At the 2014 American Urological Association (AUA) Annual Meeting, held in Orlando, Florida, from May 16 to 21, 2014, more than 2000 posters, abstracts, and videos were presented. The editors of Reviews in Urology have culled an enormous volume of information from this premier source and present those findings that are most relevant to the practicing urologist.

Prostate Cancer

A number of thought-provoking presentations on prostate cancer (PC) were made at this year’s annual meeting of the AUA, ranging from abstracts dealing with risk stratification for biochemical recurrence following radical prostatectomy, to exciting new reports of treatment options for men with metastatic castrate-resistant prostate cancer. Several of these are particularly worthy of mention.

Gandaglia and colleagues¹ challenged the status quo when they posited that men who undergo prostate biopsy and are found to have low-volume Gleason 3 + 4 = 7 PC—but who otherwise meet active surveillance (AS) criteria for low-risk ­disease—may actually have very little increased risk of adverse pathology at radical prostatectomy (RP) as compared with men who meet strict AS criteria. In a single-center study of patients undergoing RP between 2010 and 2013, 330 men were identified who could have been stratified to AS based on preoperative characteristics per the Prostate Cancer Research International Active Surveillance (PRIAS) protocol (prostate-­specific antigen [PSA] level ≤ 10 ng/mL; PSA density < 0.2 ng/mL/cc; biopsy Gleason score 6; positive biopsy cores ≤ 2; clinical stage ≤ T2) following extended template biopsy of at least 10 cores (median 14 cores). An additional 36 men were identified who met all PRIAS criteria except for having Gleason 3 + 4 = 7 disease. Adverse outcome criteria on final pathology following RP were defined as pathologic Gleason score 8 to 10, extracapsular extension, seminal vesicle invasion, and lymph node invasion. Among men who met all PRIAS criteria, these four adverse outcomes were met after RP in 6 (1.8%), 19 (5.7%), 5 (1.5%), and 4 (1.2%) men, respectively. Conversely, among men who met PRIAS AS criteria but who additionally had Gleason 3 + 4 = 7 disease preoperatively, post-RP adverse outcomes were recorded for 8 (2.2%), 22 (5.9%), 7 (1.9%), and 6 (1.6%) men, respectively. Biochemical recurrence-free survival rates among PRIAS and Gleason 3 + 4 = 7 cohorts were 96.1% and 95.7%, respectively (P = .9). Although based on only a sampling of 4 years of maximum follow-up and a relatively small sample size, these findings challenge the dogma that Gleason 3 + 4 = 7 disease is an absolute contraindication to AS.

Selkirk and coworkers² ask the interesting question of whether earlier PSA screening in men with known BRCA1 and BRCA2 mutations would detect disease at an earlier clinical stage. Although we know that BRCA1 and BRCA2 mutations lead to more aggressive pathology and decreased cancer-specific survival, it has not yet been shown whether BRCA mutation leads to detectable alterations in PSA kinetics. Theoretically, detection of abnormal PSA kinetics among genetically at-risk men might allow identification of clinically relevant disease at an earlier clinical stage. The investigators compared two groups of men in the multicenter Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial, those either with or without BRCA1 or -2 mutations, and sought to identify differences in PSA values, PSA age-specific medians, PSA velocity, and PSA doubling time. Eighty-seven BRCA carriers and 83 control subjects were enrolled, with a mean age of 53 years and average follow-up of 34.5 months. Overall, there was no difference in mean PSA velocity between the two groups (P = .996). Thirteen men (6 control subjects and 7 carriers) met criteria for prostate biopsy. Of six biopsies performed (two control subjects and four carriers), to date, four incidents of prostate cancer were diagnosed (zero control subjects, one BRCA1, and three BRCA2). Although these observations recapitulate the finding that BRCA1 and BRCA2 carriers are at an increased risk for PC, it seems that pre-RP PSA kinetics of BRCA carriers are not necessarily different from those of noncarriers. This argues against the utility of modified PSA screening protocols for known BRCA carriers.

Partin and colleagues³ presented work describing a role for epigenetic analysis of PC-negative prostate biopsy cores. Significant numbers of men with persistent pretest risk factors for PC are rebiopsied despite initial negative biopsy results. In this abstract, the authors argue that epigenetic testing provides a useful adjunct to traditional biopsy in that it can enhance the negative predictive value (NPV) of a negative biopsy. The DOCUMENT (Detection of Cancer Using Methylated Events in Negative Tissue) study evaluated 3687 histopathologically negative biopsy core samples from 350 men from five urologic centers, with all included men undergoing repeat biopsy within 24 months. All biopsies were reviewed by a single blinded, senior pathologist. Gene markers GSTP1, APC and RASSF1 were tested with a multiplexed methylation-specific PCR (MSP) assay. The epigenetic assay resulted in an NPV of 88% (95% confidence interval [CI], 85%-91%). Conversely, detection of cancer-associated DNA-methylation in the first biopsy was associated with an odds ratio for PC of 2.33 (95% CI, 1.27-4.01; P= .004) when controlled for in a multivariate model. These findings from a US population confirm similar results previously reported in a European population, namely that epigenetic analysis has a role in increasing the NPV of first biopsy and thereby reducing subsequent unnecessary biopsy.

Karnes and colleagues⁴ also reported on strategies designed to decrease the number of negative repeat biopsies by understanding differences in PSA kinetics between men with PC and those with benign disease. “Benign” patterns of PSA kinetics exist that identify men at low risk of harboring PC, thereby eliminating the need for multiple repeat biopsies that would add little information to that already gleaned from the PSA kinetics themselves. What sets this study apart from others is that PSA kinetics was analyzed following biopsy, after the pathologic result was already known. These authors analyzed a large dataset of 28,314 men, age 50 to 75 years (median 64 y), who had biopsies from 2001 to 2012 that did not find prostate cancer and had at least three PSA tests over at least 2 years prior to biopsy and at least one additional test within 1 to 13 months following the biopsy. Statistical modeling was used to characterize PSA kinetics both before and following biopsy. An assumption was made that post-biopsy PSA kinetics fit a benign pattern, then it would stand to reason that delaying that very same biopsy result would have had minimal impact on clinical course, as the biopsy result would have had a high likelihood of remaining negative at a subsequent point in time. Based on observation of postbiopsy PSA kinetics, up to 80% of the biopsies performed in the study could have been delayed without increasing the chance of identifying PC. In other words, simply waiting longer to obtain a biopsy, while tracking PSA kinetics at the same time to make sure they fit a benign profile, may allow us to significantly reduce the number of unnecessary biopsies in a subset of men.

Sundi and colleaguess from Baltimore reported preoperative predictors for men who will have early biochemical recurrence (BCR) from PC. The ability to predict early BCR is of clinical import, as men who are destined for BCR may benefit from early multimodal therapy. A single-institution database of over 20,000 men who underwent RP was used to identify 1471 men who had either early or late BCR, in which early BCR was defined as BCR within 1 year of RP. Given that those with National Comprehensive Cancer Network (NCCN) high-risk features are more likely to recur, a subset of 753 NCCN high-risk men were identified, and 41 alternate multivariable criteria were assessed among this subpopulation for their ability to predict early BCR. The authors found that the criteria that best identified those likely to experience early BCR are primary Gleason pattern 5 on biopsy or ≥ 4 cores containing pattern 4 (odds ratio 3.17; P < .001). These criteria included 26.7% of NCCN high-risk men. These same criteria were also associated with men who proved to be at elevated risk of subsequent metastasis and cancer-specific death. These findings could be useful in developing a rationale for early multimodal therapy for men at the highest risk of BCR following extirpative therapy.

Babcook and coworkers⁶ from Cleveland presented a novel way of inhibiting growth of castrate-resistant prostate cancer (CRPC). Overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR) and decreased AMP-activated protein kinase (AMPK) activity are known to promote survival in CRPC cells. Simvastatin (SIM), a potent HMG-CoAR inhibitor, and metformin (MET), an AMPK activator, are familiar pharmaceuticals with relatively benign side effect profiles, as opposed to docetaxel (Dtx), which, although a current mainstay of systemic therapy for CRPC, is associated with a host of consequential side effects. In this study, SIM and MET were used in combination on both CRPC cells in culture, and additionally on CRPC cells inoculated into mice, where mice were given oral dosing of 3.5 to 7.0 mg/g/d SIM or 175 to 350 mg/g/d MET alone or in combination, in comparison with 24 mg/g intraperitoneally-injected Dtx, for 9 weeks. In vitro, the combination of SIM and MET was found to cause G1-phase cell cycle arrest in CRPC cells. In vivo, CRPC cells inoculated into mice were antagonized by the combination of SIM and MET, leading to inhibition of tumor growth, progressive cachexia, and metastasis to bone. Although Dtx treatment in vivo had a similar therapeutic effect, it also caused significant side effects in mice, including death, whereas there was no apparent short-term toxicity in the SIM/MET group. Although studies in humans are needed, combination therapy with SIM and MET may prove a safe therapeutic avenue for a subset of men with CRPC.

Another recent addition to the armamentarium for CRPC is radium Ra 223 dichloride (Ra-223), or alpharadin, a potent α-particle emitter with a short 11.4 day half-life that was approved for use by the US Food and Drug Adminstration in 2013 for metastatic CRPC (mCRPC). The short half-life of Ra-223 yields benefits in terms of decreased myelotoxicity and nephrotoxicity as compared with the alternatives samarium-153 and strontium-89. Bienz and colleagues⁷ report the short-term pain evolution, side effects, and hematologic profile of patients with mCRPC undergoing Ra-223 treatment. Nineteen mCRPC patients underwent Ra-223 therapy, and 21.5% of the cohort reported improved pain relief at the first ­follow-up (median 27 days following Ra-223 injection). By the third follow-up (median 35 days following the third injection), 50% of the cohort reported pain relief. Diarrhea was noted in 31.6% of patients and bone pain flair response was observed in 26.3% of patients undergoing Ra-223 therapy, with a 21.3% mean platelet reduction observed by the third injection. From these early data the authors demonstrate a role for Ra-223 in the treatment of mCRPC bone pain, as up to 50% of patients have symptom relief after three treatments with manageable side effects. Whether further improvements in bone pain and an ­advantage in cancer-specific survival will be demonstrated remains to be seen in future studies, although these early results are ­certainly promising. 

[Adam J.M. Kern, MD,
Alan W. Partin, MD, PhD]

Dr Partin receives research funding from MDx Health.

Pediatric Urology

The AUA and the Society of Pediatric Urology held their second joint annual meeting this year in Orlando, Florida. Once again, the 1-day subspecialty meeting the day before the full AUA meeting expanded to 3 full days of pediatric urology education. Joint sessions offered a scientific program covering pediatric tumor, trauma, stones, hydronephrosis, the solitary kidney, hypospadias, varicocele, disorders of sexual differentiation, and dysfunctional voiding and neurogenic bladder reconstruction, as well as urinary tract infection (UTI) and vesicoureteral reflux (VUR). Panel discussions on a variety of subjects included management of ureteroceles and duplication anomalies, ethical and legal aspects of disorders of sexual development (DSD), and current management of pediatric bowel and bladder dysfunction. The focus of the AUA pediatric review is on plenary session presentations. 

John Duckett Memorial ­Lecture

Pediatric Pyelonephritis and Renal Scarring: Current Concepts on Pathogenesis and Reflections on the American Academy of Pediatrics and National Institute for Health and Care Excellence Guidelines.

Dr. Gil Rushton discussed the current concepts in pediatric pyelonephritis and renal scarring.⁸ He noted that host factors including anatomic malformations, intrinsic immune factors (both local and systemic), and bowel and bladder dysfunction must be weighed against bacterial virulence in determining the risk of recurrent pyelonephritis and subsequent renal scarring for any given patient. Host factors can be impacted upon, but there is no therapeutic intervention to alter one’s intrinsic immunity. Our detection methods diagnose VUR and acute pyelonephritis, as well as subsequent renal scarring. 

More recently, American Academy of Pediatrics has altered its recommendation for a voiding cystourethrogram (VCUG) following a first time febrile UTI in children under the age of 2 years. They now rely heavily on renal sonography. If the sonogram shows no abnormality, such as hydronephrosis, renal scarring, or findings suggestive of obstruction or high grade VUR, then no VCUG is indicated. A VCUG is recommended for recurrent febrile UTIs or atypical infections. Dr. Rushton noted that only 1% to 2% of patients with obstructive uropathy present with febrile UTI and that sonography is only half as sensitive as dimercaptosuccinic acid scanning (DMSA) for the detection of renal scarring.  

Most would agree that over-diagnosis has led to over-treatment in the past. This would imply that under-diagnosis may lead to under-treatment of clinically significant VUR. We have learned about risk factors for renal scarring from studies using serial DMSA scans. Those risk factors include recurrent pyelonephritis, delay in antibiotic treatment, severity of VUR and initial renal inflammatory response, and bowel and bladder dysfunction (BBD). 

Although studies using only DMSA scanning may be sufficient to predict VUR grade III through V and renal scarring, this approach is associated with higher costs and radiation exposure. 

Studies examining biomarkers as a proxy for DMSA scan abnormalities and clinically significant VUR show promise, especially procalcitonin.  Dr. Rushton noted that advances in technology may help to improve risk-stratification of patients in the future. 

AUA Clinical Guidelines: Cryptorchidism

Dr. Julia Barthold presented an overview of the new AUA Clinical Guidelines on cryptorchidism.⁹  The panel headed by Dr. Thomas Kolon made many recommendations, including those clarifying the use of sonography, timing of orchiopexy, and treatment options. 

After reviewing 704 articles, the panel developed statements presented in the guideline as Standards, Recommendations, or Options. The strength of the evidence was rated A (high), B (moderate), or C (low), and in the absence of sufficient evidence, the information was provided as clinical principles or expert opinion. (See https://www.auanet.org/education/guidelines/cryptorchidism.cfme for details.) The highlights of the presentation are reviewed.

Diagnosis

• It is important to note the gestational history and age of boys with undescended testis (UDT) at birth because a significant number of premature and/or low birth weight babies have UDT. 

• Genital examination with palpation of the testes at each visit is important because the testis will descend in up to 43% of boys with congenital cryptorchidism by age 3 months, and, in some, ascent of the testis will occur.

• Correcting for gestational age, referral to a pediatric urologist should be made at 6 months of age.

• Phenotypic male neonates require evaluation for possible DSD. This applies to boys with increasing severity of hypospadias and UDT.  In the former case, once congenital adrenal hyperplasia is ruled out, a Müllerian-inhibiting substance level should be obtained to evaluate for anorchia.

• Ultrasound and other imaging modalities are discouraged prior to referral of the patient to a specialist.

• Retractile testes should be monitored annually.

Treatment

• Hormone therapy is not recommended to induce testicular descent.

• Surgery is indicated in those between age 6 to 18 months.

• Palpable testes can be addressed via an inguinal or scrotal approach.

• Examination under anesthesia to reassess position is indicated prior to open or laparoscopic assessment.

• At the time of exploration, the testicular vessels need to be assessed to determine whether a transabdominal orchiopexy can be performed or whether the vessels need to be divided for a two-stage approach.

• In patients with a normal contralateral testis in which there are very short vessels and vas deferens, dysmorphic or very hypoplastic testis, or postpubertal age, orchiectomy should be considered.

Antimicrobial Prophylaxis for Children With Vesicoureteral VUR: Results of the RIVUR Study

Dr. Saul Greenfield reported on the recently published study on Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux: Results of the RIVUR Study.¹⁰ Over the past decade, the use of antibiotic prophylaxis in children with VUR has been controversial. Previous randomized studies have lacked a placebo or observational group, thus leaving the question of surgery versus prophylaxis unanswered. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial was a 2-year multisite, randomized, placebo-controlled study involving 607 children with VUR (grade I-IV) diagnosed after one or two febrile or symptomatic UTIs. The investigators evaluated the efficacy of antibiotic prophylaxis (trimethoprim-sulfamethoxazole) in preventing recurrent infections and renal scarring. DMSA scanning was performed at baseline and after 1 and 2 years. Catheterization or suprapubic aspiration was used to collect specimen in non–toilet-trained children. The development of antibiotic resistance was also evaluated. 

Most of the participants were girls (91%), and the median age was 1 year. The majority (80%) had grade II or III VUR, and 8.3% had grade IV. Almost half of the group had bilateral VUR. Interestingly, 53% of those toilet-trained children had BBD.

Compliance with medication administration was generally good, with about 75% reporting giving the medication about 75% of the time. Recurrent UTI occurred in 111 of 607 children (117 recurrences), with 72% being febrile. Importantly, the risk of a febrile or symptomatic infection was decreased by 50% in those children on prophylaxis (39/302) versus those on placebo (72/305). This reduction in infections was most effective in those whose first time infection was febrile (60%) and those with BBD (80%). Of the 87 of 111 with a first time recurrence with Escherichia coli, isolates were more resistant to trimethoprim-­sulfamethoxazole, prophylaxis (63%) versus placebo (19%).

No significant difference was found between the two treatment groups in the occurrence of renal scars whether severe or new scars since baseline. 

This is an excellent study supporting the use of antimicrobial prophylaxis for children with VUR, especially those who presented with a febrile UTI and those with BBD. 

[Ellen Shapiro, MD, FACS, FAAP]

References

1. Gandaglia G, Suardi N, Abdollah F, et al. Can we consider patients with limited biopsy Gleason score 314 eligible for active surveillance? Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. Abstract MP69-01.
2. Selkirk C, Hatcher D, Powers J, et al. PSA values and kinetics of BRCA1 and BRCA2 mutation carriers at high risk for prostate cancer. Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. Abstract MP69-05.
3. Partin A, Klein E, Marks L, et al. Multicenter validation study of a tissue methylation assay to predict histopathologically cancer-negative repeat prostate biopsies. Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. Abstract MP63-14.
4. Karnes R, Rawson L, MacKintosh, R, et al. Delay in a biopsy to allow for additional PSA testing often can eliminate the need for the biopsy. Presented at: 2014 American Urological Association Annual ­Meeting; May 16-21, 2014; Orlando, FL. Abstract MP63-03.
5. Sundi D, Wang V, Pierorazio P, et al. Selection criteria for early biochemical recurrence in a high-risk radical prostatectomy cohort. Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. Abstract MP46-06.
6. Babcook M, Shukla S, Sramkoski M, et al. Simvastatin and ­metformin: a deadly combination for metastatic ­castration-resistant prostate cancer. Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. Abstract PD27-06.
7. Bienz M, Alom M, Mouravieva V, et al. Early experience of radium-223 treatment for metastatic castrate resistant prostate cancer: a preliminary report. ­Presented at: 2014 American Urological Association Annual Meeting; May 16-21, 2014; Orlando, FL. ­Abstract MP70-01.
8. Rushton G Jr. John Duckett Memorial Lecture: Pediatric pyelonephritis and renal Scarring: current concepts on pathogenesis and reflections on the AAP and NICE guidelines H. Presented at: Focus on Pediatrics Plenary session; 2014 American ­Urological Association Annual Meeting; May 18, 2014; ­Orlando, FL. 
9. Barthold J. AUA Clinical Guidelines: Cryptorchidism. Presented at: 2014 American Urological Association Annual Meeting; May 19, 2014; Orlando, FL. 
10. The RIVUR Trial Investigators. Antimicrobial prophylaxis for children with vesicoureteral VUR. N Engl J Med.2014;370:2367-2376. 

Reviewed by Adam J.M. Kern, MD and Alan W. Partin, MD, PhD, The Johns Hopkins Medical Institutions, Baltimore, MD; Ellen Shapiro, MD, FACS, FAAP, New York University School of Medicine, New York, NY