Historical Contribution: 1928, Colston, Vas Ligation for the Prevention of... Epididymitis

1928

Vas ligation for the prevention of preoperative and postoperative epididymitis J. A. C. Colston Journal of the American Medical Association 1928  90: 526-527

In the early 1900's, epididymitis was a common problem for men dealing with obstructive uropathy from both benign and malignant conditions of the prostate and bladder.  Colston comments on the sequelae of epididymitis:

"... while it is rarely a dangerous complication, it plays an important part in increasing the length of hospitalization of the patient and usually has a markedly depressing effect on the morale. In some extremely sick patients with lowered resistance, the added effect of this infection may prove to be too much for the individual to withstand, and in such cases, fortunately rare, the fatal outcome may be directly attributed to the added burden of the epididymitis. Then, too, in the very rare case in which a blood stream infection develops, either during the preparatory treatment or postoperative course, the septicemia often appears directly after the epididymitis, so that in some of these cases, at least, the epididymis may be considered as the portal of entry of the infection into the circulation."

It the modern era, it is rare to think about epididymitis as a cause of sepsis and mortality, however without modern diagnostics and antimicrobials, this was a very real clinical scenario.

The development of epididymitis was of particular interest following prostatectomy (for both benign and malignant disease), where the rate of epididymitis was approximately 20% regardless of approach (suprapubic or perineal).  To address this issue, a number of other urologists advocated open ligation of the vas deferens through a small scrotal incision, and dropped the rate of epididymitis to 4%.

To improve upon this technique, Colston described a method of temporary ligation that removed the need for an incision and had fewer complications.  Dr. Colston used an Allis clamp to isolate the vas deferens and then ligated it, externally, with a silk suture.  The suture was tied to the scrotal skin, treated daily with antibiotic and removed after 7-8 days.

At the suggestion of his resident, Edwin Alyea, Colston transitioned from performing the ligation in the operating room while under anesthesia and prior to prostatectomy to performing the ligation at the bedside prior to surgery without local anesthetic.  He described no complications (other than suture irritation at the skin) and a dramatically reduced rate of epididymitis.

This may represent the first description of the "no scalpel vasectomy" -- although for dramatically different indications than we perform that operation today!!

Read the entire manuscript using the link above or 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! 

The Basics of Testis Cancer Diagnosis: Epidemiology & Presentation

Testis Cancer is a rare cancer, with approximately 9,000 boys and men being diagnosed each year.  Fortunately, the cure rates are excellent -- only 400 men will die of testis cancer each year -- leaving about 20,000 survivors with cancer and 200,000 cured of the disease in the US at any given moment.[1] Testis cancer affects mostly young men and boys, therefore the diagnosis can create tremendous anxiety and uncertainty for the patient and their family.

Here we review the Basics of Testis Cancer Diagnosis.

EPIDEMIOLOGY

As stated above, approximately 9,000 men and boys are diagnosed with testis cancer each year; 400 will die of the disease, 20,000 are surviving with the disease and 200,000 have been cured.  Testis cancer is the most common malignancy among men 20-40 years old and is the 2nd most common malignancy in young men 15-19 years old (leukemia is #1).[2]  Corresponding to these statistics, there are three, well-known age peaks for testis cancer:

• Infancy
• Age 30-40 years
• Age 60

Most cases (about 70%) present as a unilateral mass confined to the testicle (a cancer in only one testicle).  Approximately 30% of men will present with metastatic disease -- the most common sites being the retroperitoneum and the lungs.[3]  Bilateral tumors (tumors in both testicles) can appear synchronously or metachronously (at the initial diagnosis or develop later), but is extremely rare, occuring in 2% or less of patients.[4]

RISK FACTORS

There are 4 risk factors for testis cancer:

• Cryptorchidism (an undescended testicle) [5-7]
• 4 to 6-fold risk of developing cancer in the undescended testicle
• 2 to 3-fold risk is orchidopexy (surgical lowering of the testicle) occurs before puberty.
• A slight increased risk also exists in the normal, descended testicle (relative risk 1.74).
• Family history of testicular cancer [8-11]
• 8 to 12-fold risk if a brother with testis cancer
• 2 to 4-fold risk if father with testis cancer
• Average age at diagnosis is 2-3 years younger than general population if a first-degree relative has testicular cancer
• Personal history of testicular cancer [4,12]
• Only 2% of testis cancer patients will have cancer in both testicles, but...
• 12-fold risk if a history of testis cancer
• higher in younger men
• higher in seminoma
• Intratubular germ cell neoplasia (ITGCN) [13,14]
• Most testis cancer arise from the precursor lesion known as ITGCN (or carcinoma-in-situ, CIS)
• ITGCN is present adjacent to testis cancer in 80-90% of patients
• If ITGCN is present, the risk of subsequent testis cancer is:
• 50% at 5 years
• 70% at 7 years

CLINICAL PRESENTATION

Most testis cancers present as a mass confined to the testicle.  Therefore, the most common presentation is a painless testicular mass.  Most of these masses are palpable and of significant size (a few to several centimeters).  Small, non-palpable lesions without pain and in the absence of distant disease have a higher likelihood of being a benign tumors.  In a number of studies, upwards of 80% of non-palpable, asymptomatic masses that are 2cm or smaller will be benign tumors.[15-18]  Benign lesions may include testicular cysts, small infarcts, Leydig cell nodules, or small Leydig cell or Sertoli cell tumors.

Serious, acute pain is associated with rapidly growing tumors and associated hemorrhage or infarction (if the tumor outgrows its blood supply).  Most patients with pain complain of dull scrotal discomfort or heaviness.  Rarely trauma can lead to a diagnosis, mostly because it brings a mass or pain to the patient's awareness.  

For the upwards of 30% of men who present with metastatic cancer, symptoms of metastases can be the presenting complaint. Bulky retroperitoneal lymphadenopathy can lead to abdominal mass; abdominal, flank or back pain due to direct invasion or obstruction of muscles, blood vessels or the ureters; lower extremity swelling if the IVC is compressed or gastrointestinal symptoms if the intestines are involved.  Pulmonary metastases can present as chest pain, shortness of breath and cough.

As testis cancers can lead to diminished spermatogenesis, infertility can be the initial presentation in rare men.  

DIAGNOSIS

The mainstays of diagnosis are scrotal ultrasound and serum tumor markers.

Serum tumor markers are covered in a previous blog (click here).  

Scrotal Ultrasound

Scrotal ultrasound often demonstrates an intratesticular, hypoechoic (dark) mass.  Testis cancers are often vascular (or hypervascular), although the absence of blood flow does not rule out a testis cancer.  Even in patients with suspicion of metastatic cancer, a scrotal ultrasound should be used to identify an active primary tumor or a "burned-out" testicular mass -- which is typically a small, impalpable scar or calcification.  Radical orchiectomy should strongly be considered for any intra-testicular mass and suspicion of testis cancer.

Advanced Imaging

Abdominal and Pelvic CT scan can be performed before or after orchiectomy to evaluate the retroperitoneum.  An initial chest x-ray should be performed to rule-out involvement in the lungs.  Chest CT is only warranted if suspicion of pulmonary disease on x-ray.  Routine imaging of the brain or bones is not recommended unless specific symptoms.   

Summary

• Testis cancer is a rare entity, affecting approximately 9,000 men and boys each year; however the cure rate is excellent, leaving approximately 200,000 survivors in the US.
• Testis cancer is the most most common cancer in men aged 20-40, and 2nd most common in men age 15-19 years old.
• The main risk factors for testis cancer are cryptorchidism (undescended testis), a family or personal history of testis cancer or ITGCN.
• The most common presentation is a painless, palpable testis mass.
• 70% of cancers are confined to the testicle.
• Symptoms are often related to metastatic invasion in the retroperitoneum or lungs.
• Diagnosis involves routine imaging and bloodwork involving scrotal ultrasound, serum tumor markers and abdominal imaging.

To read more about Testis Cancer follow this link.

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









[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Horner MJ, Ries LAG, Krapcho M,et al: SEER Cancer Statistics Review, 1975–2006. Bethesda (MD): National Cancer Institute, 2009.
[3]  McGlynn KA, Devesa SS, Graubard BI,et al: Increasing incidence of testicular germ cell tumors among black men in the United States. J Clin Oncol 2005; 23: 5757-5761
[4] Fossa SD, Chen J, Schonfeld SJ,et al: Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst 2005; 97: 1056-1066
[5] Dieckmann KP, Pichlmeier U: Clinical epidemiology of testicular germ cell tumors. World J Urol 2004; 22: 2-14
[6] Wood HM, Elder JS: Cryptorchidism and testicular cancer: separating fact from fiction. J Urol 2009; 181: 452-461
[7] Akre O, Pettersson A, Richiardi L,et al: Risk of contralateral testicular cancer among men with unilaterally undescended testis: a meta-analysis. Int J Cancer 2009; 124: 687-689.
[8] Hemminki K, Chen B: Familial risks in testicular cancer as aetiological clues. Int J Androl 2006; 29: 205-210.
[9] Mai PL, Chen BE, Tucker K,et al: Younger age-at-diagnosis for familial malignant testicular germ cell tumor. Fam Cancer 2009; 8: 451-456.
[10] Sonneveld DJ, Sleijfer DT, Schrafford Koops H,et al: Familial testicular cancer in a single-centre population. Eur J Cancer 1999; 35: 1368-1373
[11] Westergaard T, Olsen JH, Frisch M,et al: Cancer risk in fathers and brothers of testicular cancer patients in Denmark: a population-based study. Int J Cancer 1996; 66: 627-631.
[12] Theodore C, Terrier-Lacombe MJ, Laplanche A,et al: Bilateral germ-cell tumours: 22-year experience at the Institut Gustave Roussy. Br J Cancer 2004; 90: 55-59.
[13] Dieckmann KP, Skakkebaek NE: Carcinoma in situ of the testis: review of biological and clinical features. Int J Cancer 1999; 83: 815-822.
[14] Montironi R: Intratubular germ cell neoplasia of the testis: testicular intraepithelial neoplasia. Eur Urol 2002; 41: 651-654.
[15] Connolly SS, D’Arcy FT, Gough N,et al: Carefully selected intratesticular lesions can be safely managed with serial ultrasonography. BJU Int 2006; 98: 1005-1007, discussion 1007.
[16] Giannarini G, Dieckmann KP, Albers P, Heidenreich A, Pizzocaro G: Organ-sparing surgery for adult testicular tumours: a systematic review of the literature. Eur Urol 57(5): 780-790, 2010.
[17] Hindley RG, Chandra A, Saunders A,et al: Impalpable testis cancer. BJU Int 2003; 92: 572-574.
[18] Shilo Y, Zisman A, Raz O, Lang E, Strauss S, Sandbank J, Segal M, Siegel YI, Leibovici D: Testicular sparing surgery for small masses. Urol Oncol 30(2): 188-191, 2012.

Carcinoma In Situ of the Bladder: Beware of this Non-Invasive Cancer

Approximately 75,000 people are diagnosed with urothelial cancer of the bladder each year.[1]  It is estimated that nearly 300,000 people are walking around right now with bladder cancer in a variety of stages.  Fortunately, most people -- approximately 70% -- have non-invasive urothelial cancers or cancers that do not invade the detrusor muscle of the bladder.[2]  In general, non-invasive urothelial cancers are, in their own right, not dangerous.  However, even non-invasive high-grade cancers can progress to invasive disease and therefore have the potential to be fatal.

Bladder Cancer Staging.

Non-invasive cancers are stratified into stage Ta (70%) or confined to the lining of the bladder (i.e. urothelium), T1 (20%) invading the lamina propria (superficial layer of the bladder) or carcinoma in situ (CIS, 10%).[2]  CIS is a high-grade urothelial malignancy that is confined to the superficial-most layers of the bladder.  Although CIS is considered a non-invasive malignancy, it should not be considered a benign or indolent cancer.

Here we review some of the data regarding CIS.

CLINICAL PRESENTATION

While many bladder cancers (13-34%) present with gross hematuria (visible blood in the urine);[3,4] CIS is notorious for presenting with irritative voiding symptoms.[5]  Upwards of 80% of patients with CIS will present with irritative voiding symptoms.[6]

RISK OF PROGRESSION

In many cancers, CIS is considered a "pre-malignant" lesion.  This is NOT true for bladder cancer.  In fact, CIS of the bladder should be thought of as a flat, high-grade cancer and a precursor to invasive disease.  This is supported by a number of studies and findings:

• The subsequent risk of CIS to progress to muscle-invasive or metastatic urothelial cancer is 40% or greater, especially if concomitant papillary tumors are present.[7,8]  
• Of patients who undergo cystectomy for CIS alone, upwards of 20% will be found to have invasive cancer at final pathology.[9]  
• Patients with T1 disease who undergo cystectomy have a 6% risk of upstaging at final pathology; however patients with T1 disease and concomitant CIS have a 55% risk of upstaging.[10]
• In a number of surgical series, CIS is one of the most important prognostic characteristics after tumor grade.[11,12]
• 20% of patients with CIS alone will die at 10 years.[13]

MANAGEMENT OF CARCINOMA IN SITU

CIS can be difficult to manage as it cannot be resected in the same sense as a papillary tumor as CIS is often flat, difficult to visualize and multifocal.  In addition, CIS can be very difficult to find.  In patients with irritative symptoms and/or positive high-grade cytology, a number of strategies can be employed to evaluate the bladder for the presence of CIS including (1) random, cold-cup bladder biopsies or (2) fluorescence cystoscopy.

Once diagnosed, CIS is best treated with intravesical BCG (please see prior blog entries BCG For Bladder Cancer: Why it Works, How it Works and Success Rates for Intravesical BCG Treatments for Bladder Cancer).  BCG is approved by the FDA (Food & Drug Administration) for the treatment of CIS and is the preferred initial intravesical treatment for CIS according to the AUA (American Urological Association) Guideline for the Management of Nonmuscle Invasive Bladder Cancer.

• The initial tumor-free response after induction BCG is as high as 84%.[14,15]
• Approximately 50% of patients experience a durable response for 4 years or longer.
• Approximately 30% of patients experience a response for 10 years.[16]

However, patients who do not respond to BCG have an incredibly high rate of progression; 95% of patients who do not respond to an induction course of BCG will progress to worse disease.[17,18]

There are a number of other chemotherapies that can be used for the treatment of CIS including adriamycin, gemcitabine and thiotepa.  In North America, BCG is used most frequently due to a higher response rate (68% complete response for CIS vs. 49% for other chemotherapies) in a number of studies.[19,20]

Many patients with CIS will be refractory to an initial course of intravesical treatment.  If first-line treatment fails, especially if the first line was chemotherapy, a second course of BCG can be given as 30-50% of patients will respond to this second course.[21,22]  More than two courses of any medication are not recommended as 80% of patients who fail two courses will fail a third, and can be a harbinger of rapidly progressive, dangerous disease.

Patients with CIS who fail BCG should strongly consider an "early" cystectomy.  While removal of the bladder for non-invasive disease can be considered drastic:

• 50% of patients with non-muscle invasive disease will be found to have muscle-invasion at cystectomy
• 15% of muscle-invasive cancers will have micrometastatic disease [23]
• The long-term survival for patients with non-muscle invasive disease approaches 90%, which is significantly higher than patients with muscle-invasive cancers.[24,25]

SUMMARY

• Carcinoma in situ (CIS) is a high-grade, flat cancer of the bladder with potentially aggressive behavior
• The first line treatment for CIS in intravesical BCG treatment
• Patients who do not respond to intravesical treatment should strongly consider cystectomy due to the high rates of progression to advanced disease.

For additional information regarding BCG treatments check out the following blog entries:
BCG For Bladder Cancer: Why it Works, How it Works
Success Rates for Intravesical BCG Treatments for Bladder Cancer

This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.










[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Ro JY, Staerkel GA, Ayala AG,et al: Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am 1992; 19: 435-453
[3] Lee LW, Davis E: Gross urinary hemorrhage: a symptom, not a disease. JAMA 1953; 153: 782-784
[4] Varkarakis MJ, Gaeta J, Moore RH,et al: Superficial bladder tumor: aspects of clinical progression. Urology 1974; 4: 414-420
[5] Mohr DN, Offord KP, Owen RA,et al: Asymptomatic microhematuria and urologic disease: a population-based study. JAMA 1986; 256: 224-229
[6] Zincke H, Utz DC, Farrow GM,et al: Review of Mayo Clinic experience with carcinoma in situ. Urology 1985; 26: 39-46
[7] Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am 2003;30:765–6.
[8] Althausen AF, Prout GR, Daly JJ,et al: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116: 575-580
[9] Farrow GM, Utz DC, Rife CC,et al: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 1976; 36: 2495-2501
[10] Masood S, Sriprasad S, Palmer JH,et al: T1G3 bladder cancer—indications for early cystectomy. Int Urol Nephrol 2004; 36: 41-44
[11] Koch MO, Smith JA: Natural history and surgical management of superficial bladder cancer (stages Ta/T1/Tis). In Vogelzang N, Miles BJ(eds)Comprehensive textbook of genitourinary oncology. Baltimore: Lippincott Williams & Wilkins, 1996, pp.405-415
[12] Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J,et al: Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 2000; 163: 73-78
[13] Herr HW, Badalament RA, Amato DA,et al: Superficial bladder cancer treated with bacillus Calmette-Guérin: a multivariate analysis of factors affecting tumor progression. J Urol 1989; 141: 22-29
[14] Lamm DL, Blumenstein BA, Crissman JD,et al: Maintenance bacillus Calmette-Guérin immunotherapy for recurrent Ta,T1 and carcinoma in situ TCC of the bladder: a randomized SWOG study. J Urol 2000; 163: 1124-1129
[15] Lamm DL, Riggs DR, Bugaj M,et al: Prophylaxis in bladder cancer: a meta-analysis. J Urol 2000; 163: 151
[16] Herr HW, Wartinger DD, Fair WR,et al: Bacillus Calmette-Guérin therapy for superficial bladder cancer: a 10-year follow-up. J Urol 1992; 147: 1020-1023
[17] Coplen DE, Marcus MD, Myers JA,et al: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guérin: analysis of possible predictors of response free of tumor. J Urol 1990; 144: 652-657
[18] Harland SJ, Charig CR, Highman W,et al: Outcome in carcinoma in situ of bladder treatment with intravesical bacille Calmette-Guérin. Br J Urol 1992; 70: 271
[19] O'Donnell MA: Advances in the management of superficial bladder cancer. Semin Oncol 2007; 34: 85-97
[20] Sylvester RJ, van der Meijden A, Witjes JA,et al: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005; 66: 90-107
[21] Brake M, Loertzer H, Horsch R,et al: Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology 2000; 55: 673-678
[22] Pansadoro V, De Paula F: Intravesical bacillus Calmette-Guérin in the treatment of superficial transitional cell carcinoma of the bladder. J Urol 1987; 138: 299-301
[23] Chang SS, Cookson MS: Radical cystectomy for bladder cancer: the case for early intervention. Urol Clin North Am 2005; 32: 147-155
[24] Amling C, Thraser J, Frazier H,et al: Radical cystectomy for stages Ta, Tis, and T1 transitional cell carcinoma of the bladder. J Urol 1994; 151: 31
[25] Freeman JA, Esrig D, Stein JP,et al: Radical cystectomy for high-risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995; 76: 833-839

Tumor Markers for Testicular Cancer

Testicular cancer is one of the few cancers associated with tumor markers.  It is not clear why testicular cancers release these markers.  Most testis cancers that secrete tumor markers are non-seminomatous germ cell tumors (NSGCT) and 85% of NSGCT will secrete at least one tumor marker.  These cancers often develop from the germ cells in the testis that have the potential to transform into a variety of cell types.  It is hypothesized that as these germ cells turn into cancer cells, they turn on genes and secrete proteins usually only released during fetal development.[1,2]

Despite the lack of understanding as to the cause of elevated tumor markers, these markers are well-established to help in the diagnosis, prognosis, treatment and monitoring of testis cancer.  However, many patients and their families are confused about where tumor markers come from, what an elevation in a level means, and how markers should change over time.  Here we review the basic regarding the three important tumor markers for testicular cancer:

• HCG (human chorionic gonadotropin)
• AFP (alpha fetoprotein)
• LDH (lactate dehydrogenase)

alpha-fetoprotein (AFP)

NORMAL RANGE <40 micrograms/L

HALF-LIFE 5-7 days

AFP is a protein secreted by the fetal yolk sac, liver and gastrointestinal tract and appears in high levels in the blood of the fetus.[3]  AFP can be secreted by NSGCT that contain embryonal carcinoma, yolk sac tumor or teratoma.  By definition, seminoma or choriocarcinoma do not secrete AFP.  Therefore any patient with an elevated AFP must have a non-seminomatous component of testis cancer.

AFP can be elevated in patients with a number of other malignancies including with hepatocellular (liver) carcinoma, cancer of the stomach, pancreas, biliary tract and lung.  In addition, AFP elevation is associated with a number of non-malignant diseases including diseases of the liver and the rare diseases ataxic telangiectasia and hereditary tyrosinemia.  

human chorionic gonadotropin (HCG)

NORMAL RANGE <5 IU/L

HALF-LIFE 24-36 hours

HCG is a glycoprotein produced by the placenta to maintain the corpus luteum during pregnancy.  HCG can be elevated in a number of other malignancies including cancers of the liver, lung, pancreas and stomach.[3]  In germ cell tumors of the testis, including both seminomas and NSGCT, cancerous cells can transform into syncytiotrophoblasts (a normal component of the placenta) and secrete HCG.  Levels greater than 5,000 IU are usually indicative of NSGCT and, in NSGCT, higher levels of HCG are associated with a worse prognosis.  However, HCG-producing seminoma (approximately 15% of seminomas) has the same prognosis as seminoma that does not produce HCG.[4]  

The HCG molecule is cross-reactive with another protein, leutenizing hormone (LH).  Hypogonadal men can have elevated LH levels and subsequently falsely elevated HCG levels - administration of exogenous testosterone can help distinguish HCG elevation from hypogonadism from HCG from testis cancer.  In addition, marijuana smoking has been associated with an elevated HCG level.

lactate dehydrogenase (LDH)

NORMAL RANGE 1.5-3.2 microkat/L

HALF-LIFE 24 hours

LDH is a cellular enzyme found in every tissue in the body.  Highest concentrations of LDH in normal tissue are found in muscle (including skeletal, cardiac and smooth muscle), liver and brain.  LDH is expressed on chromosome 12p, which is often amplified in testis cancer cells.  LDH is less specific for testis cancer than HCG or AFP.  However, elevated LDH levels are correlated to high tumor burden in seminoma and recurrence in NSGCT.[5,6]

Future blogs will address the prognostic information gained by tumor marker levels at the time of diagnosis, after orchiectomy or other treatments.

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

[1] Uriel, J. Retrodifferentiation and the fetal patterns of gene expression in cancer. Adv. Cancer Res. 29, 127–174 (1979).

[2] Abelev, G. I. Alpha-fetoprotein as a marker of embryo-specific differentiations in normal and tumor tissues. Transplant Rev. 20, 3–37 (1974).

[3] Richie, J. & Steele, G. in Campbell-Walsh Urology (eds Wein, A. J., Kavoussi, L. R., Novick, A. C., Partin, A. W. & Peters, C. A.) 893–935 (Saunders, 2006).

[4] Weissbach, L. et al. Prognostic factors in seminomas with special respect to HCG: results of a prospective multicenter study. Seminoma Study Group. Eur. Urol. 36, 601–608 (1999).

[5] Skinner, D. G. & Scardino, P. T. Relevance of biochemical tumor markers and lymphadenectomy in management of nonseminomatous testis tumors: current perspective. J. Urol. 123, 378–382 (1980).

[6] Stanton, G.  et al. Treatment of patients with advanced seminoma with cyclophosphamide, bleomycin, actinomycin D, vinblastine and cisplatin [abstract]. Proc. Am. Soc. Clin. Oncol. 2, 1 (1983).

Historical Contribution: 1926, Waters, Deep Roentgen-Ray Therapy in the... Bladder

1926

Deep Roentgen-Ray therapy in the treatment of carcinoma of the bladder C. A. Waters Journal of the American Medical Association 1926  87: 1618-1620

In this short publication in the Journal of the American Medical Association (JAMA), Dr. Waters describes the outcomes of 120 patients with bladder cancer treated with an early form of external beam radiotherapy.  This was a heterogeneous group of patients, comprised of patients with papillomas, non-invasive and infiltrating carcinomas of the bladder.

It's an incredibly interesting article as Dr. Waters makes several commentaries about the treatment of bladder cancer and the use of radiation therapy before presenting his data and conclusions.

First, Dr. Waters describes the side effects and the cumulative effects of repeat treatments: "One of the most serious complications in the treatment of bladder tumors, following irradiation of any kind, is a burn...  the earliest symptoms of radiation intoxication may be mentioned nausea, vomiting, prostration, diarrhea, rectal burning, and tenesmus."

Second, he describes palliation.  Waters and colleagues were faced with patients with advanced urothelial cancers, with symptoms similar to those we see today in patients with advanced disease.  Importantly, he noted that:

"Despite the disturbing reactions that are not wholly avoidable, the relief afforded to two symptoms of bladder cancer, namely, root pains and hematuria, justifies the treatment. Even when no other benefit is obtainable, these two distressing symptoms fail to be relieved with roentgen-ray therapy."

Third, he reviews the treatments available for bladder cancer at this time period and their relative efficacy:

• radical partial cystectomy - only 10% of infiltrating carcinomas are amenable to complete resection, otherwise "technically difficuly, and now rarely justifiable."
• fulguration - extremely successful in the treatment of papillomas, "worse than useless in the treatment of papillary carcinomas."
• radium therapy - a new chapter in the treatment of bladder tumors
• intravesical application adequately treats superficial papillary tumors (only about 15% of cases though)
• in combination with fulguration can treat about 75% of presenting cancers
• in some cases, made it possible to "destroy extensive infiltrating growths that were hopelessly inoperable."

From his observations and treatments, he makes the following five conclusions:

1. The best treatment for superficial papillary carcinoma, whether localized or extensive, is a combination of deep roentgen-ray therapy with applications of radium applied directly to the surface of the growth.  However, this treatment causes severe ulceration and burns to the bladder mucosa.
2. By the combination of radium with roentgen-ray treatment as outlined, most of these tumors can be destroyed with a minimum amount of injury to the bladder, and in many instances with but little or no irritation of the bladder mucosa.
3. Radical resection should be carried out whenever feasible.
4. Radium and roentgen-ray treatment should be used for inoperable tumors, but the dose should be limited.
5. Bladder cancers frequently recur, therefore patients should return often for cystoscopic examinations.

Read the entire manuscript using the link above or 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! 

Faculty Spotlight: Arthur Burnett, Restoring Sexual Function

Arthur L. Burnett, II, MD, MBA
Patrick C. Walsh Distinguished Professor of Urology
Director, Basic Science Laboratory in Neurourology
Director, Sexual Medicine Fellowship Program
Faculty Member, Cellular and Molecular Medicine
Graduate Training Program

Arthur L. Burnett, II, MD, MBA, surgeon and neurourologist, is a pioneer in the area of sexual medicine.  Many of his patients are men with prostate cancer who are worried about impotence after radical prostatectomy.  But other men of all ages come to see Burnett for help with issues ranging from ejaculatory disturbances, to libidinal problems, and may need treatment ranging from pharmacotherapy, to injection therapy, to prosthetics, to genital reconstruction following injury or cancer.

Protecting Nerves: Burnett's discovery with Johns Hopkins neuroscientist Solomon Snyder that nitric oxide plays a crucial role in erection led to development of the drug Viagra for erectile dysfunction.[1]  For nearly three decades, much of his lab and clinical work has focused on protecting the integrity of the neurovascular bundles responsibile for erection, easily damaged even in the "nerve-sparing" radical prostatectomy developed by Johns Hopkins urologist Patrick Walsh, MD.  "It may even be from traction, or even that the adjacent dissection somehow exposes the nerves to injury," Burnett says, "Something causes them to sustain an inflammatory setback."

In groundbreaking studies of rats with nerve injury and erectile dysfunction similar to that found in men after radical prostatectomy, he has tested many inflammation-fighting agents and growth factors designed to "preserve, nourish, regenerate and restore nerves to normal function."  One of these is an agent used to combat anemia, erythropoeitin (EPO).  Burnett previously led studies investigating the effects of EPO on erectile function recovery in a rat model of cavernous nerve injury;[2] and now he is investigating those promising results in humans.  In a randomized, controlled clinical trial, still actively enrolling patients, Burnett is studying EPO's ability to enhance nerve function.  EPO is injected the day before, the day of, and the day after radical prostatectomy.

In other work, Burnett has targeted the fragile network of blood vessels and chambers within the penis.  Even though they're not directly traumatized by surgery, "these structures may degenerate or shrivel," he says, "and thus contribute to poor recovery of erectile function in some men after surgery."  To fight this, Burnett is testing such blood vessel-strengthening agents as angiotensin II type 1 receptor antagonists.  In another clinical trial, he is testing an external vibration nerve-stimulatory device, which he helped develop, that may be applied under a specific protocol after surgery.

If you, a loved one, or a patient is interested in one of Dr. Burnett's trials, please call the Urology Clinic at the Brady Urological Institute (410) 955-6100 for an appointment with Dr. Burnett.

Help for incontinence and impotence: Having both urinary incontinence and impotence after radical prostatectomy should be a rare complication, but some men find themselves in this situation and need help.  For the last 13 years, Burnett has offered a successful operation that restores urinary continence and potency at the same time --- implantation of an inflatable penile prosthesis and an artificial urinary sphincter.  "It provides efficient and rapid resumption of both functional disorders, " he says.

Burnett is also conducting further research into utilization and prediction modeling for penile prosthesis surgery.  Dr. Burnett explains,

"Our goal is to approach everything we do thoughtfully and rigorously, so that we can make advances based on what is scientifically meaningful."

This blog entry is extracted from the "Johns Hopkins Urology: News for Physicians from Johns Hopkins Medicine," Spring 2014.




[1] Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH.  Nitric oxide: a physiologic mediator of penile erection.  Science. 1992 Jul 17;257(5068):401-3.
[2] Allaf ME, Hoke A, Burnett AL.Erythropoietin promotes the recovery of erectile function following cavernous nerve injury.J Urol. 2005 Nov;174(5):2060-4.

Circulating Tumor Cells for Prostate Cancer

Recent advances in technology have made it possible to locate circulating tumors cells (CTCs) in the blood of patients with metastatic cancer of the breast, colon and prostate.  Prior to CTCs, the only options for the diagnosis and monitoring of metastatic cancer were biopsy of metastatic deposits and inference from imaging like CT, MRI and PET scans.  CTCs offer a number of advantages to traditional biopsy or imaging:

• CTCs can be measured in blood, which is easy, cheap, have relatively little pain and risks associated with them.
• CTCs can be used as a biomarker; once isolated, viable CTCs can be processed and analyzed to identify:
• the type of CTC in circulation
• aggressiveness of the cancer
• potential response to specific treatments (like chemotherapy)
• CTCs can be measured over time, adding a new dimension to the ability to measure resistance or responsiveness to therapies.

CTCs are emerging as a promising prognositic factor in men with metastatic, castrate-resistant prostate cancer.  Here we review some the recent data regarding CTCs in prostate cancer.  

CTCs as a Biomarker

Through a variety of techniques, prostate cancer CTCs have been analyzed for a variety of markers that can define the aggressiveness of the prostate cancer and have the potential to predict clinical outcomes.  These markers encompass a number of established protein and genetic markers of prostate cancer aggressiveness including: chromosomal abnormalities, epidermal growth factor receptor (EGFR) expression,  androgen receptor (AR) gene amplification, telomerase activity and TMPRSS2-ERG status.[1-6]

CTCs as Predictors of Oncologic Outcomes

High CTC counts are associated with more advanced disease including higher PSA levels, bone metastases (compared to soft tissue metastases), volume of bone metastases by imaging and laboratory markers (lactate dehydrogenase and alkaline phosphatase).[7,8]

High CTC counts predict men who develop castrate-resistant prostate cancer, and the relative length of survival and response to chemotherapy for men who have already developed castrate-resistant prostate cancer.[7-10] In one study of men receiving chemotherapy for metastatic, castrate-resistant prostate cancer, low CTC counts (<5) were associated with a longer survival prior to initiating chemotherapy.  In the same study and others, men who's CTC counts dropped to <5 while on additional therapy also had a longer survival compared to men who had no response in CTC count.[9-11]

The best cutoff value for CTC has yet to be established, with most studies reporting the clinically important cutoff to be between 3-5 CTC.[8,9]

CTCs have demonstrated prognostic abilities in hormone-sensitive disease,[8] in mCRPC treated with a variety of first-line therapies,[9,11] and in mCRPC treated with second-line hormonal therapy.[10]

A recent, large, prospectively phase III trial was completed by SWOG (Southwest Oncology Group) evaluating CTCs in men with metastatic, castrate-resistant prostate cancer receiving docetaxel chemotherapy (standard first-line chemotherapy).  This study validated 5 CTC as a valuable cut-point in this population as men with <5 CTCs at enrollment had an improved overall survival (26 vs. 13 months) and that a rising CTC count while on chemotherapy was associated with worse overall survival.[12]

Summary

• CTCs have the opportunity to change the way we manage advanced prostate cancer and other malignancies.
• CTCs can serve as biomarkers to indicate the aggressiveness of prostate cancer cells.
• Increasing CTC counts are associated with worse oncologic outcomes in a number of trials for men with advanced prostate cancer - however the exact cutoff point for CTCs has yet to be determined.
• Future studies will help define the role of CTCs in prostate cancer.

[1] Shaffer DR, Leversha MA, Danila DC, et al. (2007) Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res 13:2023–2029.

[2] Danila DC, Anand A, Sung CC, et al. (2011) TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur Urol 60:897–904.

[3] Jiang Y, Palma JF, Agus DB, et al. (2010) Detection of androgen receptor mutations in circulating tumor cells in castration-resistant prostate cancer. Clin Chem 56:1492–1495.

[4] Lin HK, Zheng S, Wiliams AJ, et al. (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16:1–8.

[5] Moreno JG, Miller MC, Gross S, et al. (2005) Circulating tumor cells predict survival in patients with metastatic prostate cancer. Urology 65:713–718

[6] Xu T, Lu B, Tai YC, et al. (2010) A cancer detection platform which measures telomerase activity from live circulating tumor cells captured on a microfilter. Cancer Res 70:6420–6426.

[7] Danila DC, Heller G, Gignac GA, et al. (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13:7053–7058. Abstract/FREE Full Text
[8] Goodman OB Jr, Symanowski JT, Loudyi A, et al. (2011) Circulating tumor cells as a predictive biomarker in patients with hormone-sensitive prostate cancer. Clin Genitourin Cancer 9:31–38.

[9] de Bono JS, Scher HI, Montgomery RB, et al. (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302–6309.
[10] Scher HI, Heller G, Molina A, et al. (2011) Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol 29(suppl):293s, abstr LBA4517.

[11] Scher HI, Jia X, de Bono JS, et al. (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: A reanalysis of IMMC38 trial data. Lancet Oncol 10:233–239.

[12] Goldkorn A, Ely B, Quinn DI, Tangen CM, Fink LM, Xu T, Twardowski P, Van Veldhuizen PJ, Agarwal N, Carducci MA, Monk JP 3rd, Datar RH, Garzotto M, Mack PC, Lara P Jr, Higano CS, Hussain M, Thompson IM Jr, Cote RJ, Vogelzang NJ.Circulating Tumor Cell Counts Are Prognostic of Overall Survival in SWOG S0421: A Phase III Trial of Docetaxel With or Without Atrasentan for Metastatic Castration-Resistant Prostate Cancer.J Clin Oncol. 2014 Apr 10;32(11):1136-42. doi: 10.1200/JCO.2013.51.7417. Epub 2014 Mar 10.