this technique. period is between 4.2 and 17.3 d (5th–95th percentile) and
At 10 weeks after onset, all the patient’s skin lesions and recommend isolation for case contacts is for 21 d [12]. The
penile oedema had resolved. patient needs to know, given the epidemiological context,
that he should seek medical attention for penile oedema
4. Discussion and avoid contact with people because it could be caused
by MPXV. Symptoms are usually self-limiting, but some
We described 14 male patients with genitourinary involve- patients may experience complications such as pneumonia,
ment due to MPXV infection. The pattern usually described encephalitis, and keratitis.
is centrifugal: lesions evolve simultaneously and there is Penile oedema occurred in 43% of the patients in our
greater involvement at the distal level (extremities and sample. This figure is higher than the 15.7% reported by
face) [5]. Genitourinary involvement has been described Patel et al. [7], probably because our series included only
for some cases [8,11] and may suggest that the route of patients with genitourinary involvement. Penile oedema
acquisition was via sexual contact [9]. Especially in case has a variable evolution time and may persist for as long
number 1, there was a high suspicion of sexual transmission as 21 d, as in patient 1 (despite examination under anaes-
owing to the granular lesion in the rectum; however, it was thesia), which is why we believe that a surgical approach
not possible to detect genetic fragments of the pathogen in should only be used in patients with purulent collections.
the rectal biopsy. So far, only cutaneous sequelae due to MPXV infection
In this series, 43% of patients (n = 6) presented for have been reported [5]. However, we have found that penile
consultation because of a lesion in the genitourinary area lymphoedema can persist for weeks. Long-term studies are
as the initial symptom. Hence, urologists have a fundamen- needed to rule out sequelae such as urethral strictures and
tal role in the differential diagnosis of MPXV disease [2], infertility in the medium to long term.
as it can be confused with other STDs such as secondary In our series, 50% of patients were HIV-positive (on
syphilis and lymphogranuloma venereum [11]. Skin lesions antiretroviral treatment) and just one (7%) was syn-
may take days or weeks to appear, and therefore the chronously diagnosed with HIV. In previous series, the
is similar to counts previously published (354–664 cells/

ll) [5,7].
Following our experience, we recommend STD screening
for all patients diagnosed with MPXV, as 29% of patients in
previous reports had STDs [4]. In our series, other STDs
coexisted in 43% of the patients. We suggest inclusion of
MPXV in the differential diagnosis of STDs, as 1.33% of
patients with other STDs had asymptomatic MPXV disease
in a Belgian series [13].
Tecovirimat has been proposed for supportive care given
its efficacy against this disease in animal models and phase
1 and 2 studies [14]. Its use is currently considered safe,
with few adverse events, and it appears to reduce the dura-
tion of symptoms and hospitalisation time [8]. Among our
cohort, a request for tecovirimat for patient 1 was submit-
ted because of the torpid evolution, but the request was
denied because the criteria for complications established
by the authorising bodies were not met. Prior immunisation
with smallpox vaccine may have a protective effect and
reduce symptoms, so this is now indicated for prevention
of MPXV disease in patients at high risk [15].
5. Conclusions
MPXV disease is currently being transmitted between

humans. Penile oedema and involvement of the genitouri-
nary tract are common, and in many cases is the main
symptom prompting medical consultation. It is vital for
urologists and surgeons to be aware of this disease for a cor-
rect differential diagnosis with regards other STDs, with
which it can be confused or coincide.
Author contributions: Pau Sarrio-Sanz had full access to all the data in
accuracy of the data analysis.
Study concept and design: Sarrio-Sanz, Gomez-Garberi, Martinez-

Cayuelas.
Acquisition of data: Delgado-Sanchez, Bernabeu-Cabezas, Peris-Garcia,
Nakdali-Kassab, Olarte-Barragan, Egea-Sancho.
Analysis and interpretation of data: Sarrio-Sanz, Gomez-Garberi,
Martinez-Cayuelas, Sanchez-Caballero.
Fig. 2 – Imaging performed at the time of diagnosis for patient 1. (A) Drafting of the manuscript: Sarrio-Sanz, Gomez-Garberi.
Noncontrast computed tomography scan showing oedema of the subcuta-
Critical revision of the manuscript for important intellectual content:
neous cellular tissue of the penis. There is thickening of the wall of the
distal rectum and anal canal, and loss of fatty planes. (B) Magnetic Martinez-Cayuelas, Ortiz-Gorraiz.
resonance imaging showing marked thickening of the subcutaneous Statistical analysis: Sarrio-Sanz.
cellular tissue of the penis, with thickness >2 cm. There is diffuse thickening Obtaining funding: None.
of the tunica albuginea. Corpora cavernosa and corpus spongiosum of
Administrative, technical, or material support: Nakdali-Kassab, Sanchez-
normal size and intensity. Irregular thickening of the walls of the anus and
lower rectum. (C) Penile ultrasound. The corpora cavernosa and corpus Caballero.
spongiosum are preserved. There is thickening of the subcutaneous cellular Supervision: Ortiz-Gorraiz, Martinez-Cayuelas.
tissue with no abscesses or collections. Other: None.
Financial disclosures: Pau Sarrio-Sanz certifies that all conflicts of inter-

number of HIV-positive patients has varied between 0% and est, including specific financial interests and relationships and affiliations
22.5–41% [4,5,8]. It has been postulated that HIV infections relevant to the subject matter or materials discussed in the manuscript
with severe immunosuppression could favour infection or (eg, employment/affiliation, grants or funding, consultancies, honoraria,
aggravate symptoms [5]. In our series, patient 1 had the stock ownership or options, expert testimony, royalties, or patents filed,
most severe monkeypox case, the only patient diagnosed received, or pending), are the following: None.
synchronously with HIV and therefore without HIV treat-

ment. The median CD4-positive cell count for our patients Funding/Support and role of the sponsor: None.
References [8] Adler H, Gould S, Hine P, et al. Clinical features and management of
human monkeypox: a retrospective observational study in the UK.
[1] Costello V, Sowash M, Gaur A, et al. Imported monkeypox from Lancet Infect Dis 2022;22:1153–62. 10.1016/S1473-3099(22)00228-6.
international traveler, Maryland, USA, 2021. Emerg Infect Dis [9] Hammerschlag Y, MacLeod G, Papadakis G, et al. Monkeypox infection
2022;28:1002–5. 10.3201/eid2805.220292. presenting as genital rash, Australia, May 2022. Euro Surveill
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from Nigeria – Dallas, Texas, July 2021. Morb Mortal Wkly Rep [10] Patrocinio-Jesus R, Peruzzu F. Monkeypox genital lesions. N Engl J
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022-01742-y.

Monkeypox and the Urologist: Playing an Important Role in This

Emerging Global Outbreak
James W.F. Catto a,b,*

a
Academic Urology Unit, University of Sheffield, Sheffield, UK; b Department of Urology, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
In this issue of European Urology, Gomez-Garberi et al [1] The incubation period for monkeypox is usually
report on a series of patients with monkeypox who pre- between 6 and 13 d [4] and most infected individuals pre-
sented to either the urology or internal medicine depart- sent with fever, headache, muscle aches, fatigue, and lym-
ment at the University Hospital of San Juan de Alicante in phadenopathy [5]. This last feature is a distinctive sign that
Spain. They highlight the high frequency of genital symp- can help in differentiating monkeypox from other viral ill-
toms and signs, and that urologists must be prepared to nesses with similar symptoms (eg, chicken pox, measles,
play a key role in diagnosing this infection. This report is and smallpox). Approximately 1–3 d after the fever starts,
timely as we witness a global outbreak and because, until skin eruptions emerge on the face, extremities, and
now, many urologists might have been unaware of mucous membranes. Lesions can be located on the genital
monkeypox. organs and, as detailed by Gomez-Garberi et al [1], it is
Monkeypox is a viral zoonosis that is transmitted these eruptions that may be the initial presenting symp-
between humans or from an animal host, such as a rodent, tom for many individuals. Treatment is mostly aimed at
squirrel, or nonhuman primate. Transmission is via direct symptom relief, including shortening the duration of
contact with blood, bodily fluids, or cutaneous/mucosal symptoms [6] and preventing further spread, including
lesions. Few individuals are hospitalised and very few die use of vaccination [7].
from the infection. Human infections were first diagnosed There are important take home messages for our readers.
in 1970 and, up until the mid 2000s, seemed to be contained First, as demonstrated, an awareness of this diagnosis is
within central and west Africa. From 2003 onwards, an important [1]. Gomez-Garberi et al [1] report that most
increasing number of cases outside of endemic areas, individuals had genital eruptions, although one man pre-
including Europe and North America, were identified. How- sented with fever and penile oedema without a clear source.
ever, the number of new cases was low and most were self- He had lymphadenopathy at presentation, but it was 21 d
contained. That was until 2021, when there were two before skin lesions developed. Anogenital lesions were seen
reports of monkeypox in the USA for individuals who had in most infected individuals (eg, 73% of those documented
visited Nigeria [2]. In May 2022, multiple cases of monkey- by the SHARE-net Clinical Group [4]) so this atypical pre-
pox infection were reported in Portugal, Spain, and Canada sentation may be seen in many units. Second, in the current
[3]. Over the next few days, cases were identified in Aus- outbreak there are at-risk populations and awareness of
tralia, the UK, Belgium, Switzerland, Israel, and the USA. these will help in identifying cases. Thornhill et al [4]
At the time of writing, there have been 49 974 confirmed reported 528 individuals with infection, of whom 98% were
cases in 92 nonendemic regions (https://www.cdc.gov/ gay or bisexual, 75% were white, and 41% also had human
poxvirus/monkeypox/response/2022/world-map.html), immunodeficiency virus (HIV) infection; the median age
including 18 416 new diagnoses in the USA (Fig. 1). was 38 yr. It was thought that transmission was mostly

* Academic Urology Unit, The Medical School, University of Sheffield, Sheffield, UK. Tel. +44 114 226 1229.
E-mail address: j.catto@sheffield.ac.uk
Fig. 1 – Global distribution of new monkeypox cases up to August 2022. Retrieved from https://ourworldindata.org/explorers/monkeypox [11].
via sexual activity, and the data from Gomez-Garberi et al through testing, treat local symptoms and the patient with
[1] support this hypothesis (eg, 71% of those with infection sensitivity, and then reduce the spread through education.
were men who had sex with men, the median age was 42 yr,
and HIV was found in 57%). Third, co-infection with other Conflicts of interest: The author has nothing to disclose.
sexually transmitted diseases is common, so thorough

References
screening is advocated. Finally, the authors helpfully detail
steps that a urologist should take when identifying a case [1] Gomez-Garberi M, Sarrio-Sanz P, Martinez-Cayuelas L, et al.
of monkeypox. A diagnosis should be confirmed (including Genitourinary lesions due to monkeypox. Eur Urol 2022;82:625–30.
any appropriate notifications) and symptoms treated. [2] Looi MK. Monkeypox: what we know about the 2022 outbreak so
far. BMJ 2022;378:o2058.
Patients should be managed with sensitivity (without stig- [3] Kumar N, Acharya A, Gendelman HE, Byrareddy SN. The 2022
matisation) and encouraged to talk to their contacts (for outbreak and the pathobiology of the monkeypox virus. J
education and enhanced testing) to reduce any local spread Autoimmun 2022;131:102855.
[4]. The duration of viral shedding (after resolution of [4] Thornhill JP, Barkati S, Walmsley S, et al. Monkeypox virus infection
in humans across 16 countries — April–June 2022. N Engl J Med
lesions) is unknown, so the use of condoms for 8 wk is 2022;387:679–91.
advocated. [5] Adler H, Gould S, Hine P, et al. Clinical features and management of
Targeted vaccination has been introduced and it is hoped human monkeypox: a retrospective observational study in the UK.
Lancet Infect Dis 2022;22:1153–62.
that studies will inform the best application [8,9]. Molecular
[6] Sherwat A, Brooks JT, Birnkrant D, Kim P. Tecovirimat and the
epidemiology and genomics are unravelling why the viral treatment of monkeypox — past, present, and future considerations.
demographics have changed and how this might have an N Engl J Med 2022;387:579–81.
impact in the future [10]. It is likely that these studies will [7] Gruber MF. Current status of monkeypox vaccines. NPJ Vaccines
2022;7:94.
deliver better treatments and effective vaccines. While the [8] Mahase E. Monkeypox: gay and bisexual men with high exposure
current monkeypox outbreak is a cause for concern, we risk will be offered vaccine in England. BMJ 2022;377:o1542.
should be measured in our response. In contrast to HIV [9] Kupferschmidt K. Scientists scramble to set up monkeypox vaccine
trials. Science 2022;377:696–7.
and COVID-19, most individuals recover fully and fatalities
[10] Rothenburg S, Yang Z, Beard P, et al. Monkeypox emergency: urgent
are mostly rare. While some monkeypox strains do have questions and perspectives. Cell 2022;185:3279–81.
higher rates of pathogenicity, vaccines exist. Our role as [11] Mathieu E, Spooner F, Dattani S, Ritchie H, Roser M. Monkeypox
urologists will be to consider the diagnosis, confirm this 2022. https://ourworldindata.org/monkeypox.
Platinum Priority – Brief Correspondence

Editorial by Juan Gómez Rivas, Jeremy Yuen-Chun Teoh, Giovanni Cacciamani on pp. 637–638 of this issue
Optimal Dissemination of Scientific Manuscripts via Social Media: A

Prospective Trial Comparing Visual Abstracts Versus Key Figures in
Consecutive Original Manuscripts Published in European Urology
Zachary Klaassen a,b,*, Emily Vertosick c, Andrew J. Vickers c, Melissa J. Assel c, Giacomo Novara d,
Cathy Pierce e, Christopher J.D. Wallis f,g, Alessandro Larcher h, Matthew R. Cooperberg i,
James W.F. Catto j, Alexander Kutikov k
a
Section of Urology, Department of Surgery, Medical College of Georgia-Augusta University, Augusta, GA, USA; b Georgia Cancer Center, Augusta, GA, USA;
c
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; d Department of Surgery, Oncology, and
Gastroenterology, Urology Clinic, University of Padua, Padua, Italy; e European Association of Urology, Arnhem, The Netherlands; f Division of Urology,
Department of Surgery, University of Toronto, Toronto, ON, Canada; g Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada;
h
Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy; i Department of Urology, University of California-San Francisco Medical Center,
San Francisco, CA, USA; j Academic Urology Unit, University of Sheffield, Sheffield, UK; k Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia,
PA, USA
Article history: Visual abstracts (VAs) are graphical representations of the key findings in manuscripts
Accepted January 19, 2022 and have been adopted by many journals to improve content dissemination via social
media. We sought to assess whether VAs, compared to key figures (KFs), increased
Associate Editor: reader engagement via social media using articles published in European Urology. We
Todd M. Morgan prospectively randomized 200 consecutive new publications to representation on
Twitter and Instagram using either a VA (n = 99) or a KF (n = 101). Randomization
was stratified by prostate cancer content. The primary outcome was Twitter impres-
Keywords:
sions. Secondary outcomes included Twitter total engagements, link clicks, likes, and
Visual abstract retweets, as well as Instagram likes. Analysis of covariance was conducted using the
Social media stratification variable as a covariate. We found that Twitter impressions were greater
Twitter for tweets containing VAs compared to KFs (8385 vs 6882; adjusted difference 1480,
Urology 95% confidence interval [CI] 434–2526; p = 0.006). VA use was also associated with more
Instagram retweets and likes (p < 0.002), but fewer full-article link clicks than KFs (60 vs 105,
adjusted difference 45, 95% CI 21–70; p = 0.0004). The choice between VA and KF should
depend on the relative value given to impressions versus full-article link clicks.
Patient summary: We found that use of a visual abstract increases the social media
reach of new urology articles when compared to key figures from the manuscript, but
was associated in a significantly lower click-through rate. In the increasingly virtual
world of academic medicine, these findings may assist authors, editors, and publishers
with dissemination of new research.
* Corresponding author. Medical College of Georgia at Augusta University, Georgia Cancer Center,
Augusta, GA 30912, USA. Tel. +1 706 7212519; Fax: +1 706 7212548.
E-mail address: zklaassen19@gmail.com (Z. Klaassen).
Over the past decade, the dissemination of academic research social media posting, block-stratified by prostate cancer or
has increasingly utilized social media platforms, including non-prostate cancer with block size 4. Randomization was
Twitter, Facebook, and Instagram [1–3]. A visual abstract performed using a password-protected database that
(VA) is a graphical representation of the key findings of a ensured full allocation concealment. The primary outcome
manuscript; VAs have been adopted by many medical jour- was Twitter impressions. Secondary outcomes included
nals as a strategy to improve dissemination of their publica- Twitter total engagements, link clicks, likes, and retweets,
tions [4]. A previous study on the literature for general as well as Instagram likes. All VAs were created by the Euro-
surgery showed that VA tweets had more Twitter impres- pean Urology digital media editor with a consistent format
sions, shares, and article visits to the publisher’s website in throughout the study. Each article was ‘‘live’’ on Twitter/
comparison to tweets containing only the article title [4]. A Instagram (Fig. 1) for 2 wk, after which the primary and sec-
subsequent prospective study on nephrology literature ondary outcome data were collected from @EUplatinum
showed that tweets containing VAs had more than twice as tweet analytics and entered into a prospective database.
many views as citation-only tweets and tweets containing a Variables of interest included the number of Twitter follow-
key figure (KF) [5]. Notably, both of these prospective studies ers for the first and senior authors and oncology (vs non-
included fewer than 50 articles. To the best of our knowledge, oncology) and robotic surgery (vs nonrobotic surgery) pub-
no large-scale prospective trial has been conducted using new lications. Analysis of covariance was conducted using the
urology publications. The aim of this study was to perform a stratification variable (prostate/non-prostate) as a covari-
prospective trial of VAs versus KFs for social media dissemina- ate. As there was a clear and obvious relationship between
tion of articles published in European Urology. time and outcome (including an increase in @EUplatinum
Consecutive new articles published in European Urology followers)—there were approximately 6000 more engage-
(original articles, systematic reviews, or brief correspon- ments for the last 25 compared to the first 25 articles—we
dence articles) were randomized to either a VA or KF for added day from the start of the trial as a covariate.
Fig. 1 – Representative examples of visual abstracts on (A) Twitter and (B) Instagram (highlighting the three panels of the visual abstract) and key figures on
(C) Twitter and (D) Instagram) for dissemination on social media.
Table 1 – Social media endpoints
Endpoint Mean (SD) Adjusted difference (95% CI) p value

Key figure Visual abstract
Twitter impressions a 6882 (3785) 8385 (4370) 1480 (434–2526) 0.006
Twitter total engagements 428 (430) 547 (465) 116 ( 6 to 239) 0.062
Twitter retweets 16 (16) 24 (18) 8 (3–12) 0.002
Twitter link clicks 105 (110) 60 (57) 45 ( 70 to 21) 0.0004
Twitter likes 31 (29) 46 (34) 15 (6–23) 0.001
Instagram likes 29 (23) 35 (18) 5 ( 0 to 11) 0.054
CI = confidence interval; SD = standard deviation.
a
Primary outcome.
Between April 2019 and February 2021, 200 publications from an article, which is not readily available via a KF tweet,
were randomized, of which 101 were allocated to KF and 99 in comparison to VAs, which provide a summary snapshot
to VA social media dissemination. The study was designed of the article. Alternatively, readers attracted by KFs may
to have 80% power for detection of a difference in Twitter be more nuanced consumers of the literature and appreci-
impressions of 2000, assuming a standard deviation (SD) ate a fuller understanding of the entire article. Ultimately,
of 5000. Groups were well balanced at baseline; in particu- authors may wish to asynchronously post their manuscripts
lar, the time at which tweets were sent was similar for each on social media using both a VA and a KF, thus taking
type of tweet. There were slightly more followers for the VA advantage of both consumption effects. Third, this is the
tweets (Supplementary Table 1). The groups were relatively first trial assessing social media dissemination of academic
well balanced with regard to original articles, reviews/ literature to incorporate Instagram likes as an outcome. VAs
guidelines, and brief correspondence articles. Most publica- had more likes than KFs on Instagram, which can probably
tions were oncology articles, with prostate cancer being the be explained by the ability to break VAs into specific panels
most common disease site (50%), followed by urothelial on Instagram for easy and ‘‘swipeable’’ complete summaries
carcinoma (25%). of the content. Given that clicking on an article link in the
The primary outcome of Twitter impressions favored VA caption for an Instagram post is not feasible, this is likely
(8385, SD 4370) over KF (6882, SD 3785) tweets (p = 0.006). to have a detrimental effect on KF posts, which do not sum-
All other outcomes, with the exception of link clicks, marize the full article.
favored VAs (Table 1), although the difference did not meet This prospective trial revealed that VAs increased the
the conventional level of statistical significance for total social media dissemination of urology articles compared
Twitter engagements (p = 0.062) or Instagram likes (p = to KFs, albeit at the expense of full-article link clicks to
0.054). There were significantly more link clicks for the KF the journal’s website. To the best of our knowledge, we
articles (105 vs 60; p = 0.0004). In a sensitivity analysis are the first to show that KFs but not VAs promote article
adjusted for the number of Twitter followers for the first link clicks, and thus the choice between VA and KF should
and senior authors, the difference between the groups was depend on the relative value given to impressions versus
slightly lower for the primary endpoint, with 1282 (95% full-article link clicks. In the increasingly virtual world of
confidence interval 239–2324; p = 0.016) more impressions academic medicine, these findings may assist authors, edi-
for VA tweets. tors, and publishers with dissemination of new research.
This prospective trial of new publications in European
Urology demonstrated that VAs improved dissemination of
Author contributions: Zachary Klaassen had full access to all the data in
research compared to KFs according to Twitter impressions,
retweets, and likes as metrics. Although the differences
were not statistically significant, Twitter total engagements
and Instagram likes also favored VAs. However, article link Study concept and design: Klaassen, Vickers, Pierce, Cooperberg, Catto,
clicks (which represent direct engagement with the full Kutikov.
article on the journal publisher’s website) favored KFs. Acquisition of data: Klaassen, Vickers, Kutikov.
There are several notable findings from this trial. First, Analysis and interpretation of data: Klaassen, Vertosick, Vickers, Assel,
because VAs are more visually appealing, easier to navigate, Catto, Kutikov.
and deliver more of the article’s story, they appear to lower Drafting of the manuscript: Klaassen, Vickers.
barriers to likes and retweets on Twitter. However, given Critical revision of the manuscript for important intellectual content: Klaas-
that all VAs in this study were created by a single person, sen, Vertosick, Vickers, Assel, Novara, Pierce, Wallis, Larcher, Cooperberg,
it is possible that the results reflect the comparison of KFs Catto, Kutikov.
with VAs created by one individual, whereas if the compar- Statistical analysis: Vertosick, Vickers, Assel.
isons were made to more general VAs (created by several Obtaining funding: None.
individuals) the results might be different. Second, KFs Administrative, technical, or material support: Pierce, Catto, Kutikov.
had more article link clicks, perhaps because social media Supervision: Catto, Kutikov.
users having to dig deeper to find the take home message Other: None.
Financial disclosures: Zachary Klaassen certifies that all conflicts of inter- References
est, including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript [1] Sathianathen NJ, Lane 3rd R, Condon B, et al. Early online attention
(eg, employment/affiliation, grants or funding, consultancies, honoraria, can predict citation counts for urological publications: the
#UroSoMe_Score. Eur Urol Focus 2020;6:458–62.
stock ownership or options, expert testimony, royalties, or patents filed,
[2] Nolte AC, Nguyen KA, Perecman A, et al. Association between Twitter
received, or pending), are the following: None. reception at a national urology conference and future publication
status. Eur Urol Focus 2021;7:214–20.
Funding/Support and role of the sponsor: None. [3] Loeb S, Taylor J, Butaney M, et al. Twitter-based Prostate Cancer
Journal Club (#ProstateJC) promotes multidisciplinary global
scientific discussion and research dissemination. Eur Urol
Acknowledgments: We would like to thank Ms. Emma Redley for her 2019;75:881–2.
hard work as a social media administrative assistant for European Urology. [4] Ibrahim AM, Lillemoe KD, Klingensmith ME, Dimick JB. Visual
abstracts to disseminate research on social media: a prospective,
case-control crossover study. Ann Surg 2017;266:e46–8.
Peer Review Summary [5] Oska S, Lerma E, Topf J. A picture is worth a thousand views: a triple
crossover trial of visual abstracts to examine their impact on
research dissemination. J Med Internet Res 2020;22:e22327.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.eururo.2022.01.041.

Can We Measure the Academic Impact of Social Media?
Juan Gómez Rivas a,b,*, Jeremy Yuen-Chun Teoh b,c, Giovanni Cacciamani b,d
a
Department of Urology. Hospital Clinico San Carlos, Madrid, Spain; b Young Academic Urologists, European Association of Urology, Arnhem, The Netherlands;
c
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China; d Keck School of Medicine, Catherine and Joseph Aresty Department of
Urology, USC Institute of Urology, Los Angeles, CA, USA
In this issue of European Urology, Klaassen et al. [1] report from children to the elderly, use tablets, laptops, and mobile
that use of a visual abstract increased the social media phones that are connected to the internet and thus to SoMe.
(SoMe) reach of new urology articles when compared to Klaassen et al. [1] used Twitter impressions as their primary
key figures, but was associated with a significantly lower outcome and engagements, link clicks, likes, and retweets
click-through rate. With enormous amounts of content as secondary outcomes, as well as Instagram likes. Mixing
uploaded daily onto SoMe, it is logical that visual and the results for these two SoMe channels is probably not
appealing images such as infographics are a more effective the best way to go, as the users, usefulness, and target audi-
way of reaching people rather than key figures constructed ence of the two platforms are entirely different. Currently,
from written text on the investigations carried out in a Twitter is perhaps the public SoMe platform with the great-
study. A quote that could be translated to all languages is est dissemination of health care information and provides
‘‘A picture is worth a thousand words’’, meaning that com- the broadest possible opportunities for news, knowledge
plex and multiple ideas can be converted into a single image sharing and networking among health professionals [3],
that is more effective than a text description. But why are but is it the most ‘‘visual’’ one? Probably not. Instagram
visuals so appealing? It is a matter of evolution based on: users have grown over the past years, with more than 600
(1) simplicity: the brain processes visuals much faster than million monthly active users. While Instagram is famous
text and retains 80% of what we see versus 20% of what we for the collections of photos shared on profiles, it has
read; (2) colors: people make a subconscious judgment on become one of the mainstays of any digital marketing strat-
initially viewing an image, and 62–90% of that assessment egy. The Instagram format creates an opportunity to com-
is based on color alone; (3) memory: if we read a text-only municate visually; its users are 58 times more likely to
statement, we will remember 10% of the information, comment, like, or share a post in comparison to Facebook
whereas when shown the text along with a relevant image, users, and 120 times more likely in comparison to Twitter
we are 65% more likely to recall the information [2]. users [4]. TikTok is a SoMe application that publishes short
Regardless of what has been published on SoMe and videos, with more than 750 million monthly users world-
urology in the past decade, many questions still stand. (1) wide in 2022. With TikTok use on the rise, there is an
Is Twitter still one of the best SoMe platforms for profes- increasing tendency for patients and family members to
sional proposes? (2) What is the role of new media (eg, Tik- seek medical information online, but many authors [5–7]
Tok and Instagram, among others) in engaging new have found misinformation lacking scientific evidence
generations in our specialty? (3) Can a more significant reported for various conditions on TikTok. Patients, family
presence on SoMe be translated into a larger academic members, and caregivers without a medical background
portfolio? can have difficulty in verifying and ensuring the credibility
We have witnessed an explosion in the development and of information posted on this application.
dissemination of information. The world is connected, and The final statement by Klaassen et al. [1] is, ‘‘in the
information crosses borders in seconds. Millions of people, increasingly virtual world of academic medicine, these find-

* Corresponding author. Department of Urology, Hospital Clínico San Carlos, Calle Profesor Martín Lagos s/n, 28040 Madrid, Spain. Tel. + 34 91
3303760.
E-mail address: juangomezr@gmail.com (J.G. Rivas).
ings may assist authors, editors, and publishers with dis- metrics, and how to apply these novel measures to a curric-
semination of new research’’. Dissemination is out of the ular point of view.
discussion when talking about the potential use of SoMe;
the $1 000 000 question would be: does a greater presence
on SoMe translate into having more citable papers (as part
of an authentic academic profile)? It will be interesting to
References
follow up on the 200 randomized articles and see if there
is any difference in the number of citations in the long [1] Klaassen Z, Vertosick E, Vickers AJ, et al. Optimal dissemination of
run. Alternative metrics to traditional, citation-based met- scientific manuscripts via social media: a prospective trial
rics are also increasingly used [8]. These are complementary comparing visual abstracts versus key figures in consecutive
original manuscripts published in European Urology. Eur Urol.
to traditional metrics such as downloads and citations, and
2022;82:633–6.
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and used on SoMe. Altmetrics are available in almost all learning approach for visual and textual data analysis in the digital
indexed urology journals. They are becoming widely used economy. Commun Assoc Inf Syst 2020;47:04708. https://doi.org/
in academia by individuals (as evidence of influence for pro- 10.17705/1CAIS.04708.
[3] Rivas JG, Socarrás MR, Blanco LT. Social media in urology:
motion and tenure and in applying for grants), institutions opportunities, applications, appropriate use and new horizons.
(for benchmarking overall performance), libraries (for mak- Cent Eur J Urol 2016;69:293–8. https://doi.org/10.5173/
ing collections), and publishers (to benchmark their perfor- ceju.2016.848.
mance in specific subject areas). Active promotion of a [4] Dixon S. Number of Instagram users worldwide from 2020 to 2025.
Statista 2022. https://www.statista.com/statistics/183585/
paper via SoMe channels will probably increase its Altmet-
instagram-number-of-global-users/.
ric score, but the question arises as to whether this will also [5] O’Sullivan NJ, Nason G, Manecksha RP, O’Kelly F. The unintentional
increase citations and downloads of the paper. In the psy- spread of misinformation on ‘TikTok’; a paediatric urological
chiatry and neurology field, Peres et al. [9] found that diffu- perspective. J Pediatr Urol 2022;18:371–5. https://doi.org/10.1016/
sion on SoMe of a more highly promoted paper led to a j.jpurol.2022.03.001.
[6] Xu AJ, Taylor J, Gao T, Mihalcea R, Perez-Rosas V, Loeb S. TikTok and
significantly greater number of citations and downloads. prostate cancer: misinformation and quality of information using
However, the use of Twitter or SoMe activity as a journal validated questionnaires. BJU Int 2021;128:435–7. https://doi.org/
impact factor or personal impact factor remains controver- 10.1111/bju.15403.
sial and challenging to quantify objectively, as the public [7] Teoh JY, Cacciamani GE, Gomez RJ. Social media and misinformation
in urology: what can be done? BJU Int 2021;128:397. https://doi.org/
nature of the information shared on SoMe raises concerns
10.1111/bju.15517.
about bias in the way information is spread, so this metric [8] Nocera AP, Boyd CJ, Boudreau H, Hakim O, Rais-Bahrami S.
is influenced by unmeasured factors such as reposts or Examining the Correlation Between Altmetric Score and Citations
retweets by ‘‘influencers’’ and the use of ‘‘inorganic’’ posting in the Urology Literature. Urology. 2019 Dec;134:45–50. https://doi.
by brands and publishers. There is no doubt that SoMe is org/10.1016/j.urology.2019.09.014, Epub 2019 Sep 24 PMID:
31560915.
here to stay and is the way to communicate among young [9] Peres MF, Braschinsky M, May A. Effect of Altmetric score on
generations, and thus academia should embrace it. How- manuscript citations: a randomized-controlled trial. Cephalalgia. In
ever, there are still many gaps on how to use SoMe in an press. https://doi.org/10.1177/03331024221107385.
academic way, how it can be quantified using alternative
Surgery in Motion
Robotic Radical Prostatectomy for Prostate Cancer in Renal

Transplant Recipients: Results from a Multicenter Series
Giancarlo Marra a,b,c,*, Marco Agnello a, Andrea Giordano a, Francesco Soria a, Marco Oderda a,
Charles Dariane d, Marc-Olivier Timsit d, Julien Branchereau e, Oussama Hedli e, Benoit Mesnard e,
Derya Tilki f,g,h, Jonathon Olsburgh i, Meghana Kulkarni i, Veeru Kasivisvanathan i,j, Alberto Breda k,
Luigi Biancone l, Paolo Gontero a, collaborators y
a
Department of Surgical Sciences, University of Turin and Città della Salute e della Scienza, Turin, Italy; b Department of Urology, Institut Mutualiste
Montsouris and Université Paris Descartes, Paris, France; c Department of Urology, Hôpital Tenon, Paris, France; d Department of Urology, Hôpital Européen
Georges Pompidou and Necker Hospital, Paris, France; e Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France; f Martini-Klinik Prostate
Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; g Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg,
Germany; h Department of Urology, Koc University Hospital, Istanbul, Turkey; i Department of Urology, Guy’s Hospital, London, UK; j Division of Surgery,
University College London, London, UK; k Department of Urology, Fundacio Puigvert, Barcelona, Spain; l Department of Nephrology, University of Turin and
Città della Salute e della Scienza, Turin, Italy
Article history: Background: Despite an expected increase in prostate cancer (PCa) incidence in the
Accepted May 26, 2022 renal transplant recipient (RTR) population in the near future, robot-assisted radical
prostatectomy (RARP) in these patients has been poorly detailed. It is not well under-
Associate Editor: stood whether results are comparable to RARP in the non-RTR setting.
Alexandre Mottrie Objective: To describe the surgical technique for RARP in RTR and report results from our
multi-institutional experience.
Keywords: Design, setting, and participants: This was a retrospective review of the experience of
Prostate cancer four referral centers.
Renal transplant Surgical procedure: Transperitoneal RARP with pelvic lymph node dissection in selected
Treatment patients.
Robotic radical prostatectomy Measurements: We measured patient, PCa, and graft baseline features; intraoperative
and postoperative parameters; complications, (Clavien classification); and oncological
and functional outcomes.
Results and limitations: We included 41 men. The median age, American Society of
Anesthesiologists score, preoperative renal function, and prostate-specific antigen were
60 yr (interquartile range [IQR] 57–64), 2 points (IQR 2–3), 45 ml/min (IQR 30–62), and
6.5 ng/ml (IQR 5.2–10.2), respectively. Four men (9.8%) had a biopsy Gleason score >7.
The majority of the patients (70.7%) did not undergo lymphadenectomy. The median
y
Collaborators: Federica Peretti and Claudia Filippini, Department of Surgical Sciences, University of
Turin and Città della Salute e della Scienza, Turin, Italy; Constance Thibault, Department of Urology,
Hôpital Européen Georges Pompidou and Necker Hospital, Paris, France; Cedric Lebacle and Jacques
Irani, Department of Urology, Kremlin-Bicêtre Hospital, Le Kremlin-Bicêtre, France; Oscar Rodriguez-
Faba and Josep M. Gaya, Department of Urology, Fundacio Puigvert, Barcelona, Spain.
* Corresponding author. Department of Surgical Sciences, University of Turin, Italy, C.so Bramante
88, 10100 Turin, Italy.
E-mail address: drgiancarlomarra@gmail.com (G. Marra).
operating time, hospital stay, and catheterization time were 201 min (IQR 170–250), 4 d
(IQR 2–6), and 10 d (IQR 7–13), respectively. At final pathology, 11 men had extrapro-
static extension and seven had positive surgical margins. At median follow-up of 42
mo (IQR 24–65), four men had biochemical recurrence, including one case of local PCa
persistence and one local recurrence. No metastases were recorded while two patients
died from non–PCa-related causes. Continence was preserved in 86.1% (p not applicable)
and erections in 64.7% (p = 0.0633) of those who were continent/potent before the pro-
cedure. Renal function remained unchanged (p = 0.08). No intraoperative complications
and one major (Clavien 3a) complication were recorded.
Conclusions: RARP in RTR is safe and feasible. Overall, operative, oncological, and func-
tional outcomes are comparable to those described for the non-RTR setting, with graft
injury remaining undescribed. Further research is needed to confirm our findings.
Patient summary: Robot-assisted removal of the prostate is safe and feasible in patients
who have a kidney transplant. Cancer control, urinary and sexual function results, and
surgical complications seem to be similar to those for patients without a transplant,
but further research is needed.
1. Introduction results from our series, which, to the best of our knowledge,
is the largest multicenter series to date.
Prostate cancer (PCa) remains the most frequent non-skin
solid neoplasm among male kidney transplant recipients 2. Patients and methods
(RTRs) [1,2]. Over the next few decades, a rise in RTR cases
2.1. Data collection
is expected for several reasons. First, there is an overall
increase in the number of transplants being performed. Sec- We retrospectively collected data for men undergoing RARP for histolog-
ond, the characteristics of the RTR population are changing, ically documented cN0M0 PCa after kidney transplant at four European
with more than half of cases now older than 50 yr, and tertiary referral centers between February 2009 and April 2019. All
approximately 10 000 kidney transplant surgeries per- patients underwent staging according to the European Association of
formed yearly in the USA and Europe [3–5]. Third, consider- Urology (EAU) guidelines (axial abdominal imaging with multiparamet-
able technological and medical advances mean that the life ric magnetic resonance imaging [mpMRI] and/or a computed tomogra-
expectancy of these patients has increased, and is now phy [CT] scan and bone scan). Three men also had a preoperative
almost 20 yr for recipients in their fifties [3–5]. positron emission tomography (PET) scan negative for extraprostatic
In this context, several issues remain unsolved, including extension (choline n = 1; prostate-specific membrane antigen [PSMA]
whether RTR patients with PCa are at risk of worse oncolog- n = 2). Two physicians independently reviewed the data quality (G.M.
ical and functional results and whether there is an optimal and F.P.). Centers were recontacted for data revision in cases of uncer-
tainty or missing information.
PCa management strategy in this setting [5–7]. Nonetheless,
the number of PCa cases diagnosed and described in the RTR
2.2. Surgical technique
population is low [5,7].
Among PCa treatment options, robot-assisted radical We performed transperitoneal RARP using a da Vinci Xi (n = 20) or Si
prostatectomy (RARP) has gradually emerged over the past (n = 21) robotic platform. No relevant surgical and/or technical differ-
two decades and is now by far the technique most fre- ences between the two platforms were identified.
quently performed for surgical treatment of PCa [8]. How- When performing RARP in the RTR setting, some steps need to be
ever, the paucity of reports on PCa cases in the RTR highlighted and kept in mind.
setting is even more evident in this context. As highlighted
by two recent systematic reviews, fewer than 50 RARP pro- 2.2.1. Trocar placement and bladder drop/Retzius space development
cedures have been described, mainly deriving from small The trocar scheme was as previously described for standard RARP using
single-center case series or case reports and using different four robotic arms (10-mm ports) and two ports for the assistant (12-mm
AirSeal and 5-mm port). Before placing the lateral ports, the graft site
approaches [5,7]. Despite promising outcomes, there is an
must be visualized and identified (Fig. 1A, B). The anatomical location
important lack of direct evidence to support the robotic
of the graft site remains key during bladder drop and development of
approach in this context.
the Retzius space.
On the one hand, RTR-specific factors, including
immunosuppression, the anatomical site of the graft in
2.2.2. Ipsilateral pelvic lymphadenectomy
the iliac fossa, and potential pelvic tissue adhesions, may When performing lymphadenectomy ipsilateral to the graft site, tissues
impact surgical outcomes [9,10]. On the other hand, the risk can sometimes be fibrotic because of the previous transplant surgery. In
of graft-related complications, including a decrease in renal addition, the transplanted ureter route and the site of arterial anastomo-
function and the risk of graft rejection, is not well acknowl- sis (either on the common or external iliac artery) must be kept in mind;
edged [5,7,11]. in this phase, identification and isolation of the ureter are recommended
The aim of the present study was to describe our surgical (Fig. 1C). We find robotic magnification and three-dimensional vision
approach for RARP in the RTR setting and to report initial helpful during this step.
Fig. 1 – Critical steps during robot-assisted radical prostatectomy in renal transplant recipients. (A) Trocar placement and extracorporeal location of the graft
site in a patient with two previous kidney transplants. (B) Graft identification before placing the lateral ports in a patient with two previous transplants. (C)
Identification and isolation of the graft ureter. (D) Excretory computed tomography phase showing a transplanted ureter located anteriorly and close to the
prostate gland.
2.2.3. Anterior dissection PSA >0.1 ng/ml at least 6 wk after surgery; Biochemical recurrence (BCR)
An excretory CT scan may help in locating the transplanted ureter during was considered as undetectable PSA after RARP that subsequently
preoperative planning. Depending on the previous transplant surgery, increased to >0.2 ng/ml.
the transplanted ureter can be found anterior to the bladder (Fig. 1D)
and to the prostate. In the case of an anteriorly located ureter, when dis-
2.5. Statistical analysis
section and isolation are performed, the ureter should not be skele-
tonized to minimize devascularization and the chance of related
Results are reported as the median and interquartile range (IQR) for con-
complications. In cases involving a pyelo-ureteral anastomosis for trans-
tinuous variables and the frequency and percentage for categorical vari-
plant of the native ureter, the ureter route was located in an orthotopic
ables. To evaluate possible differences in functional outcomes before and
site.
after RARP, univariate analysis was performed using the Kruskal Wallis
test and the Bowker symmetry test for continuous and categorical vari-
2.2.4. Subsequent steps ables, respectively. Statistical analysis was conducted using SAS version
The subsequent surgical steps do not differ from those for a conventional 9.4 (SAS Institute, Cary, NC, USA).
RARP approach [12].
3. Results
2.3. Study outcomes
The primary outcome was a description of the surgical technique for 3.1. Baseline characteristics
RARP in the RTR setting. Secondary outcomes included assessment of:
We included a total of 41 men. Baseline demographic and
(1) oncological results after RARP, including positive surgical margin
kidney transplant characteristics are listed in Table 1. The
(PSM) status, BCR, systemic progression, cancer-specific survival (CSS),
and overall survival (OS); (2) functional outcomes; and (3) complica-
median age and ASA score at surgery were 60 yr (IQR 57–
tions, including graft-related complications.
64) and 2 points (IQR 2–3), respectively. The median preop-
erative renal function was 45 ml/min (IQR 30–62). The most
frequent cause of renal failure was chronic glomeru-
2.4. Outcome variables lonephritis (31.7%) and the majority of patients had a single
Continence was recorded in terms of the number of pads used per day
transplant (92.7%), mainly from a single cadaver donor
and was categorized as full continence (no pads), terminal dribbling, (70.7%).
mild incontinence (one pad/d), moderate incontinence (two pads/d), or Table 2 lists the PCa characteristics before RARP. The
severe incontinence three or more pads/d). Complications were graded median time from transplant to PCa diagnosis was 118 mo
using the Clavien-Dindo classification in accordance with the EAU guide- (IQR 57–184) and the median PSA was 6.5 ng/ml (IQR
lines on reporting of complications, with major complications consid- 5.2–10.2). Only four men (9.8%) had a biopsy Gleason score
ered as those of Clavien grade 3 [13]. Preoperative comorbidity >7. Preoperative mpMRI was performed in 83% of the
status was recorded using the American Society of Anesthiologists patients, of whom four (9.8 %) had a suspicion of extracap-
(ASA) score. Biochemical persistence was defined as a first postoperative sular extension.
Table 1 – Patient and kidney transplant baseline characteristics Table 2 – Baseline PCa characteristics
Parameter Result Parameter Result

Patients (n) 41 Median time from transplant to PCa diagnosis, mo (IQR) 118 (57–
Median age, yr (interquartile range) 60 (57–64) 184)
Race, n (%) Familial PCa history (n) 0
Caucasian 37 (90.2) Median prostate-specific antigen, ng/ml (IQR) 6.5 (5.2–
African American 2 (4.9) 10.2)
Asian 2 (4.9) Suspicious digital rectal examination, n (%) 32 (78.0)
Median body mass index, kg/m2 (interquartile range) 26 (24–28) Gleason score, n (%)
Smoking status, n (%) 3+3 9 (21.9)
Active smoker 1 (2.4) 3+4 24 (58.5)
Former smoker 5 (12.2) 4+3 4 (9.7)
Diabetes, n (%) 7 (17.1) 4+4 2 (4.9)
Median American Society of Anesthesiologists score 2 (2–3) 4+5 2 (4.9)
(interquartile range) Biopsy cores
Transplant and kidney failure Median number taken, n (IQR) 14 (12–24)
Preoperative renal function Median number positive, n (IQR) 5 (3–8)
Median creatinine, mg/dl (interquartile range) 2.0 (1.36–2.6) Median maximum PCa length, mm (IQR) 9.5 (6–12.75)
Median estimated glomerular filtration rate, ml/min 45 (29.7–61.8) Preoperative multiparametric magnetic resonance
(interquartile range) imaging
Renal failure type, n (%) No 7 (17.0)
Chronic 40 (97.6) Yes 34 (83.0)
Acute 1 (2.4) With contrast 32 (94.1)
Cause of renal failure, n (%) Without contrast 2 (5.9)
Chronic glomerulonephritis 13 (31.7) Negative 1 (2.9)
Autosomal dominant polycystic kidney disease 8 (19.5) Positive (1 index lesion) 28 (82.4)
Diabetic nephropathy 3 (7.3) Positive (>1 lesion) 5 (14.7)
Nephrosclerosis 3 (7.3) Extracapsular extension 4 (12.5)
Vesicoureteral reflux 2 (4.9) Seminal vesicle invasion 1 (3.1)
Chronic pyelonephritis 1 (2.4) IQR = interquartile range; PCa = prostate cancer,
Other 10 (2.4)
Previous dialysis, n (%) 32 (78.0)
Number of kidney transplants, n (%)
1 transplant 38 (92.7)
2 transplants 3 (7.3)
Type of first transplant, n (%)
Single cadaver 29 (70.7)
Singe living donor 11 (26.8)
Double cadaver 0
Table 3 – Intraoperative characteristics for robot-assisted radical
Transplant site, n (%) prostatectomy and pathological results
Left iliac fossa 15 (36.6)
Parameter Result
Right iliac fossa 24 (58.5)
Immunosuppression Intraoperative characteristics
mTOR inhibitors, n (%) 1 (2.4) Lymphadenectomy, n (%)
Antiproliferative agents, n (%) 2 (4.9) No 29 (70.7)
Calineurin inhibitors, n (%) 31 (75.6) Contralateral 10 (24.4)
Steroids, n (%) 12 (29.2) Contralateral + limited ipsilateral 2 (4.9)
Median time from immunosuppression to treatment, 130 (64–202) Nerve-sparing surgery, n (%)
mo (interquartile range) No 20 (48.8)
Unilateral 5 (12.2)
Bilateral 13 (31.7)
Median operating time, min (IQR) 210 (170–250)
3.2. Surgical and pathological characteristics Median estimated blood loss, ml (IQR) 300 (200–400)
Intraoperative blood transfusion, n (%) 2 (4.8)
Intraoperative RARP characteristics and pathology results Median hospital stay, d (IQR) 4 (2–6)
Median catheterization time, d (IQR) 10 (7–13)
are detailed in Table 3. The majority of the men did not Surgeon experience, n (%)
undergo lymphadenectomy (70.7%). Only two men had 0–50 procedures 4 (9.7)
bilateral lymphadenectomy, which was less extensive on 50–100 procedures 2 (4.9)
100–500 procedures 31 (75.6)
the graft side; the median number of contralateral nodes >500 procedures 4 (9.7)
removed was 4.5 (IQR 3–7), with two ipsilateral nodes Postoperative pathology
removed in one patient and four in the other patient. The Gleason score, n (%)
3+3 11 (26.8)
median operating time, hospital stay, and catheterization 3+4 20 (48.8)
time were 201 min (IQR 170–250), 4 d (IQR 2–6), and 10 4+3 4 (9.8)
d (IQR 7–13), respectively. At final pathology, four men 4+4 3 (7.3)
4+5 1 (2.4)
had Gleason score >7, 11 had extraprostatic extension, pT stage, n (%)
and seven had PSM. T2 29 (70.7)
T3 11 (26.8)
pN stage, n (%)
3.3. Oncological outcomes Nx 29 (70.7)
N0 12 (29.2)
Median follow-up was 42 mo (IQR 22–64). Overall, four N1 0 (0.0)
Median number of nodes removed, n (IQR) 6 (4–7)
men underwent adjuvant radiotherapy at a median time Positive margins, n (%) 7 (17.1)
of 6 mo (IQR 4–6) after RARP. Two men experienced BCR IQR = interquartile range.
and two experienced PSA persistence. One man had local
disease persistence at 3 mo (PSMA PET) and one had local Renal function remained unchanged after RARP (crea-
recurrence at 94 mo (mpMRI and choline PET). None of tinine p = 0.42; estimated glomerular filtration rate [eGFR]
the patients experienced systemic progression. At last p = 0.08).
follow-up, two patients had died, both for non–PCa- No intraoperative complications were recorded. Three
related causes, while 36 patients were alive with no evi- patients (7.3%) experienced four complications. One man
dence of PCa and three were receiving androgen deprivation had postoperative hemorrhage requiring embolization 5 d
therapy (ADT). after surgery (Clavien 3a) and blood transfusions, and expe-
rienced pyelonephritis14 d after the intervention, which
3.3.1. High-risk PCa was managed with intravenous antibiotics (Clavien 2).
Overall, 13 patients had high-risk PCa according to initial One man had a urinary tract infection, managed with intra-
PSA >20 ng/ml alone (n = 1), initial PSA >20 ng/ml and venous antibiotics (Clavien 2). One patient experienced
pT3 stage (n = 1), Gleason score >7 alone (n = 1), Gleason renal insufficiency 10 d after RARP due to recurrence of
score >7 and pT3 stage (n = 3), or pT3 stage alone (n = 7). glomerulonephritis requiring intravenous medical treat-
Baseline and pathological characteristics for this group are ment (Clavien 2).
presented in Supplementary Table 2. Three received adju-
vant radiation therapy and ADT (n = 1 for PSM). At overall
4. Discussion
median follow-up of 36 mo (IQR 14–60), two patients had
BCR (one with local recurrence on PSMA PET) diagnosed
as hormone-sensitive nonmetastatic disease and are receiv- We have described the most challenging surgical steps for
ing ADT, while the remaining patients are alive with no evi- RARP in the RTR setting. To the best of our knowledge, the
dence of PCa. results we report are from the largest series to date. Several
findings are of interest.
First, the procedure was safe. No major events occurred
3.4. Functional outcomes and morbidity
intraoperatively and only one major postoperative compli-
Results for functional outcomes and renal function are pre- cation was recorded. Other postoperative morbidities were
sented in Fig. 2 and Supplementary Table 1. The majority of mainly of low impact and rare, suggesting that RARP does
men retained their continence (86.1%) after RARP. not have a higher risk of complications in the RTR setting.
Twenty-seven men (81.2%) had stable erectile function Interestingly, half of these complications were of an infec-
(n = 11 potent before the procedure and n = 16 with phos- tious type. Although the overall numbers were low, this
phodiesterase 5 medication or no erections before RARP). issue certainly requires further investigation to evaluate
Six men lost their erectile function (18.2%). Overall, erectile the clinical impact of an immunosuppression regimen to
function significantly decreased after the procedure prevent graft rejection on postoperative infections. Finally,
(p = 0.0143). no injuries to grafts or transplanted ureters were described.
Fig. 2 – Renal function in terms of (A) creatinine and (B) estimated glomerular filtration rate (eGFR). (C) Continence and (D) erectile functional outcomes.
In our view, preoperative planning with an excretory CT From a clinical perspective, when indicated, robotic sur-
scan (if eGFR allows a venous contrast injection) to visualize gery can be a valuable way to treat PCa in the RTR setting.
the ureteral location and appropriate visualization and, Our results mirror those of the majority of published series
when necessary, isolation during surgery, may be of value in terms of cancer control, functional outcomes, and safety,
in avoiding graft injuries. Renal function did not seem to suggesting that the procedure does not differ much from
be influenced and remained stable overall after RARP. RARP in conventional patients overall [5,7]. Nonetheless, a
Second, functional outcomes were also acceptable and recently published robotic series described relevant RARP
did not seem to be hampered in the RTR setting. In terms morbidity in an RTR cohort, with high-grade and overall
of continence, the vast majority of patients achieved pad- complications being experienced by 10.2% and 51.2% of
free status. As previously described for transplant patients, men, respectively [19]. Further studies are thus needed to
even though graft implantation improves erectile function confirm our findings in terms of morbidity.
compared to dialysis, only half of the cohort were potent From a research perspective, we increased the evidence
before surgery [14]. Nonetheless, almost two-thirds of the available on the feasibility of RARP. Importantly, in the con-
men who were potent before surgery retained their erectile text of the description of the surgical technique in RTR, the
function. role of graft ipsilateral lymphadenectomy needs to be care-
Third, the frequency of lymphadenectomy ipsilateral to fully weighed. As complications may have more relevant
the graft was poor in our series. This does not seem surpris- consequences in RTR in comparison to the general popula-
ing considering the theoretical risk/benefit ratio for the pro- tion, future research should better investigate complication
cedure. On the one hand, lymph node dissection does not rates in larger series. In addition, the risk cutoff to apply in
seem to improve survival and oncological outcomes in the deciding on whether to perform ipsilateral lymphadenec-
overall PCa scenario [15,16]. On the other hand, the proxim- tomy in this setting may differ in comparison to the cutoff
ity of the vascular anastomosis and the transplanted ureter for the general population [15]. Finally, our view is based
increases the technical challenge. Furthermore, the impact on a limited and preliminary experience and further evi-
of lymphadenectomy-related complications can be poten- dence is required to define the feasibility and usefulness
tially devastating, as they may cause graft loss. This can of and the optimal technique for ipsilateral lymphadenec-
happen both directly, via vascular and urinary intraproce- tomy in the RTR setting.
dural injuries, and indirectly, via less common but equally Our work is not without limitations. The retrospective
graft-threatening complications, including venous throm- nature and, despite being the largest available series, the
bosis and hematoma/lymphocele that can potentially com- relatively small number of patients with limited follow-up
press adjacent structures [5,17]. Nonetheless, these may have caused underestimation of short- and long-term
complications remain relatively rare and ipsilateral lym- complications. Multiple surgeons with different degrees of
phadenectomy, when performed, was feasible in the RTR experience performed the procedures. While this strength-
setting. Similarly, no complications were detailed in our ens the reproducibility of the results, indications for lym-
most recent cases, which were not included in the present phadenectomy and procedural steps may have suffered
series because of short follow-up. In our view, correct iden- from slight variability across different centers. In addition,
tification and isolation of the ureter and graft vessels help in although reports are currently limited for the RTR setting,
minimizing risks. Robotic magnification and three- other robotic techniques may be of interest [20], including
dimensional vision may increase the procedural precision the Retzius-sparing approach, which decreases vicinity to
and feasibility during this challenging step. On the basis of the graft by sparing its anatomical site in comparison to
our preliminary experience, when in expert hands and indi- the standard approach. This may potentially further
cated, lymphadenectomy should not be precluded upfront. increase the safety of the procedure and results are eagerly
Importantly, the possibility that secondary fibrotic adher- awaited.
ence after lymphadenectomy may hamper a subsequent As the quality of the present study and other available
ipsilateral graft should also be kept in mind. Although no studies remains low, prospective data are warranted to con-
ureteric injuries were described, in cases with favorable firm our findings and the possible impact of immunosup-
PCa features and/or surgeons not willing to perform ipsilat- pression on complications, morbidity, and cancer control.
eral lymphadenectomy, keeping the peritoneum on the side Prospective comparisons with RARP in conventional cohorts
of the transplant intact may further minimize this risk. and with other surgical [21] and nonsurgical approaches in
Fourth, oncological control seems to be acceptable at RTR should also be performed.
short- to intermediate-term follow-up. The PSM rate was
relatively low, including the group with high-risk PCa
[18]. This finding is in line with the absence of anatomical 5. Conclusions
and technical differences for the periprostatic part of the
surgery. No patients experienced systemic progression and RARP in RTR is safe and feasible. Attention should be paid to
the vast majority remained free of disease. This is in line some key surgical steps. Overall, operative, oncological, and
with PCa being diagnosed mainly at a localized stage functional outcomes seem comparable to those described
according to previous reports [5] and possibly to PSA for patients without a renal transplant, with graft injury
screening being performed in our cohort at the time of first remaining undescribed. Further research is needed to con-
renal transplant and during periodic follow-up visits. firm our findings.
Author contributions: Andrea Giordano had full access to all the data in [4] Kramer A, Pippias M, Stel VS, et al. Renal replacement therapy in
the study and takes responsibility for the integrity of the data and the Europe: a summary of the 2013 ERA-EDTA Registry annual report
with a focus on diabetes mellitus. Clin Kidney J 2016;9:457–69.
[5] Marra G, Dalmasso E, Agnello M, et al. Prostate cancer treatment in
renal transplant recipients: a systematic review. BJU Int
Study concept and design: Marra, Agnello, Biancone, Gontero. 2018;121:327–44.
Acquisition of data: Marra, Agnello, Giordano. [6] Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence
Analysis and interpretation of data: Marra, Agnello, Giordano, Oderda, before and after kidney transplantation. JAMA 2006;296:2823–31.
[7] Hevia V, Boissier R, Rodríguez-Faba Ó, et al. Management of
Biancone, Gontero.
localised prostate cancer in kidney transplant patients: a
Drafting of the manuscript: Marra, Soria, Oderda, Gontero. systematic review from the EAU Guidelines on Renal
Critical revision of the manuscript for important intellectual content: All Transplantation Panel. Eur Urol Focus 2018;4:153–62.
authors. [8] Lowrance WT, Eastham JA, Savage C, et al. Contemporary open and
robotic radical prostatectomy practice patterns among urologists in
Statistical analysis: Marra, Soria.
the United States. J Urol 2012;187:2087–93.
Obtaining funding: None. [9] Bootun R. Effects of immunosuppressive therapy on wound healing.
Administrative, technical, or material support: Marra, Agnello, Giordano. Int Wound J 2013;10:98–104.
Supervision: Biancone, Gontero. [10] Säemann M, Hörl WH. Urinary tract infection in renal transplant
Other: None. recipients. Eur J Clin Investig 2008;38:58–65.
[11] Ojo A, Wolfe RA, Agodoa LY, et al. Prognosis after primary renal,
transplant failure and the beneficial effects of repeat
transplantation: multivariate analyses from the United States
Financial disclosures: Andrea Giordano certifies that all conflicts of inter-
Renal Data System. Transplantation 1998;66:1651–9.
est, including specific financial interests and relationships and affiliations [12] Martini A, Falagario UG, Villers A, et al. Contemporary techniques of
relevant to the subject matter or materials discussed in the manuscript prostate dissection for robot-assisted prostatectomy. Eur Urol
(eg, employment/affiliation, grants or funding, consultancies, honoraria, 2020;78:583–91.
stock ownership or options, expert testimony, royalties, or patents filed, [13] Mitropoulos D, Artibani W, Graefen M, et al. Reporting and grading
of complications after urologic surgical procedures: an ad hoc EAU
received, or pending), are the following: None.
Guidelines Panel assessment and recommendations. Eur Urol
2012;61:341–9.
[14] Rahman IA, Rasyid N, Birowo P, Atmoko W. Effects of renal
Funding/Support and role of the sponsor: None. transplantation on erectile dysfunction: a systematic review and
meta-analysis. Int J Impot Res. In press. https://doi.org/10.1038/
s41443-021-00419-6.
Acknowledgments: Giancarlo Marra’s work at Institut Mutualiste Mon- [15] Heidenreich A. Still unanswered: the role of extended pelvic
tsouris is funded by a grant from the European Urological Scholarship lymphadenectomy in improving oncological outcomes in prostate
Programme. cancer. Eur Urol 2021;79:605–6.
[16] Lestingi JFP, Guglielmetti GB, Trinh QD, et al. Extended versus
limited pelvic lymph node dissection during radical prostatectomy
for intermediate- and high-risk prostate cancer: early oncological
Ethics considerations: All patients underwent robotic radical prostatec-
outcomes from a randomized phase 3 trial. Eur Urol
tomy and provided written informed consent. All procedures performed 2021;79:595–604.
in the study were in accordance with the ethical standards of the institu- [17] Cacciamani GE, Maas M, Nassiri N, et al. Impact of pelvic lymph
tional and/or national research committee and with the 1964 Helsinki node dissection and its extent on perioperative morbidity in
patients undergoing radical prostatectomy for prostate cancer: a
Declaration and its later amendments or comparable ethical standards.
comprehensive systematic review and meta-analysis. Eur Urol
Oncol 2021;4:134–49.
Supplementary data [18] Novara G, Ficarra V, Mocellin S, et al. Systematic review and meta-
analysis of studies reporting oncologic outcome after robot-assisted
radical prostatectomy. Eur Urol 2012;62:382–404.
Supplementary data to this article can be found online at [19] Felber M, Drouin SJ, Grande P, et al. Morbidity, perioperative
https://doi.org/10.1016/j.eururo.2022.05.024. outcomes and complications of robot-assisted radical
prostatectomy in kidney transplant patients: a French multicentre
study. Urol Oncol 2020;38:599.e15–21.
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Bladder Cancer
Elevated T-cell Exhaustion and Urinary Tumor DNA Levels Are

Associated with Bacillus Calmette-Guérin Failure in Patients with
Non–muscle-invasive Bladder Cancer
Trine Strandgaard a,b, Sia Viborg Lindskrog a,b, Iver Nordentoft a, Emil Christensen a,b,
Karin Birkenkamp-Demtröder a,b, Tine Ginnerup Andreasen a,b, Philippe Lamy a, Asbjørn Kjær a,b,
Daniel Ranti c,d, Yuanshuo Alice Wang c,d, Christine Bieber c,d, Frederik Prip a,b, Julie Rasmussen a,b,
Torben Steiniche b,e, Nicolai Birkbak a,b, John Sfakianos d, Amir Horowitz c,
Jørgen Bjerggaard Jensen b,f, Lars Dyrskjøt a,b,*
a
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; b Department of Clinical Medicine, Aarhus University, Aarhus, Denmark;
c
Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
d
Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; e Department of Pathology, Aarhus University Hospital, Aarhus,
Denmark; f Department of Urology, Aarhus University Hospital, Aarhus, Denmark
Article history: Background: The functional status of immune cells in the tumor microenvironment and
Accepted September 6, 2022 tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk
non–muscle-invasive bladder cancer (NMIBC).
Associate Editor: Objective: To characterize molecular correlates of post-BCG high-grade (HG) recurrence
James Catto using multiomics analysis.
Design, setting, and participants: Patients with BCG-treated NMIBC (n = 156) were
Keywords: included in the study. Metachronous tumors were analyzed using RNA sequencing
Bladder cancer (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for
Bacillus Calmette-Guérin immuno-oncology–related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187).
Response Outcome measurements and statistical analysis: The primary endpoint was post-BCG HG
Biomarkers recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher’s exact tests were used
T-cell dysfunction for analyses.
Results and limitations: BCG induced activation of the immune system regardless of clin-
ical response; however, immunoinhibitory proteins were observed in the urine of
patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was
associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients
with post-BCG T-cell exhaustion had high expression of genes related to cell division
and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors
was associated with worse post-BCG HG recurrence–free survival (HGRFS; p = 0.002).
This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors
(UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015).
* Corresponding author. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-
Jensens Boulevard 99, 8200 Aarhus N, Denmark. Tel. +45 78455320.
E-mail address: lars@clin.au.dk (L. Dyrskjøt).
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load
(p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA
clearance identified patients at high risk of recurrence (p = 0.018). The retrospective
design and partial overlap for analyses are study limitations.
Conclusions: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor sub-
type and pre-BCG tumor characteristics may identify patients at high risk of post-BCG
HG recurrence. Urinary measurements have potential for real-time assessment of treat-
ment response.
Patient summary: A dysfunctional immune response to bacillus Calmette-Guérin (BCG)
therapy may explain high-grade recurrences of bladder cancer.
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
1. Introduction survival (HGRFS) were calculated from the end of BCG treatment until
the first recurrence or HG recurrence/progression, respectively, or the
end of follow-up. Patients were censored at the end of follow-up in
Treatment for high-risk non–muscle-invasive bladder can-
the absence of an event.
cer (NMIBC) includes intravesical instillations with the
Samples were collected before and after BCG treatment. A total of
immunotherapy bacillus Calmette-Guérin (BCG) [1].
195 tumors were analyzed using whole-exome sequencing (WES), 170
Despite high initial response rates, a study found that up
tumors using RNA sequencing, 190 urine supernatants using Olink pro-
to 42% of patients experienced recurrence after complete
teomics, and 187 urine supernatants using deep-targeted sequencing
BCG therapy, with progression in 14% [2,3].
(Supplementary Fig. 1 and Supplementary Table 1).
It is thought that BCG acts via activation of both the
innate and the adaptive immune systems, thereby promot- 2.2. Urine proteomic analysis
ing lasting antitumor effects [4]. On chronic antigen stimu-
lation, CD8 T cells may enter a dysfunctional, exhausted Urine samples were analyzed for the presence of 92 immuno-oncology–
state characterized by sustained expression of inhibitory related proteins using Olink (Supplementary Table 2).
receptors such as PD-1, CTLA-4, and CD244, and loss of
2.3. RNA sequencing
effector functions such as cytokine secretion and prolifera-
tion [5–7]. Several immune checkpoint inhibitor therapeu- RNA sequencing was performed using either a ScriptSeq (EpiCentre)
tics are now approved for treatment of various cancer library preparation or a KAPA RNA HyperPrep Kit (RiboErase HMR;
types, including bladder cancer (BC), but with limited suc- Roche) for library preparation.
cess for many tumors, indicating a need for a greater under-
standing of the underlying immune mechanisms [8]. The 2.4. WES
PD-1 inhibitor pembrolizumab was recently approved for
WES library construction and capture were performed using an Illumina
the treatment of BCG-unresponsive high-risk BC with carci-
TruSeq DNA kit and SeqCap EZ v3.0 capture or a Twist Library prepara-
noma in situ [9]. High PD-L1 expression has been associated
tion EF kit and Twist Human Core Exome Capture kit.
with BCG-unresponsiveness in patients with NMIBC, linking
immune inhibitory pathways to BCG failure [10]. 2.5. Deep-targeted sequencing of urinary tumor-derived DNA
In this study we integrated multiomics data and serial (tdDNA)
liquid biopsies from a clinically well-characterized patient
cohort to delineate molecular correlates of high-grade For deep-targeted sequencing of tdDNA from urine supernatants, we
(HG) NMIBC recurrence after BCG treatment. designed three tumor-guided next-generation sequencing panels with
10–71 patient-specific mutations (Supplementary Table 3; TWIST Bio-
science) and used modified Twist protocols for library preparation and
2. Patients and methods capture in combination with unique molecular identifiers. DeepSNV
was applied for mutation quantification.
The Supplementary material provides full details of the clinical samples
and analyses. 2.6. Gene expression signatures
2.1. Patients, biological samples, and clinical follow-up Tumor samples were classified according to the UROMOL2021 system
[11]. RNA-based immune cell populations were estimated using estab-
A total of 156 patients with NMIBC, all treated with at least five cycles of lished gene expression signatures (Supplementary Table 4) [12,13].
BCG and preferably with a long disease course, were retrospectively The residuals from linear regression between the mean expression of
selected for the study. As few patients were treated with maintenance five genes related to immunoinhibitory processes (PDCD1, CTLA4, LAG3,
BCG in this study, post-BCG HG recurrence was defined as recurrence HAVCR2, and KLRG1; Fig. 2G) and the estimated level of CD8 T cells were
of HG urothelial carcinoma within 2 yr after the end of BCG induction used as indicators of the CD8 T-cell adjusted exhaustion level for all
treatment or progression to muscle-invasive BC (MIBC) any time during tumors.
follow-up. The end of follow-up was defined as the last of the following: We defined a post-BCG exhaustion predictor as the ratio between the
last cystoscopy, last tumor detected, cystectomy, progression, or metas- identified genes upregulated in pre-BCG tumors from patients with post-
tases. Post-BCG recurrence-free survival (RFS) and HG recurrence–free- BCG exhausted and nonexhausted tumors, respectively (Supplementary
Fig. 1 – Urinary detection of immuno-oncology–related responses. (A–C) All or the 15 most significantly different proteins are named (paired t test).
Blue = significant Benjamini-Hochberg–adjusted p value (q value) <0.1. Grey = not significant. Dotted lines indicate a significance level of 0.05. (A) Numerical
difference in mean normalized protein expression unit (NPX) values between paired pre-BCG and post-BCG urine samples for (A) all patients (n = 66), (B)
patients without post-BCG HG recurrence (n = 27), and (C) patients with post-BCG HG recurrence (n = 39). (D) Comparison of mean urinary level of proteins
grouped by biological features between the groups without and with post-BCG HG recurrence for pre-BCG and post-BCG samples (n = 107 and n = 83,
respectively; Wilcoxon rank-sum test) with unadjusted p values. BCG = bacillus Calmette-Guérin; HG = high grade.
Table 5). An optimal cutpoint for the post-BCG exhaustion predictor 3. Results
according to time to post-BCG HG recurrence was determined using
the R package survminer (cutpoint = 0.68).
3.1. Patient characteristics and analyses
In total, 156 patients with NMIBC who received at least five

2.7. Statistical analysis instillations of BCG were retrospectively included in the
Cox regression, log-rank tests, Wilcoxon rank-sum tests, t tests, paired
study and samples were analyzed as indicated in Supple-
t tests, Pearson correlation, and Fisher’s exact tests were used as
mentary Figure S2A. Patients were followed for a median
appropriate. More information is provided in the Supplementary of 5.5 yr after BCG (4.8 yr for patients with HG recurrence
material. and 6.1 yr for patients without HG recurrence). Whenever
Fig. 2 – Gene expression in tumors from the groups with and without post-BCG HG recurrence. (A) Distribution of transcriptomic classes in pre-BCG and post-
BCG tumor samples. (B) Kaplan-Meier plot of post-BCG high-grade recurrence–free-survival (HGRFS) for 126 patients stratified by transcriptomic class for pre-
BCG samples (log-rank test). The median HGRFS for patients without an event was 14.2 mo. (C) Distribution of pre-BCG transcriptomic classes in the post-BCG
non-HG and HG recurrence groups (Fisher’s exact test). Three patients were omitted from the analysis owing to a lack of post-BCG follow-up. (D) Sankey plot
of transcriptomic classes before and after BCG for 39 patients. (E) RNA-based immune cell infiltration in pre- and post-BCG samples from the groups with and
without post-BCG HG recurrence (Wilcoxon rank-sum test). (F) Spider plots of the expression level of selected immune-related genes from pre-BCG samples
(top) and post-BCG samples (bottom). Genes with unadjusted significantly different expression between the groups with and without post-BCG HG recurrence
are denoted (*p 0.05, **p 0.01, ***p 0.001; Wilcoxon rank-sum test). (G) Comparison of expression levels of selected immune inhibitory markers between
the groups with and without post-BCG HG recurrence (Wilcoxon rank-sum test). BCG = bacillus Calmette-Guérin; HG = high grade.
Table 1 – Clinical characteristics of the patient cohort
Variable All patients BCG HG recurrence BCG non-HG recurrence p valuea

(n = 156) (n = 70) (n = 83)
Median age, yr (IQR) 71 (62–76) 71 (63–76) 70 (62–76) 0.5
Sex, n (%) 0.3
Female 33 (21) 17 (24) 15 (18)
Male 123 (79) 53 (76) 68 (82)
Smoking status, n (%) 0.4
Current 61 (39) 24 (34) 37 (45)
Former 74 (47) 36 (51) 36 (43)
Never 20 (13) 9 (13) 10 (12)
Unknown 1 (0.6) 1 (1.4) 0 (0)
Median consumption, pack-years (IQR) 24 (12–40) 19 (11–40) 28 (15–40) 0.13
Progression to MIBC, n (%) <0.001
Progression 33 (21) 33 (47) 0 (0)
No progression 120 (77) 37 (53) 83 (100)
FU <2 yrb 3 (1.9) 0 (0) 0 (0)
AT stage and grade, n (%) 0.037
T1 HGc 45 (29) 25 (36) 18 (22)
T1 LG 9 (5.8) 4 (5.7) 5 (6.0)
Ta HG 46 (29) 24 (34) 22 (27)
Ta LG 56 (36) 17 (24) 38 (46)
Pre-BCG stage and grade, n (%) 0.5
CIS 23 (15) 13 (19) 9 (11)
T1 HGd 45 (29) 22 (31) 22 (27)
T1 LG 7 (4.5) 3 (4.3) 4 (4.8)
Ta HGd 45 (29) 19 (27) 25 (30)
Ta LG 36 (23) 13 (19) 23 (28)
Pre-BCG concomitant CIS, n (%) 37 (24) 19 (27) 16 (19) 0.2
Pre-BCG reTURBT, n (%) 0.055
Yes 38 (24) 22 (31) 15 (18)
No 118 (76) 48 (69) 68 (82)
Pre-BCG tumor status, n (%) 0.083
Primary tumor 49 (31) 17 (24) 31 (37)
Recurrent tumor 107 (69) 53 (76) 52 (63)
Pre-BCG EAU risk group, n (%) 0.4
Very high risk 35 (22) 19 (27) 15 (18)
High risk 64 (41) 28 (40) 34 (41)
Intermediate risk 57 (37) 23 (33) 34 (41)
Previous mitomycin C treatment, n (%) 10 (6.4) 2 (2.9) 8 (9.6) 0.11
Median post-BCG FU, yr (IQR) 5.5 (2.8–8.2) 4.8 (2.2–8.4) 6.1 (3.6–8.1) 0.10
BCG = bacillus Calmette-Guérin; FU = follow-up; HG = high grade; LG = low grade/G2; CIS = carcinoma in situ; TURBT = transurethral resection of bladder tumor
(samples collected within 120 d after TURBT were considered reTURBT); IQR = interquartile range; EAU = European Association of Urology; AT = analyzed tumor
(tumor sample undergoing whole-exome or RNA sequencing analysis closest to BCG initiation or diagnosed tumor).
a
Wilcoxon rank-sum test, Pearson’s v2 test, or Fisher’s exact test, as appropriate.
b
Less than 2 yr of FU after BCG in patients who died from causes other than bladder cancer.
c
The pathology description was inadequate for three samples. For simplicity, they have been included as T1 HG tumors.
d
Tumor grade was missing for two samples. For simplicity, they have been included as HG tumors.
possible, we included pre- and post-BCG paired samples. inflammatory T-cell responses [14–16], as well as other pro-
Tumors were included for WES and RNA sequencing and teins related to immunoinhibitory pathways, including PD-
urine samples for Olink and tdDNA analyses. Overlap of 1, PD-L1, and CD5 (Fig. 1C). This was not observed for
sample analyses is shown in Supplementary Figure S2B. patients without post-BCG HG recurrence (Fig. 1B). Group-
Table 1 lists the clinical characteristics of the patients. ing of the proteins by biological function revealed that
patients with post-BCG HG recurrence had significantly
3.2. Urinary protein profile for BCG-treated patients higher post-BCG levels of proteins related to chemotaxis
(p = 0.017). Changes in proteins related to suppression of
We analyzed 190 urine samples collected within 4 mo
tumor immunity (p = 0.065) and vascular and tissue remod-
before and after BCG treatment from 124 patients, including
eling pathways (p = 0.066) were not statistically significant
paired samples from 66 patients, using Olink proteomics.
(Fig. 1D). No significant differences were observed between
Comparison of paired samples revealed upregulation of a
the post-BCG non-HG and HG recurrence groups in pre-BCG
multitude of proteins, including CXCL9, CXCL11, CXCL10,
samples.
PD1, and TRAIL, on BCG treatment (Fig. 1A; Supplementary
Table 2). Stratification of the analysis according to clinical
3.3. Gene expression subtypes and deconvolution of immune
response revealed general immune system activation after
cell populations in pre- and post-BCG tumors
treatment in both groups, indicating a general immune acti-
vation with BCG (higher expression of the cytokines CXCL9, A total of 170 samples (126 pre-BCG and 44 post-BCG) were
CXCL10, and CXCL11; Fig. 1B, C). In addition, patients with classified according to the UROMOL2021 system [11],
post-BCG HG recurrence had significantly higher post-BCG including 39 paired samples. The majority of pre-BCG
levels of CD70, which has been linked to inhibition of tumors were of the high-risk class 2a subtype, whereas
the immune infiltrated subtype, class 2b, was relatively E2F targets (p < 0.001), interferon gamma response
more common in post-BCG tumors (Fig. 2A). Patients with (p < 0.001), and inflammatory response (p < 0.001; Fig. 3E).
class 2a and 2b tumors before BCG had significantly worse
post-BCG HGRFS (p = 0.015; Fig. 2B). Furthermore, URO- 3.5. Genomic correlates to response and exhaustion
MOL2021 subtypes for 123 pre-BCG tumors were signifi-
We sought to identify genomic features of pre-BCG tumors
cantly associated with post-BCG HG recurrence
predictive of post-BCG HG recurrence and exhaustion. Pre-
(p = 0.033), possibly explained by better prognosis for class
BCG tumors from patients without post-BCG HG recurrence
1 and class 3 tumors (Fig. 2C). Analysis of paired pre- and
demonstrated fewer indels in comparison to tumors from
post-BCG tumors revealed that 43.6% of the patients
patients in the HG recurrence group (p = 0.055; Supplemen-
remained in or shifted to class 2b after BCG treatment
tary Fig. 3). No differences were observed for single-
(Fig. 2D). Importantly, classification after BCG (p = 0.3),
nucleotide variants (p = 0.9). We performed de novo extrac-
post-BCG HG recurrence (p = 0.8), and post-BCG exhaustion
tion of mutational signatures and identified six signatures,
status (p = 0.9) were not associated with the time from
but no association with post-BCG HG recurrence or a high
treatment to tumor sampling (Supplementary Fig. 2C–E).
level of CD8 T-cell exhaustion after BCG was observed (Sup-
We estimated immune cell populations from the RNA
plementary Figs. 3–5). No other genomic features in pre-
sequencing data using established gene expression signa-
BCG tumors were associated with a high level of CD8 T-
tures [12,13]. The post-BCG HG recurrence group had a
cell exhaustion after BCG (Supplementary Fig. 4). We also
higher total immune infiltration score after BCG
performed a gene-level permutation test to assess if muta-
(p = 0.046; Fig. 2E). Higher post-BCG levels of dendritic cells
tion status of specific genes in pre-BCG samples was predic-
(p = 0.036), exhausted CD8 T cells (p = 0.017), and mast cells
tive of post-BCG CD8 T-cell exhaustion (n = 42). We found,
(p = 0.043) were associated with post-BCG HG recurrence,
among others, that MUC4 was more frequently mutated in
while no immune cell populations were associated with
the post-BCG high-exhaustion group (p = 0.002) and FGFR3
response before BCG treatment. We analyzed the expres-
in the low-exhaustion group (p = 0.025; Fig. 4A). Further-
sion of genes involved in selected biological processes asso-
more, we investigated correlations between neoantigen
ciated with immune response and found no significantly
levels in the tumors and exhaustion status. Patients with a
differentially expressed genes between the post-BCG non-
high neoantigen load in pre-BCG tumors had a significantly
HG and HG recurrence group in pre-BCG samples (Fig. 2F).
higher exhaustion level in post-BCG tumors (p = 0.017;
However, after BCG, the HG recurrence group had signifi-
Fig. 4B). Neoantigen burden was not significantly associated
cantly higher expression levels of the immune inhibitory
with post-BCG HG recurrence (Supplementary Fig. 3H).
marker genes PD1, KLRG1, HAVCR2, CTLA4, and LAG3, among
others (Fig. 2F, G) [5]. 3.6. Urinary tdDNA as a measure of response
To investigate possible correlations between post-BCG HG

3.4. Exhaustion of T cells in the tumor microenvironment recurrence and urinary tdDNA levels and dynamics, we ana-
To further explore the impact of CD8 T-cell exhaustion on lyzed 187 pre- and post-BCG urine samples from 104
BCG response, we estimated an exhaustion score adjusted patients, including 83 paired samples, via deep-targeted
for CD8 T-cell infiltration for all tumors (Fig. 3A). A higher sequencing of tumor-specific mutations. We observed sig-
level of CD8 T-cell exhaustion was associated with post- nificantly higher post-BCG levels of tdDNA in the post-
BCG HG recurrence (pre-BCG, p = 0.056; post-BCG, BCG HG recurrence group (p = 0.003), while there was no
p = 0.002; Fig. 3B and Supplementary Fig. 2F). Notably, difference for pre-BCG samples (p = 0.5; Fig. 4C). The
post-BCG tumors with excessive CD8 T-cell exhaustion exhaustion status of pre- and post-BCG tumors was signifi-
were all associated with post-BCG HG recurrence cantly associated with tdDNA levels in both pre-BCG
(p = 0.029; Supplementary Fig. 2G, H). (p = 0.008) and post-BCG (p = 0.012) urine samples
We repeated the modeling to define the level of CD8 T- (Fig. 4D). Furthermore, when focusing on paired samples,
cell adjusted exhaustion for tumors in the UROMOL2021 we observed that patients with tdDNA clearance after BCG
cohort. These samples were also analyzed using multiplex treatment had significantly better post-BCG RFS compared
immunofluorescence and immunohistochemistry to deter- to patients without tdDNA clearance (p = 0.018; Fig. 4E).
mine the level of immune cell infiltration and PD1/PD-L1
3.7. Pre-BCG predictors of post-BCG exhaustion and HG
protein expression. We observed that high PD1 protein
recurrence
expression was significantly associated with a higher
RNA-based exhaustion score (p < 0.001; Fig. 3C and Supple- We analyzed the prognostic and predictive role of clinical
mentary Fig. 2I). variables and identified pre-BCG predictors of post-BCG
To determine possible pre-BCG markers of post-BCG CD8 CD8 T-cell exhaustion and HG recurrence. Using the ratio
T-cell exhaustion, we identified differentially expressed between differentially expressed genes in pre-BCG tumors,
genes between pre-BCG tumors from patients with higher a post-BCG exhaustion predictor (ExhP) was established.
and lower exhaustion in post-BCG tumors (Fig. 3D). We Patients with tumors predicted to have low post-BCG
found that pathways related to the cell cycle and immune exhaustion had superior HGRFS compared to patients with
response in particular were significantly enriched in tumors predicted to have high post-BCG exhaustion
pre-BCG tumors from patients with higher exhaustion in (p = 0.002; Fig. 5A). The association between HGRFS and
post-BCG tumors, including G2M checkpoint (p < 0.001), post-BCG ExhP levels was confirmed in two independent
Fig. 3 – T-cell exhaustion. (A) Correlation between CD8 T-cell score and exhaustion score. Green = lower exhaustion (residuals 0.1). Purple = higher
exhaustion (residuals >0.1). Pearson correlation was used to determine the correlation coefficient R and p value. (B) CD8 T-cell adjusted exhaustion score in
the post-BCG non-HG and HG recurrence groups pre- and post-BCG (Wilcoxon rank-sum test). (C) Association between RNA-based exhaustion status and PD1
expression from immunohistochemistry (IHC) in the UROMOL cohort (Wilcoxon rank-sum test). (D) Differentially expressed genes in pre-BCG tumors from
patients with higher and lower exhaustion of post-BCG tumors (n = 39) identified using a Wilcoxon rank-sum test. Only genes with mean expression >0 across
all samples were included. Purple indicates p < 0.05 and a mean fold change (FC) >0.5; green indicates p < 0.05 and mean FC < -0.5. (E) Hallmark pathways
significantly upregulated in pre-BCG tumors from patients with higher or lower exhaustion of post-BCG tumors, respectively (Fisher’s exact test).
BCG = bacillus Calmette-Guérin; HG = high grade.
cohorts of pre-BCG NMIBC tumors (p = 0.003, Fig. 5A; and post-BCG HGRFS, possibly indicating BCG failure, whereas
p = 0.014, Supplementary Fig. 6A). Notably, the level of FGFR3 mutations were associated with better post-BCG
post-BCG exhaustion was still associated with HGRFS when HGRFS (p = 0.011; Fig. 5B). Multivariable Cox regression
restricting the analysis to class 2a tumors (Supplementary analysis identified post-BCG ExhP (p = 0.018) and URO-
Fig. 6). To summarize the results, univariate Cox regression MOL2021 class (p=0.012) as independent predictors of
analysis showed that high tumor grade (p = 0.004), URO- HGRFS when adjusted for tumor grade. A simplified sche-
MOL2021 class 2a and 2b (p = 0.002), and high post-BCG matic representation of pre-BCG predictors of response
ExhP (p = 0.002) were significantly associated with worse and post-BCG exhaustion is provided in Fig. 5C.
Fig. 4 – Genomics and post-BCG HG recurrence. (A) Gene-level permutation test on mutation status of specific genes and post-BCG CD8 T-cell exhaustion
(Wilcoxon rank-sum test). (B) Neoantigen load (upper 1/3 vs lower 2/3) in pre-BCG tumors correlated to exhaustion level in post-BCG tumors (Wilcoxon rank-
sum test). (C) Per-sample mean of urinary tdDNA copies per ml (1 is added to all sample levels) in all pre- and post-BCG urine samples from the post-BCG non-
HG and HG recurrence groups (Wilcoxon rank-sum test). (D) Per-sample mean of urinary tdDNA copies per ml (1 is added to all sample levels) in all pre- and
post-BCG urine samples and exhaustion status of pre- and post-BCG tumors (Wilcoxon rank-sum test). (E) Kaplan-Meier plot of post-BCG recurrence-free
survival (RFS) for patients with and without tdDNA clearance post-BCG (log-rank test). BCG = bacillus Calmette-Guérin; HG = high grade; tdDNA = tumor-
derived DNA; RFS = recurrence-free survival.
4. Discussion predictors of worse post-BCG HGRFS in our cohort and in

two validation cohorts from de Jong et al. Furthermore,
We identified T-cell exhaustion as a possible explanation for pre-BCG tumors from patients with post-BCG exhaustion
post-BCG HG recurrence. We established a CD8 T-cell had higher expression of genes related to cell cycle and
exhaustion score and demonstrated that patients with immune pathways, possibly indicating a more aggressive
post-BCG HG recurrence had significantly higher exhaus- and immunoactive phenotype. It has been shown that
tion levels. We then developed a post-BCG ExhP score using mutations alter tumor immunogenicity by increasing T-
pre-BCG gene expression levels related to post-BCG exhaus- cell responses via the generation of neoantigens [17]. How-
tion. We showed that high post-BCG ExhP scores were ever, chronic stimulation of T cells (eg, by neoantigens)
Fig. 5 – Transcriptomic and genomic features predict post-BCG high-grade recurrence–free-survival (HGRFS). (A) Kaplan-Meier plot of post-BCG HGRFS for 126
patients (study cohort, top) and 151 patients (validation cohort B, bottom) stratified by post-BCG exhaustion prediction in pre-BCG samples (log-rank test). (B)
Forest plot of hazard ratios calculated from univariate and multivariable Cox regressions of post-BCG HGRFS using clinical and molecular features of pre-BCG
tumors or pre-BCG urine characteristics. Dots represent hazard ratios and horizontal lines the corresponding 95% confidence interval (CI); p values were
calculated using the Wald test. Benjamini-Hochberg correction was applied for adjustment of multiple testing (p.adjust). Tumor grade was included for
multivariable Cox regression analysis of possible predictors that were significant on univariate analysis (p.multi). n indicates the number of patients in each
analysis. The European Association of Urology (EAU) risk score [25] was calculated for the BCG-inducing tumor. (C) Simplified schematic representation of
identified pre-BCG variables predictive of T-cell exhaustion and BCG HG recurrence (created with BioRender.com). LG = low grade; HG = high grade;
TURBT = transurethral resection of bladder tumor; BCG = bacillus Calmette-Guérin; tdDNA = tumor-derived DNA; ExhP = exhaustion predictor.
increases the risk that T cells will enter a dysfunctional state we cannot determine if class 2b has worse prognosis after
of exhaustion [6], indicating a delicate balance between T- BCG, and additional larger studies are needed. Notably, de
cell states. Our results support this immunological balance Jong et al. [18] recently reported three subtypes for pre-
and show that BCG treatment leads to exhaustion and BCG tumors related to BCG response and identified a group
post-BCG HG recurrence in some patients, which has also of unresponsive patients.
been suggested by others [10]. Furthermore, our results MUC4 was mutated significantly more often in pre-BCG
suggest that a protumorigenic tumor microenvironment tumors from patients with post-BCG exhaustion. In a recent
may be more pronounced in patients whose pretreatment study on colon cancer, mutations in MUC4 were linked to
tumors are characterized by high activity in cell division activation of immune-system signaling pathways and
and immunological pathways and with high neoantigen enhancement of the antitumor immune response [19]. This
loads. Lindskrog et al. [11] hypothesized that class 2b link might explain the observation of correlation to exhaus-
tumors respond poorly to BCG. In the current study, we tion through BCG-induced overactivation of the immune
found that pre-BCG class 2a and 2b tumors had the worst system. Conversely, FGFR3 mutations have been linked to
post-BCG HGRFS when compared to class 1 and class 3 noninflamed tumors, suggesting a role of FGFR3 in T-cell
tumors, which may simply reflect the prognostic value of exclusion in BC [20,21]. Although differences in tumor sam-
the classification system. On the basis of our current study pling time relative to BCG were observed, no statistically
significant correlations were observed between sampling relevant to the subject matter or materials discussed in the manuscript
time from BCG and post-BCG HG recurrence, exhaustion (eg, employment/affiliation, grants or funding, consultancies, honoraria,
status, or UROMOL2021 subtype. This suggests that the stock ownership or options, expert testimony, royalties, or patents filed,
highlighted results are not explained by differences in sam- received, or pending), are the following: Lars Dyrskjøt has sponsored
pling time. research agreements with C2i, AstraZeneca, Natera, Photocure, and Fer-
ring; has an advisory/consulting role at Ferring; and is Chairman of the
Urinary tdDNA may reflect both local bladder neoplastic
Board of BioXpedia A/S. Jørgen Bjerggaard Jensen is a proctor for Intuitive
disease, and disseminated disease with presence of urinary
Surgery; is an advisory board member for Olympus Europe, Cephaid, and
tdDNA from renal clearance [22], making monitoring of
Ferring; and has sponsored research agreements with Medac, Photocure
tdDNA potentially useful in the NMIBC setting. Here, we
ASA, Cephaid, and Ferring. The remaining authors have nothing to
observed that tdDNA levels and dynamics were associated
disclose.
with disease outcome after BCG treatment. Low levels of
tdDNA after BCG treatment could be the result of both sur-
gical removal of the tumor and the effect of BCG. However, Funding/Support and role of the sponsor: This work was funded by Fer-
since all patients received both treatments and differences ring Pharmaceuticals, the Danish Cancer Society, Aarhus University, Dag-
were observed between the post-BCG non-HG and HG mar Marshalls Fond, Christian Larsen og Dommer Ellen Larsens Legat,
recurrence groups, tdDNA may have a predictive role that Fabrikant Einar Willumsens Mindelegat, the Danish Medical Association,
needs to be investigated further. Danish Cancer Biobank, and Dansk Kræftforskningsfond. The sponsors
Taken together, these results could be used to guide clin- had a role in review of the manuscript.
ical decision-making if validated in clinical trials. A possible

intervention could be treatment with immunomodulatory Acknowledgements: We thank all the technical personnel at the Depart-
agents in combination with BCG, as is currently being inves- ment of Molecular Medicine, Aarhus University Hospital, for sample han-
tigated [23,24]. Furthermore, close follow-up of patients via dling and processing.
serial liquid biopsy monitoring during and after treatment
could potentially guide treatment interventions and
Data sharing statement: The current legislation on data sharing requires
improve clinical management.
that sensitive (including pseudonymized) data can only be shared follow-
ing approval by the National Committee on Health Research Ethics in
Denmark of the project and by the Danish Data Registry.
5. Conclusions
Peer Review Summary

Our results highlight several correlates to post-BCG HG
recurrence and we showed that CD8 T-cell exhaustion
may be a key factor. Pre-BCG prediction of post-BCG CD8 Peer Review Summary and Supplementary data to this arti-
T-cell exhaustion has the potential to identify patients at cle can be found online at https://doi.org/10.1016/j.eururo.
high risk of post-BCG HG recurrence, and urinary measure- 2022.09.008.
ment of proteins and tdDNA could be used to monitor treat-
ment response. If validated in clinical trials, this strategy References
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Words of Wisdom
Re: Tranexamic Acid in Patients Undergoing Noncardiac tunistic fashion for treatment and prophylaxis of bleeding
Surgery after surgery for benign prostatic hyperplasia.
Devereaux PJ, Marcucci M, Painter TW, et al Postoperative bleeding is not uncommon in major uro-
logical surgery: In a nationwide cystectomy analysis from
N Engl J Med 2022;386:1986–97
Sweden, Mortezavi et al [7] found that the probability of
intraoperative and/or postoperative blood transfusions for
Expert’s summary: open cystectomy was 50.8%. In their study population, Dev-
Tranexamic acid is an antifibrinolytic drug that reduces eraux et al [1] found a reduction in the risk of transfusion
mortality after polytrauma and the risk of bleeding compli- from 12% to 9.4%, representing an absolute difference of
cations after complex operations such as cardiac surgery. 2.6% and a relative difference of 21.67%. Extrapolating these
Because of limited data for patients undergoing noncardiac differences to a cystectomy scenario with a four times
surgery, Deveraux et al [1] initiated a randomized trial com- higher risk of transfusion of approximately 50% would
paring tranexamic acid with placebo for patients undergo- result in an absolute difference close to 10%.
ing major noncardiac surgery who had a clearly defined Postoperative bleeding can lead to further complications
risk of perioperative bleeding and of cardiovascular compli- and/or interventions. Bleeding after organ-sparing surgery
cations. The trial was designed to recruit a total of 10 000 for kidney tumors, for example, often requires reinterven-
patients, but had to be closed after enrolment of 9500 tions (surgical or other interventions) that can deteriorate
patients because of recruitment problems during the or even destroy kidney function. A reduction in the risk of
COVID-19 pandemic. bleeding therefore seems worth the effort and not just
In the tranexamic acid group, a bleeding event according because of the common shortage of blood products. Dis-
to a composite measure was observed in 433 patients cussing the use of tranexamic acid with our colleagues from
(9.1%), which was significantly lower (p > 0.001, two-sided anesthesiology often ends in controversy regarding the risk
test for superiority) than in the placebo group (561 events, of cardiovascular side effects, even when described as mar-
11.7%). A cardiovascular event (composite measure) was ginal by Devereaux et al [1]. Guideline recommendations
observed in 14.2% of patients in the tranexamic acid group for urological procedures would therefore be more than
as compared to 13.9% in the placebo group. The difference desirable. Furthermore, the trial published by Devereaux
seems marginal, but noninferiority could not be proven at et al underlines the value of prospective trials, even for
a statistically significant level. Analysis of secondary and drugs that we have used for decades.
tertiary endpoints revealed a significant reduction in bleed-
ing independently associated with death (8.7% vs 11.3%)
Conflicts of interest: The author has nothing to disclose.
and transfusion of at least one unit of packed red cells
(9.4% vs 12%), among others. The differences are described References
as consistent across all surgery types, and more than 10%
of patients had urological procedures. The authors conclude [1] Devereaux PJ, Marcucci M, Painter TW, et al. Tranexamic acid in
that patients will have to weigh a clear beneficial reduction patients undergoing noncardiac surgery. N Engl J Med 2022;386:
in the incidence of bleeding complications against the low 1986–97.
[2] Roberts I, Shakur H, Afolabi A, et al. The importance of early
probability of a small increase in cardiovascular events. treatment with tranexamic acid in bleeding trauma patients: an
exploratory analysis of the CRASH-2 randomised controlled trial.
Lancet 2011;377:1096–101.e1–2.
Expert’s comments: [3] CRASH-3 Trial Collaborators. Effects of tranexamic acid on death,
Tranexamic acid reduces mortality in bleeding trauma disability, vascular occlusive events and other morbidities in patients
patients with or without brain involvement when given as with acute traumatic brain injury (CRASH-3): a randomised,
early as possible [2,3]. Large trials also demonstrated reduc- placebo-controlled trial. Lancet 2019;394:1713–23.
[4] Sentilhes L, Sénat MV, Le Lous M, et al. Tranexamic acid for the
tions in the incidence and intensity of postoperative bleed- prevention of blood loss after cesarean delivery. N Engl J Med
ing in patients after cesarean section and after cardiac 2021;384:1623–34.
surgery [4,5]. Smaller trials also suggested a similar effect [5] Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients
for orthopedic procedures [6]. At least in Germany, urolo- undergoing coronary-artery surgery. N Engl J Med 2016;376:136–48.
[6] Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim
gists have used tranexamic acid for decades in an oppor-
W. Use of antifibrinolytic therapy to reduce transfusion in patients
undergoing orthopedic surgery: a systematic review of randomized * Department of Urology and Pediatric Urology, Saarland University and
trials. Thromb Res 2009;123:687–96. Saarland University Medical Center, Kirrberger Strasse 100, 66424
[7] Mortezavi A, Crippa A, Kotopouli MI, Akre O, Wiklund P, Hosseini A. Homburg/Saar, Germany.
Association of open vs robot-assisted radical cystectomy with E-mail address: michael.stoeckle@uks.eu.
mortality and perioperative outcomes among patients with bladder
cancer in Sweden. JAMA Netw Open 2022;5:e228959.
0302-2838/Ó 2022 European Association of Urology. Published by
* Elsevier B.V. All rights reserved.
Michael Stöckle
Department of Urology and Pediatric Urology, Saarland University and https://doi.org/10.1016/j.eururo.2022.08.020
Saarland University Medical Center, Homburg/Saar, Germany
Re: Global Burden of Bacterial Antimicrobial Resistance in somewhat different findings, the overall global burden of
2019: A Systematic Analysis AMR is consistent worldwide.
Antimicrobial Resistance Collaborators
Typical AMR uropathogens, such as Escherichia coli, Kleb-
siella pneumoniae, Pseudomonas aeruginosa, Enterobacter
spp., and enterococci, are among the top ten most important
Lancet 2022;399:629–55 pathogens causing AMR-related mortality, and AMR urinary
tract infections are responsible for at least 250 000 deaths
Experts’ summary:
per year [3]. This shows that urology and urological infec-
When Jim O’Neill, a macroeconomist, published his final tions are in the eye of the AMR hurricane and highlights
report on global antimicrobial resistance in 2016 [1], pre- the need for a comprehensive action plan. Antimicrobial
dicting that 10 million people could die in 2050 from bacte- stewardship principles for prophylaxis and therapy will
rial infections due to antimicrobial-resistant (AMR) become increasingly important, and should be included in
pathogens, the responses from the scientific community guideline development and followed in everyday clinical
were heterogeneous. The current lack of comprehensive practice.
AMR surveillance data, especially for low- and middle-
income countries (LMICs), was annotated as a draw-back Conflicts of interest: The authors have nothing to disclose.
to reliably model data for the future [2]. This highly relevant
publication on global antimicrobial resistance from the References
Antimicrobial Resistance Collaborators [3] provides an all-
encompassing view of current global AMR and its health [1] Antimicrobial Resistance Collaborators. Global burden of bacterial
antimicrobial resistance in 2019: a systematic analysis. Lancet
burden, using many sophisticated epidemiological research
2022;399:629–55.
techniques to ensure reliable data capture, including from [2] O’Neill J. Tackling drug-resistant infections globally: final report and
LMICs. This research group compiled huge amounts of data recommendations. London: Review on antimicrobial resistance;
and metadata on global AMR and its burden from ten differ- 2016.
ent source types, and estimated AMR and linked deaths and [3] de Kraker ME, Stewardson AJ, Harbarth S. Will 10 million people die
a year due to antimicrobial resistance by 2050? PLoS Med 2016;13:
disability-adjusted life years for a variety of bacterial patho- e1002184.
gens and pathogen-drug combinations in 204 countries. The [4] World Health Organization. Antimicrobial resistance. Geneva,
authors conclude that their models estimated that 4.95 mil- Switzerland: WHO; 2021.
lion deaths worldwide in 2019 were associated with or [5] US Centers for Disease Control and Prevention. Antibiotic resistance
threats in the United States. Atlanta, GA: US Department of Health
attributable to AMR. In particular, methicillin-resistant Sta-
and Human Services; 2019.
phylococcus aureus, multidrug-resistant enterobacteria
(MDR), and MDR tuberculosis were causative organisms. Florian M.E. Wagenlehner *
Florian Dittmar
Experts’ comments: Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig University,
This very extensive epidemiological publication repre- Giessen, Germany
sents the most comprehensive analysis of current global
AMR to date and also presents the burden for the year * Corresponding author. Clinic for Urology, Pediatric Urology and
2019. The report covers all super-regions of the world, Andrology, Justus-Liebig University, Rudolf-Buchheim Strasse 7, 35392
Giessen, Germany.
including LMICs, and reveals significant differences
E-mail address: florian.wagenlehner@chiru.med.uni-giessen.de (F.M.E.
between regions. The most prominent AMR pathogens and
Wagenlehner).
pathogen-drug combinations involved include those identi-
fied in reports from the World Health Organization [4] and
the US Centers for Disease Control and Prevention [5]. The
Elsevier B.V. All rights reserved.
estimated almost 5 million deaths associated with or attri-
butable to AMR in 2019 represent a first reliable data set
and make the prediction for 2050 by O’Neill [1] appear very
realistic. Although different geographical regions showed
undergoing orthopedic surgery: a systematic review of randomized * Department of Urology and Pediatric Urology, Saarland University and
trials. Thromb Res 2009;123:687–96. Saarland University Medical Center, Kirrberger Strasse 100, 66424
[7] Mortezavi A, Crippa A, Kotopouli MI, Akre O, Wiklund P, Hosseini A. Homburg/Saar, Germany.
Association of open vs robot-assisted radical cystectomy with E-mail address: michael.stoeckle@uks.eu.
mortality and perioperative outcomes among patients with bladder
cancer in Sweden. JAMA Netw Open 2022;5:e228959.
* Elsevier B.V. All rights reserved.
Michael Stöckle
Department of Urology and Pediatric Urology, Saarland University and https://doi.org/10.1016/j.eururo.2022.08.020
Saarland University Medical Center, Homburg/Saar, Germany
Re: Global Burden of Bacterial Antimicrobial Resistance in somewhat different findings, the overall global burden of
2019: A Systematic Analysis AMR is consistent worldwide.
Antimicrobial Resistance Collaborators
Typical AMR uropathogens, such as Escherichia coli, Kleb-
siella pneumoniae, Pseudomonas aeruginosa, Enterobacter
spp., and enterococci, are among the top ten most important
Lancet 2022;399:629–55 pathogens causing AMR-related mortality, and AMR urinary
tract infections are responsible for at least 250 000 deaths
Experts’ summary:
per year [3]. This shows that urology and urological infec-
When Jim O’Neill, a macroeconomist, published his final tions are in the eye of the AMR hurricane and highlights
report on global antimicrobial resistance in 2016 [1], pre- the need for a comprehensive action plan. Antimicrobial
dicting that 10 million people could die in 2050 from bacte- stewardship principles for prophylaxis and therapy will
rial infections due to antimicrobial-resistant (AMR) become increasingly important, and should be included in
pathogens, the responses from the scientific community guideline development and followed in everyday clinical
were heterogeneous. The current lack of comprehensive practice.
AMR surveillance data, especially for low- and middle-
income countries (LMICs), was annotated as a draw-back Conflicts of interest: The authors have nothing to disclose.
to reliably model data for the future [2]. This highly relevant
publication on global antimicrobial resistance from the References
Antimicrobial Resistance Collaborators [3] provides an all-
encompassing view of current global AMR and its health [1] Antimicrobial Resistance Collaborators. Global burden of bacterial
antimicrobial resistance in 2019: a systematic analysis. Lancet
burden, using many sophisticated epidemiological research
2022;399:629–55.
techniques to ensure reliable data capture, including from [2] O’Neill J. Tackling drug-resistant infections globally: final report and
LMICs. This research group compiled huge amounts of data recommendations. London: Review on antimicrobial resistance;
and metadata on global AMR and its burden from ten differ- 2016.
ent source types, and estimated AMR and linked deaths and [3] de Kraker ME, Stewardson AJ, Harbarth S. Will 10 million people die
a year due to antimicrobial resistance by 2050? PLoS Med 2016;13:
disability-adjusted life years for a variety of bacterial patho- e1002184.
gens and pathogen-drug combinations in 204 countries. The [4] World Health Organization. Antimicrobial resistance. Geneva,
authors conclude that their models estimated that 4.95 mil- Switzerland: WHO; 2021.
lion deaths worldwide in 2019 were associated with or [5] US Centers for Disease Control and Prevention. Antibiotic resistance
threats in the United States. Atlanta, GA: US Department of Health
attributable to AMR. In particular, methicillin-resistant Sta-
and Human Services; 2019.
phylococcus aureus, multidrug-resistant enterobacteria
(MDR), and MDR tuberculosis were causative organisms. Florian M.E. Wagenlehner *
Florian Dittmar
Experts’ comments: Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig University,
This very extensive epidemiological publication repre- Giessen, Germany
sents the most comprehensive analysis of current global
AMR to date and also presents the burden for the year * Corresponding author. Clinic for Urology, Pediatric Urology and
2019. The report covers all super-regions of the world, Andrology, Justus-Liebig University, Rudolf-Buchheim Strasse 7, 35392
Giessen, Germany.
including LMICs, and reveals significant differences
E-mail address: florian.wagenlehner@chiru.med.uni-giessen.de (F.M.E.
between regions. The most prominent AMR pathogens and
Wagenlehner).
pathogen-drug combinations involved include those identi-
fied in reports from the World Health Organization [4] and
the US Centers for Disease Control and Prevention [5]. The
estimated almost 5 million deaths associated with or attri-
butable to AMR in 2019 represent a first reliable data set
and make the prediction for 2050 by O’Neill [1] appear very
realistic. Although different geographical regions showed
Re: Sequential Intravesical Gemcitabine and Docetaxel for with material costs increasing for BCG, a benefit may be seen
Bacillus Calmette-Guérin-naïve High-risk Nonmuscle- with alternative agents [2]. This value may be further real-
invasive Bladder Cancer ized when the significant side-effect costs of BCG are consid-
McElree IM, Steinberg RL, Martin AC, et al ered [2]. Notwithstanding, alternative adjuvant intravesical
therapies for NMIBC have shown great promise. However,
J Urol 2022;208:589–99
further characterization is warranted regarding clinical out-
comes and the cost-effectiveness of these regimens.
Experts’ summary:
McElree et al [1] investigated the effectiveness of a sequen-
tial combination of gemcitabine and docetaxel for bacillus
Calmette-Guérin (BCG)-naïve high-risk non–muscle-inva-
sive bladder cancer (NMIBC). A total of 107 patients under- Acknowledgments: This study was conducted with the support of
went six weekly intravesical instillations of sequential a Department of Defense Peer Reviewed Cancer Research Program
gemcitabine and docetaxel followed by monthly mainte- (PRCRP) Career Development Award (W81XWH1710576) and
nance for 2 yr. Recurrence-free survival (RFS) was the pri- National Institutes of Health (NIH) Loan Repayment Program.
mary outcome. Median follow-up was 15 mo. At 24 mo,
RFS of 82% and an overall survival rate of 84% were References
reported, with no incidence of disease progression or mor-
[1] McElree IM, Steinberg RL, Martin AC, et al. Sequential intravesical
tality due to bladder cancer. A total of 60 patients (56%) gemcitabine and docetaxel for bacillus Calmette-Guérin-naïve high-
experienced 92 adverse events, of which urinary fre- risk nonmuscle-invasive bladder cancer. J Urol 2022;208:589–99.
quency/urgency (n = 46), hematuria (n = 16), and dysuria [2] Ourfali S, Ohannessian R, Fassi-Fehri H, Pages A, Badet L, Colombel M.
(n = 10) were the most common. Induction therapy was Recurrence rate and cost consequence of the shortage of bacillus
Calmette-Guerin Connaught strain for bladder cancer patients. Eur
halted in four patients because of hematuria (n = 3) and uri-
Urol Focus 2021;7:111–6.
nary frequency (n = 1). [3] Ward K, Kitchen MO, Mathias SJ, Khanim FL, Bryan RT. Novel
intravesical therapeutics in the treatment of non-muscle invasive
bladder cancer: horizon scanning. Front Surg 2022;9:912438.
Experts’ comments: [4] Balasubramanian A, Gunjur A, Weickhardt A, et al. Adjuvant
BCG has been the gold-standard adjuvant treatment for NMIBC therapies for non-muscle-invasive bladder cancer: advances during
for more than 40 yr. However, its recent shortage has been BCG shortage. World J Urol 2022;40:1111–24.
[5] Williams SB, Howard LE, Foster ML, et al. Estimated costs and long-
associated with a significant impact on patient outcomes (in-
term outcomes of patients with high-risk non-muscle-invasive
creasing recurrence) and strain on medical systems [2]. As a sil- bladder cancer treated with bacillus Calmette-Guerin in the
ver lining, this shortage has encouraged the investigation of Veterans Affairs health system. JAMA Netw Open 2021;4:e213800.
new adjuvant intravesical protocols, some typically reserved
for patients with BCG-resistant disease. These vary from Mehraban Kavoussi y
hyperthermic mitomycin C, single-agent gemcitabine, and Ali A. Nasrallah y
Stephen B. Williams *
immunotherapy agents to a synergistic combination of gemc-
itabine and docetaxel, as summarized above. Early data show Division of Urology, The University of Texas Medical Branch, Galveston, TX,
that these novel therapies are well tolerated by patients and USA
are promising options for BCG-unresponsive disease [3,4].
However, current alternative treatments for BCG-naïve * Corresponding author. Division of Urology, Department of Surgery,
patients remain sparse. The results from the present study University of Texas Medical Branch, 301 University Boulevard, Galveston,
for a combination therapy that is readily available at most TX 77555, USA.
institutions represent an excellent RFS rate in comparison to

E-mail address: stbwilli@utmb.edu (S.B. Williams).
historical BCG data.
In addition to efficacy, it is important to consider the cost
of intravesical treatment for NMIBC. The median cost for
adjuvant BCG treatment of NMIBC is nearly $30 000 at 1 yr
and $55 000 at 2 yr [5]. Cost-effectiveness data are sparse
for alternative adjuvant intravesical therapies. However,
Re: Sperm Count is Increased by Diet-induced Weight Loss Experts’ summary:

and Maintained by Exercise or GLP-1 Analogue Treatment: Anderson et al. [1] analyzed the effects of weight loss on
A Randomized Controlled Trial sperm count, concentration, and motility. This was a ran-
domized controlled double-blind study in otherwise
Anderson E, Juhl CR, Kjoller ET, et al.
healthy men with body mass index (BMI) of 32–43 kg/m2
Hum Reprod 2022;37:1414–22 who were assigned to an initial 8-wk low-calorie diet fol-
Re: Sequential Intravesical Gemcitabine and Docetaxel for with material costs increasing for BCG, a benefit may be seen
Bacillus Calmette-Guérin-naïve High-risk Nonmuscle- with alternative agents [2]. This value may be further real-
invasive Bladder Cancer ized when the significant side-effect costs of BCG are consid-
McElree IM, Steinberg RL, Martin AC, et al ered [2]. Notwithstanding, alternative adjuvant intravesical
therapies for NMIBC have shown great promise. However,
J Urol 2022;208:589–99
further characterization is warranted regarding clinical out-
comes and the cost-effectiveness of these regimens.
Experts’ summary:
McElree et al [1] investigated the effectiveness of a sequen-
tial combination of gemcitabine and docetaxel for bacillus
Calmette-Guérin (BCG)-naïve high-risk non–muscle-inva-
sive bladder cancer (NMIBC). A total of 107 patients under- Acknowledgments: This study was conducted with the support of
went six weekly intravesical instillations of sequential a Department of Defense Peer Reviewed Cancer Research Program
gemcitabine and docetaxel followed by monthly mainte- (PRCRP) Career Development Award (W81XWH1710576) and
nance for 2 yr. Recurrence-free survival (RFS) was the pri- National Institutes of Health (NIH) Loan Repayment Program.
mary outcome. Median follow-up was 15 mo. At 24 mo,
RFS of 82% and an overall survival rate of 84% were References
reported, with no incidence of disease progression or mor-
[1] McElree IM, Steinberg RL, Martin AC, et al. Sequential intravesical
tality due to bladder cancer. A total of 60 patients (56%) gemcitabine and docetaxel for bacillus Calmette-Guérin-naïve high-
experienced 92 adverse events, of which urinary fre- risk nonmuscle-invasive bladder cancer. J Urol 2022;208:589–99.
quency/urgency (n = 46), hematuria (n = 16), and dysuria [2] Ourfali S, Ohannessian R, Fassi-Fehri H, Pages A, Badet L, Colombel M.
(n = 10) were the most common. Induction therapy was Recurrence rate and cost consequence of the shortage of bacillus
Calmette-Guerin Connaught strain for bladder cancer patients. Eur
halted in four patients because of hematuria (n = 3) and uri-
Urol Focus 2021;7:111–6.
nary frequency (n = 1). [3] Ward K, Kitchen MO, Mathias SJ, Khanim FL, Bryan RT. Novel
intravesical therapeutics in the treatment of non-muscle invasive
bladder cancer: horizon scanning. Front Surg 2022;9:912438.
Experts’ comments: [4] Balasubramanian A, Gunjur A, Weickhardt A, et al. Adjuvant
BCG has been the gold-standard adjuvant treatment for NMIBC therapies for non-muscle-invasive bladder cancer: advances during
for more than 40 yr. However, its recent shortage has been BCG shortage. World J Urol 2022;40:1111–24.
[5] Williams SB, Howard LE, Foster ML, et al. Estimated costs and long-
associated with a significant impact on patient outcomes (in-
term outcomes of patients with high-risk non-muscle-invasive
creasing recurrence) and strain on medical systems [2]. As a sil- bladder cancer treated with bacillus Calmette-Guerin in the
ver lining, this shortage has encouraged the investigation of Veterans Affairs health system. JAMA Netw Open 2021;4:e213800.
new adjuvant intravesical protocols, some typically reserved
for patients with BCG-resistant disease. These vary from Mehraban Kavoussi y
hyperthermic mitomycin C, single-agent gemcitabine, and Ali A. Nasrallah y
Stephen B. Williams *
immunotherapy agents to a synergistic combination of gemc-
itabine and docetaxel, as summarized above. Early data show Division of Urology, The University of Texas Medical Branch, Galveston, TX,
that these novel therapies are well tolerated by patients and USA
are promising options for BCG-unresponsive disease [3,4].
However, current alternative treatments for BCG-naïve * Corresponding author. Division of Urology, Department of Surgery,
patients remain sparse. The results from the present study University of Texas Medical Branch, 301 University Boulevard, Galveston,
for a combination therapy that is readily available at most TX 77555, USA.
institutions represent an excellent RFS rate in comparison to

E-mail address: stbwilli@utmb.edu (S.B. Williams).
historical BCG data.
In addition to efficacy, it is important to consider the cost
of intravesical treatment for NMIBC. The median cost for
adjuvant BCG treatment of NMIBC is nearly $30 000 at 1 yr
and $55 000 at 2 yr [5]. Cost-effectiveness data are sparse
for alternative adjuvant intravesical therapies. However,
Re: Sperm Count is Increased by Diet-induced Weight Loss Experts’ summary:

and Maintained by Exercise or GLP-1 Analogue Treatment: Anderson et al. [1] analyzed the effects of weight loss on
A Randomized Controlled Trial sperm count, concentration, and motility. This was a ran-
domized controlled double-blind study in otherwise
Anderson E, Juhl CR, Kjoller ET, et al.
healthy men with body mass index (BMI) of 32–43 kg/m2
Hum Reprod 2022;37:1414–22 who were assigned to an initial 8-wk low-calorie diet fol-
lowed by randomization to either placebo, exercise, GLP1, dardized exercise regimen, treatment dosing schedule, and
or GLP1 + exercise groups for 52 wk. Semen samples were semen collection procedure. Whether these significant
collected initially, after the 8-wk low-calorie intervention, increases in sperm concentration and sperm count trans-
and after 52 wk. Sperm concentration increased 1.49 fold lated to improvements in fertility remains to be studied.
(95% confidence interval [CI] 1.18–1.88; p < 0.01) and total Nevertheless, we finally have solid evidence for recom-
sperm count 1.41-fold (95% CI 1.07–1.87; p < 0.01) after mending weight loss for male partners with low sperm
the 8-wk diet intervention. These improvements were sus- counts in couples who are attempting conception.
tained at 52 wk in participants who maintained their
weight loss but not in men who regained weight. No
Conflicts of interest: Soum Lokeshwar and Alexandra M. Geada have
changes were noted in semen volume, sperm motility, or
nothing to disclose. Ranjith Ramasamy is a consultant for Aytu Bio-
motile sperm count [1].
sciences, Boston Scientific, Coloplast, Endo Pharmaceuticals, and Nestle
Health Sciences; has received grants from Aytu Biosciences, Boston Scien-
Experts’ comments: tific, Coloplast, and Endo Pharmaceuticals; and is an investigator for
The authors present compelling evidence that sustained Direx.
weight loss can improve sperm concentration and overall
sperm count. It is reassuring that sperm count increased References
by almost 50% and was maintained after 1 yr in the men
who maintained their weight loss. This was a substudy for [1] Andersen E, Juhl CR, Kjøller ET, et al. Sperm count is increased by
diet-induced weight loss and maintained by exercise or GLP-1
men with obesity enrolled in the S-LiTE study that demon- analogue treatment: a randomized controlled trial. Hum Reprod
strated that the combination of exercise and liraglutide 2022;37:1414–22. https://doi.org/10.1093/humrep/deac096.
improved healthy weight loss maintenance more than [2] Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss
either intervention alone [2]. However, in the substudy, maintenance with exercise, liraglutide, or both combined. N Engl J
Med 2021;384:1719–30. https://doi.org/10.1056/NEJMoa2028198.
semen parameters beyond the initial improvement with
[3] Håkonsen LB, Linn Berger L, Thulstrup AM, et al. Does weight loss
diet-induced weight loss were not additionally improved improve semen quality and reproductive hormones? Results from a
by liraglutide or exercise. cohort of severely obese men. Reprod Health 2011;8:24. https://doi.
The findings from the S-LiTE substudy are consistent org/10.1186/1742-4755-8-24.
[4] Mir J, Franken D, Andrabi SW, Ashraf A, Rao K. Impact of weight loss
with previous studies. Håkonsen et al. [3] demonstrated
on sperm DNA integrity in obese men. Andrologia 2018;50:e12957.
improved semen parameters in obese men (BMI >33 kg/ [5] Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of
m2) where weight loss led to significantly increased sperm liraglutide on obesity-associated functional hypogonadism in men.
count, semen volume, testosterone, SHBG and AMH. Inter- Endocr Connect 2019;8:195–202. https://doi.org/10.1530/ec-18-
estingly, these findings were more significant for men with 0514.
[6] Lokeshwar SD, Patel P, Fantus RJ, et al. Decline in serum testosterone
the greatest weight loss. It has also been shown that weight
levels among adolescent and young adult men in the USA. Eur Urol
loss in obese men leads to an improvement in sperm DNA Focus 2021;7:886–9. https://doi.org/10.1016/j.euf.2020.02.006.
integrity, with a significant decrease in mean DFI observed
in men who lost weight [4]. Soum D. Lokeshwar a
The present study did not include the total testosterone Alexandra M. Geada b
(TT) level or the effect of the GLP1 receptor agonist and Ranjith Ramasamy c,*
weight loss on TT. Jensterle et al. [5] investigated the effects a
Department of Urology, Yale School of Medicine, New Haven, CT, USA
of liraglutide on obesity-associated functional hypogo- b
Department of Urology, Medical University of South Carolina, Charleston, SC,
nadism. In a cohort of 30 men, patients were randomized USA
to receive liraglutide or 1% transdermal gel testosterone c
Department of Urology, University of Miami Miller School of Medicine,
replacement therapy. Both cohorts experienced a significant Miami, FL, USA
increase in TT and the liraglutide cohort also had an average
* Corresponding author. Department of Urology, University of Miami
weight loss of 7.9 kg. TT levels in young adult men have
Miller School of Medicine, 1600 NW 10th Avenue #1140, Miami, FL 33136,
declined in the USA in the past two decades, with lower
USA.
TT associated with elevated BMI [6]. Given the close rela- E-mail address: ramasamy@miami.edu (R. Ramasamy).
tionship of TT to semen parameters and the seemingly
inverse rise in BMI and fall in TT, it would be interesting 0302-2838/Ó 2022 European Association of Urology. Published by
to see if TT levels in men in the S-LiTE study increased with Elsevier B.V. All rights reserved.
weight loss and correlated with semen parameters. https://doi.org/10.1016/j.eururo.2022.08.016
Regardless of the modest cohort size and the within- and
between-subject variation in semen parameters, the pre-
sent study was a randomized controlled trial with a stan-
Re: A Randomized, Single-blind Clinical Trial Comparing Experts’ summary:

Robotic-assisted Fluoroscopic-guided with Ultrasound- Hamamoto and colleagues introduced a novel robot-
guided Renal Access for Percutaneous Nephrolithotomy assisted fluoroscopy-guided (RAF) renal access procedure
Taguchi K, Hamamoto S, Okada A, et al. and tested it in this randomized, single-blind clinical trial
comparing surgical outcomes for 71 mini-percutaneous
nephrolithotomy (PCNL) procedures. The primary outcome
J Urol 2022;208:684–94
lowed by randomization to either placebo, exercise, GLP1, dardized exercise regimen, treatment dosing schedule, and
or GLP1 + exercise groups for 52 wk. Semen samples were semen collection procedure. Whether these significant
collected initially, after the 8-wk low-calorie intervention, increases in sperm concentration and sperm count trans-
and after 52 wk. Sperm concentration increased 1.49 fold lated to improvements in fertility remains to be studied.
(95% confidence interval [CI] 1.18–1.88; p < 0.01) and total Nevertheless, we finally have solid evidence for recom-
sperm count 1.41-fold (95% CI 1.07–1.87; p < 0.01) after mending weight loss for male partners with low sperm
the 8-wk diet intervention. These improvements were sus- counts in couples who are attempting conception.
tained at 52 wk in participants who maintained their
weight loss but not in men who regained weight. No
Conflicts of interest: Soum Lokeshwar and Alexandra M. Geada have
changes were noted in semen volume, sperm motility, or
nothing to disclose. Ranjith Ramasamy is a consultant for Aytu Bio-
motile sperm count [1].
sciences, Boston Scientific, Coloplast, Endo Pharmaceuticals, and Nestle
Health Sciences; has received grants from Aytu Biosciences, Boston Scien-
Experts’ comments: tific, Coloplast, and Endo Pharmaceuticals; and is an investigator for
The authors present compelling evidence that sustained Direx.
weight loss can improve sperm concentration and overall
sperm count. It is reassuring that sperm count increased References
by almost 50% and was maintained after 1 yr in the men
who maintained their weight loss. This was a substudy for [1] Andersen E, Juhl CR, Kjøller ET, et al. Sperm count is increased by
diet-induced weight loss and maintained by exercise or GLP-1
men with obesity enrolled in the S-LiTE study that demon- analogue treatment: a randomized controlled trial. Hum Reprod
strated that the combination of exercise and liraglutide 2022;37:1414–22. https://doi.org/10.1093/humrep/deac096.
improved healthy weight loss maintenance more than [2] Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss
either intervention alone [2]. However, in the substudy, maintenance with exercise, liraglutide, or both combined. N Engl J
Med 2021;384:1719–30. https://doi.org/10.1056/NEJMoa2028198.
semen parameters beyond the initial improvement with
[3] Håkonsen LB, Linn Berger L, Thulstrup AM, et al. Does weight loss
diet-induced weight loss were not additionally improved improve semen quality and reproductive hormones? Results from a
by liraglutide or exercise. cohort of severely obese men. Reprod Health 2011;8:24. https://doi.
The findings from the S-LiTE substudy are consistent org/10.1186/1742-4755-8-24.
[4] Mir J, Franken D, Andrabi SW, Ashraf A, Rao K. Impact of weight loss
with previous studies. Håkonsen et al. [3] demonstrated
on sperm DNA integrity in obese men. Andrologia 2018;50:e12957.
improved semen parameters in obese men (BMI >33 kg/ [5] Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of
m2) where weight loss led to significantly increased sperm liraglutide on obesity-associated functional hypogonadism in men.
count, semen volume, testosterone, SHBG and AMH. Inter- Endocr Connect 2019;8:195–202. https://doi.org/10.1530/ec-18-
estingly, these findings were more significant for men with 0514.
[6] Lokeshwar SD, Patel P, Fantus RJ, et al. Decline in serum testosterone
the greatest weight loss. It has also been shown that weight
levels among adolescent and young adult men in the USA. Eur Urol
loss in obese men leads to an improvement in sperm DNA Focus 2021;7:886–9. https://doi.org/10.1016/j.euf.2020.02.006.
integrity, with a significant decrease in mean DFI observed
in men who lost weight [4]. Soum D. Lokeshwar a
The present study did not include the total testosterone Alexandra M. Geada b
(TT) level or the effect of the GLP1 receptor agonist and Ranjith Ramasamy c,*
weight loss on TT. Jensterle et al. [5] investigated the effects a
Department of Urology, Yale School of Medicine, New Haven, CT, USA
of liraglutide on obesity-associated functional hypogo- b
Department of Urology, Medical University of South Carolina, Charleston, SC,
nadism. In a cohort of 30 men, patients were randomized USA
to receive liraglutide or 1% transdermal gel testosterone c
Department of Urology, University of Miami Miller School of Medicine,
replacement therapy. Both cohorts experienced a significant Miami, FL, USA
increase in TT and the liraglutide cohort also had an average
* Corresponding author. Department of Urology, University of Miami
weight loss of 7.9 kg. TT levels in young adult men have
Miller School of Medicine, 1600 NW 10th Avenue #1140, Miami, FL 33136,
declined in the USA in the past two decades, with lower
USA.
TT associated with elevated BMI [6]. Given the close rela- E-mail address: ramasamy@miami.edu (R. Ramasamy).
tionship of TT to semen parameters and the seemingly
inverse rise in BMI and fall in TT, it would be interesting 0302-2838/Ó 2022 European Association of Urology. Published by
to see if TT levels in men in the S-LiTE study increased with Elsevier B.V. All rights reserved.
weight loss and correlated with semen parameters. https://doi.org/10.1016/j.eururo.2022.08.016
Regardless of the modest cohort size and the within- and
between-subject variation in semen parameters, the pre-
sent study was a randomized controlled trial with a stan-
Re: A Randomized, Single-blind Clinical Trial Comparing Experts’ summary:

Robotic-assisted Fluoroscopic-guided with Ultrasound- Hamamoto and colleagues introduced a novel robot-
guided Renal Access for Percutaneous Nephrolithotomy assisted fluoroscopy-guided (RAF) renal access procedure
Taguchi K, Hamamoto S, Okada A, et al. and tested it in this randomized, single-blind clinical trial
comparing surgical outcomes for 71 mini-percutaneous
nephrolithotomy (PCNL) procedures. The primary outcome
J Urol 2022;208:684–94
was the success rate for single-puncture access, with sev- existing robotic surgical systems, PCNL would extraordinar-
eral other secondary outcomes considered (stone-free rate, ily benefit from a robotic system able to convey all the
complication rate, parameters measured during renal three-dimensional (3D) anatomical coordinates during per-
access, and fluoroscopy time). The RAF-guided access, sup- cutaneous access (ie, at the level of the target calyx), irrespec-
ported by an artificial intelligence (AI) platform for auto- tive of patient positioning. Technological developments in
mated needle targeting, was compared with the terms of 3D preoperative and intraoperative navigation,
traditional ultrasound-guided technique. There was no dif- robotics, AI, and robotic engineering will play a role in
ference in the single-puncture success rate between the endourology along the way paved by this pioneering study.
two groups. Moreover, the authors demonstrated a higher
success rate for percutaneous puncture performed by
untrained endourologists when the RAF technique was used
in comparison to the ultrasound technique (100% vs 86%;
References
p = 0.025). The stone-free rate and other secondary out-
comes were similar in both groups. [1] Lovegrove CE, Elhage O, Khan MS, et al. Training modalities in robot-
assisted urologic surgery: a systematic review. Eur Urol Focus
2017;3:102–16. https://doi.org/10.1016/j.euf.2016.01.006.
Experts’comments: [2] Hughes T, Ho HC, Pietropaolo A, Somani BK. Guideline of guidelines
During the past 20 yr, the introduction of robotic surgery for kidney and bladder stones. Turk J Urol 2020;46(Suppl 1):S104–12.
in urology has enhanced the development of more struc- [3] de la Rosette J, Laguna MP, Rassweiler JJ, Conort P. Training in
percutaneous nephrolithotomy—a critical review. Eur Urol
tured procedural curricula and led to improvements in sur-
2008;54:994–1001.
gical training [1]. By contrast, the major technological [4] Tepeler A, Armağan A, Akman T, et al. Impact of percutaneous renal
advances in endourology were not prompted by robotics. access technique on outcomes of percutaneous nephrolithotomy. J
In this setting, PCNL involves several challenges, mainly Endourol 2012;26:828–33. https://doi.org/10.1089/end.2011.0563.
owing to the lack of standardization and the many technical
Eugenio Ventimiglia a,b,*
variations in positioning and execution. Thus, after more
Christian Corsini a,b
than 40 yr since its first description, the major concern hin-
Francesco Montorsi a,b
dering PCNL diffusion is still the steep learning curve, espe- Andrea Salonia a,b
cially when it comes to achieving appropriate renal access Ioannis Kartalas Goumas c
[2,3]. Therefore, the authors should be commended for
a
introducing and testing a semi-robotic approach to percuta- Division of Experimental Oncology/Unit of Urology, Urological Research
neous renal access. Here we try to explain the possible lim- Institute, IRCCS Ospedale San Raffaele, Milan, Italy
b
Vita-Salute San Raffaele University, Milan, Italy
itations of this approach and how an endourological robotic c
Department of Urology, Istituto Clinico Beato Matteo, Vigevano, Italy
strategy could be implemented.
The authors developed a device assisting percutaneous * Corresponding author. Division of Experimental Oncology/Unit of Urol-
puncture according to the so-called bull’s eye technique, ogy, Urological Research Institute, IRCCS Ospedale San Raffaele, Via
which is known to be the simplest one to learn and master Olgettina 60, 20132 Milan, Italy.
[4]. Since the comparison arm of the study involved ultra- E-mail address: eugenio.ventimiglia@gmail.com (E. Ventimiglia).
sound-guided puncture, it is difficult to argue that the advan-
tages reported are actually related to robotic assistance 0302-2838/Ó 2022 European Association of Urology. Published by
rather than to the technique itself. Moreover, possible short- Elsevier B.V. All rights reserved.
comings of this technique are the greater X-ray exposure and https://doi.org/10.1016/j.eururo.2022.08.021
the complexity of adapting it to supine PCNL. In relation to
Re: MRI-guided Focused Ultrasound Focal Therapy for cer in the treated area, and only one grade 3 adverse event.
Patients with Intermediate-risk Prostate Cancer: A Phase However, 60% of the patients enrolled in the trial had resid-
2b, Multicentre Study ual cancer in their prostate on repeat biopsy, and 40% of
these cancers were GG 2. Nevertheless, on the basis of
Ehdaie B, Tempany CM, Holland F, et al.
their defined primary endpoint, the authors conclude that
Lancet Oncol 2022;23:910–8 this approach is both safe and effective for treating GG 2
and GG 3 cancers.
Experts’ summary:
Experts’ comments:
The authors conducted a trial in which 194 patients were
While any technology that can improve a patient’s quantity
assessed for eligibility and 101 patients, 79 with grade
or quality of life should be welcomed, the authors’ conclu-
group 2 (GG 2) and 22 with GG 3 prostate cancer, were trea-
sion that focal therapy is ‘‘safe and effectively treats grade
ted with magnetic resonance imaging–guided focused
group 2 or 3 prostate cancer’’ is of real concern given their
ultrasound ablation. The joint primary outcomes were (1)
data.
efficacy, defined by the authors as the absence of GG 2
First, it is necessary to distinguish a technology that can
cancer in the treated area on prostate biopsy 6 mo and 24
ablate prostate tissue from one that provides a patient ben-
mo after treatment, and (2) adverse events. The authors
efit. The primary endpoint of 88% of men having no GG 2
report that at 24 mo, 88% of the patients had no GG 2 can-
was the success rate for single-puncture access, with sev- existing robotic surgical systems, PCNL would extraordinar-
eral other secondary outcomes considered (stone-free rate, ily benefit from a robotic system able to convey all the
complication rate, parameters measured during renal three-dimensional (3D) anatomical coordinates during per-
access, and fluoroscopy time). The RAF-guided access, sup- cutaneous access (ie, at the level of the target calyx), irrespec-
ported by an artificial intelligence (AI) platform for auto- tive of patient positioning. Technological developments in
mated needle targeting, was compared with the terms of 3D preoperative and intraoperative navigation,
traditional ultrasound-guided technique. There was no dif- robotics, AI, and robotic engineering will play a role in
ference in the single-puncture success rate between the endourology along the way paved by this pioneering study.
two groups. Moreover, the authors demonstrated a higher
success rate for percutaneous puncture performed by
untrained endourologists when the RAF technique was used
in comparison to the ultrasound technique (100% vs 86%;
References
p = 0.025). The stone-free rate and other secondary out-
comes were similar in both groups. [1] Lovegrove CE, Elhage O, Khan MS, et al. Training modalities in robot-
assisted urologic surgery: a systematic review. Eur Urol Focus
2017;3:102–16. https://doi.org/10.1016/j.euf.2016.01.006.
Experts’comments: [2] Hughes T, Ho HC, Pietropaolo A, Somani BK. Guideline of guidelines
During the past 20 yr, the introduction of robotic surgery for kidney and bladder stones. Turk J Urol 2020;46(Suppl 1):S104–12.
in urology has enhanced the development of more struc- [3] de la Rosette J, Laguna MP, Rassweiler JJ, Conort P. Training in
percutaneous nephrolithotomy—a critical review. Eur Urol
tured procedural curricula and led to improvements in sur-
2008;54:994–1001.
gical training [1]. By contrast, the major technological [4] Tepeler A, Armağan A, Akman T, et al. Impact of percutaneous renal
advances in endourology were not prompted by robotics. access technique on outcomes of percutaneous nephrolithotomy. J
In this setting, PCNL involves several challenges, mainly Endourol 2012;26:828–33. https://doi.org/10.1089/end.2011.0563.
owing to the lack of standardization and the many technical
Eugenio Ventimiglia a,b,*
variations in positioning and execution. Thus, after more
Christian Corsini a,b
than 40 yr since its first description, the major concern hin-
Francesco Montorsi a,b
dering PCNL diffusion is still the steep learning curve, espe- Andrea Salonia a,b
cially when it comes to achieving appropriate renal access Ioannis Kartalas Goumas c
[2,3]. Therefore, the authors should be commended for
a
introducing and testing a semi-robotic approach to percuta- Division of Experimental Oncology/Unit of Urology, Urological Research
neous renal access. Here we try to explain the possible lim- Institute, IRCCS Ospedale San Raffaele, Milan, Italy
b
Vita-Salute San Raffaele University, Milan, Italy
itations of this approach and how an endourological robotic c
Department of Urology, Istituto Clinico Beato Matteo, Vigevano, Italy
strategy could be implemented.
The authors developed a device assisting percutaneous * Corresponding author. Division of Experimental Oncology/Unit of Urol-
puncture according to the so-called bull’s eye technique, ogy, Urological Research Institute, IRCCS Ospedale San Raffaele, Via
which is known to be the simplest one to learn and master Olgettina 60, 20132 Milan, Italy.
[4]. Since the comparison arm of the study involved ultra- E-mail address: eugenio.ventimiglia@gmail.com (E. Ventimiglia).
sound-guided puncture, it is difficult to argue that the advan-
tages reported are actually related to robotic assistance 0302-2838/Ó 2022 European Association of Urology. Published by
rather than to the technique itself. Moreover, possible short- Elsevier B.V. All rights reserved.
comings of this technique are the greater X-ray exposure and https://doi.org/10.1016/j.eururo.2022.08.021
the complexity of adapting it to supine PCNL. In relation to
Re: MRI-guided Focused Ultrasound Focal Therapy for cer in the treated area, and only one grade 3 adverse event.
Patients with Intermediate-risk Prostate Cancer: A Phase However, 60% of the patients enrolled in the trial had resid-
2b, Multicentre Study ual cancer in their prostate on repeat biopsy, and 40% of
these cancers were GG 2. Nevertheless, on the basis of
Ehdaie B, Tempany CM, Holland F, et al.
their defined primary endpoint, the authors conclude that
Lancet Oncol 2022;23:910–8 this approach is both safe and effective for treating GG 2
and GG 3 cancers.
Experts’ summary:
Experts’ comments:
The authors conducted a trial in which 194 patients were
While any technology that can improve a patient’s quantity
assessed for eligibility and 101 patients, 79 with grade
or quality of life should be welcomed, the authors’ conclu-
group 2 (GG 2) and 22 with GG 3 prostate cancer, were trea-
sion that focal therapy is ‘‘safe and effectively treats grade
ted with magnetic resonance imaging–guided focused
group 2 or 3 prostate cancer’’ is of real concern given their
ultrasound ablation. The joint primary outcomes were (1)
data.
efficacy, defined by the authors as the absence of GG 2
First, it is necessary to distinguish a technology that can
cancer in the treated area on prostate biopsy 6 mo and 24
ablate prostate tissue from one that provides a patient ben-
mo after treatment, and (2) adverse events. The authors
efit. The primary endpoint of 88% of men having no GG 2
report that at 24 mo, 88% of the patients had no GG 2 can-
cancer in their targeted region at 24 mo is a technology cial stability at risk by treating these patients with focal
question, not a patient-focused one. Whether focal therapy therapy outside of a clinical trial. Rather, we support the
effectively treats patients with GG 2 cancer is unclear at conduct of appropriately designed randomized trials with
best, when 40% of patients still had GG 2 cancer on biopsy clinically meaningful endpoints to determine if focal ther-
at just 24 mo after treatment. Among men with GG 3 can- apy truly is safe and effective compared to standard of care
cer, 59% had residual GG 2 cancer remaining. The absence therapies.
of any benefit from treatment for such a high proportion of
men, particularly those with GG 3 cancers, is highly prob-
Conflicts of interest: WAH reports research and travel support
lematic. Furthermore, these numbers are almost surely
provided to institution from Elekta AB, Stockholm, Sweden.
underestimates of residual disease given the known proba-
bility of undersampling from biopsy. As these patients had a References
median age of 63 years, it seems very likely that the major-
ity will require radical therapy. For comparison, the positiv- [1] Zelefsky MJ, Kollmeier M, McBride S, et al. Five-year outcomes of a
ity rate for whole-gland prostate biopsy after modern phase 1 dose-escalation study using stereotactic body radiosurgery
prostate radiotherapy is 7–8% [1]. Thus, to suggest that for patients with low-risk and intermediate-risk prostate cancer. Int J
Radiat Oncol Biol Phys 2019;104:42–9. https://doi.org/10.1016/j.
these data support focal therapy as being effective regard- ijrobp.2018.12.045.
ing a true patient benefit is premature at best. [2] Klotz L. Active surveillance in intermediate-risk prostate cancer. BJU
Second, what is deemed safe is relative to the current Int 2020;125:346–54. https://doi.org/10.1111/bju.14935.
standard of care. When the bar for many of these men is [3] Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation
therapy for localized prostate cancer: a systematic review and meta-
active surveillance, almost any toxicity is of concern [2].
analysis of over 6,000 patients treated on prospective studies. Int J
The current study reports a grade 3 toxicity rate of 1% Radiat Oncol Biol Phys 2019;104:778–89. https://doi.org/10.1016/j.
from focal therapy, and grade 1–2 toxicity rates of 15% ijrobp.2019.03.051.
for hematuria, urinary incontinence, and urinary retention. [4] Kishan AU, Dang A, Katz AJ, et al. long-term outcomes of stereotactic
Although not graded as a toxicity, 100% of patients would body radiotherapy for low-risk and intermediate-risk prostate cancer.
JAMA Netw Open 2019;2:e188006. https://doi.org/10.1001/
be considered to have experienced grade 2 toxicity from jamanetworkopen.2018.8006.
catheter placement, something not required with external [5] Thompson JE, Sridhar AN, Shaw G, et al. Peri-operative, functional
beam radiotherapy. Of note, contemporary trials of image- and early oncologic outcomes of salvage robotic-assisted radical
guided radiotherapy also report grade 3 toxicity rates of prostatectomy after high-intensity focused ultrasound partial
ablation. BMC Urol 2020;20:81. https://doi.org/10.1186/s12894-
1%, and neither radical prostatectomy nor radiotherapy
020-00656-9.
require serial biopsies [3,4]. Perhaps more importantly,
the high rates of residual tumor after focal therapy will William A. Hall a,*
necessitate frequent use of salvage therapies. The true Jonathan Shoag b,c
safety of salvage therapy after focal therapy is not estab- Daniel E. Spratt d
lished with quality evidence, and concerns regarding
a
increased toxicity have been reported [5]. The true safety Department of Radiation Oncology, Medical College of Wisconsin,
Milwaukee, WI, USA
of focal therapy, especially when 60% of patients have resid- b
Department of Urology, University Hospitals Cleveland Medical Center, Case
ual cancer in their prostate gland 24 mo after treatment, Western Reserve University School of Medicine, Cleveland, OH, USA
must take into account the additional cost and toxicity of c
Department of Urology, New York-Presbyterian Hospital, Weill Cornell
radical salvage therapy over long-term follow-up. Thus, Medicine, New York, NY, USA
d
we would argue that safety has not been established, as Department of Radiation Oncology, University Hospitals Seidman Cancer
the majority of these men will require further local therapy Center, Case Western Reserve University, Cleveland, OH, USA
with an unknown side-effect profile.
* Corresponding author. Department of Radiation Oncology, Medical
In summary, we believe that the conclusions regarding College of Wisconsin, 8701 W Watertown Plank Rd,
the safety and efficacy of this therapy are inaccurate. In Milwaukee, WI 53226, USA.
our view, the current study demonstrated that focal ther- E-mail address: whall@mcw.edu (W.A. Hall).
apy, even in this highly selected patient population,
resulted in unacceptably high rates of residual cancer and 0302-2838/Published by Elsevier B.V. on behalf of European Association
toxicity, both of which are expected to increase with longer of Urology.
follow-up. Before adopting an experimental therapy not https://doi.org/10.1016/j.eururo.2022.08.027
endorsed by national guidelines that lacks even level 2 evi-
dence, we urge the genitourinary oncology community to
not put patients’ quality of life, long-term health, and finan-
Research Letter
BlaDimiR: A Urine-based miRNA Score for Accurate Bladder Cancer

Diagnosis and Follow-up
Cristian Suarez-Cabrera a,b,c,*, Lidia Estudillo d, Erik Ramón-Gil a, Mónica Martı́nez-Fernández a,b,c,y,
Jorge Peral c, Carolina Rubio a,b,c, Iris Lodewijk a,b,c, Álvaro Martı́n de Bernardo c,
Ramón Garcı́a-Escudero a,b,c, Felipe Villacampa e,à, José Duarte e, Federico de la Rosa e,
Daniel Castellano e, Félix Guerrero-Ramos e, Francisco X. Real b,f,g, Núria Malats b,d,
Jesús M. Paramio a,b,c, Marta Dueñas a,b,c,*
Bladder cancer (BC) represents a clinical and social chal- two-miRNA signature able to accurately discriminate BC
lenge owing to its high incidence and frequent recurrences, patients from healthy individuals. To evaluate the diagnos-
as well as the limited advances in disease management [1]. tic performance of this signature in urine, we carried out a
Current noninvasive diagnostic strategies, such as urine two-stage analysis. We first used a proof-of-concept study
cytology, offer specificity close to 85% but sensitivity close cohort (cohort 3; n = 143) to validate the test and then con-
to 44% [2,3], making cystoscopy the gold standard for diag- firmed the results using a blinded validation cohort (cohort
nosis and follow-up of BC patients. However, even though 4; n = 82) comprising samples from urological patients
cystoscopy achieves 85–90% sensitivity in detecting exo- showing symptoms suspicious of BC, with (prevalent) or
phytic tumours, it is operator-dependent, with a high rate without (incident) a history of a prior bladder tumour
of false-positive results, and its performance is limited for (Fig. 1A).
the diagnosis of flat lesions (65–70% sensitivity). In addi- Cohort 1 was used to carry out a microarray-based tran-
tion, after cystoscopy, more than 20% of patients experience scriptome study, in which 201 miRNAs were detected. This
micturition-related symptoms >48 h after the procedure study revealed 34 miRNAs with statistically significant dif-
[4]. Thus, BC is the tumour with the highest lifetime cancer ferential expression between normal (n = 10) and tumour
management cost per patient for health systems. BC also (n = 28) tissue samples after adjustment of p values. Of
has an extremely negative impact on patients’ quality of life these miRNAs, 18 were overexpressed and 16 were under-
[5]. expressed in tumours compared to normal bladder tissue
Against this background, there is an urgent need for (Fig. 1B). We next validated 33 of these miRNAs in cohort
diagnostic and follow-up procedures that improve BC man- 2 (41 normal-tumour tissue paired samples) using reverse
agement and decrease the morbidity associated with cur- transcription-qualitative polymerase chain reaction (RT-
rent methods. This has led to the development of several qPCR), and found that all were differentially expressed
urine-based diagnostic kits [3]. However, even tests with (Fig. 1B). As our aim was to develop a diagnostic system that
sensitivity higher than that of cytology have lower speci- could be easily translated into clinical practice, we selected
ficity, hindering their ability to replace the gold-standard a small set of miRNAs consisting of the top differentially
combination to date [6]. expressed miRNAs (the most significant adjusted p values
In the present study, we used four study cohorts to iden- and the highest fold change and area under the receiving
tify and validate miRNAs with excellent diagnostic perfor- operating characteristic [ROC] curve [AUC] values). Among
mance in urine samples. The first two cohorts were used the underexpressed miRNAs, miR-145, miR-143, miR-
to identify (cohort 1; n = 38) and validate (cohort 2; n = 125b, and miR-99a had AUC values >0.85; among the over-
82) miRNAs differentially expressed in tumours compared expressed miRNAs, miR-182, and miR-96 had AUC values
to normal urothelial tissue, from which we identified a >0.85 (all p < 0.001; Fig. 1B). However, since miR-143 and
y
Present address: Translational Molecular Unit, Galicia Sur Health Research Institute, Vigo, Spain.
à
Present address: Urology Department, Clínica Universidad de Navarra, Madrid, Spain.
C <0.001
D Cohort 2: Tissue samples Cohort 3: Urine samples
40 0.009
35 0.002 20 1.5 1.8
<0.001
Ratio Ct miR-145/miR-182
<0.001
miR-145 Urine (Ct)
miR-182 Urine (Ct)
1.6
Logit(p) values
35
30 10 1.0
1.4
30 1.2
25 0 0.5
1.0
25
20 -10 0.0 0.8
Healthy Tumour
Healthy Tumour Healthy Tumour Tumour Normal Healthy Tumour
tissue tissue
AUC = 0.66 AUC = 0.7 AUC = 0.91 AUC = 1 AUC = 0.97

100 100 100 100 100
80 80 80 80 80
Sensitivity (%)
Sensitivity (%)
Sensitivity (%)
Sensitivity (%)
Sensitivity (%)
60 60 60 60 60
40 40 40 40 40
20 20 20 20 20
0 0 0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
100 − specificity (%) 100 − specificity (%) 100 − specificity (%) 100 − specificity (%) 100 − specificity (%)
Fig. 1 – Identification of BC-associated miRNAs. (A) Sample set description. Scheme showing the four study cohorts used in the study. Patient age is shown as
the median (range). (B) Differential miRNA expression profiling and tissue validation. List of 18 overexpressed (pink) and 16 underexpressed (blue) miRNAs in
tumours compared to normal bladder tissue (obtained from the tissue discovery cohort). For the discovery cohort, log2FC and adjusted p values are shown.
For the validation cohort, statistical differences and AUC values and their significance are shown. Validation results with a significant difference (p < 0.001)
are displayed in bold. (C) Comparison of Ct values for miR-145 and miR-182 and the logit(p) values [logit(p) = (1.905 3 CtmiR-145) - (2.055 3 CtmiR-182) - 0.48] for
urine between healthy donors and BC patients (proof-of-concept cohort 3) and the corresponding ROC curves. (D) Ratios of Ct values for the best miRNAs for
comparison between normal and tumour tissue (tissue validation cohort 2) and urine from healthy donors and BC patients (proof-of-concept cohort 3), and
the corresponding ROC curves. In C and D, median (interquartile range) values are shown. BC = bladder cancer; Ct = cycle threshold; FC = fold change; M =
male; F = female; HG = high grade; LG = low grade; Tx = unknown stage; NA = not assigned; N.D. = not determined; ROC = receiver operating characteristic; AUC
= area under the ROC curve.
A Urine proof-of-concept cohort (cohort 3)

Total cohort BC pa ents Healhy donors Total AUC= 0.97
Posi ve 109 2 111 Sensi vity= 92%
Nega ve 10 22 32 Specificity= 92%
Total 119 24 143 PPV= 98%
NPV= 69%
Urine valida on cohort (cohort 4)
Total cohort BC pa ents Urological controls Total AUC= 0.96
Total 40 42 82 PPV= 86%
NPV= 92%
Incident cases BC pa ents Urological controls Total AUC= 0.96
Total 19 21 40 PPV= 86%
NPV= 95%
Prevalent cases BC pa ents Urological controls Total AUC= 0.95
Total 21 21 42 PPV= 86%
NPV= 90%
B C D
Total 1.8 Incident Prevalent
1.8
1.8
<0.001
<0.0001 <0.001
<0.0001 <0.001
<0.0001
1.6
1.6 1.6
1.4
1.4 1.4
1.2 1.2
1.2
1.0 1.0
1.0
0.8 0.8
0.8
Urological BC Urological BC Urological BC
controls patients controls patients controls patients
AUC= 0.96 AUC= 0.96 AUC= 0.95

100 100 100
80
Sensitivity (%)
80
Sensitivity (%)
80
Sensitivity (%)
60 60 60
40 40 40
20 20 20
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
100 − specificity (%) 100 − specificity (%)
100 − specificity (%)
E Haematuria
<0.0001
<0.001
<0.0001
<0.001
Grade Risk
1.8 0.6440
0.6 <0.0001
<0.0001
<0.001 1.8 <0.001
1.8
0.9954
>0.9 <0.0001
<0.001 0.9326
>0.9
1.6 0.7364 0.2230 Urological controls
0.7 0.2 1.6 <0.001 0.9780
<0.0001 >0.9 Low risk
1.6
1.4
Intermediate risk
1.4
1.4 High risk
1.2
1.2 Very high risk
1.2
1.0
pT2 pTaG2
1.0 pTa 1.0
pT1 pT1G3
0.8
Haematuria No Haematuria No
haemaeturia haematuria 0.8 0.8
G1 G2 G3 Urological LR HR
BC patients Urological controls controls
Fig. 2 – BlaDimiR validation. (A) Summary of BlaDimiR assay results and diagnostic predictive values in the two urine cohorts. (B–D) Comparison of the miR-
145/miR-182 ratio for urine between urological controls and bladder cancer (BC) patients and the corresponding receiver operating characteristic curves in
the blinded validation cohort for (B) the total cohort, (C) incident cases, and (D) prevalent cases (D). Dashed lines represent the diagnostic threshold for the
BlaDimiR system. (E) Comparison of the miR-145/miR-182 cycle threshold (Ct) ratio for urine from BC patients and urological controls with or without
haematuria, with different histological tumour grades and low risk (LR) or high risk (HR) of recurrence and progression. Dot plots show the median
(interquartile range). AUC = area under the receiver operating characteristic curve; PPV = positive predictive value; NPV = negative predictive value.
miR-145 are part of a bicistronic transcript in which miR- and high-grade tumours (Fig. 2E and Supplementary
145 fared better, we decided to exclude miR-143. Fig. 2B). BlaDimiR was also able to detect low-risk tumours
On the basis of the results, we evaluated these biomark- with very similar accuracy to that for high-risk BC, missing
ers in a proof-of-concept cohort (cohort 3) of urine samples just two out of 11 high-risk tumours (Fig. 2E and Supple-
from BC patients (n = 119) and healthy donors (n = 24). After mentary Fig. 2C). Comparison of BlaDimiR results with cys-
obtaining cycle threshold (Ct) values for the different miR- toscopy (or other imaging techniques) and cytology used as
NAs in urine samples, we carried out a logistic regression the gold standard proved very good diagnostic accuracy
analysis as a classification model to determine which miR- with an overall improvement in classification of BC and con-
NAs showed potential predictive capacity in this biofluid trols (Supplementary Fig. 3).
(Supplementary Fig. 1). Only miR-145 and miR-182 showed In summary, we have developed BlaDimiR, a new diag-
statistically significant diagnostic predictive performance (p nostic system based on quantification of only two miRNAs
< 0.01 in both cases), with the following linear relationship: (miR-145 and miR-182). BlaDimiR has unprecedented BC
logit(p) = (1.905 CtmiR-145) (2.055 CtmiR-182) 0.48 diagnostic accuracy and could easily be implemented in
(Supplementary Fig. 1). By applying this equation to obtain any molecular pathology laboratory. miR-145 has been
the corresponding predictive score, we were able to classify described as a tumour suppressor in BC and is reported to
BC patients and healthy donors with an AUC of 0.91 (p < be underexpressed in more aggressive disease [8] with a
0.0001), in contrast to AUCs obtained with independent Ct direct regulation effect on FCS1 expression [9]. It has also
values for miR-145 (0.66) and miR-182 (0.7) alone been found that miR-182 is significantly higher in BC tissues
(Fig. 1C). However, since Ct values are not normalised, RT- than in normal urothelium and is associated with shorter
qPCR variations and technical errors could affect the results overall survival [10] and with BC in urine samples [11].
and lead to variability in the parameters or coefficients The BlaDimiR diagnostic method has specificity values com-
associated with each miRNA. For that reason and to meet parable to those reported for cytology, and sensitivity val-
the need for a good normalisation factor for urine samples ues even higher than those obtained with cystoscopy, and
[7], we hypothesised that use of a combination (as a ratio) better than those achieved with almost all diagnostic tests
of an overexpressed and an underexpressed miRNA in the based on detection of molecular markers in urine previously
same RNA sample from a BC patient could be a good described [3,12]. Despite the small sample sizes in the dis-
within-sample normalisation method. Thus, we evaluated covery and proof-of-concept phases, the robust results
the diagnostic performance of the miR-145/miR-182 ratio obtained indicate a good diagnostic prediction system. It
in cohort 2 (tissue) and cohort 3 (urine). We obtained an is noteworthy that this diagnostic precision was confirmed
AUC of 1 (100% sensitivity and specificity) for tissue sam- using a study design aimed at establishing diagnostic accu-
ples from cohort 2, and an AUC of 0.97 (92% sensitivity racy in patients with a suspicion of BC, with minor impact of
and specificity, with a positive predictive value [PPV] of the presence of haematuria, demonstrating very good diag-
98% and negative predictive value [NPV] of 69%) for urine nostic accuracy for detection of low- and high-risk tumours
samples from cohort 3 (Fig. 1D). In this way, we maximised and with positive results independent of the occurrence of a
the discriminating capacity of both markers, as well as the previous tumour. This is an unprecedented advantage, since
score obtained via the regression model, and solved possible most of the tests described to date show lower performance
associated technical problems. On the basis of these results, for recurrent than for de novo cases [13]. The most impor-
the miR-145/miR-182 score was selected for further valida- tant limitations of the study are the small sample size and
tion and designated as a new diagnostic assay called BlaDi- its single-centre nature. In this regard, further validation
miR (bladder diagnostic miRNAs). in a real-world setting is needed, and we are now focused
We next carried out a blind evaluation of BlaDimiR for BC on generating a larger and multicentre study to further val-
diagnosis using cohort 4, including 82 urine samples from idate the robustness of the diagnostic accuracy.
urological patients (detailed description in Fig. 1A). Using The excellent diagnostic performance of BlaDimiR, com-
the previous cutoff value for cohort 3 (>1.11), we found very bined with very good correspondence to gold-standard
high diagnostic accuracy for BlaDimiR assay in this cohort, techniques, could also reduce the frequency of current inva-
with an AUC of 0.96, sensitivity of 93%, and specificity of sive follow-up tests in daily clinical practice if replaced by
86% (Fig. 2A,B). Using this threshold, we missed only three this noninvasive, urine-based, easy, inexpensive, and robust
out of 40 BC cases and misdiagnosed six cases as BC for system.
patients who did not have a tumour (3 incident and 3 preva-
lent). Moreover, the BlaDimiR assay was equally good for Conflicts of interest: The authors have nothing to disclose.
diagnosis of BC in the incident and prevalent cohorts, with
an AUC of 0.96 and 0.95, respectively (Fig. 2C,D), and sensi- Funding/Support and Role of Sponsor: This study was supported by Insti-
tivity, specificity, PPV and NPV 85% in both groups tuto de Salud Carlos III (DTS20/00043 to Marta Dueñas) and was co-
(Fig. 2A). BlaDimiR performance was largely unaffected by funded by grants from the European Regional Development Fund for
the occurrence of microscopic or macroscopic haematuria, Science and Innovation (SAF2015-66015-R and PID2019-110758RB-I00
with very high albeit slightly lower predictive accuracy to Jesús M. Paramio) and Instituto de Salud Carlos III (CIBERONC no.
(Fig. 2E and Supplementary Fig. 2A). Importantly, the diag- CB16/12/00228 to Jesús M. Paramio, CB16/12/00452 to Núria Malats,
nostic accuracy of BlaDimiR was not affected by tumour and CB16/12/00453 to Francisco X. Real). Iris Lodewijk is supported by
grade, with very similar performance observed for low- a predoctoral fellowship from the Spanish Association against Cancer
(grant number PRDMA19024LODE). Mónica Martínez-Fernández is sup- systematic review. J Urol 2003;169:1975–82. 10.1097/01.ju.
ported by the Miguel Servet programme (CP20/00188) of Instituto de 0000067461.30468.6d.
[7] Martínez-Fernández M, Paramio JM, Dueñas M. RNA detection in
Salud Carlos III and the European Social Fund (‘‘Investing in your future’’).
urine: from RNA extraction to good normalizer molecules. J Mol
Diagn 2016;18:15–22. 10.1016/j.jmoldx.2015.07.008.
[8] Dip Júnior NG, Reis ST, Srougi M, Dall’Oglio MF, Leite KRM. Expression
Ethical considerations: Informed consent was obtained from all patients
profile of microRNA-145 in urothelial bladder cancer. Int Braz J Urol
and the studies were approved by the ethics committee for clinical 2013;39:95–101. 10.1590/S1677-5538.ibju.2013.01.12.
research of University Hospital 12 de Octubre (CEIC: 12/196; 18/426; [9] Chiyomaru T, Enokida H, Tatarano S, et al. miR-145 and miR-133a
16/139). The informed consent was also approved by the local ethics function as tumour suppressors and directly regulate FSCN1
expression in bladder cancer. Br J Cancer 2010;102:883–91.
committee.
10.1038/sj.bjc.6605570.
[10] Hirata H, Ueno K, Shahryari V, et al. Oncogenic miRNA-182-5p
targets Smad4 and RECK in human bladder cancer. PLoS One
Data-sharing statement: Data sets for the miRNA expression microarray
2012;7:e51056.
analyses have been deposited in GEO as GSE38264 (https://www.ncbi. [11] Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine
nlm.nih.gov/geo/query/acc.cgi?acc=GSE38264). microRNA as tumor marker: microRNA-126 and microRNA-182 are
related to urinary bladder cancer. Urol Oncol 2010;28:655–61.
10.1016/j.urolonc.2009.01.027.
Peer Review Summary [12] Zhu CZ, Ting HN, Ng KH, Ong TA. A review on the accuracy of
bladder cancer detection methods. J Cancer 2019;10:4038–44.
10.7150/jca.28989.
Peer Review Summary and Supplementary data to this arti- [13] Ribal MJ, Mengual L, Lozano JJ, et al. Gene expression test for the
cle can be found online at https://doi.org/10.1016/j.eururo. non-invasive diagnosis of bladder cancer: a prospective, blinded,
2022.08.011. international and multicenter validation study. Eur J Cancer
2016;54:131–8. 10.1016/j.ejca.2015.11.003.
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EUROPEAN UROLOGY 82 (2022) e165–e166
Letter to the Editor
Re: James W.F. Catto, Pramit Khetrapal, Federico Ricciardi, threshold, the latest European Association of Urology guide-
et al. Effect of Robot-assisted Radical Cystectomy with lines suggest that a patient should not be denied a neoblad-
Intracorporeal Urinary Diversion vs Open Radical der on the basis of age alone. Elderly patients derive the
Cystectomy on 90-Day Morbidity and Mortality Among greatest benefit from robotic RC, with an advantage in
Patients with Bladder Cancer: A Randomized Clinical Trial. terms of length of stay that exceeds the benefit for younger
JAMA 2022;327:2092–103 patients [3].
Physical recovery was faster in the iROC robotic arm,
with less disability and better chair-to-stand test results
Radical cystectomy (RC) is a complex surgical procedure.
at 5 and 12 wk. These secondary endpoints took 26 wk to
The main aim of minimally invasive surgery is to minimize
become comparable between approaches.
surgical morbidity and improve recovery. The iROC trial
Given the faster recovery, patients undergoing robotic
compared the open and robotic approaches for RC and
surgery may be at higher risk of decisional regret concern-
demonstrates an advantage of robotics in terms of days alive
ing the diversion type. In the perioperative period, the pri-
and out of the hospital over 90 d [1]. The benefits were evi-
mary concern relates to cancer treatment, whereas patient
dent immediately after surgery in the trial, in which all
priorities focus primarily on regaining a sense of normalcy
robotic diversions were performed intracorporeally, thus
and quality of life thereafter [4]. A better body image and
reducing peritoneal exposure and improving tissue
faster physical functioning may support higher quality of
handling.
life with orthotopic diversions [4].
The authors should be commended for this randomized
Furthermore, it should be noted that the indications for
clinical trial and for the use of intracorporeal reconstruction
RC have been expanded in recent years. With the inclusion
for the diversion, a major strength that overcomes the main
of non–muscle-invasive disease at high risk of progression,
limit of the previous RAZOR trial (use of extracorporeal
a larger number of long-term RC survivors are expected and
diversion); however, it should be noted that only 11%
patient awareness about all the diversion types available is
patients in iROC underwent neobladder reconstruction in
required to limit decisional regret.
both the open arm and the robotic arm. The rate is consis-
In this setting, mastering of all reconstructive tech-
tent with recent national reports that showed a decrease
niques—regardless of the surgical approach—is the very
in utilization of orthotopic diversions over time coinciding
basis for providing balanced counseling and guiding the
with the spread of minimally invasive techniques [2].
selection for each individual patient.
The rate of neobladder reconstruction in iROC seems to
be low given the mean age of patients (69 yr), the propor-
tion of cases with an Eastern Cooperative Oncology Group Conflicts of interest: The authors have nothing to disclose.
performance score of 0 (81%), and the renowned expertise

of the surgeons. No oncological explanation can be inferred, References
as 50% of patients had pT0 or non–muscle-invasive bladder
[1] Catto J, Khetrapal P, Ricciardi F, et al. Effect of robot-assisted radical
cancer (pTis/pTa/pT1) and only 8% had a positive surgical cystectomy with intracorporeal urinary diversion vs open radical
margin. cystectomy on 90-day morbidity and mortality among patients with
From an oncological standpoint, orthotopic substitution bladder cancer: a randomized clinical trial. JAMA 2022;327:
and conduit diversion are similar in terms of local or distant 2092–103. 10.1001/jama.2022.7393.
[2] Almassi N, Bochner BH. Ileal conduit or orthotopic neobladder:
metastasis, except for secondary urethral recurrences,
selection and contemporary patterns of use. Curr Opin Urol 2020;30:
which are less common for neobladder (1.5–7%) [3]. How- 415–20. 10.1097/MOU.0000000000000738.
ever, some reasons support the use of an orthotopic diver- [3] Witjes JA, Bruins HM, Carrión A, et al. EAU guidelines on muscle-
sion, regardless of the surgical approach. invasive and metastatic bladder cancer. Arnhem, The
Neobladder reconstruction represents an excellent Netherlands: European Association of Urology; 2022.
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option for appropriate candidates and daytime and night- latent Dirichlet allocation in processing free-text personal goals
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e166 EUROPEAN UROLOGY 82 (2022) e165–e166
Bernardo Rocco a,b

Maria Chiara Sighinolfi a,b,*
a
University of Milan, La Statale, Milan, Italy
b
ASST Santi Paolo e Carlo, Milan, Italy
*Corresponding author. ASST Santi Paolo e Carlo, via Rudini 8, Milan,

Italy.
E-mail address: sighinolfic@gmail.com (M.C. Sighinolfi).
July 26, 2022

Reply to Bernardo Rocco and Maria Chiara Sighinolfi’s the most common issues for patients with bladder cancer
Letter to the Editor re: James W.F. Catto, Pramit Khetrapal, are fatigue, loss of sexual function, and financial concerns
Federico Ricciardi, et al. Effect of Robot-assisted Radical (rather than body image) [10]. Third, the current trend in
Cystectomy with Intracorporeal Urinary Diversion vs Open cystectomy is towards reducing the burden of surgery
Radical Cystectomy on 90-Day Morbidity and Mortality through prehabilitation [11], enhanced recovery [5], and
Among Patients with Bladder Cancer: A Randomized minimal access approaches. These lead to fewer complica-
Clinical Trial. JAMA 2022;327:2092–103 tions, faster discharge, quicker recovery, and mean that
fewer patients are judged unfit for radical surgery. This is
Lacking the Evidence for Neobladder Use After Radical
important given that population-wide data show that many
Cystectomy
patients with invasive cancers do not receive any radical
treatment [12]. In many series, neobladder use leads to
We thank the authors for their kind comments regarding longer hospital stays and longer learning curves before
our publication [1]. They question the neobladder rate in inpatient stays reach those seen with ileal conduits [13].
our trial and suggest consequences regarding decision Finally, competition from cystectomy-sparing approaches
regret. We agree that the rate of neobladder use was lower is building and thus many patients wishing to avoid a stoma
in the iROC trial (11%) than in historical series and that rates or incontinence are looking at trimodal therapy rather than
of neobladder use are falling globally [2]. For example, radical surgery.
neobladder use fell from 33% in 2006 to 27% by 2014 in Ger- In conclusion, we agree with the authors that surgeons
many [3], from 22% in 2011 to 15% by 2015 in the USA [4], undertaking radical cystectomy need to work within multi-
and from 42% to 10% in Sheffield [5], and was only 7.2% in disciplinary teams and offer all suitable choices to affected
the UK in 2014–2015 [6]. Thus, the iROC cohort reflects this individuals. These include neobladder reconstruction, open
trend. Multicentre series suggest that rates of neobladder and robotic surgery, bladder-sparing approaches, and
use vary with neoadjuvant chemotherapy administration chemotherapy. We commend the authors for their out-
(lower neobladder rate with chemotherapy), reimburse- comes among older patients and agree that decision regret
ment, gender, and patient performance status [4].While is best avoided via comprehensive counselling and patient
we agree that the introduction of robotic surgery (and a education.
need for simpler intracorporeal reconstruction) may have
encouraged the trend away from neobladder use, the global
data suggest that a change was happening before wider dis-
semination of robotic cystectomy. We suspect that there are
other contributory factors. References
First, there remains a lack of high-quality evidence that a
neobladder offers superior health-related quality of life [1] Catto JWF, Khetrapal P, Ricciardi F, et al. Effect of robot-assisted
(HRQOL) to an ileal conduit and for which patients it is best radical cystectomy with intracorporeal urinary diversion vs open
radical cystectomy on 90-day morbidity and mortality among
used. Despite more than 50 yr of work in the field [7], the patients with bladder cancer: a randomized clinical trial. JAMA
best evidence comes from observational comparative stud- 2022;327:2092–103.
ies with imbalanced cohorts. These suggest that neobladder [2] Almassi N, Bochner BH. Ileal conduit or orthotopic neobladder:
recipients have a marginally superior body image and that selection and contemporary patterns of use. Curr Opin Urol
2020;30:415–20.
patients typically balance the risks of a stoma (eg, the need
[3] Groeben C, Koch R, Baunacke M, et al. Urinary diversion after radical
for appliances and the risk of herniation) with the risks of cystectomy for bladder cancer: comparing trends in the US and
nocturnal incontinence and the need for bladder training Germany from 2006 to 2014. Ann Surg Oncol 2018;25:3502–9.
[8]. Despite the surgical differences, no other significant dif- [4] Bachour K, Faiena I, Salmasi A, et al. Trends in urinary diversion
ferences are seen across many dimensions of health [9]. Sec- after radical cystectomy for urothelial carcinoma. World J Urol
2018;36:409–16.
ond, 10-yr population-wide patient-reported outcome [5] Pang KH, Groves R, Venugopal S, Noon AP, Catto JWF. Prospective
surveys report that age and fitness are the greatest determi- implementation of enhanced recovery after surgery protocols to
nants of HRQOL (rather than treatment received) and that radical cystectomy. Eur Urol 2018;73:363–71.
[6] Jefferies ER, Cresswell J, McGrath JS, et al. Open radical cystectomy James W.F. Catto a,b,c,*
in England: the current standard of care – an analysis of the British Pramit Khetrapal c
Association of Urological Surgeons (BAUS) cystectomy audit and Gareth Ambler d
Hospital Episodes Statistics (HES) data. BJU Int 2018;121:880–5. Norman R. Williams e
[7] Studer UE, deKernion JB, Zimmern PE. A model for a bladder Chris Brew-Graves f
replacement plasty by an ileal reservoir – an experimental study in
John D. Kelly c, on behalf of the iROC Study Team
dogs. Urol Res 1985;13:243–7.
[8] Clements MB, Atkinson TM, Dalbagni GM, et al. Health-related a
Department of Oncology and Metabolism, University of Sheffield, Sheffield,
quality of life for patients undergoing radical cystectomy: results of
UK
a large prospective cohort. Eur Urol 2022;81:294–304. b
[9] Ali AS, Hayes MC, Birch B, Dudderidge T, Somani BK. Health related Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust,
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c
orthotopic neobladder and ileal conduit diversion. Eur J Surg Oncol Division of Surgery & Interventional Science, University College London,
2015;41:295–9. London, UK
d
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systematic and interdisciplinary review. Eur Urol 2022;81:157–67.
[12] John JB, Varughese MA, Cooper N, et al. Treatment allocation and *Corresponding author. Department of Oncology and Metabolism, The
survival in patients diagnosed with nonmetastatic muscle-invasive Medical School, University of Sheffield, Beech Hill Road, Sheffield S10
bladder cancer: an analysis of a national patient cohort in England. 2RX, UK. Tel. +44 114 2261229; Fax: +44 114 2712268.
Eur Urol Focus 2021;7:359–65. E-mail address: j.catto@sheffield.ac.uk (J.W.F. Catto).
[13] Collins JW, Tyritzis S, Nyberg T, et al. Robot-assisted radical
cystectomy (RARC) with intracorporeal neobladder – what is the August 30, 2022
effect of the learning curve on outcomes? BJU Int 2014;113:100–7.
EUROPEAN UROLOGY 82 (2022) e169
Re: Daniel J. Lee, Ryan Hausler, Anh N. Le, et al. Association carriers is small, as in this case, potential misclassification
of Inherited Mutations in DNA Repair Genes with Localized of even two or three screened controls will significantly
Prostate Cancer. Eur Urol 2022;81:559–67 impact the results.
It is also important to be cognisant that the very small
Red Flags in Association Analyses for Rare Variants
number of variant carriers combined with multiple analyses
of clinical variables is problematic. For example, in Table 2
We read with interest the article by Lee et al. [1] character-
[1], for cases who carry a pathogenic DDR variant, the
ising the contribution of rare, likely pathogenic variants in a
majority of cells contain fewer than five individuals, which
selected set of 17 DNA damage repair (DDR) genes to pros-
renders the statistical comparisons presented misleading.
tate cancer risk in a case-control cohort. The authors con-
Furthermore, while Table 3 [1] presents data for a large
clude that mutation rates in a cohort with localised
number of clinicopathological measures, it is not possible
prostate cancer ‘‘were not significantly different from those
to draw any meaningful conclusions; this raises concerns
in cancer-free controls’’. At first glance, a worrisome aspect
regarding multiple comparisons, which are not discussed.
of the data is that seven of the 17 DDR genes had a higher
A report of the actual age of the participants at diagnosis
frequency of likely pathogenic mutations among screened
or time of record linkage, and a comment on the likely cap-
controls in comparison to cases. Closer examination reveals
ture of diagnoses, together with acknowledgement of mul-
several additional red flags in the presentation of the data
tiple comparisons, is needed. We agree with the assertion
that appear to have been missed by reviewers. Notably,
by Lee et al. [1] that it is important to examine population
age at enrolment in the Penn Medicine biobank is reported
cohorts, but such studies require appropriately robust anal-
as an apparent proxy for age at diagnosis/age at data link-
yses recognising the challenges posed by rare variants.
age, and there is a lack of attention to the significant age
discrepancy between cases and controls. Our examination
of the supplementary data reveals that 18 of the 79 (21%) Conflicts of interest: The authors have nothing to disclose.
variant carriers in the ‘‘cancer-free controls’’ were younger
than 56 years at enrolment in the Penn Medicine biobank, References
compared to just three of the cases. A further red flag is
[1] Lee DJ, Hausler R, Le AN, et al. Association of inherited mutations in DNA
the number of rare variants reported for the BRCA2 gene, repair genes with localized prostate cancer. Eur Urol 2022;81:559–67.
which has a well-characterised association with substan- [2] Darst BF, Dadaev T, Saunders E, et al. Germline sequencing DNA
tially higher prostate cancer risk [2,3]. The authors report repair genes in 5545 men with aggressive and nonaggressive
prostate cancer. J Natl Cancer Inst 2021;113:616–25.
that BRCA2 pathogenic variants are at a higher frequency
[3] Stone L. The IMPACT of BRCA2 in prostate cancer. Nat Rev Urol
in screened controls than in the gnomAD cohort. Examina- 2019;16:639.
tion of the supplementary data reveals that 6/14 (43%)
of the ‘‘cancer-free’’ control BRCA2 variant carriers were Joanne L. Dickinson *
younger than 55 years at enrolment. In comparison, only Georgea R. Foley
Liesel M. FitzGerald
one out of 13 (8%) cases with a BRCA2 variant were
younger than 55 years at enrolment, while ten (77%) were Menzies Institute for Medical Research, University of Tasmania, Hobart,
aged 65 years. Notably, the mean age at diagnosis pub- Australia
lished for men with a pathogenic BRCA2 mutation is 61
*Corresponding author. Menzies Institute for Medical Research, Univer-
years [3]. In addition, linkage of the selected controls to only
sity of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia.
the Penn Medicine hospital records and Penn Medicine Can- E-mail address: jo.dickinson@utas.edu.au (J.L. Dickinson).
cer database (in 2019) may represent incomplete capture of
cancer diagnoses. When the number of DDR gene variant August 18, 2022
DOI of original articles: https://doi.org/10.1016/j.eururo.2021.09.029; https://doi.org/10.1016/j.eururo.2022.08.025.
Reply to Joanne L. Dickinson, Georgea R. Foley, and Liesel therefore, again it is expected that the association would
M. FitzGerald’s Letter to the Editor re: Daniel J. Lee, Ryan be weaker in our study. A similar case could be made for
Hausler, Anh N. Le, et al. Association of Inherited NBN given its association with aggressive PC [6,7]; however,
Mutations in DNA Repair Genes with Localized Prostate the mutation rates reported for our biobank are extremely
Cancer. Eur Urol 2022;81:559–67. Red Flags in Association
low for NBN.
Analyses for Rare Variants
When choosing a cancer-free cohort for studies of rare
variant associations, one must balance the inclusion of
We appreciate the opportunity to discuss the interpretation
younger individuals who may develop the disease after
of our data on rare mutation rates in cancer risk genes in
enrollment with inclusion of older individuals who have
patients with prostate cancer (PC) [1]. We compared muta-
a genetic survival bias. These limitations have the opposite
tion rates in unselected biobank patients with PC to two
effect of artificially deflating and inflating odds ratios,
cohorts of cancer-free individuals, an unselected biobank
respectively, when compared to a disease cohort. We
cohort and gnomAD, given the individual limitations of both
therefore chose to include all individuals from two sepa-
data sets for rare variant analyses. The gnomAD mutation
rate control cohorts. An age-matched case-control study
rates are derived from individuals ‘‘who were not ascer-
of individuals with and without PC undergoing whole-gen-
tained for having cancer’’ [2,3]; therefore, the limitations
ome sequencing would be ideal, but extremely costly. We
include no age at enrollment, no long-term follow-up, and
therefore performed a robust analysis of biobank data,
potentially lower depth sequencing. The PC-free biobank
appropriately acknowledged the limitations, and believe
cohort includes data on age at enrollment and long-term
it is an important addition to the literature on PC germline
follow-up. Age at biobank enrollment was not used as a
risk.
proxy for age at PC diagnosis or data linkage for individuals
without PC; actual age at diagnosis is reported for patients
with PC. Individuals were enrolled in the biobank between Conflicts of interest: The authors have nothing to disclose.
March 10, 2000 and June 1, 2019, and manual chart review
was performed in 2021 for all patients to confirm PC status.
Our study in no way disputes BRCA2 association with PC. References
Burden testing in biobank individuals with versus without
[1] Lee DJ, Hausler R, Le AN, et al. Association of inherited mutations in
PC reached statistical significance for BRCA2 without correc- DNA repair genes with localized prostate cancer. Eur Urol
tion for multiple testing in Europeans. The median age at 2022;81:559–67.
enrollment in the biobank for BRCA2+ PC-free individuals [2] Gudmundsson S, Karczewski KJ, Francioli LC, et al. Addendum: the
mutational constraint spectrum quantified from variation in 141,456
was 68 yr, and all patients had between 2 and 21 yr since
humans. Nature 2021;597:E3–4.
enrollment and remained without PC at final manual chart [3] Gudmundsson S, Singer-Berk M, Watts NA, et al. Variant
review. BRCA2- associated PC is aggressive [4]; therefore, interpretation using population databases: lessons from gnomAD.
it may be expected that the association would be weaker Hum Mutat 2022;43:1012–30.
[4] Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are
in our study, in which only 15% of patients had Gleason
associated with higher risk of nodal involvement, distant metastasis,
grade group 4–5 disease and patients with metastatic dis- and poor survival outcomes in prostate cancer. J Clin Oncol
ease were excluded. 2013;31:1748–57.
Dickinson et al [5] claim that mutation rates for multiple [5] Karlsson Q, Brook MN, Dadaev T, et al. Rare germline variants in ATM
predispose to prostate cancer: a PRACTICAL Consortium study. Eur
genes are higher in the biobank patients without PC; how- Urol Oncol 2021;4:570–9.
ever, the differences are marginal. Of these seven genes, five [6] Darst BF, Dadaev T, Saunders E, et al. Germline sequencing DNA
have no known association with PC. The mutation rates for repair genes in 5545 men with aggressive and nonaggressive
prostate cancer. J Natl Cancer Inst 2021;113:616–25.
ATM are well within the range of rates reported for cases
[7] Wokolorczyk D, Kluzniak W, Huzarski T, et al. Mutations in ATM,
and controls in individual PRACTICAL studies [5]. It has also NBN and BRCA2 predispose to aggressive prostate cancer in Poland.
been shown that ATM is associated with aggressive PC [6]; Int J Cancer 2020;147:2793–800.
DOI of original articles: https://doi.org/10.1016/j.eururo.2022.08.026; https://doi.org/10.1016/j.eururo.2021.09.029.
https://doi.org/10.1016/j.eururo.2022.08.025.
0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 82 (2022) e170–e171 e171
Daniel J. Lee
Ryan Hausler
Kara N. Maxwell *
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,

USA
*Corresponding author. Perelman School of Medicine, University of

Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA. Tel. +1
215 898 6944; Fax: +1 215 573 7039.
E-mail address: kara.maxwell@pennmedicine.upenn.edu
(K.N. Maxwell).
August 24, 2022

Re: Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, p.F109S, p.G244S, p.M246V, p.R280K, c.993+1del, p.?, p.
et al. Inherited TP53 Variants and Risk of Prostate Cancer. R337C, and p.R342*). The Chompret criteria were fulfilled
Eur Urol 2022;81:243–50 in these 13 PCa cases from the TP53 database, with a median
age of 60 yr and an isolated PCa phenotype in 8/13 carriers.
Off-core Li-Fraumeni Syndrome Spectrum Cancers: Increas- Some variants were associated with two or more PCa cases
ing Interest for Prostate Cancer? in the family history (p.F109S, p.G244S, p.M246V, p.R280K,
and p.R337H).
Li-Fraumeni syndrome (LFS) has long been studied using High-throughput sequencing technologies have
TP53 single-gene testing according to the Chompret clinical enhanced our knowledge of PCa biology by identifying dri-
criteria, which do not include prostate cancer (PCa) [1]. ver mutations in tumors that are predictive of response to
Maxwell et al. [2] retrospectively characterized 67 PCa targeted therapies, as well as potential germline variants
cases with LFS with 37 distinct germline TP53 (gTP53) vari- associated with poor outcomes, which has facilitated adap-
ants (from 132 LFS families and 6850 PCa cases with tumor tion of risk assessments and ushered in the era of precision
sequencing) from the data sets from four American centers. medicine. Nevertheless, clinicians should consider that
They found significantly higher risk in the LFS PCa group genes are not equivalent in terms of risk, and actionability
than in the control group (9.1-fold higher, 95% confidence is the main concern. In comparison to localized stages,
interval 6.2–14; p < 0.0001) with late-onset aggressive PCa advanced PCa has a higher incidence of germline mutations
forms (Gleason score 8) and mainly harboring TP53 p. among genes mediating DNA repair processes (11.8%),
R181H and p.R181C [2]. mainly involving BRCA2, which has implications for cancer
This prompted us to retrospectively review 12 687 treatments using PARP inhibitors and potential associations
sequenced samples from patients referred for clinical suspi- with ATM, BRCA1, RAD51D, and PALB2 [3]. The role of TP53 in
cion of hereditary cancer predisposition and identified 82 dis- PCa is still emerging and controversial. Identification of
tinct confirmed gTP53 variants classified as pathogenic or germline TP53 variants can change PCa clinical practice,
likely pathogenic with an allele frequency 40% among 194 such as avoiding radiotherapy and conventional genotoxic
LFS patients (105 index cases [ICs] + 89 relatives) with fol- chemotherapy, as well as adapting surveillance and family
low-up at Institut Gustave Roussy. We focused on clinical screening strategies [4]. Some data that are important to
and genetic results for 70 males (28 ICs + 42 relatives) and integrate are the variant type (TP53 dominant-negative
identified five PCa cases with five different gTP53 variants variants are associated with higher cancer risk), penetrance,
to those reported by Maxwell et al: c.672+1G>C p.?, p. and functional test results. International collaborations are
R196*, p.T125=, p.R267G, and p.S378fs. The median age was needed to decipher the tumorigenesis of TP53 in PCa and
49 yr and the Chompret criteria were fulfilled in most cases. to update the Chompret criteria if needed.
A family history of PCa was found in only one case p.T125=.
For the cases with p.R196* and p.R267G, lung cancer occurred Conflicts of interest: The authors have nothing to disclose.
prior to PCa in never-smoker men. At initial diagnosis, pros-
tate-specific antigen was <10 ng/ml (4/4 cases). Available Ethics statement: Informed consent was obtained from each screened
Gleason scores were <8 in 3/4 cases with c.672+1G>C p.?, p. patient.
R196*, and p.R267G, and the International Society of Urolog-
ical Pathology grade was 2, which represents less severe Peer Review Summary
disease than in the series described by Maxwell et al. [2].
In parallel, we exported PCa data from the TP53 database Peer Review Summary to this article can be found online at
hosted by the National Cancer Institute, formerly known as https://doi.org/10.1016/j.eururo.2022.07.038.
the IARC gTP53 database (R20, July 2019; https://tp53.isb-
cgc.org). A review identified only 13 PCa cases with a molec- References
ularly confirmed gTP53 variant; these comprised eight dif- [1] Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni
ferent variants, mainly dominant-negative, of which seven syndrome from TP53 mutation carriers. J Clin Oncol 2015;33:
were not common to the Maxwell et al. series and our data: 2345–52.
[2] Maxwell KN, Cheng HH, Powers J, et al. Inherited TP53 variants and
Hela Sassi a,*
risk of prostate cancer. Eur Urol 2022;81:243–50.
Olivier Caron b
[3] Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene
Etienne Rouleau a,c
mutations in men with metastatic prostate cancer. N Engl J Med
2016;375:443–53. a
[4] Frebourg T, Bajalica Lagercrantz S, Oliveira C, et al. Guidelines for the Tumor Genetic Section, Medical Biology and Pathology Department, Insitut
Li–Fraumeni and heritable TP53-related cancer syndromes. Eur J Gustave Roussy, Villejuif, France
b
Hum Genet 2020;28:1379–86. Oncogenetic Department, Insitut Gustave Roussy, Villejuif, France
c
AMMICa UAR3655/US23, Insitut Gustave Roussy, Villejuif, France
*Corresponding author. Tumor Genetic Section, Medical Biology and

Pathology Department, Insitut Gustave Roussy, Villejuif, France.
E-mail address: hela.sassi@gustaveroussy.fr (H. Sassi).
July 31, 2022

Re: Jens Bedke, Brian I. Rini, Elizabeth R. Plimack, et al. checkpoint inhibitor (ICI)-mediated activation of the
Health-related Quality of Life Analysis from KEYNOTE-426: immune system and can occur in any organ system, requir-
Pembrolizumab plus Axitinib Versus Sunitinib for ing a wide range of diagnostic considerations [5]. Such irAEs
Advanced Renal Cell Carcinoma. Eur Urol. 2022;82:427–39 include colitis, hepatitis, pneumonitis, and hypothyroidism,
as well as cardiovascular irAEs, which have the highest mor-
I read with great interest the study by Bedke et al. [1] evalu- tality risk [5]. As ICI drugs achieve tumor control with pro-
ating health-related quality of life (HRQoL) for patients in longed immune activation, clinicians need more time to
KEYNOTE-426 on the efficacy and safety of pembrolizumab manage the full spectrum of long-term irAEs that may
+ axitinib versus sunitinib in advanced/metastatic renal cell potentially persist, progress, or even emerge over time [5].
carcinoma (RCC). Pembrolizumab + axitinib extended overall Although general AEs were described in the main report
survival (OS) and prolonged progression-free survival (PFS) for the KEYNOTE-426 trial, I recommend that the authors
over sunitinib, while HRQoL did not differ between the should additionally discuss and report irAEs from PROs
two groups. These findings add new insights to the and address management of these immune-related toxici-
KETNOTE-426 trial and support first-line prescription of ties to better help their patients [2].
pembrolizumab + axitinib as a standard of care for In summary, the current study provides important
advanced/metastatic RCC. However, there are several exploratory findings, but these results could be more
concerns. detailed and more conclusive and should be translated with
First, the Functional Assessment of Cancer Therapy Kid- caution. Once again, I appreciate these novel findings and
ney Cancer Symptom Index-Disease Related Symptom congratulate the authors on their achievements.
(FKSI-DRS) was used as a patient-reported instrument to
measure tumor-specific symptoms. According to the pri- Conflicts of interest: The author has nothing to disclose.
mary report for the KEYNOTE-426 trial, more than 50% of
the patients (444/861, 51.6%) were from rest of the world
besides North America and Western Europe [2]. Patient- Peer Review Summary
reported outcomes (PROs) are associated with self-educa-
tion, socioeconomic status, the level of community health Peer Review Summary to this article can be found online at
care, the availability of local medical care, and the degree https://doi.org/10.1016/j.eururo.2022.08.038.
of development of the local medical industry, among other
factors, which suggests the possibility of great differences
among patients of diverse regions regarding PROs [3]. In References
other words, patients from developed regions such as North
America and Western Europe might perform well in PRO [1] Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life
analysis from KEYNOTE-426: pembrolizumab plus axitinib versus
completion and exhibit better compliance in comparison sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82:427–
to patients from the rest of the world. Besides gender-speci- 39.
fic and other factors, it has been suggested that region- [2] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus
specific PROs should be taken into consideration [3,4]. sunitinib for advanced renal-cell carcinoma. N Engl J Med
2019;380:1116–27.
The authors used the Quality of Life Questionnaire-C30
[3] Atkinson TM, Wagner JS, Basch E. Trustworthiness of patient-
to evaluate potential adverse events (AEs) and HRQoL [1]. reported outcomes in unblinded cancer clinical trials. JAMA Oncol
Some 75.0% of patients (646/861) in KEYNOTE-426 had 2017;3:738–9.
two or more organ metastases and 24.4% (210/861) had [4] Hertler C, Seiler A, Gramatzki D, Schettle M, Blum D. Sex-specific and
one organ metastasis [2]. Given the high proportion of gender-specific aspects in patient-reported outcomes. ESMO Open
2020;5(Suppl 4):e000837.
patients with distant metastasis, immune-related AEs [5] Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-
(irAEs) from PROs should be specifically analyzed and checkpoint inhibitors: epidemiology, management and surveillance.
reported. irAEs arise from unintended effects of immune Nat Rev Clin Oncol 2019;16:563–80.
Binghao Zhao *
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese

Academy of Medical Sciences and Peking Union Medical College, Beijing, PR
China
State Key Laboratory of Complex Severe and Rare Diseases, Peking Union
Medical College Hospital, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing, PR China
*Department of Neurosurgery, Peking Union Medical College Hospital,

Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100730, PR China. Fax: +86 10 69152530.
E-mail address: zhaobhao@126.com (B. Zhao).
August 24, 2022

Re: Bernadett Szabados, Mark Kockx, Zoe June Assaf, et al. and nonresponders to TIL therapy, and suggested that
Final Results of Neoadjuvant Atezolizumab in Cisplatin- CD39 determines T-cell fate and the therapeutic effect to
ineligible Patients with Muscle-invasive Urothelial Cancer some extent.
of the Bladder. Eur Urol 2022;82:212–22 Owing to the prospective nature of their clinical trial,
Szabados et al were able to analyze the relationship
We congratulate Szabados et al. [1] on reporting the final
between baseline and post-treatment biomarker levels
results from ABACUS, which has important implications
and patient outcomes, but did not explore the correlation
for the use of neoadjuvant atezolizumab in cisplatin-ineligi-
between the change in biomarker expression after treat-
ble patients with muscle-invasive bladder cancer (BC). The
ment and prognosis. Elucidation of whether changes in bio-
authors suggest that biomarkers were associated with can-
marker expression reflect the effect of treatment on
cer prognosis, including TMB, PD-L1, FAP, MHC I, FOXP3, cir-
patients would provide an interesting insight. We encour-
culating tumor DNA, and CD39. Among these, CD39 is a
age the authors to investigate in greater depth the associa-
novel biomarker. They found increased levels of CD39+/
tion of biomarkers with patient prognosis and response to
CD8+ T cells in tumors responding after treatment and
neoadjuvant therapy in BC.
claimed that CD39 has not previously been described as a
Finally, the role of CD39 in BC, especially in T cells, needs
potential biomarker in urothelial carcinoma, opening new
to be validated in more studies. We expect more researchers
avenues in this field.
to join this new field.
Although we completely agree that prognostic biomark-
ers may be useful in monitoring clinical benefit and choos-
ing patients for adjuvant treatment after neoadjuvant Conflicts of interest: The authors have nothing to disclose.
therapy, we must point out that there is still some contro-
versy regarding CD39 that requires further elaboration. References
We would first like to state that we have no intention of
[1] Szabados B, Kockx M, Assaf ZJ, et al. Final results of neoadjuvant
arguing about who first introduced CD39 in bladder cancer
atezolizumab in cisplatin-ineligible patients with muscle-invasive
research, especially in T cells. However, in previous urothelial cancer of the bladder. Eur Urol 2022;82:212–22.
research, we found that CD39 plays an important role in [2] Zhu W, Zhao Z, Feng B, et al. CD8+CD39+ T cells mediate anti-tumor
BC and could be a potential prognostic biomarker, and cytotoxicity in bladder cancer. Onco Targets Ther 2021;14:2149–61.
[3] Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer. Nat Rev
CD8+CD39+ T cells mediate antitumor cytotoxicity in BC [2].
Immunol 2020;20:739–55.
Further discussion of CD39, whose function in tumors is [4] Duhen T, Duhen R, Montler R, et al. Co-expression of CD39 and
still controversial, is also warranted. CD39, the rate-limiting CD103 identifies tumor-reactive CD8 T cells in human solid tumors.
enzyme in the hydrolysis of extracellular ATP/ADP, partici- Nat Commun 2018;9:2724.
pates in the generation of adenosine, widely expressed in [5] Krishna S, Lowery FJ, Copeland AR, et al. Stem-like CD8 T cells
mediate response of adoptive cell immunotherapy against human
various cells in the tumor microenvironment, including
cancer. Science 2020;370:1328–34.
immune cells and tumor cells, among others. Some
researchers have hypothesized that CD39 upregulation Zihan Zhao
clears the costimulatory signal caused by extracellular Hongqian Guo
ATP, thereby suppressing immunity [3]. Therefore, CD39- Rong Yang *
targeting agents have recently entered clinical trials and
Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital
are being used in combination with other immune check-
of Nanjing University Medical School, Institute of Urology, Nanjing University,
point inhibitors [3]. Adding to the evidence from Szabados
Nanjing, China
et al [1] and our previous study [2] that CD39 in CD8+ T cells
has a positive antitumor effect, Duhen et al. [4] found that *Corresponding author. Department of Urology, Nanjing Drum Tower
CD39 could have potential as a biomarker to identify Hospital, The Affiliated Hospital of Nanjing University Medical School,
tumor-reactive CD8+ T cells in human head and neck cancer. Institute of Urology, Nanjing University, 321 Zhongshan Road, Nanjing,
Jiangsu 210008, China. Tel. +86 25 83106666.
Interestingly, Krishna et al. [5] compared the phenotypic
E-mail address: doctoryr@gmail.com (R. Yang).
differences of tumor-infiltrating lymphocytes (TILs) in
melanoma between patients with a complete response August 24, 2022
Reply to Leonard P. Bokhorst and Berdine L. Heesterman’s trol. The fact that at 10 yr we still observed an absolute clin-
Words of Wisdom re: High-dose Radiotherapy and Risk- ical benefit of nearly 12% for all endpoints in the high-risk
adapted Androgen Deprivation in Localised Prostate group treated with LTAD should not be dismissed. We have
Cancer (DART 01/05): 10-Year Results of a Phase 3 tried to avoid categorical affirmations as the authors have
Randomised, Controlled Trial. Eur Urol. 2022;82:441 made in their expert comment. We are aware of the limita-
tions of our 10-yr analysis and the relevance of contextual-
ising our results in the framework of other more extensive
The DART 01/05 trial was designed to determine whether
trials with combined systemic therapy to make simplistic
long-term androgen deprivation (LTAD) is superior to
assumptions. High-risk localised PCa is a clinically relevant
short-term AD (STAD) when combined with high-dose
and heterogeneous disease state with a wide spectrum of
radiotherapy. The primary endpoints were designed for
intrinsic aggressiveness that develops in ageing patients. A
assessment at 5 yr. The results confirmed that 2 yr of adju-
personalised treatment approach based on tumour aggres-
vant AD yielded a clinically significant outcome, specifically
siveness and a balance between efficacy and toxicity is the
in patients with high-risk disease. Because of the indolent
cornerstone of PCa management. We believe that selected
clinical evolution of prostate cancer (PCa), we completed
men with a less aggressive disease profile and/or severe
monitored follow-up of 10 yr to assess the long-term effect
comorbidities could do well with a short or intermediate
of high-dose radiotherapy and AD in a patient population
AD regimen of 6–12 mo when combined with high-dose
susceptible to death from other comorbid age-related ill-
radiotherapy [3]. Conversely, patients with very high-risk
nesses. In our Lancet Oncology paper [1] we presented the
PCa will require intensification of treatment, as reported
10-yr analysis, which mainly focused on metastasis-free
by Attard et al [5]. For the remaining subgroup of patients
survival, overall survival, and cause-specific survival, taking
with high-risk disease, and until new trials are available,
into account competing risks of non-PCa mortality. The def-
data from DART01/05 make it wise to consider LTAD as
initions of the endpoints and the details of the statistical
the standard treatment.
methodology extensively reported in the paper are not
problematic but are complex, and in accordance with
well-recognised standards and guidelines in PCa trials. Conflicts of interest: Almudena Zapatero reports speaker honoraria from
After extended 10-yr follow-up and a prespecified Fine Astellas Pharma and Janssen; advisory board honoraria from Bayer; a tra-
and Gray analysis to account for the competing risk of vel grant from Recordati; and research grants from AstraZeneca, Grupo de
death, we were unable to support the statistical benefit of Investigación en Oncología Radioterápica/Sociedad Española de Oncología
LTAD reported at 5 yr. However, at 10 yr we did observe Radioterápica (GICOR/SEOR), and the National Health Investigation Fund
persistent absolute benefits of 13.5% for biochemical dis- (FIS). The remaining authors have nothing to disclose.
ease-free survival, 11.6% for metastasis-free survival, and
11.5% for overall survival among patients with high-risk dis- References
ease treated with LTAD in comparison to those receiving
STAD. This is not an isolated finding. Our results are consis- [1] Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy
tent with data from other clinical trials in the high-risk PCa and risk-adapted androgen deprivation in localised prostate cancer
(DART 01/05): 10-year results of a phase 3 randomised, controlled
setting [2,3]. We also confirmed that patients with interme- trial. Lancet Oncol 2022;23:671–81.
diate-risk PCa treated with high-dose radiotherapy do not [2] Kishan AU, Steigler A, Denham JW, et al. Interplay between duration
benefit from LTAD. of androgen deprivation therapy and external beam radiotherapy
We thank Borkhorst and Heesterman [4] for their inter- with or without a brachytherapy boost for optimal treatment of
high-risk prostate cancer. A patient-level data analysis of 3 cohorts.
est in the DART01/05 trial and their critical review. Their
JAMA Oncol 2022;8:e216871. 10.1001/jamaoncol.2021.6871.
expert comment includes a well-intentioned but probably [3] Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy
simplistic analysis of our results. The fact that we could use and duration with definitive radiotherapy for localised prostate
not confirm a statistically significant benefit in our series cancer: an individual patient data meta-analysis. Lancet Oncol
at 10 yr does not mean that there is no benefit from LTAD. 2022;23:304–16.
[4] Bokhorst LP, Heesterman BL. Re: High-dose radiotherapy and risk-
We are probably facing an evolving scenario in which age- adapted androgen deprivation in localised prostate cancer (DART 01/
ing patients are increasingly susceptible to death from 05): 10-year results of a phase 3 randomised, controlled trial. Eur
comorbid diseases but have PCa that is mostly under con- Urol 2022;82(4):441. 10.1016/j.eururo.2022.07.004, In press.
0302-2838/Ó 2022 European Association of Urology Published by Elsevier All rights reserved.
[5] Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and

Almudena Zapatero a,*
prednisolone with or without enzalutamide for high-risk non-
Felipe A. Calvo b,c
metastatic prostate cancer: a meta-analysis of primary results from
Carmen Gonzalez San-Segundo b
two randomized controlled phase 3 trials of the STAMPEDE platform
protocol. Lancet 2022;399:447–60. Ana Alvarez b
a
Department of Radiation Oncology, Hospital Universitario de La Princesa,
Health Research Institute, Madrid, Spain
b
Radiation Oncology Department, Hospital General Universitario Gregorio
Marañón, Madrid, Spain
c
Radiation Oncology Department, Clínical Universitaria de Navarra, Madrid,
Spain
*Corresponding author at: Department of Radiation Oncology, Hospital

Universitario de La Princesa, Health Research Institute, Madrid, Spain.
Tel. +34 9 15202315; Fax: +34 9 15202315.
E-mail address: almudena.zapatero@salud.madrid.org (A. Zapatero).
August 24, 2022

Erratum
Erratum to ‘‘Effect of Simulation-based Training on Surgical

Proficiency and Patient Outcomes: A Randomised Controlled Clinical
and Educational Trial’’ [Eur Urol 2022;81:385–393]
Abdullatif Aydın a,*, Kamran Ahmed a,b, Takashige Abe c, Nicholas Raison a, Mieke Van Hemelrijck d,
Hans Garmo d, Hashim U. Ahmed e,f, Furhan Mukhtar a, Ahmed Al-Jabir a, Oliver Brunckhorst a,
Nobuo Shinohara c, Wei Zhu g, Guohua Zeng g, John P. Sfakianos h, Mantu Gupta h,
Ashutosh Tewari h, Ali Serdar Gözen i, Jens Rassweiler i, Andreas Skolarikos j, Thomas Kunit k,
Thomas Knoll l, Felix Moltzahn m, George N. Thalmann m, Andrea G. Lantz Powers n, Ben H. Chew o,
Kemal Sarica p, Muhammad Shamim Khan a,q, Prokar Dasgupta a,q, On behalf of the SIMULATE Trial
Group
Umair Baig, Haleema Aya, Mohammed Husnain Iqbal, Francesca Kum, Matthew Bultitude,
Jonathan Glass, Azhar Khan, Jonathan Makanjuola, John E. McCabe, Azi Samsuddin,
Craig McIlhenny, James Brewin, Shashank Kulkarni, Sikandar Khwaja, Waliul Islam,
Howard Marsh, Taher Bhat, Benjamin Thomas, Mark Cutress, Fadi Housami, Timothy Nedas,
Timothy Bates, Rono Mukherjee, Stuart Graham, Matthieu Bordenave, Charles Coker,
Shwan Ahmed, Andrew Symes, Robert Calvert, Ciaran Lynch, Ronan Long, Jacob M. Patterson,
Nicholas J. Rukin, Shahid A. Khan, Ranan Dasgupta, Stephen Brown, Ben Grey,
Waseem Mahmalji, Wayne Lam, Walter Scheitlin, Norbert Saelzler, Marcel Fiedler,
Shuhei Ishikawa, Yoshihiro Sasaki, Ataru Sazawa, Yuichiro Shinno, Tango Mochizuki,
Jan Peter Jessen, Roland Steiner, Gunnar Wendt-Nordahl, Nabil Atassi, Heiko Kohns, Ashley Cox,
Ricardo Rendon, Joseph Lawen, Greg Bailly, Trevor Marsh
a
MRC Centre for Transplantation, King’s College London, King’s Health Partners, London, UK; b Department of Urology, King’s College Hospital NHS Foundation
Trust, King’s Health Partners, London, UK; c Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; d School of Cancer and
Pharmaceutical Studies, King’s College London, London, UK; e Department of Surgery and Cancer, Imperial College London, London, UK; f Department of
Urology, Imperial College Healthcare NHS Trust, London, UK; g Department of Urology, Minimally Invasive Surgery Centre, First Affiliated Hospital of
Guangzhou Medical University, Guangzhou, China; h Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; i Department of
Urology, SLK Kliniken, University of Heidelberg, Heilbronn, Germany; j 2nd Department of Urology, Sismanoglio Hospital, National and Kapodistrian University
of Athens, Athens, Greece; k Department of Urology and Andrology, Paracelsus Medical University, Salzburg, Austria; l Department of Urology, Klinikum
Sindelfingen-Böblingen, University of Tübingen, Sindelfingen, Germany; m Department of Urology, University of Bern, Bern, Switzerland; n Department of
Urology, Dalhousie University, Halifax, NS, Canada; o Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; p Department of
Urology, Biruni University Hospital, Istanbul, Turkey; q Urology Centre, Guy’s and St. Thomas’ NHS Foundation Trust, King’s Health Partners, London, UK
The publisher regrets that the contributors from the SIMULATE Trial Group were not indexed in the original article. This has
now been corrected as above.
The publisher would like to apologise for any confusion or inconvenience that this oversight might have caused.

* Corresponding author. MRC Centre for Transplantation, Southwark Wing, Guy’s Hospital, King’s College London, London SE1 9RT, UK.
E-mail address: abdullatif.aydin@kcl.ac.uk (A. Aydın).
e180
european urology 82 (2022) e180–e181
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Malmo European Urologists
Sweden Tel.: +31 26 3890680
Website: aaeu.uroweb.org/members
6.12.2022 ART in Flexible - Step 2 Contact: European School of Urology

Berlin Tel.: +31 26 3890680
Germany Email: esu@uroweb.org
Website: www.artinflexible.uroweb.org
14.12.2022 ESU Course on Update on Prostate Cancer to be held during the Contact: European School of Urology (ESU)
Cairo National Congress of the Egyptian Association of Urology Tel.: +31 26 3890680
Egypt E-mail: esu@uroweb.org
Website: www.uroweb.org/education
2.2–3.2.2023 ESU-ESOU Masterclass on Nonmuscle-invasive Bladder Cancer Contact: European School of Urology
Prague Tel.: 31 26 3890680
Czech Republic E-mail: esu@uroweb.org
16.2–18.2.2023 URO Berlin Skills Teaching and Training Contact: European School of Urology
Berlin Tel.: +31 26 3890680
Website: www.urobestt.uroweb.org
17.2–18.2.2023 Testosterone Therapy and Sexual Dysfunction Contact: Harvard Medical School + Beth Israel
Orlando, FL Deaconess Medical Center
USA Tel.: +1 617 3848600
Email: ceprograms@hms.harvard.edu
Website: https://hmstestosteronecourse.com
10.3–13.3.2023 38th Annual EAU Congress Contact: European Association of Urology

Milan Tel.: +31 26 3890680
Italy E-mail: info@eaucongress.org
Website: eau23.org
11.3–12.3.2023 23rd Meeting of the European Association of Urology Nurses Contact: Congress Consultants B.V.
Milan Tel.: +31 26 3890680
Italy E-mail: info@eaucongress.org
Website: www.eaun23.org
30.3–31.3.2023 ESU_ESUT Masterclass on Operative Management of Contact: European School of Urology

Heilbronn Benign Prostatic Obstruction Tel.: +31 26 3890680
Website: www.urobestt.uroweb.org
6.4–7.4.2023 ESU-ESOU Masterclass on Muscle-invasive Bladder Cancer Contact: European School of Urology
Nijmegen Tel.: +31 26 3890680
The Netherlands Email: esu@uroweb.org
european urology 82 (2022) e180–e181 e181
26.5–27.5.2023 8th Baltic meeting in conjunction with the EAU Contact: European School of Urology (ESU)
Riga Tel.: +31 26 3890680
Latvia E-mail: esu@uroweb.org
15.6–18.6.2023 60th ERA Congress Contact: European Renal Association

Milan Tel.: +39 0521 989078
Italy E-mail: secretariat@era-online.org
Website: www.era-online.org/en/milan2023/
16.6–17.6.2023 ESU-ESUT Masterclass on Urolithiasis Contact: European School of Urology (ESU)

Patras Tel.: +31 26 3890680
Greece E-mail: esu@uroweb.org
30.6–2.7.2023 EAU UROonco: A meeting steered by the EAU Section of Contact: EAU Section of Oncological Urology
Gothenburg Oncological Urology Tel.: +31 26 3890680
Sweden Website: https://meeting.uroonco.uroweb.org
30.6–2.7.2023 STEPS Programme Contact: European Association of Urology

Gothenburg Tel.: +31 26 3890680
Sweden E-mail: esu@uroweb.org
Website: www.meeting.uroonco.uroweb.org
10.7–14.7.2023 ESU-Weill Cornell Masterclass in General urology Contact: European School of Urology (ESU)
Salzburg Tel.: +31 26 3890680
Austria E-mail: esu@uroweb.org
Acknowledgement to Reviewers
We would like to sincerely thank each and every reviewer who dedicated his or her time and expertise to reviewing manu-
scripts for European Urology, the Platinum Journal, from March 1, 2022 to August 28, 2022. The collaboration with the
reviewers is essential to the success of European Urology which is why each member of the Editorial Board at Large is identifi
ed according to their participation and support. Without their help, European Urology would not be as successful as it is
today. We look forward to continuing this fruitful collaboration in the future.
Firas Abdollah Faik, Detroit Spyridon Basourakos, New York Ronald Chen, Kansas City
E. Jason Abel, Madison Jens Bedke, Tuebingen Ying-Bei Chen, New York
Robert Abouassaly, Cleveland Karim Bensalah, Rennes Douglas Cheung, Toronto
Andre Abreu, Los Angeles Imad Bentellis, Nice John Cheville, Rochester
Ari Adamy, Curitiba Jacob Berchuck, Boston Joseph Chin, London
Sola Adeleke, London Alejandro Berlin, Toronto Edmund Chiong, Singapore
Jan Adolfsson, Stockholm Riccardo Bertolo, Rome Woonyoung Choi, Baltimore
Neeraj Agarwal, Salt Lake City Bimal Bhindi, Calgary Ananya Choudhury, Manchester
Rahul Aggarwal, San Francisco Marco Bianchi, Milan Peter Choyke, Bethesda
Ardalan Ahmad, Toronto Mehmet Bilen, Atlanta Bilal Chughtai, New York
Hashim Ahmed, London Anders Bjartell, Malmo Felix Kyoung-Hwan Chun, Frankfurt
Sascha Ahyai, Göttingen Truls Bjerklund Johansen, Oslo Eric Chung, Woolloongabba
Olof Akre, Stockholm Peter Black, Vancouver Joseph Clark, Hershey
Ilker Akyol, Istanbul Christopher Blick, Oxford Timothy Clinton, New York
Shaheen Alanee, Detroit Luca Boeri, Milan Alexander Cole, Boston
Peter Albers, Düsseldorf Stéphane Bolduc, Québec Samantha Conroy, Sheffield
Peter Albertsen, Connecticut Gernot Bonkat, Basel Niall Corcoran, Parkville
Simone Albisinni, Bruxelles Joost Boormans, Rotterdam Rohann Correa, London
Mario Álvarez-Maestro, Madrid Marco Borghesi, Genova Andres Correa, Rockledge
Umberto Anceschi, Rome Tudor Borza, Madison Elisabetta Costantini, Terni
Christopher Anderson, New York Carlo Andrea Bravi, Milan Massimiliano Creta, Naples
Emmanuel Antonarakis, Minneapolis Sabine Brookman-May, Regensburg Fabio Crocerossa, Catanzaro
Alessandro Antonelli, Italy Oscar Brouwer, Amsterdam Megan Crumbaker, Darlinghurst
Salvador Arlandis, Valencia Andrea Brunner, Innsbruck Francisco Cruz, Porto
Andrew Armstrong, Durham Nicolòmaria Buffi, Milano Roland Dahlem, Hamburg
M Hammad Ather, Karachi Laura Bukavina, Cleveland David D’Andrea, Vienna
Thomas Atwell, Rochester Berk Burgu, Ankara Burcu Darst, Los Angeles
François Audenet, Paris Tommaso Cai, Trento Prokar Dasgupta, London
Etienne Audet-Walsh, Québec city Matthew Campbell, Houston Atreya Dash, Seattle
Herbert Augustin, Graz Riccardo Campi, Florence Timothy Daskivich, Los Angeles
Riccardo Autorino, Richmond Geraldine Cancel-Tassin, Paris Brian Davis, Rochester
Kara Babaian, Illinois Umberto Capitanio, Milan Johann de Bono, London
Darius Bagli, Toronto Paolo Capogrosso, Milan Bram De Laere, Ghent
Aditya Bagrodia, Dallas Maria Carlo, New York Cosimo De Nunzio, Rome
Amit Bansal, Delhi Marco Castagnetti, Padova Marco De Sio, Napoli
Devanshu Bansal, New Delhi Elena Castro, Madrid Xavier Deffieux, Paris
Christopher Barbieri, New York Jozefina Casuscelli, München Paolo Dell’Oglio, Milan
Yuval Bar-Yosef, Tel-Aviv Francesco Ceci, Milan Neil Desai, Dallas
Laurence Baskin, San Francisco Christopher Chapple, Sheffield Robert Dess, Ann Arbor
Wout Devlies, Belgium Christopher Harding, Samuel Lambert, Cambridge

Piet Dirix, Antwerp Newcastle-upon-Tyne Rianne Lammers, Groningen
Steeve Doizi, Paris Vanessa Hayes, Sydney Alessandro Larcher, Milano
Tanya Dorff, Duarte Axel Heidenreich, Cologne Aaron Laviana, Los Angeles
Hugo Dupuis, Rouen Brian Helfand, Evanston Nathan Lawrentschuk, Heidelberg
Shin Egawa, Tokyo Rui Henrique, Porto Massimo Lazzeri, Milan
Michael Eisenberg, Stanford Claire Hentzen, Paris Tiffany Le, New York
Sean Elliott, Minneapolis Cameron Herberts, Vancouver Michael Leapman, New Haven
Ahmed R. EL-Nahas, Mansoura Michelle Higgins, Baltimore John Leppert, Stanford
Laura Elst, Leuven Sarah Holt, Seattle Roger Li, Tampa
Wouter Everaerts, Leuven James Hotaling, Salt Lake City Evangelos Liatsikos, Patras
Christian Fankhauser, Leuven Helen Hougen, Miami Stanley Liauw, Chicago
Fawzy Farag, Sohag Henkjan Huisman, Nijmegen Mark Linch, London
Khaled Fareed, Cleveland Tanja Hüsch, Mainz Michael Liss, San Antonio
Pauline Filippou, Seattle Syed Hussain, Sheffield Börje Ljungberg, UmeÍ
Christopher Filson, Atlanta Ryan Hutchinson, Dallas Simon Lo, Seattle
Neil Fleshner, Toronto Melissa Huynh, London Stacy Loeb, New York
Michael Fraser, Toronto Cristian Ilie, King’s Lynn Christopher Logothetis, Houston
Susanne Fuessel, Dresden Brant Inman, Durham Yohann Loriot, Villejuif
Mauro Gacci, Florence Ilaha Isali, Cleveland Tamara Lotan, Baltimore
Antonio Galfano, Milano Kazuto Ito, Takasaki Yair Lotan, Dallas
Andrea Gallina, Lugano William Jackson, Ann Arbor Giovanni Lughezzani, Milan
Matthew Galsky, New York Michelle Jacobs, Ann Arbor Scott Lundy, Cleveland
Giorgio Gandaglia, Milan Isuru Jayaratna, New York Stephan Madersbacher, Wien
Peter Gann, Chicago Christian Jensen, Herlev Avinash Maganty, Ann Arbor
Tullika Garg, Danville Song Jiang, New York Giuseppe Magistro, München
Stephanie Gazdovich, Montreal Eric Jonasch, Houston Gabriel Malouf, Strasbourg
Arvin George, Ann Arbor Ibrahim Jubber, Sheffield Brandon Manley, Tampa
Daniel Geynisman, Philadelphia Panagiotis Kallidonis, Patras Jodi Maranchie, Pittsburgh
Francesco Giganti, London Sophia Kamran, Boston Laura Marandino, Milan
Kevin Ginsburg, Detroit Anil Kapoor, Hamilton Sarah Markt, Cleveland
François Giuliano, Garches Markos Karavitakis, Athens Giancarlo Marra, Turin
Juan Gomez Rivas, Madrid Veeru Kasivisvanathan, London Timothy Masterson, Indianapolis
Paolo Gontero, Torino Tadas Kasputis, Ann Arbor Joaquin Mateo, Barcelona
Javier Gonzalez, Madrid Max Kates, Baltimore Benjamin Maughan, Salt Lake City
John Gore, Seattle Michael Kattan, Cleveland Tobias Maurer, Hamburg
Stavros Gravas, Larissa Dharam Kaushik, San Antonio Allison May, Ann Arbor
Francesco Greco, Bergamo Sari Khaleel, New York Suzanne Merrill, Hershey
Samantha Greenberg, Salt Lake City Jonathan Khalifa, Toulouse Axel Merseburger, Kiel
Justin Gregg, Houston Zine-Eddine Khene, Rennes Andrea Minervini, Florence
Jon Griffin, Sheffield Pramit Khetrapal, London Sukhbinder Minhas, London
Nikolaos Grivas, Heraklion Eiji Kikuchi, Kawasaki Maria Carmen Mir, Valencia
Viktor Grünwald, Essen Simon Kim, Aurora Thomas Mitchell, Hinxton
Bertrand Guillonneau, Berlin William Kim, Chapel Hill Hiroshi Miyamoto, Rochester
Roman Gulati, Seattle Lisa Kinget, Leuven Parth Modi, Ann Arbor
Shilpa Gupta, Cleveland Amar Kishan, Los Angeles Steven Monda, Sacramento
Gopal Gupta, Maywood Noam Kitrey, Ramat-Gan Bruce Montgomery, Seattle
Naomi Haas, Philadelphia Anders Kjellman, Stockholm Keiichiro Mori, Vienna
Boris Hadaschik, Essen Zachary Klaassen, Augusta Alessandra Mosca, Candiolo
Bernhard Haid, Linz Thomas Knoll, Sindelfingen Matthew Mossanen, Cambridge
Christopher Haiman, Los Angeles Elizabeth Koehne, Seattle Hadi Mostafaei, Wien
A Ari Hakimi, New York Fumitaka Koga, Tokyo Nicolas Mottet, Unias
Zachary Hamilton, St Louis Manish Kohli, Salt Lake City Kent Mouw, Boston
Robert Hamilton, Toronto Christian Kollmannsberger, Vancouver Pavlos Msaouel, Houston
Taha Hamoda, Jeddah Badrinath Konety, Minneapolis Declan Murphy, Melbourne
Raquibul Hannan, Dallas Glen Kristiansen, Bonn Madhur Nayan, Cambridge
Aaron Hansen, Toronto Nils Kroeger, Greifswald Andrea Necchi, Milan
Heidi Hanson, Draper Chris Labaki, Boston Giulio Nicita, Firenze
Noboru Hara, Niigata Maria Pilar Laguna, Istanbul Melianthe Nicolai, The Hague
Anobel Odisho, San Francisco Keyan Salari, Boston Renea Taylor, Melbourne
Dana Ohl, Ann Arbor Renee Saliby, Cambridge Benjamin Teply, Omaha
Brock O’Neil, Salt Lake City Pippa Sangster, London Mario Terlizzi, Villejuif
Sumanta Pal, Duarte Kemal Sarica, Cevizli-Istanbul Nikesh Thiruchelvam, Cambridge
Karl Pang, London J. Sauvain, Vesoul R. Houston Thompson, Rochester
William Parker, Kansas City Jack Schalken, Nijmegen Narhari Timilshima, Toronto
Vipul Patel, Celebration Martin Schoenthaler, Freiburg Jeffrey Tosoian, Nashville
Hiten Patel, Chicago Florian Schroeck, Lebanon Karim Touijer, New York
Anup Patel, London Tyler Seibert, La Jolla Olivier Traxer, Paris
Jacob Patterson, Sheffield Roland Seiler, Bern Dean Troyer, Norfolk
Kathryn Penney, Boston Ege Serefoglu, Istanbul Igor Tsaur, Mainz
Nathan Perlis, Toronto John Sfakianos, New York Samra Turajlic, London
Rodrigo Pessoa, Rochester Majid Shabbir, London Baris Turkbey, Bethesda
Max Peters, Utrecht Vidit Sharma, Rochester Manuela Tutolo, Leuven
Andrew Peterson, Durham Eugene Shenderov, Baltimore Aaron Udager, Ann Arbor
Benoit Peyronnet, Rennes Jonathan Shoag, New York Lucas Van Aelst, Leuven
Ryan Phillips, Baltimore Neal Shore, Myrtle Beach Siska Van Bruwaene, Kortrijk
Phillip Pierorazio, Philadelphia Roswitha Siener, Bonn Roderick van den Bergh, Utrecht
Anna Plym, Solna Mesrur Selcuk Silay, Istanbul Michiel van der Heijden, Amsterdam
Francesco Porpiglia, Turin Matthew Simmons, Bend Theodorus Van der Kwast, Toronto
Camillo Porta, Bari Giuseppe Simone, Rome Henk van der poel, Amsterdam
Sima Porten, San Francisco Karandeep Singh, Ann Arbor Carl Van Haute, Leuven
James Porter, Seattle Udit Singhal, Ann Arbor Mieke Van Hemelrijck, London
Benjamin Pradere, Vienna Nirmish Singla, Dallas Geert van Leenders, Rotterdam
Mark Preston, Boston Tristan Sissung, Bethesda Pim van Leeuwen, Amsterdam
Megan Prunty, Cleveland Shankar Siva, East Melbourne Bas van Rhijn, Amsterdam
Marcus Quek, Maywood Andreas Skolarikos, Athens Gillian Vandekerkhove, Vancouver
Francois Radvanyi, Paris Ted Skolarus, Ann Arbor Thomas Vandenbroeck, Leuven
M.S. Rahnama’i, Maastricht Angela Smith, Chapel Hill Domenico Veneziano, Reggio Calabria
Pawel Rajwa, Vienna Ioannis Sokolakis, Würzburg Grégory Verhoest, Rennes
Ranjith Ramasamy, Miami Abhishek Solanki, Chicago Sita Vermeulen, Nijmegen
Dima Raskolnikov, Seattle Bhaskar Somani, Southampton Paolo Verze, Naples
Adam Reese, Philadelphia Guru Sonpavde, Boston Philippe Denis Violette, London
Zachery Reichert, Ann Arbor Adam Sowalsky, Bethesda Antonia Vlahou, Athens
Yacov Reisman, Amstelveen Anne-Francoise Spinoit, Gent Tatjana Vlajnic, Basel
Sebastiaan Remmers, Rotterdam Michael Staehler, Munich Christopher Wallis, Nashville
Matthew Rettig, Los Angeles Stats Stats, New York Mary Elizabeth Westerman,
Christopher Ricketts, Bethesda Pär Stattin, Uppsala New Orleans
Malte Rieken, Basel Kristian Stensland, Ann Arbor Daniela Wittmann, Ann Arbor
Benjamin Ristau, Farmington Franziska Stolzenbach, Hamburg Alan Wolfe, Maywood
Grégoire Robert, Bordeaux Jens-Uwe Stolzenburg, Leipzig Henry Woo, Sydney
Dudley Robinson, London Konrad Stopsack, Cambridge Bjorn Wullt, Lund
Javier Romero Otero, Madrid Nora Sundahl, Kortrijk Alexander Wyatt, Vancouver
Derek Rosario, Sheffield Cristian Surcel, Bucharest Jianfeng Xu, Evanston
Eduard Roussel, Leuven Louis Surlemont, Rouen Sarah Yentz, Ann Arbor
Olivier Rouviere, Lyon Lisette ’t Hoen, Rotterdam Wesley Yip, New York
Steven Rowe, Baltimore Ruchika Talwar, Philadelphia Jindan Yu, Chicago
Giorgio Ivan Russo, Catania Hung-Jui Tan, Chapel Hill Joseph Zabell, Cleveland
Paul Russo, New York Wei Phin Tan, New York Homayoun Zargar, Melbourne
Vasileios Sakalis, Thessaloniki Jeremy Taylor, Ann Arbor Zachary Zumsteg, Los Angeles

European Urology - Volume 82, Issue 6

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EDITOR EMERITUS (1975–2005) EDITOR EMERITUS (2006–2013)

Claude Schulman, Belgium Francesco Montorsi, Italy

STATISTICAL EDITOR STATISTICAL ASSOCIATE EDITOR STATISTICAL ASSOCIATE EDITOR

SURGERY IN MOTION EDITOR IMAGING EDITOR WORDS OF WISDOM EDITOR

MEDICAL ONCOLOGY EDITOR RADIATION ONCOLOGY EDITOR

MANAGING EDITOR EDITORIAL OFFICE ASSISTANT COPY EDITOR

Hashim Ahmed, UK Jack Elder, USA Valeria Panebianco, Italy

The Platinum Hall of Fame is online only at http://www.sciencedirect.com/science/journal/03022838/82/6

Best Scientific Paper Prizes 2000 to the Present 2006

2012 F. Porpigalia, M. Manfredi, F. Mele, M. Cossu, E. Bollito, A. Veltri,

2018 F.K.-H. Chun, M. Graefen, A. Briganti, A. Gallina, J. Hopp,

European Urology 2011;59:823–831 2016

2022 Platinum Award Winners 2018

Reviewer of the Year 2008 September: Sabine Brookman-May (Germany)

2016 Reviewers of the Month October: Jacob Patterson (UK)

Bladder Cancer First-in-human Intravesical Delivery of Pembrolizumab Identiﬁes Immune 602

Re: A Randomized, Single-blind Clinical Trial Comparing Robotic-assisted Fluoroscopic- 660

Congress Calendar Congress Calendar e180

Acknowledgement to Reviewers e182

Methods Modernizing Statistical Reporting in Medical Journals:

Andrew J. Vickers *, Daniel D. Sjoberg

How Advanced Imaging Will Guide Therapeutic Strategies for

1. Introduction 2. Patient stratification

3. Lesion localisation and treatment planning 4.1. Image-guided intraoperative surgery

Shaping the Undergraduate Curriculum in Europe: Consensus

1. Introduction addition, it has been recorded that undergraduate exposure

Platinum Priority – Review – Prostate Cancer

Androgen Receptor Signaling Inhibitors in Addition to Docetaxel

Article info Abstract

* Corresponding author. Department of Urology, Medical University of Vienna, Wahringer Gurtel 43

1. Introduction 2. Evidence acquisition

2.4. Risk of bias assessment

Idenﬁcaon of studies via databases and registers

Records idenﬁed through PUBMED, Web of Science,

Records excluded aer tle and abstract

Records excluded aer evaluaon

Studies included in meta-analysis

EUROPEAN UROLOGY 82 (2022) 584–598

Meta-analysis of ARSI + DOC + ADT vs Network meta-analysis

EUROPEAN UROLOGY 82 (2022) 584–598

Platinum Priority – Editorial

Triplet Therapy: Entering the Metaverse of Metastatic

Hannah E. Dzimitrowicz, Andrew J. Armstrong *

DOI of original articles: https://doi.org/10.1016/j.eururo.2022.08.002

Disease De novo/synchronous metastases Relapsed/metachronous metastases

Platinum Priority – Bladder Cancer

First-in-human Intravesical Delivery of Pembrolizumab Identifies

Article info Abstract

1. Introduction pants had to have a Eastern Cooperative Oncology Group performance of

trial of intravesical administration of an immune check-

This is a phase 1 dose-escalation study using the 3 + 3 design with four

3. Results weeks until week 17 (first cystoscopy), and then every 4

Table 2 – Adverse events attributed to BCG or pembrolizumab

Event, no. (%) Grade 1 or 2 Grade 3 Grade 4 Grade 5

5. Conclusions Analysis and interpretation of data: All authors.

racy of the data analysis.

Funding/Support and role of the sponsor: This study was supported by

Platinum Priority – Editorial

The Evolving Role of Locally Delivered Checkpoint Inhibitors in

Dickon Hayne a,b,c,*, Andrew Redfern a,b,d

Platinum Priority – Review – Kidney Cancer – Editor’s Choice

The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell

Article info Abstract