Wednesday, December 17, 2014

Testicular Self-Exam: Why There Is Nothing Wrong with a Regular Feel


This blog entry is a continuation of "The Importance of Testicular Self-Examination," posted December 1, 2014.

In summation, the cure rate for localized testicular cancer approaches 99% and drops to 75% for men with metastatic disease – often requiring chemotherapy and/or major surgery to achieve cure. The United States Preventative Services Task Force (USPSTF) recommends against regular testicular self-exam (TSE), citing a "moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits."[1] The USPSTF recommendation is based on the relatively low incidence of testicular cancer, the high cure rate, unknown performance statistics of examination (when performed by patient or physician) for diagnosis and uncertainty if TSE leads to finding earlier stage disease; and the risks and costs associated with a false-positive test.

Each of the shortcomings mentioned by the USPSTF are addressed here:

LOW INCIDENCE, HIGH CURE RATE

It is true that testicular cancer only affects 8,000 men per year and that the survival for all comers in approximately 95%.[2] Thankfully, only a few hundred men die per year of testicular cancer – however that means there are hundreds of thousands of survivors in the US and around the world. These young men have been exposed to chemotherapy, radiation treatments, major surgeries and repeated CT scans for surveillance. Most, if not all treatments, influence hormone function, fertility and general quality-of-life – translating into a huge impact on a young population with many life-years ahead of them! Therefore, while there are fewer testicular cancer patients than other diseases, these patients have longer to live and the consequences of treatment are just as important as other cancers!!

UNKNOWN PERFORMANCE OF TESTICULAR SELF-EXAMINATION

It has to be conceded that there is no evidence that TSE is effective for the diagnosis of testicular cancer or helps find men at an earlier stage of disease. However, lack of evidence does not mean that TSE is not effective – it means that no study has effectively investigated the role of TSE in an at-risk population. We do know that length of patient- and physician-related delay is directly related to the stage of cancer at diagnosis; the median delay for men with Stage I, II and III cancer was 75, 101 and 134 days respectively.[3] In addition, delay in diagnosis has been associated with higher rates of chemotherapy and lower survival rates.[4]

THE RISKS/HARMS OF TESTICULAR SELF-EXAM

TSE is a painless, easy to perform self-examination technique. The risks of performing a TSE are undergoing an unnecessary office visit, ultrasound or surgery for a benign mass. Associated with a false-positive TSE can be anxiety-provoking and lead to other psychological stresses. Overcoming the risks of TSE requires education; both that an abnormality on TSE does not necessarily mean cancer and that when found early, the treatments are minor and the cure-rate high!

COST-EFFECTIVENESS

A recent study by Aberger and colleagues, from the University of Kansas Medical Center, investigated the costs associated with TSE in a theoretical model.[5] The most expensive treatment for testicular cancer is the combination of chemotherapy and surgery for an advanced testicular cancer, costing on average $50,000 per patient. Compared only to the immediate costs of an office-visit with a physician or a scrotal ultrasound, the treatment of one advanced stage testicular cancer is equal to:
  • 320 office visits for a benign, but worrisome TSE
  • 185 office visits with a scrotal ultrasound for a worrisome TSE
  • 81 office visits with scrotal ultrasound and tumor markers for a suspicious TSE
  • 6-7 office visists with scrotal ultrasound and tumor markers leading to a radical orchiectomy
  • 2-3 early-stage testicular cancers treated with active surveillance for five years
Given the nearly $48 million spent on the men with metastatic cancer in 2013, any improvement in early diagnosis and stage could dramatically improve costs for this disease. Importantly, this cost analysis does not consider the long-term sequelae of the treatment of testicular cancer including hormone replacement or fertility treatments which can be extremely expensive over a lifetime.

 

SUMMARY

The USPSTF recommendations regarding TSE are based on very little existing evidence. From the perspective of the USPSTF, the potential for harms, outweighs the lack of demonstrable benefit for TSE. I would respectfully disagree, stating that while the cure rate of testicular cancer is wonderful, the burden of the disease is greatly underappreciated. Even if a free, painless self-examination leads to an unnecessary doctor's visit, saving one man from advanced disease is well worth the "risks and costs" of TSE.

 

This blog was written by Phillip M. Pierorazio, MD, Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.

 









[1] U.S. Preventive Services Task Force. Screening for Testicular Cancer: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement. Ann Intern Med. 2011;154(7):483-486.

[2] SEER Stat Fact Sheets: Testis Cancer, http://seer.cancer.gov/statfacts/html/testis.html

[3] Bosl, G. J., N. J. Vogelzang, A. Goldman, E. E. Fraley, P. H. Lange, S. H. Levitt, et al. 1981. Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet 2:970–973.
[4] Moul JW, Paulson DF, Dodge RK, et al: Delay in diagnosis and survival in testicular cancer: impact of effective therapy and changes during 18 years. J Urol 1990; 143: pp. 520-523
[5] Aberger M, Wilson B, Holzbeierlein JM, Griebling TL, Nangia AK. Testicular self-examination and testicular cancer: a cost-utility analysis. Cancer Med. 2014 Aug 8. doi: 10.1002/cam4.318. [Epub ahead of print]

Tuesday, December 16, 2014

Historical Contribution: 1951, Hodges, Gilbert & Scott, Renal Trauma


1951
Hodges CV, Donald RG, Scott WW. Renal Trauma: A Study of 71 Cases. J Urol. 1951;56;5:627-37.


In 1951, axial imaging was not available for the diagnosis and staging of renal trauma. Given shortcomings in diagnostics, the invasiveness of existing diagnostics (i.e. retrograde pyelogram), and the, in general, favorable outcomes associated with renal trauma, the consensus of most general surgeons and urologists was to manage renal trauma conservatively. Expert opinion at the time stated:

"the majority of patients with renal trauma may be treated conservatively with the expectation that the injured kidney will recover sufficient function to be a useful and serviceable organ."
"extensive urologic investigation, including cystoscopy and retrograde pyelography, immediately after renal injury is usually unnecessary and often undesirable"
"in the majority of cases, medical treatment will be followed by functional results which are satisfactory, although various types of anatomic abnormalities may persist."
"most kidney injuries should be left alone. If the renal· pelvis is reasonably intact, the patient will soon recover. If the contour of the pelvis is blasted beyond recognition, nephrectomy is necessary."
The authors of this manuscript poke a number of holes in the argument for conservative treatment:
  1. The favorable outcomes of patients managed "conservatively" is biased by the inherent self-selection of severe renal trauma – those patients with the most severe injuries succumb to those injuries, those left for "conservative" management have an inherently improved chance at survival.
  2. Late complications (abscess, hydronephrosis, pyonephrosis, etc.) can cause complete loss of renal function.
  3. Unassociated renal diseases (hydronephrosis, malignancy of cortex or renal pelvis, cysts or polycystic kidney disease) are unrecognized in the setting of trauma and may have implications for future management.
  4. Patients undergoing "conservative" management can undergo protracted convalescence for weeks or years.
The authors therefore created a diagnostic and therapeutic algorithm based stratification of 71 renal injuries seen at the Johns Hopkins Hospital (1930-1948). They classified injuries as (1) minor, (2) major and (3) critical injuries.

Minor Injuries

Definition: Parenchymal damage without rupture of the capsule of extension of the defect into the collecting system.
Prevalence: 66.2%
Presentation: Do not present in shock, may have hematuria that resolves within 48-72 hours. Pain, when present, also improves within 72 hours.
Most importantly, excretory and retrograde pyelogram demonstrates integrity of the collecting system (– "the greatest single criterion for placing injuries in the minor group").
Management: Urography.
Average Hospitalization: 8 days

Major Injuries

Definition: Parenchymal damage with rupture of the capsule or calyces.
Prevalence: 32.4%
Presentation: Often presents as mass around the kidney and hematuria. Shock may or may not be present (and may be delayed for hours or days). Hematuria and symptoms persist for several days.
Extravasation on excretory or retrograde pyelogram indicates a "major" injury.
Management:

  • Immediate Surgery: 39% for repair or nephrectomy
  • Delayed Surgery: 48% (21 days to 35 years after trauma) for incapacitating sequelae of injury.
  • Conservative Management: 13%; of which 85.7% developed renal disease of "severe proportions" requiring future nephrectomy.

Average Hospitalization: 19.1 days (if operated on), 20 days (if conservative management)

Critical Injuries

Definition: Extension into or disruption of the renal vessels.
Prevalence: 1.4%
Presentation: Exquisite pain, early and profound shock; urography is not necessary nor does it yield valuable information if the vasculature is disrupted.
Management: Immediate surgery.
Average Hospitalization: 11 days

 

While our grading of renal trauma has developed into a more complex system, many of the principles outlined in this 1951 manuscript hold true today.

AAST (American Association for the Surgery of Trauma): 
http://www.aast.org/library/traumatools/injuryscoringscales.aspx


Also of interest are images of lower and upper pole heminephrectomy to preserve kidney function on the injured side (below).




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, December 15, 2014

Application Season for Urology Residency: What to look for in a resident? A residency program?

Each year, medical students around the country apply for a position in a residency program. Urology is an extremely competitive "match" process in which each applicants submits a rank list of programs they would prefer to train. In turn, each program submits a rank list of the applicants they would prefer. In the end, a computer algorithm matches applicants and programs. In 2014, 534 applicants registered for 285 positions in 118 urology programs around the country. Of those 534, 446 participated in the match. Approximately 75% of the applicants are men. Interestingly, men and women have the same match rate – approximately 65%.


THE INTERVIEW TRAIL

The application process can be an exciting and brutal process for resident applicants. Applicants have the opportunity to travel around the country, meet a variety of urologists in a variety of settings, and learn a tremendous amount about the field. Practically, most graduating medical students seeking a residency in urology apply to between 30 and 40 programs. On average, they participate in 12 interviews (range 8-15) over a 20 day (14-30) period. Interview-related expenses (mostly travel-related) are approximately $4,000 ($2,000-5,200) per applicant, averaging out to be approximately $330 per interview.[1]



At the Brady Urological Institute at Johns Hopkins in 2014, 260 applications were submitted for review (national average is 253 applications). Of those 260 applicants, we selected 39 (15%) for interviews and accept 3 (1.2% of applicants to the Brady, 0.5% of all applicants) to continue on as residents.

 

THE INTERVIEW PROCESS

Each urology program conducts their selection and interview process in an independent fashion that suits their needs. Programs can vary by the number of residents they accept on a yearly basis (between one and five), number of faculty, clinical (patient) volume and areas of focus or expertise; geographic location as well as urban or rural hospital and number of hospitals; patient population, and academic versus clinically-focused program.

The Brady Urological Institute, located in Baltimore City, Maryland, graduates three residents per year. Residents are trained in a three hospital settings: the Johns Hopkins Hospital, the Johns Hopkins Bayview Medical Center, and the Johns Hopkins Children's Center. Residents are trained by a large, clinically and academically-productive faculty. While the Brady is most well-known for the treatment of urologic oncology, the faculty is composed of experts in sexual medicine, infertility, stone disease, endourology, robotic surgery, reconstructive urology, female and neurourology in both adult and pediatric populations.


Misop Han, MD. Program Director
of the Brady Residency Program.
The Brady holds two interview days for applicants, typically at the end of November or early December. The night before the interview applicants are invited to dinner with current residents (preceded by "happy hour" with the faculty). Interestingly, most resident applicants find the time with the residents to be the most important interview day activity – highlighting the "feel" of the program given off by interacting with current residents.[2] Therefore a dedicated dinner away from faculty, allows both resident applicants and residents to get a good feel for each other in a pressure-free environment.


The applicants are invited to a breakfast with the faculty, which is followed by Grand Rounds. The Grand Rounds topic is typically a senior resident presenting the summation of their lab year of research. Following Grand Rounds, Misop Han, MD and Program Director of the Urology Program, gives a general overview of the program followed by Dr. Patrick C. Walsh's "A Brief History of Urology at Hopkins" – a perennial applicant favorite. From there the applicants are interviewed by the majority of the faculty, usually in pairs. In a survey, most medical students indicated they preferred from 5-7 faculty interviews throughout the course of a work-day.[2] While respondents of this survey indicated that interviewing with more than one faculty member at a time would be "intimidating," we have excellent feedback from our applicants about our "teamed" approach to applicant interviews. Participants recognize that meeting with two faculty at a time allows them to meet more faculty and often provides contrasting interview styles that generates a more comfortable discussion and understanding of the applicant.


CHOOSING A RESIDENT

There is much more art than science to picking a good residency class. Performance as a surgical intern has been shown to predict future "excellence" as a urology resident.[3] And while higher applicant rank and better letters of recommendation are more common for "excellent" residents, determining the quality of resident from medical school performance can be challenging.


H. Ballentine Carter, MD
Each program may have different criteria for selecting incoming residents based on their identity and needs. Some programs rely more heavily on clinical acumen while some focus on academic productivity. At the Brady, we are looking for future leaders of the field. First, we are looking for pleasant and reliable people with whom to work. The relationship between faculty and resident requires an incredible amount of trust, as residents are often entrusted to "care" for a faculty members' patients to varying degrees. Dr. H. Ballentine Carter, MD makes the summation, "First, a nice person that would be enjoyable to work with, someone who has good communication skills. Secondly, a track record of academic excellence, not necessarily basic science record."


Arthur L. Burnett, MD
While academic productivity prior to residency is not a requisite, Dr. Arthur L. Burnett, MD explains, "The best residency applicant is one who shows commitment to excellence and aspires to make meaningful contributions in urology. A track record of accomplishment suggests who this person is." Urology residents who write more papers during residency have greater academic "productivity" following graduation – however, there is no data on medical students.[4]




Lastly, enthusiasm, initiative and drive are important qualities. "Whether they share your exact academic interests or not, the best residents and mentees are the ones who are enthusiastic about their interests – it's easy to guide them to success, while trying to motivate the unmotivated is difficult," says Phillip M. Pierorazio, MD.

 

CHOOSING A PROGRAM

Similarly, choosing a program is also more art than science and choosing a program is an incredibly individualized process. There are many wonderful training programs in urology around the country – most applicants will be highly successful at a variety of those programs. There are certainly factors that play a role that should be considered. We recommend each applicant create their own "deal-breakers" and consider how any combination of the following factors may contribute to their professional development.

  • Clinical Volume: How busy are the faculty? How busy are the residents? The feeling is always that more surgery leads to better training, but that is not always the case. Some students learn better in volume, some with a more focused, mentored approach. Certainly considering the volume of specialty cases is important for someone considering a career in subspecialty care (i.e. oncology, female urology, etc.). However, urology is certainly a surgical specialty and resident operative experience is consistently among the highest ranked criteria by applicants.[2]
  • Perceived Strength of Faculty: These are your teachers and mentors. How well do they teach and mentor? How well do you think you will get along with them?
  • Academic Productivity: Some programs are incredibly academically focused and productive; others pride themselves on excellent clinical and patient care.
  • Vision of the Program/Vision of the Chairman: where is the program now and where is it going? Residency training is either five or six years. Things can change over that time, considering the trajectory of the program over a given time is important.
  • Geography: Urban versus rural setting? Nearness to family or support structure? Good for families or a young, professional population for single residents? Consider the proximity to arts, leisure and travel which are important "escapes" from residency.
  • Resident Life: Are the residents married? Single? With children? How many per year? Do they get along? Your co-residents do not need to be your best friends, but you do need to work with them for many years.
  • Five or Six Years: 70% of residents want to participate in research or scholarly activity, however only 33.5% preferred or are indifferent to a dedicated year of research. 76% preferred to do a year of research in fellowship.[5] However, greater research time during residency is associated with more publications, and a greater number of publications during residency is associated with future academic productivity.[4]
Number of Publications as related to Months of Research.  From Yang et al [4].
  • Specialty Hospitals: Veterans Association (VA) and Children's Hospitals offer unique opportunities for residency training.


 

When selecting a program for residency, these criteria should be considered and prioritized by each applicant. It may offer an improved framework, from which to create a rank-list. Advice from faculty at the Brady includes:

"First, a talented faculty with broad experience and views. Second, a strong research program in place for those interested in academics."
H. Ballentine Carter, MD


"An excellent residency training program provides quality role models and mentors in diverse academic areas foremost and opportunities to develop one's expertise and knowledge."

Arthur L. Burnett, MD


 

As interview season is wrapping up we wish all residency applicants good luck and we look forward to meeting our future residents!

 


 

[1] Kerfoot BP, Asher KP, McCullough DL. Financial and educational costs of the residency interview process for urology applicants. Urology. 2008 Jun;71(6):990-4. doi: 10.1016/j.urology.2007.11.102. Epub 2008 Mar 4.
[2] Jacobs JC, Guralnick ML, Sandlow JI, Langenstroer P, Begun FP, See WA, O'Connor RC. Senior medical student opinions regarding the ideal urology interview day. J Surg Educ. 2014 Nov-Dec;71(6):878-82. doi: 10.1016/j.jsurg.2014.05.009. Epub 2014 Jun 26.
[3] Grewal SG, Yeung LS, Brandes SB. Predictors of success in a urology residency program. J Surg Educ. 2013 Jan-Feb;70(1):138-43. doi: 10.1016/j.jsurg.2012.06.015. Epub 2012 Aug 2.
[4] Yang G, Zaid UB, Erickson BA, Blaschko SD, Carroll PR, Breyer BN. Urology resident publication output and its relationship to future academic achievement. J Urol. 2011 Feb;185(2):642-6. doi: 10.1016/j.juro.2010.09.097. Epub 2010 Dec 18.
[5] Peyton CC, Badlani GH. Dedicated research time in urology residency: current status. Urology. 2014 Apr;83(4):719-24. doi: 10.1016/j.urology.2013.09.072. Epub 2014 Feb 5.

Friday, December 12, 2014

A New Treatment CHAARTED for Men with Metastatic Prostate Cancer

Men with metastatic prostate cancer are traditionally treated with hormonal treatment, otherwise known as androgen deprivation treatment (ADT). Prostate cancer is a male cancer, and cutting male hormones (i.e. androgens) can cause the cancer to regress. Unfortunately, all prostate cancers will eventually learn to grow without androgens – a state called castration-resistant prostate cancer (CRPC). Once a man developed CRPC, they were often given chemotherapy. However, CRPC is an aggressive, hard to kill cancer and the effects of chemotherapy were often short-lived. Through research done greater than a decade prior, researchers found that docetaxel chemotherapy could prolong the life of men with advanced cancer. Mario Eisenberger, MD, Professor of Oncology and Urology at Johns Hopkins, was part of the prior docetaxel studies demonstrating a small benefit.

Nearly 10 years ago, investigators from the Eastern Cooperative Oncology Group (ECOG) decided to try a different paradigm – treating metastatic prostate cancer with chemotherapy much in earlier in the course of disease. The CHAARTED trial, was a phase III, randomized study enrolling 790 from 2006-2012 with metastatic prostate cancer. Dr. Eisenberger explains, "The idea behind CHAARTED was that if docetaxel is effective against cells that no longer respond to hormones at late stages, then it could be even more effective if we gavit it early, when there are far fewer hormone-insensitive cells around."

The CHAARTED trial was sponsored by the National Cancer Institute and led by Christopher Sweeny, MBBS of the Dana Farber Cancer Institute/Harvard Cancer Center and Johns Hopkins participated in the study. Patients were randomized to either receive (1) ADT or (2) ADT with docetaxel chemotherapy. This work was presented at the 2014 ASCO (American Society of Clinical Oncology) Meeting, demonstrating that six cycles of docetaxel with standard ADT extended the lives of newly diagnosed men with metastatic prostate cancer by nearly 18 months. The median overall survival for patients receiving ADT alone was 44 months and 58 months for men receiving ADT and docetaxel (P=0.003) – a major improvement in survival. The biggest benefit was seen in men with high-volume metastatic disease (more than three metastatic lesions on bone scan). Importantly, the side effects were minimal and manageable.

Michael Carducci, MD, Professor of Oncology and Urology at Johns Hopkins and Chairman of the ECOG Genitourinary Group stated, "This has the potential to be a major game-changer. Based on these results, it seems now that men diagnosed with metastatic disease will do well to include a medical oncologist in their care team to seek the advisability of early chemotherapy, in addition to hormone therapy."


Drs. Mario Eisenberger, MD and Michael Carducci, MD



Read more about CHAARTED at: http://www.cancernetwork.com/asco-2014/blogs/asco-2014-plenary-session-results-chaarted-trial

Quotations are extracted from DISCOVERY: Special Centennial Edition, Volume 11, Winter 2015, by the Patrick C. Walsh Prostate Cancer Research Fund.

 


 

Wednesday, December 10, 2014

Radiation Therapy after Prostate Surgery, Part IV: Radiation Side Effects


Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners. 

In the fourth part in this blog series, we review the statements from the ASTRO/AUA Guideline regarding radiation toxicity, side effects and the data supporting them.

To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.
To read Part II: Subgroup Analyses of Adjuvant Radiation for Prostate Cancer click here.
To read Part III: Salvage Radiation Therapy for Prostate Cancer click here.

 

The last portion of the ASTRO/AUA Guidelines focuses on radiation-related toxicities or side effects.

The Guideline Statements

Guideline Statement 9. Patients should be informed of the possible short-term and long-term urinary, bowel, and sexual side effects of radiotherapy as well as of the potential benefits of controlling disease recurrence. (Clinical Principle)


The Evidence

Radiation therapy can cause both acute (short-term) and chronic (long-term) side effects. Most short-term side effects are minor in nature, do not require additional treatment, and improve spontaneously within a few weeks of radiation therapy. Minor, short-term side effects include irritative voiding symptoms, rare urinary retention, irritative bowel habits (most commonly frequency including diarrhea) and minor bleeding in the urine or stool.  

There are a few problematic chronic side-effects that can be serious. These side effects are related to the ability of radiation therapy to destroy tissues, specifically the microscopic blood supply, that keeps many tissues healthy and functional. Loss of microscopic blood supply can lead to scarring and strictures, non-healing wounds and fistulae, and subsequent problems like urinary retention and the need for operations to bypass radiation-induced problems. The SWOG study presents the best data regarding these post-radiation toxicities.

Rectal bleeding or proctitis requiring intervention occurs in approximately 3% of patients following adjuvant radiation therapy. Urethral stricture occurs in upwards of 18% of patients receiving radiation (and 9.5% of patients with surgery alone). Strictures can lead to urinary retention, urinary incontinence or fistulae between the bladder and rectum. Strictures can also occur in the ureters causing blockage of one or both ureters; or can occur in the rectum – thankfully these strictures are rare, <1% of patient post-radiation will develop bowel or ureter strictures.

Urinary incontinence (without evidence of stricture) occurs in 6.5% of men post-radiation (and 2.8% of men following surgery alone). In other studies the rates of incontinence following adjuvant radiation therapy can be as high as 40-50%.[1] For that reason, most practitioners will recommend waiting for continence to return after radical prostatectomy before undergoing adjuvant radiation therapy. Radiation therapy before the return of continence increases the risk of permanent incontinence dramatically.

Summary


  • Radiation therapy after radical prostatectomy can be associated with both short- and long-term side effects.
  • Most short-term side effects are mild in nature and pass without treatment.
  • Rarely, serious long-term side effects can occur including rectal bleeding, proctitis, stricture disease (of the urethra, ureters or rectum), and urinary incontinence.
  • Radiation therapy can affect the return of urinary continence following surgery, therefore most practitioners recommend allowing the return of urinary function prior to initiating radiation therapy.


This blog was written by Mark W. Ball, MD.  Mark is a 5th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.
 


 







[1] Suardi N, Gallina A, Lista G, Gandaglia G, Abdollah F, Capitanio U, Dell'Oglio P, Nini A, Salonia A, Montorsi F, Briganti A. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol. 2014 Mar;65(3):546-51. doi: 10.1016/j.eururo.2013.01.027. Epub 2013 Feb 4.

Tuesday, December 9, 2014

Historical Contribution: 1949, Haines & Grabstald, Xylocaine


1949
Haines JS, Grabstald H. Xylocaine: A New Topical Anesthetic in Urology. J Urol. 1949;62;6:901-2.


 

Xylocaine (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide), more commonly known as Lidocaine, was first described by Swedish scientists Lofgren and Lundquist in 1943. Interestingly, Lundquist performed the first local anesthetic experiments using xylocaine on himself.[1] A number of subsequent studies demonstrated, "high degrees of anesthetic potency both for surface and infiltration purposes."




In this 1949 manuscript published in the Journal of Urology, Haines and Grabstald describe the use of xylocaine in 250 transurethral procedures varying from passage of sounds to fulguration of bladder tumors. They used approximately 10cc in men and a xylocaine-soaked applicator (placed in the urethra) in women. They describe no untoward effects and tolerability in a wide range of applications including transurethral fulguration of multiple tumors and recurrent dilations of urethral strictures in soldiers who suffered pelvic injuries. Xylocaine became widely marketed as a topical and local anesthetic in 1949 – around the time of this report – and continues to be one of the most widely used topical and local anesthetics around the world!

As an interesting side note, the authors make an important disclosure in the footnotes - the xylocaine in this report was supplied by Astra Pharmaceuticals (a Swedish company founded in 1913, which would later merge with the British, Zeneca Group in 1999 to form AstraZeneca).


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. Löfgren N (1948). Studies on local anesthetics: Xylocaine: a new synthetic drug(Inaugural dissertation). Stockholm, Sweden: Ivar Heggstroms.

Monday, December 8, 2014

Factors underlying prostate cancer racial disparities


The most recent statistics from the American Cancer Society estimate that 29,000 men will die of prostate cancer (PCa) in 2014 (the most of any urologic cancer), and an astounding 233,000 men will be diagnosed with PCa.[1] This 10-fold difference between incidence and mortality in PCa is due to the fact that many men do not die from but rather die with indolent, non-aggressive disease. Yet PCa certainly has lethal potential, as evidenced by 29,000 cancer-related deaths per year. This implies that the most important question in this disease is to identify which patients with PCa have lethal disease, thus allowing physicians and patients to determine which PCa cases may be safely monitored, whereas others require aggressive curative treatments such as radical prostatectomy or radiation therapy.

In this context, PCa is also unique in that there are tremendous racial disparities in prostate cancer. Specifically, black American men are twice as likely to be diagnosed with, and die from, PCa as white American men.[1] It has been suggested that black men may be prone to develop intrinsically more aggressive types of PCa. If this is true, then it is possible that understanding the biologic basis of aggressive PCa in black men may lend cancer researchers important insights into distinguishing lethal PCa in general.

 

ENVIRONMENT OR BIOLOGY?

Some investigators have reported that black men with PCa have worse outcomes and lower survival due to environmental factors—namely, systematic differences in socioeconomic status (income, education, zip code, marital status, etc). Is it environment or biology? One study looking at men in the Chicago area found that demographic variables seemed to explain higher PCa-specific mortality rates in black men,[2] while multiple others show that black men with PCa have worse survival even after controlling for socioeconomic factors.[3–5] Overall, the literature suggests that associations between socio-demographics and racial disparities in PCa outcomes are minimal at best.

At the same time, there is a compelling body of evidence to suggest that there are important biological differences that may cause PCa to demonstrate increased lethal potential in black men. In a study of black and white patients who otherwise were very similar and had equal rates of PCa screening and healthcare access, Moul et al. found that black men had much higher prostate specific antigen (PSA) values; and that the reason for this is that, while gram for gram black men's cancers made the same amount of PSA as white men, black men simply had much larger tumors.[6] Researchers who looked at Detroit area epidemiologic data in a careful fashion concluded that, while young black men and young white men seem to have equal rates of PCa, black men have a two- to four-fold higher risk of developing high grade and metastatic PCa over their lifetimes.[7]

 

RESEARCH FROM JOHNS HOPKINS

To go back to the original dilemma in PCa, the big question is to differentiate men who have aggressive PCa and require radical treatments such as surgery from men who are likely to have indolent PCa and may be safely monitored. To this end, leading clinicians have devised a management option, called active surveillance (AS), to monitor men with PCa who have favorable (low) risk characteristics. AS involves periodic physical exams, PSA tests, and prostate biopsies to ensure that men with low-risk PCa are safe to be monitored conservatively. At the same time, this strategy re-directs patients to curative surgery or radiation therapy if aggressive PCa features are detected on the monitoring protocol (such as high grade cancer on biopsy). This strategy is overall very successful – for men who are monitored in this manner, cancer specific mortality rates among the world's largest AS programs are very low-- <1%.8 There is a problem with this data, however: black men are underrepresented in the largest studies of AS (only 5-7% of these cohorts). Knowing what we know about PCa disparities in black men, what can we say about the safety of AS for black men with low risk PCa?

We were able to study very large cohorts of men with PCa who have either undergone radical prostatectomy (RP) or active surveillance (AS) at Johns Hopkins to obtain important insights into this question. First, we studied men with very low risk PCa who would have qualified for any AS program (AS eligibility criteria vary slightly among different programs) but instead underwent immediate RP. Very low risk PCa is characterized by meeting all of the following criteria: PSA <10 ng/ml, Gleason sum <7, clinical stage <T2a, number of positive cores <3, percent cancer per core ≤50, and PSA density ≤0.15 ng/ml/cc.9 Even among men who met all very low risk characteristics, black men were found to have significantly worse pathologic findings at RP as compared to whites (Figure 1); and most notable among these findings was pathologic upgrading. In findings published in Journal of Clinical Oncology, black men with Gleason sum 6 on biopsy were found to have Gleason sum 7 or more on final pathology at a rate of 27%, while upgrading only occurred in 14% of white men.[10]



 

In a separate study in Urology, of men who were very low risk and were monitored on AS, black men were at significantly higher risk of being reclassified with high grade prostate cancer (biopsy Gleason sum 7 or more) on biopsy, when compared to white men (Figure 2).[11]



 

Furthermore, in findings published in Urology,[12] when we studied black and white men in all risk categories who underwent RP, we discovered that after adjusting for clinical and pathologic factors, black race was an independent risk factor for experiencing biochemical recurrence after treatment among men in the very low-, low-, and intermediate-risk categories. Our findings are consistent with results of a national study of black and white men with low-risk PCa that found that black men were significantly more likely to die from PCa despite 'curative' treatment.[13] (This study and ours all adjusted for socioeconomic variables.)

This evidence is disconcerting, as it points to the fact that PCa demonstrates a distinctly higher level of clinical aggressiveness in black men. Why is this the case? First we did a study of very low risk black and white men who underwent RP, and completed a detailed microscopic exam of their surgical specimens to precisely map out their tumor nodules. Many men with PCa are found to have multiple islands of cancer within their prostate glands. Each of these nodules has a characteristic size and grade (cellular aggressiveness). The dominant nodule is defined as the largest cancer nodule with the highest Gleason grade—which would be expected to be the most important contributor to oncologic outcomes in these patients. In finding published in Journal of Urology, we found that black men had higher tumor volumes and were more likely to have multiple islands of cancer within their prostate glands.[14] The most striking finding was tumor location (Figure 3).



 


The dominant nodule was much more likely to be located in the anterior aspect of the prostate gland (a distinct anatomic nodule that is difficult to sample with conventional biopsy techniques), whereas the dominant nodule was more likely to be located peripherally in the posterior aspect of the prostate in white men. When considering only high grade dominant nodules, these race-specific anatomic differences were more even more pronounced. Thus it appears that PCa in black men is biologically distinct, as evidenced by its predisposition to be located in the anterior aspect of the prostate gland (findings consistent with an earlier study of men with low risk PCa as well).[15]

Presently we are performing advanced genome-wide RNA and oncogene expression studies using tumor specimens from matched multi-institutional cohorts of black and white men, across a wide spectrum of risk characteristics. What investigators at Johns Hopkins, including Dr. Edward Schaeffer and Dr. Ashley Ross, are beginning to uncover are distinct molecular subtypes that characterize cancers that tend to occur in black men. Some of these molecular subtypes are also associated with specific zones of the prostate gland and are associated with aggressive or lethal PCa outcomes. In findings to be published and presented in Spring 2015 at the annual meeting of the American Urological Association, these findings will reveal important insights into the biologic basis of PCa racial disparities and simultaneously signify important clues into the underpinnings of lethal PCa overall.

SUMMARY

  • Differences in outcome for black men in the United States cannot be explained by socioeconomic factors alone, the biology of prostate cancer is different in black men than white men.
  • Given similar "low-risk" features,
    • Black men have worse cancer at the time of radical surgery.
    • Black men have higher rates of progression to worse disease while on active surveillance.
  • Black men are more likely to have large tumors in the anterior of the prostate – an area that is notoriously difficult to biopsy, possibly explaining why they are found to have worse cancer later.
  • Future studies will address the genetic differences in prostate cancers of black men.

 

This blog was written by Debasish Sundi, MD. Dr. Sundi is a Chief Resident at the Brady Urological Institute and looking forward to a career in urologic oncology.

 


 


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11.     Sundi D, Faisal FA, Trock BJ, et al. Reclassification rates are higher among African American men than Caucasians on active surveillance. Urology. October 2014.
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