Tuesday, September 23, 2014

Historical Contribution: Jewett, Palpable Prostatic Nodule, 1956

1956

 

Jewett HJ. Significant of the Palpable Prostatic Nodule. J Am Med Assoc. 1956. 160(10):838-9.


Prior to PSA testing (only prevalent in the late 1980's), the diagnosis of prostate cancer relied on clinical examination – namely the digital rectal examination (DRE). The presence of a palpable nodule on DRE was not specific for prostate cancer as "the malignant nodule has no palpable characteristics that can be relied upon to distinguish it from the benign." In fact, only 50% of nodules contained cancer. Based on the examination of over 200 men (and their palpable nodules) over a 50 year period, Dr. Jewett and researchers at the Brady Urological Institute were able to note a few patterns in the diagnosis of prostatic nodules:

  • Benign and malignant nodules occupied the same anatomic areas of the prostate with the exception of the "median furrow" or central zone – no cases of cancer were noted in this area.
  • There was no difference in palpable characteristics between benign and malignant tumors.
    • Characteristics examined included: elevated vs. flat, smooth vs. irregular, sharp edges, and stony induration.
    • Of note, stony induration was believed to be indicative of cancer, however 75% of cases with stony induration were demonstrated to be benign.
Importantly, Jewett recognized that DRE was not sufficient for staging in many cases. In fact, in 72% of cases, the DRE understaged or "underestimated" the presence of disease including seminal vesicle invasion. In patients with seminal vesicle invasion or involvement of perivesicular tissues, the prognosis was notably poor. Therefore, Jewett emphasized the danger of "watchful waiting" in cases of malignancy as the current state of prostate cancer diagnostics did not allow for accurate staging. He did hedge, stating that "the greater the distance from the nodule to the seminal vesicles the less likely the latter are to be involved."




The last point to be taken from this manuscript is the commentary of prostate cancer epidemiology in the US in the mid-1900's. Between 1905-1945, 72 patients were "biopsied" for a palpable nodule; from 1945-1955 that number doubled to 139 patients. Jewett credited family physicians with increasing awareness of prostate cancer and the benefit or early intervention (radical prostatectomy) for localized disease with the dramatic increase in prostate cancer diagnoses. With an eerie resemblance of current controversies regarding PSA screening and prostate cancer mortality, Jewett was vexed by the underappreciation of prostate cancer incidence and death by the major health organizations in the US (Federal Security Agency and US Public Health Services). These organizations noted that prostate cancer was the 3rd leading cause of cancer death in the US (preceded by stomach and lung) but did not acknowledge the importance of DRE screening. Jewett felt these was easily preventable and that a dramatic improvement in prostate cancer mortality could be made:
"Since prostatic cancer is within easy reach of the examining finger and generally commences as a small, operable cancer, the responsibility of the general practitioner for the early detection of this disease, in a curable stage, is plainly evident."
To read the entire manuscript, follow the link above or click here.

As the Brady Urological Institute approaches its centennial, we present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the article each year with the highest number of citations is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

 

Monday, September 22, 2014

Aggressive Cancer May be Missed: For African American Men, Active Surveillance May Be Risky

If you are an African American man, you should take prostate cancer very seriously because, unfortunately, your life may depend on it. No other group of men in the world shares your risk for getting prostate cancer, of getting the kind that needs to be treated, of having it diagnosed at a later stage, and of dying from it. Now, important research by Brady investigators has shown that even the "best" kind of prostate cancer -- the kind that seems to be very low-risk, the kind that could be treated with active surveillance -- may not be as benign in African American men.

 

Edward Schaeffer, MD, PhD
Urologist, Edward Schaeffer, MD, PhD, was always curious about a striking paradox in prostate cancer… Active surveillance is a highly successful management strategy for men with very low risk prostate cancer yet African American men are more likely to be diagnosed with and die from prostate cancer. Thus was conservative management of African American men a wise choice?


To find out, Drs. Schaeffer, H. Ballentine Carter, MD, Debasish Sundi, MD, Ashley E. Ross, MD, PhD, and their research team, studied 1,801 men who met the National Comprehensive Cancer Network's criteria for very low-risk prostate cancer and were candidates for Active surveillance but elected to undergo immediate prostatectomy instead. The groups consisted of 256 African American men, 1,473 white men, and 72 men of other race. The team investigated pathologic and cancer specific outcomes between the three racial groups. The results were striking: "Surprisingly," says Schaeffer, "African American men had threefold higher rates of more advanced, aggressive disease, which resulted in much poorer outcomes, compared to white men." In other words, their cancer turned out to be more aggressive and more extensive than the initial biopsy and physical exam had suggested.

 

This publication, in the Journal of Clinical Oncology, prompted Schaeffer to team up with renowned prostate pathologist Jonathan Epstein, MD, to study these prostate cancers in more detail. Epstein scrutinized prostatectomy specimens from these men and found that, compared to Caucasian men, the tumors in African American men were larger, of higher grade, and more likely to appear in areas of the prostate that was distinctive from white men (W) in the study. This work was published simultaneously in the Journal of Urology and demonstrated that African American (AA) men had high-grade cancers on the top of the prostate, anterior to the urethra, 59 percent of the time. (see figure) 



Debasish Sundi, MD
"This is an area of the prostate that is particularly difficult to sample with standard biopsy approaches and may be why the more aggressive cancers were "missed" more often in Black men" says lead author on the studies, Dr Sundi. "Unique biopsy protocols or prostate imaging with MRI may help identify these more aggressive anterior tumors," Schaeffer adds, "It also suggests that there may be biologic differences in the prostates of African American men that drive these tumors to develop in a different location and will be a key area of our research in the future"

 

"Although Guideline panels encourage active surveillance as the preferred option for men with very low-risk prostate cancer," explains Schaeffer, "The favorable outcomes achieved for men in active surveillance are based on studies that under-represent African American men." In fact, barely a tenth of the men in most active surveillance programs are black, yet the results are generalized as applying to all men equally Because "very low-risk" cancers in African American men seem different from those in other men, Schaeffer believes that "we need race-specific recommendations" for the treatment of very-low risk cancer. "African American men need to understand these risks when they choose treatment for their prostate cancer. Specifically, they need to know that if they decide on active surveillance, aggressive cancer may be missed."

To read the manuscripts discussed in this blog, follow the links above or the references below.

Sundi D, Ross AE, Humphreys EB, Han M, Partin AW, Carter HB, Schaeffer EM. African American men with very low-risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them?  J Clin Oncol. 2013 Aug 20;31(24):2991-7. doi: 10.1200/JCO.2012.47.0302. Epub 2013 Jun 17.

Sundi D, Kryvenko ON, Carter HB, Ross AE, Epstein JI, Schaeffer EM.  Pathological examination of radical prostatectomy specimens in men with very low risk disease at biopsy reveals distinct zonal distribution of cancer in black American men.  J Urol. 2014 Jan;191(1):60-7. doi: 10.1016/j.juro.2013.06.021. Epub 2013 Jun 14.

To read more about this topic:

From Brady Urological Institute Discovery, Winter, 2014:
http://urology.jhu.edu/newsletter/2014/prostate_cancer_2014_3.php

From the ASCO (American Society of Clinical Oncology) Post, September, 2013:
http://www.ascopost.com/issues/september-1,-2013/active-surveillance-of-very-low-risk-prostate-cancer-might-not-be-suitable-option-for-african-american-men.aspx

Friday, September 19, 2014

Hopkins Researchers Contribute to "Molecular Family History" for Prostate Cancer


Two of the biggest risk factors for prostate cancer are family history and ancestry. Men of Northern European and African descent have the highest risk of being diagnosed with cancer and aggressive prostate cancer, while a number of studies demonstrate that Asian men may have a lower risk of prostate cancer. Recent improvements in technology make assessment of a person's genome (or genetic code) more facile and affordable. One such method examines SNP (single nucleotide polymorphisms) as they vary from person-to-person and group-to-group. This is a method of "DNA fingerprinting" used by many forensic investigators. Evaluating SNP over a large population can provide data to locate changes in the genome that put a population at risk of prostate cancer. A number of studies have examined SNP in populations of European descent, African-Americans, Japanese and Latino patients.[1-7]

A recent study, in which researchers from Johns Hopkins participated, combined data from a number of these populations to find common genetic causes of prostate cancer around the world. The study combined data on over 87,000 men and found 23 new genetic variants that increase a man's risk of prostate cancer. These variants are found in "non-coding" portions of the genome – DNA regions that regulate genes rather than actually make proteins in the body. It is believed that these variants in the genome explain 33% of the familial risk of prostate cancer.

William Isaacs, PhD and Alan Partin, MD, PhD
William B. Isaacs, PhD, Professor of Urology and Oncology led the Hopkins initiative with Chairman of the Brady Urological Institute, Alan W. Partin, MD, PhD. Dr. Partin commented, "Inheriting any single one of these genetic variants has only a small effect of prostate cancer risk. However, a subset of men will inherit many of these variants, putting them at substantially increase risk for the disease, from three to six times the population average. Men with these risk levels may benefit from disease screening at earlier ages."

Dr. Isaacs states, 
the identification of prostate cancer-related SNPS could serve as a "molecular family history" to enable better screening guidelines and therapies.

The entire manuscript can be found in the March, 2014 issue of Nature Genetics.[1]


Al Olama, A.A., et al., A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet, 2014. advance online publication.

Quotations from this blog are from the press release, "Large Study Reveals New Genetic Variants that Raise Risk for Prostate Cancer," 
from Johns Hopkins Medicine and Vanessa Wasta.

REFERENCES
[1] Eeles, R.A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391 (2013).
[2] Eeles, R.A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).
[3] Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).
[4] Schumacher, F.R. et al. Genome-wide association study identifies new prostate cancer susceptibility loci. Hum. Mol. Genet. 20, 3867–3875 (2011).
[5] Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).
[6] Cheng, I. et al. Evaluating genetic risk for prostate cancer among Japanese and Latinos. Cancer Epidemiol. Biomarkers Prev. 21, 2048–2058 (2012).
[7] Haiman, C.A. et al. Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet. 7, e1001387 (2011).

Thursday, September 18, 2014

Brady Presentations at the Mid-Atlantic American Urological Association Meeting, 2014



The Mid-Atlantic Section of the American Urological Association has met annually since 1941. This year the meeting is in Baltimore and offers the opportunity for urologists in practice, small and large hospitals to meet, share ideas and build lasting relationships. This year the Brady Urological Institute is well-represented. Some of the highlights include:
Arthur L. Burnett, MD, MBA
  • A special topic lecture by Arthur Burnett on the "Efficacy of Early Penile Rehabilitation Following Radical Prostatectomy: Myth or Reality," Thursday, 3pm.
  • Point/Counterpoint sessions led by:
    • Stephen Schatz on Endoscopic Management of BPH, Friday, 10:45am
    • Trinity Bivalacqua on BCG Refractory Superficial Bladder Cancer, Friday, 4:00pm
  • Video Case Discussion of laparoscopic and robotic complications by Christian Pavlovich and Misop Han
In addition, faculty members, research fellows and residents will be giving over 25 podium and poster presentations over the course of three days. 

A full schedule of the Brady events are listed below.
To see the full listing of presentations and abstracts click here


ThurSDAY, September 18

SCIENTIFIC SESSION 1: 2-3pm

6. Percent Lymph Node Involvement Predicts Mortality after Inguinal Lymph Node Dissection for Penile Cancer. Mark W. Ball, Joan Ko, Deborah Kaye, George Netto, Stephania Bezerra, Arthur L Burnett, Trinity Bivalacqua.

MODERATED POSTER SESSION 1: 2-3pm

MP7.     Sickle Cell Disease in Priapism: Disparities in Care? Gregory A. Joice, Max Kates, Nikolai Sopko, Johanna Hannan, Trinity Bivalacqua.
MP9. Quantification of Feulgen Stain (DNA) Nuclear Morphometry Predicts Prostate Cancer Aggressiveness. Aniq ur rehman Gajdhar, Guangjing Zhul, James E. Verdone, Christine Davis, Jonathan I. Epstein, Robert W. Veltri.
MP11.     A Human Prostatic Bacterial Isolate Alters the Prostatic Microenvironment and Accelerates Prostate Cancer Progression. Brian W. Simonsl, Nicholas M. Durham, Tullia Bruno, Joseph Grosso, Anthony Schaeffer, Ashley E. Ross, Paula Hurley, David M. Berman, Charles G. Drakel, Praveen Thumbikaf, Edward M. Schaeffer.

DISPLAY POSTERS: 2P-8P

P5. Rnaseh2a Roles In Regulating Prostate Cancer Cell Cycle And Survival. Zhenhua Huang, Sr., Edward Schaeffer, Sr., Ashley Ross.
P15. Priapism Impact Profile (PIP) Questionnaire: Development and Initial Evaluation. Arthur L Burnett, Uzoma A. Anele, Irene N. Trueheart.
P17. Identification of Men With The Highest Risk of Early Disease Recurrence After Radical Prostatectomy. Debasish Sundi, Vinson Wang, Phillip M. Pierorazio, Misop Han, Alan W. Partin, Phuoc Tran, Ashley E. Ross, Trinity Bivalacqua.
P19. Robotic Retroperitoneal Lymph Node Dissection for Clinical Stage I NSGCT: Initial Study of Feasibility and Comparative Analysis. Mark W. Ball, GautamJayram, MichaelA. Gorin, Phillip M. Pierorazio, Mohamad E. Allaf.
P20. Grade Reclassification on Active Surveillance: Age Matters. Jeffrey Tosoian, Bruce Trock, Max Kates, Patricia Landis,Jonathan I. Epstein, H. Ballentine Carter.
P23. National Resource Utilization In Radical Cystectomy For Bladder Cancer. Jen Jane Liu, Nilay Gandhi, Christian Pavlovich, Trinity Bivalacqua.
P24. Glycolysis Is Necessary For Cell Motility And Cytoskeleton Remodeling In Epithelial To Mesenchymal Transition In Prostate Cancer Cells. Takumi Shiraish P,Jessie Huang, James E. Verdone, James Hernandez', Steven M. Mooney, StevenS. An, Kennth J. Pienta.
P25. Predicting the Risk of Non Organ Confined Prostate Cancer When Perineural Invasion Is Found on Biopsy. Michael A. Gorin, Heather Chalfin, Jonathan I. Epstein, Zhaoyong Feng, Alan W. Partin, Bruce Trock.
P27. Secondary Re Closure in Classic Bladder Exstrophy: The Johns Hopkins Experience. Brian M. Inouye, Heather N. DiCarlo, Ezekiel E. Young, Ali Tourchi,John Gearhart.

SPECIAL TOPIC LECTURE: 3-345p

"Efficacy of Early Penile Rehabilitation Following Radical Prostatectomy: Myth or Reality" -- Presenter: Arthur Burnett, M.D.

SCIENTIFIC SESSION 2: 330-4pm


8. 5-year Analysis of A MultiInstitutional, Prospective Clinical Trial of Delayed Intervention And Surveillance For Small Renal Masses: The Dissrm Registry. Phillip M. Pierorazio, MichaelA. Gorin, Mark W. Ball, Bruce Trock, Mohamad E. Allaf.
14. Do PreBiopsy Rectal Swabs for FluoroquiQolone Resistance Reduce Prostate BiopsyRelated Infections? Jason E. Michaud, Aniq Gajdhar, Lucinda Robinson, Stephen M. Schatz, Pravin K. Rao, E. James Wright, Christian P. Pavlovich.

MODERATED POSTER SESSION 2: 3:45-4-45pm

MP14. Phenotypic Heterogeneity in Small Renal Masses. Mark W. Ball, Stephania Bezerra, Michael A. Gorin, Christian P. Pavlovich, Phillip M. Pierorazio, George]. Netto, Mohamad E. Allaf.
MP16. Risk Factors for IntraProstatic Incision Into Malignant Glands at Radical Prostatectomy Nathaniel Readal, SungWoo Park, Bruce Trock, Elizabeth Humphreys, Jonathan I. Epstein, Alan W. Partin, Misop Han.
MP17. Predict Prostate Cancer Aggression with Multiple Biomarkers Using a Novel Quantitative Tissue Immunoassay. Guangjing Zhul, Zhi Uu, Christhunesa S. Christudass,Jonathan I. Epstein, Hui Zhang, Joon Yong Chung, Stephen M. Hewitt, Robert W. Veltri.
MPI5. Erectile Dysfunction after Recurrent Ischemic Priapism in Patients With and Without Sickle Cell Disease: A Characterization and Comparative Analysis of Risk Factors. Uzoma A. Anele, Irene N. Trueheart, Arthur L Burnett.
MP22. The Financial Impact of Robotic Technology for Partial and Radical Nephrectomy. Max Kates, Mark W. Ball, Hiten D. Patel, Michael A. Gorin, PhillipP. Pierorazio, Mohamad E. Allaf.
MP24. Increased a actin and TGFj31 Levels in Bladder Exstrophy Smooth Muscle Cells. Ezekiel E. Young', Eric Z Massanyi, Heather DiCarlo, Brian Inouye, John P. Gearhart, Larissa A. Shimoda.

FRIDAY, September 19

SCIENTIFIC SESSION 3: 745-9am

21. Long:-term Erectile Function Outcomes of Patients In A Randomized Controlled Trial of Nightly Vs OnDemand Penile Rehabilitation With Sildenafil After Nerve sparing Radical Prostatectomy. Nilay M. Gandhi, Lynda Z. Mettee, Zhaoyong Feng, Bruce Trock, Christian P. Pavlovich.
22. Variability in Medicare Utilization and Payment Among Urologists. Joan S. Ko, Heather Chalfin, Bruce Trock, Zhaoyong Feng, Elizabeth Humphreys, Sung-Woo Park, H. Ballentine Carter, Misop Han.

POINT-COUNTERPOINT: 1045-1130am

Endoscopic Management of Benign Prostatic Hyperplasia (BPH):Greenlight KTP laser vs. Bipolar TURP -- Moderator: Stephen Schatz, MD
Greenlight KTP: Gregg Eure, M.D. Urology of Virginia, Virginia Beach, VA
Bipolar TURP: William Jaffe, M.D. Penn Presbyterian Medical Center, Philadelphia, PA

VIDEO CASE PANEL DISCUSSION: 2-3pm

Management of Intraoperative Laparoscopic and Robotic Complications (or what to do when the sh.. hits the fan)
Moderators: Misop Han, M.D., Johns Hopkins Hospital, Baltimore, MD; Christian Pavlovich, M.D., Johns Hopkins, Baltimore, MD
Panelists:
David Chen, M.D., Fox Chase Cancer Center, Rockledge, PA
Costas Lallas, M.D., Thomas Jefferson University, Philadelphia, PA
Thomas Jarrett, M.D., George Washington University, Washington, DC

SCIENTIFIC SESSION 4: 3-4pm

25. Robotic Simple Prostatectomy for Symptomatic Large-Gland BPH: Safety, Feasibility, and Comparative Analysis. Mark W. Ball, GautamJayram, Christian P. Pavlovich, Misop Han.
28. Neoadjuvant Chemotherapy Prediction of Extravesical Cancer Control Based Off Pathologic Staging. Nilay M. Gandhi, Alex Baras,Jen Jane-Uu, Mark Schoenberg, George Netto, Trinity Bivalacqua.
30. African American Race is Associated with Adverse Oncologic Outcomes Following Prostatectomy: LongrTerm Follow Up. Farzana Faisal, Debasish Sundi, Ashley     Ross, Elizabeth R Humphreys, Alan W. Partin, Misop Han, Edward M. Schaeffer.

POINT-COUNTERPOINT: 4-445pm

BCG Refractory Superficial Bladder Cancer: Early Cystectomy vs.Salvage Intravesical Therapy
Moderators: Matthew Kaag, M.D., Penn State Hershey Medical Center, Hershey, PA
Early Cystectomy: Thomas Guzzo, M.D., University of Pennsylvania, Philadelphia, PA
Salvage Intravesical Therapy: Trinity Bivalacqua, M.D., Ph.D., Johns Hopkins Medical Center, Baltimore, MD

Wednesday, September 17, 2014

Defining the Immune Response in Cavernous Nerve Injury after Radical Prostatectomy


Schematic cross section in the mid-prostate demonstrating the
neurovascular bundle (NVB) and technique of high-anterior
release to prevent "traction" nerve injury.  From Nielsen etal,
High Anterior Release of the Levator Fascia Improves
Sexual Function Following Open Radical Retropubic
Prostatectomy, Journal of Urology, 182 (2), 2008.
The discovery of neurovascular bundle and the establishment of nerve-sparing radical prostatectomy enabled preservation of erectile function after radical prostatectomy (RP) [1,2,3]. Nonetheless, 9%-86% of men undergoing RP will still experience some degree of erectile dysfunction (ED) following RP [4]. A major cause of post-operative ED following RP is cavernous nerve (CN) injury from surgical maneuvers. Traditionally CN injury was believed to be caused by direct transection, crush injury or electrical injury from cautery. More recently, surgical "maneuvers" such as excessive traction or torque have been implicated in CN injury. Therefore, mitigating CN injury and CN regeneration are keys to regain potency.

The immune system is believed to play a major role in repair mechanisms following CN injury. Inhibiting inflammation and the inflammatory response may prevent injury and neurological deficits. In addition, genes involved in injury and repair of the major pelvic ganglion (MPG, the source of the nerves that control erections) in response to CN injury may serve as therapeutic targets for new medications or treatments. Several significant molecular themes have been identified in the immune mechanism of CN injury including transcriptional regulation, chemokines, oxidative stress, apoptosis, and inflammatory cytokines. A number of these cytokines, including tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and chemokines related to macrophage induction including monocyte chemoattractant protein-1 (MCP-1) have been investigated as therapeutic targets. A prior study from the Brady Urological Institute led by Johanna Hannan, PhD, demonstrated a temporal increase in neuroinflammation in the MPG following CNI that was mediated by cytokines (TNF-α, TGF-β) and macrophages (M1 and M2) that may result deleterious effects on neuronal cell survival and nerve regeneration.[6] To further investigate these mechanisms, it is hypothesized that an increase in TNF-α in the MPG and subsequent neuroinflammation contribute to impaired CN regeneration.


Model of cavernous nerve injury in the male rat.
From pelvipharm.com.
To test this hypothesis, researchers at the Brady Urological Institute have created and use an animal model to investigate post-operative ED following RP – the male rat with bilateral cavernous injury (BCNI) [5]. Under general anesthesia, a rat's prostate is exposed via mid-line abdominal incision. The CN and the major pelvic ganglion (MPG), which projects the CN, are located posterolataral to the prostate. To create a rat with BCNI, the CN of each side is crushed with forceps.

A total of six MPGs were harvested from 3 control rats and cultured in Matrigel® with (n = 3) or without TNF-α (20 ng/mL, n=3). Neurite outgrowth length was measured 48 and 72 hours after culture and indicates the animals ability to regenerate injured nerves. We measured the longest neurites in each area (25-40 neurites / MPG) and compared the averages to evaluate the effect of exogenous TNF-α on neurite outgrowth from MPGs.

Average neurite lengths of MPGs cultured with TNF-α at 48 and 72 hours were significantly shorter than those of the control group (329±12.2 μm and 384±13.1 μm, p<0.01 at 48 hours; 369±14.5 and 462±20.0 μm, p<0.01 at 72 hours) (Figure 1). These results demonstrate that exogenous TNF-α treatment inhibits neurite outgrowth from MPGs.

Average neurite lengths of the control groups and the groups cultured with TNF-α at 48 hours
(A) and at 72 hours (B) after culture. * indicates significant difference.

Interestingly, neurite outgrowth patterns were different between the 2 groups. Neurites of the control group tended to grow equally, while neurites of the TNF-α group did not (Figure 2.).

Representative images of neurite outgrowth patterns. (A) Neurites of the control group grew equally. (B) Neurite lengths of the TNF-α were either as long as the average length of the control group or much shorter than that.

In the TNF-α group, some neurites were as long as the average length of the control group and others were much shorter than that. In order to demonstrate this difference of neurite outgrowth patterns quantitatively, we measured all the neurites measurable and made histograms of neurite lengths. Histograms of the control group showed almost normal distribution. On the other hand, histograms of the TNF-α group showed heavy-tailed distribution (Figure 3.).

The histograms of the neurite lengths in the control group and the TNF-α group at
(A) 48 hours and at (B) 72hours. The control group showed almost normal distribution, while the
histograms of the TNF-α group showed heavy-tailed distribution.
Variances of each group were calculated and compared. There was no significant difference of the variances between the 2 groups at 48 hours but the variance of the TNF-α group was significantly larger than the control group's at 72 hours (Figure 4).
The variances of the neurite lengths in the control group and the TNF-α group at
(A) 48 hours and at (B) 72hours. * indicates significant difference.

SUMMARY

This study provides additional evidence that exogenous TNF-α inhibits neurite outgrowth inhibition from the MPG. This suggests that TNF-α inhibition may be a future therapeutic target to prevent post-operative ED following RP. In addition, this study indicates that exogenous TNF-α does not inhibit all the neurites from MPGs. Accordingly, TNF-α may inhibit specific types of neurites, such as parasympathetic nerves. Further investigation is required to clarify the types of neurites inhibited by TNF-α.


This blog was written by Hotaka Matsui, a post-doctoral research fellow and graduate of the National Institute of Public Health in Japan. This work is the result of collaborative work with Johanna L. Hannan, Xiaopu Liu and Trinity J. Bivalacqua and is supported by the National Institute of Health (NIH) R03 Grant DK101701-01.

 


 


 

References:
[1]    Walsh PC and Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492.
[2]    Walsh PC: The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy. J Urol 2007;177:1632.
[3]    Walsh PC, Lepor H and Eggleston JC: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983;4:473.
[4]    Burnett AL, Aus G, Canby-Hagino ED et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178:597.
[5]    Hannan JL, Kutlu O, Stopak BL et al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J Sex Med 2014;11(6):1442
[6]    Hannan JL, Weyne E, Albersen M et al. Cavernous nerve injury induced temporal increase in neuroinflammation and cytokine induction in the major pelvic ganglion of the rat. American Urological Association Annual Meeting 2014. Orlando, FL. MP43-10

Tuesday, September 16, 2014

Historical Contribution: What makes the prostate grow? WW Scott, 1953

1953

Scott WW. What Makes the Prostate Grow. J Urol. 1953;70:3:477-88.


William Wallace Scott, MD
This manuscript is the transcript of a 1952 lecture given to the Western Section of the American Urological Assocation by William Wallace Scott, second Director of the Brady Urological Institute at Johns Hopkins. 

Dr. Scott opens by stating,
"Understanding fully that we don't know precisely what makes the prostate grow, I shall endeavor to outline what might be considered the present status of the problem and, if time permits, indulge in a little biological extrapolation."
Throughout his speech, Scott describes a variety of animal experiments that demonstrate the effects of endocrine manipulation of prostatic size, histology and function. He credits the residents of the Brady with most of the work.

He starts with embryology and works through the natural history of prostate growth. Scott notes that placental male mammals are the only animals born with prostates. In the final trimester of pregnancy, the prostate undergo dramatic changes in epithelial content – a change believed to occur under the influence of gonadal hormones as the timing coincides with changes in the breast, uterus and vagina of female animals. After birth, the prostate regresses, not repeating the changes observed in the last trimester until puberty, when the maturing testes gain hormonal function. The prostate remains dormant until a number of decades later, when nodular hyperplasia and carcinoma can develop. Based on these data, Scott believed "the best working hypothesis is that both benign hyperplasia and cancer of the prostate results from a disturbance of the ratio and quantity of androgens and estrogens in older men."


To support his argument, Dr. Scott reviews the effects of castration on the adult prostate. It was well-established that castrating a variety of animals (bulls, dogs, and mice) results in a small, firm and fibrotic prostate that lost the ability to create prostatic secretions. It was commonly believed at the time, that castration resulted in androgen withdrawal and without androgen stimulation, the prostate would regress. Scott felt this supposition was wrong – or at least unsupported by the existing evidence. While the exact role of the Leydig and Sertoli cells were unknown, Scott felt that there was adequate evidence that a preponderance of once cell type could lead to an androgen-like (masculinizing) or estrogen-like (feminizing) phenotype, respectively; and he believed loss of androgens did not tell the complete story of prostatic growth. To test this hypothesis, he gave testosterone and estrogen in a variety of animal experiments. He was able to demonstrate:
  • Re-growth of prostatic tissue after castration if the animal was challenged with testosterone
  • Restoration of secretory function after castration with testosterone replacement
  • Conflicting results demonstrating both prostate growth and shrinkage with exogenous estrogen administration
  • Estrogen supplementation after castration can result in prostate growth
  • Estrogen supplementation did NOT counteract testosterone replacement in the castrate animal, leading to prostatic growth after castration
Scott recognized that the adrenal glands were a source of extragonadal androgens and stressed that understanding the hypophysis and pituitary axis were essential to understanding the influence of hormones on the prostate. To investigate this hypothesis, Scott undertook a variety of experiments to manipulate the HPA (hypothalamic-pituitary-adrenal axis) and observe the effects on the prostate. In one such experiment, Scott and colleagues observed profound atrophy of prostate cancer after hypophysectomy (pituitary removal) in a patient with intact testes and adrenal glands. 

In addition, it was well-known that the liver metabolized estrogens, but its role in androgen metabolism was not known. Scott provided evidence that the liver is a "physiologic filter" for testosterone, inactivating the androgen and leading to feminizing effects. In an elaborate surgical experiment, Drs. Grayhack and Harris (residents at the Brady) created an adrenal shunt in dogs so that adrenal androgens would first pass through the liver, effectively removing all systemic androgen from circulation (see figure). 


An "experimental" shunt by Drs. Grayhack and Harris, very different from what most urologists know as today as the Grayhack shunt.  The surgery demonstrated in the figure shunts blood from the adrenal directly into the portal circulation as an experimental treatment for castrate-resistant prostate cancer.
They believed this surgery could change the management of castration-resistant prostate cancer… unfortunately this problem still alludes us.

In summation, this is a fascinating piece collating and synthesizing the data regarding hormones and prostatic growth 12 years after the seminal work by Huggins and Hodges.[1]  

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


 

[1] 1. Huggins, C., and Hodges, C. V.: Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate, Cancer Research 1:293, 1941.


 

Monday, September 15, 2014

PSA Screening for Prostate Cancer: Evidence As Interpreted by the Guidelines

Prostate-specific antigen (PSA) is an enzyme secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen, allows sperm to swim freely and facilitates pregnancy. PSA is present in small quantities in the blood of men with healthy prostates, but can be elevated in the presence of prostate cancer or other prostate diseases. PSA screening for prostate cancer is a hotly debated subject. Physician associations have created guidelines for prostate cancer screening which often differ, leaving patients exasperated. To understand the guidelines for PSA screening, an evaluation of the history of PSA screening and the available evidence can be instructive.


PSA HISTORY

PSA was first discovered in the 1970's and was approved in the 1980's by the FDA to monitor prostate cancer recurrence. In 1991, Catalona et al. published a seminal paper in the New England Journal of Medicine showing that PSA was a good predictor of a prostate cancer diagnosis.[1] PSA soon became a widely used screening test throughout the United States for asymptomatic men. Following this, the incidence of prostate cancer skyrocketed. The figure below from SEER data displays this rapid increase. Prior to routine PSA testing, 1 in 10 men were diagnosed with prostate cancer. After widespread PSA testing, 1 in 6 men were diagnosed with prostate cancer. Correspondingly, in the mid 90's mortality due to prostate cancer began to decline at a rate of approximately 4% per year, as seen in the graph below. This may have been due to an increase in PSA screening, however, some have suggested it is due to earlier and increasingly aggressive prostate cancer treatments beginning around the same time period.


Prostate cancer incidence and mortality before, during and after the introduction of PSA testing, 1975-2011.


PSA & EVIDENCE FROM THE SCREENING TRIALS

Eventually, a number of randomized control trials were performed to determine if screening for prostate cancer using PSA conferred a prostate cancer survival benefit. Perhaps the two best designed studies were the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) which are summarized below.[2,3]


PLCO
ERSPC
Cohort size
76,693
162,243
Age range
55-74
55-69
PSA interval
Annually for 6 years
Every 2 to 4 years
Median follow-up
~13 years
~13 years
Contamination
~77%
~20%
PCSM RR

(screen v control)
1.08
0.79

In summary, PLCO is an American trial that enrolled men aged 55-74 to a screening or non-screening arm. After 10 years of follow-up there was no improvement in prostate cancer specific mortality in the screened group. However, this study has been criticized for its high level of contamination. This refers to the fact that a large percentage of men in the non-screening arm (approximately 77%) had a PSA level tested during the study. PLCO did not compare screening to non-screening; it compared routine screening to opportunistic screening, which is highly prevalent in the US.

The ERSPC is a European trial of men aged 55 to 69 randomized to a screened arm that received PSA screening every 2 to 4 years and a non-screening group. The contamination rate was much lower in the ERSPC trial as routine PSA tests are uncommon throughout Europe. The 13 year update of this study was recently published, and it shows that a man's risk of dying of prostate cancer is 21% less when screened for prostate cancer. 781 men would need to be screened and 27 cancers would need to be diagnosed to save one life from prostate cancer.[3]

While the evidence supporting a mortality benefit for prostate cancer is somewhat conflicting, evidence related to the harm of screening are not. Below is a table that summarizes some of the negative aspects of screening that have been cited in the literature.


HarmEstimateSource
False positive75.9%Proportion w PSA >3, negative bx (ERSPC)
Overdiagnosis66%
23-42%
Screen detected, 4 year interval (ERSPC)
Modelling studies (Heijnsdijk et al 2009) [4]
Post-biopsy fever4%Loeb et al 2012 ERSPC [5]
Post-biopsy hospitalization1%Loeb et al 2012 ERSPC [5]
Hematuria/hematospermia20-50%Post-biopsy (ERSPC)
Incontinence/ED20-30%All treatment types (Chou et al 2011, USPSTF meta-analysis) [6]
Death1-5/1000Within 1 month of surgery (Chou et al 2011, USPSTF meta-analysis) [6]



THE GUIDELINES

Based on the above information the American Urological Association (AUA), The National Comprehensive Cancer Network (NCCN) and the Unites States Preventative Services Task Force (USPSTF) have created guidelines that physicians and patients can use to make decisions about prostate cancer screening.


The AUA assembled a panel of experts in the field, led by Johns Hopkins professor Dr. H. Ballentine Carter. The AUA Guideline, "Early Detection of Prostate Cancer," recommend screening men aged 55-69 only after an informed decision is made by the patient following a discussion of the risks and benefits. There is no high-quality evidence showing that men under 55 do not benefit from screening, rather, there is an absence of evidence - the ERSPC and PLCO only included men over 55. For men 70 and older with less than 10-15 years life expectancy screening for prostate cancer is not recommended.  


The NCCN also assembled a group of leading urologists and created guidelines. For men interested in screening, they recommend obtaining a baseline PSA at age 45-49. This initial value has been shown to be highly predictive of prostate cancer development up to 30 years later. If the PSA is less than 1 (the median value for men in this age group), they should not be retested until age 50. If the PSA is greater than 1, PSA should be retested every 1 to 2 years. Men 50 to 70 should undergo PSA testing and can be retested every 1 to 2 years. The NCCN recommends exercising caution in testing men over 70, and suggests limiting it to men with few to no comorbidities.


The USPSTF, a panel composed of primary care physicians, also creates best practice recommendations through guidelines. Unlike the AUA and NCCN, they discourage PSA testing of all age groups, regardless of risk status. They place a relatively higher value on the results of the PLCO trial as it is an American study and is presumably more applicable to our population than a European study. In regards to the high level of contamination, they feel that there was still an increased incidence of prostate cancer in the screened group, and yet no prostate cancer mortality benefit was observed. In regards to the results of the ERSPC, the USPSTF notes that while there was an improvement in prostate cancer specific mortality, but no difference in overall mortality. It is important to note that the ERSPC authors specifically did not design the study with overall mortality as a primary endpoint. The USPSTF notes that the harms of prostate cancer screening are well known and thus outweigh an as of yet unproven benefit.


SUMMARY

Unfortunately, until more data is available the debate over prostate cancer screening will continue- leaving patients and physicians to come to their own conclusions based on individual priorities. To paraphrase Dr. Patrick Walsh
the studies discussed above are conducted from a population-based perspective. An urologist evaluating a patient has an individual and personal perspective. They see a patient's general health, family history, fears and wishes. For that man, the desire to avoid dying of prostate cancer often prompts PSA screening. 
With a quality study showing a decrease in prostate cancer mortality, PSA screening will likely continue until there is solid evidence that men are not being saved from prostate cancer death.


The Blog was written by Wesley Ludwig, MD. Dr. Ludwig is an urology resident at the Brady Urological Institute at Johns Hopkins.

 




REFERENCES
[1] Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991 Apr 25;324(17):1156-61. Erratum in: N Engl J Med 1991 Oct 31;325(18):1324.
[2] Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, Fouad MN, Isaacs C, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, O'Brien B, Ragard LR, Clapp JD, Rathmell JM, Riley TL, Hsing AW, Izmirlian G, Pinsky PF, Kramer BS, Miller AB, Gohagan JK, Prorok PC; PLCO Project Team. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan 18;104(2):125-32. doi: 10.1093/jnci/djr500. Epub 2012 Jan 6.
[3] Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, Kwiatkowski M, Lujan M, Määttänen L, Lilja H, Denis LJ, Recker F, Paez A, Bangma CH, Carlsson S, Puliti D, Villers A, Rebillard X, Hakama M, Stenman UH, Kujala P, Taari K, Aus G, Huber A, van der Kwast TH, van Schaik RH, de Koning HJ, Moss SM, Auvinen A; for the ERSPC Investigators. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014 Aug 6. pii: S0140-6736(14)60525-0. doi: 10.1016/S0140-6736(14)60525-0. [Epub ahead of print]
[4] Heijnsdijk EA, der Kinderen A, Wever EM, Draisma G, Roobol MJ, de Koning HJ. Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer. Br J Cancer. 2009 Dec 1;101(11):1833-8. doi: 10.1038/sj.bjc.6605422. Epub 2009 Nov 10.
[5] Loeb S, van den Heuvel S, Zhu X, Bangma CH, Schröder FH, Roobol MJ. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol. 2012 Jun;61(6):1110-4. doi: 10.1016/j.eururo.2011.12.058. Epub 2012 Jan 5.
[6] Chou R, Dana T, Bougatsos C, Fu R, Blazina I, Gleitsmann K, Rugge JB. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct.