Tuesday, July 29, 2014

Historical Contribution: Jewett, UPJ Obstruction, 1940.


H. J. Jewett.  Stenosis of the ureteropelvic juncture - Congenital and acquired.  Journal of Urology, 1940  44: 247-258.

Ureteropelvic junction (UPJ) obstruction is a partial or total blockage at the place where the kidney and the ureter are joined. UPJ obstruction is more common in children than in adults and often resulting from a congenital abnormality and is the most common cause of hydronephrosis (swelling of the renal pelvis, where urine collects from the kidney) detected on prenatal ultrasound or in newborns.  UPJ obstruction impedes the flow of urine, causing it to build up and resulting in hydronephrosis and has the potential complications of recurrent infection and kidney damage.

In this manuscript from 1940, Dr. Jewett reviews the cases of 71 patients with hydronephrosis and a UPJ obstruction.  Dr. Jewett found that 4 patients had stricture, 24 had a crossing vessel causing obstruction and the remaining 43 patients had an obstruction of unclear etiology.  In classifying these patients, in whom the etiology of the obstruction was unclear, Jewett found that a crossing vessel was the culprit in 10.

Drawing of a case of congenital stenosis of the ureteropelvic juncture associated with accessory renal vessel.
In the patients with a crossing vessel, Dr. Jewett made the following observations (that still hold true today):
  • UPJ obstruction without a crossing vessel is 3x more common than with a crossing vessel
  • The average age of onset in this cohort is younger (13 versus 24 years-old)
  • A crossing vessel is not always associated with UPJ obstruction (24 cases)
  • UPJ obstruction with a crossing vessel is characterized by a delicate and thin proximal ureter, as opposed to obstruction cases by trauma or inflammation.
In the remaining 33 patients, the UPJ obstruction was caused by a combination of inflammation and infection (16).  Under the microscope, these patients had a thickened, fibrous stricture at the UPJ.

Importantly, Jewett also identified 17 patients in which there was no crossing vessel or inflammatory reaction. Through careful pathologic and histologic analysis, Jewett concluded these patients had a congenital UPJ obstruction.  

Drawing of a case of congenital stenosis of the ureteropelvic juncture without associated vessels.
Therefore, Dr. Jewett embarked on an autopsy analysis of 11 embryos, 50 stillborn children and 200 consecutive urograms.  He was able to determine the relative frequencies of UPJ obstruction and its etiologies:
  • Normal UPJ (85%)
  • UPJ Obstruction (15%)
    • Bands and kinks (5.6%)
    • Crossing renal vessel (33.8%)
    • Congenital Stenosis (60.5%)
In addition, from these studies he concluded: 
It is possible, therefore, that a ureteropelvic juncture represents a minimal narrowing which, when present in marked degree, becomes a congenital stenosis.     
In the group of cases comprising inflammatory strictures, it is impossible to determine with any degree of certainty whether the inflammatory reaction was primary or whether it was superimposed upon a simple congenital stenosis.
Finally, he theorized a model by which hydronephrosis would develop from stenosis and was accelerated by crossing vessels, infection, high ureteral insertion and, possibly, rapid growth during puberty.  This model, developed 70 years ago, has changed very little in our most contemporary understanding of the UPJ obstruction.

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

Monday, July 28, 2014

Dogs Detect Prostate Cancer: Give Hope for Better Diagnostic Test

German shepherds, Liu and Zoe, were trained to detect
prostate cancer in urine samples.
The diagnosis of prostate cancer is most often prompted by an elevated PSA (prostate specific antigen) level, or less commonly an abnormal digital rectal examination. An abnormality in PSA or digital rectal examination often prompts a prostate biopsy – almost X performed per year in the United States. However, PSA testing and digital rectal examination are far from perfect (See our prior blog on PSA Screening Controversies). Part of this stems from the fact that both normal and cancerous prostate cells make PSA. Distinguishing a normal PSA from a "cancerous" PSA can be very difficult. Therefore, the accuracy of detecting prostate cancer following an abnormal PSA test is only 30% - with a lot of room for improvement!!

An average dog nose has 200 million olfactory or smell-
sensing cells!  The average human has 5 million.
PSA is not the only molecule that prostate and prostate cancer cells release. For many years, researchers have been looking at the urine of men with and without prostate cancer in search of a better diagnostic test. Recently, researchers in Italy used two highly trained German shepherds to evaluate urine samples of men with and without prostate cancer – and the dogs were correct 98% of the time. Dogs have a dramatically stronger sense of smell than humans. The average human nose has approximately 5 million olfactory cells that detect volatile (airborne) compounds (our sense of smell) – dogs have 200 million. We have known this for years, making use of our canine friends in law enforcement, to detect drugs and bombs; and in medicine. In several studies, dogs have been able to detect the onset of epileptic seizures and to aid in the diagnosis of breast, lung and bladder cancers.

This study was completed in Italy with two German shepherds, a team of urologists, veterinarians, dog handlers, and over 900 urine samples from patients with and without prostate cancer. Three-hundred and sixty two men had prostate cancer in various stages, from very early, low-risk cancer to metastatic disease; the 540 men in the control group had neither benign prostatic hyperplasia nor prostate cancer. The dogs were exposed to half a dozen specimens at a time and were trained to sit down when they detected a cancer. The dogs were accurate in detecting either cancer or no cancer in 98% of cases. In fact, the sensitivity (or ability of the dogs to rule out cancer) was >99%; and if they identified cancer, they were right 97% of the time (specificity).

One of the biggest problems in using dogs in "sniffing" tests is that they can pick up on queues from their trainers. In this experiment, the trainers were completely blinded to the samples and the dogs were left to determine the status of the urine on their own. To ensure well-trained dogs, the process of teaching the dogs to smell cancer took over six months.

One of the biggest questions that remains is what were the dogs actually smelling? The dogs could be smelling a single molecule present in the cancer or a combination of chemicals produced by the cancer cells. In fact, it may not even be a cancer molecule, but a product of the microenvironment of that man's prostate that allowed the cancer to grow in the first place. Additional laboratory studies using complex gas chromatographers or "electronic noses" are needed to determine the exact molecule or chemicals present in the urine of men with prostate cancer. Whether dogs are in the future of prostate cancer detection remains to be seen, but this study proves that there is something detectable in the urine of men with prostate cancer that can be detected with incredible precision!

This study was presented by Dr. Gian Luigi Taverna, MD, at the American Urological Association (AUA) Annual Meeting in Orlando, Florida in May.  Read the abstract below:

PD19-01: Prostate Cancer Urine Detection Through Highly-Trained Dogs’ Olfactory System: A Real Clinical Opportunity 
Gianluigi Taverna*, Milan, Italy, Lorenzo Tidu, Grosseto, Italy, Fabio Grizzi, Guido Giusti, Mauro Seveso, Alessio Benetti, Rodolfo Hurle, Silvia Zandegiacomo, Luisa Pasini, Alberto Mandressi, Pierpaolo Graziotti, Milan, Italy
Abstract: PD19-01 
Introduction and Objectives: The analysis of volatile organic compounds (VOCs) in urines is a promising approach to cancer detection. Here, we establish the level of accuracy at which a rigorously trained canine olfactory system can recognize specific prostate cancer-VOCs in urine samples, thus reducing unnecessary prostate biopsies, and pinpointing patients at high-risk for prostate cancer. 
Methods: A total of 677 subjects were investigated. All the subjects included in the study were placed in one of two main Groups: Prostate Cancer Group (n = 320) and Control Group (n = 357). Prostate Cancer Group includes patients with PC ranging from those at very-low risk to metastatic PC. Control Group includes a large and heterogeneous cohort of healthy subjects or patients affected by non-neoplastic diseases or non-prostatic tumors. Each patient's clinical status and therapeutic regiment was known. We took into consideration all predictive values currently used in the clinical practice for prostate cancer management. Two dogs and a full-time, highly specialized, multidisciplinary team was dedicated. We have standardized a “work training” procedure and eliminated any possible olfactory interference. Each test was carried out blindfold. 
Results: The dogs achieved the following performances: Dog 1: sensitivity 100%, specificity 97.8%, accuracy 98.9%. Dog 2: sensitivity 98.6%, specificity 95.9%; accuracy 97.3%. When considered together, Dogs 1 + 2, we found an accuracy of 98.1% with a sensitivity of 99.2% and a specificity of 97.1%. Whether excluded the female control sub-groups we found that Dog 1 achieved a sensitivity of 100% and a specificity of 97.9%, while Dog 2 a sensitivity of 98.6% and a specificity of 94.5%. When evaluating the wrongly detected cases no differences were found between epidemiological, clinical or histopathological characteristics. 
Conclusions: The present study first demonstrates that a trained canine olfactory system detects specific PC-VOCs in urine samples from a large number of patients with PC at different stages and risks versus a heterogeneous control group, which is unthinkable in current clinical urological practice. Thanks to the early intuition, we have definitely turned what used to seem a myth into a real clinical opportunity.

Friday, July 25, 2014

Cryptorchidism: The Undescended Testicle

Cryptorchidism is the technical term for an undescended testicle.  Undescended testes are the most common congenital abnormality of the male genitals occurring in approximately 1 in 600 live births.  Most undescended testes will descend spontaneously, so the incidence is about 1% full-term infants at one year.  However, up to 1/3rd of premature boys will have one or more undescended testes.

This blog will review the proposed mechanisms of cryptorchidism and treatment options.

Embryology and Etiology

During development of the male embryo, the primitive testicles form near the developing kidneys.  As the embryo grows, the testicles remain relatively still while the embryo grows and lengthens.  Under the influence of testosterone and other hormones, the testicles exit the abdominal cavity and settle in the scrotum at about the 8th month of pregnancy - explaining why the incidence of cryptorchidism is much higher in premature infants.

There are a number of theories to explain why testicles fail to descend.  There are some known genetic causes and approximately 14% of boys with cryptorchidism have a positive family history.  Additional support for genetic causes of cryptorchidism include a number of mouse models with culprit genes and the observation that infants with severe congenital syndromes, like congenital adrenal hyperplasia, Klinefelter's disease, autosomal trisomy or disorders of sexual differentiation, will often have cryptorchidism. Maternal obesity is associated with an increased risk of cryptorchidism, as is low birth weight and cesarean section delivery.  Finally, environmental exposure to "endocrine disruptors" that elevate estrogens or decrease androgens may affect the ultimate descent of the testicle.

Locations of undescended testicles.
Undescended testicles are usually found along the path of normal descent.  The path of descent can be halted in the abdomen, inguinal canal or high in the scrotum.
Intra-abdominal testicle.
Less commonly, testicles can be found in ectopic locations - the most common ectopic location is in the superficial inguinal pouch of Denis Browne.

Retractile Testis

Retractile testes are occasionally misdiagnosed for cryptorchidism.  Retractile testes are normally descended testicles that ascend or retract into the inguinal region due to a strong cremasteric reflex.  The cremaster muscle is the muscle of the spermatic cord that can pull the testicle upward when the inner thigh is stroked. The management for retractile testis is observation as approximately 30% will descend, 40% will remain retractile (but not have any problems), and 30% will ascend and require intervention.

Management of Cryptorchidism

There are a number of goals in the management of undescended testicles:

  1. Preserve fertility
  2. Prevent and monitor for testis cancer
  3. Repair inguinal hernia
  4. Reduce the risk of testicular torsion
Sperm form from germ cells in testicle.  Germ cells function ideally at 2 degrees cooler than normal body temperature - which is why they settle outside of the body in the scrotum.  If the testicles fail to descend, the germ cells will deteriorate at about 18 months.  The rates of infertility for men with cryporchidism is 10-13%.  
Cryptorchidism is the number one risk factor for testicular cancer.  (See our prior blog on The Basics of Testis Cancer Diagnosis: Epidemiology & Presentation for more details)  Boys and men with cryptorchidism have a higher risk than the general population for developing testis cancer in both the undescended testicle and the normal, undescended testicle. In addition, surgically lowering a testicle reduces (but does not erase) the risk of testis cancer.  In addition, lowering the testicle facilitates surveillance.

Both inguinal hernia and testicular torsion are more common in boys with undescended testis.  Upwards of 90% of boys with undescended testicles and 50% of ectopic testicles will have an associated, congenital inguinal hernia.  In addition, acute testicular torsion is more common in these boys and the salvage rate is much lower (<10%) than the general population.

Non-Surgical Management

Human chorionic gonadotropin (HCG) increases testosterone production by the testis.  In approximately 25% of patients, the testicle will descend.  Success rates are higher for lower testicles and works best for patients with testicles in the high scrotum or low inguinal canal.  However, approximately 15% of the successfully treated testicles will "re-ascend."  HCG should not be given to newborns or post-pubertal males.  Side effects include temporary masculinization and premature closure of epiphyseal plates and growth arrest.

Surgical Management

Surgery is the gold standard for the treatment of cryptorchidism.  Surgery is typically deferred to 1 year of age, given that most undescended testicles will descend by one year of age.  For boys with ectopic or high undescended testicles (who have a low likelihood of spontaneous descent), surgery can be done at six months or later when the risks of anesthesia are improved.  

The most common surgery for a palpable, undescended testicle is called orchiopexy.  The goal of orchiopexy is to lengthen the spermatic cord so that the testicle can  be brought down to the scrotum without tension on the vascular blood supply to the testicle.  With good fixation techniques (using a subdartos pouch and stay suture or pledgit), the success rate for orchiopexy is 89%.

For patients with non-palpable testicles, the initial step in management is to locate the testicle.  This is usually achieved with diagnostic laparoscopy - placing a camera in the abdomen to look for an intra-abdominal testicle.  Most commonly, a viable intra-abdominal testis is found (37%), spermatic vessels are found entering the inguinal canal (40%) or a "peeping" testicle is found at the inguinal ring (11%).  If a testicle is found or supsected of being present, attempts should be made to place it in the scrotum.  If an intra-abdominal testis is found, a variety of procedures can be performed to lower the testicle.  The success rates for correcting an intra-abdominal testis are lower than an inguinal orchiopexy and vary from 67-77%.  If spermatic vessels are found but no testicle is seen, efforts should then be made to locate the testicle in the inguinal canal, perform an inguinal exploration and orchiopexy if possible.  Less commonly, blind-ending spermatic vessels are found (10%) indicating that the testicle never developed or lost its blood supply early in development.  

The major complication for orchiopexy is testicular atrophy, which is caused by damage to the testicular blood supply.  

For more information on cryptorchidism, visit Pediatric Urology at the Children's Center at Johns Hopkins.

Wednesday, July 23, 2014

Renal Cell Carcinoma: Implications of Histology

Renal cell carcinoma (RCC) is the most common kidney tumor worldwide.  In the United States, kidney cancer affects approximately 65k people and kills about 14k people per year.[1]  By definition, all RCC are adenocarcinomas -- meaning they derive from epithelium, or the lining, of the renal tubules that filter and conduct urine.  However, RCC represents several distinct entities including:

  • Clear-cell RCC
  • Papillary RCC
  • Chromophobe RCC
  • Collecting duct carcinoma
  • Renal medullary carcinoma
  • Translocation tumors
  • Tubulocystic RCC
  • Clear Cell (Tubulo) Papillary RCC
  • Acquired Cystic Disease–associated RCC
  • Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential (Multilocular Cystic RCC)
  • Hybrid Oncocytic/Chromophobe Tumors
After a biopsy or surgery to remove a tumor, the pathology report will often define the tumor as one of these entities.  This blog will review the definitions and implications of some of the most common tumor histologies.

Clear-Cell Renal Cell Carcinoma

Clear-cell RCC under the microscope.
Clear-cell RCC is the most common RCC, accounting for 70-80% of all tumors.  Clear-cell RCC was formerly known as "conventional" RCC.  In general, they are well-cricumscribed, yellow and lobulated tumors.  They can have necrosis, hemorrhage or invade vascular structures around the kidney.  The cells of clear-cell RCC are full of glycogen, cholesterol and phospholipids which are washed out during the specimen processing - giving these cells their characteristics clear appearance.  Upwards of 75% of clear-cell tumors have a defect in the von Hippel-Lindau (VHL) gene on chromosome 3.  


Patients with clear-cell RCC have a worse prognosis, in general, when compared to patients with papillary or chromophobe RCC.  However, most systemic therapies are designed to target clear-cell RCC and therefore, most responses for immuno- and other systemic therapies have been in clear-cell RCC patients.  

Papillary Renal Cell Carcinoma

Papillary RCC accounts for 10-15% of RCC tumors, making it the second most common tumor subtype. Papillary RCC was previously known as "chromophilic" RCC.  Papillary RCC have a few important clinical correlations:

  • commonly found in patients with end-stage renal disease
  • commonly found in patients with acquired cystic disease
  • often multifocal, upwards of 40% of papillary RCC are found in more than one site in the kidney
Papillary RCC (webpathology.com)
On imaging, they are often less intense than clear-cell or other "enhancing" tumors -- they can be mistaken for cysts.   While these are solid masses, like other forms of RCC, the cells grow in a papillary or tubular configuration, forming stalks of tumor cells rather than flat sheets.  There are two distinct patterns of growth under the microscope, in cytogenetics and molecular staining.

Papillary Type 1: 
  • more common form
  • dark cells with scant cytoplasm
  • associated with Hereditary Papillary RCC Syndrome 
Papillary Type 2: 
  • less common
  • eosinophilic (red) cells with abundant cytoplasm
  • sporadic forms of Papillary Type 2 are not necessarily dangerous
    • these tumors are potentially aggressive when associated with the hereditary Leiomyomatosis and RCC Syndrome -- these tumors are now given their own distinction and are no longer lumped with Type 2 tumors.

Common cytogenetic abnormalities in papillary RCC are trisomy 7 and 17, and loss of the Y chromosome.


Most papillary RCC are low-grade and upwards of 80% are confined to the kidney.  While papillary RCC can still present with advanced and dangerous cancers, when compared to clear-cell RCC by stage and grade, papillary RCC is believed to have a better prognosis.  However, papillary RCC is generally not responsive to systemic and immuntherapies for advanced cancer.

Chromophobe Renal Cell Carcinoma

Chromophobe RCC represents only 3-5% of RCC.  Unlike clear-cell and papillary RCC, which derive from the proximal tubule of the nephron, chromophobe RCC derives from the collecting duct.  Under the microscope, chromophobe RCC cells are recognized by a perinuclear "halo" or clear cytoplasm around the nucleus; and microvesicles which can be seen with electron microscopy or with Hale's colloidal iron stain. The most common cytogenetic abnormality is loss of a whole chromosome (usually 1, 2, 6, 10, 13, 17, and 21).


In general, chromophobe RCC has a better prognosis than clear-cell RCC when localized and are most patients are diagnosed with a small, early-stage, low-grade tumor.  However, chromophobe cancers have a worse prognosis when present with advanced disease (sarcomatoid features or metastases) and are resistant to all current forms of immunotherapy.

Collecting Duct Carcinoma

As the name suggests, collecting duct carcinoma derives from the collecting duct (or Bellini's duct) of the nephron and are also known as Bellini tumors.  They account for less than 1% of RCC.  Collecting duct carcinoma often presents in younger patients with advanced disease and is unresponsive to most therapies, leading to a poor prognosis.

Renal Medullary Carcinoma

Also a rare and aggressive form of cancer, renal medullary carcinoma often presents in young, African-Americans with sickle-cell trait with a locally advanced tumor and metastatic disease.  The prognosis is poor.

Translocation Tumors

Translocation tumors are a relatively new diagnostic entity and describes a relatively common form of RCC in children.  While RCC is less than 5% of renal tumors in children (Wilms and neuroblastoma are much more common), >50% of the RCC are translocation tumors.  These tumors are rare in adults, but may be more common in patients exposed to chemotherapy for a prior malignancy.  Under the microscope, these tumors represent a combination of both clear-cell and papillary RCC.  The term "translocation" defines these tumors as they uniformly demonstrate chromosomal translocations involving the TFE3 transcription factor gene (maps to Xp11.2 locus).


As these tumors are a relatively new entity, data regarding outcomes is still premature.  Children have a relatively good prognosis, even with nodal (but not distant) metastases with >90% alive at about 5 years. Data suggests that adults have a worse prognosis, more often presenting with advanced disease and with an average survival of 1-2 years.  Interestingly, these tumors can metastasize 20 to 30 years after an initial diagnosis - so long-term follow-up is required.

[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

Other Resources:
Campbell SC, Lane BR. "Malignant Renal Tumors" in Campbell-Walsh Urology, 10th Edition.  Wein, Kavoussi, Novick, Partin and Peters (Eds.).  Philadelphia: Elsevier, 2012. chapter 49, page 1413-1474.

Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel.The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.  Am J Surg Pathol. 2013 Oct;37(10):1469-89. doi: 10.1097/PAS.0b013e318299f2d1.

Tuesday, July 22, 2014

Historical Contribution: Leadbetter & Burkland, Hypertension in Unilateral Renal Disease, 1938.


WF Leadbetter, CE Burkland. Hypertension in unilateral renal disease.  - The Journal of Urology, 1938; 39:5, 611-26.

In the 1930's, it was well-established that bilateral renal disease - either obstructive or vascular - could lead to hypertension.  These findings were understood both in laboratory models and corroborated with clinical findings in patients with obstruction due to benign prostatic hyperplasia, vascular nephritis, polycystic kidney disease and polyarteritis nodosa.  In laboratory experiments, scientists were able to induce hypertension with unilateral renal injuries due to a variety of mechanisms: direct surgical destruction of a kidney, ligation of unilateral renal vessels, radiation damage to a kidney and ligation of the ureter to name a few.  However, a consistent clinical correlation was lacking.

Therefore, Drs. Leadbetter and Burkland present a case in which unilateral renal disease resulted in hypertension, and the hypertension resolved with removal of the diseased kidney.  The patient was 5 year-old boy with an ectopic, pelvic kidney and hypertension (consistently 150-170 systolic and 70 diastolic) for a number of years.  Following nephrectomy, the patients blood pressure decreased to normal and persisted there throughout follow-up.

This manuscript is:
1) a wonderful anatomic description of a pelvic kidney
At this point the ectopic kidney could be readily palpated lying over the promontory of the sacrum between the iliac vessels just below the bifurcation of the aorta.  It was necessary to bluntly incise a connective tissue layer, which corresponded to Gerota's fascia, before the anterior surface of the kidney could be exposed...Study of the kidney in situ showed that the artery and vein came from above to enter the hilum of the kidney just above the pelvis, lay in a deep grove on the anterior surface of the kidney, and were under considerable tension.  The renal artery appeared unusually small.

2) correlation between meticulous clinical measurements,observation and anatomy/pathology to arrive at a hypothesis of pathophysiology

The surface [of the kidney] showed great irregularity with numerous grooves and depressionswhich corresponded to its relationship with the renal artery and vein, the right iliac artery, and the surface of the sacrum...The renal artery was of small caliber and several cross sections showed at a point about 1cm. from the hilum of the kidney partial occlusion.
Interestingly, there was no evidence of inflammatory or infectious disease and the glomeruli were normal in appearance.

3) important evidence and hypothesis for unilateral disease causing hypertension.  

The authors hypothesized that "renal ischemia" produces nervous impulses that reflexly cause a rise in blood pressure.  Part of this was believed to be a compensatory phenomenon to preserve renal blood flow in a condition of compromised flow.  Possibly, the kidney secretes a hormone or substance in response to impaired local circulation that exercises a pressor action.  Today we know that all three of these mechanisms exist in renovascular hypertension.

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

Monday, July 21, 2014

Systemic Treatment of Renal Cell Carcinoma: Programmed Death Ligand 1 Inhibitors

Greater than 80% of renal tumors are renal cell carcinoma (RCC), of which about 70% is of clear-cell pathology.[1]   There are about 64,000 new RCC cases and 14,000 deaths from RCC each year, but due to increased imaging it is thought that we are catching these cancers at an earlier stage, when they are still resectable.  Unfortunately, mortality rates have not decreased and the burden of metastatic disease persists.[2]  Twenty to thirty percent of patients present with metastatic cancer and 20-30% of patients who have resectable disease later return with systemic disease following surgical management, whether it be partial or radical nephrectomy.[3,4] This underscores the necessity of management options outside of surgery.

RCC has largely been termed “chemoresistant,” meaning response to existing cytotoxic chemotherapeutic agents has been limited.  Therefore, cancer doctors and researchers continue to search for different forms of systemic treatments.[5]  In the early 1990s, immunotherapy was successfully used as systemic treatment for RCC.  The idea for this treatment came from the wide range in prognoses among patients with seemingly similar disease burden -- for example, among patients with similarly sized tumors (whether small or large), some were cured with surgery alone while patients with very similar tumors developed metastatic cancer and died.  In addition, a significant proportion of patients would have spontaneous regression of metastatic disease once the primary tumor was surgically removed.  Both of these observations suggest an interaction between the immune system and disease.[6,7] Ultimately, immunotherapies (like IFN-alpha and IL-2) were found to be more effective than previously attempted chemotherapies.  More recently, targeted therapies were developed to interrupt specific portions of the cell-cycle and endothelial attachment processes in clear-cell RCC.[8]

The idea of targeted therapy and theories of the immunoresponsive nature of clear cell RCC were combined to focus on specific parts of the immune interaction.   Among others, one important interaction is the Programmed Death Ligand 1 (PD-L1) interaction between the tumor cells and the immune cells.  T-cells are immune cells that target “foreign” cells in the body and trigger an immune response to kill those cells.  T-cells have receptors that have evolved (through genetic mutations and recombinations) to be specific for different surface proteins that may found in the cells of the body.  In a normal, healthy person, T-cells will even recognize normal, healthy cells.  However there are mechanisms to prevent the T-cell from killing good cells – a process called “anergy” which leads to T-cell death (or apoptosis).  One such signaling pathway is the PD-L1 on the healthy cell interacts with the receptor on the healthy cell (Figure 1).
Figure 1. T-Cell Recognizing Healthy Cell via PD-1-PD-L1 Interaction and Inducing Cell Death (Apoptosis).
If the T-cell identifies a tumor cell, it will not get the normal signal that it is a healthy cell, the T-cell can initiate processes to kill the tumor cell (Figure 2).
Figure 2. T-Cell Recognizing Tumor Cell without PD-1-PD-L1 Interaction.

However, some cancers like kidney cancer, can “trick” the T-cell into thinking the tumor cell is a normal, healthy cell.  One mechanism these cancers use is to express PD-L1, allowing tumor cell to escape the immune system and proliferate (Figure 3).[9]
Figure 3. Tumor Cell Expressing PD-L1 and Avoiding Detection by Immune System.

It has been noted that patients with tumors that have high expression of PD-L1 have a worse prognosis, which further suggests its involvement in the lifecycle of the disease -- although there is significant heterogeneity in expression of PD-L1 within individuals.[10]    Drugs have been developed that target both the PD-L1 on the tumor cells and the PD-1 receptor on the T-cells.  Nivolumab is the drug furthest along in the drug approval process that targets PD-1 on the T-cell.  There have been significant responses to this agent among about 30% patients who had failed treatment with the targeted therapies and enrolled in the trials. Interestingly, responses were only seen in patients who had clear-cell RCC that expressed PD-L1.[11] This response in patients who had failed the first-line targeted therapy shows promise for these novel agents. The heterogeneity of expression suggests it could play a future role in multimodal therapy.

This blog was written by Jason Cohen, Medical Student at Johns Hopkins Medical School.  Jason recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Programmed Death Ligand 1 Inhibitors: Systemic Treatment of Renal Cell Carcinoma" from which this blog is inspired. Jason is looking forward to a career in urology.

[1]  Siegel R et al. CA Cancer J Clin 2014; 64:9.
[2]  Hollingsworth et al. J Natl Cancer Inst. 2006; 98:1331
[3]  Curti B et al. J Am Med Assoc 2004; 292: 97
[4]  Levi D et al. J Urol 1998; 159: 1163
[5]  Chung EK et al. Am J Clin Oncol 2011; 34: 150
[6]  Oliver RT et al. Br J Urol 1989; 63: 128
[7]  Vogelzang NJ et al. J Urol 1992; 148: 1247
[8]  Rini BI et al. Lancet 2009; 373: 1119
[9]  Dong H et al. Nat Med 2002; 8: 793
[10]  Thompson RH et al. PNAS 2004; 101: 17174
[11]  Topalian SL et al. N Engl J Med 2012; 366: 2443

Friday, July 18, 2014

The "Evolution" of Advanced Prostate Cancer Research

Ken Pienta, MD and Director of Research
at the Brady Urological Institute
Prostate cancer affects approximately 230k men per year in the US.  Fortunately, over 90% of men present with localized, treatable prostate cancer.  Unfortunately, approximately 30k men still die of the disease each year in the United States.[1]  Advanced prostate cancer is treated with hormonal therapy, chemotherapy or radiation treatment in combination or alone.  As prostate cancer is a male cancer and driven by testosterone, hormone therapies can shrink and limit the growth of cancer cells.  Chemotherapy and radiation kill rapidly dividing cancer cells -- and have some effect on prostate cancer cells.  In them men who die of prostate cancer, the cancer cells learn or "evolve" to escape these treatments.  

In this blog entry, Ken Pienta, MD and Director of Research at the Brady Urological Institute, discusses how our understanding of advanced prostate cancer has "Evolved" to meet this challenge.  Dr. Pienta was recently awarded a $1.5 million Challenge Award from Prostate Cancer Research Foundation and Movember organizations to investigate circulating tumor cells and disseminated tumor cells in men with metastatic prostate cancer.

"Our understanding of how advanced prostate cancer changes over time is rapidly evolving. Prostate cancer changes over time because it mutates as part of its innate instability of its DNA as well as mutations that develop as the cancer adapts to the therapy to which we subject it (therapeutic pressure). As our understanding of prostate cancer evolution during progression grows, the challenge is to effectively sequence and combine our growing armamentarium of therapeutic agents for maximal patient benefit -- the right drugs, in the right combinations, given at the right time.  

It is especially important to anticipatie the need for therapy before it is clinically apparent; i.e. to move beyond anatomically-based clinical decisions and prognostication to biologically (marker)-driven therapy prediction. Treatment with androgen deprivation therapy (castration therapy, hormonal therapy) inevitably leads to the development of castrate resistant prostate cancer. The second generation anti-androgen (supra-castration) therapies, while effective, are leading to the emergence of new types of prostate cancer. Three phenotypes/genotypes of CRPC after treatment with second-generation agents appear to be increasing in prevalence and remain resistant to treatment: NeuroEndocrine Prostate Cancer (NEPC), Persistent AR – Dependent Prostate Cancer (PADPC), and Androgen Receptor Pathway Independent Prostate Cancer (APIPC). 

It is clear that new treatment paradigms, taking into account cancer cell genetic and epigenetic pathways, contributing factors within the microenvironment, and the macroenvironment of the host / patient need to be developed for this diverse group of diseases."