Historical Contribution: 1937, Dees and Colston, Sulfanilamide in Gonococcal Infections

Electron micrograph of gonococcus. (from gov.uk)

1937

The use of sulfanilamide in gonococcal infections. Dees JE, Colston,  JAC.   JAMA 1937; 108: 1855.

In 1935, para-aminobenzenesulfonamide (sulfanilamide) emerged as an effective treatment for streptococcal infections.  Subsequent experiments in mice and humans proved that sulfanilamide was an effective treatment for menignococcic infections.  Given that sulfanilamide was proven to be non-toxic at high doses in humans and its clinical efficacy against meningococcus, allowed Drs. Dees and Colston to embark on a clinical trial of sulfanilamide in gonoccocal infections.

In 19 patients, the diagnosis of gonococcal urethritis was confirmed with visualization of cellular diplococci in urethral discharge or centrifuge of collected urine.  In all patients, active urethral discharge disappeared in 1-7 days, with most patients improved within 3 days.  Gonococci were eliminated from the urethral discharge in 2-5 days for the majority of patients -- as did the majority of symptoms.  Some patients did have a slower response to the treatment, and the authors hypothesized this could be due to non-compliance or an abnormality of metabolism of the medication.

They concluded that sulfanilamide was of "great value" and:

This preliminary report is therefore presented for the purpose of stimulating the careful use of this drug in clinics where large numbers of gonococcic infections can be closely followed, so that an accurate evaluation of sulfanilamide in the treatment of gonococcic infections can be determined and the optimum dosage and possible deleterious effects further studied.

This manuscript serves as the first example of sulfa-medications in the treatment of urinary tract infections.

To read the entire manuscript click on 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! 

Lymph Node Dissection for Renal Cancer

CT Scan showing a large right renal mass and enlarged
lymph node between the kidney and inferior vena cava.

Lymph node dissection (LND) is an integral portion of many cancer surgeries including those of the colon, breast and prostate. However, the role of lymphadenectomy (or lymph node dissection) in the management of renal cell carcinoma (RCC) remains controversial mainly because of the poor overall survival for patients with metastatic RCC in their lymph nodes or beyond.  The cancer-specific survival (CSS) for these patients is in the range of 5-35% at 5 years.[1]

In this blog we will highlight some of the important data regarding LND and RCC.

Certain or Uncertain Lymphatic Drainage of Renal Cell Carcinoma?

Early anatomic studies demonstrate a system of predictable lymphatic drainage from the kidneys; with the right kidney draining through the precaval, retrocaval, and interaortocaval nodal groups from right to left, and the left kidney draining to left-sided only regions including para-aortic, preaortic, and retroaortic nodal groups.[2]  Surgical series confirmed this drainage pattern with primary landing zones (paracaval for right, paraaortic for left) being involved prior to involvement of additional nodes.  However, they also note that perihilar lymph nodes (lymph nodes closest to the kidney) are rarely involved and often skipped, with 45% of hilar nodes negative despite other ipsilateral lymph nodes involved.[3]

Retroperitoneal lymph node locations.  From Crispen et al.
European Urology, 2011. [3]

However, looking at the epidemiologic data, upwards of 30% of patients with RCC will present with metastatic disease; however, only 3-10% will have lymph node involvement only.  Of the patients with metastatic disease, upwards of 40% will have no lymph node involvement - indicating that RCC, unlike other cancer, can spread without first involving the regional lymph nodes.  

Correlation of Clinically-Positive Lymph Nodes to Pathologically-Positive Lymph Nodes

Radical nephrectomy specimen
with tumor and lymph node that
correlate to the CT Scan above.

The subsequent consideration is: how well do we predict lymph node positive disease?  The answer is pretty poorly.  Many patients with large and/or bulky kidney tumors will have enlarged lymph nodes on imaging. However, the correlation with enlarged lymph nodes on imaging and cancer in those nodes is poor.  In fact, enlarged lymph nodes on CT scan correlate to metastatic RCC in only 32-43% of patients and a false-positive rate of 58%.[4-6]  In addition, The false-negative rate is estimated to be 4%, meaning many patients without lymph nodes on imaging will ultimately have positive lymph nodes at the time of surgery.[6]

Improved Staging, Improved Survival?

LND has been demonstrated to improve staging in a number of studies.  Rates of lymph node positive disease have been demonstrated to be higher in patients who had more lymph nodes removed.[7]

While it is generally accepted that LND improves staging, it is not clear if this translates into a tangible survival benefit.  Some studies demonstrate an improvement in cancer-specific survival (CSS) with lymphadenectomy.  This is rooted in the belief that LND may remove metastatic disease and be curative in some patients with lymph node positive disease.[8]

In studies where systematic LND was routinely performed and a benefit was observed:

• In a study of over 2,500 patients, for those with positive lymph nodes, 22% were disease-free at 44 months [9]
• Of the recurrences, the majority were detected within 4 months of nephrectomy and 51% were at multiple organ sites
• In a study of over 500 patients, CSS was significantly better for patients who underwent a systematic, extended lymph node dissection (66%) when compared to those who had only clinically abnormal lymph nodes removed (58%, p<0.01).[10]  
• In a study on 800 patients, 5% with positive lymph nodes and 9% with positive lymph nodes and metastatic disease:
• For patients without clinically evident nodal disease, survival was not impacted by LND.
• For patients with distinct clinical nodal disease, survival was positively impacted by cytoreductive nephrectomy, LND and postoperative immunotherapy.
• LND was predictive of survival in multivariable analysis of lymph node positive patients.[11]
• In a study of 10,000 patients in the National SEER (Surveillance, Epidemiology, and End Results) Database:
• For patients with negative lymph nodes, there was no effect on CSS with increasing extent of LND. 
• An absolute survival increase of 10 % (39–49 %) at 5 years was seen in patients with one positive lymph node in whom ten lymph nodes were removed indicating that the number of lymph nodes removed correlates to an improvement in CSS.[12]

However, a number of studies fail to find a survival benefit in patients with positive lymph nodes who underwent LND.[13,14]

How about Level 1 Evidence?

The biggest argument against LND is a prospective, randomized trial of LND versus standard radical nephrectomy run by the EORTC (European Organization for Research and Treatment of Cancer) Genitourinary Group.[15]  Nearly 800 patients were randomized to radical nephrectomy alone (n = 389) or nephrectomy plus LND (n = 383). Only 4% of patients had positive lymph nodes and there was no improvement in survival in patients undergoing LND.  However, >70% of the patients had clinically localized and organ-confined (pT1-2) or low-grade RCC, allowing critics to argue that LND would have been unlikely to benefit these patients.  Importantly, there were no differences in complication rates between the two groups - definitively demonstrating that LND does not increase the morbidity of the operation.

Who Should Undergo Lymphadenectomy (LND)?

There are a number of predictive models that identify patients most at risk of having positive lymph nodes at the time of surgery.  Many of these models use criteria like tumor and lymph node size to predict positive lymph nodes; however these models also include pathological features like grade, stage and sarcomatoid features.[16]  Other studies have used pre-operative variables only (clinical tumor stage, clinical nodal status, presence of metastases, and tumor size), however are limited by small number of patients with positive lymph nodes and non-standardized lymph node dissection.[17]

Summary

In general, the evidence is clear that patients with low-risk RCC do not benefit from lymphadenectomy.  These include patients with clinically-localized (T1, 7cm or less) or biopsy-proven, low-grade (Grade 1 or 2) disease.  

LND should be strongly considered in patients with high-risk RCC who have the potential to have positive lymph nodes and therefore benefit from their removal.  These include patients with:

• Large, clinically-localized tumors: upwards of 40% of cT2 (>7cm) tumors will have pathological T3 disease
• Locally-invasive tumors: cT3 or cT4 disease
• Clinically enlarged lymph nodes
• Limited metastatic disease, especially if an isolated site can be resected
• Biopsy-proven, high-grade RCC (Grade 3 or 4)

Other considerations:

• Many radical nephrectomy surgeries can be performed laparoscopically, however LND can be challenging with standard laparoscopy.  Robot-assisted laparoscopy may facilitate lymph node dissection by affording the surgeon more control near the great vessels in the body.
• There is no, well-agreed upon consensus regarding LND.  While the risks of LND are relatively low, not all patients will benefit from a LND and careful thought should go into the decision to perform a LND.

Phillip M. Pierorazio, MD is an Assistant Professor of Urology & Oncology, Director of the DISSRM Registry for Kidney Cancer and Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  








[1] Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003 Jun 15;97(12):2995-3002.
[2] Parker AE (1935) Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. Am J Anat 56:409–443
[3] Crispen PL, Breau RH, Allmer C et al (2011) Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol 59:18–23
[4] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
[5] Hutterer GC, Patard JJ, Perrotte P, Ionescu C, de La Taille A, Salomon L, Verhoest G, Tostain J, Cindolo L, Ficarra V, Artibani W, Schips L, Zigeuner R, Mulders PF, Valeri A, Chautard D, Descotes JL, Rambeaud JJ, Mejean A, Karakiewicz PI. Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram.  Int J Cancer. 2007 Dec 1;121(11):2556-61.
[6] Studer UE, Scherz S, Scheidegger J et al (1990) Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144:243–245.
[7] Terrone C, Guercio S, De Luca S, Poggio M, Castelli E, Scoffone C, Tarabuzzi R, Scarpa RM, Fontana D, Rocca Rossetti S. The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int. 2003 Jan;91(1):37-40.

[8] Freedland SJ, Dekernion JB. Role of lymphadenectomy for patients undergoing radical nephrectomy for renal cell carcinoma. Rev Urol. 2003 Summer;5(3):191-5.

[9]  Delacroix SE Jr, Chapin BF, Chen JJ et al (2011) Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol 186:1236–1241

[10] Herrlinger A, Schrott KM, Schott G, Sigel A.  What are the benefits of extended dissection of the regional renal lymph nodes in the therapy of renal cell carcinoma.J Urol. 1991 Nov;146(5):1224-7.

[11] Pantuck AJ, Zisman A, Dorey F et al (2003) Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 169:2076–2083

[12] Whitson JM, Harris CR, Reese AC et al (2011) Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol 185:1615–1620.

[13]  Terrone C, Cracco C, Porpiglia F et al (2006) Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49:324–331

[14] Feuerstein MA, Kent M, Bazzi WM, Bernstein M, Russo P. Analysis of lymph node dissection in patients with ≥7-cm renal tumors. World J Urol. 2014 Jan 9.

[15] Blom JH, van Poppel H, Marechal JM et al (2009) Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 55:28–34

[16] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469

[17] Capitanio U, Abdollah F, Matloob R et al (2013) When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative assessment of risk of lymph node invasion at surgery and of lymph node progression during follow-up. BJU Int 112:E59–E66

Underactive Bladder: A New Entity in Voiding Dysfunction?

Overactive bladder (OAB) is a very common urologic entity and complaint among urologic patients.  OAB represents a constellation of symptoms including urgency, with or without incontinence, frequency and nocturia.[1]  See our prior blog entry on Female Incontinence for more details on OAB.  There are a number of causes of OAB and subsequently OAB can be related to a variety of coincident urologic diagnoses like bladder outlet obstruction in men, pelvic organ prolapse in women, neurologic or systemic diseases like diabetes.  In addition, OAB has a number of excellent treatments progressing from behavioral therapy (i.e. modifying fluid intake) to medications, and finally surgical devices (like Interstim or Tibial Nerve Stimulation).

Underactive bladder (UAB) is similar to OAB in that it represents a constellation of symptoms and has a number of etiologies and coincident urologic diagnoses.  Symptoms of UAB are strangely similar to OAB and can include:

• urgency
• frequency
• nocturia
• hesitancy
• straining to void
• sensation of incompete voiding
• urinary retention
• incontinence (overflow or urgency)

UAB may occur without symptoms or associated diseases.  However, some associated diseases and causes of UAB (are once again similar to OAB and) include:

• neurologic disease
• muscle disease or failure (includes the detrusor (bladder) muscle or muscles of the pelvic floor)
• age-related
• medication-related
• bladder outlet obstruction (most commonly benign prostatic hyperplasia in men) [2,3]

Unlike OAB, there are no good treatments for UAB.  Therefore UAB remains an underappreciated entity and therefore is lacking in understanding and concensus regarding its diagnosis and treatment.  Previous attempts at classifying UAB used the terminology detrusor underactivity (DU) to indicate an inability of the detrusor (or bladder) muscle to contract with enough force to expel urine.  Recent studies indicate the UAB is more common than previously predicted.

• In a study of 1,179 men and women older than 65 years-old with non-neurogenic voiding dysfunction and lower urinary tract symptoms (LUTS) [4]
• 40% of men and 13.3% of women had DU (similar to UAB)
• the proportion of patients with DU increased with age
• A study of 181 elderly patients with LUTS identified DU in 48% of men and 12% of women. [5]
• 40% of men in this study had bladder outlet obstruction (BOO), only 10% of men with DU had BOO

UAB can notably cause long-term, chronic issues including urinary retention requiring catheterization, urinary incontinence and/or recurrent urinary tract infections.  

Therefore the First International CURE-UAB (Congress of Urologic Research and Education on UnderActive Bladder) was held in Washington, DC in February 2014 in the hopes of addressing some of the shortcomings in the uderstanding of UAB.  The CURE-UAB was founded and led by David Chancellor, BS, Vikas Tyagi, MD and Michelle Gruber, BS.  Over 100 health care experts met at the congress to discuss, define and outline research goals for the future of UAB.  The meeting and subsequent research is funded by the NIH (National Institutes of Health).  To find out more about UAB, visit the website: http://www.underactivebladder.org/

[1] Chapple CR, Artibani W, Cardozo LD, et al. The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. BJU Int 2005;95:335–40.
[2] van Koeveringe GA, Vahabi B, Andersson KE et al: Detrusor underactivity: a plea for new approaches to a common bladder dysfunction.  Neurourol Urodyn 2011; 30: 723.
[3] Osman NI, Chapple CR, Abrams P et al: Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, and diagnosis. Eur Urol 2014; 65: 389.
[4] Jeong SJ, Kim HJ, Lee YJ et al: Prevalence and clinical features of detrusor underactivity among elderly with lower urinary tract symptoms: a comparison between men and women. Korean J Urol 2012; 53: 342.
[5] Abarbanel J and Marcus EL: Impaired detrusor contractility in community-dwelling elderly presenting with lower urinary tract symptoms. Urology 2007; 69: 436.

Historical Contribution: 1935, Lewis, Langworthy & Dees, Motor Pathways of the Bladder

1935

Bladder abnormalities due to injury of motor pathways in the nervous system L. G. Lewis, O. R. Langworthy and J. E. Dees. Journal of the American Medical Association, 1935.

Little was known about the nervous innervation of the bladder in 1935.  A constellation of symptoms and a number of deficits were attributed to injuries to the sensory pathways of the bladder.  While two motor pathways were described: one from the cerebral cortex and one from the midbrain (the pontine micturation center), the subsequent deficits were not well understood.

To investigate the motor innervation of the bladder, Lewis, Langworthy and Dees create a precursor to the modern cystometrogram (urodynamics) - a relatively simple device made of a catheter and manometer filled with water and coupled to a recording device (see figure).  The authors catalogue the findings in a normal patient a demonstrate low-pressure filling and a normal sensation at around 200cc of water.















The authors then investigate and describe the outcomes of patients with three distinct patterns of voiding:

1. Bilateral cortical lesions (lesion #1) - leading to a small capacity bladder and involuntary contractions.
2. Unilateral cortial lesions (lesion #2) - patients with left-sided lesions had normal bladder capacity, those with right-side lesions had decreased bladder capacity leading the authors to believe that bladder control was heisphere-dominant.
3. Spinal cord injuries (lesion #3) - these patients demonstrated a variety of findings, all of which demonstrated abnormal filling, volumes and contractions.  

In summary, they make a number of important observations that define function of the urinary system:

• Normal micturition depends on a steady rise of bladder pressure of sufficient strength and duration to empty the viscus completely. When waves occur rhythmically and frequently, they do not have the strength or duration for efficient emptying.
• The cerebral cortex controls the smooth muscle of the bladder, enabling the bladder to hold large amounts of fluid at a relatively low pressure (below the level of discomfort). Without conrtical control, bladder capacity decreases and frequency of urination is common.
• Many of the frequency and urgency symptoms following neurologic injury can be considered as uninhibited smooth muscle reflexes (analagous to a "knee-jerk" reflex).

To read the entire manuscriptclick on the title above 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! 

Surgery for Testicular Cancer: Orchiectomy

While scrotal ultrasound and serum tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase) are the first steps in the diagnosis of a testis cancer, the diagnosis is not confirmed until an orchiectomy (surgical removal of the testicle) is performed.  The standard-of-care for the removal and treatment of testis cancer is a radical orchiectomy.  This is the most common operation performed for testis cancer worldwide. However, as our understanding of this disease and surgical technique has improved, testis-sparing surgery or partial orchiectomy has become an option for some patients.

This blog entry will briefly discuss important considerations for men undergoing orchiectomy for testis cancer.

RADICAL ORCHIECTOMY

Rationale

This surgery involves removing the testicle and spermatic cord where it exits the body to identify and likely treat the majority of cancers localized to the testis.  As a male fetus develops, the testes develop near the fetal kidneys.  As the fetus grows, the testicles separate from the kidneys and, at about the eighth month of pregnancy, the testicles exit the body wall to rest in the scrotum (this is why premature infants have a higher likelihood of having undescended testicles).  Therefore the blood supply, lymphatic drainage and nerves to the testicle originate near the kidney on that side.  Once these structures exit the body through the internal inguinal ring they fuse with muscles of the body wall to form the spermatic cord.  To correctly stage and prevent any cancer from spreading, the spermatic cord must be taken as high toward or inside the body as possible -- hence the incision in the groin rather than the scrotum.

For men whose cancer has spread from the testicle and who have metastatic testis cancer (elsewhere in the body) or in the lymph nodes of the retroperitoneum, radical orchiectomy is an important first step in the diagnosis and management of disease.  Knowing the type of cancer may help guide chemotherapy or radiation treatments.

Surgery

Adapted from Gottesman JE. In: Crawford ED, editor.
Current genitourinary cancer surgery.
Philadelphia: Lea & Febiger; 1990. p. 319.

The surgery can be performed under general or local anesthetic.  An approximately 5-10cm incision is made in the groin, just above the pubic tubercle (pubic bone) near the inguinal ligament.  This incision facilitates access to both the testicle and the proximal inguinal canal.  The skin incision is relatively painless, so a larger incision should be made to facilitate delivery of a large testicular tumor or to help with access to the spermatic cord.  The incision is carried down to the external oblique fascia (the outermost layer of the body wall).  The external oblique creates a tunnel through which the spermatic cord travels -- a hernia can form when there is weakness in these layers of the body wall.  Once the external oblique fascia is identified, the cord can then be identified exiting the external spermatic ring.  The cord should be isolated and the external fascia will need to be opened to gain access to the internal ring and to take the spermatic cord where it exits the body.  This can be done in either order.  Care should be taken to separate and preserve the ilioinguinal nerve which travels along the spermatic cord.  Once the cord is isolated, an occlusive, but non-crushing clamp or elastic drain can be used to stop blood supply to and from the testicle.  This prevents any "shedding" of tumor cells when the testicle is manipulated.  The testicle can then be "delivered" from the scrotum.  To deliver the testicle the scrotum can be inverted until the testicle is visible, facilitating dissection of the testicle from its scrotal contents.

Once the testicle and spermatic cord are entirely free from the inguinal canal, the testicle can be removed.  The spermatic cord should be ligated in two packets - one containing the gonadal artery and one containing the vas deferens (sperm duct) and its associated artery.  A large, non-absorbable suture should also be tied to the distal spermatic cord to facilitate easy identification in the case that a retroperitoneal lymph node dissection needs to be performed in the future.  Care should be taken to close the external oblique fascia to the level of the external ring to prevent future hernia.

Complications

The biggest risk of a radical orchiectomy is hematoma (or bleeding into the scrotum).  It is very common for the scrotum to be bruised, swollen and tender for 2-4 weeks after surgery.  However, a large, purple-appearing scrotum can indicate a hematoma.  Hematoma can be prevented with a compressive dressing, tight-fitting undergarments and/or ice packs.
Ilioinguinal nerve injury can occur if the nerve is damaged during dissection of the spermatic cord.  This is more common in men who underwent prior inguinal surgery (usually for an undescended testicle or hernia repair) and can occur during dissection or be inadvertently trapped in the closure of the external oblique fascia.  The deficit is often decreased sensation to the medial thigh, scrotum or base of the penis.  It is often transient, but can take several weeks or months to improve.
Inguinal hernia can occur if the external oblique fascia is not closed properly or if the closure breaks down.  It is important to minimize strenuous activities for 2-4 weeks to prevent development of a hernia.

Made by Coloplast. 

Testicular Prosthesis

Prostheses should be offered to all men undergoing orchiectomy.  Not all men want a prosthesis -- it is a personal decision.  The prosthesis should be measured in the operating room with the patient asleep.  The goal should be to match the remaining testicle in size taking into account a cancerous testicle can be larger or smaller than normal, and the scrotal skin will make a prosthesis look larger once implanted.

TESTIS-SPARING SURGERY (PARTIAL ORCHIECTOMY)

Rationale

While radical orchiectomy remains the standard-of-care for the diagnosis and treatment of testis cancer, there are a couple of circumstances where testis-sparing surgery is advocated.  The primary indications are in men with:

• bilateral testis cancers (either synchronous, at the same time; or metachronous, that develop some time after the first testicle is removed)
• the standard-of-care would be to remove both testicles under suspicion of cancer, however the implications regarding fertility and testosterone replacement are well-established
• small, palpable testis masses and normal serum tumor markers
• these men have a low, but significant risk of having a benign mass or non-germ cell cancer that does not require orchiectomy
• if a testis cancer is confirmed, a radical orchiectomy is completed
• small, non-palpable, ultrasound detected testis mass with normal tumor markers
• approximately 80% likelihood of benign mass [1] 

Some urologists advocate for testis-sparing surgery even for men with germ cell tumors of the testicle.  While some evidence indicates that this can be done safely in some patients, it is not a proven or well-established technique.[2,3]  Before undergoing testis-sparing surgery, an extensive consultation should occur with the patient and their family regarding expectations and possible outcomes in the operating room.

Surgery

Tumor being identified with
intra-operative ultrasound.

The beginning portion of a testis-sparing surgery is identical to a radical orchiectomy.  Once the testicle is "delivered," the testis-sparing portion should begin.  The tunica vaginalis should be opened vertically to expose the testicle and intraoperative ultrasound should be used to identify the mass, rule-out other masses and create a surgical plan.  The testicle should be iced down for 10 minutes prior to placing a tourniquet or non-crushing clamp on the spermatic cord.  Once the testicle has been iced, a clamp or tourniquet should be placed on the cord.  The tunica albuginea (which houses the tubules of the testicle) should be opened horizontally above the mass.  The mass can often be "shelled" out of the surrounding tubules with a margin of 3-5mm.  Surgical loupes or a microscope can be used to facilitate dissection with a clean margin.  Bipolar forceps can be used to control any bleeding to prevent injury to the remaining tubules.  The mass should then immediately go to pathology for frozen analysis - an expert genitourinary pathologist should evaluate the mass when possible.

If the patient has a normal contralateral testicle and cancer is confirmed in the mass, a completion radical orchiectomy should be performed.

Tumor (in clamp) being dissected from normal testis.

If the patient has (or had) cancer in the contralateral testicle, the pathologist should confirm negative margins before leaving the remainder of the testicle.  If any suspicion of residual cancer, the testicle should be removed.  Once again, the standard-of-care is bilateral orchiectomy and testosterone can easily be replaced.

Complications

The complications are the same for radical orchiectomy and testis-sparing surgery.  In addition, even if testis-sparing surgery is performed, surgery can result in infertility or hypogonadism if the internal blood supply to the testicle is harmed or if the tubules are disrupted.

Summary

Radical orchiectomy is the standard-of-care for men with suspicion of testis cancer and is therefore the most common operation done for testicular cancer.  Testis-sparing surgery (or partial orchiectomy) is a novel approach suitable for some patients.

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  










[1] 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. 2010 May;57(5):780-90. doi: 10.1016/j.eururo.2010.01.014. Epub 2010 Jan 20.
[2] Brunocilla E, Gentile G, Schiavina R, Borghesi M, Franceschelli A, Pultrone CV, Chessa F, Romagnoli D, Ghanem SM, Gacci M, Martorana G, Colombo F.  Testis-sparing surgery for the conservative management of small testicular masses: an update.  Anticancer Res. 2013 Nov;33(11):5205-10.
[3] Leonhartsberger N, Pichler R, Stoehr B, Horninger W, Steiner H.  Organ preservation technique without ischemia in patients with testicular tumor.  Urology. 2014 May;83(5):1107-11. doi: 10.1016/j.urology.2013.12.021. Epub 2014 Feb 21.

Additional References/Resources:
Joel Sheinfeld MD and George J. Bosl MD.  Surgery of Testicular Tumors in Campbell-Walsh Urology, Tenth Edition. 2012,  871-892.

Donald A. Elmajian and Dennis D. Venable.  Radical orchiectomy in Hinman's Atlas of Urologic Surgery, Third Edition.  2012. 353-356.

New AUA Guidelines for Kidney Stones

Brian Matlaga, MD

The American Urological Association (AUA) recently released GUIDELINES FOR THE MEDICAL MANAGEMENT OF KIDNEY STONES.  Kidney stones are a common problem in the United States and are a disease with a high-rate of recurrence.  There are well-proven, effective treatments for the prevention of kidney stones.  However there is evidence that these treatment regimens are underutilized.  Brian Matlaga, MD, Associate Professor of Urology and Director of Stone Disease at the Brady Urological Institute was a member of the guideline committee tasked with standardizing the treatment of kidney stones.  Here he reviews some of the important features of the new Guideline.  Salient point are broken down into Evaluation, Dietary Therapies, Pharmacologic Therapies and Follow-Up.  Important studies are referenced.

EVALUATION

All patients with a newly diagnosed stone should undergo a screening evaluation.
This should include a dietary and medical history, serum chemistry evaluation, urinalysis and urine culture, and a stone analysis.

Important aspects of the medical history include signs, symptoms and comorbidities associated with stone disease (renal tubular acidosis, primary hyperparathyroidism, diabetes, gout, obesity); a dietary history (fluid, calcium, protein and fruit/vegetable intake); and pertinent medications (topiramate, zonisamide, acetazolamide, triamterene, probenecid, protease inhibitors, vitamin C).

When examining a serum chemistry:

• high calcium and low phosphate can indicate primary hyperparathyroidism
• a serum parathyroid hormone level should be checked only if primary parathyroidism is suspected
• low bicarbonate, low potassium and increased chloride may indicate distal renal tubular acidosis
• increased uric acid can indicate low pH or hyperuricosuria

A stone analysis should be obtained at least once for a patient with stones:

• cystine stones indicate cystinuria
• uric acid stones identify low urinary pH as a target for treatment
• struvite stones may coincide with recurrent urinary tract infections

24-hour metabolic testing should be completed in high-risk patients, interested first-time stone formers and recurrent stone formers.  This is based on data that supersaturation levels in 24-hour urinalyses consistently reflect stone composition and preventive treatments can result in reduction of supersaturation levels in most patients.[1]  

"High-risk" stone formers include those with:

• Family history 
• GI disease/bowel resection
• Gout
• Type II diabetes mellitus
• Obesity
• Distal renal tubular acidosis
• Primary hyperparathyroidism
• Nephrocalcinosis
• Recurrent urinary tract infections
• Children or adolescents
• Solitary kidney

DIET THERAPIES

Clinicians should recommend that all stone formers:

• increase fluid intake to achieve a urine volume of 2.5L each day.  
• limit sodium intake
• consume 1000-1200 mg/day of dietary calcium [2,3]  

Patients with uric acid stones, or calcium stones with high urinary uric acid, should limit intake of animal protein.

PHARMACOLOGIC THERAPIES

Thiazide diuretics should be offered to patients with high or relatively high urinary calcium and recurrent calcium stones.[4]
Potassium citrate should be offered to all patients with recurrent calcium stones and low urinary citrate.[5]
Thiazide diuretics and/or potassium citrate should be offered to patients with recurrent calcium stones and no other identifiable metabolic abnormalities.[6]

Allopurinol should be offered to patients with recurrent calcium oxalate stones, hyperuricosuria and normal urinary calcium.  Allopurinol should not be offered as first-line therapy to patients with uric acid stones, rather treatments to alter urinary pH should be considered.

FOLLOW-UP

Urinary parameters are believed to precede stone recurrence, therefore serial urine collections should be obtained to assess changes in stone risk factors.  Success of any treatment should therefore be gauged by improvement in urinary risk factors and ultimately into reduction in stone events.

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This blog entry was extracted from a recent presentation by Brian Matlaga, MD, the AUA GUIDELINES FOR THE MEDICAL MANAGEMENT OF KIDNEY STONES.  The Guideline Committee was led by Margaret S. Pearle, MD, PhD, Chair, and David S. Goldfarb, MD, Vice-chair.  To read the entire Guideline Document click on the link above or here.

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[1] Parks et al, KI 51: 894, 1997

[2] Borghi et al, J Urol 155: 839, 1996

[3] Borghi et al, NEJM 346:77, 2002

[4] Pearle, Roehrborn et al, J Endourol 13, 1999

[5] Barcelo et al, J Urol 150: 1761, 1993

[6] Ettinger et al, J Urol 158: 2069, 1997

Historical Contribution: 1934, Waters, Lewis & Frontz, Radiotherapy for Renal Cancer

1934

Hohman LB, Scott WW. A Combined Psychiatric and Urologic Study of Sexual Impotenct. Southern Medical Journal. 1933;29;1:59-76.

This manuscript starts with a case description, a 52 year-old man presents with a large renal mass, palpable "It is evident in this case we were dealing with an extremely radiosensitive tumor."  
through his abdomen, firm to the touch and extended 11cm beneath the margin of his ribs.  He was treated with external radiotherapy in preparation for surgery, but never came back to the hospital for nephrectomy.  He lived greater than 5 years without additional treatment, prompting the authors to conclude,

Today we know that renal cell carcinoma is actually an extremely radioresistant tumor.  However, this manuscript is a fascinating look into the understanding of renal cell carcinoma in 1934.  Here are some salient points made by the authors:

• Radiation was often used in cases that were felt unresectable or in the presence of metastatic disease.  Marked reduction in the size of the primary tumor was observed in many of these cases.
• Size reduction was almost immediate.
• Delay in surgery resulted in regrowth of tumor.
• Because imaging techniques were poor, response to radiation was measured by palpation.
• "...the percentage of cures will probably not be materially increased until earlier diagnosis makes possible the institution of treatment before metastases has occurred."
• hematuria as the first symptom should call for a thorough evaluation of the urinary tract.
• Radiosensitivity is based on tumor cell type, with "tumors that revert to the embryonic type of growth and present a considerable degree of anaplasia are most radiosenstive" -- an observation made by Ewing.
• Renal cortical tumors (hypernephromas) demonstrated a fair response with regard to size.
• Renal pelvis tumors (papillary urothelial tumors) did not respond to radiation.
• In addition, papillary renal cell carcinomas did not respond to radiation; "there were no areas of necrosis, no large cysts, and no blood-filled spaces."

• Interestingly, necrosis was a common finding after irradiation - without a control group, it makes you wonder how many large, renal cortical tumors have necrosis as a baseline.
• At the doses of radiation given, there were no changes to the normal renal parenchyma surrounding the tumors, but doses were limited by side effects: skin erythema and nausea.
• However, extensive morphological changes were noted in the radiosensitive tumors with fibrosis, hyalinization and necrosis.  
• The nephrectomy in patient case number 2 was performed by leaving "pedicle clamps" in place for 9 days after surgery before removing them - without an issue!
• The authors highlight a number of important oncological principles of time (some still current):
• minimize palpation of the tumor to prevent shedding of tumor cells
• the renal pedicle should be ligated prior to manipulation (for the same reason)

Click here or on the link above to read the entire manuscript.

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!