Molecular Markers for Renal Cell Carcinoma

Nonprostate Urologic Oncology

REVIEWING THE LITERATURE News and Views From the Literature Prostatitis Diagnosis of Interstitial Cystitis: Another Look J. Curtis Nickel, MD, FRCSC Queen’s University, Kingston, Ontario [Rev Urol. 2000;2(2):167] F or the last decade of the 20th century, the diagnosis of interstitial cystitis was based on consensus criteria developed at the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) Interstitial Cystitis Workshop, held in 1987.1 These criteria were designed to identify a homogenous subgroup of patients for research purposes so that epidemiologic, diagnostic, and treatment protocols could be evaluated comparatively. These criteria became a de facto definition and served for many clinical urologists as the basis for the clinical diagnosis of interstitial cystitis. Despite widespread use of the NIDDK criteria, however, many clinicians and researchers in the field felt that their strict application would miss many patients who could benefit from a diagnosis of interstitial cystitis. An important paper published by the Interstitial Cystitis Database (ICDB) study group in early 1999 was an attempt to remedy that problem and may have been overlooked by urologists. The study and its conclusion have far-reaching implications for the diagnosis of interstitial cystitis as we start the first decade of a new century. The Diagnosis of Interstitial Cystitis Revisited: Lessons Learned From the National Institutes of Health Interstitial Cystitis Database Study Hanno PM, Landis JR, Mathews-Cook Y, et al. J Urol. 1999;161:553-557. teria, since the intention of the ICDB study was to follow the progression of the disease in all subtypes of the syndrome. The ICDB study included all interstitial cystitis–like cases. To have a diagnosis of interstitial cystitis following the traditional NIDDK diagnostic criteria, patients must have either glomerulations on cystoscopic examination or a classic Hunner ulcer. They must also have either pain associated with the bladder or urinary urgency. The NIDDK diagnosis of interstitial cystitis also includes multiple exclusion criteria.1 The most striking difference between the ICDB eligibility criteria and the NIDDK criteria is that cystoscopy was optional for entry in the ICDB study. The 2 objectives of the study were to determine whether the NIDDK criteria for interstitial cystitis were still useful as a research definition and as a clinical diagnostic definition. Of the 379 patients, 118 met all possible NIDDK criteria. Almost 90% of these 118 patients were classified by ICDB study physicians as definitely/very likely to have interstitial cystitis. Of the total group of 379 patients, 71% were described as definitely/very likely to have interstitial cystitis. The research value of the NIDDK criteria was confirmed for defining a population suitable for research and study. Strict application of NIDDK criteria, however, would miss approximately two thirds of patients whom experienced clinicians regard as definitely/very likely to have interstitial cystitis. The NIDDK criteria may not be suitable as a definition of the clinical syndrome of interstitial cystitis. Interstitial cystitis remains a clinical syndrome regardless of how we attempt to define it or subsequently devise confirming diagnostic tests. Patients with significant, bothersome urinary frequency and pain of long duration that is found to be unrelated to all known causes should be considered as having interstitial cystitis. As we learn more about this clinical entity and as specific etiologies are discovered, the frequency of this generalized diagnosis of interstitial cystitis may actually diminish. Reference 1. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Md, August 28-29, 1987. J Urol. 1988; 140:203-206. The ICDB study sponsored by the NIH and NIDDK is a large, multicenter, observational study designed to determine the treated history of interstitial cystitis and to identify common patient characteristics. The entry requirements for the ICDB study were considerably less stringent than the NIDDK cri- continued SUMMER 2000 REVIEWS IN UROLOGY 167 Reviewing the Literature continued Benign Prostatic Hyperplasia Improving the Safety of TURP Claus G. Roehrborn, MD, FACS The University of Texas Southwestern Medical Center, Dallas [Rev Urol. 2000;2(2):168-171] I n the late 1980s, higher long-term mortality rates were reported for transurethral resection of the prostate (TURP) than for suprapubic or retropubic open prostatectomy (OPEN). The overall relative risk (RR) calculated for 4 large-scale studies was 1.26 (95% confidence interval 0.99-1.59) for TURP versus OPEN, according to the Agency for Health Care Policy and Research (AHCPR) guidelines on benign prostatic hyperplasia (BPH), published in 19941 (Table 1). An analysis of the causes of death showed that the excess mortality following TURP was caused mainly by cardiovascular problems, especially acute myocardial infarction. Explanations offered to account for the differences in delayed mortality rates include differences in patient comorbidities and selection biases. If higher rates of delayed mortality are seen with TURP, then one might expect more significant changes in cardiac function during the performance of a TURP, compared with an open prostatectomy. This issue has been addressed in the literature since the publication of the AHCPR guidelines. An additional study assessing hemodynamic changes during OPEN and TURP has recently been published. Haemodynamic Changes Detected During Open Prostatectomy and Transurethral Resection for Benign Prostatic Hyperplasia D’Addessi A, Perilli V, Ranieri R, et al. Scand J Urol Nephrol. 1999;33:176-180. This paper examines hemodynamic changes in 60 patients who underwent prostatectomy by either the TURP (n = 18) or OPEN (n = 42) procedure. On average, patients were 65 to 67 years old, and the procedure lasted 65 minutes for TURP and 60 minutes for OPEN. The TURP patients received 1660 mL of intravenous fluids versus 2500 mL in the OPEN group. Two patients in the OPEN group received a transfusion; no patients in the TURP group did. On average, 13 ±4 L of irrigation fluid was used for patients in the TURP group. TURP was performed as a low-pressure procedure with 168 REVIEWS IN UROLOGY SUMMER 2000 suprapubic aspiration, and the irrigating fluid was kept at 50 cm above the bladder (0.54% mannitol and 2.7% sorbitol). The room temperature and the irrigation fluid were kept at 21°C. All patients received general anesthesia from the same team of anesthesiologists, and there were no significant differences in the anesthetic practices between the 2 groups. Hemodynamic parameters were assessed: • Before induction of anesthesia. • After tracheal/endotracheal intubation. • During the surgical procedure (during the incision of the bladder neck for OPEN and 10 minutes after the beginning of the resection for TURP). • After the closure of the bladder for OPEN and before the placement of the catheter for TURP. • 1 hour after recovery from anesthesia. Both groups experienced a decrease in body temperature, which peaked at measurement point 5 (0.47°C and 0.54°C for TURP and OPEN, respectively). In both groups, investigators noted a decrease in cardiac output. However, there were no differences between the 2 groups. Cardiac output decreased from 3.30 to a minimum of 2.28 at time points 4 and 5, respectively, for patients in the TURP group, while in the OPEN group, it decreased from 3.19 to a low of 2.07 at time point 4. Systemic vascular resistance increased in both groups without any significant differences between them. The decrease in cardiac output was 32% and 36% for TURP and OPEN, and the increase in systemic vascular resistance was 28% and 31% for TURP and OPEN, respectively. These results are remarkably similar to those of other studies in the literature.6 This study fails to show any significant hemodynamic differences between patients treated by TURP or OPEN using the same anesthetic techniques, the same group of anesthesiologists, and the same urologic surgeon in a contemporary series. Thus, it is hard to prove that delayed mortality rates might differ on the basis of perioperative and early postoperative hemodynamic changes. Double-Blind Randomized Study of Symptoms Associated With Absorption of Glycine 1.5% or Mannitol 3% During Transurethral Resection of the Prostate Hahn RG, Sandfeldt L, Nyman CR. J Urol. 1998;160:397-401. An important issue in the safety of TURP procedures is the type of irrigation fluid used. Before isotonic solutions were available, water was used as an irrigant; however, this was associated with significant morbidity because of water intoxication and intravascular hemolysis. Currently, the most commonly used fluids for irrigation are glycine 1.5% and the isomer hexols, or the 6-carbon alcohols mannitol and Reviewing the Literature Table 1 Relative Risks of Mortality, TURP versus OPEN, in 4 Studies Reference Source and Adjustments RR 95% CI Concato, 19922 Yale-New Haven Hospital, Conn; chart-review data; adjustments: comorbidity (Kaplan-Feinstein), age 0.91 0.47 - 1.76 Andersen, 19903 Male Danish population; database data; adjustments: comorbidity, age 1.19 1.15 - 1.24 Roos, 19894 Subset from University Hospital, Winnipeg, Canada; database data; adjustments: comorbidity 1.45 1.15 - 1.83 Malenka, 19905 Subset from Health Science Center, Winnipeg, Canada; chart-review data; adjustments: comorbidity (Charlson), age 1.48 1.09 - 2.01 Combined analysis Hierarchical Bayes 1.26 0.99 - 1.59 TURP, transurethral radical prostatectomy; OPEN, suprapubic or retropubic open prostatectomy; RR, relative risk; CI, confidence interval. sorbitol, which both act as osmotic diuretics, in slightly varying concentrations. Solutions approximating 3% of either of the 6-carbon alcohols are most often used. Given the many years of experience with both solutions, it is surprising that until recently, no randomized trials tested the superiority of one over the other. Dr Hahn and associates performed a double-blind, randomized study of the symptoms associated with absorption of either glycine 1.5% or mannitol 3% during standard TURP in patients from a single hospital who received spinal anesthesia. The irrigating fluid bags contained 1 of the 2 solutions; both included ethanol 1%, which was used as a marker for fluid absorption. Absorption was quantified by analyzing the concentration of ethanol in the expired air every 10 minutes throughout the operation. Twice as many symptoms were noted after the procedure as during the procedure; the most common were bradycardia, acute arterial hypotension, and nausea. The incidence rates of these complications increased dramatically with increased volumes of absorbed fluid (Table 2). Although there was no difference between groups with respect to circulatory symptoms, neurologic symptoms were more common in the group receiving glycine 1.5%. The majority of the differences between the symptoms of each group was due to a higher incidence of nausea during postoperative convalescence. It is noteworthy that the incidence of neurologic symptoms/nausea was not affected by increasing amounts of absorbed irrigant from 500 to 1000 mL to more than 1500 mL using mannitol 3%, while the same symptoms increased significantly with the use of glycine 1.5%. The neurologic symptoms associated with glycine absorption are either the result of cerebral edema or complications related to its metabolism. Cerebral edema results from a decrease in serum sodium concentration caused by dilution and by urinary loss of sodium ions associated with osmotic diuresis. However, not all the differences in symptoms produced by glycine versus mannitol can be explained by hyponatremia alone. Direct toxicity and metabolism of glycine can account for some symptoms. Glycine is, in part, converted in the liver to glyoxalate, and oxalate is then excreted in the urine. Glycine is also deaminated to release ammonia, which is detectable in 46% of patients undergoing TURP in which glycine is used as an irrigant. The rates of metabolism of glycine by these 2 routes are dose-dependent, and the deamination route resulting in ammonia production predominates at higher levels. Blood Ammonia Levels After Intravenous Infusion of Glycine Solution With and Without Ethanol Hahn RG, Sandfeldt L. Scand J Urol Nephrol. 1999;33:222-227. In a group of 20 healthy male volunteers aged 21 to 44 with a mean body weight of 83 kg, Dr Hahn and associates (who have contributed greatly to our understanding of the morbidity of TURP as it pertains to absorption of irrigation flu- SUMMER 2000 REVIEWS IN UROLOGY 169 Reviewing the Literature continued Table 2 Perioperative Symptoms in TURP Patients Receiving Intraoperative Glycine 1.5% or Mannitol 3% Intraoperative Symptom* Postoperative Incidence (%) Mean severity Incidence (%) Mean severity Bradycardia 8 1.0 17 1.5 Hypotension 21 1.3 25 1.8 Circulatory Neurologic Blurred vision 2 2.0 4 1.5 Nausea 10 1.4 37 1.5 Vomiting — — 12 1.6 Uneasiness 8 1.0 6 1.0 Confusion 4 1.5 6 1.3 Tiredness 6 1.3 2 1.0 TURP, transurethral radical prostatectomy. *Symptoms that occured in more than 1 patient are listed. Symptoms not on the checklist include prickling sensations of the skin (10%), chills during surgery (6%), and postoperative abdominal pain (6%). id, particularly to the toxicity of glycine) recently studied blood ammonia levels after intravenous infusion of glycine 1.5% solution with and without additional ethanol. The rationale for these experiments was the documented elevation of blood ammonia levels caused by the metabolism of glycine and the aggravation of mental symptoms associated with absorption of the fluid. The researchers were prompted to perform these experiments in volunteers because no marked hyperammonemia was found in a series of TURP patients in whom ethanol was used to indicate absorption of the glycine solution into the bloodstream (by measuring ethanol in the exhaled air). Since the metabolism of ethanol has profound effects on intermediate metabolism, it may retard the rate of formation of ammonia in the liver, thus resulting in low blood ammonia levels. In the 40 intravenous infusion experiments done, 10 volunteers received a slow infusion of 1000 mL of glycine 2.2% over 50 minutes with and without ethanol 1%. The other 10 volunteers received a rapid infusion of 15 mL/kg of glycine 1.5% with and without ethanol 1% infused over 30 minutes. Each volunteer served as his own control, being first infused with ethanol, then without, or vice versa. There was a significant increase in blood ammonia levels noted when either glycine or glycine-ethanol was given in either protocol. The overall blood ammonia levels were higher 30 minutes after the infusion than before the start of the infusion, but there was no statistically significant difference in the increase in ammonia based on whether ethanol had been added to the irrigation fluid. However, slow infusion increased 170 REVIEWS IN UROLOGY SUMMER 2000 the level more than fast infusion did. There were no changes noted in heart rate or mean arterial pressure. Thus, this study shows no evidence that ethanol reduces blood ammonia levels after infusion of glycine. Ethanol is metabolized by a capacity-limited process that occurs at the maximum rate when about 500 mL of glycine 1.5% plus ethanol 1% is absorbed. Alcohol reduces the rate of gluconeogenesis in the liver, where metabolism of most amino acids also takes place. Moreover, it promotes hypoglycemia in fasting subjects, although blood glucose levels are usually stable in patients who absorb glycine-ethanol solutions during TURP. The suggested mechanisms by which ethanol might interfere with glycine metabolism are speculative but may involve reduced availability of nicotinamide-adenine dinucleotide for the glycine cleavage system, which is the main pathway for degradation of glycine in mammals. This could also slow down the amount of ammonia produced during conversion of serine to pyruvate. The interindividual variation in the blood ammonia response was large: 70% of the volunteers showed a slight increase in blood ammonia levels with no resemblance to symptoms of the TURP syndrome; 15% showed no change; and 15%, a marked increase. The wide distribution of responses could explain why marked hyperammonemia is responsible for only a minority of the symptoms of the TURP syndrome. These studies may lead the reviewer to the cautious conclusion that, indeed, use of 6-carbon alcohols such as mannitol and/or sorbitol is safer than use of glycine 1.5% solution when performing TURP. While circulatory and he- Reviewing the Literature modynamic changes do occur (the first reviewed study indicates that these changes also occur after OPEN), mental and neurologic changes and nausea are considerably reduced, particularly in patients with large prostates who absorb significant amounts of fluid. The addition of ethanol, which theoretically might lower the toxicity of glycine (as discussed by Hahn and Sandfeldt), did not do so. In fact, the increase in the ammonia level observed with glycine infusion is quite unpredictable and subject to significant interindividual variability. These studies suggest that hemodynamic changes cannot be the sole explanatory variable for increased delayed mortality because of cardiovascular problems—specifically, acute myocardial infarction. However, physicians concerned about the immediate intraoperative and perioperative well-being of their patients might choose mannitol- or sorbitol-based irrigation fluid, especially if the prostate is of such size that irrigation with considerable amounts of fluid might be predicted. References 1. Clinical Practice Guideline Number 8: Benign Prostatic Hyperplasia: Diagnosis and Treatment. Rockville, Md: US Department of Health and Human Services, Agency for Health Care Policy and Research; 1994. AHCPR publication 94-0582. 2. Concato J, Horwitz RI, Feinstein AR, et al. Problems of comorbidity in mortality after prostatectomy. JAMA. 1992;267:1077-1082. 3. Andersen TF, Bronnum-Hansen H, Sejr T, Roepstorff C. Elevated mortality following transurethral resection of the prostate for benign hypertrophy! But why? Med Care. 1990;28:870-879. 4. Roos NP, Wennberg JE, Malenka DJ, et al. Mortality and reoperation after open and transurethral resection of the prostate for benign prostatic hyperplasia. N Engl J Med. 1989;320:1120-1124. 5. Malenka DJ, Roos N, Fisher ES, et al. Further study of the increased mortality following transurethral prostatectomy: a chart-based analysis. J Urol. 1990;144: 224-228. 6. Evans JW, Singer M, Chapple CR, et al. Haemodynamic evidence for cardiac stress during transurethral prostatectomy. BMJ. 1992;304:666-672. Nonprostate Urologic Oncology Molecular Markers for Renal Cell Carcinoma Allan J. Pantuck, MD, Amnon Zisman, MD, Arie S. Belldegrun, MD, FACS University of California, Los Angeles, School of Medicine [Rev Urol. 2000;2(2):171-172] F or renal cell carcinoma (RCC), the TNM (tumor, node, metastasis) staging system and histopathologic grade provide the most time-tested and useful prognostic information. Other factors that may confer independent prog- nostic information are under active investigation, however, and are generating great interest. These investigational prognostic features range from evaluation of patient-related factors, such as performance status, to measures of overall DNA content, such as flow cytometry, to the evaluation of molecular markers (such as P53 and bcl-2) using immunohistochemistry. Although several of these candidate modalities have been shown to provide prognostic information, multivariate analysis (controlling for stage and grade) reveals that most do not supply independent information. Recently, as the genetics of RCC have become better understood, microsatellite analysis has become an exciting new technique under investigation. This technology permits detection of cancer-specific DNA alterations, including additions, deletions, and loss of heterozygosity. Diagnosis of Renal Cancer by Molecular Urinalysis Eisenberger CR, Schoenberg M, Enger C, et al. J Natl Cancer Inst. 1999;91(23):2028-2032. Eisenberger and colleagues at The Johns Hopkins University School of Medicine investigated the value of using technology based on polymerase chain reaction as a noninvasive method for the detection of RCC. The investigators collected samples of peripheral blood and urine before surgical intervention in 30 patients with renal lesions. Control samples were taken from 8 patients presenting with hematuria caused by nephrolithiasis and 8 patients without a history of genitourinary disease. Based on known patterns of DNA alterations in RCC, 28 microsatellite markers were chosen for exploration. DNA from tumor samples, urine, peripheral lymphocytes, and serum was processed, labeled with radioactive primers, and then separated in a polyacrylamide gel. The 28 markers were then used to compare nonmalignant (lymphocyte) DNA with the same areas from the samples (tumor, urine, or serum). Of the 30 patients with renal lesions, 25 had malignant tumors, whereas 5 had benign (oncocytoma, angiomyolipoma) tumors. Nineteen (76%) of the 25 patients with malignant tumors were found to have at least 1 microsatellite alteration in urinary DNA, and 15 (60%) had at least 1 alteration in serum DNA. In all cases, tumor DNA was found to exhibit the identical genetic alteration. Of the 5 patients with benign tumors, 60% displayed DNA alterations in urine, but not in serum, that also matched the changes in tumor DNA. None of the healthy subjects and none of the patients with stones displayed microsatellite alterations in either urine or blood. Thus, the sensitivity and specificity of microsatellite alterations in patients’ urine used to diagnose a renal mass were 73% and 100%, respectively. The authors did not note an association between microsatellite instability and tumor stage, and they did not at- SUMMER 2000 REVIEWS IN UROLOGY 171 Reviewing the Literature continued tempt to correlate DNA findings to survival or prognosis. The potential applications of this noninvasive molecular diagnosis by urinalysis are intriguing. It could be used to screen patients presenting with hematuria to differentiate tumoral from other etiologies. The pattern of DNA alterations in urine, but not in serum, that was found in benign renal masses could serve as a basis to help differentiate malignant from benign tumors and identify patients, particularly those who are elderly or with serious comorbidities, who might benefit from a watchful waiting approach. Further studies using different DNA microsatellite markers may reveal additional alterations with greater diagnostic or prognostic value. The interesting results presented certainly justify larger, prospective studies to determine the clinical utility of this molecular approach. Pediatric Urology Cryptorchidism and Overactive Bladder Ellen Shapiro, MD, FACS, FAAP New York University School of Medicine, New York [Rev Urol. 2000;2(3):172-174] I nvestigators from Children’s Hospital of Philadelphia try to determine whether testicular biopsy can be avoided during orchiopexy if one can predict germ cell count by measuring testicular volume. Pediatric urologists from Boston Children’s Hospital report the long-term results of conservative therapy for children with overactive bladder. Testicular Volume Does Not Predict Germ Cell Count in Patients with Cryptorchidism Noh PH, Cooper CS, Snyder HM III, et al. J Urol. 2000;163:593-596. A total germ cell count of less than 0.2 germ cells per tubule in the biopsies of prepubertal boys with undescended testes (UDT) is highly predictive of infertility in adulthood.1,2 Some investigators have treated this subset of boys with postorchiopexy intranasal gonadotropins, and an improvement has been shown in their spermiograms.3,4 Since the volume of the UDT is usually less than that of the contralateral gonad, and since decreased volume has correlated with impaired spermatogenesis later in adulthood, researchers at Children’s Hospital of Philadelphia examined whether testicular volume can predict germ cell count so 172 REVIEWS IN UROLOGY SUMMER 2000 as to obviate the need for testicular biopsy at the time of orchiopexy. Noh and colleagues reported their 10-year experience with 723 patients younger than 9 years with UDT (unilateral in 619, bilateral in 104). Their patients had no inguinal surgery or preoperative hormonal therapy. At the time of orchiopexy, testicular volume was determined using a formula to measure the volume of an ellipsoid, and bilateral testicular biopsies were performed. These authors showed that testicular volume has a weak but direct correlation with the number of germ cells per tubule. This correlation was found not to be clinically useful, because there was too wide a range of germ cells per tubule associated with a specific testicular volume at any given age studied. Therefore, using testis volume alone, one cannot distinguish those testes with less or more than 0.2 germ cells per tubule. Intraoperative testicular biopsies are required to determine germ cell numbers if one is going to proceed with postoperative hormonal therapy in patients at greatest risk for infertility. Testis biopsy at the time of orchiopexy is not universally performed, nor would it be universally accepted by all parents, since the undescended testis is already diminished in size. It has been shown that there is poor correlation between sonographic measurements and measurements using the Prader and Takihara punched-ring orchidometers.5 The authors present no data demonstrating that the intraoperative measurements are reproducible or that their interobserver variability is negligible. If there is some method to standardize the measurements, this may reduce the variability found in germ cell numbers per tubule at each age, thereby making testicular volume a more reliable predictor of germ cell number. In one study, measurements obtained with the Seager orchidometer correlated best with sonographic measurements.5 Finally, studies of testicular volume in adults with infertility have shown that mean testicular volume correlates with follicle-stimulating hormone and luteinizing hormone levels, total sperm count, and sperm concentration.6,7 It is unclear why testicular volume does not correlate with germ cell volume in prepuberty. It is possible that the correlation exists between volume and testicular function in the adult because the adult testis is larger and more accurately measured. Preoperative sonography may improve the margin of error when measuring prepubertal testes. References 1. Hadziselimovic F, Hecker E, Herzog B. The value of testicular biopsy in cryptorchidism. Urol Res. 1984;12:171-174. 2. Cortes D, Thorup JM, Lindenberg S. Fertility potential after unilateral orchiopexy: an age independent risk of subsequent infertility when biopsies at surgery lack germ cells. J Urol. 1996;156:217-220. 3. Bica DTG, Hadziselimovic F. Buserelin treatment of cryptorchidism: a randomized, double-blind, placebo-controlled study. J Urol. 1992;148:617-621. 4. Hadziselimovic F, Herzog B. Treatment with a luteinizing hormone-releasing hormone analogue after successful orchiopexy markedly improves the chance of fertility later in life. J Urol. 1997;158:1193-1195. 5. al Salim A, Murchison PJ, Rana A, et al. Evaluation of testicular volume by three Reviewing the Literature orchidometers compared with ultrasonographic measurements. Br J Urol. 1995; 76:632-635. 6. Takihara H, Costentino MJ, Sakatoku J, Cockett ATK. Significance of testicular size measurement in andrology. II. Correlation of testicular size with testicular function. J Urol. 1987;137:416-419. 7. Bujan L, Mieusset R, Mansat A, et al. Testicular size in infertile men: relationship to semen characteristics and hormonal blood levels. Br J Urol. 1989;64:632-637. The Overactive Bladder in Childhood: Long-Term Results With Conservative Management Curran MJ, Kaefer M, Peters C, et al. J Urol. 2000;163:574-577. Curran and coworkers reviewed the current diagnostic and treatment strategies for the overactive bladder in childhood. This report from Boston Children’s Hospital is based on 30 children who have undergone formal urodynamics testing for refractory enuresis associated with diurnal incontinence, frequency, or urgency. All children had not responded to timed voiding and had no improvement with decreased fluid intake and nighttime wakening. Anticholinergic therapy had failed in 13. Urinalysis and cultures were negative within the 2 years before the study. No child in this group had a neurologic problem or urinary tract anomaly. All children had at least 12 months of follow-up. A urodynamics study with electromyographic evaluation demonstrated uninhibited detrusor contractions (UDCs) in all cases. Anticholinergic or antispasmodic therapy was then started. If only partial success was achieved, a second anticholinergic drug, desmopressin, or imipramine was added. Biofeedback was also started in those children with a small bladder capacity and poor external sphincter activity in response to a UDC. Normal bladder capacity in ounces was estimated as one half of patient age in years +6.1 The patients received oxybutynin chloride (18), hyoscyamine (3), imipramine (1), or glycopyrrolate (1). Another 7 (23%) required combination therapy. Only 1 child received desmopressin in addition to an anticholinergic medication. Mean patient age at presentation was 10.9 years, while average age at symptom resolution was 14.3 years. Most patients (21) had complete resolution of symptoms, while 5 had partial resolution, defined as 5 days or more between incontinent episodes and/or a 50% decrease in daytime symptoms. Eight of 21 patients (38%) required the medication throughout the follow-up period, 3 of whom had undergone biofeedback therapy. There was a trend to suggest that girls were more likely to improve than boys and that half or greater of estimated bladder capacity was associated with a favorable outcome. These authors suggest that medical management is indicated in children with idiopathic detrusor activity. The overactive bladder of childhood can be successfully managed with medical therapies in the majority of children, with resolution of symptoms, using only conservative measures. Patients whose symptoms are refractory to medical ther- apy should undergo urodynamics testing. Formal testing is also suggested in: • Children older than 10 years with enuresis. • Children older than 6 years with day and nighttime enuresis who fail a trial of anticholinergic medication. • Children older than 5 years with enuresis and encopresis. The authors also recommend MRI evaluation when a child’s condition is refractory to all treatment strategies or there are significant radiographic changes or urodynamic evidence of detrusor-sphincter dyssynergia. This article was accompanied by an editorial from Saul Greenfield, MD,2 who suggested that since the study’s data show that more than 25% of patients require 2-drug therapy, a second drug should be instituted before urodynamics testing. Dr. Greenfield also noted that 38% of those who improved required continuous therapy, while the remainder of the children had symptom resolution. He commented that because there was no control group, the rate of spontaneous resolution cannot be determined. The authors recommend only a voiding cystourethrogram; however, I perform a renal sonogram to assure that there are no upper tract changes. Before starting an anticholinergic agent, there cannot be any degree of constipation, since this will only worsen with therapy. Even when use of oxybutynin chloride has not resulted in immediate continence, I do not discontinue the drug immediately. I prefer to evaluate the child with urodynamics studies while he or she receives oxybutynin chloride to determine the level of bladder instability on a single agent. Also, when using imipramine during the day, I obtain a pre- and 1 week post-treatment electrocardiogram to assure that the corrected QT interval is 0.44 seconds or less to avoid syncopal episodes. Although there is no published experience on the use of tolterodine in neurologically normal children, its efficacy and tolerability have recently been studied in children with meningomyelocele.3 Although this study included only 22 children, the data suggest that in 10 of the children previously receiving oxybutynin chloride, urodynamic parameters (bladder volume, detrusor hyperreflexia, and compliance) were similar to those observed while they received oxybutynin chloride. In patients who had no previous medication, no change in leak point pressure was observed on tolterodine. In the 6 patients who had adverse side effects with oxybutynin chloride, none experienced an adverse effect on tolterodine. One patient who had no adverse effects with intravesical oxybutynin chloride had facial flushing with the first dose of tolterodine. This resolved by dividing the dosage into 3 doses per day rather than 2. It is of interest that many of the children with idiopathic overactive bladder showed resolution of symptoms at about the time of puberty and that there was a trend to suggest that girls were more likely to improve than boys. Although cause and effect cannot be proved in this small subset, one SUMMER 2000 REVIEWS IN UROLOGY 173 Reviewing the Literature continued must keep in mind the effects of hormones on the muscarinic cholinergic receptor (MChR) density of the bladder. We have shown that estrogen administration down-regulated the MChR density of the rabbit bladder.4 This may lend some insight as to why girls’ symptoms improve with the onset of puberty. References 1. Kaefer M, Zurakowski D, Bauer SB. Estimating normal bladder capacity in children. J Urol. 1997;158:2261-2264. 2. Greenfied SP. The overactive bladder in childhood [editorial]. J Urol. 2000;163: 578-579. 3. Goessl C, Sauter T, Michael T, et al. Efficacy and tolerability of tolterodine in children with detrusor hyperreflexia. Urology. 2000;55:414-418. 4. Shapiro E. Effect of estrogens on the weight and muscarinic cholinergic receptor density of the rabbit bladder and urethra. J Urol. 1986;135:1084-1087. Incontinence Stress Urinary Incontinence Michael B. Chancellor, MD University of Pittsburgh School of Medicine [Rev Urol. 2000;2(3):174-177] W hy does the incidence of stress urinary incontinence rise dramatically with age? Why do some men, especially older men, have significant stress urinary incontinence after an uncomplicated radical prostatectomy when everything seemingly has gone right and the sphincter was apparently preserved? Strasser and colleagues propose a provocative hypothesis: sphincter muscle undergoes apoptosis with aging. This unique theory should open up new avenues of research toward better management and even prevention of stress incontinence. The second article, by McDougall and associates, is the best study thus far that attempts to determine if laparoscopic bladder suspension is as good as or better than transvaginal suspension. Urinary Incontinence in the Elderly and Age-Dependent Apoptosis of Rhabdosphincter Cells Strasser H, Tiefenthaler M, Steinlechner M, et al. Lancet. 1999;354:918-919. This was an autopsy study that demonstrated a progressive linear decrease in density of striated muscle fibers of the rhabdosphincter occurring with age in both men and women. The 174 REVIEWS IN UROLOGY SUMMER 2000 authors hypothesize that apoptic cell death may be playing a major role in urinary incontinence in the elderly. Strasser and coworkers evaluated the urinary sphincters of 23 clinically healthy cadavers (16 male, 7 female). Cadavers were chosen randomly, with consideration given only to age (5 weeks to 92 years). Histologic sections were taken from 3 different levels of the rhabdosphincter and of the urethra. An in situ cell death detection kit was employed to detect apoptosis in the urethra and the rhabdosphincter. In the rhabdosphincter and the urethra, the relative volume densities of the muscle fibers, the diameters, and the apoptotic index were determined. The authors found an age-dependent occurrence of apoptosis of striated muscle fibers in the rhabdosphincter. In individuals younger than 20, virtually no apoptotic cells were found. In individuals older than 20, apoptotic cells in the rhabdosphincter were distributed randomly. Contrary to the age-dependent apoptosis seen in the striated sphincter fibers, there were no significant changes in cell densities of the urethral smooth muscle cells or in the diameter of the urethra and the rhabdosphincter. This report suggests that sphincter muscle apoptosis may be the main cause for the higher incidence of urinary incontinence seen with advancing age. Loss of striated muscle cells may eventually lead to urinary incontinence. If this hypothesis is confirmed, therapeutic approaches that prevent or delay apoptosis (such as antiapoptosis intervention at the time of radical prostatectomy) or help replace muscle cells in the rhabdosphincter will be worthy of serious investigation. For example, an area of research priority in my laboratory at the University of Pittsburgh has been the engineering of autologous muscle-derived stem-cell tissue for urinary incontinence. This new apoptosis theory and our research fit together beautifully. Laparoscopic Bladder Neck Suspension Fails the Test of Time McDougall EM, Heidorn CA, Portis AJ, Klutke CG. J Urol. 1999;163:2078-2081. This study compared long-term success rates of laparoscopic versus transvaginal bladder neck suspension. One hundred patients with anatomic stress urinary incontinence underwent extraperitoneal laparoscopic bladder neck suspension (with securing of endopelvic fascia to the Cooper ligament [58]) or transvaginal Raz bladder neck suspension (42). Age, mean body mass index, preoperative bladder capacity, and postvoid residual volume were similar in the 2 groups. Mean follow-up was 45 months (range, 14 to 71 months) in 50 laparoscopy patients and 59 months (range, 35 to 72) in 29 transvaginal patients. At follow-up, only 15 (30%) of 50 laparoscopy group and 10 (35%) of 29 trans- Reviewing the Literature vaginal group patients were continent. Difference in the success rates of the 2 groups was not statistically significant. Mean time to failure for both groups was 18 to 24 months. Mean operative time was greater for the laparoscopy group (100 minutes) than for the transvaginal group (45 minutes) (P < .001). Mean estimated blood loss was 74 mL for the laparoscopy and 84 mL for the transvaginal group. After long-term follow-up, the authors concluded that bladder neck suspension using laparoscopy had poor success rates for patients with stress urinary incontinence and stressed the need for evaluating such new surgical techniques for at least 2 years to determine efficacy. Why is laparoscopic bladder neck suspension not successful? First, there is reduced inflammatory response at the surgical site, with the result that fibrosis, which can provide fixation of the endopelvic fascia to the posterior symphysis pubis, may also be reduced. Second, intrinsic sphincter dysfunction may be a component in anatomic stress incontinence; this may compromise the results of a bladder neck suspension procedure. In summary, although use of lap- W INNER OF aroscopy for patients with stress urinary incontinence allows them minimal postoperative discomfort, short-term urinary diversion, and a quick return to activities, in the long term, success rates are poor. The NIH is in the final process of picking 5 centers to start a multicenter, prospective, randomized study of stress incontinence surgical techniques. Perhaps a comparison of laparoscopic Burch colposuspension versus pubovaginal sling would be a good idea. I have tried a few laparoscopic Burch suspensions, but for me, it takes quite a bit longer than a pubovaginal sling procedure. In addition, I know that my patients with a pubovaginal sling will be cured of stress incontinence more than 90% of the time regardless of urethral hypermobility and/or intrinsic sphincter deficiency and regardless of how many previous failed suspensions they have had. At this time, I cannot give such a good prognosis to patients who desire a laparoscopic Burch procedure. In addition, I have not read a report or seen a method in which a laparoscopic sling procedure can be done as quickly and as cheaply as a conventional sling procedure. ■ M ED R EVIEWS D RAWING “Are you usually lucky?” Reviews in Urology asked Edward J. Kirsh, MD, winner of the Palm VII drawing at the MedReviews booth at the 95th American Urological Association Annual Meeting in Atlanta. “No,” replied Dr Kirsh. “This is the first time I’ve won anything of substance. I plan to use it for both business and personal organization.” Dr Kirsh, who is in the department of urology at MacNeal Hospital in Berwyn, Ill, was among the international group of urologists visiting the booth of MedReviews, LLC, publisher of Reviews in Urology and Reviews in Cardiovascular Medicine. This 1993 graduate of Boston University School of Medicine combines his practice in general urology with his special interests in bladder and prostate cancer. He also finds time to teach in the family practice residency program and at hospital medical conferences, and to coauthor papers for national journals on such varied topics as phytotherapy, leiomyomas, and bladder cancer. His interests after hours include sports card collecting, exercise, and travel (he was a recent visitor to Morocco and Spain). Congratulations, Dr Kirsh! SUMMER 2000 REVIEWS IN UROLOGY 177