AUA 2011

A new randomized, controlled phase III trial reported at Tuesday’s Plenary Session found that denosumab, a novel RANK ligand inhibitor, significantly improved bone metastasis-free survival in men with castrate resistant prostate cancer (CRPC).

“This is the first large, randomized trial to demonstrate that targeting the bone microenvironment prevents bone metastasis in men with prostate cancer,” said Matthew R. Smith, M.D., PhD, Associate Professor of Medicine at Harvard Medical School and Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Boston.

“Compared to placebo, denosumab significantly increased bone metastasis-free survival, time to first bone metastasis, and time to symptomatic bone metastasis. Overall rates of adverse events were similar between the groups. Hypocalcemia and osteonecrosis of the jaw, the known adverse effects of denosumab, were frequently observed,” Dr. Smith said.

“Based on the results of this global randomized, controlled trial, we conclude that denosumab is a potentially new and important treatment option for men with castrate resistant prostate cancer,” he added.

The study, known as Dmab ‘147, compared the treatment effect of denosumab with placebo on prolonging bone metastasis free survival in 1,432 men with hormonerefractory, or castrate resistant, prostate cancer and rapidly rising PSA levels who had no bone metastases at baseline. The primary end point of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary end points including time to first occurrence of bone metastasis (excluding death) and overall survival.

“Bone metastases are common in men with advanced prostate cancer and represent a major cause of morbidity and mortality. Bone metastases result in significant health and economic burdens,” Dr. Smith said.

“There have been meaningful advances in the management of metastatic, castrate resistant prostate cancer, including new chemotherapy, immunotherapy, and androgen inhibitors. To date, however, no therapy has been shown to be effective in delaying the development of bone metastases in men with non-metastatic CRPC. Prevention of bone metastasis, therefore, represents an important unmet medical need,” he added.

“The development of bone metastasis involves reciprocal interactions between tumor cells and bone, the so-called vicious cycle of bone metastasis. Denosumab is a human monoclonal antibody that binds and activates the RANK ligand, a key mediator of osteoclast differentiation and survival,” Dr. Smith explained.

“Denosumab is superior to zoledronic acid for the prevention of skeletal negative events in men with CRPC and bone metastasis, and is approved for use in this setting,” he said.

The Dmab ‘147 study included castrate resistant men with prostate cancer who were at high risk for bone metastasis based on a serum prostate specific antigen (PSA) concentration less than 50 ng/ml and/or a doubling time of less than 10 months. The median age of the patients was 74 years, and the median time from prostate cancer diagnosis to study entry was 6.1 years.

Denosumab treatment was discontinued if bone metastases developed. About 42 percent of the patients in the placebo group and 35 percent of patients in the denosumab group developed bone metastases.

“The median bone metastasis-free survival was 25.2 months in the placebo group and 29.5 months in the denosumab group,” Dr. Smith said. “The difference in median bone metastasis-free survival between the groups was 4.2 months.”

The median time to first bone metastasis was 29.5 months in the placebo group and 33.2 months in the denosumab group. Overall survival was similar between the denosumab and placebo groups. The median overall survival time in both groups was approximately 44 months.

The study investigators defined progression-free survival as freedom from bone metastasis and investigator determined progression. “Compared with placebo, denosumab tended to improve the overall progression-free survival, with a hazard ratio of 0.89 and a p value of 0.93,” Dr. Smith said.

“The most common adverse events were distributed equally between the placebo and denosumab groups,” he continued. “Hypocalcemia and osteonecrosis of the jaw are recognized adverse events with denosumab and other osteoclast targeted therapies, and as expected, we observed higher rates of these conditions in the denosumab treated subjects. Among men who received denosumab, 12 (1.7 percent) had hypocalcemia and 33 (4.6 percent) experienced osteonecrosis of the jaw.”

The risk factors for osteonecrosis of the jaw include prior tooth extraction and poor dental hygiene. “Most of these cases were managed conservatively, and only two subjects required bone resection. As of February 2011, 13 cases (39 percent) had resolved,” Dr. Smith said.

The RANK ligand pathway, first discovered in the mid 1990s, is believed to play a central role in cancer-induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis, cancer invasion is facilitated by bone destruction. Hence, increased bone resorption due to increased RANK ligand expression appears to augment bone metastasis.

Denosumab prevents the RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting the release of growth factors, making the environment less conducive to tumor growth, according to the drug’s manufacturer.

AUA President Datta G. Wagle, M.D., will deliver the annual Presidential Address at 10:25 a.m. Wednesday during the Plenary Session in Hall D of the Walter E. Washington Convention Center. Dr. Wagle has titled his address, What is AUA? Progress, Relevance and Commitment.

“As we reflect on what has occurred in recent months and envision what lies ahead, perhaps it is appropriate to consider these words of President John F. Kennedy: ‘Change is the law of life. Those who look only to the past or present are certain to miss the future’,” Dr. Wagle said. “Changes facing us in the third millennium are far different, but they too require vision, determination, collaboration and a full commitment as we focus our efforts on shaping the future of health care in general, and urology in particular in our community and our country.”

As is often the case with Presidential Addresses, Dr. Wagle’s presentation will be a bit nostalgic. “In the third week of May 2011, I will begin the graceful glide toward the twilight of my active, rewarding and highly educational professional career. It has been a good experience,” he said.

By the end of his term as AUA President, Dr. Wagle will have dealt with more than 4,500 e-mails relating to AUA business and chaired three AUA Board of Directors meetings. “I’ve been amazed by what can be done with tight scheduling and the support of the committed AUA staff of 130, as well as discipline and farsighted fiscal planning,” he said.

“I was able to attend five great section meetings — South Central, Northeastern, New England, New York and Western,” he continued. “Each AUA section has its own personality. And for me, each one was a signature event. I regret that I was unable to attend the Southeastern, North Central and Mid-Atlantic section meetings.”

While representing the AUA at the annual meetings of international medical societies, Dr. Wagle said he learned that the AUA provides an educational and organizational model for many professional urological organizations, both domestic and international. “American urologists practice in a privileged, professional environment compared with that of many of our international colleagues,” he said. “AUA is eager to share expertise, advances in knowledge and surgical techniques with other countries.”

New ventures the AUA became involved with during Dr. Wagle’s tenure include pelvic reconstructive surgery, male health, global philanthropy, an emphasis on research, and the establishment of 2 new committees for advanced practice nurses and physician assistants.

“How can urology become part of the solution to health care reform in the United States? We should strive to be flexible, realistic, adaptive, creative and innovative. We should promote fairness, open communication and teamwork. We should accept responsibility for our actions and accountability for outcomes,” Dr. Wagle said. “We should be committed to expanding services provided to underserved populations and truly believe in an all-inclusive organization that represents the diverse community that serves at all levels of the system.”

Before becoming AUA President, Dr. Wagle chaired UROPAC for AUA and the American Association of Clinical Urologists (AACU). He was succeeded by Gary Kursh, M.D. “This year more than 300 urologists visited the halls of Congress to drive our issues on a one-on- one basis,” Dr. Wagle said. “We owe gratitude to them as well as to the staff of the AUA and the AACU, who made this possible. Thanks to the efforts of Dr. Kursh, UROPAC this year reached past the million dollar mark in fundraising for the first time.”

AUA has been active in the legislative process, working on its own as well as with the American Medical Association, American College of Surgeons and Alliance of Specialty Medicine. “Special thanks go to Dr. Steve Schlossberg, Chair of the AUA Health Policy Council, and Dr. David Penson, Vice Chair,” Dr. Wagle said.

“The success of any organization lies in three words — adapt, adopt, adept. Be informed, be involved and be invested,” he said.

“First, I thank the Northeastern Section for making it possible for me to be AUA President. Second, thanks to those who have contributed time and effort to make this great professional organization of ours what it is today. Thanks also to Dr. Robert Flanigan, AUA Secretary; Dr. Elspeth McDougall, Chair of Education; Executive Director Michael Sheppard; the Section representatives; and the Board of Directors for making this a memorable year of problem solving,” Dr. Wagle said.

“My special thanks also go to our past presidents, Drs. Brendan Fox, John Barry and Paul Schellhammer, for being my mentors and guides during this presidency,” Dr. Wagle added.

Photoselective vaporizat ion of the prostate (PVP) with a GreenLight™ laser has recently emerged as an alternative to transurethral resection of the prostate (TURP) and may supplant medical therapy for benign prostat ic hyperplasia (BPH) patients.

Results from a prospective trial comparing photoselective vaporization of the prostate (PVP-120) to transurethral resection of the prostate were reported in a Late Breaking News lecture during Tuesday’s Plenary Session. The trial was proposed and supported by the Ministry of Health and Long-term Care of the Province of Ontario, Canada.

The trial was undertaken following a study by Canada’s Program for Assessment of Technology in Health. After initially reviewing the status of the BPH disease process within the Province of Ontario, a meta-analysis was completed to determine if further trials were needed.

“In this situation trials were indicated,” said J. Paul Whelan, M.D., the Braley- Gordon Chair of Urology, and Division Head of Urology at McMaster University in Hamilton, Ontario.

“Benign prostatic hyperplasia costs were reviewed,” he continued. “There were 10,000 bed-days being used in the Province of Ontario for TURP and this suggested to the Province that further investigation was necessary.”

When the Ministry looked at costs associated with TURP versus PVP, it was concluded that approximately 3½ years of combination therapy was equivalent to the cost of the PVP procedure. “Their hope was that if we provided another option in terms of surgical treatment that more patients might select definitive therapy,” Dr. Whelan said.

When the meta-analysis was completed, it was determined that there were significant flaws in BPH studies. The studies were small, they were usually industry sponsored, hard to blind, and randomizing of ten resulted in patients withdrawing from the trials. In addition, there was short follow-up, particularly in the area of durability, and there was a changing gold standard in terms of TURP.

Subsequently, a multi-institutional, nonrandomized, non-blinded trial of PVP for the treatment of BPH was undertaken with a contemporary matched cohort of TURP patients.

“The primary end point is change in the International Prostate Symptom Score (I-PSS) at 6 months post operatively and there were a series of secondary end points including resource utilization, cost data, quality of life, and cost-effectiveness,” Dr. Whelan said. “The only significant difference in the demographics is that the TURP group was older, at 72 years, and this became an issue in evaluating employment.”

At 6 months the change in I-PSS, the primary end point, was exactly the same between the two groups. With regard to the secondary endpoints, there was an improvement in the EQ-5-D of 0.045 in the PVP group.

“This is quite significant in that an increase of 0.03 is what’s seen in coronary artery bypass grafting,” Dr. Whelan said. “So there is a significant improvement in quality of life in both groups, but particularly in the PVP group.”

There was a decrease in prostate specific antigen in both groups after surgery, but this was greater in the TURP group and may ref lect the learning curve for surgeons inexperienced in the PVP procedure.

The PVP procedures did take longer at 64 minutes compared to 44 minutes for TURP. However, the PVP group was largely outpatient compared to a mean length of stay of 1.4 days for TURP.

In the PVP cohort, nocturia went from 3.9 to 1.6 at 6 months and patients were not discharged with or later require narcotic pain medication.

“The limitations of the study are that it is a non-randomized trial and there is a small cohort of TURP patients. We, like others, had difficulty recruiting patients to the TURP arm, but they are contemporary and they are balanced,” Dr. Whelan said.

“Our conclusions from this trial is that GreenLight PVP provides outpatient treatment of lower urinary tract symptoms with similar outcomes to TURP,” he said. “The procedure times were a bit longer but there was no change in the hemoglobin and the treatments were completed as an outpatient. Quality of life was improved in both groups but particularly the PVP group showed an improvement in quality of life.”

The Urological Association of Asia (UAA) Society Lecture featured UAA President Allen Wen-Hsiang Chiu, M.D., PhD, talking about the interrelationship between health policy and health care. Dr. Chiu straddles the fields of both urology and public policy as Deputy Mayor of the Taipei City Government in Taiwan and Professor of Urology/Surgery at the National Yang-Ming University School of Medicine and the Taipei Medical University.

In his lecture, Dr. Chiu described the major differences between public health policymakers and health care providers; the importance of bio-informative, genomic, and molecular epidemiology; and the concept of tailoring health care to individual patients.

“The purpose of my talk is to try to broaden the horizons of urologists for their future career development,” Dr. Chiu said. “Physicians need to equip themselves with knowledge of preventive medicine as early in their careers as possible. Public health issues should be strengthened in urologic education, and in residency and fellowship training. Urologists must not only cure disease but also prevent disease from occurring.”

“In this millennium, molecular biology and advanced imaging technology have helped us understand how better to predict the outcomes of certain diseases,” he continued. “Medical scientists are beginning to identify unique molecular markers for various diseases that will make it possible to predict outcomes in the future for any particular individual.”

According to Dr. Chiu, most medical students start their careers as residents engaged in learning skills essential for patient care right after graduation from medical school. Only a few take on the task of public health. Even fewer will become a health policymaker well trained in epidemiology and with a strong public health background.

“When it comes to conventional medical education, epidemiology and public health issues usually get less attention than they deserve. Then, after years of clinical practice, physicians may become increasingly unfamiliar with public health issues. As a result, few physicians are able to become competent health policymakers, and I am no exception. It’s important to understand that opportunity belongs to the people who have early preparation,” Dr. Chiu said.

“I believe a medical caregiver treats clinically detectable diseases in a passive manner, but a public health promoter needs to actively detect subclinical diseases. In addition, a medical caregiver focuses on a single patient or a group of individuals, while a public health promoter exercises his professional expertise for the whole population,” he added.

“A medical caregiver emphasizes the depth of medical care, and a public health promoter focuses on a wide spectrum of disease,” Dr. Chiu continued. “A medical caregiver is like an actor on stage and the public health promoter is like a director behind the scenes. The treatment provided by a medical caregiver is assessed by short-term results, while the outcome of public health policy needs long-term observation.”

Dr. Chiu said he believes that the practice of medicine is narrowly defined as a profitable business by many, but the field of public health traditionally is not considered to be a profitable career, and the practice of medicine is loosely defined as science, while public health is characterized as social science.

“A good urological training program should help equip young urologists with skills and expertise in both medical science and public health to narrow the gap between medical care and preventive medicine. Urologists nowadays have to have a global vision and insights so they can gain a good grasp of events worldwide that affect medical care. Physicians also need to have a sense of the balance between local and global issues so we can create a harmonic global medical society,” Dr. Chiu said.

“I believe we can decide the future of health care if we dare to take on the challenges that lie before us in both medical care and public health policymaking,” Dr. Chiu concluded.

Since the onset of American combat operations in 2001, there have been approximately 42,000 U.S. casualties, 15,000 of which required evacuation from foreign lands back to the U.S. The current trend in the management of these patients is to move the wounded soldiers closer to home earlier in their recovery for intermediate and longterm care.

“This reduces the burden on the families that participate in their care,” said Col. James Jezior, M.D., who described the U.S. military’s approach to caring for combat wounded soldiers with pelvic injuries in a Late Breaking News lecture during Tuesday’s Plenary Session. Dr. Jezior is Chief of Urology Service at Walter Reed Army Medical Center and National Naval Medical Center in Washington, D.C.

A consequence of moving the soldiers closer to home is the participation of urologists previously uninvolved in this kind of combat care. This includes urologists at Veterans Administration facilities as well as civilian urologists.

The most common condition requiring urological evaluation and treatment is pelvic injury from improvised explosive devices (IEDs). The body armor currently used by the U.S. military protects the major core organs, reducing the likelihood of immediate death. However, the body armor exposes the pelvis and lower extremities to greater injury.

The rapid application of tourniquets on the battlefield reduces hemorrhaging, allowing more time for wounded soldiers to be transported and given medical care at well-equipped facilities in the field. This has led to improved survival rates, but also yields an increased complexity to the injuries seen by surgeons in the U.S.

Dr. Jezior used the example of an injured Navy Seal to demonstrate the rapid evacuation, of soldiers wounded in battle.

“He was injured by an anti-personnel mine in the mountains of Kandahar Province in the early morning hours of 9 September 2009,” Dr. Jezior said. “Treated and stabilized by a forward surgical team, he was transported to Bagram Air Force Base and received his first surgical care by 9:00 p.m. that evening. By the next morning he was at Landstuhl Medical Center in Germany and by 12 September returned to the United States.”

Only four days after an injury that occurred halfway around the world, the Navy Seal was receiving care in his nation’s capitol.

From October 2003 to February 2011, 135 military personnel underwent urological surgery at the Walter Reed Army and National Naval Medical Center. Of these, 77 percent of the injuries were caused by IEDs. The most common urological injury seen was to the scrotum, at around 50 percent, which was compounded by testicular injury in 43 percent of these patients. Of these patients, 13 percent lost both testicles.

“Less common but more complex are urethral injuries, at 21 percent [of the cases], penile soft tissue injuries at 24 percent, and devastating penile amputations at 6 percent,” Dr. Jezior said. “Our current management for these patients includes wound irrigation and débridement followed by skin coverage for open wounds, and then a period to allow for physical rehabilitation, prosthetic fitting, and ambulation.”

Ambulation is followed by delayed reconstruction of the penile and urethral injuries. This is concluded with longterm management of sexual, social, and reproductive issues.

The initial irrigation and débridement are performed by numerous trips to the operating room. This allows for tissue with questionable viability to be evaluated and preserves as much genital skin as possible.

High pressure irrigation is no longer performed and has been replaced by low pressure, large volume irrigation, often using 5 to 10 liters per case. An important adjunct is the vacuum-assisted closure device that improves wound healing and reduces the number of painful dressing changes.

“It’s impossible to determine the likelihood of the external sphincter and pelvic floor mechanisms of function in these early injuries,” Dr. Jezior said. “It has been our policy to correct them despite that risk of incontinence.”

There is renewed interest in percutaneous nephrolithotomy (PCNL) for kidney stone management in urological practice, according to Jean de la Rosette, M.D., Chairman of the Clinical Research Office of the Endourology Society (CROES) and principal investigator of the CROES Global Study on PCNL.

“PCNL is back. It was done in the 1970s but then shock wave lithotripsy came along and took over everything in stone management. Now we see that shock wave is not that good, and suddenly we are witnessing a renaissance of PCNL, with people saying it is more effective,” said Dr. de la Rosette, who is also Chairman of Urology at the Academic Medical Center University Hospital of the University of Amsterdam.

Dr. de la Rosette will give a State-of-the-Art Lecture on the CROES PCNL study during Wednesday’s Plenary Session. His 20-minute presentation will begin at 8:45 a.m. in Hall D of the Walter E. Washington Convention Center.

The CROES study was designed to assess the current indications, perioperative morbidity and stone-free outcomes for PCNL worldwide. During a two year period, 96 medical centers around the world, including academic centers, centers of excellence and nonacademic community centers, gathered real life data on treatment outcomes from the 5,803 patients enrolled in the study. The study revealed that PCNL remains an effective treatment for stones with a low rate of major complications and a high success rate.

“I will give an overview of how PCNL is practiced worldwide as well as the results of our sub-analyses of patient data,” Dr. de la Rosette said. “Among other things, we looked at percutaneous access for urinary tract dilatation and patient positioning for the procedure.”

Dr. de la Rosette and his colleagues evaluated which method of tract dilation was most effective, whether by balloon or metallic serial dilators. “Surprisingly we found out from this large dataset that serial, or telescopic, dilators caused less bleeding than balloons,” he said.

“In a further analysis we found not only that the type of dilator used was important, but also the size of the dilatation, which means that a bigger hole in the kidney results in relatively more bleeding than a smaller hole,” Dr. de la Rosette explained. “We hope that this finding will encourage the urologic community and manufacturers to improve the available devices and bring down morbidity.”

The researchers also analyzed the ideal position for the patient undergoing PCNL, whether prone or supine. “The supine position is popular, especially in parts of Europe, because it is easier for the anesthesiologist to control the patient safely, and it allows the physician to perform a combined ureteroscopy procedure and PCNL. We found that morbidity outcomes were better with the supine approach,” Dr. de la Rosette said.

“The next thing we looked at was the results of PCNL for staghorn calculi — that is, very big stones — in terms of the number of staghorn stones being treated, morbidity and stone-free rates,” he continued. “We had access to the largest series of cases ever collected on staghorn calculi and found that these stones can be treated safely and effectively with PCNL.”

Other sub-analyses the CROES group performed indicated that PCNL can be done safely in rare cases of malrotated kidneys, kidneys in the small pelvis and kidneys shaped like a horseshoe. “It may be more difficult to gain access to these types of kidneys, but the procedure can be performed as safely as PCNL procedures for normal kidneys,” Dr. de la Rosette said.

“Stone management comprises up to 30 percent of every urologist’s practice,” he added. “Our ongoing study is based on the largest collection of data on PCNL that exists today. We encourage all urologists to look at the outcomes.”

Evidence presented in a State-of-the-Art Lecture during yesterday’s Plenary Session indicated a strong association between the formation of kidney stones and the presence or development of the metabolic syndrome and cardiovascular disease (CVD) in patients who develop kidney stones.

In the lecture, Dean G. Assimos, M.D., Professor of Surgical Sciences-Urology at Wake Forest University School of Medicine in Winston-Salem, North Carolina, cited several studies, including a recently published analysis of data from the Coronary Artery Risk Development in Young Adults Study showing that nephrolithiasis and atherosclerosis have common systemic risk factors and that kidney stones were associated with a 60 percent increased risk of carotid atherosclerosis, even after adjusting for major atherosclerotic risk factors.

In addition, a case-controlled study of the residents of Olmsted County, Minnesota, assessed the risk of a “kidney stone former developing myocardial infarction,” Dr. Assimos said. “Despite controlling for other medical comorbidities, a stone former was at 31 percent increased risk of sustaining a myocardial infarction.”

Another case-controlled study, again done among residents of Olmsted County, revealed that kidney stone formation was a significant risk for the development of chronic kidney disease. “In this study, the hazard ratio was 1.42,” Dr. Assimos said. “It is well documented that chronic kidney disease is a significant risk factor for cardiovascular disease.”

An analysis of the National Health and Nutrition Examination Survey III (NHANES III) showed that people with the metabolic syndrome had 2 times the risk of developing a kidney stone than those without signs of the metabolic syndrome. This analysis also demonstrated a positive correlation between the prevalence of kidney stones and the components of the metabolic syndrome, including obesity, hypertension, insulin resistance, increased serum triglycerides, and low high-density lipoprotein cholesterol levels.

“A screening renal ultrasound study done on a fairly large cohort of people with the metabolic syndrome in southern Italy demonstrated that 10.3 percent of patients with the metabolic syndrome had renal stones,” Dr. Assimos added. “This is 10 times higher than rates reported from renal ultrasound screening studies of the general adult population.”

The causative factors underlying the associations between stone formation and the metabolic syndrome and CVD include low urinary pH levels. “Low urinary pH is the major driving factor for the formation of uric acid stones,” Dr. Assimos said. “Studies have demonstrated that there is a negative correlation between BMI and urinary pH, meaning that those who are obese will have lower urinary pH.”

People with the combination of obesity and low urinary pH also excrete greater amounts of calcium and oxalate, which are risk factors for the development of calcium oxalate kidney stones.

The reasons for lower urinary pH in obese individuals are not fully known, but one hypothesis is that these individuals do not produce ammonium effectively in the proximal tubule.

Dr. Assimos’ own research with his team at Wake Forest has identified a possible new pathway for the endogenous synthesis of oxalate. It involves the metabolism of the reactive dialdehyde glyoxal, which is stimulated by oxidative stress. The hypothesis behind the research is that glyoxal metabolism may be linked with increased oxalate excretion in people with obesity and diabetes.

Based on the evidence he presented, Dr. Assimos concluded: “There is strong evidence that stone formation is associated with cardiovascular disease, the metabolic syndrome, and a number of systemic disorders. We as urologists need to be cognizant of these associations and counsel our patients about these associations, as they might benefit from cardiovascular screening and lifestyle changes.”

The standard of care for upper tract transitional cell carcinoma (TCC) is on the move. Nephroureterectomy has been the preferred and often unquestioned automatic option for upper tract TCC. But clinicians today are taking a second look at laser ablation of noninvasive urothelial tumors of low metastatic potential, either in situ or using other techniques such as percutaneous resection to remove the superficial tumor while sparing the kidney.

“Just like we are not removing all bladders for all bladder urothelial tumors, maybe we should rethink the paradigm that has us removing all kidneys and ureters for all urothelial tumors of the upper urinary tract and develop a bit more sophisticated and individualized strategy,” said Anup Patel, M.D., FRCS, a consultant urological surgeon at St. Mary’s Hospital, Imperial College of Medicine, London. “Instruments and technology have evolved in the past two decades. Ureteroscopes have become smaller and more flexible, and capable of complex movements. Energy sources have also become smaller and more flexible, and we have digital imaging available in the upper urinary tract.”

Dr. Patel will examine the evolution of upper tract TCC management in the European Association of Urology Lecture, Challenging Dogma: Current Role of Endourology and Renal Preservation in Upper Tract TCC Management. His 20-minute lecture will begin at 10:40 a.m. during the Plenary Session today in Hall D of the Walter E. Washington Convention Center.

The development of smaller, more flexible ureteroscopes and accessories continues to advance practice, Dr. Patel continued. Precise digital imaging has replaced shadowy x-rays that cannot distinguish a blood clot from a tumor and have caused some kidneys to be excised needlessly. Instrumentation allows urologists to obtain material by multiple biopsies and cytology to characterize upper tract tumors more accurately. Like prostate and kidney cancers, TCCs come in a variety of shapes, sizes and danger of spread.

“The question is: Is a tumor like every other tumor, or are they all the same? Does it matter if we start treating each tumor and each patient in a slightly different and more sophisticated way? We already know that one single treatment does not fit every patient,” Dr. Patel said.

“This new paradigm is based on the accuracy of grading and staging cancers, and looking at other factors such as size and multifocality, all of which play into the risk for recurrence or a lethal outcome,” he continued. “For multifocal disease, if we take kidneys out too quickly, particularly for a nonlethal tumor, the patient is more likely to get recurrences. We would expect to see these recurrences not only in the bladder, which means a lifetime of endoscopic surveillance of the urothelium that remains, but potentially a tumor in the other kidney. Then the patient is in serious trouble, facing both kidneys being removed and dialysis. The morbidity and cost of dialysis are not insignificant.”

These changes in upper tract TCC management are following a pathway that urologists have taken in the past. New treatment data discussed in March at the EAU annual congress in Vienna showed that shock wave lithotripsy, long the standard of care for renal stones, is being replaced by ureteroscopic procedures in some countries. The treatment of bladder cancer has already shifted from radical cystectomy to more selective treatment based on individual patient and tumor characteristics. Upper tract TCC is in the early stages of a similar shift to more precise treatment based on individual patient and tumor characteristics.

“Essentially I’m talking about an individualized paradigm of natural orifice surgery rather than procedures that make new holes,” Dr. Patel said. “Cystoscopy was the first natural orifice procedure in urology, and ureterorenoscopy is merely an extension of this principle and also a natural orifice procedure. The same endo-oncology, risk stratified paradigm is developing in upper tract TCC as a result of the improvement in instrumentation, accessories and training.”

“Training is key,” he continued, “because this is a highly precise and delicate surgery that is much more challenging in the kidney since it is an organ that moves with breathing than it is in the bladder, which is a stationary target. It requires specialist or fellowship training. This is not a procedure for everybody to attempt and we need to concentrate cases in key centers in order to feed future multicenter clinical trials involving large numbers of patients. But ureterorenoscopy is the way the paradigm will evolve to facilitate both renal preservation and, beyond that, quality of life.”

For patients with polycystic kidney disease slated to undergo renal transplant for end stage renal disease, urologists are faced with the dilemma of whether to perform bilateral nephrectomy at the time of transplant or a staged nephrectomy before or after the transplant procedure.

During yesterday’s Plenary Session, two experts in urological surgery participated in a Point-Counterpoint debate over the Management of Polycystic Kidneys in Renal Transplant Patients—Concomitant or Staged Nephrectomy? Each surgeon provided strong arguments for choosing one option over the other.

“Our task this morning is to debate the timing of native nephrectomy in polycystic kidney disease patients who are candidates for transplantation,” said moderator Venkatesh Krishnamurthi, M.D., a urologist at the Cleveland Clinic.

Autosomal polycystic kidney disease (PKD) affects approximately one in 1,000 people. The renal manifestations of the condition include hypertension, kidney stones, infection, and bleeding. By age 60, nearly half of PKD patients will have advanced renal insufficiency and require dialysis or transplantation.

“Simultaneous bilateral nephrectomy should definitely be offered as an option in the setting of a need for kidney transplant with a living donor,” said the first debater, Michael Phelan, M.D., a urologist at the University of Maryland Medical Center and Assistant Professor of Surgery at the University of Maryland School of Medicine.

“So that will frame the argument: Patients are not on dialysis but need a transplant, and there is a living donor available as well as symptoms in the pulses of the kidney patient,” he continued. “The options would be to transplant the patient alone, do a staged procedure, do cystic decortication — but I would argue that the best procedure would be a simultaneous bilateral nephrectomy at the time of transplantation.”

Why not a staged procedure? That would require two anesthesias, Dr. Phelan pointed out. “If you have a pre-transplant nephrectomy, you would need hemodialysis and there are some detrimental effects of that,” he said. “If you pursue a post-transplant nephrectomy, there are wound issues you need to be concerned about. There is the potential for injury to the transplanted organ and hypotensive issues with the transplanted organ.”

Hemodialysis can be associated with activation of cytokines, T-cells, and the complement system. “There are also infectious disease issues to be concerned about,” said Dr. Phelan, noting that 12 percent of all deaths from hemodialysis are related to infectious diseases.

With post-transplant nephrectomy, there are also wound related concerns, including wound infection. “In the setting of immunosuppression, the wound infection complications are as high as 50 percent,” Dr. Phelan said.

“In conclusion, I would like to say that the simultaneous procedure can be done successfully. The risks must be outlined in informed consent, and a team approach is essential. Resuscitation is essential, and pexy of the graft is essential,” Dr. Phelan said. Patrick Luke, M.D., Co-Director of the Multiorgan Transplant Program at the London Health Sciences Centre and Associate Professor of Surgery at the University of Western Ontario, London, countered Dr. Phelan and noted that transplantation and nephrectomy are not always the best combination.

“Dr. Phelan has shown that simultaneous bilateral nephrectomy can be done, but it is really only limited to the living donor situation. The argument for transplantation alone or transplantation with cyst ablation is probably the best,” Dr. Luke said.

“Which is the primary procedure we are trying to accomplish? I think that’s the transplant. It’s life prolonging and it improves the quality of life of patients. The nephrectomy is used just to create space, for early satiety, for pain, and rarely for hematuria or infection,” Dr. Luke continued.

“It’s important when you actually add something to a procedure that has been well established for 50 years that you really don’t change the transplant procedure all that much,” he added.

“The transplant is performed with an extraperitoneal approach, so you don’t get a torsion of the kidney, and urinary leaks are kept extraperitoneal,” Dr. Luke noted. “We want to minimize the potential for complications and bleeding.”

Dr. Luke cited a study showing that 27 percent of renal transplant patients treated with a simultaneous nephrectomy had major complications while none of the study patients treated with a staged procedure experienced complications. There was also a 63 percent reoperation rate in the patients treated with the combined procedure vs. zero percent in patients who underwent the staged procedure.

Dr. Luke said he prefers post-transplant nephrectomy to pre-transplant nephrectomy because patients have restored renal and platelet function.

“Dr. Phelan has shown us that simultaneous combined kidney transplant and nephrectomy is feasible, but there is no evidence that simultaneous nephrectomy is superior,” Dr. Luke said. “There is a higher transfusion rate associated with it, a higher complication rate associated with it, and the finite risk of graft torsion. It really does jeopardize the primary procedure.”

To conclude the debate, Dr. Krishnamurthi provided a brief summary: “Probably the best approach is an individualized one,” he said. “A patient in whom you think the nephrectomy may be straightforward, may be an appropriate candidate for a simultaneous procedure. Alternatively, if the procedure is perceived to be complicated, it’s probably better to perform a staged procedure.”

A paradigm shift toward personalized medicine is under way in health care, and the trend is rapidly transforming the face of medicine, according to Daniel Theodorescu, M.D., Ph.D., who will deliver a State-of-the-Art Lecture today on Personalized Medicine in Bladder Cancer. His 20-minute presentation will begin at 8:50 a.m. during this morning’s Plenary Session in Hall D of the Walter E. Washington Convention Center.

“The purpose of my lecture is to broadly explain what personalized medicine is in the genomic era and give examples of how it may be useful in the management of bladder cancer,” said Dr. Theodorescu, the Paul Bunn Professor of Surgery and Pharmacology, and Director of the University of Colorado Comprehensive Cancer Center.

“Personalized or individualized medicine is not a new concept,” he continued. “Early examples include the use of family histories to assess the risk of tumor development. However, because not all individuals with family histories of cancer carry hereditary risk, not all such patients are at higher risk of cancer development.”

Genetic tests are available today to help determine cancer risk and the risk of tumor progression. Genetic testing and molecular markers are helping physicians determine which patients are at risk for certain cancers and which patients will respond to various treatment protocols.

“We have better tools now to stratify patients in terms of the risk of getting cancer, getting an aggressive cancer or developing metastases from the primary cancer,” Dr. Theodorescu said.

In his lab at the University of Colorado Comprehensive Cancer Center, Dr. Theodorescu and his colleagues have focused on identifying the molecular mechanisms leading to bladder cancer metastasis and the potential application of this knowledge to patients with bladder cancer. One of his accomplishments has been the identification of a new metastasis suppressor gene, RhoGDI2, in human cancer. Expression of this gene has been shown to be an independent prognostic marker for disease specific survival in patients with bladder cancer. Its mechanism of action in suppressing the spread of cancer was found to be via the immune system (J Clin Invest 2011;121(1):132-47).

“A major advance that has opened new opportunities in personalized care is the ability to manipulate and interrogate nucleic acid — DNA and RNA. Interrogating nucleic acid in some form or interrogating proteins in certain forms is the cornerstone of molecular diagnostics and prognostics,” Dr. Theodorescu said.

“In addition to physical exams, imaging studies, histologic and cytologic screening, over time the identification of DNA, RNA proteomic, micro-RNA and epigenetic biomarkers in body fluids will become more routine in detecting cancer in its nascent stages,” he said.

“We can use these new tools not only on body fluids, such as urine and blood, but also on tumor tissue and normal tissue,” he continued. “In bladder cancer, for example, normal tissue can harbor genetic mutations in urothelium damaged by a carcinogenic insult. Analyzing tumor tissue can help us determine how the tumor will respond to therapy and whether the patient needs cystectomy or can handle TURBT [transurethral resection of bladder tumor], for example.”

New tests and approaches to the diagnosis and treatment of bladder cancer are currently under investigation. One recent study used cDNA microarray technology to develop gene expression profiles from biopsies of bladder tissue from patients with invasive bladder cancer who were subsequently treated with MVAC (methotrexate, vinblastine, doxorubicin) neoadjuvant chemotherapy (Cancer Res 2009;69 (21):8302-9).

“A tectonic shift is occurring in how we will practice medicine on the economic and clinical practice levels, and on the scientific levels,” Dr. Theodorescu said. “I suspect everyday urological practice will be very different in 10 to 15 years.”

The field of genomics is having an enormous impact on the diagnosis, treatment and prevention of all types of cancer. The search is on for genes associated with prostate cancer, but such genes, if they exist, are challenging to find, according to Kathleen A. Cooney, M.D., FACP, who will give a State-ofthe- Art Lecture on Prostate Cancer Susceptibility Genes during this morning’s Plenary Session. Her 20-minute lecture will begin at 11:00 a.m. in Hall D of the Walter E. Washington Convention Center.

Dr. Cooney will provide an update on the ongoing research designed to identify genes that convey a susceptibility to prostate cancer. She will also provide some information about the technology being used to find these genes.

“I’ll address the search for genes as well as the challenges involved in this field. It is a puzzle to many clinicians and researchers why prostate cancer susceptibility genes have been so much harder to find compared to genes that contribute to hereditary breast or colon cancer,” said Dr. Cooney, Professor of Internal Medicine and Urology, Chief of Hematology/Oncology, and Associate Director for Faculty Affairs for the University of Michigan Comprehensive Cancer Center at the University of Michigan Medical School in Ann Arbor.

“I will review the impact of family history on the risk of prostate cancer and discuss what we know and also what we don’t know with regard to testing men in families with multiple cases of prostate cancer, both for establishing genetic risk and for diagnosing prostate cancer in unaffected family members,” she said.

Since 1995, Dr. Cooney has been the principal investigator for the Prostate Cancer Genetics Project (PCGP) at the University of Michigan. The purpose of this project is to determine possible genetic causes of prostate cancer through the study of men with early onset and/or a family history of prostate cancer. Candidates are individuals who have been diagnosed with prostate cancer at age 55 or younger and families with two or more living family members with prostate cancer.

“The biggest challenge in hereditary prostate cancer research is that it has been very hard to find the rare highly penetrant genes that are the equivalent of BRCA1 and BRCA2 genes for breast cancer. There has been some debate in the field as to whether these genes actually exist. I, for one, believe they do,” Dr. Cooney said.

“For our prostate cancer research project, we’ve collected DNA samples from young men with prostate cancer as well as men with a positive family history of prostate cancer, and we’ve conducted a number of research studies over the years looking for cancer susceptibility genes. We have identified a broad region on chromosome 17 containing BRCA1 that appears to be linked to prostate cancer in a subset of families with multiple cases of early onset prostate cancer,” she explained.

“Based on earlier work from the PCGP, we don’t think that BRCA1 mutations account for this linkage, and we are actively sequencing additional genes in the region to try to find what we believe would be a hereditary prostate cancer gene,” Dr. Cooney added.

Another ongoing research project she is involved with is looking into early onset prostate cancer. “Prostate cancer is a disease of older men, but about 10 percent of all cases are actually diagnosed in younger men under the age of 55, and the number of cases in young men seems to be increasing,” she said. “There is also some epidemiologic data that prostate cancer in some young men may be more clinically aggressive.”

This second project is a genome wide association study using DNA samples from nearly 1,000 men with early onset prostate cancer, and evaluating a large number of single nucleotide polymorphisms or variants to identify genes that may be associated with early onset prostate cancer. Early work from the PCGP has confirmed the hypothesis that young men diagnosed with prostate cancer have more of the common prostate cancer risk variants than older men with prostate cancer.

“If we can find novel genes that cause prostate cancer within families, these genes may provide new insights into the biology of prostate cancer,” Dr. Cooney explained. “However, there are also clinical implications for our research. If we can identify the genetic factors responsible for multiple cases of prostate cancer within families, this information can be used for genetic based risk assessment.”

The Prostate Cancer Genetics Project is still enrolling patients. For more information, call 800-723-9170 or go online to www.cancer.med.umich.edu/prevention/pcgp.shtml.

Physician ownership of ancillary services has recently been under attack in the mainstream media, and urology in particular has been the target of lobbying efforts by other specialties.

David F. Penson, M.D., MPH, clarified the AUA’s official position on physician-owned ancillary services yesterday in a Point-Counterpoint debate during the first Plenary Session of the 2011 Annual Meeting. “Protecting patient access to high quality urologic care by maintaining the in-office ancillary ownership exception remains a top legislative priority of the AUA,” said Dr. Penson, who moderated the debate.

Brent Hollenbeck, M.D., Associate Professor in the Department of Urology at the University of Michigan Health System, Ann Arbor, spoke against the practice. “It’s fitting that we are talking about this timely topic in the shadow of the Capitol. The growth of health care spending in this country is unsustainable,” said Dr. Hollenbeck, noting that health care spending reached 17.6 percent of gross domestic product in 2009 compared to 7.2 percent in 1970.

Citing an article he co-wrote that was published in The Journal of Urology® last year, Dr. Hollenbeck showed that self-employed urologists had higher rates of imaging tests ordered than hospital-employed urologists.

“Although we alluded to different possibilities that underlie these differences, one that we suggested was that the incentives afforded through ownership may be driving this trend. This drew the particular ire of the readership,” he said. “In fact, the literature is replete with examples of how self-referral is associated with higher rates of utilization.”

To combat overutilization through self-referral, the Stark Law was enacted in 1989 and has been amended numerous times. More than 20 exceptions have been written into the law because of the recognized efficiency advantages of self-referral.

“However, policymakers believe that the in-office ancillary exception — the one we’re talking about today — is the primary reason for Stark’s ineffectiveness to curtail utilization,” Dr. Hollenbeck said.

He presented data suggesting that self-referral for advanced imaging studies increases the cost for an episode of care by an average of 4 to 12 percent. He also showed data indicating that same-day delivery of in-office ancillaries is uncommon, which is in contrast to the purported efficiency cited by proponents of physician-owned ancillary services.

Peter M. Knapp, M.D., FACS, a private practice urologist and President of Urology of Indiana, countered Dr. Hollenbeck as a proponent of what Dr. Knapp termed “integrated” urological services.

“Unfortunately, physician ownership of ancillary services implemented to provide efficient care to patients has been opposed by radiologists and other non-clinicians as part of a turf battle outlined in a 1999 editorial in Radiology,” Dr. Knapp said. “The authors encouraged the national radiology organizations to engage in local turf battles to help protect radiologists against encroachment by other physicians.”

Dr. Knapp said that physician-owned ancillary services benefit patients by enhancing the physician’s ability to provide patient access to quality care, efficient service, and cost-effective medicine. Without access to in-office ancillary services, patients with urologic symptoms are sent to outside laboratories and imaging centers before going to outside hospitals for therapeutic procedures, he said.

“In Dr. Hollenbeck’s world of fragmented care with no in-office ancillary services, urologists would be unable to provide patients in-office prostate ultrasound, bladder scans, urodynamics, and laboratory services including urinalysis, semen analysis, and PSA testing,” Dr. Knapp said.

He went on to quote Paul Lange, M.D., who warned in a 2008 Journal of Urology editorial that this “fragmented” approach would eventually relegate urologists to the role of a proceduralist, depriving patients access to experts in urologic disease who could provide integrated urologic care and disease management in urology centers of excellence.

“Patients are better served in a comprehensive, integrated urology practice which includes integrated urologic services,” Dr. Knapp said. “They are no longer ancillary, but integral to the evaluation and treatment of urology patients.”

Such integrated services include laboratory, advanced imaging, radiation oncology, infusion therapy, and ambulatory surgery provided by vertically integrated participating specialists who provide in-house multidisciplinary urologic care.

Dr. Knapp cited a study of follow-up imaging utilization that compared physician-owned versus non physician-owned radiology centers. The study demonstrated that the physician-owned group was less likely to order follow-up imaging and urologists were far less likely to order it.