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.

AUA Highlights: Testis Cancer, by Dr. Pierorazio

Although a relatively rare malignancy, testis cancer affects approximately 9k men and boys each year.  While not as common or popular as some other urological malignancies, representation in the scientific sessions at the 2014 American Urological Association (AUA) Annual Meeting in Orlando, Florida was excellent.  Here are some of the thematic highlights, click on the links below to read the abstracts:

1. Access to care, epidemiological variation and cost-effectiveness in the treatment of testis cancer.

Because testis cancer is a rare disease, understanding of early symptoms, screening and access to health care can have huge implications regarding the treatment and eventual outcomes of disease.  The following presentations addressed some of these issues.  

In a study of nearly 6,000 men in the SEER (Surveillance, Epidemiology, End Results) database, uninsured men were more likely to present with advanced or metastatic disease, get radiation therapy if they had Seminoma (indicating advanced disease) and die of testis cancer.
PD5-02: The impact of lack of insurance on testicular cancer prognosis in young patients in the United States. Data from the SEER data base. Mohamed Kamel*, Mohammed Elfaramawi, Supriya Jadhav, Rodney Davis, Little Rock, AR.

In another study involving the National Cancer Database Registry, investigators from Vanderbilt University looked at compliance rates with the National Comprehensive Cancer Network (NCCN) Guidelines - which recommend serum tumor markers be drawn prior orchiectomy.  The authors found that young patients, low income patients, those treated at an academic center outside of the South or Midwest were more likely to be treated in compliance with the NCCN Guidelines.
MP10-03: The Influence of Access to Care on Adherence to Clinical Practice Guidelines for Testis Cancer.  C.J. Stimson*, Zachary Reardon, Nashville, TN, Sanjay Patel, Chicago, IL, Harras Zaid, Samuel Kaffenberger, Daniel Barocas, Matthew Resnick, Sam Chang, Nashville, TN

In a second study using the National Cancer Database Registry, researchers looked at over 75k men with testis cancer and found that non-Caucasian men had higher rates of advanced (Stage III) disease and worse overall survival.  African-American men had the highest rates of testis cancer-specific death.

MP10-05: Influence of race on outcomes in testicular cancer: Analysis of 75902 patients in the National Cancer Database.  Claudio Jeldres*, Craig R. Nichols, Khanh Pham, Seattle, WA, Sia Daneshmand, Los Angeles, CA, Christian Kollmannsberger, Vancouver, Canada, Brandon Hayes-Lattin, Portland, OR, Erika Wolff, Katherine Odem-Davis, Christopher R. Porter, Seattle, WA

In a cost-effectiveness analysis, researchers from Kansas City, Kansas examined the role of testicular self-examination in asymptomatic men.  Using Medicare reimbursements to estimate costs, they calculated that the cost of treating an advanced stage testis cancer was roughly $50k, while the costs of office evaluation ranged from $150-600, and the cost of an orchiectomy for early-stage disease is approximately $20k.  Therefore, they concluded - contrary to the recommendation of the US Preventative Services Task Forces (USPSTF) - that testicular self-examination is cost-effective and should not be discouraged.
MP10-11: TESTICULAR SELF-EXAMINATIONS: A COST ANALYSIS. Michael Aberger*, Bradley Wilson, Jeffrey Holzbeierlein, Tomas Griebling, Ajay Nangia, Kansas City, KS

2. Treatment of early stage disease.

The treatment of Clinical Stage 1 testis cancer is evolving (click here to see our blog on the treatment of clinical stage 1 NSGCT).  Most patients are cured with orchiectomy alone, and the remainder can be salvaged with chemotherapy and/or surgery.  Therefore active surveillance is emerging as the most common management strategy for these patients with primary retroperitoneal lymph node dissection (RPLND) and chemotherapy as second options.  However, given the young age and relatively good health of men with testis cancer, the long-term implications of each management strategy are not fully realized.  These presentations address this topic.

To investigate the use of active surveillance for Stage 1 testis cancer, researchers in this study used data from the 75k men in the National Cancer Database Registry with testicular cancer.  For Clinical Stage 1 Seminoma, they found the rates of active surveillance increased from 25% to 55% over the time period from 1998-2011 with a concomitant decrease in radiation from 72% to 28%.  Interestingly, for non-seminomatous germ cell tumors the rates of active surveillance remained stable (58-66%) while rates of primary chemotherapy increased (28%) and retroperitoneal lymph node dissection (RPLND) decreased (12.9%) in 2011.  However, in 2011, 50% of patients with cT1a disease received chemotherapy and not active surveillance.
PD5-04: United States trends in patterns of care in clinical stage I testicular cancer: Results from the National Cancer Data Base (1998-2011).  Claudio Jeldres*, Craig R. Nichols, Khanh Pham, Seattle, WA, Sia Daneshmand, Los Angeles, CA, Christian Kollmannsberger, Vancouver, Canada, Brandon Hayes-Lattin, Portland, OR, Erika Wolff, Katherine Odem-Davis, Christopher R. Porter, Seattle, WA

In a retrospective study of 48 men with clinical stage 1 seminoma on active surveillance, only 2 patients recurred giving a 95% recurrence free survival at 3 years.
MP10-06: Lower-Than-Expect Relapse Rate Among Contemporary Patients with Clinical Stage I Seminoma Managed on Surveillance.  Cesar Ercole*, Cleveland, OH, Estefania Linares, Madrid, Spain, Maria Mir, Yaw Nyame, Daniel Greene, Timothy Gilligan, Andrew Stephenson, Cleveland, OH

In an update of prospective, single arm, phase II clinical trial, 40 patients with high-risk clinical stage 1 non-seminomatous germ cell tumors received one cycle of BEP (Bleomycin, Etoposide and Cisplatinum chemotherapy).  With 15-years of follow-up, one patient recurred and died of metastases, three developed a contralateral testis tumor and three developed a secondary malignancy.
MP10-09: Fifteen years after treatment with one adjuvant cycle of Etoposide, Bleomycin and Cisplatin chemotherapy outcomes in patients with high risk nonseminomatous germ cell tumors clinical stage I. Extended follow up of a prospective single arm clinical trial cohort. Alvaro Vidal Faune*, George N. Thalmann, Martin Fey, Urs E. Studer, Bern, Switzerland

3. Retroperitoneal lymph node dissection (RPLND) for advanced (retrocrural) disease

While the overall survival rate for patients with testis cancer is excellent, after chemotherapy, some patients will develop chemotherapy-resistant teratoma that must be resected surgically.  One of the more challenging locations for a teratoma is behind the diaphragm in the retrocrural space.  At Johns Hopkins, we do these surgeries with either thoracic or vascular surgeons depending on the location and appearance of the tumor.

Two of the leading centers in the treatment of advanced testicular cancer, Indiana University and Memorial Sloan Kettering Cancer Center in New York, presented their experiences with retrocrural metastases.  In both series, the majority of tumors were teratoma.  A variety of incisions were described, with the most common being an abdominal approach with trans-diaphragmatic access when necessary.  Both centers prescribed to joint surgery involving both urology and thoracic surgery.  At Johns Hopkins, we do these surgeries with either thoracic or vascular surgeons depending on the location and appearance of the tumor.
PD5-05: SURGICAL MANAGEMENT OF RETROCRURAL DISEASE IN TESTIS CANCER: OUTCOMES AND EVOLUTION OF PRACTICE.  Hristos Kaimakliotis*, K Clint Cary, Jose Pedrosa, Timothy Masterson, Richard Bihrle, Kenneth Kesler, Richard Foster, Indianapolis, IN
PD5-06: Retrocrural dissection during retroperitoneal lymph node dissection for testicular cancer.  Itay Sternberg*, Brett Carver, Melanie Bernstein, Joel Sheinfeld, New York, NY

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


Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  

Historical Contribution: 1932, Colston & Lewis, Clinical Review of Prostate Cancer

1932

Carcinoma of the Prostate: A Clinical and Pathological Study J. Colston and L. Lewis Southern Medical Journal 1932  25: 696-703

Lloyd G. Lewis, MD

John Archibald Campbell (JAC) Colston was a John Hopkins urologist who worked closely with HH Young during the early 1900's.  Along with Young, he performed perineal prostatectomies and shaped the treatment and understanding of prostate cancer during this time period.  He served with the allied forces during World War I.

LLoyd G. Lewis graduated the Brady Residency in 1933.  He was remembered as a superb surgeon and co-author of The Physiology of Micturation, 1940 after undertaking a number of laboratory experiments involving the innervation of the feline bladder.  During World War II, Lewis served as Chief of Urology at Walter Reed General Hospital in Washington, DC and succeeded in having Walter Reed approved for residency training during his time there.

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In the early 1930's, the only means for detection of prostate cancer was a palpable lesion or symptomatic presentation, namely urinary obstruction.  As such, Colston and Lewis review the history of prostate cancer treated at the Brady since its founding in 1915 through 1932 and note that most prostate cancers "will be found to have progressed beyond the limits of the capsule or into the seminal vesicles so that a complete removal is impossible."  In fact, in 1,040 cases of prostate cancer over 17 years, only 36 cases were found to be eligible for radical prostatectomy.  When they reviewed the over 3,700 prostate operations, they found an additional 58 cancers that  were found during operations for presumed benign growth.

Through their thorough review, they were able to make a number of important observations that describe the understanding of prostate cancer at the time, but help shape our modern understanding of the disease today.  Some of the important observations are detailed below.

Colston and Lewis were able to classify prostate cancer patients into one of three categories:

1. cases suitable for radical prostatectomy
2. cases too extensive for radical surgery, but asymptomatic
3. cases too extensive for radical surgery, but with significant symptoms that require palliative treatment; either:
• radiation treatment
• intra-urethral treatment (or suprapubic diversion)
• palliative, perineal prostatectomy

Colston and Lewis were able to describe the anatomic location of prostate cancer within the gland by examining whole prostate glands removed during radical surgery.  They found the "posterior lamella involved in all cases;" and the lateral lobes involved in the majority.  

They described metastatic and local growth patterns.  Thirty percent of men presenting with prostate cancer had metastases at this time.  For the men with local extension, they reviewed infiltration patterns through the seminal vesicles and never into Denonvillier's fascia "explained by the lack of lymphatics in this thick fascial membrane."  In addition, they noted that, "The rapidity of growth depends on the particular type of tumor, and it may be said that the more cellular the tumor, the more rapid the extension," an early description of the grading of prostate cancer.

In addition, they review the available treatments for the symptoms associated with advanced prostate cancer: urinary obstruction, hematuria and pain.  These symptoms could be treated radiation, transurethral and/or perineal procedures.

Finally, they conclude that, "Every effort should be made by earlier diagnosis to increase the percentage of cases suitable for radical operation, which gives normal micturation with perfect control in most cases."

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! 

AUA Highlights: Infertility, by Dr. Rao

Male infertility was well represented at AUA (American Urological Association) Annual Meeting 2014 in Orlando, Florida. In the plenary session, the risks of increased paternal age were outlined. Notably, children of older fathers are at higher risk of autism, schizophrenia, and achondroplasia (dwarfism). Although the relative increase in incidence of these conditions is alarming, the overall incidence remains low, even in children of older fathers. (Click here to see the video of this Critical Discussion: Advanced Paternal Age - What Are the Real Risks?)

A topic that received continued attention is the increased use of testosterone. This is of particular importance for men with impaired fertility. Use of testosterone replacement therapy causes reversible infertility in most men, however some patients may not recover even after discontinuing the medication. It is critical that men with low testosterone and infertility should not be treated with testosterone replacement therapy, but other alternative medications should be considered instead.

Much research was presented on the outcomes after varicocele. Notably, a meta-analysis of previous studies showed an improvement in pregnancy and life birth rates after varicocele repair in couples using assisted reproductive techniques such as IVF and ICSI. In addition, successful sperm retrieval rates were higher in men who underwent extraction procedures after varicocele repair compared to men with untreated varicoceles. (PD24-01; see below)

In addition, many studies were presented that investigated various genes and DNA modifications that may play a role in infertility. However, none of these will cause immediate change in the treatment of infertile men. Currently, here at the Brady, we are collaborating with many Hopkins scientists to investigate molecular causes for infertility. These studies include finding unidentified genes causing infertility, investigating whether transposons are interrupting critical DNA sequences of sperm production, and identifying other molecules that may play roles and in male infertility treatment for male contraception.

This blog was written by Pravin Rao, M.D., Assistant Professor and Director of Reproductive Medicine and Surgery at the Brady Urological Institute at Johns Hopkins.

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PD24-01: The role of varicocele repair prior to assisted reproductive technology 

Saneal Rajanahally*, Houston, TX, Edgar Kirby, Karen Crowell, Robert Coward, Chapel Hill, NC

Abstract: PD24-01 

Introduction and Objectives 

While it has been established that varicoceles can contribute to infertility, and that varicocele repair (VR) can improve semen parameters such that fertility can be achieved, the relationship between VR and subsequent success with assisted reproductive technologies (ART) has yet to be definitively elucidated. This study is a systematic review the available literature describing the impact of VR on ART outcomes. 

Methods 

A PubMed search from 1/1982-9/2013 was performed to identify prospective, prospective-controlled, and retrospective studies addressing the relationship between VR and ART outcomes in couples with male factor infertility. Studies were excluded if they did not include fertilization, pregnancy, and/or live birth rates. Statistical analysis was performed using Fisher’s exact test. 

Results 

Seven studies were identified (1 prospective, 4 prospective controlled, 2 retrospective). Five of 7 studies utilized intracytoplasmic sperm injection (ICSI), 1 reported in vitro fertilization (IVF) outcomes, and 1 used intrauterine insemination (IUI). There was no difference in fertilization rate between surgical and non-surgical groups (67.8% vs 66.1%). However, 245 of 505 patients (48.5%) who underwent VR achieved pregnancy compared with 199 of 475 (41.9%) with untreated varicocele (p<0.05). Live birth rate was significantly higher after VR (n=314, 46.5%) in comparison to the uncorrected varicocele cohort (n=374, 32.1%, p<0.001). Pregnancy (11.8% vs. 6.3%, p<0.05) and live birth rate (11.8% vs. 2.1%, p<0.05) per IUI cycle were both significantly higher in patients after VR in comparison to those untreated. Individuals with non-obstructive azoospermia (NOA) had a significantly higher sperm retrieval rate after VR (n=140, 57.1%) than those with NOA and untreated varicocele (n=218, 38.9%, p<0.005). 

Conclusions 

Available data in this systematic review demonstrate a higher pregnancy and live birth rate in men after VR compared with those with uncorrected varicoceles, along with increased sperm retrieval rates in men with NOA. The positive impact that VR may have on ART outcomes should be discussed with couples with male factor infertility due to varicocele. 

Date & Time: May 19, 2014 3:30 PM-5:30 PM 

Session Title: Infertility: Therapy 

Sources of Funding: None 

Bladder Cancer Institute to Open at Hopkins

Approximately 75,000 people are diagnosed with urothelial cancer of the bladder each year.[1]  It is estimated that nearly 300,000 people are walking around right now with bladder cancer in a variety of stages and that the annual costs of bladder cancer care approach $4 billion in the United States.  However, bladder cancer receives very little media coverage, public attention and subsequently, little funding exists for bladder cancer research relative to other malignancies.  There is therefore a definite need for a focused, comprehensive research program to improve our understanding and treatment of bladder cancer.

To meet this need, Baltimore-area commercial real estate developer Erwin L. Greenberg and his wife Stephanie Cooper Greenberg have pledged a $15 million gift through the Erwin and Stephanie Greenberg Foundation to create the Johns Hopkins Greenberg Bladder Cancer Institute. Their gift is the largest bladder cancer research gift ever given to Johns Hopkins and is part of a $45 million co-investment with Johns Hopkins University that will support a multidisciplinary team from the Johns Hopkins Kimmel Cancer Center.  Beneficiaries of the gift include faculty and researchers from the Brady Urological Institute, Departments of Radiation Oncology and Molecular Radiation Sciences, and Departments of Oncology, Pathology and Surgery.  Leaders of this team include:

Alan W. Partin, Director of the Brady
and Theodore DeWeese, Chair of
Radiation Oncology

BRADY UROLOGICAL INSTITUTE

• Trinity J. Bivalacqua, MD, PhD, Director of Urologic Oncology 

• Alan W. Partin, MD, PhD, Chairman, Professor and Director of Urology

RADIATION ONCOLOGY

• Theodore DeWeese, MD, PhD, Chair of the Department of Radiation Oncology and Molecular Radiation Sciences

MEDICAL ONCOLOGY

• Charles G. Drake, MD, PhD 

• Noah Hahn, MD  

According to Johns Hopkins officials, no other institution in the world houses a collaborative program with this expansive scope and intensive focus on bladder cancer. The Institute will begin formal operations in 2014.

William Nelson, MD, PhD

“We are so very grateful to the Greenbergs for this transformational gift, which supports our shared vision of saving lives with an institute dedicated to developing innovative research and treatments for bladder cancer patients,” says William Nelson, M.D., Ph.D., Director of the Kimmel Cancer Center.

“Bladder cancer is not as well-known among the general public as other cancers,” says Theodore R. DeWeese, M.D. “This new institute will provide needed resources to increase awareness, education, and new research and treatments related to this disease.”

Trinity J. Bivalacqua, MD, PhD, shares, "We have an incredible history and clinical experience at Hopkins treating many, many patients with bladder cancer.  We also participate in world-class research to improve our understanding and treatment of the disease.  With the start of the Greenberg Institute, we have the ability to be true world leaders in the treatment, research and delivery of care to the many patients with bladder cancer."

“Stephanie and I have been committed to cancer programs for many years. We recognize that there are many ways we could focus our resources but wanted to concentrate on one of the least supported cancers. We’re excited to be part of creating a comprehensive bladder cancer initiative that will bring new resources for patients and could ultimately save thousands of lives,” says Erwin Greenberg.

Portions of this blog, specifically quotes, were extracted from "$45 Million Co-Investment to Fund Johns Hopkins Greenberg Bladder Cancer Institute" from Johns Hopkins Medicine. http://www.hopkinsmedicine.org/news/media/releases/45_million_co_investment_to_fund_johns_hopkins_greenberg_bladder_cancer_institute

May is national bladder cancer awareness month. Learn more about bladder cancer signs, symptoms and current treatment options at the Brady Urological Institute Website and from prior blog entries.

[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

Historical Contribution: 1930, Andres, Medical Aspects of... BPH

1930

Andres EC.  Medical Aspects of the Treatment of Benign Prostatic Hypertrophy.  Amer J of Surgery. 1930;9;3:502-6.

By the 1930's it was well established that benign prostatic hypertrophy (BPH, now known as benign prostatic hyperplasia) was the leading cause of urinary obstruction in elderly men, requiring intervention in nearly 85% of these men.  The progression of BPH was well-established, from changes in the bladder leading to retrograde changes in the ureter, kidney and eventually the nephrons.  Andrus astutely noted that progressive renal deterioration was due to the back pressure of urine, recurrent infections and underlying renal disease in this elderly population.

Interestingly, Andres made the observation that patients with progressive urinary obstruction due to BPH also had dramatic effects on their cardiovascular system.  He noted that patients were often clinically fluid overloaded and their hearts suffered through this with compensatory left ventricular hypertrophy and fibrotic changes in the aorta.

To combat these cardiovascular changes, Andres recommended that patients rest, make changes to the diet, and keep hydrated to prevent the effects of azotemia.  If unable to tolerate oral hydration, "A siIver cannula is inserted into a superficial vein, usually on the foot,and is tied in pIace. Through this normal saIt soIution is injected continuously, reguIated by a drop device quite simiIar  to the Murphy drip so that the patient receives not more than IOO to 200 C.C. per hour. In this fashion Iarge amounts of fluid may be given over a period of days and so sIowIy that the circulation is not embarrassed thereby."

In addition, Andres recommended digitalis to stabilize the myocardium and an operation if the obstruction was refractory to the conservative, medical treatments described above.

In summation, Andres depicted the comorbid conditions (specifically cardiovascular) common in the elderly man presenting with obstruction from BPH.  He defined a management algorithm that progressed from acute stabilization, laboratory evaluation, medical treatment and finally surgery if needed.

Finally, Andres, a medical doctor at Johns Hopkins offered the following acknowledgement:

The author desired to express his appreciation to Dr. Hugh H. Young for permission to follow these cases on his service, and to acknowledge with thanks the assistance of the staff of the Brady Urological Institute.

To read the entire manuscript click on the title 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 2014 Outstanding Posters

The American Urological Association (AUA) Annual Meeting, 2014 has been a tremendous success for the Brady Urological Institute.  With greater than 60 faculty and research presentations over a five day period, members of the Brady team have been extremely busy sharing our discoveries with the world.  On Saturday, May 18, 2014, 36 presentations were awarded "Outstanding Poster" designations for the entire meeting in three categories: benign disease, oncology and research.  Brady researchers were awarded two Outstanding Poster Awards, which we share below:

OUTSTANDING POSTER #1

OP1-04: Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Chemotherapy in Muscle Invasive Urothelial Carcinoma 

Alexander Baras*, Nilay Gandhi, Enrico Munari, Sheila Faraj, Mohammad Hoque, Mark Schoenberg, Trinity Bivalacqua, George Netto, Baltimore, MD

Summary: Neoadjuvant chemotherapy improves survival for patients undergoing radical cystectomy for muscle-invasive urothelial cancers of the bladder.  The greatest survival benefit is seen in those patients in whom all cancer is eradicated from the bladder (pT0).  However, the prognosis for patients who fail to respond to chemotherapy or progress while on chemotherapy is poor.  Predicting who will and will not respond to chemotherapy has huge importance in this area.  Researchers from Hopkins identified two genetic markers that could be identified from tissue obtained prior to chemotherapy, to assess the potential response to the medication.  Further studies are needed, however these data may help identify patients best served by chemotherapy and those who should forego chemotherapy for a rapid cystectomy.

Introduction and Objectives Neoadjuvant chemotherapy (NAC) results in 5-10% increase in 5-year survival rate in muscle invasive bladder cancer (MIBC) patients. More importantly, those who achieve a complete response (ypT0) have a 5 year survival rate of 80% as opposed to 40% for those who do not. However, NAC is not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, are yet to be translated into clinical practice. 
Methods mRNA expression data from a prior report on a NAC-treated MIBC cohort (Kato et. al) were analyzed in combination with the antibody database of the Human Protein Atlas (HPA). We identified classifier candidate biomarkers that can be detected by immunohistochemistry (IHC) in TURB biopsy material prior to NAC. The candidate biomarkers were subsequently validated in an independent cohort of 52 MIBC specimens. Response to NAC was defined as the lack of residual MIBC at cystectomy. 
Results By filtering based on large amplitude mRNA changes and the area under the receiver operator curve (AUROC), we identified 21 genes whose mRNA expression profiles differentiate response to NAC (n=33), Figure 1A. Using the HPA, we found that commercially available antibiodies to the protein products of 8 of these genes exhibited differential staining across a set of urothelial carcinomas cataloged in the HPA. In addition, 12 normal tissues were identified from the HPA that can serve as positive and negative controls for the 8 proteins. Our initial studies with 2 of these markers in a multivariate logistic regression model have yielded strong performance (80% accuracy) in identifying patients in our independent validation cohort that are not likely to benefit from NAC due to chemoresistance (Fischer’s exact test p-value 0.02), Figure 1B & 1C. 
Conclusions We illustrate the feasibility of translating gene expression signature data on NAC response into an IHC classifier applicable to TURB specimens. The performance achieved by the initial two markers in our study is being further characterized and the other putative protein markers are being assessed in our TMA cohort. 

OUTSTANDING POSTER #2

OP1-10: Rho-kinase inhibition prevents nNOS uncoupling in the MPG, erectile dysfunction and increases neuronal outgrowth following cavernous nerve injury 

Johanna Hannan*, Xiaopu Liu, Ahmet Hoke, Arthur Burnett, Trinity Bivalacqua, Baltimore, MD
Funding: NIH K08DK090370 and Urology Care Foundation.

Summary: Post-radical prostatectomy erectile dysfunction is a major issue faced by many patients and urologists today.  In order to potentially improve ED, inhibition of molecules that potentiate nerve injury, RhoA and RhoKinase (ROCK), an experimental medication was given to rats with a nerve injury.  This experiemental medication, U-27632, a ROCK inhibitor, improved post-nerve injury erectile function by preventing nitric oxide degeneration and promoting nerve regrowth and regeneration.  This may be a medication suitable to prevent post-prostaetectomy ED in the future.

Introduction and Objectives RhoA and Rho-kinase (ROCK) are implicated in the inhibition axonal growth/neurite sprouting, and neurodegeneration via regulation of inflammation and apoptosis following peripheral nerve injury. We hypothesize that degeneration of the cavernous nerve (CN) after injury is due to increased RhoA/ROCK signaling in the major pelvic ganglion (MPG) leading to neuronal nitric oxide synthase (nNOS) uncoupling and nerve degeneration. This study aimed to characterize the role of ROCK inhibition in preserving erectile responses, penile contractions, nNOS uncoupling and neurite outgrowth following bilateral cavernous nerve injury (BCNI). 
Methods Male Sprague-Dawleys rats (12 wks) were separated into sham, BCNI and BCNI treated with Y-27632 (ROCK inhibitor, 5 mg/kg twice daily; n=8/group). 14 days after BCNI, groups underwent CN stimulation to determine erectile function. Penes were dissected and contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) were assessed. MPGs were excised and protein (Western blots) and gene expression (q-PCR) of nNOS and growth associated protein 43 (GAP43) were assessed. Additional MPGs (n=3/group) were cultured in reduced growth factor matrigel for 48h and neurite growth was measured. 
Results While erectile function was severely decreased in BCNI rats, daily administration of Y-27632 improved erections 2-fold (p<0.05). nNOS MPG gene expression was decreased by 50% after BCNI and recovered to sham levels with Y-27632 (p<0.05). nNOS uncoupling was increased in BCNI MPGs and completely prevented in y-27632 treated rats (p<0.05). Cavernous contractile responses to PE were unchanged. EFS-mediated penile contractions were significantly lower following BCNI and treatment with Y-27632 increased EFS-mediated contractions 2-fold compared to sham and BCNI penes (p<0.05). MPG neurite outgrowth was unchanged in sham and BCNI; however, BCNI+Y MPGs had significantly increased growth (S:328±9μm; BCNI:349±14μm; BCNI+Y:405±11μm, p<0.05). GAP43, a growth protein highly expressed during axonal regeneration, was increased 25% following BCNI and 30% with Y-27632 treatment indicating treatment increased axonal growth. 
Conclusions Inhibition of ROCK preserved erections, prevented nNOS uncoupling, mediated increased neurite growth and increased nerve-mediated penile contractions in BCNI rats. Preventing the activation of RhoA/ROCK signaling in the MPG and CN after injury may inhibit neurodegeneration and post-radical prostatectomy erectile dysfunction. 


For more Brady Urological Presentations, visit the AUA2014 Website or stay tuned.

2014 American Urological Association (AUA) Annual Meeting: Kickoff

Today marks the start of the Annual American Urological Association (AUA) Annual Meeting in Orlando, Florida.  This annual meeting hosts approximately 20,000 urologists from around the world and offers an exciting forum in which new guidelines are released for a variety of disease states, new research and breakthroughs in urology are showcased, and advances in technology are displayed for everyone to see.

The Brady Urological Institute is once again represented very strongly at this year's meeting.  Below you can find links to calendars showing (1) the faculty appearances and presentations throughout the meeting and (2) each poster, podium and video session where urology research from Johns Hopkins is being presented.

In total, there are 17 faculty presentations and 45 research presentations over the 5 day meeting.  Some of the highlights include:

FACULTY PRESENTATIONS

• Dr. H Ballentine Carter will be addressing the Early Detection of Prostate Cancer and discussing last year's AUA Prostate-Specific Antigen Best Practice Statement at:
• Plenary II: Crossfires in Urology on Friday, May 16th at 1pm in the Chapin Theater.
• American Society for Men's Health (ASMH) Meeting on Monday, May 19th at 230pm in the Orange County Convention Center (OCCC), Room W224G.
• Society Presidential Addresses:
• Dr. Arthur L. Burnett, Sexual Medicine Society of North America (SMSNA), Saturday, May 17, 730am Hyatt Regency BR R&S
• Dr. Jennifer Dodson, Society of Women in Urology (SWIU), Sunday, May 18th, 630am in the Hyatt Regency Orlando BR M
• Dr. Brian Matlaga will be discussing the management of kidney stones at:
• Confederacion Americana de Urologia (CAU), "Overview of Renal Calculi," Saturday, May 17th at 130pm in the Valencia Board Room of the OCCC.
• Plenary I, "Point Counterpoint: Sterile Urine Before PCNL, One Week of Antibiotic Therapy," Monday, May 19th at 933am in the OCCC Valencia Ballroom.
• ROCK Society (Research on Calculus Kinetics), "What is the Preferred Management of Proximal Ureteral Stones: Medical Expulsive Therapy, Surgical Therapy," on Monday, May 19th at 420pm in the OCCC, W314.
• Dr. Ken Pienta will be giving the Coffey Lecture at the joint SBUR (Society for Basic Urologic Research)/ SUO (Society of Urologic Oncology) Meeting on "Cancer and Metastases: What Ecology Can Teach Us."
• Dr. Alan Partin will be discussing "Prostate Cancer Tissue Methylation as a Marker for Repeat Biopsy: Update from the MATLOC and DOCUMENT Trials" at the joing BAUS/BJUI/USANZ Meeting, Sunday, May 18th, at 220pm in the Hyatt Regency BR P.

RESEARCH PRESENTATIONS

• Dr. Trinity Bivalacqua's group will be presenting over 13 posters and podiums on a variety of topics incuding urothelial cancer, penile cancer, erectile dysfunction and return of sexual function after pelvic surgery.  Two of those posters were selected as Outstanding Posters and will be presented on Saturday, May 17th at 1pm in the OCCC W303.
• Baras, Gandhi, Munari, Faraj, Hoque, Schoenberg, Bivalacqua and Netto.  "Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Chemotherapy in Muscle Invasive Urothelial Carcinoma."
• Hannan, Liu, Hoke, Burnett and Bivalacqua. "Rho-kinase inhibition prevents nNOS uncoupling in the MPG, erectile dysfunction and increases neuronal outgrowth following cavernous nerve injury."
• The Kidney Cancer Research Team, led by Dr. Mohamad Allaf will be presenting 11 posters and podiums.  Highlights include:
• Results from the Multi-Institutional Consortium of Robotic Partial Nephrectomy.
• Assessment of complications following Radical and Partial Nephrectomy in NSQIP.
• Robotic Retroperitoneal Lymph Node Dissection for Stage 1 Testis Cancer.
• Dr. Phillip Pierorazio will be championing the six presentations from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry looking at comparative oncologic outcomes, selection criteria, growth kinetics and quality of life for patients undergoing active surveillance or surgery for small kidney tumors.

Click here to download the full calendar of Faculty Presentations.

 Click here to download the full calendar of Research Presentations.

Aristolochic Acid, Balkan Nephropathy, Chinese Herbal Nephropathy: A Saga of Upper Tract Urothelial Cancer

Urothelial cancer refers to cancer of the lining of the urinary tract.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.

There are a number of risk factors for the development of upper tract urothelial cancer (UTUC).  Most of these risk factors are related to chronic exposure to carcinogens.  This blog will focus on one of the more rare, but interesting dietary risk factors for UTUC, Aristolochic Acid.  The other known risk factors for UTUC are:

• smoking - the most important modifiable risk factor
• coffee - higher risk of UTUC if >7 cups of coffee per day [1]
• not as big an impact if cigarette smoking is considered
• analgesics - phenacetin, caffeine, codeine, acetaminophen, and aspirin or other salicylates have all been implicated
• arsenic - discovered in Taiwan, where drinking wells are contaminated by arsenic; natives have a higher risk of Blackfoot Disease and UTUC, both believed to be caused by arsenic [2] 
• occupation - chronic exposure to chemicals, dyes, asphalt, tar, petroleum and plastics

Aristocholic Acid - For many years, it was observed that rates of UTUC were higher in the Balkans of Southeastern Europe (Bosnia, Bulgaria, Croatia, Romania, and Serbia) and many Asian countries including China and Taiwan.  The incidence of UTUC in the US is approximately 0.7-1.0 per 100,000 person-years.[3]  In these affected Asian countries and Balkan families, the risk of UTUC rises dramatically, reaching as high as 100-200x the risk of the general population.[4,5]  

The The Balkan Peninsula, popularly referred to as the Balkans,
is a geographical region of Southeast Europe. The region takes
its name from the Balkan Mountains that stretch from
the east of Bulgaria to the very east of Serbia.

China and Taiwan.

Both regions share a common plant genus, Aristolochia (which includes over 500 plant species), that is commonly incorporated into the diet.  In the Balkans, Aristolochia plants grow as weeds alongside wheat and are incorporated into locally produced breads and bread-products.  In Asia, Aristolochia plants are incorporated into many herbal and natural remedies.  While the higher rate of UTUC runs in families, studies demonstrate that the increased risk of UTUC is related to diet and not genetics.   These studies include examination of both molecular markers that implicate diet, and epidemiologic studies that demonstrate that family members who leave home early in life are less likely to develop UTUC.[6,7]

Aristolochia Plant Species, of which over 500 individual species exist.
These plants are known for their strong scent and are often nicknamed
"Birtwort," referring to the birth canal-like shape of the plants.   

A number of studies validate Aristolochic Acid (AA) as a strong carcinogen, demonstrating higher rates of somatic DNA mutations in patients exposed to long-term AA.[8,9]  AA creates DNA mutations by entering the cell nucleus, binds to DNA where it can cause replication errors.[10]  

Patients with AA-related UTUC often present with multiple and/or bilateral, low-grade tumors.[7]  Women, patients with large tumors (>3cm) and invasive tumors (T3 or T4) have worse outcomes.[11]

SUMMARY

• Aristolochic Acid is a risk factor for the development of UTUC through chronic dietary exposure.
• Laboratory studies demonstrate mechanisms by which AA exposure can cause cancer.
• Epidemiologic studies demonstrate increased risk of UTUC related to dietary exposure and not familial genetics.
• Countries of the Balkans and Eastern Asia are two areas in the world where AA ingestion can be considered an endemic cause of UTUC.

[1] Ross RK, Paganini-Hill A, Landolph J,et al: Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter. Cancer Res 1989; 49: 1045.

[2] Tan LB, Chen KT, Guo HR,et al: Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU Int 2008; 102: 48-54.

[3] Munoz JJ, Ellison LM: Upper tract urothelial neoplasms: incidence and survival the last 2 decades. J Urol 2000; 164: 1523-1525.

[4] Petkovic SD: Epidemiology and treatment of renal pelvic and ureteral tumors. J Urol 1975; 114: 858-865.

[5] Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper tract urothelial carcinoma in Taiwan. Urology, 2002.  59: 681.

[6] Grollman AP, Shibutani S, Monya M,et al: Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007; 104: 12129-12134.

[7] Radovanovic Z, Krajinovic S, Jankovic S,et al: Family history of cancer among cases of upper urothelial tumours in the Balkan nephropathy area. J Cancer Res Clin Oncol 1985; 110: 181.

[8] SL Poon, ST Pang, JR McPherson, et al. Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool.Sci. Transl. Med. 5, 197ra101 (2013)

[9] M. L. Hoang, C.-H. Chen, V. S. Sidorenko, et al.  Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing. Sci. Transl. Med. 5, 197ra102 (2013)

[10]  Chen, C., et al. (2012) Aristolochic acid-associated urothelial cancer in Taiwan. Proceedings of the National Academy of Sciences 109(21) 8241-46.

[11] Dragicevic D, Djokic M, Pekmezovic T,et al: Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia. BJU Int 2007; 99: 1357-1362.

Historical Contribution: 1928, Colston, Vas Ligation for the Prevention of... Epididymitis

1928

Vas ligation for the prevention of preoperative and postoperative epididymitis J. A. C. Colston Journal of the American Medical Association 1928  90: 526-527

In the early 1900's, epididymitis was a common problem for men dealing with obstructive uropathy from both benign and malignant conditions of the prostate and bladder.  Colston comments on the sequelae of epididymitis:

"... while it is rarely a dangerous complication, it plays an important part in increasing the length of hospitalization of the patient and usually has a markedly depressing effect on the morale. In some extremely sick patients with lowered resistance, the added effect of this infection may prove to be too much for the individual to withstand, and in such cases, fortunately rare, the fatal outcome may be directly attributed to the added burden of the epididymitis. Then, too, in the very rare case in which a blood stream infection develops, either during the preparatory treatment or postoperative course, the septicemia often appears directly after the epididymitis, so that in some of these cases, at least, the epididymis may be considered as the portal of entry of the infection into the circulation."

It the modern era, it is rare to think about epididymitis as a cause of sepsis and mortality, however without modern diagnostics and antimicrobials, this was a very real clinical scenario.

The development of epididymitis was of particular interest following prostatectomy (for both benign and malignant disease), where the rate of epididymitis was approximately 20% regardless of approach (suprapubic or perineal).  To address this issue, a number of other urologists advocated open ligation of the vas deferens through a small scrotal incision, and dropped the rate of epididymitis to 4%.

To improve upon this technique, Colston described a method of temporary ligation that removed the need for an incision and had fewer complications.  Dr. Colston used an Allis clamp to isolate the vas deferens and then ligated it, externally, with a silk suture.  The suture was tied to the scrotal skin, treated daily with antibiotic and removed after 7-8 days.

At the suggestion of his resident, Edwin Alyea, Colston transitioned from performing the ligation in the operating room while under anesthesia and prior to prostatectomy to performing the ligation at the bedside prior to surgery without local anesthetic.  He described no complications (other than suture irritation at the skin) and a dramatically reduced rate of epididymitis.

This may represent the first description of the "no scalpel vasectomy" -- although for dramatically different indications than we perform that operation today!!

Read the entire manuscript using the link above or 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! 

The Basics of Testis Cancer Diagnosis: Epidemiology & Presentation

Testis Cancer is a rare cancer, with approximately 9,000 boys and men being diagnosed each year.  Fortunately, the cure rates are excellent -- only 400 men will die of testis cancer each year -- leaving about 20,000 survivors with cancer and 200,000 cured of the disease in the US at any given moment.[1] Testis cancer affects mostly young men and boys, therefore the diagnosis can create tremendous anxiety and uncertainty for the patient and their family.

Here we review the Basics of Testis Cancer Diagnosis.

EPIDEMIOLOGY

As stated above, approximately 9,000 men and boys are diagnosed with testis cancer each year; 400 will die of the disease, 20,000 are surviving with the disease and 200,000 have been cured.  Testis cancer is the most common malignancy among men 20-40 years old and is the 2nd most common malignancy in young men 15-19 years old (leukemia is #1).[2]  Corresponding to these statistics, there are three, well-known age peaks for testis cancer:

• Infancy
• Age 30-40 years
• Age 60

Most cases (about 70%) present as a unilateral mass confined to the testicle (a cancer in only one testicle).  Approximately 30% of men will present with metastatic disease -- the most common sites being the retroperitoneum and the lungs.[3]  Bilateral tumors (tumors in both testicles) can appear synchronously or metachronously (at the initial diagnosis or develop later), but is extremely rare, occuring in 2% or less of patients.[4]

RISK FACTORS

There are 4 risk factors for testis cancer:

• Cryptorchidism (an undescended testicle) [5-7]
• 4 to 6-fold risk of developing cancer in the undescended testicle
• 2 to 3-fold risk is orchidopexy (surgical lowering of the testicle) occurs before puberty.
• A slight increased risk also exists in the normal, descended testicle (relative risk 1.74).
• Family history of testicular cancer [8-11]
• 8 to 12-fold risk if a brother with testis cancer
• 2 to 4-fold risk if father with testis cancer
• Average age at diagnosis is 2-3 years younger than general population if a first-degree relative has testicular cancer
• Personal history of testicular cancer [4,12]
• Only 2% of testis cancer patients will have cancer in both testicles, but...
• 12-fold risk if a history of testis cancer
• higher in younger men
• higher in seminoma
• Intratubular germ cell neoplasia (ITGCN) [13,14]
• Most testis cancer arise from the precursor lesion known as ITGCN (or carcinoma-in-situ, CIS)
• ITGCN is present adjacent to testis cancer in 80-90% of patients
• If ITGCN is present, the risk of subsequent testis cancer is:
• 50% at 5 years
• 70% at 7 years

CLINICAL PRESENTATION

Most testis cancers present as a mass confined to the testicle.  Therefore, the most common presentation is a painless testicular mass.  Most of these masses are palpable and of significant size (a few to several centimeters).  Small, non-palpable lesions without pain and in the absence of distant disease have a higher likelihood of being a benign tumors.  In a number of studies, upwards of 80% of non-palpable, asymptomatic masses that are 2cm or smaller will be benign tumors.[15-18]  Benign lesions may include testicular cysts, small infarcts, Leydig cell nodules, or small Leydig cell or Sertoli cell tumors.

Serious, acute pain is associated with rapidly growing tumors and associated hemorrhage or infarction (if the tumor outgrows its blood supply).  Most patients with pain complain of dull scrotal discomfort or heaviness.  Rarely trauma can lead to a diagnosis, mostly because it brings a mass or pain to the patient's awareness.  

For the upwards of 30% of men who present with metastatic cancer, symptoms of metastases can be the presenting complaint. Bulky retroperitoneal lymphadenopathy can lead to abdominal mass; abdominal, flank or back pain due to direct invasion or obstruction of muscles, blood vessels or the ureters; lower extremity swelling if the IVC is compressed or gastrointestinal symptoms if the intestines are involved.  Pulmonary metastases can present as chest pain, shortness of breath and cough.

As testis cancers can lead to diminished spermatogenesis, infertility can be the initial presentation in rare men.  

DIAGNOSIS

The mainstays of diagnosis are scrotal ultrasound and serum tumor markers.

Serum tumor markers are covered in a previous blog (click here).  

Scrotal Ultrasound

Scrotal ultrasound often demonstrates an intratesticular, hypoechoic (dark) mass.  Testis cancers are often vascular (or hypervascular), although the absence of blood flow does not rule out a testis cancer.  Even in patients with suspicion of metastatic cancer, a scrotal ultrasound should be used to identify an active primary tumor or a "burned-out" testicular mass -- which is typically a small, impalpable scar or calcification.  Radical orchiectomy should strongly be considered for any intra-testicular mass and suspicion of testis cancer.

Advanced Imaging

Abdominal and Pelvic CT scan can be performed before or after orchiectomy to evaluate the retroperitoneum.  An initial chest x-ray should be performed to rule-out involvement in the lungs.  Chest CT is only warranted if suspicion of pulmonary disease on x-ray.  Routine imaging of the brain or bones is not recommended unless specific symptoms.   

Summary

• Testis cancer is a rare entity, affecting approximately 9,000 men and boys each year; however the cure rate is excellent, leaving approximately 200,000 survivors in the US.
• Testis cancer is the most most common cancer in men aged 20-40, and 2nd most common in men age 15-19 years old.
• The main risk factors for testis cancer are cryptorchidism (undescended testis), a family or personal history of testis cancer or ITGCN.
• The most common presentation is a painless, palpable testis mass.
• 70% of cancers are confined to the testicle.
• Symptoms are often related to metastatic invasion in the retroperitoneum or lungs.
• Diagnosis involves routine imaging and bloodwork involving scrotal ultrasound, serum tumor markers and abdominal imaging.

To read more about Testis Cancer follow this link.

This blog was written by Phillip M. Pierorazio, MD, Director of the Division of Testis Cancer at the Brady Urological Institute at Johns Hopkins.









[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Horner MJ, Ries LAG, Krapcho M,et al: SEER Cancer Statistics Review, 1975–2006. Bethesda (MD): National Cancer Institute, 2009.
[3]  McGlynn KA, Devesa SS, Graubard BI,et al: Increasing incidence of testicular germ cell tumors among black men in the United States. J Clin Oncol 2005; 23: 5757-5761
[4] Fossa SD, Chen J, Schonfeld SJ,et al: Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst 2005; 97: 1056-1066
[5] Dieckmann KP, Pichlmeier U: Clinical epidemiology of testicular germ cell tumors. World J Urol 2004; 22: 2-14
[6] Wood HM, Elder JS: Cryptorchidism and testicular cancer: separating fact from fiction. J Urol 2009; 181: 452-461
[7] Akre O, Pettersson A, Richiardi L,et al: Risk of contralateral testicular cancer among men with unilaterally undescended testis: a meta-analysis. Int J Cancer 2009; 124: 687-689.
[8] Hemminki K, Chen B: Familial risks in testicular cancer as aetiological clues. Int J Androl 2006; 29: 205-210.
[9] Mai PL, Chen BE, Tucker K,et al: Younger age-at-diagnosis for familial malignant testicular germ cell tumor. Fam Cancer 2009; 8: 451-456.
[10] Sonneveld DJ, Sleijfer DT, Schrafford Koops H,et al: Familial testicular cancer in a single-centre population. Eur J Cancer 1999; 35: 1368-1373
[11] Westergaard T, Olsen JH, Frisch M,et al: Cancer risk in fathers and brothers of testicular cancer patients in Denmark: a population-based study. Int J Cancer 1996; 66: 627-631.
[12] Theodore C, Terrier-Lacombe MJ, Laplanche A,et al: Bilateral germ-cell tumours: 22-year experience at the Institut Gustave Roussy. Br J Cancer 2004; 90: 55-59.
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