Historical Contribution: 1922, Young, Cure of Incontinence with Epispadias

1922

Surgery for epispadias.  An operation for the cure of incontinence associated with epispadias. Young H.H.    J Urol 1922; 7:1. 

In the early 20th century, external procedures could be done to correct the cosmetic appearance but were powerless to cure incontinence.  Dr. Young reviews the existing literature and surgical attempts to provide continence in these patients.  He describes techniques of tubularization, attempts to increase urethral sphincter resistance, and other techniques - none of which achieve adequate social continence for more than a couple of hours.

Then Young describes a case of rectourethral fistula where he was able to restore continence to the patient.  By opening the perineum and reconstitution of the internal and external urethral sphincters, Young restored continence to the patient. From these observations, Young postulated that restoring the internal and external sphincters from an anterior approach could restore continence in young boys and men with epispadias.*

Dr. Young then describes two cases where he was able to restore continence to young men with epispadias. His description of the surgical technique is meticulously detailed.  In addition to creating the surgical technique, Young created surgical instruments to help place the difficult sutures needed for this surgery (as he did for many innovative surgeries).  See the "Boomerang Needle Holder" in the figures below.

In summation, Dr. Young concludes that: 1) continence can be restored during the repair of epispadias, 2) that incontinence is associated with a dilation of the proximal urethra, specifically involving the external sphincter and 3) restoring the external sphincter and "normal" anatomy of the proximal urethra can restore continence perfectly.

Finally, one of the finest aspects of this manuscript are the wonderful medical drawing by William P. Didusch including the abnormal anatomy of the epispadias deformity and methods of penile reconstruction.

Epispadias defect before repair.

Cosmetic appearance after Young's epispadias repair.

*This is reminiscent of the classic story Dr. Patrick C. Walsh tells about discovering the cavernous nerves of the penis.  In a fortuitous event, Dr. Walsh performed a radical prostatectomy and a patient was potent afterwards.  The nerves that innervate the penis, Dr. Walsh postulated, must therefore run outside the prostate and can be spared during radical surgery.  The rest, they say, is history.

To read the entire manuscript follow the link above or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

AUA Highlights: Kidney Cancer, by Dr. Pierorazio

Kidney cancer is one of the major diseases treated by urologists and urologic oncologists.  Kidney cancer was well represented at this year's 2014 American Urological Association (AUA) Annual Meeting in Orlando, Florida.  Kidney cancer had a major seat in the AUA plenary sessions and the Society of Urologic Oncology (SUO) Meeting.  In addition, the scientific sessions were well attended and lively discussion often ensued.  Here are some of the highlights and commentary from the meeting, click on the links below to see webcasts or read the abstracts:

During the AUA Plenary: CROSSFIRE - CONTROVERSIES IN UROLOGY, kidney cancer thought-leaders Michael Jewett, Inderbir S. Gill, MD, MCh, Robert G. Uzzo, MD, Michael Blute, MD and John Libertino, MD debated "Minimally Invasive Partial Nephrectomy is the New Gold Standard for Renal Cancer."  (Follow the link above or click here to see the debate)  In general, the debate lacked strong evidence and was an endorsement of expert opinions.  However, Dr. Uzzo did an excellent job and laid out the argument, showing that while no Level 1 Evidence exists comparing minimally-invasive and open Partial Nephrectomy (PN), population-based data demonstrates an ever-increasing use of minimally-invasive surgery (MIS) and improved perioperative outcomes (length of stay, decreased blood loss and lower complications) for MIS.  However, oncologic outcomes (most importantly margin rates and cancer-specific survival) are equivalent between the two approaches.  Drs. Blute and Libertino argued for the continued use of open PN, citing the equivalent oncologic outcomes.  My take home was: there is a role for both minimally-invasive and open partial nephrectomy.  Outcomes are similar and the surgeon should perform the best operation for that given patient and tumor.

In the SUO Meeting, topics ranged from clinically localized to metastatic kidney cancer.  A major topic of focus at this meeting and throughout the week was clinical heterogeneity in kidney cancer. James Hsieh, MD, PhD, laid out an elegant argument for a "River Model" instead of "Branched Evolution" (akin to a tree) for the genetic evolution of kidney tumors.  He argued that as kidney tumors grow and progress, the genetics diverge and converge along several pathways, instead of following a number of linear progressions.  Other topics of interest including percutaneous renal mass biopsy and the treatment of metastatic disease.  Dr. Jewett discussed biopsy for all patients demonstrating a 94% concordance rate of low-grade renal cell carcinoma (RCC) in their Canadian series.  While these concordance rates are promising, they should be taken with consideration that most patients with small renal masses have low-grade tumors and therefore these numbers are skewed to predict insignificant disease.  In contrast, Dr. Uzzo argued for a more thoughtful approach and biopsy in only those patients in whom it would change mangement.  With regard to metastatic cancer, Dr. Figlin laid out a thoughtful paradigm for the treatment of advanced cancers based on objective response to systemic therapy, rather than picking from the list of options currently advocated by groups like the National Comprehensive Cancer Network (NCCN).

KIDNEY CANCER PSEUODOCAPSULE & ENUCLEATION

A number of posters and podiums focused on the biologic boundaries of renal cell carcinoma and its implications for positive surgical margins, enucleation and cancer control.  Alessandro Volpe and colleagues from Milan, Italy demonstrated that 40-50% of RCC invade the pseudocapsule and those tumors had a worse prognosis.  A group from Germany found that patients with a margin of 1mm or less had a higher rate of disease recurrence and kidney cancer death.  Finally, Dr. Ronald Boris and colleagues from Indiana looked at patients with clear-cell RCC and the complete tumor capsule and surrounding inflammation around the tumor.  They found that RCC rarely demonstrated capsular invasion, however found "gaps" in the tumor capsule gaps more often in late stages indicating there may be a loss of immune “control” over capsular penetration when elucidating the aggressive behavior of advanced ccRCC.

PD10-06: Classification of pseudocapsular invasion in organ-confined renal cell carcinoma: correlation with histological variables and prognostic impact.  Alessandro Volpe*, Antonia Di Domenico, Novara, Italy, Enrico Bollito, Turin, Italy, Cristina Bozzola, Novara, Italy, Riccardo Bertolo, Turin, Italy, Luisa Zegna, Paolo De Angelis, Novara, Italy, Daniele Amparore, Francesco Porpiglia, Turin, Italy, Carlo Terrone, Novara, Italy
PD10-08: Prognostic impact of tumor surrounding renal parenchyma in nephron sparing surgery – Is simple enucleation really enough? Stefan Aufderklamm*, Jörg Hennenlotter, Tilman Todenhöfer, Nicolas Senghaas, Georgios Gakis, Marcus Scharpf, Arnulf Stenzl, Christian Schwentner, Tuebingen, Germany
MP30-21: Pathologic variances in tumor capsule properties of clear cell renal cell carcinoma across various clinical stages Joseph M. Jacob*, Dibson D. Gondim, Jose A. Pedrosa, Muhammad T. Idrees, Ronald S. Boris, Indianapolis, IN

ACTIVE SURVEILLANCE FOR KIDNEY CANCER

Active surveillance (AS) was a hot topic given the recent questions of overtreatment in other diseases like prostate cancer.  The Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry is a multi-institutional study led by Johns Hopkins, that has followed nearly 200 patients over the past 5 years.  Six abstracts demonstrated results from DISSRM:

• PD10-09: DISSRM Score is an objective scoring system composed of age, ECOG performance status, tumor size, tumor complexity (RENAL Nephrometry) and Cardiovascular Index that identifies patients most suitable for AS.
• MP54-03: The 1st surveillance image for patients on AS can lead to highly variable growth rates.  Over the course of a year or more, most patients demonstrate a slow growth rate (approximately 1mm/year), however this can be grossly overestimated by the high-variability of GR in the first image within a few months of starting surveillance.  Hear the webcast at UroToday.
• MP54-04: Patients on AS have a decreasing GFR equivalent to patients undergoing PN, while both were superior to Radical Nephrectomy (RN).  It appeared that renal function was unaffected by tumor size or GR, however should be considered when choosing a management strategy.
• MP54-05: Quality-of-life was not adversely affected for patients on AS; in fact they had worse perception of physical health (reflecting their increased comorbidities and advanced age), but no change in mental health over time.
• MP64-09: In this analysis, tumors close to the renal hilum and collecting system had higher growth rates that other tumors, perhaps indicating more aggressive tumors, but at a minimum providing expectations for patients undergoing AS.
• PD17-06: With a median follow-up of 2 years, but a maximum of 5 years, the overall survival was equivalent among patients undergoing immediate treatment of AS. No patients undergoing AS died of kidney cancer.

Other groups also looked at AS cohorts: 

• PD17-04, PD17-05: Dr. Mehrazin and colleagues from Fox Chase looked at their AS experience and found that complex tumors were more likely to grow rapidly and examined outcomes for their patients with larger, cT1b renal tumors.  They found similar growth kinetics for larger and smaller tumors.  They found 34% of patients underwent surgery, but no patients died of kidney cancer.
• MP59-20: Dr. Dorin and colleageus looked at a conglomerate of small renal and complex cystic masses and found low growth rates and progression.  They found that GR decreased with increasing mass size and a 35% rate of intervention at 10-years.

PD10-09: The DISSRM Score: Objective Scoring System Identifies Patients with Small Renal Masses Most Suitable for Active Surveillance.  Phillip Pierorazio, Deborah Kaye*, Baltimore, MD, Matthew Danzig, Rashed Ghandour, New York, NY, Peter Chang, Robert Hartman, Andrew Wagner, Boston, MA, James McKiernan, New York, NY, Mohamad Allaf, Baltimore, MD

MP54-03: First Surveillance Image for Patients with a Small Renal Mass Should Not Determine Outcome: Results from the DISSRM Registry.  Phillip Pierorazio, Nathaniel Readal*, Baltimore, MD, Matthew Danzig, Rashed Ghandour, New York, NY, Peter Chang, Robert Hartman, Andrew Wagner, Boston, MA, James McKiernan, New York, NY, Mohamad Allaf, Baltimore, MD

MP54-04: Partial Nephrectomy is Equivalent to Active Surveillance in Preserving Renal Function for Patients with Small Renal Masses.  Matthew Danzig*, Rashed Ghandour, Srinath Kotamarti, Tina Schubert, Arindam RoyChoudhury, New York, NY, Phillip Pierorazio, Baltimore, MD, Ketan Badani, New York, NY, Mohamad Allaf, Baltimore, MD, James McKiernan, New York, NY

MP54-05: Mental Health Not Affected by Active Surveillance for Patients with Small Renal Masses: Quality of Life Results from the DISSRM (Delayed Intervention and Surveillance for Small Renal Masses) Registry.  Phillip Pierorazio, Michael Gorin*, Baltimore, MD, Matthew Danzig, Rashed Ghandour, New York, NY, Peter Chang, Robert Hartman, Andrew Wagner, Boston, MA, James McKiernan, New York, NY, Mohamad Allaf, Baltimore, MD

MP64-09: Prospective Analysis of Tumor Growth Rates Based on Patient Comorbidities and Imaging Characteristics from the DISSRM Registry: Implications for Future Nephron-Sparing Surgery.  Phillip Pierorazio, Mark Ball*, Baltimore, MD, Matthew Danzig, Rashed Ghandour, New York, NY, Peter Chang, Robert Hartman, Andrew Wagner, Boston, MA, James McKiernan, New York, NY, Mohamad Allaf, Baltimore, MD

PD17-06: Active surveillance for small renal masses non-inferior to primary intervention: 5-year analysis of the multi-institutional, prospective DISSRM (delayed intervention and surveillance for small renal masses) Registry.  Phillip Pierorazio, Mark Ball*, Baltimore, MD, Matthew Danzig, Rashed Ghandour, New York, NY, Peter Chang, Robert Hartman, Andrew Wagner, Boston, MA, James McKiernan, New York, NY, Mohamad Allaf, Baltimore, MD

PD17-04: EXPERIENCE WITH ACTIVE SURVEILLANCE (AS) IN PATIENTS WITH RENAL MASS >4cm: ASSESSMENT OF GROWTH KINETICS AND OUTCOMES.  Reza Mehrazin*, Marc C. Smaldone, Alexander Kutikov, Jeffrey J. Tomaszewski, Tianyu Li, Timothy Ito, Philip Abbosh, Rosalia Viterbo, Richard E. Greenberg, David Y.T. Chen, Robert G. Uzzo, Philadelphia, PA

PD17-05: Tumor Anatomic Complexity Predicts Growth Kinetics of Renal Masses Under Active Surveillance.  Reza Mehrazin*, Marc C. Smaldone, Brian Egleston, Charlie Concodora, Jeffrey J. Tomaszewski, Philip Abbosh, Timothy Ito, Jason Lomboy, Alexander Chow, Rosalia Viterbo, Richard E. Greenberg, David Y.T. Chen, Alexander Kutikov, Robert G. Uzzo, Philadelphia, PA

MP59-20: Active Surveillance of Renal Masses: An Analysis of Growth Kinetics and Clinical Outcomes Stratified by Radiological Characteristics at Diagnosis.  Ryan Dorin, Antonio Cusano*, Max Jackson, Stuart Kesler, Anoop Meraney, Steven Shichman, Hartford, CT

IMPROVING THE DIAGNOSIS OF KIDNEY CANCER

A number of presentations demonstrated improved diagnostic techniques. Differentiating RCC and oncocytoma can be difficult based on enhanced axial imaging.  Simply looking at the presence of hematuria improved the ability to discriminate between the two entities (MP36-14).  In addition, using clinical parameters including tumor size, sex and RENAL nephrometry score could improve the ability to determine benign histology, malignant histology and potentially aggresive tumors (MP40-09).  For instance, women with <3cm tumors and low-complexity tumors had only a 64% chance of malignancy and on 9% had high-grade tumors; while 90% of men with >3cm tumors and nephrometry scores >8 had RCC and 35% had high-grade cancers.  Hear the webcast of this study at UroToday.

MP36-14: Can Hematuria be Used to Predict RCC vs. Oncocytoma Histology? Michael Hanzly*, Terry Creighton, Christine Murekeyisoni,, Elizabeth Devine, Shervin Badkhshan, Michael Mungillo, Thomas Schwaab, Eric Kauffman, Buffalo, NY

MP40-09: Preoperative predictors of malignancy and unfavorable pathology for clinical T1a renal tumors treated with partial nephrectomy.  Mark Ball*, Michael Gorin, Baltimore, MD, Sam Bhayani, St. Louis, MO, Craig Rogers, Detroit, MI, Michael Stifelman, New York, NY, Jihad Kaouk, Homayoun Zargar, Cleveland, OH, Susasn Marshall, New York, NY, Jeffrey Larson, St. Louis, MO, Phillip Pierorazio, Mohamad Allaf, Baltimore, MD

IMPROVING RENAL FUNCTIONAL OUTCOMES AFTER SURGERY

In an impressive, "out-of-the-box" presentation in a basic science section, Drs. Alexander and Dorai from New York Medical College used 5'AMP to induce a gobal hypometabolic state similar to to hibernation and were able to attenuate the effects of renal ischemia in an animal model (MP29-09).  A number of studies looked at surgically-induced chronic kidney disease (CKD-S).  Researchers found that patients who developed CKD-S had worse overall and cancer-specific survival (PD16-02).  The group from Columbia University found that there were no differences in renal functional outcomes or overall survival for patients undergoing PN or RN if they had no CKD or Stage 3 CKD and the only benefits with respect to nephron-sparing surgery was found in patients with intermediate levels of CKD (PD17-10).  Another study found that the benefits of PN were not observed in patients >65 years of age (MP54-20).  The benefits of nephron-sparing surgery with respect to renal function are well understood, however the patients who most benefit from nephron-sparing surgery is still to be defined.  

A number of other studies examined ischemia time and parenchyma saved during PN to predict renal functional outcomes.  Important observations from presentations included: there was no difference between zero ischemia and warm ischemia <30 minutes (MP54-13) and that quantity, not quality of parenchyma saved predicted renal functional outcome (PD17-03).  Finally, an important study using SEER, showed that patients with low-grade or any T1 clear-cell RCC with end-stage renal disease should proceed directly to transplant without a waiting time as there risk of recurrence was negligible and not increased due to immunosuppression (MP59-10).

MP29-09: INDUCTION OF HYPOMETABOLISM AS A NOVEL STRATEGY TO EXTEND WARM ISCHEMIA TIME IN PARTIAL NEPHRECTOMIES.  Bobby Alexander*, Meris James, Andrew Fishman, Michael Grasso, Thambi Dorai, Valhalla, NY
PD16-02: IMPACT OF RENAL SURGERY ON OVERALL, ONCOLOGIC, AND CARDIAC MORTALITY IN PATIENTS WITH STAGE I RENAL CELL CARCINOMA AND WITHOUT PREOPERATIVE RENAL INSUFFICIENCY.  Jason Woo*, Michael Liss, Nishant Patel, San Diego, CA, Reza Mehrazin, Memphis, TN, Hak Lee, San Diego, CA, Anthony Patterson, Jim Wan, Memphis, TN, Ithaar Derweesh, San Diego, CA
PD17-10: Renal Failure Following Partial vs Radical Stratified by Preoperative CKD Stage.  Solomon Woldu*, Matthew Danzig, Rashed Ghandour, Aaron Weinberg, Natasha Leigh, Ruslan Korets, Ketan Badani, James McKiernan, Guarionex Joel DeCastro, New York, NY
MP54-20: Overall survival and renal function of partial and radical nephrectomy among older patients with localized renal cell carcinoma: multicenter study.  Jae Seung Chung*, Busan, Korea, Republic of, Seok Soo Byun, Sang Eun Lee, Sung Kyu Hong, Sang Chul Lee, Seongnam, Korea, Republic of, Chang Wook Jeong, Hyeon Hoe Kim, Cheol Kwak, Ja Hyeon Ku, Seoul, Korea, Republic of, Yong June Kim, Cheongju, Korea, Republic of, Seok Ho Kang, Sung Hoo Hong, Won Suk Choi, Seoul, Korea, Republic of
MP54-13: The effects of prolonged warm ischemia on late renal function after robotic partial nephrectomy.  Oktay Akca*, Homayoun S. Zargar, Luis Felipe Brandao, Humberto Laydner, Riccardo Autorino, Jayram Krishnan, Dinesh Samarasekera, George P. Haber, Robert J. Stein, Jihad H. Kaouk, Cleveland, OH
MP59-10: Immunosuppression does not worsen disease-specific survival among patients with renal carcinoma who have undergone renal transplantation.  Bhalaajee Meenaski-Sundaram*, Oklahoma City, OK, Oluwakayode Adejoro, Sean Elliot, Minneapolis, MN, Puneet Sindhwani, Joel Slaton, Oklahoma City, OK
PD17-03: POORLY FUNCTIONING KIDNEYS RECOVER FROM ISCHEMIA DURING PARTIAL NEPHRECTOMY AS WELL AS STRONGLY FUNCTIONING KIDNEYS.  Maria Carmen Mir*, Toshio Takagi, Rebecca Campbell, Nidhi Sharma, Erick Remer, Jianbo Li, Sevag Demirjian, Jihad Kaouk, Steve C Campbell, Cleveland, OH

KIDNEY CANCER SURVIVAL & TREATMENT OF ADVANCED DISEASE

Finally, in the area of advanced disease, the group from MD Anderson demonstrated that lymph node dissection was protective in patients with T4 and metastatic disease (MP36-20).  For patients with renal vein thrombus, BMI<20, preoperative anemia, renal fat invasion, non-clear cell histology and grade 4 disease predicted survival (PD16-04).  Another presentation demonstrated that blood transfusion, in a dose-dependent fashion, was associated with worse survival for patients undergoing surgery for RCC (PD16-03).  Patients with >1cm and multiple lung nodules were more likely to have metastatic RCC (PD17-07).  When considering patients at highest risk for recurrence, those who recurred within 1 year of initial surgery had the highest mortality from RCC with rates of cancer-specific mortality decreasing with later follow-up (MP40-14).

MP36-20: Survival and Prognostic Variables Predicting Survival in T4 Renal Cell Carcinoma.  Dae Y. Kim*, Christopher G. Wood, Angie Busch, Wei Qiao, Pheroze Tamboli, Eric Jonasch, Nizar M. Tannir, Surena F. Matin, Jose A. Karam, Houston, TX
PD16-04: CURATIVE SURGERY IN RCC WITH THROMBUS; A COMPREHENSIVE RISK MODEL FROM A MODERN MULTICENTER ANALYSIS.  Tyler M. Bauman*, Madison, WI, Vitaly Margulis, Dallas, TX, Christopher G. Wood, Houston, TX, William P. Christensen, Madison, WI, Vishnukamal Golla, Houston, TX, Ramy F. Youssef, Laura-Maria Krabbe, Dallas, TX, David F. Jarrard, Tracy M. Downs, E. Jason Abel, Madison, WIPD16-03: The Impact of Perioperative Blood Transfusion on Survival Following Nephrectomy for Non Metastatic Renal Cell Carcinoma.  Brian Linder*, R. Houston Thompson, Bradley Leibovich, John Cheville, Christine Lohse, Dennis Gastineau, Stephen Boorjian, Rochester, MN
PD17-07: The Clinical Significance of Indeterminate Pulmonary Nodules in Renal Cell Carcinoma.  Roy Mano*, Emily Vertosick, Alexander Sankin, Michael Chevinsky, Yaniv Larish, Christopher Jakubowski, Andreas Hoetker, A Ari Hakimi, Daniel Sjoberg, Oguz Akin, Paul Russo, New York, NY
MP40-14: Predictors of cancer-specific survival after disease recurrence in patients with renal cell carcinoma: The effect of time to recurrence.  Malte Rieken*, Luis Kluth, Evanguelos Xylinas, New York, NY, Umberto Capitanio, Alberto Briganti, Milan, Italy, Laura-Maria Krabbe, Vitaly Margulis, Dallas, TX, Jay Raman, Mikhail Regelman, Hershey, PA, Tobias Klatte, Vienna, Austria, Matthew Kent, Daniel Sjoberg, New York, NY, Alexander Bachmann, Basel, Switzerland, Shahrokh Shariat, Vienna, Austria

To read the entire abstract follow the links below:
For podium presentations (PD5-), click here.
For poster presentations (MP10-), click here.

Phillip M. Pierorazio, MD is an Assistant Professor of Urology & Oncology, Director of the DISSRM Registry and Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  

100 Years of Urological History: The Brady Centennial Approaches

The Brady Urological Institute at Johns Hopkins opened January 21, 1915.  The Brady has a long standing history of excellence and discovery in the diagnosis and treatment of urological disease.  In preparation for the momentous celebration, we launch a webpage celebrating the rich history of urology as it happened through our Institute.  On the webpage you will find:

• Our greatest discoveries
• Brief biographies of a number of important figures in our history:
• James Buchanan "Diamond Jim" Brady, our benefactor
• The four Directors of the Brady Urological Institute:
• Hugh Hampton Young
• William Wallace Scott
• Patrick C. Walsh
• Alan W. Partin
• Historic Books with full biographies of HH Young, WW Scott
• Classic Photos and Videos 
• Presentations by Dr. Patrick C. Walsh and Donald S. Coffey reviewing the historical narrative or the Brady Urological Institute

While the centennial will be celebrating our Institute, we will review the history of urology through the last century in the framework of the "Heritage of Excellence" at Johns Hopkins.  Over the upcoming months, we will be introducing some of the more intriguing and interesting parts of our history through this blog.  This page will be continuously updated with links to the website and entries as they become available.  

We look forward to sharing our history with you!

Check out our Centennial Website by clicking here.

Nanoparticles and Prostate Cancer

Amarnath Mukherjee, PhD

Nanoparticles are small objects having a diameter in the nano-meter range (10-9 m) which behave as small individual particles. Over the last two decades, nanoparticles have made its impact in every area of science and technology. This is because they possess distinct properties (attributed to their small size and high surface to volume ratio) which can be explored for unique use. For example, iron-oxide based nanoparticles have been simultaneously used both in imaging (as MRI contrast agents) and therapy (through hyperthermia or drug delivery). [1] Amarnath Mukherjee, PhD, is a researcher in the Brady Urological Insitute at Johns Hopkins, who is studying the use of nanoparticle for potential cancer therapy/diagnosis with Shawn E. Lupold, PhD, and Co-Director of the Prostate Cancer Program at the Sidney Kimmel Cancer Center at Hopkins.

Prostate Specific Membrane Antigen (PSMA) is an established target for cancer therapeutic and imaging agents due to its high expression on the surface of prostate cancer cells and within the neovasculature of other solid tumors. Drs. Mukherjee and Lupold have developed a humanized anti-PSMA antibody conjugated silica-coated iron oxide nanoparticles for PSMA-specific cell binding – a iron oxide nanoparticle that can hone specifically to prostate cancer cells. [2] Customized assays utilizing iron spectral absorbance and Enzyme-Linked Immunoassay (ELISA) were developed to screen nanoparticle formulations for immunoreactivity and PSMA-targeting. Antibody and PSMA-specific targeting of the optimized nanoparticle was evaluated using an isogenic PSMA-positive and PSMA-negative cell line pair. These nanoparticles and the methods used to validate their function support the promise of targeted theranostic agents for future treatment of prostate and other cancers.

Although nanoparticles offer significant promise for new mode of diagnosis and therapy, they come with new challenges. For example, Iron oxide nanoparticles capable of generating localized heat are reshaping the concept of targeted and focal hyperthermia as a cancer therapy. Traditional hyperthermia (or energy ablation) uses energy sources to destroy a target lesion, usually localized with imaging like CT, MRI or ultrasound. However, nanoparticle-mediated hyperthermia is different than traditional hyperthermia in a few senses. First, nanoparticle-mediated hyperthermia has the ability to target microscopic foci of cancer not seen on traditional imaging. In addition, traditional hyperthermia often destroys tissues, both malignant and benign, within a “killzone” created by the energy source. Drs. Mukherjee and Lupold have studied and compared (using temperature sensitive secreted luciferase-based reporter gene system) thermal stress response, at the cellular level, to macroscopic and NP hyperthermia. [3] The results indicate that cells can detect mild heat stress from nanoparticles at temperatures too low to measurably alter the macroscopic temperature of the system – indicating that the target cells can be “cooked” without damaging nearby normal cells. The results also suggest that cells which were closer to the nanoscopic heat source experienced greater thermal stress. Further characterization of the nature of nanoparticle heating and its relationship to macroscopic hyperthermia is needed prior to moving nanoparticle research into human experiments and the clinic.

[1] N. Ahmed, H. Fessi, A. Elaissari, Drug discovery today 2012, 17, 928-934.
(http://www.ncbi.nlm.nih.gov/pubmed/22484464)
[2] A. Mukherjee, T. Darlington, R. Baldwin, et al ChemMedChem 2014.
(http://www.ncbi.nlm.nih.gov/pubmed/24591351)
[3] A. Mukherjee, M. Castanares, M. Hedayati, et al Nanomedicine (Lond) 2014.
(http://www.ncbi.nlm.nih.gov/pubmed/24547783)

 

Historical Contribution: 1921, Macht & Bloom, The Effect of Radical Prostatectomy on Rats

1921

Macht DI, Bloom WM.  Effect of Prostatectomy on the Behavior of Albino Rats.  J of Urol. 1921;1: 29-41

This article appeared in the 1921 Journal of Urology as part of a series on the "Physiological and Pharmacological Studies of the Prostate Gland."  In the introduction, Macht and Bloom describe the impetus for such research:

"The recent advances in our knowledge of internal secretions have caused not only physiologists but also clinicians to be on the lookout for manifestations pointing to a possible derangement in the functions of various glands.  To this the prostate gland is no exception."

They describe an observed associated between psychopathic or neuropathic symptoms associated with the internal secretions of the prostate gland and thus embark on a series of animal experiments.  In fact, a popular patient series of the time period described a significant number of patients with benign and malignant prostate issues to have melancholia, hallucinations and psychoses.  In addition, controversy existed about the influence of prostate surgery on mental health; with many urologists believing that "complete extirpation of the prostate gland has no bearing on the character and mental efficiency of the patients" and, in some cases, may "improve in health of body and mind after prostatic operations."

Even in contemporary times, many urologists and physicians have seen patients extremely affected by their urinary and/or sexual issues (both before and after urological surgery).  In fact, "bother" drives most of the treatment algorithms for benign prostatic hypertrophy in modern Urological Association guidelines.  As Macht and Bloom elude to, "clinical data are very unreliable" and deciphering if mental disturbances were associated with or caused by prostate issues had not been properly investigated.  Therefore, Macht and Bloom endeavored to see if they could alter the "character, mentality and neuromuscular coordination" of animals after their prostate was removed.

The main experiment from this study involves memory testing through a well-established protocol of experimentation with albino rats in a circular maze (figure).

Circular maze used to test rate of learning, behavior and memory-habit in rats undergoing prostatectomy.

In total, 28 rats were randomized to prostatectomy or control, and then observed as they learned the maze.  Average days to learn the maze in the prostatectomy rats was 8.2 days and 9.9 days in the control rats - a difference that was not statistically different.

These data, along with other minor experiements, led Macht and Bloom to conclude that "endocrine function of the prostate gland bears no relation to the mental efficiency of the animals."

To read the entire manuscript click on the link above or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Faculty Spotlight: Stephen Schatz, Innovative Treatments of BPH

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are incredibly common.  Approximately 40% of 50-year old men with have histologic evidence of BPH at autopsy, this number increases to 80% for 80-year men.  Over the same time period, mean prostate volume increases from an average baseline of 15-25 grams at age 50 to 25-40 grams at age 80.  In addition, the percentage of men with moderate-to-severe LUTS increases with age.[1]  When LUTS are bothersome, treatment options for BPH include medication and, when medications fail, surgery.

Stephen Schatz, MD

The traditional surgery for BPH is the transurethral resection of the prostate (TURP).   This operation has long been considered the "gold standard" for symptom relief.  But now, instead of chipping away at the prostate, says urologist Stephen Schatz, "we are doing far more procedures using either bipolar electrosurgical vaporization or laser vaporization techniques."  Essentially, vaporization destroys prostatic tissue using a high-energy source that coagulates as it destroys, preventing bleeding.

"Vaporization techniques are demonstrated to be safer than traditional TURP, with results that are entirely comparable" in terms of the durability and degree of symptoms relief, and retreatment rates are quite low.[2]  

With vaporization, the only significant downside is temporary worsening of irritative urinary symptoms (frequency, urgency and burning) immediately afterward.  But, Schatz says, "I have found this always gets better, and the long-term improvement is profound in most men.  It's a great alternative to long-term medical treatment," which takes longer to achieve an effect and does not provide as great a relief of symptoms.

Although Schatz performs all the surgical procedures, he prefers bipolar vaporization.  "I can see the prostate clearly as I work, without bleeding obscuring my view," he says.  Immediately afterwards, he adds, "the urine is almost always clear."  Only about 5% of patients stay overnight.  In addition, the rates of erectile dysfunction lower than with TURP because there is no electricity arcing outside the prostate and potentially injuring the cavernous nerves.

For men with BPH and low-risk prostate cancer...

Schatz and colleagues are even able to use vaporization on men with low-risk prostate cancer in Johns Hopkins' active surveillance program who are significantly bothered by LUTS.  "We continue to follow them regularly with biopsies and PSA tests," he says, "but the cancer doesn't get in the way of their treatment."

For men with very large prostate...

Schatz performs a simple prostatectomy - enucleation of the prostate, going in through a skin incision and through the bladder - robotically.  In a case series of more than 50 patients, Johns Hopkins urologists have reported outcomes that are comparable to the results from open surgery, but with clear decreases in perioperative blood loss.

For men who are poor candidates for surgery...

Schatz and interventional radiologist Mark Lessne are conducting a multicenter trial comparing prostatic artery embolization with traditional TURP, using very rigorous outcome measures, measuring prostates and performing urodynamics before and after, and tracking quality of life indices to see how patients respond.  The angiography procedure, done through the femoral artery, takes less than three hours and has "essentially no blood loss and no absorption of any fluids," Schatz says.  Symptoms improvement comes gradually as prostate tissue dies.  Click on the following link to see our prior blog entry on prostatic artery embolization.

Schatz suspects that within a few years, this treatment will be offered to men who "may not be candidates for even minimally invasive surgery, but who have significant symptoms not helped all that much by medications."

This blog entry is extracted and modified from the "Johns Hopkins Urology: News for Physicians from Johns Hopkins Medicine," Spring 2014.

[1] Roehrborn, Claus G., MD.  Benign Prostatic Hyperplasia : Etiology, Pathophysiology, Epidemiology, and Natural History [Book] Campbell-Walsh Urology, chapter 91, Pages 2570-2610.e10 Copyright © 2012, 2007, 2002, 1998, 1992, 1986, 1978, 1970, 1963, 1954 by Saunders, an imprint of Elsevier Inc.
[2] Teng J1, Zhang D, Li Y, Yin L, Wang K, Cui X, Xu D.  Photoselective vaporization with the green light laser vs transurethral resection of the prostate for treating benign prostate hyperplasia: a systematic review and meta-analysis.  BJU Int. 2013 Feb;111(2):312-23. doi: 10.1111/j.1464-410X.2012.11395.x. Epub 2012 Nov 13.

AUA Best Abstracts from the Residents

The American Urological Assocation (AUA) Annual Meeting is a wonderful opportunity for urology residents, trainees and medical students to showcase the hard-work and research they have performed, as well as to meet other urologists, learn about the field and see cutting edge data.  Each of the residents below attended this year's AUA Meeting in Orlando, Florida to present individual research.  In addition to presenting their own work, they attended scientific sessions and interacted with other researchers.  Each resident has selected their own "Highlights" from the meeting and discuss them below.

To read the entire abstract follow the links below:
For podium presentations (PD5-), click here.
For poster presentations (MP10-), click here.

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Nilay Gandhi, MD; Senior Assistant (U3) Resident

**MP34-07: Differential Gene Expression In Responsive Versus Recurrent Non-muscle Invasive High-grade Urothelial Carcinomas After Induction BCG. Philip Ho*, Daniel Willis, Houston, TX, Saad Aldousari, Kuwait, Kuwait, Charles Guo, Colin Dinney, Xifeng Wu, Ashish Kamat, Houston, TX

Interesting research assessing mRNA differential expression identifying significant increase in the expression of genes involved with cell cycle progression, cell death/necrosis/apoptosis, and migration of antigen presenting cells. Extremely important to identify predictors of BCG response given likelihood of patient side effects and up to 40% failure rate after induction BCG.
**Also selected by Max Kates (below)


MP55-13: INTRAOPERATIVE BLOOD TRANSFUSION DURING RADICAL CYSTECTOMY INCREASES THE RISK OF DEATH FROM BLADDER CANCER COMPARED TO POSTOPERATIVE TRANSFUSION.  E. Jason Abel*, Madison, WI, Brian J. Linder, Rochester, MN, Tracy M. Downs, Tyler M. Bauman, Madison, WI, R. Houston Thompson, Prabin Thapa, Rochester, MN, Octavia N. Devon, Madison, WI, Robert F. Tarrell, Igor Frank, Matthew K. Tollefson, Rochester, MN, David F. Jarrard, Madison, WI, Stephen A. Boorjian, Rochester, MN

Assessment of 360 patients identifying 30% increased risk of death from bladder cancer in patients receiving intraoperative transfusion compared to those postoperatively. Also noted within older patients with more advanced stage disease. Critiques include likely multifactorial, requires stage for stage assessment to identify true clinical impact, no neoadjuvant chemo pts included.

Debasish Sundi, MD; Senior Assistant (U3) Resident

MP61-19: A novel role of the transcription factor TCF21 as a suppressor of bladder cancer metastasis.  Sima Porten*, Beat Roth, Jonathan Melquist, Woonyoung Choi, Shanna Pretzsch, Jolanta Bondaruk, Charles Guo, Bogdan Czerniak, David McConkey, Colin Dinney, Houston, TX

The transcription factor TCF21 may serve as a mediator of the transition from local to metastatic urothelial cancer.  A number of studies focused at this year's AUA looked at gene expression in the transition from local, to invasive, to metastatic urothelial cancer.  I am intrigued by this transition, and a better understanding of these gene transcripts, like the transciption factor in this presentation, may improve our understanding (and therefore treatment) of urothelial cancer metastases.


**PD34-08: Disparities in survival for California men with prosate cancer are more associated with socioeconomics than either race or insurance status. Thenappan Chandrasekar*, Kari Fish, Christopher Evans, Ralph DeVere White, Marc Dall'Era, Sacramento, CA

The podium is one of the three reports of Black race as an independent risk factor for adverse oncologic outcomes after radical prostatectomy after controlling for SES.  The other two include a 15 year-old study of SEER from our colleagues at UCSF and work done at Johns Hopkins by Farzana Faisal (below).
**Also selected by Farzana Faisal (below).

Mark W. Ball, MD; Lab Resident

MP59-18 Chronic Kidney Disease Due to Surgery (CKD-S): Relative Rates of Progression and Survival. Sevag Demirjian*, Cleveland, OH, Brian Lane, Grand Rapids, MI, Ithaar Derweesh, La Jolla, CA, Toshio Takagi, Amr Fergany, Steven Campbell, Cleveland, OH

This study evaluated progression of renal failure in a cohort of patients with GFR < 60 after surgery by classifying as  surgical chronic kidney diseaes (CKD) (normal  GFR before surgery) and medical CKD (low GFR before surgery) and a medical CKD only cohort. Overall patients with surgical CKD has less progression and increased overall survival compared to patients in either medical CKD cohort. This work bolsters previous work from the authors that shows a clear distinction between medical and surgical CKD.

MP54-20: Overall survival and renal function of partial and radical nephrectomy among older patients with localized renal cell carcinoma: multicenter study.  Jae Seung Chung*, Busan, Korea, Republic of, Seok Soo Byun, Sang Eun Lee, Sung Kyu Hong, Sang Chul Lee, Seongnam, Korea, Republic of, Chang Wook Jeong, Hyeon Hoe Kim, Cheol Kwak, Ja Hyeon Ku, Seoul, Korea, Republic of, Yong June Kim, Cheongju, Korea, Republic of, Seok Ho Kang, Sung Hoo Hong, Won Suk Choi, Seoul, Korea, Republic of

This multi-institutional study from Korea evaluated renal functional outcomes in patients >65 after radical and partial nephrecotmy. The authors found an increased incidence of new onset CKD in the RN cohort compared to partial nephrectomy (66.7 vs 26.3) but no difference in overall survival. Although not a perfect study and far from the whole story, this study addds another piece of evidence that may help define the ideal candidates for nephron-sparing surgery.

Jeffrey Tosoian, MD; Junior (U1) Resident

MP55-06: Prostate sparing cystectomy: 20 years single center experience.

Laura Mertens*, Richard Meijer, Remco de Vries, Jakko Nieuwenhuijzen, Henk van der Poel, Axel Bex, Bas van Rhijn, Wim Meinhardt, Simon Horenblas. Amsterdam, Netherlands.

These authors reported their experience over 20 years with performing prostate-sparing cystectomy (PSC) for muscle-invasive bladder cancer (MIBC) or refractory high risk non-MIBC, as opposed to the conventional radical cystoprostatectomy (RC), which is the generally accepted standard of care. They describe excellent disease-specific survival of 76.2% and 66.5% at 2 and 5 years, respectively. Functional outcomes were similarly impressive, with daytime continence, nighttime continence, and erectile function maintained in 96.2%, 81.9%, and 89.7%, respectively. 

As a junior resident who continues to learn about both standard and non-standard therapies, this abstract caught my attention because it diverged from my expectations. I am eager to compare these findings with the more conventional cystoprostatectomy. The authors note one local recurrence in the remnant prostatic epithelium, and I would be interested to learn more about this patient’s subsequent course. If this recurrence could presumably have been avoided by performing conventional RC, that raises an important question: as both patients and urologic oncologists, are we willing to risk one unnecessary recurrence for the possibility of improved functionality? I suspect the answer may vary significantly based on who you ask.

MP27-13: The impact on the type of ureteral stent to patient symptoms using USSQ : A prospective randomized controlled study.  Hyoungkeun Park*, Sangrak Bae, Sunghyun Paick, Hyunwoo Kim, Jutae Seo, Joonchul Kim, Wonhee Park, Yongsoo Lho, Hyeonggon Kim. Seoul, Korea.

These authors performed a randomized controlled trial comparing stent-related symptoms in patients treated with a conventional double-j ureteral stent versus a newly emerging stent which contains a softer distal end.  While the softer distal tip stents were designed with hopes of improving stent-related symptoms, hey ultimately found no significant differences between the two stent groups in reported urinary symptoms or pain as reported by the visual analogue pain scale.

This abstract stood out to me because it investigates what any urologic resident will tell you is a very common problem. In addition to being prevalent, stent pain is rather peculiar by nature. From patient to patient, stent-related symptoms can vary from completely absent to moderately severe, and our treatment options are largely limited. Studies have shown that alpha-blockers (e.g. tamsulosin) reduce stent-related symptoms, and others have suggested that additional agents such as anticholinergics (e.g. oxybutynin) or urinary tract analgesics (e.g. phenazopyradine) may improve patient symptoms. Regardless, these authors investigated a mechanical advancement in stent material with aims of decreasing discomfort. While their findings were negative, this abstract can help guide subsequent trials aimed at reducing symptoms associated with the all-too-common problem of stent pain.

Max Kates, MD; Junior (U1) Resident

For me, the theme of this years AUA was personalized medicine.  Nowhere was this more apparent than with bladder cancer, where we are heading towards a treatment paradigm of therapy tailored towards  tumor biology.  The following 3 abstracts fit squarely in this trend.

MP28-14: Targeting HER2 with Trastuzumab-DM1 (T-DM1) in HER2-overexpressing bladder cancer.  Tetsutaro Hayashi*, Wolfgang Jaeger, Igor Moskalev, Shannon Awrey, Na Li, Ladan Fazli, Vancouver, Canada, Wataru Yasui, Akio Matsubara, Hiroshima, Japan, Peter Black, Vancouver, Canada

In this study, the authors first identified HER2 overexpressing bladder cancer cell lines and then tested whether an agent targeting Her-2 had antitumor effects.  Bladder cancer has multiple tumor pathways, and this study gave insight into the future of bladder cancer care, where patients will be tested for protein expression, and their treatments will then be tailored to their specific species of bladder cancer.

MP34-14: Targeting epidermal growth factor receptor using photoimmunotherapy in the treatment of bladder cancer.  Sam Brancato*, Piyush Agarwal, Bethesda, MD

This study also foreshadowed the way medicine, oncology, and bladder cancer care will be  managed in the long-run.  Specific cell surface receptors on the urothelium that were upregulated in bladder malignancy were targeted using a monoclonal antibody that is bound to a flourescent dye, and targets in this case EGFR receptor.  A very unique technology will be interesting to follow as it moves beyond preclinical data.

MP34-07: Differential Gene Expression In Responsive Versus Recurrent Non-muscle Invasive High-grade Urothelial Carcinomas After Induction BCG.  Philip Ho*, Daniel Willis, Houston, TX, Saad Aldousari, Kuwait, Kuwait, Charles Guo, Colin Dinney, Xifeng Wu, Ashish Kamat, Houston, TX

The implications of this study is the BCG failure should be able to be identified prior to treatment by understanding the tumor's biology.  Treatment can then be tailored towards non BCG treatments in these refractory groups.  Ultimately,the tumor will provide a therapeutic blueprint for what will work in treating the cancer.

Hiten Patel, MD; Incoming Urology Resident

PD34-09: Does Prostate Cancer Gleason Pattern 3 Lack the Potential for Metastasis? Michael Vacchio*, Bo Xu, Diana Mehedint, Christine Murekeyisoni, Gissou Azabdaftari, James Mohler, Eric Kauffman, Buffalo, NY

The study provides further evidence that Gleason pattern 3 prostate cancer defined by the 2005 International Society of Urological Pathology guidelines lacks metastatic ability. It is important to note that tertiary pattern 4 or 5 was excluded. Although 1 of 451 patients had distant metastasis at a mean of 76 months, blinded pathologist re-review led to upgrading of the patient's prostatectomy specimen to Gleason 7 (12 of 18 men with biochemical failure who had negative margins were also upgraded).


PD31-03: Statin use and Survival after prostate cancer diagnosis in the Finnish Prostate Cancer Screening Trial.  Teemu Murtola*, Tampere, Finland, Liisa Määttänen, Kimmo Taari, Helsinki, Finland, Teuvo Tammela, Anssi Auvinen, Tampere, Finland

A dose-response relationship in statin use and prostate cancer mortality was observed among 6,220 men diagnosed with prostate cancer in the screening trial. The magnitude comparing users and non-users was impressive (HR 0.33 (0.23-0.49)) and supports more research into the relationship in the future. That being said, it is important to consider what the practical financial and side effect implications would be if the eventual debate is on widespread statin use as a preventative measure for men without high cholesterol - a group where the benefit, if any, is likely to be much lower.

Farzana Faisal, Medical Student

I found these two abstracts most interesting because they got me thinking about the research we are doing at Hopkins on racial disparities in prostate cancer.

PD34-08: Disparities in survival for California men with prostate cancer more associated with socioeconomics than either race or insurance status. Chandrasekar T, Fish K, Evans C, White RD, Dall'Era M.

These authors looked at over 360,000 men with PCa in the California Cancer Registry and found that SES, more so than race or insurance status, was the most important predictor of cancer specific survival and overall survival for men with localized or regional disease. These findings seem to contradict what we are showing with the Hopkins cohort - that AA race increases the risk of adverse pathology and BCR. However, a closer look at their data shows that AA race was still an independent predictor of survival outcomes even after adjusting for SES and insurance, and thus can be taken together with our findings to support the role of race as a biological contributor to tumor aggression and disparities in AA men.

MP78-06: Surgeon volume and disparities in postoperative complications among black men. Ruhotina N, Konijeti R, Reese S, Chung BL, Kibel A, Trinh QD, Chang SL.

This study concluded that lower access to high volume surgeons may be responsible for the increased risk of major Clavien complications post-prostatectomy for AA men. It's interesting to think about this factor of surgeon experience in terms of the increased risk of adverse pathology seen in AA men at prostatectomy, especially positive margins. This particular abstract prompted our group to start investigating the role of surgeon proficiency as factor in margin status and perhaps racial disparities.

Jason Cohen, Medical Student

PD34-01: Comparison of radical treatment and mortality in patients with non-metastatic prostate cancer in England and USA.  Ashwin Sachdeva*, Jan van der Meulen, Mark Emberton, Paul Cathcart, London, United Kingdom.

I thought it was interesting to see the differences in outcomes based on the variations in screening and treatment approaches.  It is something we do not get to see and is difficult to study with our own populations.

PD31-04: Do Environmental Factors Modify the Genetic Risk of Prostate Cancer? Stacy Loeb*, New York, NY, Sarah Peskoe, Corinne Joshu, Baltimore, MD, Wen-Yi Huang, Bethesda, MD, Richard Hayes, New York, NY, H. Ballentine Carter, William Isaacs, Elizabeth Platz, Baltimore, MD

This was an interesting talk on things that are often heard in the lay literature, with some corresponding data.  It also looks like it would lead to many research possibilities.


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Read the entire abstracts:
For podium presentations (PD5-), click here.
For poster presentations (MP10-), click here.