Friday, January 30, 2015

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.


Tuesday, January 27, 2015

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

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! 

Monday, January 26, 2015

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:

Diamond Jim Brady, The New York Times.

Wednesday, January 21, 2015

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.

Tuesday, January 20, 2015

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

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 1st 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! 


Wednesday, January 14, 2015

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?
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.
[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.

Tuesday, January 13, 2015

Historical Contribution: 1961, Stamey, Renovascular Hypertension

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! 


Monday, January 12, 2015

Quality of Life in the Treatment of Clinically-Localized, Small Renal Masses

There are a number of management strategies for patients with clinically-localized, small renal masses (SRM, clinical stage T1) including radical nephrectomy (RN), nephron-sparing surgery (NSS; includes partial nephrectomy, PN, and ablative technologies), and active surveillance. Fortunately survival rates are excellent regardless of treatment [1]. And with recent level I evidence indicating no difference in oncologic or renal-functional outcomes for healthy patients undergoing PN and RN,[2,3] quality-of-life (QOL) is becoming an increasingly important consideration for these patients.

This blog will review what is known regarding QOL in the management of SRM.


Radical Nephrectomy versus Nephron-Sparing Surgery

Most of the studies evaluating QOL in patients undergoing RN and NSS evaluate patients undergoing open surgery (in fact, there are no studies evaluating patients undergoing minimally-invasive PN). In addition, most of these studies employ a cross-sectional survey in which all patients from a given institution were sent a QOL questionnaire at some time period after surgery. Very few studies evaluate patients undergoing surgery in the more ideal, prospective fashion.

Cross-Sectional Studies

It is generally understood that patients undergoing RN and PN are very different patient populations. RN patients are often older, have more comorbidities and larger tumors. Patients undergoing PN are subjected to a higher risk surgery, but have the benefit of preservation of a kidney. 
Despite these differences, a study of the baseline QOL in patients undergoing RN and PN found no difference in general perceived health or QOL among the groups.[4] A more in-depth analysis indicating that patients undergoing PN had better QOL scores related to physical health, while patients undergoing RN had better mental health QOL scores at baseline.
A number of studies indicate that overall QOL is similar following RN and PN.[5-7] The study by Poulakis et al. indicated that patients undergoing PN had higher physical health QOL scores [7], and while the study by Clark et al. did not demonstrate a difference in QOL between RN and PN, those patients with more renal parenchyma (tissue) saved had higher QOL scores.[6] In general, these studies found that while NSS did not predict QOL, comorbidities, tumor size and renal function after surgery related strongly to overall QOL.
In contrast, a study by Ficarra et al. found that patients undergoing PN had improved QOL. Specifically they found lower rates of anxiety and depression in patients undergoing PN; and fewer patients had an impairment of their general health.[8]

Prospective Studies

In a study comparing radio-frequency ablation (RFA) to laparoscopic RN, Onishi et al. found that patients undergoing RFA were older and sicker with resultant lower QOL scores at baseline. However, over the course of six months following surgery, patients undergoing RFA had improvements in QOL while those undergoing RN had a significant detriment to physical functioning, physical health, pain and general health.[9] In the study by Parker et al., patients undergoing RN had improved cancer-related QOL (indicating less fear of cancer recurrence). However, many domains of QOL (including physical health and fear of recurrence) were related to renal function – which was significantly better in patients undergoing PN.[10]


Minimally-Invasive versus Open Surgery

As stated above, most studies evaluate open RN and NSS. Studies evaluating laparoscopic and open surgery indicate that patients undergoing laparoscopic surgery have a quicker return to baseline QOL, but at one year both groups achieve similar QOL.[10] A recent systematic review of this literature indicates that:
  • With regard to RN, laparoscopic surgery has improved perioperative outcomes and related QOL.
  • With regard to NSS, PN results in better preservation of renal function and related QOL regardless of approach. [11]


Active Surveillance and Watchful Waiting

Little QOL data exists in the SRM literature regarding active surveillance (AS) or watchful waiting (WW) programs. Analogous data from prostate cancer AS programs suggest that men do not fare worse in terms of their mental and physical wellbeing compared to those that choose to undergo active intervention [12-15], however there may be increased anxiety, particularly if tumor growth or progression is found.[16]
In a two-year study of patients undergoing WW, greater illness uncertainty was related to poorer general health, cancer-related QOL and higher distress. While physical health-related QOL decreased over the two-year period, intrusive thoughts and avoidance behaviors improved; and mental health-related QOL did not change with time.[17]
In an ongoing prospective study of AS and surgery for SRM, early data indicates that physical health-related QOL is significantly higher at baseline for patients who undergo surgery. While this difference persists throughout follow-up, mental health-related QOL (including depression and anxiety) is not adversely affected for patients undergoing AS over time and when compared to surgery patients.[18]



While there are many shortcomings in the data regarding QOL in the management of SRM, the little data that exists indicates that:
  • There is likely little difference in QOL for healthy patients undergoing RN and PN.
  • A perceived QOL benefit to PN (and other NSS) may be related to preservation of renal function and tissue.
  • While there is no long-term difference in QOL related to open or laparoscopic surgery, patients undergoing laparoscopic surgery may have a quicker return to baseline QOL on average.
  • WW and AS for SRM does not appear to adversely affect mental health-related QOL.


This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology.




[1] Patel HD, Kates M, Pierorazio PM, Hyams ES, Gorin MA, Ball MW, Bhayani SB, Hui X, Thompson CB, Allaf ME. Survival after diagnosis of localized T1a kidney cancer: current population-based practice of surgery and nonsurgical management. Urology. 2014 Jan;83(1):126-32. doi: 10.1016/j.urology.2013.08.088. Epub 2013 Nov 16.
[2] Van Poppel H, Da Pozzo L, Albrecht W, Matveev V, Bono A, Borkowski A, Colombel M, Klotz L, Skinner E, Keane T, Marreaud S, Collette S, Sylvester R. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011 Apr;59(4):543-52. doi: 10.1016/j.eururo.2010.12.013. Epub 2010 Dec 22.
[3] Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol. 2014 Feb;65(2):372-7. doi: 10.1016/j.eururo.2013.06.044. Epub 2013 Jul 2.
[4] Arnold ML, Thiel DD, Diehl N, Wu KJ, Ames S, Parker AS. Comparison of baseline quality of life measures between renal cell carcinoma patients undergoing partial versus radical nephrectomy. BMC Urol. 2013 Oct 22;13:52. doi: 10.1186/1471-2490-13-52.
[5] Clark PE, Schover LR, Uzzo RG, Hafez KS, Rybicki LA, Novick AC. Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue. Urology. 2001 Feb;57(2):252-6.
[6] Gratzke C, Seitz M, Bayrle F, Schlenker B, Bastian PJ, Haseke N, Bader M, Tilki D, Roosen A, Karl A, Reich O, Khoder WY, Wyler S, Stief CG, Staehler M, Bachmann A. Quality of life and perioperative outcomes after retroperitoneoscopic radical nephrectomy (RN), open RN and nephron-sparing surgery in patients with renal cell carcinoma. BJU Int. 2009 Aug;104(4):470-5. doi: 10.1111/j.1464-410X.2009.08439.x. Epub 2009 Feb 23.
[7] Poulakis V, Witzsch U, de Vries R, Moeckel M, Becht E. Quality of life after surgery for localized renal cell carcinoma: comparison between radical nephrectomy and nephron-sparing surgery. Urology. 2003 Nov;62(5):814-20.
[8] Ficarra V, Novella G, Sarti A, Novara G, Galfano A, Cavalleri S, Artibani W. Psycho-social well-being and general health status after surgical treatment for localized renal cell carcinoma. Int Urol Nephrol. 2002-2003;34(4):441-6.
[9] Onishi T, Nishikawa K, Hasegawa Y, Yamada Y, Soga N, Arima K, Yamakado K, Hoshina A, Sugimura Y. Assessment of health-related quality of life after radiofrequency ablation or laparoscopic surgery for small renal cell carcinoma: a prospective study with medical outcomes Study 36-Item Health Survey (SF-36). Jpn J Clin Oncol. 2007 Oct;37(10):750-4. Epub 2007 Oct 17.
[10] Parker PA, Swartz R, Fellman B, Urbauer D, Li Y, Pisters LL, Rosser CJ, Wood CG, Matin SF. Comprehensive assessment of quality of life and psychosocial adjustment in patients with renal tumors undergoing open, laparoscopic and nephron sparing surgery. J Urol. 2012 Mar;187(3):822-6. doi: 10.1016/j.juro.2011.10.151. Epub 2012 Jan 15.
[11] MacLennan S, Imamura M, Lapitan MC, Omar MI, Lam TB, Hilvano-Cabungcal AM, Royle P, Stewart F, MacLennan G, MacLennan SJ, Dahm P, Canfield SE, McClinton S, Griffiths TR, Ljungberg B, N'Dow J; UCAN Systematic Review Reference Group; EAU Renal Cancer Guideline Panel. Systematic review of perioperative and quality-of-life outcomes following surgical management of localised renal cancer. Eur Urol. 2012 Dec;62(6):1097-117. doi: 10.1016/j.eururo.2012.07.028. Epub 2012 Jul 20.
[12] Vasarainen H, Lokman U, Ruutu M, Taari K, Rannikko A. Prostate cancer active surveillance and health-related quality of life: results of the Finnish arm of the prospective trial. BJU international. Jun 2012;109(11):1614-1619.
[13] Wilcox CB, Gilbourd D, Louie-Johnsun M. Anxiety and health-related quality of life (HRQL) in patients undergoing active surveillance of prostate cancer in an Australian centre. BJU international. Mar 2014;113 Suppl 2:64-68.
[14] Daubenmier JJ, Weidner G, Marlin R, et al. Lifestyle and health-related quality of life of men with prostate cancer managed with active surveillance. Urology. Jan 2006;67(1):125-130.
[15] van den Bergh RC, Essink-Bot ML, Roobol MJ, et al. Anxiety and distress during active surveillance for early prostate cancer. Cancer. Sep 1 2009;115(17):3868-3878.
[16] Johansson E, Steineck G, Holmberg L, et al. Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial. The lancet oncology. Sep 2011;12(9):891-899.
[17] Parker PA, Alba F, Fellman B, Urbauer DL, Li Y, Karam JA, Tannir N, Jonasch E, Wood CG, Matin SF. Illness uncertainty and quality of life of patients with small renal tumors undergoing watchful waiting: a 2-year prospective study. Eur Urol. 2013 Jun;63(6):1122-7. doi: 10.1016/j.eururo.2013.01.034. Epub 2013 Feb 9.
[18] Pierorazio PM, McKiernan JM, Allaf ME. Quality of Life on Active Surveillance for a Small Renal Masses versus Immediate Intervention: Interim Analysis of the DISSRM (Delayed Intervention And Surveillance For Small Renal Masses) Registry. AUA Annual Meeting, 2013.

Wednesday, January 7, 2015

“Lighting up” Prostate Cancer

Prostate cancer is notoriously difficult to image. In fact, traditional imaging technologies like CT (computerized tomography) and ultrasound are useless for clinically-localized disease (cancer still in the prostate). These technologies can find the prostate, but cannot reliably distinguish cancer from normal prostate gland. Recently, improvements in MRI (magnetic resonance imaging) have made this technology more useful for the diagnosis of localized prostate cancer. While the role of MRI in localized prostate cancer is being determined, the only useful imaging technologies are for patients with advanced and metastatic disease. For instance, CT scan (or MRI) can detect enlarged lymph nodes and nuclear medicine (bone) scans can find cancer that has spread to bones.

Even PET (positron emission tomography) imaging – which can detect many other cancers – is useless in prostate cancer. PET imaging makes use of a labelled glucose molecule that is taken up by rapidly dividing and growing cancer cells. Unfortunately prostate cancer is slow growing and does not pick up the glucose molecule to make it detectable.

Martin Pomper, MD, PhD
Researchers at the Brady Urological Institute and Johns Hopkins may be onto a new way to image prostate cancer using molecular genetics and PET imaging. Martin Pomper, MD, PhD, works with nanoparticle imaging technologies that preferentially bind to prostate cancer cells and emit a signal that can be detected. Instead of using a glucose pathway, Dr. Pomper has developed a nanoparticle that binds to PSMA (prostate specific membrane antigen), a protein overexpressed on prostate cancer cells. The nanoparticle sensor "only becomes activated when it encounters malignant cells, but not normal tissue, so that cancer and its metastases can be detected anywhere in the body."

PSMA-based PET imaging of a mouse model with prostate cancer tumor (yellow arrow) implanted
in the forearm of the mouse. The urinary system (kidneys, kid; bladder, bl) are also visualized in the
early imaging as the molecule is filtered by the urine. From Chen et al. [1]
Over several years, Dr. Pomper has worked to refine the molecule and technology used to image prostate cancer in the prostate and around the body. His work has been published in Nature Medicine and Cancer Research. Stay tuned as in human studies are in progress.


Portions of this story were extracted from "Molecular-Genetic Imaging Shows Individual Prostate Cancer Cells" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.



[1] Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, Sgouros G, Mease RC, Pomper MG. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011 Dec 15;17(24):7645-53. doi: 10.1158/1078-0432.CCR-11-1357. Epub 2011 Oct 31.

Tuesday, January 6, 2015

Historical Contribution: 1960, Jewett, Bladder Cancer Mechanisms of Invasion

Jewett HJ, Eversole Jr. SL. Carcinoma of the Bladder: Characteristic Modes of Local Invasion. J Urol. 1960. 83;4:383-89.


This 1960 manuscript is the transcript of a talk given by Dr. Jewett at the 1960 Annual Meeting of the American Association of Genitourinary Surgeons. Drs. Jewett and Eversole review the pathology from 303 infiltrating bladder cancers and made the following observations.

Jewett and Eversole arrived at three "characteristic modes of local invasion" in bladder cancer:
"1) as a fairly compact mass (70%)
2) as finger-like projections represented frequently as isolated masses (27%)
3) as intramural lymphatic metastases traveling in a direction more or less perpendicular to the plane of the overlying bladder mucosa (3%)"

To reach these conclusions, Jewett and Eversole first characterized the 300 specimens (from autopsy, cystectomy and transurethral resections) using Jewett's staging system: A, submucosa only; B1, less than halfway through the muscle; B2, halfway or more through the muscle; C, perivesical fat or prostate. They immediately found that the majority of cases of lymphatic invasion were stage B2 or C. In addition, well-differentiated tumors (low-grade) remained low-stage; and poorly differentiated, squamous and anaplastic tumor types were much more likely to reach the lymphatics at earlier-stages.

Using these observations, Jewett and Eversole looked closely at pathologic specimens to determine modes on invasion. They determined that many of the "early-stage" tumors were actually missed invasive tumors that invaded deeply into the bladder lymphatics as finger-like projections or perpendicularly into the bladder wall – both difficult to assess with the constraints of serial sectioning and two-dimensional pathologic analysis. While these finger-like and perpendicular growth patterns were relatively uncommon, they were more common in deeply invasive tumors (Stage B2 and C).


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! 



Monday, January 5, 2015

Journal Spotlight: Laser vs. TURP for BPH, The GOLIATH Trial

For men with bothersome lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH), transurethral surgery can improve urinary flow and symptoms for men who are not helped by medications. Transurethral resection of the prostate (TURP) is the traditional method for removing the obstructive tissue of a large, benign prostate. This involves using electrocautery to resect tissue, which is then collected from the bladder and removed from the patient. Historically, TURP is associated with a significant and excellent improvements in LUTS with a complication rate of approximately 10%.[1]

Over the past two decades a number of technologies have emerged to improve TURP including laser vaporization, bipolar TURP or vaporization, and laser enucleation of the prostate. Laser vaporization technologies are the most widely used as they were among the first new technologies introduced, are relatively easy to use and are believed the have less bleeding and improved visualization. However, no rigorous, head-to-head study has evaluated laser technology compared to the gold standard TURP – which has the benefits of being a faster operation with well-established, long-term benefits.

The GOLIATH Trial, a European multicenter, randomized study of laser vaporization versus TURP for BPH was recently published in European Urology and the 12-month update in the Journal of Urology.

Bachmann A, Tubaro A, Barber N, etal. 180-W XPS GreenLight laser vaporisation versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6-month safety and efficacy results of a European Multicentre Randomised Trial--the GOLIATH study. Eur Urol. 2014 May;65(5):931-42. doi: 10.1016/j.eururo.2013.10.040. Epub 2013 Nov 11.

Bachmann A, Tubaro A, Barber N, etal. A European Multicenter Randomized Noninferiority Trial Comparing 180 W GreenLight XPS Laser Vaporization and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 12-Month Results of the GOLIATH Study. J Urol. 2014 Sep 16. pii: S0022-5347(14)04377-8. doi: 10.1016/j.juro.2014.09.001. [Epub ahead of print]


Vital statistics of the GOLIATH Study:
  • 291 patients
  • 29 centers in 9 European countries
  • Laser vaporization: 180 Watt Greenlight-XPS™
  • TURP: monopolar or bipolar (42%) technology
Important results from this trial include:
  • No difference between laser vaporization and TURP with regard to urinary outcomes (see table):
    • IPSS (International Prostate Symptom Score)
    • IPSS Quality of life score (IPSS QOL)
    • Maximum flow rate (Qmax)
    • Post-void residual urine
    • Both treatments were associated with short-term dysuria (discomfort with voiding that resolved spontaneously) in approximately 18% of men.
  • Decreases in PSA and prostate volume were also similar among treatments.
    • Six men undergoing TURP were found to have prostate cancer; tissue is not analyzed after laser vaporization.
  • Outcomes that favored laser vaporization included:
    • Length of stay
    • Catheterization time
    • Return to stable health status
    • Fewer 30-day re-operations
  • Adverse events and re-operative rates were similar at 12 months:
    • Laser vaporization patients were more likely to undergo re-operation for bladder neck contractures and urethral strictures
    • TURP patients were more likely to undergo re-operation for bleeding
  • No difference between monopolar and bipolar TURP for any outcome.

12 Months
(Mean Value)
p Value
p Value
Qmax (ml/sec):
PVR (ml):
PSA (ng/ml):
Prostate vol (ml):


Proponents of laser technology claim this study as a victory for laser technology given economic and quality of life implications of decreased length of stay, catheterization time, return to stable health and lower, 30-day reoperation rate. However, this should be balanced with a higher rate of urethral stricture disease – which not only requires re-operation but may have serious implications for cost, quality of life and urinary continence with longer follow-up – and inability to diagnose prostate cancer (as tissue is destroyed rather than evaluated) in select patients.

Take-home: Both laser vaporization and TURP are excellent procedures for the management of LUTS due to BPH. Both result in marked improvements in symptoms at 1 year. Both are associated with short-term dysuria. Patients undergoing TURP have a higher likelihood of re-operation within 30 days due to bleeding from surgery. Patients undergoing laser vaporization have a higher likelihood of requiring a secondary procedure for bladder neck contracture or stricture disease. No one surgery is right for all patients and a surgeon may have a preference to the technology they use. The decision on type of surgery should not rely on technology, but should take into account patient characteristics and preferences as well as surgeon experience and skill set.


[1] Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med. 1995 Jan 12;332(2):75-9.

Friday, January 2, 2015

New Urine Test Shows Promise for Bladder Cancer

The majority of the 300,000 bladder cancers detected in the US each year are non-invasive bladder cancers, and, in general, are not dangerous. However, most of these patients will have recurrences and some will develop muscle-invasive, potentially fatal bladder cancer. Predicting who will "progress" to invasive disease is almost impossible and surveillance involves invasive testing including cystoscopy and biopsies of the bladder. 

Trinity J. Bivalacqua. MD, PhD
Trinity J. Bivalacqua, MD, PhD, Director of Urologic Oncology at the Brady Urological Institute explains, "Because of the high rate of tumor recurrence, we have to perform frequent follow-up cystoscopy procedures, but this results in an unacceptable rate of invasive procedures and ballooning costs." A new urine test developed at Johns Hopkins may become part of the arsenal in detecting new and recurrent bladder cancer.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been demonstrated in upwards of 66% of muscle-invasive urothelial cancers of the bladder and is the most frequently mutated gene in advanced bladder cancers.[1,2] George Netto, MD, a genitourinary pathologist at Johns Hopkins states, "These are the most common genetic alterations ever identified in early bladder cancer."

The TERT promoter gene.  From Kinde et al. [3].

George Netto, MD
Researchers from the Brady Urological Institute, including Drs. Bivalacqua and Netto with collaborators from the Ludwig Cancer Research team, investigated 76 patients with a variety of bladder cancers. The looked at TERT mutations in early tumors from these patients and in follow-up urine samples as they monitored these patients for progression. They found a high rate of TERT promoter mutations in most (approximately 75%) tumors, including both papillary and flat lesions; and tumors of low- and high-grade nature. More importantly, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur – indicating that TERT may be a strong indicator of patients likely to recur!

"These exciting results strongly support the potential future analysis of TERT promoter mutations as a urine test that can facilitate the early diagnosis of bladder cancer, before it spreads deep into the bladder wall, in patients at high risk for disease progression. The test will also give us a non-invasive alternative to the many follow-up procedures we currently need to monitor our patients for recurrence of bladder cancer. This test has great potential to save many lives."

This work was published in Cancer Research.[3]

The story was extracted from:

"Urine Test Detects New, Recurrent Bladder Cancer" in Johns Hopkins Urology: News for Physicians, Winter 2015 by Johns Hopkins Medicine.

"Can Urine Test Can Detect Bladder Cancer Early" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.


[1] Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013;339:959–61.
[2] Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr., et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021–6.
[3] Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, Allaf M, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013 Dec 15;73(24):7162-7. doi: 10.1158/0008-5472.CAN-13-2498. Epub 2013 Oct 11.