Prostatic Artery Embolization for Benign Prostatic Hyperplasia

From "Prostatic Artery Embolization Promising
for Treating Enlarged Prostate",
Radiological Society of North America

Prostatic Artery Embolization (PAE) was first described in the 1970's as a salvage approach for intractable prostatic hemorrhage.  As a secondary effect, patients embolized for bleeding experienced improvement in their lower urinary tract symptoms (LUTS) and objective reduction in prostate volume.[1]

Significant literature exists describing prostatic arterial anatomy and variants.  The preclinical research defining this anatomy was done in a porcine model.[2]  The first report of PAE for benign prostatic hyperplasia (BPH) in the peer-reviewed literature was by Carnevale and colleagues in 2010.[3]  In this initial case series, two patients had significant reductions in prostate volume and improvement in LUTS.

Since then, a number of case series and small studies demonstrate improvements in a number of parameters related to BPH.  However, none of these studies are randomized or controlled, they are often single-institution and may omit one or more meaningful outcome measures.

Pisco and colleagues reported the outcomes of 15 consecutive patients undergoing PAE. [4] Over a median follow-up of 8 months, they demonstrated an improvement in symptoms (mean IPSS decrease 6.5), improved urine flow (mean Qmax increase 3.85mL/s) and decreased prostate volume (mean volume reduction 28.9mL).  Importantly, there were no changes in PSA or erectile function indicating that PAE did not affect the cavernous arteries or nerves that control erections.  Only one patient experienced a complication (bladder wall ischemia) that did require surgical correction.

The same group has now reported (up to) 2 year outcomes for 103 patients undergoing PAE.[5]  They reported promising operative and perioperative outcomes including little reported pain (average visual analog pain score 1.6), a mean procedure time of 83 minutes, mean fluoroscopy time of 24 minutes, improvement in LUTS (mean IPSS decline 13.5 at 2 years) and urine flow rates (mean increase in Qmax 5.7mL/s).  There was no significant change in PSA or prostate volume at the 2 year mark.  

Given the strengths and shortcomings in the data regarding PAE, there is a fair amount of enthusiasm and skepticism for PAE in the urological community.  In a recent editorial in the Journal of Urology, Kevin T. McVary (Associate Editor), Professor and Chair, Division of Urology of Southern Illinois University said,

"If PAE has merit for our patients there will be no avoiding the truth...  the best way to expose it with as little risk to our patients and society is through a properly performed randomized clinical trial."

Stephen Schatz, MD

Johns Hopkins is one of 12 sites worldwide participating in a prospective, randomized trial comparing PAE to traditional transurethral resection of the prostate (TURP) for BPH.  Stephen Schatz, MD, Assistant Professor of Urology has teamed up with Kelvin Hong, MD and Mark Lessne, MD of the Deparment of Vascular and Interventional Radiology to administer the study.  The primary endpoint is the International Prostate Symptom Score (IPSS) at 12 months; and secondary endpoints will include urine flow (Qmax), post void residual, detrusor pressure, erectile function, prostate volume (by MRI) and PSA measurements.

Men interested in participating must:

• be between 50 and 79 years of age
• have an IPSS > 13
• have a prostate volume 50-80 grams
• have failed medical therapy
• be a candidate for TURP
• have no suspicion of prostate or bladder cancer 

Interested patients can call the Brady Urological Institute Clinic 410 955 6100 for an appointment with Dr. Schatz or speak with Elizabeth Fabian, the study coordinator.

This blog was written by Stephen Schatz, MD.


[1] DeMeritt JS, et.al. Relief of benign prostatic hyperplasia-related bladder outlet obstruction after transarterial polyvinyl alcohol prostate embolization. J Vasc Interv Radiol. 2000;11(6):767–770

[2] Sun F, Sánchez FM, Crisóstomo V, et al. Benign prostatic hyperplasia: transcatheter arterial embolization as potential treatment—preliminary study in pigs. Radiology. 2008;246(3):783–789.

[3] Carnevale FC1, Antunes AA, da Motta Leal Filho JM, de Oliveira Cerri LM, Baroni RH, Marcelino AS, Freire GC, Moreira AM, Srougi M, Cerri GG.  Prostatic artery embolization as a primary treatment for benign prostatic hyperplasia: preliminary results in two patients.  Cardiovasc Intervent Radiol. 2010 Apr;33(2):355-61. doi: 10.1007/s00270-009-9727-z. Epub 2009 Nov 12.

[4] Pisco JM, Pinheiro LC, Bilhim T, Duarte M, Mendes JR, Oliveira AG.  Prostatic arterial embolization to treat benign prostatic hyperplasia.  J Vasc Interv Radiol. 2011 Jan;22(1):11-9

[5] Rio Tinto H, et.al., Prostatic Artery Embolization in the Treatment of Benign Prostatic Hyperplasia: Short and Medium Follow-up.  Tech Vasc Interv Radiol. 2012 Dec;15(4):290-3.

Laparoscopic Single Site (LESS) Surgery: Innovation in Urology

Mohamad E. Allaf, MD

Laparoendoscopic single-site surgery (LESS), or surgery through a single incision, has been utilized to perform every urologic surgery that can be accomplished by traditional laparoscopy. [1]  However, LESS is only routinely performed in approximately 10% of cases as it requires a unique laparoscopic skill set and technology. [2]

Mohamad E. Allaf, MD, Associate Professor of Urology, Oncology, and Biomedical Engineering and the Director, Minimally Invasive and Robotic Surgery at Johns Hopkins routinely performs LESS nephrectomies, both for living donor kidney transplants and for patients with diseased or cancerous kidneys.



See Dr. Allaf's video on LESS nephrectomy (below).

Here we review some of the new tools, technologies and approaches with LESS urological surgeries.

To successfully perform LESS, a surgeon may use a variety of LESS-instruments.  

Covidien Single Incision Laparoscopic (SILS) Instruments

These may include articulating instruments that attempt to recapitulate the triangulation of traditional laparoscopy by using surgeon-controlled intracorporal deflection.  These instruments allow the surgeon to keep his or her hands apart while focusing the instrument tips in the patient's body.[3]  They have full range of motion, however can have difficulty tying knots as the joint forces are not as strong as standard laparoscopic instruments and have a significant learning curve associated with them.[4,5]

Novare RealHand TM (Cupertino, CA, USA) demonstrated on Vimeo.

S-Portal TM Series (Karl Storz, Tuttlingen, Germany)

Pre-bent instruments restore triangulation may have an increased ease of use and shorter learning curve, but the surgeon is unable to adjust the deflection of the instrument in difficult cases.[6]

Surgeons also have the option to use needlescopic instruments, which are 3mm or smaller (see video below).  They can be used through a LESS port or "needle-sized" skin punctures.  They use traditional laparoscopic triangulation techniques and have been demonstrated to have excellent outcomes for patients undergoing adrenal surgery.[7]

New platforms are under development to make LESS easier to learn and incorporate into larger practice models.

The Magnetic Anchoring and Guidance System (MAGS) has a intra-abdominal, moveable magnet that is stabilized externally by a larger magnet on the abdominal wall.  The magnetic system allows spacing of instruments independent of the single port access site, improving triangulation and reducing clashing of instruments.

da Vinci single port system with curved robotic cannulas,
robotic camera and laparoscopic assistant port. [9]

Robot assisted LESS (RA-LESS)  has been demonstrated for radical prostatectomy, dismembered pyeloplasty and radical nephrectomy [8].  While safe and feasible, the current, large profile of the DaVinci robotic system, robotic arm collisions and unfamiliar camera angles prevent the widespread adoption of this technique.  A single port system has been developed for use with robotic technology and successful reports exist for RA-LESS cholecystectomy. [9]

This entry was written by Mark W. Ball, MD,  4th year resident at the Brady Urological Institute.  This entry is extracted from the chapter "Future Directions in LESS" which will appear in Atlas of Laparoscopic and Robotic Single Site Surgery [Jihad H. Kaouk (Editor), Robert J. Stein (Associate Editor), and Georges-Pascal Haber (Associate Editor)].








[1] Kaouk JH, Autorino R, Kim FJ, Han DH, Lee SW, Yinghao S, et al. Laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. Eur Urol 2011 Nov;60(5):998-1005.
[2] Irwin BH, Rao PP, Stein RJ, Desai MM. Laparoendoscopic single site surgery in urology. Urol Clin North Am 2009 May;36(2):223-35, ix.
[3] Autorino R, Cadeddu JA, Desai MM, Gettman M, Gill IS, Kavoussi LR, et al. Laparoendoscopic single-site and natural orifice transluminal endoscopic surgery in urology: a critical analysis of the literature. Eur Urol 2011 Jan;59(1):26-45.
[4] Jeong CW, Kim SH, Kim HT, Jeong SJ, Hong SK, Byun SS, et al. Insufficient joint forces of first-generation articulating instruments for laparoendoscopic single-site surgery. Surg Innov 2013 Oct;20(5):466-470.
[5] Tuncel A, Lucas S, Bensalah K, Zeltser IS, Jenkins A, Saeedi O, et al. A randomized comparison of conventional vs articulating laparoscopic needle-drivers for performing standardized suturing tasks by laparoscopy-naive subjects. BJU Int 2008 Mar;101(6):727-730.

[6] Stolzenburg JU, Kallidonis P, Oh MA, Ghulam N, Do M, Haefner T, et al. Comparative assessment of laparoscopic single-site surgery instruments to conventional laparoscopic in laboratory setting. J Endourol 2010 Feb;24(2):239-245.

[7] Gill IS, Soble JJ, Sung GT, Winfield HN, Bravo EL, Novick AC. Needlescopic adrenalectomy--the initial series: comparison with conventional laparoscopic adrenalectomy. Urology 1998 Aug;52(2):180-186.

[8] Kaouk JH, Goel RK, Haber GP, Crouzet S, Stein RJ. Robotic single-port transumbilical surgery in humans: initial report. BJU Int 2009 Feb;103(3):366-369.

[9] Kroh M, El-Hayek K, Rosenblatt S, Chand B, Escobar P, Kaouk J, et al. First human surgery with a novel single-port robotic system: cholecystectomy using the da Vinci Single-Site platform. Surg Endosc 2011 Nov;25(11):3566-3573.

Success Rates for Intravesical BCG Treatments for Bladder Cancer

Nearly 60,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year and 300,000 survivors are living in the United States.  The majority of these cancers (>70%) are non-muscle invasive disease, however 40-80% of these tumors will recur within the first year and 10-25% will develop muscle-invasive disease [1]. Intravesical treatments after transurethral resection (TUR) are the mainstay of treatment for non-muscle invasive urothelial cancer (NMIUC), and bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment.  

Many patients are unsure of the implications of a diagnosis of NMIUC and many are confused about BCG and its role in their disease.  They want to know the "success rate" for BCG treatment.  Here we review the data regarding BCG and outcomes for patients with NMIUC.

BCG is a live attenuated strain of Mycobacterium bovis that elicits a variety of local immune responses which appear to correlate with its anti-tumor activity.  Widespread implementation of the BCG vaccine for the prevention of tuberculosis (TB) began in the early 1920s following the work of Albert Calmette and Camille Guérin. In the 1970's and 1980's, BCG was demonstrated to be effective in the treatment of UC of the bladder.  Since then, BCG has been validated as a superior intravesical chemotherapy for high grade NMIBC with regard to both tumor recurrence [2] and progression [3].

Following the initial diagnosis and TUR of bladder cancer, an induction course of BCG can be given.  In general, an induction course is given 2-4 weeks are TUR to prevent bacterial intravasation of a recently resected tumor location.[4] According to the Southwest Oncology Group (SWOG), it may take up to 6 months for an initial induction course of BCG to have full effect. 24% of patients with residual CIS at 3 months after induction were found to be disease free at 6 months without further BCG. A meta-analysis of 6 RCTs totaling 585 intermediate- and high-risk patients (281 TUR alone versus 304 TUR+BCG) demonstrated a 56% reduction in tumor recurrence attributable to BCG (p<0.01) [5].

When an additional 3 BCG instillations (maintenance therapy) were administered, the number of complete responders increased to 64%.  The SWOG 8507 randomized controlled trial studied 384 patients randomized to receive either maintenance BCG or no maintenance following an induction course and demonstrated a significant improvement in recurrence free survival (60% versus 41% at 5 years, p < 0.01), progression or death (76% versus 70% at 5-years, p = 0.04) and suggested an overall  survival benefit (83% at 5-years, p=0.08).[6]  More recently, large trials incorporating the SWOG maintenance protocol have confirmed that maintenance therapy reduces disease progression [7-9].  Therefore, the American Urological Association and the European Association of Urology Guidelines on NMIUC recommend maintenance therapy to include 3 weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months after completion of induction therapy. [10,11]

The biggest predictor of failure after BCG therapy and progression to muscle-invasive UC is persistence of disease following two 6 week cycles or after 6 months on the 3 week maintenance schedule. [12]

BCG is also currently approved (by the U.S. Food and Drug Administration, FDA) for the treatment of carcinoma in-situ (CIS) as well as papillary UC. For CIS, the complete response rate rises to 70% with a median time to treatment failure of 34 months and a 45% 5-year disease-free survival probability [13]. When incorporating maintenance therapy for an additional 3 weeks, the overall response rate for CIS approaches 84% [6]. A meta-analysis of 700 patients with CIS (345 BCG and 355 with alternative chemotherapy) demonstrated a 47% reduction in treatment failure with BCG (OR 0.53, p=0.02) and a 53% reduction in tumor recurrence with BCG maintenance therapy [2].

SUMMARY

• A majority of UC are non-muscle invasive bladder cancer, however a high proportion of which will either recur (40-80%) or progress to muscle invasive disease (10-25%) despite complete resection.
• Bacillus Calmette-Guérin (BCG) intravesical immunotherapy is standard of care and now recommended for high- and intermediate-risk NMIBC with complete response rates of 55-65% for Ta/T1 tumors and 70-75% for CIS.
• Maintenance BCG therapy is recommended after induction therapy using the SWOG schedule of a 6 week induction course followed by 3 weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months.

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Intravesical Immunotherapy - Bladder Cancer: Diagnosis and Clinical Management by Nilay M. Gandhi, Laura A. Bertrand, Donald L. Lamm, and Michael A. O’Donnell which will appear in newest edition of The Textbook of Bladder Cancer.

[1] Kemp TJ, Ludwig AT, Earel JK, et al. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 2005; 106: 3474-82.
[2] Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus Calmette-Guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: A meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174 (1): 86-91.
[3] Bohle A, Jocham D, and Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C in superficial bladder cancer: Formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003; 169 (1): 90-5. 
[4] Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1 and Tis): 2007 update. J Urol 2007; 178: 2314-30.
[5] Shelley MD, Kynaston H, Court J, et al: A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJUI 2001; 88 (3): 209-16.
[6] Lamm DL, Blumenstein BA, Crissman JD, et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: A randomized Southwest Oncology Group Study.  J Urol 2000; 163 (4): 1124-29.
[7] Hinotsu S, Akaza H, Naito S, et al. Maintenance therapy with bacillus Calmette-Guerin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJUI 2010; 108: 187-195. 
[8] Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57: 766-773.
[9] Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU Cancers Group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: One-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013; 63: 462-72.
[10] Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1 and Tis): 2007 update. J Urol 2007; 178: 2314-30.
[11] Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54: 303-14.
[12] Herr HW and Dalbagni G. Defining bacillus Calmette-Guerin refractory superficial bladder tumors. J Urol 2003; 169: 1706-8.
[13] Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. NEJM 1991; 325: 1205-9.

Classic Manuscripts in Urology: McGuire, 1981

Dr. Edward McGuire continues to have a long and distinguished career in urology, spanning several decades.  He is a decorated veteran of the Vietnam War.  He trained at Yale and has been faculty at Yale University; the University of Michigan, serving as Head of the Section of Urology and Neurourology and Pelvic Reconstructive Surgery; and the University of Texas Health Science Center in Houston, as Director of the Division of Urology.  Dr. McGuire has made a number of important contributions to urology including the principle of the leak point pressure, understanding surgical corrections of lower urinary tract dysfunction and pioneered the collaborative joint fellowship programs in urology and gynecology. Here we review one of his most important manuscripts and its lasting effect on urology.

McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. The Journal of  Urology. 1981 Aug;126(2):205-9.  
Pubmed.

In this paper, Dr. McGuire and colleagues evaluated 42 myelodysplastic patients with urodynamics over an average of 7 years.  They carefully defined the urodynamic characteristics of these patients:

• 86% had an open bladder neck and non-functional proximal urethra
• Only 9% had coordinated micturation while 83% had areflexic detrusor activity
• 71% had poor compliance (increased bladder pressure with increasing volume)

Most importantly, this manuscript demonstrated that 85% of patients with a detrusor leak point pressure >40cm H20 had hydronephrosis or vesicoureteral reflux (VUR) [Table 3].  Conversely, no patient in the low-pressure (<40cm H20) had VUR and only 2 had hydronephrosis.

Take Home: This manuscript is a landmark paper as it defined deleterious effects of high detrusor leak point pressures on the upper urinary tracts and defined the cutpoint at 40cm H20, widely used by urologists around the world for patients with a variety of urological issues.  

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic. 

Alternative Medications to Prevent Prostate Cancer

Many patients come to urology clinic asking about alternative medications for the prevention of prostate cancer.  Some are interested in taking a pill because other men in their families have prostate cancer and they are concerned they might be next in-line with the diagnosis.  Some men are already on alternative medications and wondering if they will actually work.  Here we review the scientific data regarding the most common supplements on the market for the prevention of prostate cancer.

Selenium and Vitamin E

Identification: Selenium - trace element and nutrient; Vitamin E - fat-soluble vitamin.  The best evidence regarding alternative medications for the prevention of prostate cancer exists for Selenium and Vitamin E.
Potential mechanism: anti-tumorigenic and antioxidant, possible effects on angiogenesis, cellular proliferation and apoptosis [1]
Preclinic evidence: numerous laboratory and epidemiologic studies indicate selenium and Vitamin E may prevent development or progression of prostate cancer [2-9]
Clinical evidence: do not prevent prostate cancer, Vit E may increase risk of prostate cancer

• SELECT (Selenium and Vitamin E Cancer Prevention) Trial, included over 35,000 men randomized to receive supplements alone or in combination was closed early due to an increased risk of prostate cancer in the men taking Vitamin E.  In fact, starting 3 years after enrollment and at a median follow-up of 7 years, men taking Vitamin E were 17% more likely to be diagnosed with prostate cancer.  [10]
• Another randomized, controlled trial of selenium for the prevention of prostate cancer in men at high-risk for disease failed to show any benefit for the prevention of prostate cancer. [11]

Curcumin

Identification: derived from turmeric

Potential Mechanism: anti-inflammtory, antiproliferative

Preclinical evidence: 

• suppresses growth of androgen-dependent prostate cancer cell line LNCaP and androgen-independent DU145 [12]
• inhibits VEGF and angiogenesis in vivo [13]
• anti-inflammatory mediators are downregulated by curcumin [14]
• curcumin can improve the effect of chemotherapy in prostate cancer cell lines [15]

Clinical evidence: None

Green Tea

Identification: used for centuries in Eastern culture and medicine, one of the most widely consumed beverages in the world, contains many compounds, most prominent is epigallocatachin-3-gallate

Potential Mechanism: apoptosis, cell-cycle arrest through anti-oxidant effects and androgen receptor effects

Preclinical Evidence: 40% reduction in tumor development and reduction in metastatic spread of cancer with coincident 70% improvement in survival in TRAMP mouse-model of prostate cancer [16]

Clinical Evidence: Mixed data showing both modest benefits and no benefit 

• In a double-blind, placebo-controlled trial in 60 men with HGPIN (high-grade prostatic intraepithelial neoplasia) at high-risk for prostate cancer, only 1 man in the group getting Green Tea developed cancer while 9 in the placebo group developed cancer [17]
• Phase II clinical trial given after prostate biopsy demonstrating cancer and before radical prostatectomy demonstrated a decrease in serum PSA and other growth factors.  [18]
• Another Phase II trial of men with advanced prostate cancer failed to demonstrate a significant decrease in PSA while a number of patients complained of significant toxicities. [19]

PC-SPES

Identification: herbal mixture of chrysanthemum, isatis, liquorice and others [20]

Potential Mechanism: enhanced effects of multiple antioxidant components

Preclinical Evidence: activity in androgen-dependent and independent cell lines [21-24]

Clinical Evidence: Harmful medication, withdrawn from the market.  PC-SPES was withdrawn from the market in 2002 due to contamination with prescription medications including warfarin and diethylstilbestrol leading to a number of significant side effects including gynecomastia, erectile dysfunction, loss of libido and blood clots (both deep venous thromboses and pulmonary emboli). [25]

Pomegranate Extract

Identification: active ingredients in the naturally occurring juice are polyphenol punicalagins and ellagic acid

Potential Mechanism: potent antioxidant, stronger than Green Tea or red wine

Preclinical Evidence: 

• inhibits nuclear factor kappa-B (NF-kB) in prostate cancer cell lines [26]
• 12% in cell proliferation and 17% increase in apoptosis in prostate cancer cell lines [27]

Clinical Evidence: Increased PSA doubling time in men with advanced cancer.  No data for prostate cancer prevention.  In a phase II clinical trial in men with rising PSA levels after surgery or radiation therapy, daily pomegranate juice increased the PSA doubling time from 15 months to 54 months.[27]

Resveratrol

Identification: compound found in the skin of grapes

Potential Mechanism: inhibits prostate cancer cell growth

Preclinical Evidence: regulates androgen receptor gene transcription, expression and degradation through a variety of mechanisms [28-31]

Clinical Evidence: None

Silbinin

Identification: natural phenol from milk thistle plant

Potential Mechanism: decreased angiogenesis, proliferation and increased apoptosis

Preclinical Evidence: decreases incidence of tumors, size of tumors and progression of tumors in TRAMP mouse model [32-33]

Clinical Evidence: None

Zyflamend

Identification: herbal blend of extracts from rosemary, turmeric, ginger, holy basil, green tea and others

Potential Mechanism: cell growth suppression and apoptosis through COX-inhibition [34]

Preclinical Evidence: inhibits androgen-dependent and independent tumor growth in mouse models [35]

Clinical Evidence: Early phase data may indicate a benefit in men at higher than normal risk to develop prostate cancer.  Phase I clinical trial in men with HGPIN at risk for developing prostate cancer demonstrated a 50% reduction in PSA levels in 50% of the men taking the medication with a lower than expected rate of progression to prostate cancer [36]

Summary

There is much pre-clinical data that alternative medications and supplements may affect the ability of prostate cancer cells to grow and flourish.  However, there is little evidence that any supplement will prevent or alter the course of prostate cancer in humans.  In fact, a number of studies have demonstrated significant detriments to taking supplements specifically for prostate cancer.  

Alluding to the fact that they are often health conscious and more likely to undergo screening, Dr. Patrick Walsh often says, 

"Men who take more than one supplement are more likely to be diagnosed with prostate cancer."  

In fact, the data may show that supra-physiologic levels of alternative medications, even if naturally occurring or based on organic compounds, may be harmful.  

For more details, two great resources for this entry and your reading are:

Klempner SJ, Bubley G.Complementary and alternative medicines in prostate cancer: from bench to bedside?  Oncologist. 2012;17(6):830-7. doi: 10.1634/theoncologist.2012-0094. Epub 2012 May 22.

Philippou Y, Hadjipavlou M, Khan S, Rane A.Complementary and alternative medicine (CAM) in prostate and bladder cancer.  BJU Int. 2013 Dec;112(8):1073-9. doi: 10.1111/bju.12062.

[1] Chan JM, Gann PH, Giovannucci EL. Role of diet in prostate cancer development and progression. J Clin Oncol 2005; 23: 8152–8160

[2] Fleshner N, Fair WR, Huryk R, Heston WD. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice.  J Urol. 1999;161(5):1651-1654

[3] Ip C, Thompson HJ, Zhu Z, Ganther HE. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention.  Cancer Res. 2000;60(11):2882-2886

[4] Jiang C, Wang Z, Ganther H, Lu J. Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells.  Cancer Res. 2001;61(7):3062-3070

[5] Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth.  Cancer Epidemiol Biomarkers Prev. 2000;9(11):1171-1182

[6] Redman C, Scott JA, Baines AT,  et al.  Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines.  Cancer Lett. 1998;125(1-2):103-110

[7] Taylor PR, Albanes D. Selenium, vitamin E, and prostate cancer–ready for prime time?  J Natl Cancer Inst. 1998;90(16):1184-1185

[8] Yoshizawa K, Willett WC, Morris SJ,  et al.  Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer.  J Natl Cancer Inst. 1998;90(16):1219-1224

[9] Zhong W, Oberley TD. Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line.  Cancer Res. 2001;61(19):7071-7078

[10] Klein EA, Thompson IM Jr, Tangen CM et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306: 1549–1556

[11] Marshall JR. Randomized phase III trial of selenium supplementation to prevent prostate cancer among men with high grade prostatic intraepithelial neoplasia. Paper presented at the 2010 American Urological Association (AUA) Annual Meeting; June 1, 2010; San Francisco, USA

[12] Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther 2008; 7: 1436–1440

[13] Gururaj AE, Belakavadi M, Venkatesh DA, Marme D, Salimath BP. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun 2002; 297: 934–942

[14] Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion and metastasis. Oncogene 2001; 20: 4188–4197

[15] Hour TC, Chen J, Huang CY et al. Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21WAF1/CIPI and C/EBP expressions and suppressing NF-kB activation. Prostate 2002; 51: 211–218

[16] Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci USA 2001; 98: 10350–10355

[17] Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 2008; 54: 472–473

[18] McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA. Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res (Phila) 2009; 2: 673–682

[19] Jatoi A, Ellison N, Burch PA et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 2003; 97: 1442–1446

[20] DiPaola RS, Zhang H, Lambert GH et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 1998; 339: 785–791

[21] de la Taille A, Buttyan R, Hayek O, et al. Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 2000;164:1229-1234.

[22] Halicka H, Ardelt B, Juan G, et al. Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC-SPES. Int J Oncol 1997;11:437-448. 

[23] Oh WK, George DJ, Hackmann K, et al. Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen independent prostate cancer. Urology 2001;57:122-126. 

[24] Tiwari RK, Geliebter J, Garikapaty VP, et al. Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 1999;14:713-719. 

[25] Sovak M, Seligson AL, Konas M et al. Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 2002; 94: 1275–1281

[26] Rettig MB, Heber D, An J et al. Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-KB-dependent mechanism. Mol Cancer Ther 2008; 7: 2662–2671

[27] Pantuck AJ, Leppert JT, Zomorodian N et al. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 2006; 12: 4018–4026

[28] Athar M, Back JH, Tang X et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 2007; 224: 274–283

[29] Harada N, Murata Y, Yamaji R et al. Resveratrol down-regulates the androgen receptor at the post-translational level in prostate cancer cells. J Nutr Sci Vitaminol (Tokyo) 2007; 53: 556–560

[30] Niu Y, Yeh S, Miyamoto H et al. Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. Cancer Res 2008; 68: 7110–7119

[31] Shi WF, Leong M, Cho E et al. Repressive effects of resveratrol on androgen receptor transcriptional activity. PLoS One 2009; 4: e7398

[32] Raina K, Rajamanickam S, Singh RP, Deep G, Chittezhath M, Agarwal R. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2008; 68: 6822–6830

[33] Singh RP, Raina K, Sharma G, Agarwal R. Silibinin inhibits established prostate tumor growth, progression, invasion and metastasis, and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice. Clin Cancer Res 2008; 14: 7773–7780

[34] Bemis DL, Capodice JL, Anastasiadis AG, Katz AE, Buttyan R. Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 2005; 52: 202–212

[35] Huang EC, McEntee MF, Whelan J. Zyflamend, a combination of herbal extracts, attenuates tumor growth in murine xenograft models of prostate cancer. Nutr Cancer 2012; 64: 749–760

[36] Capodice JL, Gorroochurn P, Cammack AS et al. Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 2009; 7: 43–51

A Vaccine To Treat Prostate Cancer Offers Hope for Advanced Cancer

Charles Drake, MD, PhD

Scientists studying many forms of cancer believe that cancer vaccines – which boost the body's immune system so that it can lead a "home front" strike against cancer cells – hold great promise.

GVAX Prostate is a cell-based vaccine, originally developed at Johns Hopkins, that may help the body target and kill prostate cancer cells. 

By itself, GVAX is not enough to vanquish metastatic prostate cancer.  Thus, scientists have been studying ways to combine it with other forms of immune-based therapy to create a multi-pronged attack. Initial, pre-clinical studies demonstrate when immune-modulators are coupled with GVAX, "one can see significant anti-tumor effects," according to Dr. Charles Drake.[1]  Recently, it has been shown by Dr Drake and colleagues that conventional hormone therapy [gonadotropin-releasing hormone (GnRH) agonists or antagonists] can further boost the anti-tumor immune response, especially when combined with cancer vaccines such as GVAX.

"The combined approach boosts the immune system in two ways."

Following from these promising laboratory results, Dr Drake has teamed up with Dr Emmanuel Antonarakis, a clinical oncologist, to conduct a clinical trial testing the combination of GVAX plus hormone therapy in men with localized prostate cancer who have elected to undergo radical prostatectomy.

Emmanuel Antonarakis, MD

Neoadjuvant trial of GVAX vaccine for intermediate- and high-risk localized prostate cancer

The GVAX Clinical Trial is being run by Dr. Emmanuel Antonarakis and Dr. Drake.  Patients are randomized to (A) degarelix (a GnRH receptor blocker or hormone treatment for advanced prostate cancer) and radical prostatectomy; or (B) GVAX, degarelix and radical prostatectomy.  Patients must have:

• Clinically localized (cT1c-cT3bN0M0) prostate cancer
• Gleason sum 7-10
• At least 2 positive cores on biopsy
• No 5-alpha reductase inhibitor use (finasteride, dutasteride)
• No autoimmune diseases requiring immunosuppresion

The trial is currently open and interested patients and physicians should contact the Brady Urological Clinic 410-955-6100 or the Prostate Cancer Multidisciplinary Clinic at Johns Hopkins 410-502-8000 for an appointment.  In addition, the direct phone number to speak to the GVAX Research Nurse is 443-287-7841.

Written in part by Emmanuel Antonarakis and extracted from "Vaccine Therapy for Prostate Cancer: Following the Recipe is Important."  in Prostate Cancer Discovery: A Publication of the Patrick C. Walsh Prostate Cancer Research Fund, Volume 10, Winter 2014.

To view the entire publication click here.



[1] Wada S, Jackson CM, Yoshimura K, Yen HR, Getnet D, Harris TJ, Goldberg MV, Bruno TC, Grosso JF, Durham N, Netto GJ, Pardoll DM, Drake CG.Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer.J Transl Med. 2013 Apr 4;11:89. doi: 10.1186/1479-5876-11-89.

Is my BPH (benign prostatic hyperplasia) genetic?

One of the more common questions heard in urology clinic is, "Did I do something wrong to get a big prostate?"  The answer is an emphatic, "No."  We explain why below.

First, benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are incredibly common:

• Approximately 40% of 50-year old men with have histologic evidence of BPH at autopsy, this number increases to 80% for 80-year men.
• Over the same time period, mean prostate volume increases 10-15 grams from an average baseline of 15-25 grams at age 50 to 25-40 grams at age 80.
• The percentage of men with moderate-to-severe LUTS varies among studies and countries, but definitely increases with age.  [1]

Second, BPH is demonstrated to have a very strong heritable component.  Some of the seminal work on the inheritance of BPH is discussed next.

In 1994, Dr. Martin Sanda examined 909 consecutive patients who underwent simple prostatectomy for benign disease at the Johns Hopkins Hospital.  After investigating the families of these patients, he determined that:

• Male relatives of men with early-onset BPH (<64 years-old) had a 66% lifetime risk of prostatectomy for BPH; compared to 17% for controls (p=0.001).
• There was a 4-fold increase in age-specific risk of prostatectomy for BPH in men who underwent prostatectomy for BPH (p=0.003).
• The risk of prostatectomy for BPH increased to 6-fold for brothers of affected men (p=0.0089).
• Segregration analyses indicated a most-likely, autosomal dominant inheritance pattern. [2]

In the same year, Dr. Alan Partin examined 10,000 twins for benign prostatic disease.  He discovered:

• The pairwise concordance for monozygotic (MZ, identical) twins was 14.7% and only 4.5% for dizygotic (DZ, fraternal) twins.  
• The relative risk for MZ twins was therefore 3.3 (p=0.008).
• Therefore, up to 49% of observed variance between twins could be attributed to genetic causes in covariance analyses. [3]

In 1997, Dr. Sanda defined the clinical and biological characteristics of familial BPH (which often presents with larger volume prostates at a younger age).  For men with familial BPH, mean prostate volume was 82.7 mL, while for men with sporadic BPH mean prostate volume was 55.5 mL (p<0.001). [4]

Journal of Urology, 1997; 157(3), 876-879.

Have any genes for BPH been identified?

Since the late 1990's, a number of studies have examined potential genes that cause BPH.  While a number of promising targets have been identified, no specific gene or genes have been identified.

So what should we know as patients and providers?

First, you have done nothing wrong to get a big prostate - this is incredibly common and can be normal condition, coincident with aging.

Second, more than likely, especially if you are young (<64 years-old), someone else in the family has a big prostate and symptoms like yours.

Third, we are very good at treating this disease and there are many options including observation, medical treatment and surgery if needed.

---

[1] Roehrborn, Claus G., MD.  Benign Prostatic Hyperplasia : Etiology, Pathophysiology, Epidemiology, and Natural History [Book] Campbell-Walsh Urology, chapter 91, Pages 2570-2610.e10 Copyright © 2012, 2007, 2002, 1998, 1992, 1986, 1978, 1970, 1963, 1954 by Saunders, an imprint of Elsevier Inc.

[2] Sanda MG, Beaty TH, Stutzman RE, Childs B, Walsh PC.Genetic susceptibility of benign prostatic hyperplasia.J Urol. 1994 Jul;152(1):115-9.

[3] Partin AW, Page WF, Lee BR, Sanda MG, Miller RN, Walsh PC.Concordance rates for benign prostatic disease among twins suggest hereditary influence.  Urology. 1994 Nov;44(5):646-50.

[4] Sanda MG, Doehring CB, Binkowitz B, Beaty TH, Partin AW, Hale E, Stoner E, Walsh PC.Clinical and biological characteristics of familial benign prostatic hyperplasia. J Urol. 1997 Mar;157(3):876-9. 

HIghlights from Johns Hopkins Prostate Research Day: Another Huge Success for Prostate Research

The Johns Hopkins 9th Annual Prostate Research Day occurred this weekend, Saturday, February 8th, in Baltimore, Maryland.  The research presented at JHPRD is, in part, sponsored by the Patrick C. Walsh Prostate Research Fund. The fund, started in 2005, is designed to attract outstanding scientists from the entire Johns Hopkins University who bring fresh thinking and new research initiatives. Each year a request for applications will be distributed to all scientists throughout Hopkins, soliciting their interest in applying for research funding in the field of prostate cancer and benign prostatic disease. The grants are reviewed by a scientific advisory board that awards funding to projects that hold the most promise.

Theodore DeWeese and Alan Partin listen to
presentations during the Research Updates.

In total, over 100 researchers and enthusiasts attended the lively and interactive meeting.  Among the guests were giants in the field of prostatic disease including Patrick C. Walsh, Alan W. Partin (Chairman and Urologist-in-Chief of the Brady), Donald S. Coffey, William Nelson (Director of the Sidney Kimmel Cancer Center at Johns Hopkins), Theodore DeWeese (Chairman of Radiation Oncology and Molecular Radiation Science), and Eric Klein (Chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic), and many others.

Farsana Faisal, a medical student dedicating a year to
urology research, presents her work at the poster session.

Over 50 posters and presentations were dedicated to improving our understanding and treatment of prostate cancer and benign prostatic diseases.
Highlights from the day and Best Poster Presentations are detailed below.

Patrick C. Walsh Prostate Cancer Research Fund Progress Reports

Targeting the Angiogenic Switch in Prostate - Hans-Joerg Hammers, M.D., Ph.D.

Dr. Hammers presented an exciting update on his work of blood vessel growth in prostate cancer. The formation of new blood vessels is critical for prostate cancer progression and its ability to spread to the bones.  Importantly, the most commonly found protein in the bones, collagen, is intimately linked to the switch that allows new blood vessels to grow. This work has important implications for preventing the progression prostate cancer in the prostate and the treatment of prostate cancer that has spread to the bones.

Phase I Trial of HSP90 Inhibition and Radiation Androgen deprivation Therapy for High-Risk Localized and Locally Advanced Prostate Cancer - Phuoc Tran, M.D., Ph.D.

Based on available preclinical data, Dr. Tran theorizes that HSP90 inhibition will be a potent tumor specific radiosensitizer for prostate cancer and proposes a Phase I clinical trial of the HSP90 inhibitor, ganetespib, in high-risk/locally advanced prostate cancer patients with radiation and hormone therapy.  We expect to find the appropriate dose of ganetespib to be used in combination with radiation and androgen deprivation for future Phase II trials.  Ultimately, this Phase I trial will lay the ground work for subsequent trials to test the hypothesis that HSP90 inhibition can be a potent tumor selective radiosensitizer for prostate cancer treatment.

Epigenomic Effects of Chronic Inflammation in Prostate Cancer Initiation and Progression - V. Yegnasubramanian, M.D., Ph.D.

In a collaborative research project, a team of researchers, led by Drs. De Marzo, Bieberich, and Yegnasubramanian, are investigating the link between inflammation, molecular alterations to prostate cells, and prostate cancer. They are harnessing the power of cutting edge genetic models, genome-wide measurements, and molecular pathology to understand the mechanistic connections between inflammation, epigenetics, and prostate pathologies including cancer. This research could have major implications for prostate cancer prevention and interception.

Production and Evaluation of a PSA-Activated Human Serum Albumin/Proaerolysin Recombinant Protein as Novel Therapy for Metastatic Prostate Cancer -John Isaacs, Ph.D.

Dr. John Isaacs presented a novel concept, based on chemical engineering principles, of a unique molecule that is activated only in prostate cancer cells and creates a hole that is unrecoverable and leads to the death of that cell.

Structural and Biophysical Characterization of Gene Silencing by MBD2 Prostate Cancer - Daniel Leahy, Ph.D.

Dan Leahy spoke about a collaborative project between the Leahy, Nelson, and Yegnasubramian labs to investigate the molecular nature of interactions between MBD2 and methylated DNA and to identify and characterize inhibitors of this interaction.  MBD2 binds to methylated DNA and inhibits expression of nearby genes, including in many cases tumor suppressor genes in cancers. The goal of this work is to identify small molecules that will de-repress tumor suppressors and inhibit growth in cancer cells.

Novel Models of Prostatic Infection and Chronic Inflammation Using Human Prostate Cancer Derived Bacterial Isolates - Karen Sfanos, Ph.D.

Dr. Sfanos presented progress on a research project involving mouse models of prostate infections.  These models are being used to study the potential contribution of pathogenic microorganisms to the development of chronic inflammation in the prostate. This chronic inflammation may in turn serves to initiate and/or promote prostate cancer development. Notable findings to date include evidence that a single bacterial infection can induce long-term chronic inflammation in the mouse prostate that appears to be dependent on the type of infecting microorganism.

Evaluation of the Long Non-Coding RNAs, PRAC,  PRAC2 and Other Non-Coding Elements as Contributors To HOXB13-Induced Prostate Carcinogenesis - William B. Isaacs, Ph.D.

Dr. William Isaacs gave a wonderful review of the known genetic causes of prostate cancer.  He updated our knowledge of the HOXB13 gene and demonstrated that genetic contributors lead to earlier prostate cancer, specifically in men with high Gleason disease.

Update - Epidemiology of Prostate Cancer and Benign Prostatic Hyperplasia - Elizabeth A. Platz, Sc.D., MPH

Elizabeth Platz presented new findings from collaborative efforts that cross epidemiology, pathology, immunology, cancer biology, and urology at JH. She reported: 1) men with asthma were much less likely to develop lethal prostate cancer years later; 2) in men who did have an indication for biopsy and no diagnosis of prostate cancer, those who have a greater extent or intensity of inflammation in their prostates had higher serum PSA; and 3) men who are overweight/obese, inactive, or who smoke have shorter and/or more variable telomere length in their prostate stromal cells. She also described preliminary investigations on whether tissue-based prognostic markers are equally as informative in heavy and lean men and whether intraprostatic inflammation is related to the experience of LUTS. At each point in her presentation, Dr Platz challenged the attendees to pursue research that might uncover explanations for these observational findings, and to think about how these findings might be incorporated into models for patient management. At the end of her presentation, she reminded the attendees that population science on prostate cancer is more than just epidemiology. She introduced Dr. Craig Pollack, faculty at the Welch Center, and a primary care physician, who conducts healthcare delivery research on prostate cancer. She also mentioned Dr. Scott Zeger, faculty in the Department of Biostatistics and Vice Provost and Director of Hopkins inHealth, who is an expert in the development of new methods and big data. Dr. Zeger is a recipient of a PCW fund award with Dr. Carter.

2014 Prostate Research Day Poster Awards

1st Place Awards (Judge Arthur Burnett Award)

Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation
Mohammad Hedayati, Michael C. Haffner, Raju R. Raval, Yonggang Zhang, Haoming Zhou, Emma J. Knight, Susan Dalrymple, John T. Isaacs, Aileen Santos, Russell Hales, William G. Nelson, Srinivasan Yegnasubramanian, Theodore L. DeWeese.  

Novel interference of androgen receptor and Pol I in prostate cancer by non-competitive inhibition in vitro and in vivo
Paul Sirajuddin, Michael Moubarek, Jhanvi Patel, Zhiming Yang, Laureen Colis, Karita Peltonen, Hester Liu, Angelo De Marzo, Charles Bieberich, Marikki Laiho, 

Honorable Distinction, 2nd Place Award

A transgenic mouse model for inducible inflammation in the prostate.
Arya Ashok, Rebecca A. Walter, Varsha Rao, Laura N. Mutton, Michael Haffner, Angela Alme, Charles G. Drake, Srinivasan Yegnasubramanian, Angelo De Marzo, Charles J. Bieberich 

Honorable Distinction, 3rd Place Award

Mesenchymal stem cells (MSC) as cell-based vectors for PSA-activated Proaerolysin to sites of prostate cancer
W. Nathaniel Brennen, Oren Levy, Sudhir Ranganath, Michael Schweizer, David Marc Rosen, Sandrine Billet, Neil Bhowmick, Samuel Denmeade, Jeffrey Karp, John Isaacs.

Honorable Mention Awards

Functional screening identifies microRNAs which alter prostate cancer sensitivity to radiation therapy
Koji Hatano, Binod Kumar, Brian Mears, Wasim Chowdhury, Ronald Rodriguez, Mohammad Hedayati, Yonggang Zhang, Theodore L. DeWeese, Shawn Lupold.

Germline variants in the ASPORIN aspartic acid repeat domain and adverse prostate cancer outcomes
Paula Hurley, Debasish Sundi, Brian Simons, Robert Hughes, Guifang Yan, Marta Gielzak, David Berman, Sarah Isaacs, William Isaacs, Luigi Marchionni, Ashley Ross, Edward Schaeffer

PTEN loss predicts upgrading of prostate cancer from biopsy to radical prostatectomy
Tamara L. Lotan, Filipe L. Carvalho, Sarah B. Peskoe, Jessica L. Hicks, Jennifer Good, Helen Fedor, Elizabeth Humphreys, Misop Han, Elizabeth A. Platz, Jeremy A. Squire, Angelo M. DeMarzo, David M. Berman.

Mechanobiology and tumor growth: Multiphysics modeling, 3D cell culture

Sai Prakash, Sean Sun, Kenneth Pienta, 

Cyclin-dependent kinase 5(CDK5) controls prostate cancer metastasis in vivo and alters tumor immune response

B.W. Simons, A. Alme, C.F. Drake, B.D. Nelkin

Reclassification rates are higher among african american men than white men on active surveillance
D. Sundi, O. Kryvenko, J. Epstein, B.J. Trock, P.K. Landis, Z. Feng, A.E. Ross, H.B. Carter, E.M. Schaeffer

Dr. John P. Gearhart closes 100th Cloacal Exstrophy at Johns Hopkins

Cloacal exstrophy is one of the most severe congenital anomalies compatible with life. Fortunately, cloacal exstrophy is rare, occurring in 1 of 200,000 to 400,000 live births and can be diagnosed reliably prenatally.[1]   Historically, surgical reconstruction of cloacal exstrophy was considered futile and untreated neonates died from prematurity, short bowel syndrome, sepsis or renal and central nervous system abnormalities.  Over the past few decades, improvements in surgical technique and anesthesia have improved the outcomes of children born with cloacal exstrophy so that nearly 100% of children survive into adulthood.  Modem treatment of cloacal exstrophy includes a number of goals that were previously unobtainable, namely obtaining secure abdominal and bladder closure; preserving renal function; achieving satisfactory continence; obtaining functional, cosmetically pleasing genitalia, and preventing the short bowel syndrome.[2-5]

John P. Gearhart, MD

The Brady Urological Institute and Department of Urology at Johns Hopkins Hospital has a long history of treating children with bladder- and cloacal-exstrophy.  In 1975, Robert Douglas Jeffs, FRCS, Chief of Pediatric Urology at the University of Toronto Sick Children's Hospital, came to the Johns Hopkins Children's Center as the first Professor of Pediatric Urology.  He pioneered the modern techniques of exstrophy closure with osteotomies and improved long-term renal function.  John P. Gearhart, MD, Professor and Director of Pediatric Urology trained under and succeeded Dr. Jeffs in 1996. Tremendous improvements have been made in the treatment of children with the exstrophy spectrum during the last 10 years.  These include improvements in the understanding of differences in collagen, smooth muscle, neural innervation and bony anatomy at the cellular level in children with exstrophy as well as clinical improvements involving osteotomies, pain control and immobilization and continence surgeries have increased success rates and outcomes. [6]

In the last year, Dr. Gearhart led the team that closed the 100th child with cloacal exstrophy at the Johns Hopkins Children's Center.  This represents the world's largest experience with cloacal exstrophy and two lifetimes of dedication and work to this disease and the children afflicted by it.  See the video, "A Milestone in Pediatric Urology" below.




The outcomes for these 100 children were recently presented at the American Academy of Pediatrics (AAP) Annual Meeting in Orlando, Florida.  Sixty patients had complete follow-up at a median of 9 years (range 1-19 years); 26 patients failed their initial closure and 34 had a successful primary closure.  Children with the highest likelihood of successful primary closure had smaller diastasis of their pelvis, were closed with both osteotomies and an external fixator; and had a delay between osteotomy and abdominal closure.

For more information, please visit Division of Pediatric Urology at the Johns Hopkins Children's Center.



[1] Meizner, I. and Bar-Ziv, J.: In utero prenatal ultrasonic diagnosis of a rare case of cloacal exstrophy. J. Clin. Ultrasound, 13: 500, 1985. 
[2] Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, Novick AC, editors. Campbell-Walsh Urology. 10th ed. Philadelphia: Elsevier; 2012. p. 3497-553.

[3] Gearhart, J. P. and Jeffs, R. D.: Techniques to create urinary continence in the cloacal exstrophy patient. J. Urol., part 2, 146: 616,1991. 

[4] Mathews R, Jeffs RD, Reiner WG, Docimo SG, Gearhart JP. Cloacal exstrophy--improving the quality of life: the Johns Hopkins experience. The Journal of urology. 1998 Dec;160(6 Pt 2):2452-6.

[5] Lund DP, Hendren WH. Cloacal exstrophy: a 25-year experience with 50 cases. Journal of pediatric surgery. 2001 Jan;36(1):68-75.

[6] The Exstrophy-Epispadias-Cloacal Exstrophy Spectrum: A New Appraisal. John P. Gearhart, MD (Guest Editor), Cenk S.N. Buyukunal, MD (Guest Editor).  Seminars in Pediatric Surgery, Volume 20, Issue 2, May 2011, Pages 61.

How to treat a Small Renal Mass with Potentially Aggressive Features

Small renal masses (SRMs) include solid, cortical tumors less than 4cm that are confined to the kidney (AJCC clinical tumor stage, cT1a).  The majority of these tumors are cured with partial nephrectomy or can be safely monitored in an active surveillance program.  However, when removed some can demonstrate aggressive features (like invasion into the fat or blood vessels surrounding the kidney, AJCC pathological tumor stage, pT3a) and have a higher risk of recurrence or death from kidney cancer.  Occasionally, patients will have a CT scan or MRI that indicates that their SRM is touching the sinus fat and ask in clinic, does that mean it is aggressive and I am not a candidate for active surveillance?  Here we review the data about SRM with potentially aggressive features.

Michael Gorin, MD

SRMs pose a management quandary as they are a biologically heterogeneous group of tumors.  Surgical series demonstrate benign pathology in 20-30% of SRMs, and for those lesions that are cancerous, the majority are low-grade and unlikely to develop metastases.[1-3]  While a statistical minority, the tumors with aggressive features account for the majority of deaths from renal cell carcinoma (RCC) in the SRM population. 

Mohamad E. Allaf, MD

Michael Gorin, MD, a resident at the Brady Urological Institute at Johns Hopkins Hospital working with Mohamad Allaf, MD, Associate Professor of Urology, Oncology, and Biomedical Engineering, and Director of Minimally Invasive and Robotic Surgery, recently evaluated a multi-institutional database of five, high-volume, academic centers performing robotic partial nephrectomy.  In a study involving over 1,000 surgically removed renal masses, they found that 5% of clincally-localized (cT1a) tumors had aggressive features when removed and were upstaged to pT3a. Of the patients that remained cT1a, <1% had a recurrence at 2 years, while 8.2% of patients upstaged to pT3a had a recurrence of cancer over the same time period (see figure).      

 

Drs. Gorin and Allaf then looked to see if imaging characteristics prior to surgery were predictive of upstaging.  They found that increasing tumor size and tumors close to the renal hilum were independent risk factors for upstaging from cT1a to pT3a.  


Therefore, they drew a number of conclusions from this data:

• It is rare for a small renal tumor to actually be invasive and simply touching the fat on imaging does not necessarily mean it is invading it.

• Patients with small renal tumors touching the sinus fat are still candidates for active surveillance understanding that larger tumors that are hilar (close to the kidney blood vessels) are more likely to be invasive .  

• For these tumors, we typically advocate a more aggressive approach.

Read the entire manuscript:
Gorin MA, Ball MW, Pierorazio PM, Tanagho YS, Bhayani SB, Kaouk JH, Rogers CG, Stifelman MD, Khalifeh A, Kumar R, Sivarajan G, Allaf ME.Outcomes and predictors of clinical T1 to pathological T3a tumor up-staging after robotic partial nephrectomy: a multi-institutional analysis.J Urol. 2013 Nov;190(5):1907-11. doi: 10.1016/j.juro.2013.06.014. Epub 2013 Jun 11.
http://www.sciencedirect.com/science/article/pii/S0022534713045849

This blog entry was written in part by Mohamad E. Allaf, MD, Associate Professor of Urology, Oncology, and Biomedical Engineering, and Director of Minimally Invasive and Robotic Surgery.

[1]  Kutikov A, Fossett LK, Ramchandani P, Tomaszewski JE, Siegelman ES, Banner MP, Van Arsdalen KN, Wein AJ, Malkowicz SB.Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging.Urology. 2006 Oct;68(4):737-40.
[2] Rothman J, Egleston B, Wong YN, Iffrig K, Lebovitch S, Uzzo RG.Histopathological characteristics of localized renal cell carcinoma correlate with tumor size: a SEER analysis.J Urol. 2009 Jan;181(1):29-33; discussion 33-4. doi: 10.1016/j.juro.2008.09.009. Epub 2008 Nov 13.
[3] Thompson RH, Hill JR, Babayev Y, Cronin A, Kaag M, Kundu S, Bernstein M, Coleman J, Dalbagni G, Touijer K, Russo P.Metastatic renal cell carcinoma risk according to tumor size.J Urol. 2009 Jul;182(1):41-5. doi: 10.1016/j.juro.2009.02.128. Epub 2009 May 17.

Dr. Patrick C. Walsh's "Confession?": Men with High-Risk Prostate Cancer May Benefit From Radical Prostatectomy

Patrick C. Walsh, MD, University Distinguished Service Professor of Urology and Chairman Emeritus at the Brady Urological Institute at Johns Hopkins Hospital is a world-renowned urologist and surgeon, best known for pioneering the anatomic approach to radical prostatectomy and his expertise regarding benign and malignant neoplasms of the prostate.

Patrick C. Walsh, MD

In the Brady's weekly Grand Rounds conference, Dr. Walsh presented his "Confession?," a current review of the literature regarding prostate cancer treatment that indicates that patients with high-risk prostate cancer may benefit most from localized treatment.  To give a little background, in the 1970's, when Dr. Walsh arrived at the Brady, the trend in oncologic surgery was to do "big operations for little cancers and little operations for big cancers." This was reinforced by Dr. Hugh Jewett and others who spent their lifetime trying to define disease states that were curable with surgery.  Before the PSA era, this was men who had a B1 nodule (palpable cancer in less than 1/2 of one lobe).[1]  The impetus for the Partin Tables, was to refine the prediction of curability to optimally select the ideal surgical candidate for radical prostatectomy (RP).  Given the morbidity of RP, it was reasonable only to operate on those patients where the chances of cure are high.

For the better part of the last few decades, the ideal patient to be cured by RP was the man with organ-confined, Gleason 6 prostate cancer.  However recent data, which we will review below, indicate there may be a benefit of RP for men who are not cured by that surgery - men with high-risk prostate cancer (HRPC).

• First, we now know that not all men with HRPC are equal.  Men can be stratified into favorable or unfavorable pathology.  Men with favorable HRPC have all Gleason pattern 4 disease that is either confined to the prostate or with extraprostatic extension (pT2-pT3a) and, 15-years after RP, 60% will be free from metastatic disease and 70% will be alive.  On the other hand, for men with unfavorable disease [any Gleason pattern 5, seminal vesicle invasion of lymph node metastases (pT3b or N1)], at 15-years, only 20% will be free from metastases and be alive.[2]
• In the randomized, Scandinavian trial of RP versus watchful waiting, the greatest benefit of surgery (in reducing metastases and mortality from prostate cancer) was in the men with high-Gleason disease.[3]
• In men with locally advanced disease, treatment with androgen deprivation therapy (ADT) and radiation therapy (RT) provides a survival benefit over ADT alone.[4]
• Contrary to standard practice, men with positive lymph nodes who undergo removal of the prostate had a survival benefit when compared to men who only underwent a staging pelvic lymphadenectomy.[5,6]
• In a propensity score-matched analysis of men with HRPC who eventually developed metastases, men who underwent primary surgery had a better prostate cancer survival when compared to men who received primary RT.[7]

Why would treating the primary tumor radically benefit men with metastatic prostate cancer?  In 1889, Paget proposed the seed and soil theory: tumor (seeds) will selectively colonize in organs with a favorable environment (soil).  Recent evidence suggests that endocrine factors released by the primary tumor in prostate cancer may create a premetastatic niche in bone-marrow derived cells, making them more receptive to tumor colonization.[8]

In summary: Complete elimination of the primary lesion may improve survival in men with advanced disease even though it many not be curative.  For this reason, biochemical and metastasis-free survival may underestimate the ultimate value of any primary treatment to the prostate.

So, how should we treat men who present with HRPC?  The STAMPEDE Trial is currently underway, examining ADT and RT to men with newly diagnosed metastatic prostate cancer with the hypothesis that treating the primary tumor may retard distant metastatic progression and prolong survival.[9] However, we also know that radiation doses up to 81 grey may be insufficient to treat HRPC.[10]  

Therefore, on an individual basis, men with HRPC who have lesions that can be completely excised should be counseled on the possible benefits of RP, with a full understanding that they will likely need adjuvant or salvage therapy (and additional therapies will have cancer benefits with quality-of-life implications).  RP is more of an option for the treatment of HRPC than it has ever been, and prostate cancer outcomes may continue to improve as we better understand high-risk disease.  There is an exciting new frontier in the fight against prostate cancer where clinical trials and protocols may define neo-adjuvant and adjuvant therapies to maximize survival for men with HRPC.

This entry is extracted from a lecture given by Patrick C. Walsh, MD on January 30, 2014 at the Brady Urological Institute and Department of Urology Grand Rounds, Johns Hopkins Hospital, Baltimore, Maryland.  

[1] Jewett HJ. The present status of radical prostatectomy for stages A and B prostatic cancer.  Urol Clin North Am. 1975 Feb;2(1):105-24.

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[3] Vickers A, Bennette C, Steineck G, Adami HO, Johansson JE, Bill-Axelson A, Palmgren J, Garmo H, Holmberg L.Individualized estimation of the benefit of radical prostatectomy from the Scandinavian Prostate Cancer Group randomized trial. Eur Urol. 2012 Aug;62(2):204-9. doi: 10.1016/j.eururo.2012.04.024. Epub 2012 Apr 19.
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[6] Cadeddu JA, Partin AW, Epstein JI, Walsh PC. Stage D1 (T1-3, N1-3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology. 1997 Aug;50(2):251-5.
[7] Shao YH, Kim S, Moore DF, Shih W, Lin Y, Stein M, Kim IY, Lu-Yao GL.Cancer-specific Survival After Metastasis Following Primary Radical Prostatectomy Compared with Radiation Therapy in Prostate Cancer Patients: Results of a Population-based, Propensity Score-Matched Analysis.  Eur Urol. 2013 May 21. pii: S0302-2838(13)00489-2. doi: 10.1016/j.eururo.2013.05.023. [Epub ahead of print]
[8] Kaplan RN, Psaila B, Lyden D.  Bone marrow cells in the 'pre-metastatic niche': within bone and beyond.  Cancer Metastasis Rev. 2006 Dec;25(4):521-9.
[9] Parker CC, Sydes MR, Mason MD, Clarke NW, Aebersold D, de Bono JS, Dearnaley DP, Ritchie AW, Russell JM, Thalmann G, Parmar MK, James ND.Prostate radiotherapy for men with metastatic disease: a new comparison in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial.BJU Int. 2013 May;111(5):697-9. doi: 10.1111/bju.12087.
[10]Zelefsky MJ, Eastham JA, Cronin AM, Fuks Z, Zhang Z, Yamada Y, Vickers A, Scardino PT.  Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix.  J Clin Oncol. 2010 Mar 20;28(9):1508-13. doi: 10.1200/JCO.2009.22.2265. Epub 2010 Feb 16.