Wednesday, October 1, 2014

Journal Spotlight: The RIVUR Study, Are Daily Antibiotics Necessary for Patients with Urinary Reflux?


Vesicoureteral reflux (VUR), or simply "reflux," is a congenital condition in which urine flows from the bladder back up towards the kidneys. An estimated 17% of children are born with or develop VUR. Reflux is present up to 30% of children with febrile urinary tract infections (UTI).[1] Urinary reflux predisposes these children to kidney infection, or pyelonephritis, which can be a serious infection requiring hospitalization. In very young babies, a single episode of pyelonephritis can lead to kidney damage and scar formation. Because of this risk, many pediatric urologists prescribe low dose, daily antibiotics to children with VUR, in an effort to prevent episodes of kidney infections. However, the benefit of prophylactic antibiotics remains controversial.

 

Hoberman, A., Greenfield, S., Matoo, K. et al.: Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. NEJM, 370: 2367, 2014


 

Recently, results from the RIVUR study (Randomized Intervention for Children with Vesicoureteral Reflux) were published and shed some light on the effects of using daily antibiotic prophylaxis in children with VUR.[above, 2] The RIVUR study was an ambitious effort by many physicians at 19 hospitals across the U.S. – Johns Hopkins was one of the leading sites. Over 600 children diagnosed with VUR were randomized to either once daily antibiotic (Bactrim, otherwise known as sulfamethoxazole and trimethoprim, TMP-SMX) versus placebo. They were followed closely with regular check-ups over the next 2 years.
    
The RIVUR study demonstrated two key things: First, children given prophylaxis had 50% fewer febrile infections over time when compared to children not taking antibiotics


In the RIVUR Study, fewer children assigned to TMP-SMX prophylaxis had a UTI than children assigned to placebo (P<0.001 by log-rank test).  As presented in the New England Journal of Medicine (2014;370:2367-2376).

However, children given antibiotics did not show less kidney scarring compared to the children not given antibiotics. This may mean that the antibiotics did not prevent scarring, OR it may mean that the kidney scarring was too small to see based on our current imaging techniques. Parents, pediatricians, and pediatric urologists may interpret the results of the RIVUR study as a reason to stop the use of antibiotics in children with VUR. In our own practice, at Johns Hopkins Children's Center, we continue to emphasize the importance of incorporating science and tailoring the treatment plan based on each child/family.

Overall, the benefits of daily antibiotics on preventing kidney damage remain controversial and the use of daily antibiotics should be balanced with patient factors, frequency of febrile UTIs and family dynamics.



Jason Michaud, MD, PhD
Ming Hsien Wang, MD
This blog was written by Jason Michaud, MD, PhD, PGY4 urology resident, and Ming-Hsien Wang, MD, Assistant Professor of Urology and Director of the Pediatric Urology Fellowship Program at the Brady Urological Institute and Johns Hopkins Children's Center.

 






References
1. Sargent, MA. What is the normal prevalence of vesicoureteral reflux? Pediatr. Radiol. Sep;30(9):587-93, 2000.
2. Hoberman, A., Greenfield, S., Matoo, K. et al.: Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. NEJM, 370: 2367, 2014

Tuesday, September 30, 2014

Historical Contribution: Burt, Finney & Scott, Steroid Response to Prostate Cancer Treatment, 1957

1957
Burt FB, Finney RP, Scott WW. Steroid Response to Therapy in Prostatic Cancer. Cancer. 1957. 10;4:825-30.

 

The discovery that prostate cancer was androgen-dependent by Huggins and Hodges in 1941, energized and dominated the field of urology for the next few decades.[1] By 1957, it was well-established that the only effective treatment for advanced prostate cancer was androgen-ablation. Dr. Scott and collaborators from Johns Hopkins hypothesized that to monitor the effectiveness of androgen-ablation, the response of endogenous steroids could be measured and catalogued. To that end, Burt, Finney and Scott, the Brady Urological Institute, summarize the understanding of steroid and steroid-responsiveness to androgen ablation therapy.

At the time of this manuscripts publication, it was established by a number of researchers that urinary excretion of 17-ketosteroids would decrease after orchiectomy or medical castration – only to rise again in patients after several months in patients with recurrent disease. However, it was unknown if there were any qualitative or quantitative differences in 17-ketosteroids among men with and without prostate cancer. Furthermore, the structure of these urinary steroids were unknown and differences, if they existed, between testicular and adrenal androgens were speculative.  Therefore, researchers from Johns Hopkins further developed and refined methods developed at Memorial Sloan-Kettering in New York City, using the enzyme glucuronidase, to separate urinary steroids into "androgen metabolites" and "corticoid metabolites" for each patient in the hopes of defining a "steroid-signature" for patients with prostate cancer.

Burt, Finney and Scott made a number of important clinical observations in this small study that confirmed and furthered the current understanding of androgens and prostate cancer.

  • As expected, six patients undergoing castration alone experienced reductions in androgen metabolites that corresponded to an immediate clinical response.
  • Estrogens (silbestrol) would decrease both androgen- and corticoid-metabolites in the urine – suggesting that silbestrol facilitates pituitary inhibition of androgens.


  • One patient experienced a prostate cancer recurrence within six weeks of orchiectomy and died 10 months later. His corticoid metabolites increased dramatically while his androgen metabolites increased only moderately indicating that the pituitary-adrenal axis played a role in recurrent disease.

  • To assess the role of the pituitary, they administered "test doses" of gonadotropin and ACTH (adrenocorticotropic hormone) before and after castration.
    • While androgen levels rose with gonadotropin, the corticoid levels remained stable.
    • ACTH had no impact on urinary steroid levels prior to orchiectomy, however dramatically increased steroid metabolites after orchiectomy.
"[T]he ratio of the androgen metabolites isolated during our investigation remained remarkably constant before and after castration, and before and after stimulation by adrenocorticotropic hormone (ACTH) or gonadotropin. Administered testosterone did not alter this ratio. This suggests a structural similarity between testicular and adrenal androgen and testosterone."
  • Two patients who failed castration and silbestrol therapy had a dramatic fall in androgen metabolites with the administration of cortisone. When cortisone levels were decreased, bone pain returned without a difference in androgen metabolite levels. It was theorized at the time, that a "cortisone-euphoria" improved symptoms of bone pain. However, Burt, Finney and Scott hypothesized that the cortisone acted on the androgen-axis and perhaps on the tumor, improving symptoms in a physiologic (and not psychiatric) manner.
  • Among ten patients with good and poor outcomes, those who did poorly had higher proportion of androgenic androsterone compared to etiocholanolone.
  • There was no lower limit of androgens, below which a clinical response could be guaranteed. Therefore, each cancer and patient had "different quantitative requirements for growth."
From these data, Burt, Finney and Scott were hoping to make objective recommendations for the management of patients with advanced prostate cancer - which they were able to partially achieve. They recommended that androgen-ablation start with estrogen (silbestrol) therapy – as estrogen would depress both gonadal and pituitary sources of androgens. If failed estrogen therapy, orchiectomy should be performed. Relapse after castration should be treated with cortisone. Scott and others previously wrote about and discussed adrenalectomy for patients refractory to all other treatments. The patient most likely to benefit from adrenalectomy would have high androgen metabolites while on cortisone therapy. Regretably, this study failed to demonstrate a single patient with only rising androgen metabolites while on systemic steroids – adding more evidence against adrenalectomy.

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

[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 29, 2014

Looking to Identify Men with High-Risk Prostate Cancer Early


Robert Veltri, PhD
Some men are diagnosed with small, low-risk prostate cancers and choose active surveillance. "However, some of these low-risk cancers may harbor molecular or other very subtle nuclear morphological features of size & shape in more aggressive cancer," says Robert Veltri, Ph.D., Associate Professor of Urology and Director of the Fisher Biomarker and Repository Laboratory at the Johns Hopkins University School of Medicine. "If these men could be identified early, we could eradicate their cancer when the disease burden is low." Morphologic features refer to the size, shape and consistency of the nucleus (or center) of a given cell.

The red flags that signal more aggressive disease early-on are extremely tiny, for example, subtle nuclear morphological alterations within the cancer cell, or differences in the levels of specific cancer-related proteins. Veltri, working with Brady Urology Institute urologists, Alan Partin, M.D., Ph.D. and H. Ballentine Carter, M.D.; and a world's expert pathologist, Jonathan I. Epstein, MD, has used highly sophisticated methods to analyze very small prostate biopsy tissue samples for ways of identifying men who appear to have more aggressive disease. Dr. Veltri is looking for a "signature" of aggressive disease that can be spotted at a diagnostic biopsy and his research is funded by the Early Detection Research Network of the National Cancer Institute and a Department of Defense.

Morphology versus morphometry for adenoma assessment. Morphometric measurements performed by quantitative, digitalized assessment of histopathology slides compared with regular pathology assessment through the microscope.  From http://www.medscape.com/viewarticle/703573_5 

Previously, Dr. Veltri demonstrated that DNA content of cancer cells and the levels of (-7)ProPSA (a precursor molecule to PSA) in biopsy tissue could predict those men selected for active surveillance that would fail.[1] Currently, he is seeking a morphologic and molecular "signature" to separate less aggressive from more aggressive prostate cancer. Veltri has analyzed 80 cases of prostate cancer that were stratified by Gleason score and also biopsy samples from 70 men on active surveillance who turned out to have aggressive cancer, and from 70 men who had mild, slow-growing disease, and came up with a test.

"The results indicate we have developed an integrated, quantitative histomorphic and molecular biomarker-based predictor for the early detection of clinically more aggressive prostate cancer," he says. These preliminary results were reported by Dr. Guangjing Zhu, a post-doctoral fellow at the annual American Association for Cancer Research's annual meeting San Diego.

 

[1] Isharwal S, Makarov DV, Sokoll LJ, Landis P, Marlow C, Epstein JI, Partin AW, Carter HB, Veltri RW. ProPSA and diagnostic biopsy tissue DNA content combination improves accuracy to predict need for prostate cancer treatment among men enrolled in an active surveillance program. Urology. 2011 Mar;77(3):763.e1-6. doi: 10.1016/j.urology.2010.07.526. Epub 2011 Jan 8.

Friday, September 26, 2014

Schaeffer Named Inaugural Evensen Professor


R. Christian B. Evensen doesn't have prostate cancer anymore, and many men in his shoes would prefer never to think about the prostate again. Instead, Evensen has become one of the best friends the Brady Urological Institute has ever had. He has given his time and generous support as of the charter founders of the Patrick C. Walsh Prostate Cancer Research Fund; served as a lay member on the committee that awards the Patrick C. Walsh Prostate Cancer Research Scholarships; as Chair of the Johns Hopkins Prostate Cancer Advisory Board; and now, he has endowed a professorship.

 

"What Chris has done is remarkable," says Patrick Walsh, M.D., University Distinguished Service Professor of Urology. "This professorship means so much to us at the Brady, because he not only has benefitted from the research and clinical discoveries we have made, he wants to help other men beat this disease, and he's helping to make this possible by supporting one of our finest clinicians and scientists."

 

R. Christian B. Evensen, Alan W. Partin
and Edward M. Schaeffer.
The inaugural recipient of the R. Christian B. Evensen Professorship, dedicated in June, is Edward M. Schaeffer, M.D., Ph.D., Associate Professor of Urology and Oncology. "I am honored to be the R. Christian B. Evensen Professor," says Schaeffer, "and I am inspired by the confidence that Chris Evensen has shown in the work we are doing."

 

Schaeffer, who directs the Brady's Prostate Cancer Program, is also Co-Director of the Prostate Cancer Multidisciplinary Clinic and Director of International Urologic Services. "Ted Schaeffer exemplifies the mission of the Brady Urological Institute by seamlessly combining surgical acumen and scientific discovery," says Walsh, who recruited Schaeffer to the Brady 13 years ago. "The central theme of his research involves understanding the clinical, biologic and molecular features of the most aggressive types of prostate cancer." Schaeffer's work is supported by the NIH, the Howard Hughes Institute, the Department of Defense, and the Prostate Cancer Foundation.

 

In laboratory work, Schaeffer has developed several novel approaches to finding how prostate cancer starts at the molecular level. He is particularly interested in understanding the basic processes that determine and drive aggressive prostate cancer, and in helping the men at highest risk of developing this most dangerous form of the disease. His most recent work on disparities in outcomes for African Americans with prostate cancer was honored by the American Society of Clinical Oncology with a 2013 Clinical Cancer Advance award. Schaeffer has also been awarded the American Urological Association's Astellas "Rising Star" award and the Howard Hughes Cilnician-Scientist Early Careers Award. He has written more than 120 peer-reviewed papers and has edited and contributed to multiple medical textbooks.

 

Evensen is the Founding and Managing Partner of Flintridge Capital Investments, an algorithmic trading firm, and Flintridge Capital Technologists, which develops these technologies. He is a Trustee of Johns Hopkins Medicine, where he is a member of the Finance Committee and Investments Subcommittee; a board member of Johns Hopkins Medicine International International; and also a board member of the Prostate Cancer Foundation, where he is the Chair of the Discovery and Translation Committee and the Development Committee; and a board member of the Prostate Cancer Foundation of Norway. He and his wife, Felicia Evensen, have six children.

Patrick C. Walsh introduces Edward M. Schaeffer as the inaugural recipient of the
R. Christian B. Evenson Professorship in Urology.



Wednesday, September 24, 2014

A Strategic Approach to Erection Recovery after Radical Prostatectomy

Radical prostatectomy has evolved over the past 30 years with improved surgical technique including optimal methods to spare erection-producing autonomic nerves located deeply within the pelvis adjacent to the prostate gland. These surgical advances have improved erectile function recovery rates after surgery. However despite current surgical proficiency for radical prostatectomy, many men still do experience delayed or incomplete recovery of erectile function status postoperatively. Thus, interest continues to better understand the basis for erectile function loss after surgery and develop strategies to promote erectile function recovery after radical prostatectomy.

A. Lateral view of the male pelvis illustrating the course and distribution of the left cavernous nerve fiber, as part of the left neurovascular bundle within intrapelvic fascia coverings. The cavernous nerve travels from the pelvicplexus proximally to the penis distally, in close anatomical relationship to the seminal vesicle, prostate, striated urethral sphincter, bladder, and rectum.  B. Anterosuperior oblique view of the same anatomical structures.  C. Anterosuperior oblique view illustrating preservation of the cavernous nervesafter bilateral nerve-sparing prostatectomy and bladder neck anastomosis to theurethral stump. The cavernous nerve fibers are preserved by division and clip-ping of small prostatic nerves alongside the prostate. When non-nerve-sparingsurgery is required for cancer eradication either unilaterally or bilaterally, wide excision of periprostatic soft tissue includes the cavernous nerves en block withthe removed surgical specimen.

Evidence supports the likely basis of erectile dysfunction associated with radical prostatectomy to relate to traumatic injury of the erection producing cavernous nerves even when they are gently dissected and preserved at the time of surgery. It is certainly clear that the very best surgical technique is needed as the first-line approach of "neuroprotection." The next frontier in this arena involves strategies directed to maximally restoring cavernous nerve function. Various strategies have been studied in this regard including nerve grafting techniques, nerve stimulation techniques, as well as application of "nerve growth factors" that may revitalize the nerve supply to the penis. Ongoing scientific work at the basic science research laboratory level is fundamental to the achievement of progress in this field. New scientific concepts will next be "translated" to the human condition applying rigorously conducted clinical trials.

 

At the Brady Urological Institute, our focus continues in an integrative manner to perform the surgery in the most proficient manner while also offering scientifically grounded options to recover erectile function at the time of surgery and in the early postoperative interval. We employ a number of strategies to improve erectile function for our patients:
  • A thorough preoperative assessment of function and counseling regarding the expectations after surgery.
  • Clinical trials involving experimental therapies to preserve erectile function at the time of surgery.
  • "Penile rehabilitation" that can be performed at the discretion of your surgeon or as part of the post-prostatectomy recovery clinic.
We believe this integrative approach offers men the best opportunity for erectile function recovery after radical prostatectomy.




This blog was written by Arthur L. Burnett, MD, MBA, FACS, Patrick C. Walsh Distinguished Professor of Urology; Director, Basic Science Laboratory in Neurourology; Director, Sexual Medicine Fellowship Program; and Faculty Member, Cellular and Molecular Medicine Graduate Training Program.

 


 


 

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, visit the Centennial Website or click here.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Monday, 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