A new trial down the “Hedgehog” pathway for men with high-risk prostate cancer

Nearly ten years ago, Johns Hopkins researchers David Berman and Philip Beachy discovered the hedgehog pathway in mice with prostate cancer.[1] This molecular pathway is turned on in the embryologic development of lung, pancreas, prostate, brain and other organs during normal development. In prostate cancer, this pathway is abnormally turned "on" as prostate cancer grows and spreads. Patrick C. Walsh, MD, describes the pathway, "It's like soil and seeds. The soil is the stroma of the prostate — the connective tissue that serves as its framework — and the cancer cells are the seeds." And the Hedgehog protein is compost, sunlight and water — everything the seeds need to grow. "If these cells spread but try to grow in poor soil, they can't survive. But if they can manufacture the Hedgehog signal, they can make the soil that they need — they can pack their lunch and take it with them."

In their original study, published in Nature,[1] Drs. Berman and Beachy demonstrated that giving drugs that could block the Hedgehog pathway, could shrink human prostate cancer tumors in animals. That model is now ready for prime-time testing in humans. Dr. Ashley Ross, MD, PhD, Assistant Professor in Urology, Oncology, and Pathology, is partnering with Emmanuel Antonarakis, MD, medical oncologist, are opening a randomized, placebo-controlled clinical trial of a highly selective Hedgehog pathway inhibitor, called LDE225 and made by Novartis. Dr. Ross explains the hypothesis of the trial:

Ashley E. Ross, MD, PhD

"By looking at gene expression patterns, we and others have found that the Hedgehog pathway appears up-regulated in men with disease that metastasizes after local therapy. Also, in men with advanced prostate cancer, Itraconazole, which inhibits the Hedgehog pathway, appears to slow the disease by a mechanism independent of the androgen receptor. Itraconazole is an antifungal drug. Recently, new, Hedgehog pathway specific drugs with much more favorable toxicity profiles are available."

Men with high-risk prostate cancer are badly in need of a drug that could potentially prevent cancer growth and metastasis. In these patients, there is always the possibility that, even after surgery or radiation therapy, some cancer cells have already escaped the prostate, are hiding somewhere in the body, and will repopulate. Use of a systemic Hedgehog inhibitor may help wipe out these "micrometastatic" cells. Dr. Ross explains,

"We need to start thinking of high-risk disease as a different type of cancer, a systemic disease, and we have to start treating them like we treat other cancers, with a systemic approach in addition to surgery and/or radiation."

The trial is open to radical prostatectomy patients at Johns Hopkins with high-risk prostate cancer: men with a Gleason score of 8 to 10, a PSA of 20 or greater, or clinical stage T3 disease. The men who receive the drug will take the pill for four weeks before radical prostatectomy. All of the men will undergo a repeat biopsy and will have a molecular profile done on their cancer cells before surgery, and then will have the radical prostatectomy specimens examined afterward. Dr. Ross explains, "It's a pharmacodynamic trial, to see if this new drug actually gets into the prostate and inhibits the Hedgehog pathway as we expect it should. Of course, men will be followed closely following prostatectomy and we will also monitor whether superior cancer control results are achieved in those who received LDE225."

 

 
This blog and quotations are extracted from:
Target: Hedgehog Pathway, New Trial Opens for Men with High-Risk Prostate Cancer in Discovery, Volume XI, Winter 2015.

Hedgehog Blockers:Can They Stop Advanced Prostate Cancer? Scientists One Step Closer To Finding Out in Prostate Cancer Discovery, Volume II, Autumn 2005.

 
[1] Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004 Oct 7;431(7009):707-12. Epub 2004 Sep 12.

 

Historical Contribution: 1963, King et al, The Bladder Neck in Childhood

1963
King LR, Mellins HZ, Scott WW. Radiographic Evaluation of the Bladder Neck in Childhood. Trans of Amer Assoc of Genito-urinary Sugeons. 1963. 55:7-12.


 
In the Transcripts of the American Association of Genitourinary Surgeons, Lowell King, Harry Mellins and William Wallace Scott detail the anatomy of voiding in 121 pediatric patients. Children ranged from one day to 17 years old. They found a number of interesting observations they describe in the manuscript:

• Approximately 40% of normal girls will have a narrowed proximal urethra – this has no bearing on incidence of vesicoureteral reflux or clinical outcomes and can therefore be considered normal.
• Of boys with outlet obstruction, about half of the patients had meatal stenosis and the other half had posterior urethral valves (PUV).
• Of boys with recurrent urinary tract infections (UTI), approximately half had a congenital abnormality of the outlet – either PUV or an ureterocele. The rest had normal anatomy but functional deficits that led to residual urine and UTI.

In conclusion, King, Mellins and Scott found that there was a characteristic appearance of the bladder neck in pediatric patients with obstruction. However, "A narrow bladder neck relative to the proximal urethra as seen in the AP view is a common finding, and is certainly not a specific sign of bladder neck contracture."

 
To read the entire manuscript: follow the link above, visit the Centennial Website 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! 

The Brady Centennial: “Diamond Jim” Brady

James "Diamond Jim" Buchanan Brady

One hundred years ago, the Brady Urological Institute opened its doors to patients. The funding for the institute came to Hugh Hampton Young as a gift from James "Diamond Jim" Buchanan Brady. Brady was a wealthy railroad tycoon who sought treatment for prostatic disease at Johns Hopkins.  His story is told in this blog.

Diamond Jim was born in New York City in 1856 to a modest household. Through a number of employment opportunities he worked himself into the railroad industry, starting first with the New York Central Railroad and gaining prominence with Manning, Maxwell and Moore (a railroad supply company), the Pressed Steel Car Company, and Vice President of the Standard Steel Company.

 
Diamond Jim had a passion for fine clothes, expensive jewelry, women and food. A NY Times article in 2008 detailed the enormity of a typical Brady diet (see picture). He is rumored to have been the first owner of an automobile in New York City (1895). His long time girlfriend was Lillian Russell, a well-known actress and singer of the times. He garnished himself and Lillian in an extensive jewelry collection – conservatively estimated to be worth $2 million at that time!

Diamond Jim also suffered from obstructive uropathy. As Diamond Jim was obese, diabetic and in poor general health, a number of hospitals in Boston, New York, and Philadelphia turned him away from open prostate surgery (the treatment of choice at the time for benign prostatic hyperplasia, BPH). Hugh Hampton Young had developed his "punch" procedure, a transurethral surgery for BPH and precursor to the modern TURP (transurethral resection of the prostate), and successfully treated Diamond Jim. Diamond Jim was so grateful he contributed $200k "for a building in which the laboratory and experimental side should play a very important role, and in which clinical material, public and private, outpatient and inpatient could be used for study, research and advancement in the field of urology."

The legacy of Diamond Jim lives on in the Brady Urological Institute which turns 100 years old this month.









Read more about Diamond Jim at:

The Brady Centennial Website:
http://urology.jhu.edu/centennial/

Diamond Jim Brady, The New York Times.

Diamond Jim Brady, Wikipedia.

James "Diamond Jim" Brady: Honored Gourmandizer

"Whether True or False, a Real Stretch," by DAVID KAMP. New York Times, Published: December 30, 2008

Centralizing Care for Testicular Cancer

A number of studies and a growing body of evidence indicates that high hospital and surgeon volume can be associated with improved outcomes for a number of surgical diseases. Research involving the Institute of Medicine[1] and a number of large, national databases including SEER (Surveillance, Epidemiology, and End Results) Cancer Program,[2] National Inpatient Sample [3] and others [4,5] indicate associations between hospital volume and outcome for a variety of cardiovascular and oncologic surgeries. While not specifically focused on urologic oncology, these studies demonstrate modest but significant improvements in mortality for radical cystectomy and nephrectomy.[3,5]
In the urologic literature, significant improvements have been demonstrated for the treatment of prostate,[6-11] bladder,[3,5,12-16] and kidney cancer[3,17-18] at high-volume centers and by high-volume surgeons. There is less, well-established literature in the treatment of testicular cancer (TC) and this blog will focus on the relationship between hospital volume and outcomes for TC.

 
A study of the Irish Testicular Tumor Registry (1980-1985) evaluated 246 patients over 41 hospitals. Inferior survival outcomes were associated with patients who received incomplete orchiectomy, were not staged by tumor markers, did not receive appropriate chemotherapy, had less frequent imaging or marker surveillance and did not have a urologist and/or oncologist involved in their care.[19] In an early study from the SWENOTECA (Swedish Norweigan Testicular Cancer) Project (1981-1986), high-volume cancer centers were associated with improved care – especially in patients with large volume, advanced disease.[20] Of 440 men treated in Scotland, 87% of 235 men treated at the highest volume center were alive at 5 years. Of the 194 treated at other, smaller centers, only 73% were alive at 5 years – much of this difference was attributed to various treatment protocols independent of other prognostic variables.[21]

In the United States, 172 men with advanced testicular cancer in the national, SEER database were matched to 133 men from MSKCC (Memorial Sloan Kettering Cancer Center) in New York (1978-1984). Survival rates were higher at MSKCC despite similar treatment regimens. The benefit at MSKCC was highest in men with minimal to moderate disease and therefore attributed to the combination of surgery and chemotherapy at this tertiary care center.[22] This relationship was validated in 380 patients with metastatic TC enrolled in an EORTC (European Organization for Research and Treatment of Cancer) Trial. The trial was conducted over 49 sites, and patients treated at the 26 sites with the fewest patients (five or fewer) had inferior survival outcomes.[23]

More recent studies from Japan have investigated the volume-outcome relationship, demonstrating increasing volume of treatment to be associated with improved survival.[24] However the rates did not achieve the survival rates demonstrated in western countries like the US or countries of Europe. Based on these data, efforts have been made to centralize TC care in a risk-adapted algorithm – as severity of disease increases, patients are referred to more centralized, specialized referral centers. One study evaluating this "centralization" demonstrated markedly improved and excellent survival in patients receiving induction chemotherapy, with the majority of patients receiving care at one, large center.[25]

While much of the data regarding hospital volume and outcome for TC patients is dated, the argument for centralization of care is poignant. As outcomes for a variety of urologic malignancies including prostate, bladder and kidney cancer are established to be improved in high-volume centers, it is rational that TC care could also be better served by centralized care – TC is a rare disease that often requires multi-disciplinary care and a thorough understanding of management options and outcomes (especially for men with advanced disease). A risk-adapted centralization, where following a diagnosis of TC patients are referred to an increasingly experienced center for the stage of their disease, may help improve outcomes for patients.  For instance, a man with early stage disease who is a candidate for active surveillance can be followed by his local urologic oncologist, and the man with high-volume metastatic disease should be referred to a large, tertiary care center with extensive experience treating men in the region.  In addition, while this blog does not discuss the costs associated with the treatment of advanced TC, centralization may provide improved population-based outcomes in a cost-effective manner and this is a disease where reimbursements may reinforce quality care.

This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology and Director of the Division of Testicular Cancer.

 

1. E.A. Halm, C. Lee, M.R. Chassin. Is volume related to outcome in health care? A systematic review and methodologic critique of the literature. Ann Intern Med, 137 (2002), p. 511
2. C.B. Begg, L.D. Cramer, W.J. Hoskins, M.F. Brennan. Impact of hospital volume on operative mortality for major cancer surgery. JAMA, 280 (1998), p. 1747
3. J.D. Birkmeyer, A.E. Siewers, E.V. Finlayson, T.A. Stukel, F.L. Lucas, I. Batista,et al. Hospital volume and surgical mortality in the United States. N Engl J Med, 346 (2002), p. 1128
4. R.A. Dudley, K.L. Johansen, R. Brand, D.J. Rennie, A. Milstein. Selective referral to high-volume hospitals: estimating potentially avoidable deaths. JAMA, 283 (2000), p. 1159
5. J.D. Birkmeyer, T.A. Stukel, A.E. Siewers, P.P. Goodney, D.E. Wennberg, F.L. Lucas. Surgeon volume and operative mortality in the United States. N Engl J Med, 349 (2003), p. 2117
6. F.J. Bianco Jr, P.T. Scardino, M.W. Kattan, A.C. Rhee, J.A. Eastham. Surgeon volume is predictor of improved outcomes in radical prostatectomy patients. J Urol, 171 (suppl.) (2004), p. 211 abstract 796
7. C.B. Begg, E.R. Riedel, P.B. Bach, M.W. Kattan, D. Schrag, J.L. Warren, et al. Variations in morbidity after radical prostatectomy. N Engl J Med, 346 (2002), p. 1138
8. J.A. Eastham, M.W. Kattan, E. Riedel, C.B. Begg, T.M. Wheeler, C. Gerigk, et al. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol, 170 (2003), p. 2292
9. L.M. Ellison, J.A. Heaney, J.D. Birkmeyer. The effect of hospital volume on mortality and resource use after radical prostatectomy. J Urol, 163 (2000), p. 867
10. J.C. Hu, K.F. Gold, C.L. Pashos, S.S. Mehta, M.S. Litwin. Role of surgeon volume in radical prostatectomy outcomes. J Clin Oncol, 21 (2003), p. 401
11. S.L. Yao, G. Lu-Yao. Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst, 91 (1999), p. 1950
12. L.S. Elting, C.A. Pettaway, H.B. Grossman, B.N. Bekele, K.R. Saldin, C.P.N. Dinney. Relationship between postoperative in-hospital mortality and annual hospital volume of cystectomies: the effect of centres of experience. J Urol, 169 (suppl.) (2003), p. 336 abstract 1301
13. H.W. Herr, J.R. Faulkner, H.B. Grossman, R.B. Natale, R. DeVere White, M.F. Sarosdy, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol, 22 (2004), p. 2781
14. H.W. Herr, J.A. Smith, J.E. Montie. Standardization of radical cystectomy: time to count and be counted. BJU Int, 94 (2004), p. 481
15. B.R. Konety, V. Dhawan, V. Allareddy, S.A. Josyln. Impact of hospital and surgeon volume on in-hospital mortality from radical cystectomy: data from the Health Care Utilization Project. J Urol, 173 (2005), p. 1695
16. B.R. Konety, V. Dhawan, V. Allareddy, M.A. O'Donnell. Association between volume and charges for most frequently performed ambulatory and nonambulatory surgery for bladder cancer is more cheaper? J Urol, 172 (2004), p. 1056
17. E.V. Finlayson, P.P. Goodney, J.D. Birkmeyer. Hospital volume and operative mortality in cancer surgery: a national study. Arch Surg, 138 (2003), p. 721
18. D.A. Taub, D.C. Miller, J.A. Cowan, J.B. Dimick, J.E. Montie, J.T. Wei. Impact of surgical volume on mortality and length of stay after nephrectomy. Urology, 63 (2004), p. 862
19. J.A. Thornhill, A. Walsh, R.M. Conroy, J.J. Fennelly, D.G. Kelly, J.M. Fitzpatrick. Physician-dependent prognostic variables in the management of testicular cancer. Br J Urol, 61 (1988), p. 244
20. N. Aass, O. Klepp, E. Cavallin-Stahl, O. Dahl, H. Wicklund, B. Unsgaard, et al. Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol, 9 (1991), p. 818
21. M.J. Harding, J. Paul, C.R. Gillis, S.B. Kaye. Management of malignant teratoma: does referral to a specialist unit matter? Lancet, 341 (1993), p. 999
22. E.J. Feuer, C.M. Frey, O.W. Brawley, S.G. Nayfield, J.B. Cunningham, N.L. Geller, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol, 12 (1994), p. 368
23. L. Collette, R.J. Sylvester, S.P. Stenning, S.D. Fossa, G.M. Mead, R. de Wit, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst, 91 (1999), p. 839
24. Suzumura S, Ioka A, Nakayama T, Tsukuma H, Oshima A, Ishikawa O. Hospital procedure volume and prognosis with respect to testicular cancer patients: a population-based study in Osaka, Japan. Cancer Sci. 2008 Nov;99(11):2260-3. doi: 10.1111/j.1349-7006.2008.00920.x.
25. Inai H, Kawai K, Kojima T, Joraku A, Shimazui T, Yamauchi A, Miyagawa T, Endo T, Fukuhara Y, Miyazaki J, Uchida K, Nishiyama H. Oncological outcomes of metastatic testicular cancers under centralized management through regional medical network. Jpn J Clin Oncol. 2013 Dec;43(12):1249-54. doi: 10.1093/jjco/hyt152. Epub 2013 Oct 6.

Historical Contribution: 1962, Hypophysectomy for Prostate Cancer, Scott & Schirmer.

1962
Scott WW, Schirmer HKA. Hypophysectomy for Disseminated Prostatic Cancer. Cancer and Hormones. 1962. 175-203.


 

WW Scott

Believing that the metastatic progression of prostate cancer was related to exogenous testosterone after castration,[What makes the Prostate Grow, WW Scott] Scott and other embarked on experimentation with hypophysectomy (removal of the pituitary) in the treatment of advanced prostate cancer with mixed results – the first patient died 11 days after surgery, but two of the next five patients had a tangible response to surgery. Between 1948 (the 1^st hypophysectomy) and 1961, 17 patients underwent hypophysectomy for the treatment of their prostate cancer.

In a detailed description of the 17 cases, Scott and Schirmer arrived at the following conclusions. While the intention of hypophysectomy was palliative (i.e. not intended to extend life), it could not be demonstrated to improve survival outcomes of these patients. Instead Scott and Schimer recognized that grade, timing of metastases and castration had the largest influence on survival times. While hypophysectomy could improve the subjective (symptoms) and objective (lab values) progression of many of these patients, they recognized that

"these comparisons are probably meaningless… they point out our lack of reliable criteria on which to base an evaluation as well as the fact that the degree of palliation depends to a great extent on when in the course of the disease any hormonal therapy is instituted."

Nevetheless, Scott and Schirmer were able to demonstrate effects of serum acid phosphatase, ketosteroids, and osseous lesions on x-ray – demonstrating some effect of hypophysectomy on these patients. They concluded that patients with (1) a previous favorable response to castration therapy and (2) evidence of persistent androgen production may benefit from this surgery.

 
To read the entire manuscript: follow the link above, visit the Centennial Website 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! 

 

MRI Improves the “Misclassification” of Men with Prostate Cancer Undergoing Active Surveillance

While prostate cancer remains one of 

Active surveillance for prostate cancer: What is it and is it right for me? PART ONE ALL CANCERS ARE NOT CREATED EQUAL PART TWO WHAT DOES IT ENTAIL

the most common cancers  in men in the US, many patients are diagnosed with indolent (or benign-behaving) prostate cancer – cancers that will not affect a man's longevity and do not require treatment. This blog has previously covered the basics of active surveillance (see inset). Over a ten year period of active surveillance, approximately one third of men will undergo a treatment for their prostate cancer. The majority of those men, approximately 70%, elected treatment due to an increased volume of cancer or Gleason score > 6 – indicating the presence of more aggressive cancer.[1] Determining who has high-grade or aggressive prostate cancer at the outset can be challenging based on traditional biopsy techniques. Dr. H. Ballentine Carter, MD, Professor of Urology and Director of the Active Surveillance Program at the Brady Urological Institute explains,

"Misclassification is the problem of relying on a prostate biopsy, which samples only a small fraction of the prostate, to reflect the biology of the entire gland. If a diagnosis of low-grade prostate cancer is made on the prostate biopsy and the patient chooses active surveillance, the risk that a higher-grade, more aggressive cancer is present within the prostate can range from 10 to 30 percent."

MRI (Magnetic resonance imaging) makes use of high-powered magnets and their influence on molecules like water (H2O) to image the body. Multi-parametric MRI (mpMRI) uses complex computer algorithms to differentiate benign from malignant tissue and has demonstrated promise in better identifying patients suitable for active surveillance. This technology relies on three characteristics of prostate cancer cells:

1. Prostate cancer cells are abnormal and can emit MRI signals different than normal tissue
2. Because cancer cells are disorganized relative to normal prostate tissue, surrounding water diffuses through cancerous tissue differently than through normal prostate
3. Cancers form with new blood vessels, these new blood vessels create abnormal diffusion of contrast materials through cancer and normal tissue

In addition, some prostate cancers can hide in areas of the prostate difficult to reach with a standard, transrectal ultrasound-guided biopsy. By assessing all of these characteristics and viewing these "hard to reach places," mpMRI can detect prostate cancers missed on biopsy.

In a recent study of 96 men on active surveillance at Johns Hopkins, Carter, with radiology colleagues Sayed Dianat and Kasia Macura, found that men with a mpMRI abnormality had a cancer 41% of the time, compared to 8% of men with a normal mpMRI. This resulted in a 65% lower risk of adverse pathology on subsequent biopsy if an active surveillance patient had a normal mpMRI.[2] 
"Our group demonstrated that when mpMRI suggested the absence of prostate cancer in a particular area of the prostate, there was a high probability that cancer was absent on multiple biopsies taken from these negative mpMRI areas."

"We are now using mpMRI routinely to help select the most appropriate candidates for active surveillance, and to help reduce the frequency of biopsies."

Therefore, mpMRI can help identify men who truly have low-risk prostate cancer, reducing the "misclassification" of these men and decreasing the number of biopsies needed in the future.

Portions of this story were extracted from "Making Active Surveillance Safer" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

 
[1] Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW, Walsh PC, Carter HB. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011 Jun 1;29(16):2185-90. doi: 10.1200/JCO.2010.32.8112. Epub 2011 Apr 4. http://jco.ascopubs.org/content/29/16/2185.long
[2] Dianat SS, Carter HB, Pienta KJ, Schaeffer EM, Landis PK, Epstein JI, Trock BJ, Macura KJ. Magnetic Resonance-invisible Versus Magnetic Resonance-visible Prostate Cancer in Active Surveillance: A Preliminary Report on Disease Outcomes. Urology. 2015 Jan;85(1):147-54. doi: 10.1016/j.urology.2014.06.085. Epub 2014 Oct 16. http://www.goldjournal.net/article/S0090-4295(14)00915-7/abstract

Historical Contribution: 1961, Stamey, Renovascular Hypertension

1961
Stamey TA, Nudelman IJ, Good PH, Schwentker FN, Hendricks F. Functional Characteristics of Renovascular Hypertension. Medicine. 1961. 40(4):347-94.


 

Thomas A. Stamey, MD

Shortly before leaving the Brady for Stamford University, where he served as chairman of urology for 26 years, Thomas A. Stamey, MD, wrote authored a 50 page manuscript summarizing the state-of-the-art of renovascular hypertension (RVH). Early in his career, Dr. Stamey was recognized as one of the world's experts on RVH and renal physiology.

This wonderfully written manuscript summarizes the existing literature regarding on RVH and comprehensively covers the range of diseases that encompass RVH from unilateral to bilateral disease, characteristics of treatable disease and the evaluation and management of many patients. Marrying the scientific literature with his clinical experience, Stamey enables the reader to understand the concepts and clinical significance of RVH as they relate to renal physiology.

While the diagnostic options and management strategies for RVH have changed dramatically from the 1960's, this manuscript offers a fascinating insight into the disease at this time period. Importantly, Stamey offers an algorithmic approach to the diagnosis and treatment of patients to assist practitioners in deciphering this complex disease state.


To read the entire manuscript: follow the link above, visit the Centennial Website 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!