Weill Medical College
Cornell Institute for Reproductive Medicine
Center for Male Reproductive Medicine and Microsurgery
State-of-the-Art Compassionate Care for the Infertile Couple
What's New in Urology
Peter N. Schlegel
, M.D, FACS.
(This review article was originally published on the Journal of American College of Surgeons 2001; 193:179-210)
Andrology & Infertility
Androgen decline in the aging male (ADAM)
Hormonal abnormalities in infertility
Pathophysiology of testicular dysfunction
Genetic factors and assisted reproduction
Benign Prostatic Hypertrophy
Devices for benign prostatic hypertrophy (BPH)
Incontinence and Voiding Dysfunction
Cause and evaluation
Sacral nerve stimulation
Infections & Inflammatory Conditions
Urinary tract infections
Renal Stone Disease
Extracorporeal shock wave Lithotripsy (ESWL)
Urologic Oncology: Prostate
Etiology and natural history
Hormonal therapy and advanced disease
Urologic Oncology: Renal Tumors
New treatment approaches
Urologic Oncology: Testis Tumors
Evaluation and etiology
Lymph node dissection
Fertility after treatment
Urologic Oncology: Transitional Cell Tumors
Evaluation and prognostic factors
Invasive bladder cancer
Upper tract transitional cell carcinoma (TCC)
Renal artery stenosis
Adrenal lesions and imaging
Female sexual dysfunction
Urology continues to be a very popular choice as a surgical field, but the health of Urology as a specialty is perhaps best depicted in the 1996 article by Miller et al. (1996). In this article, the authors demonstrated that all residents seeking a job in Urology were able to find such positions, whereas up to 10% of other residents were not successful in their specialties. The aging population makes urologic health care needs a priority. Although urology is often considered a small subset of medical care, it is important to remember that almost 45% of men in their 60s are affected by erectile dysfunction (Johannes et al., 2000), nearly 30% of all men will require intervention for benign prostatic disease during their lifetime and prostate cancer is the most commonly diagnosed non-skin cancer in men (Carter & Coffey, 1990). A high proportion of women are affected by urinary problems, including incontinence. All of these fields and others fall within the domain of urologic specialists. Given the breadth of the field, it is not possible to detail every change that has occurred recently in Urology, but the subsections below will emphasize notable events in the field.
Andrology & Infertility
From Dr. Peter Schlegel's
What's New in Urology
, JACS, October, 2001.
Androgen decline in the aging male (ADAM)
Editorial note: Recent description of the phenomenon of decreased strength, well-being and cognition that is associated with male aging has resulted in the term, ADAM. Contemporary studies delineating this phenomenon are provided below.
The study of androgen action and male reproductive dysfunction continues to expand significantly. Despite long-term discussion of similar syndromes in Europe, only recently has the definition of a disease state been associated with hormonal changes that occur in aging men. This syndrome, previously referred to as Andropause, has more recently been described as androgen decline in the aging male (ADAM; Morales et al., 2000.) The onset of ADAM is unpredictable and its manifestations are subtle and variable. It is associated with a decrease in testosterone, but also growth hormone, melatonin and dihydroepiandosterone. Clinical manifestations include fatigue, depression, decreased libido, erectile dysfunction as well as changes in cognition and mood. As the syndrome is better defined and understood, more specific treatment beyond androgen replacement is expected.
Popular over-the-counter androgenic agents such as androstenedione and dihydroepiandosterone (DHEA) have been used by an increasing proportion of the population. A study in JAMA (Leder et al., 2000) examined the effects of exogenous androstenedione on testosterone and other hormone levels in young healthy men. They found that oral androstenedione in high doses (300 mg/day) resulted in modest increases in serum testosterone levels and estradiol levels, whereas no change occurred in testosterone with lower doses. Knowledge of these changes is important in evaluation of men who are taking these medications.
Hormonal abnormalities in infertility
Other hormonal changes have been described for men with severe infertility. Pavlovich et al. (2001) reported on lower serum testosterone levels with high estradiol levels in men with infertility that was significantly different from a fertile reference group. Restoration of normal testosterone/estradiol levels was possible using treatment with oral aromatase inhibitors. An associated increase in sperm production and quality was also seen. Previously, it was thought that these men simply do not produce enough testosterone. These observations suggest that some men with severely dysfunctional testes may lose significant testosterone via aromatization to estrogens, an effect blocked by aromatase inhibitors. So, men with low testosterone levels are not always deficient in hormone production - they may actually have abnormal metabolism of the testosterone that is being produced.
Pathophysiology of testicular dysfunction
Recent observations have suggested that environmental effects on the developing testis may result in testicular dysfunction, hypospadias, undescended testes and a higher risk of testis cancer. Skakkebaek et al. (2001) referred to this condition as testicular dysgenesis syndrome. The causes are not yet clear. The mechanisms of sperm production in men with genetic disorders are also becoming more clear and leading to treatment possibilities for many individuals previously considered sterile. Blanco et al. (2001) demonstrated that many men with apparent non-mosaic Klinefelter syndrome may have subtle germ cell mosaicism, that allows production of a higher proportion of sperm with a normal genetic complement. Still, there remains a low but significant frequency of chromosome abnormalities in sperm from men with Klinefelter syndrome (Levron et al., 2000) so, genetic counseling is still required before treatment of these azoospermic men with sperm retrieval and intracytoplasmic sperm injection (ICSI). One common finding on ultrasound of testes of infertile men is a heterogeneous echo pattern of testicular parenchyma. This observation may reflect sclerotic seminiferous tubules within the testis. A study by Harris et al. (2000) noted that this finding was very common in men over age 50, and no further follow-up may be necessary for those individuals, whereas younger men at risk for testicular cancer may need additional studies.
Genetic factors and assisted reproduction
Although sperm production is dependent on hormone action, significant androgen receptor gene mutations in men with infertility are rare (<1%; Hiort et al., 2000.) Although Y chromosome partial deletions are known to cause infertility and they may be transmitted to sons produced with ICSI, they appear to occur only in the sons of fathers with non-mosaic patterns of Y partial deletions and not as common de novo events (Cram et al., 2000.) Application of assisted reproductive techniques in the United States is skyrocketing. CDC tracking suggests an increase in procedures of 11% per year in 1997, the last year for which results are available. Although this offers new options for couples, the overall average delivery rate per egg retrieval procedure was only 28%. The risk of multiple gestations (twins, higher order pregnancies) remains over 40% (SART, 2000.) For men who have had vasectomies and are interested in sperm retrieval and ICSI, there appears to be no effect of time since vasectomy (Sukcharoen et al., 2000) nor whether fresh or frozen sperm are used (Janzen et al., 2000) as long as the sperm used for ICSI are alive after freeze-thaw. The collection of sperm from men with anejaculation was reported using seminal collection devices, placed when the men are going to sleep, to allow retrieval of nocturnal emissions (Hovav et al., 1999.) Another approach is prostatic massage (Hovav et al., 2000.) The significance of microorganisms in seminal fluid continues to be debated. Cottell et al. (2000) reported that most semen cultures actually grow skin contaminants. Antibacterial skin preparation has been suggested before providing semen cultures to limit the risk of contamination (Kim & Goldstein, 1999.)
Vasectomy is used by more than 10% of married couples in the United States for contraception. These procedures are usually performed under local anesthesia in an outpatient setting. Effectiveness is reflected by low pregnancy rates after the treatment. Although different follow-up schedules have been recommended, Badrakumar et al. (2000) suggested a single semen analysis 3 months after the procedure to confirm its effectiveness. Others have suggested at least 2 semen analyses with no sperm, beginning 6-8 weeks after the procedure. The complication rates reported after vasectomy are 1-6% (Schwingl & Guess, 2000.) A very rare complication of unknown etiology is persistent post-vasectomy pain, which was treated in a small series of 13 men by Nangia et al. (2000) using vasectomy reversal. This highly selected group of patients responded well to treatment.
Benign Prostatic Hypertrophy
Medical treatment and new devices are the most news-worthy topics of publication in the management of benign prostatic diseases. Information on the natural history of the disease was provided by the PLESS (Proscar Long-Term Efficacy; Safety Study) trial. Progressive prostatic growth was documented in the placebo-treated group. Baseline serum PSA was a stronger predictor of prostate growth than age or initial volume. Men with an initial PSA greater than 2.0 ng/mL had a higher risk of subsequent prostate growth, which is a risk factor for subsequent urinary retention (Roehrborn et al., 2000.) A prospective study of men with urinary retention who were conservatively managed again showed that 55% of men voided spontaneously after an initial period of catheterization for 8 to 24 months (Kumar et al., 2000.) Men with larger prostates were less likely to be able to void after catheter removal.
A literature review of direct comparative trials of medications suggested that alpha-blockers were more effective than finasteride at improving symptoms and increasing peak flow rate. Finasteride appeared more beneficial in patients with prostate volumes >50 cc (Zimmern, 2000.) A literature review of treatment with the phytotherapy, saw palmetto, was published by Gerber et al. (2000.) He reviewed the mechanism of action and clinical results for treatment of men with benign prostatic hypertrophy (BPH). He concluded that saw palmetto has a significant effect on urinary flow rates and symptom scores compared to placebo without recognized adverse effects or serum PSA.
It has been assumed that medical treatment is providing relief for lower urinary tract symptoms (LUTS) which are caused by obstruction. The presence of obstruction is thought to be most accurately evaluated by pressure-flow studies. Sonke et al. (2000) evaluated the repeatability of pressure-flow studies and found that 42% of patients had significant differences from test to test on these studies. Another study evaluating the effects of alpha blockers on urodynamic parameters found that the majority of patients had no clear improvement in obstructive parameters during treatment, suggesting that alpha blockade improves symptoms but doesn’t necessarily relieve obstruction (Rossi et al., 2001.) Since most patients are treated for symptoms, urodynamic improvement alone may not be critical to successful management. The side effects of the alpha blocker terazosin were reported by Lepor et al. (2000) who found that dizziness, asthenia, postural hypotension and syncope occurred for 19%, 6%, 6%, and 1% of treated patients, respectively. Interestingly, dizziness and asthenia were not associated with blood pressure changes, suggesting that these complications are not necessarily related to vascular events.
Devices for benign prostatic hypertrophy(BPH)
A randomized prospective trial of contact laser prostatectomy versus visual laser coagulation suggested that relief of bladder outlet obstruction and peak flow rates were similar for both treatments (Bryan et al., 2000.) Better hemostasis was obtained with visual laser coagulation. A review of laser prostatectomy studies by Floratos et al. (2000) indicated that patients with obstruction demonstrated before the procedure on urodynamic studies predicted a better outcome. These authors supported the use of urodynamics prior to treatment.
Transurethral microwave thermotherapy (TUMT) results were reported with five year followup in 71 patients (Daehlin et al., 2000.) Only 29 of the 71 had monotherapy with TUMT - all other patients required additional treatment or had intercurrent disease affecting voiding. Only a limited number of patients had long-term benefit. The mechanism of action is not well delineated. Brehmer et al. (2000) studied the sensory threshold in the posterior urethra after TUMT. They concluded that TUMT causes decreased posterior urethral sensitivity, and the decreased sensitivity may result in improved symptoms. Use of a new prostatic urethral stent was reported by Traxer et al. (2000) in 17 men with urinary retention and contraindications to surgical intervention. The stents were placed under local anesthesia for most men and provided effective relief of retention. However, 3 patients had stent migration or pain and stents need to be changed every 1 to 6 months. The ability to remove UroLume endoprostheses was reported by Gajewski et al. (2000). Although there has been concern about how complicated removal of devices could be, devices were apparently easily removed after migration or misplacement. Only 2 serious complications (bleeding and urethral injury) occurred during removal, although most devices had to be removed in parts or wire-by-wire. No permanent disability nor malignancies were associated with use of this device in this study with brief followup.
An overview of randomized controlled trials of invasive and minimally invasive treatment modalities for LUTS was prepared by Tubaro et al. (2000.) They noted that retreatment was higher with minimally invasive therapies whereas open surgery and TURP had the lowest rates of requiring further intervention. The authors concluded that none of the minimally invasive treatments were superior to TURP from a cost/benefit standpoint, and that TURP was still the standard of effective treatment.
The incidence of erectile dysfunction in men aged 40 to 69 years was evaluated in a randomly sampled population based study of Massachusetts men (Johannes et al., 2000.) The crude incidence rate was about 26 cases per 1,000 men annually and increased with age, lower eduction, diabetes, heart disease and hypertension. These data suggest that erectile dysfunction develops in over 617,715 men per year in the United States.
Peyronie’s disease is a common cause of erectile dysfunction and numerous treatments have been proposed in uncontrolled trials. The use of extracorporeal shock wave therapy was evaluated by two groups. An uncontrolled study of 37 patients receiving 3 treatments reported 47% of patients had improvement in penile angulation with erection (Husain et al., 2000). Hauck et al. (2000) treated 22 patients in a placebo-controlled trial without evidence of treatment benefit. The use of non-absorbable plication sutures for men with congenital or Peyronie’s-associated curvature was reported by Schultheiss et al. (2000). A high failure and complication rate resulted, which supports the use of removal of an ellipse of tunica albuginea & absorbable sutures (Nesbit procedure) for optimal plication results.
Successful use of sildenafil for men with spinal cord injury (Schmid et al., 2000) or spina bifida (Palmer et al., 2000) was reported. Certainly, sildenafil has been proposed as an initial treatment for almost all causes of erectile dysfunction. Patients who do not initially respond to sildenafil or alprostadil monotherapy were evaluated in a retrospective review (Mydlo et al., 2000.) Patients were treated with a combination of sildenafil and alprostadil after failure of monotherapy and, surprisingly, 60 of 65 patients treated were satisfied with the combination after failed monotherapy. An excellent review of the diagnosis and treatment of erectile dysfunction was published by Lue et al. (2000) and is worthwhile reading as well as a reference text. A study in the New England Journal of Medicine evaluated the hemodynamic effects of sildenafil in men with severe coronary artery disease (Herrman et al., 2000.) These authors confirmed the absence of cardiovascular effects of this drug. The American College of Cardiology and The American Heart Association have both now agreed that sildenafil is safe for patients who are not taking nitrate-containing medications.
Incontinence & Voiding Dysfunction
Etiology & evaluation
Vaginal delivery of a child and simple hysterectomy have been identified as potential causative factors of female urethral dysfunction. Morgan et al. (2000) found intrinsic sphincter deficiency in 48% of patients after hysterectomy versus 24% of control patients. Chaliha et al. (2000) found no difference in the prevalence of stress incontinence or detrusor instability before and after delivery. In a comparison of valsalva and cough-induced leak-point pressure evaluation, Peschers et al. (2000) found that cough and valsalva elicited different pelvic floor responses. However, the increase in pressure is so rapid with cough that this measurement may not be as accurate as valsalva leak-point pressure evaluations. A study of general practitioners treating women for incontinence suggested that urodynamic test results have limited value (Holtedahl et al., 2000). However, general practitioners have limited treatment options, so full knowledge of the underlying bladder dysfunction is not as important as it is for urologists evaluating patients referred for evaluation. Blaivas et al. (2000) proposed urodynamic criteria for definition of bladder outlet obstruction in women with LUTS. They defined women with peak flow < 12 mL/second and maximum detrusor pressures > 20 cm as obstructed without validation.
The pathophysiology of post-prostatectomy incontinence has been variably reported as being due to bladder or sphincteric problems. This issue was evaluated in a retrospective review of 83 men after radical retropubic prostatectomy by Groutz et al (2000.) They showed that sphincteric incontinence was the most common urodynamic finding in these patients although other conditions may co-exist. Of note, 30% of men had very low urethral compliance, which was nearly synonymous with urethral scarring associated with surgery.
Sacral nerve stimulation
A novel treatment for detrusor overactivity, sacral nerve stimulation, has recently been evaluated by a number of authors. The process of test stimulation followed by permanent implantation of sacral root (S3) electrodes for incontinence electrodes was described by Janknegt et al. (2001.) Klingler et al. (2000) suggested in a urodynamic study of 11 women and 4 men that the benefits of this treatment were related to afferent stimulation of S3, resulting in reflex inhibition of the peripheral S3 nerve and subsequent relief of urgency-frequency symptoms. Hassouna et al. (2000) reported a multi-center trial of 51 patients treated for urgency-frequency with a dramatic decrease in the number of voids per day, increase in the volume per void and relief of the degree of urgency. Other trials of 14 and 30 patients were reported by Chartier-Kastler et al. (2001) and Edlund et al. (2000) with good overall results. In most series, patient results are reported as pooled urodynamic studies. The chance of an individual patient having a long-term response to this treatment in published literature is not clear. A multi-center trial of 53 patients with overactive bladder reported by Govier et al. (2001) who applied stimulation not to S3, but to the tibial nerve. They noted that 71% of treated patients were improved and were then candidates for permanent implant placement. Sacral nerve stimulation has also been applied for 177 patients with urinary retention refractory to standard therapy (Jonas et al., 2001.) A total of 69% of patients were able to eliminate catheterization at 6 months, with sustained improvement after 18 months of treatment.
Sling/suspension procedures for stress urinary incontinence and cystocele are accepted approaches in treatment of these conditions. Tension-free vaginal mesh repair was applied for grade III cystocele repair in 12 women with grade I recurrence in 3 patients. No evidence of erosion, fistula formation or pelvic infection was seen (Migliari et al., 2000.) Weber et al. (2000) compared Burch and sling procedures for stress urinary incontinence in a decision analytic model based on literature review. The overall effectiveness of the Burch procedure was 94.8% with 95.3% for the sling procedures. Complications of the development of detrusor instability or retention had potential limits to the benefits of these procedures. Choe et al. (2000) presented data on 40 consecutive women randomized to synthetic antimicrobial mesh versus vaginal wall sling. No episodes of retention or erosion occurred. The satisfaction rate was 100% for the mesh-treated patients and 80% for the vaginal wall sling patients. Although they are not widely accepted as appropriate clinical treatments any longer, Stamey and Gittes procedures for stress incontinence were compared in a long-term (mean 8.4 year follow-up) study (Nigam et al., 2000.) Progressive decreases in the proportion of successfully treated patients were seen after these procedures with 92-94% dry at 3 months, 38-64% at 1 year and 14-38% at 5 years. These results reflect why Stamey & Gittes procedures should not be applied for management of stress urinary incontinence except in rare cases where patients could not tolerate more involved procedures.
Initial treatment of the overactive bladder usually involves anticholinergic medications. Treatment effectiveness is often limited by side effects. The development of controlled-release medications was an attempt to limit these side effects while maintaining effectiveness. A trial of controlled-release versus immediate-release oxybutinin suggested that complications (moderate-to-severe dry mouth) were less with controlled-release drugs, whereas efficacy was maintained (Versi et al., 2000.) A novel treatment for detrusor hyperreflexia is intravesical resiniferatoxin, a capsaicin analog. Twenty-four treatments were provided to 14 patients with significant effectiveness and was found to be only minimally irritative (Silva et al., 2000.)
Submucosal collagen injections into periurethral tissue have been applied for stress urinary incontinence in women. Groutz et al. (2000), in a retrospective review of patients referred for tertiary treatment and using a rigorous definition of curative response, reported that only 13% of patients were classified as cured with treatment. A complete failure rate of 20% was seen. Other patients had partial responses. These poor results reflect the relatively low effectiveness of the treatment but also the patient population treated and the rigorous criteria for response applied. Madjar et al. (2000) reported on the long term follow-up of women with urinary retention managed with an intraurethral insert that contains a valve and pump mechanism activated by an external magnetic device. Fifty-six percent of treated patients had the device removed acutely (average 6 days). All patients who maintained the device long term were very satisfied with it. Occasional migration of the device (4 patients), symptomatic UTI (4 patients), dyspareunia (1 patient), and asymptomatic bacteriuria (15 patients) were noted.
The options for bladder management of quadriplegic men was reported by Mitsui et al. (2000.) Their results suggested that use of a chronic suprapubic catheter was associated with a lower rate symptomatic urinary tract infection, higher rate of renal calculus, and higher rate of bladder calculus formation relative to chronic urethral catheterization. The authors suggested that suprapubic catheterization is a viable option for patients with spinal cord injury.
Clemens et al. (2000) reviewed 14 patients who experienced pubovaginal sling erosion. They recommended that any patient with pain or vaginal discharge after pubovaginal sling should be evaluated for erosion. Evaluation should consist of physical examination and/or cystoscopy. After removal of the sling, about half of the patients will develop recurrent stress incontinence. Urinary retention was studied after surgery for stress urinary incontinence in ten women. A significant component of failure to relax the external urethral sphincter was seen initially in 6 patients, but all patients were able to void within 14 days (Fitzgerald & Brubaker, 2001.)
Infections & Inflammatory Conditions
Several conditions that account for a large proportion of urologic practice and an even higher level of frustration for urologists can be classified as infectious or inflammatory conditions. The condition of “chronic prostatitis” has been clinically recognized for years but has never been well defined nor its etiology understood. A review of published work on the topic of controlled trials of treatment for chronic abacterial prostatitis showed that there was no clear diagnostic test for this condition, and no demonstrated effective treatment (Collins et al., 2000.) Important steps toward a better understanding of this syndrome or symptom complex was made with a National Institutes of Health-organized International Prostatitis Collaborative Network workshop in 1998 (Nickel et al., 1999.) Definitions and subclassification of the chronic prostatitis/chronic pelvic pain syndrome were developed. These steps allowed for trials to better describe the disease processes involved and provide a framework for treatment protocols. One trial attempted to identify patients more likely to respond to antibiotics (Nickel et al., 2001) but could not provide prognostic information based on existing clinical data. One study reported the effect of perisphincteric injection of botulinum toxin A for patients with chronic prostatic pain (Zermann et al., 2000.)
Urinary tract infections
A prospective study of asymptomatic bacteriuria in sexually active young women waspublished in the New England Journal of Medicine (Hooton et al., 2000.) The prevalence of asymptomatic bacteria was 5-6%. Symptomatic infections occurred within one week in 8% of women with positive cultures and 1% of women with negative cultures. The development of an infection was closely associated with sexual intercourse and use of a diaphragm with spermatocide. Most infections were caused by E. Coli. A trial of the effect of cranberry juice on biofilm in spinal cord-injured patients demonstrated a significant reduction of biofilm load, compared to water treatment or baseline (Reid et al., 2001.)
A retrospective review of 50 consecutive patients with primary necrotizing fasciitis of the male genitalia was provided by Dahm et al. (2000.) Three factors predicted outcome: depth of infection, extent of infection and use of hyperbaric oxygen. Laparoscopy has been applied for a number of urologic conditions. Kim et al. (2000) have done laparoscopic nephrectomies on 13 patients with nonfunctioning tuberculous kidneys. The surgical procedure was preceded by at least 3 months of medical antituberculous therapy. This study demonstrated the feasibility of the procedure although more adhesions were seen between the affected kidney and surrounding structures. The use of gentamicin was evaluated in a literature review by Santucci & Krieger (2000.) They emphasized the use of single daily dosing (at 3-5 mg/kg) for treatment of patients with serious gram negative infections.
Interstitial cystitis remains a poorly understood syndrome. It has been proposed that this is an autoimmune condition that may be initiated by a bacterial infection. A pilot study of sequential oral antibiotics was published by Warren et al. (2000.) Of the treated patients, 48% reported overall improvement versus 24% in the placebo group with a higher adverse effect rate in the antibiotic-treated group as well. A prospective longitudinal study of patients with interstitial cystitis who were not treated demonstrated initial symptom improvement attributable to regression to the mean. There was no evidence of significant long-term change in overall disease severity with treatment. These findings support the importance of a better understanding of this symptom complex, as no effective treatments exist (Propert et al., 2000.)
The presence of even a single episode of epididymitis in children has been considered an indication for evaluation to detect a renal or ureteral anomaly as its etiology. A study from Paris challenges this assumption with data from evaluation of 38 children seen over an 8-year period (Cappele et al., 2000.) They found that only 18% of evaluated children had renal anomalies such as reflux or renal malrotation, and only one child required surgery (for ureterocele.) The frequency of anomalies was lower than expected.
A prospective placebo-controlled study of ultrasound therapy to the bladder was applied to 35 patients with primary nocturnal enuresis. Delivery of 0.8 W/cm2 was applied to the bladder 8 minutes a day for 10 days. Overall, 82% of children benefited from treatment and responses persisted for 12 months after therapy. There were no responses in placebo-treated controls (Kosar et al., 2000.) Further information on this treatment is needed in a larger trial. The role of bladder dysfunction in failure after renal transplantation was evaluated in a study from Paris in 66 boys with posterior urethral valves (Salomon et al., 2000.) In boys with symptomatic voiding dysfunction, mean serum creatinine increased after five years of followup. Closer followup of boys with symptomatic voiding problems after transplantation is warranted. A consensus survey of the Society for Fetal Urology members was reported on management of antenatally detected urological abnormalities. Only rare conditions were recommended for intervention. These may include oligohydramnios with suspected favorable renal function and the absence of life-threatening congenital anomalies. The presence of normal amniotic fluid was a contraindication to intervention regardless of the detected abnormality. However, early delivery of fetuses with severe genitourinary abnormalities, normal amniotic fluid and confirmed lung maturity is more commonly advocated now (Hernodon et al., 2000.) The group from Hopkins reported on long term outcome of epispadias repair in 93 males with epispadias alone or classic bladder exstrophy. A downward or horizontally-directed penis was obtained for 93% of boys. Early fistulas occurred for 23% of patients with 19% at 3 months. Urethral stricture occurred for 7 boys. These results were considered to be functionally and cosmetically excellent (Surer et al., 2000.) The voiding pattern of healthy preterm neonates was shown to involve a high frequency of interrupted voiding, suggesting the presence of immature detrusor-sphincter coordination. A high number of voids during sleep also indicated a more immature pattern than that seen in full term newborns (Sillen et al., 2000.) The group from Children’s Hospital in Boston reported on 25 newborns with normal neurourological evaluation after surgical repair of myelodysplasia. Subsequent neurourological deterioration occurred for 32% of infants secondary to spinal cord tethering, especially during the first 6 years of life. Close followup and intervention of these children was recommended (Tarcan et al., 2001.)
A survey of American Association of Pediatrics, Section on Urology members on standard management of vesicoureteral reflux (Herndon et al., 2001.) Urine culture is routinely performed by 64-71% of respondents and yearly VCUG or radionuclide scan for followup by 99% of respondents with ultrasound by 77%. After reflux surgery, 91% of respondents perform VCUG and ultrasound. The overwhelming majority of practitioners agree on the timing and type of radiographic studies to be used to follow children with reflux. A low incidence (2%) of renal scars in children after ureteral reimplantation was noted in a prospective study from Australia (Webster et al., 2000.) These findings suggest that surgical correction of reflux may protect kidneys better than previously believed.
Men who had previously undergone prepubertal orchiopexy were studied with ultrasound as adults. Of 22 men, tunica albugineal calcification was seen in 32%, consistent with reaction from suture or persistence of a chromic suture, which is typically not absorbed in the region of the tunics. A subtunical hypoechoic area was seen in 14% of patients and only 54% had normal ultrasound studies (Ward et al., 2000.) Cystic testicular lesions are rare but may have multiple possible etiologies. Management with partial orchiectomy and frozen section histologic analysis is the recommended management, but a complete overview is available in this reference (Garrett et al., 2000.) Comparison of boys pretreated with hCG or GnRH prior to orchiopexy versus those who received no pretreatment was provided in a study from Denmark (Cortes et al., 2000.) They found a higher number of spermatogonia per tubule in the untreated patients, suggesting a possible detrimental effect of prior hormonal therapy. The use of orchidometer for assessment of testicular volume was provided in a study from Boston Children’s (Diamond et al., 2000.) They found a strong linear relationship between orchidometer and ultrasound measurements, but they felt that orchidometer was not sufficiently accurate to determine growth impairment with sequential evaluations. Yearly ultrasound assessment was recommended for sequential analysis of relative testicular volume. A study from CHOP showed that in 723 patients, germ cell counts correlated with testicular volume. However, prediction of the cut point of <0.2 or >0.2 germ cells per tubule was not possible based on testicular volume measurements alone (Noh et al., 2000.)
The management of synchronous bilateral Wilms tumor was reported from CHOP (Cooper et al., 2000.) Preoperative chemotherapy followed by nephron-sparing surgery was recommended. Brachytherapy was recommended for treating local disease involving chemoresistant tumors. Those patients with diffuse anaplasia are not recommended to have nephron sparing surgery.
The complication rate of flaps and grafts for repair of proximal hypospadias was reported in a retrospective review of 142 patients from San Diego (Powell et al., 2000.) A higher complication rate occurred after free tubed grafts. Two-thirds of complications presented more than 1 year after surgery. Use of the dorsal inlay graft for 32 patients with coronal to penoscrotal hypospadias after chordee release was reported from Baylor (Kolon & Gonzales, 2000.) Glanuloplasty and in situ tubularization of the urethral plate was reported by Kass from Michigan for distal and midshaft hypospadias repair in 308 patients. They reported excellent overall cosmetic results with a complication rate of 9.7%, most of which occurred in mid shaft lesions (Kass & Chung, 2000.)
The use of urinary diversion or stenting after dismembered pyeloplasty was evaluated by Austin et al.(2000) in a review of 137 pyeloplasties. They found that drainage with nephrostomy tube alone resulted in few complications and an open anastomosis in 100% of cases. Use of gastrocystoplasty for bladder reconstruction was reported by Leonard from Winnipeg in a series of 23 patients in a tertiary pediatric urology practice. They found that stomach may be used for augmentation in patients with cloacal exstrophy and/or metabolic acidosis. Histamine blockers and proton pump inhibitors are commonly required for hematuria-dysuria. The symptoms of this syndrome was disabling and resulted in another form of urinary reconstruction for 3 patients (Leonard et al., 2000.) The group from Hopkins reported decreased linear growth in 82% of exstrophy patients managed with intestinal bladder augmentation, compared to 33% of controls. Close followup of patients for subtle evidence of metabolic alterations was recommended (Gros et al., 2000.)
Renal Stone Disease
Initial evaluation of the patient with presumed renal/ureteral calculus disease was investigated in two different studies. Shokeir & Abdulmaaboud (2000) performed a prospective comparison of nonenhanced helical CT and Doppler ultrasonography. They found that sensitivity and specificity of both techniques was high and very similar. Plain abdominal X-ray was compared to the scout film on a nonenhanced spiral CT in an additional study by Jackman et al. (2000.) They found that X-ray alone had a 48% sensitivity whereas a 17% sensitivity was observed on scout CT scans. Taken together, it is clear that the unenhanced spiral CT scan is the procedure of choice for patients with presumed renal/ureteral calculus disease. The CT allows detection of other abdominal conditions that may be associated with symptoms suggestive of renal/ureteral colic. A CT scout film is not as helpful as a KUB.
The contribution of dietary oxalate to urinary oxalate secretion is greater than previously recognized (Holmes et al., 2000.) Unless patients have absorptive hypercalciuria, oxalate stone formers should limit dietary oxalate. Restriction of dietary calcium can lead to increased absorption of oxalate.
There is a clear association of renal stone disease with use of indinavir in HIV-positive patients. Saltel et al. (2000) reported a cumulative incidence of indinavir stone formation of 43% for patients treated 78 weeks, with a mean time to stone formation of 23 weeks. Prevention of stone formation is primarily effected by increasing fluid intake. Medical treatment of cystinuria was reported by Barbey et al. (2000) who suggested that a regular medical program of diuresis and alkalinization markedly decreased cystine stone formation. Maintenance of more than 3 liters of urinary volume per day is critical to prevention of stone formation. Not surprisingly, patients who are not compliant with medical therapy have a higher rate of stone recurrence. For patients with spinal cord injury, there is a high risk of renal stone formation, especially within the first three months of injury. Chen et al. (2000) provided evidence of a 3-8% incidence of stone formation within the first 3 months of spinal cord injury.
Extracorporeal shock wave Lithotripsy (ESWL)
ESWL is a commonly-applied treatment for renal calculi. A review of 5,769 treatments with the Donrnier MFL 5000 lithotriptor was presented from a single center with multiple treating physicians. Stone-free and success rates were 56% and 77%, respectively. Of the 15 treating urologists at this center, the surgeon with the greatest number of patients treated, and highest mean fluoroscopy time had the highest success rate and lowest re-treatment rate. Treatment of eleven patients with ESWL was reported by Czaplicki et al. (2000) without complications. Hematuria was seen for up to 48 hours and skin ecchymosis was common, but this study suggests that treatment of patients with an underlying coagulopathy can be safely effected.
Appropriate use of ureteral stents after ureteroscopy or ESWL remains somewhat controversial. A prospective study of 44 patients ureteroscoped for removal of a large (0.6 - 1 cm) distal ureteral stone with the Swiss Lithoclast was reported by Rane et al. (2000). Based on the fact that only one patient who was not stented had significant pain postoperatively, routine stenting after ureteroscopy was not recommended. Late complications of ureteral stents were reported by Ringel et al. (2000.) Approximately one-third of patients had late complications including stent fragmentation, migration, persistent hydronephrosis or infection. Complications were seen as early as three months after placement, supporting their early replacement for patients requiring chronic stent maintenance.
Surgical exploration has been the standard approach for grade 5 renal injuries. A review of 13 grade 5 injuries was presented by Altman et al.(2000.) They found similar hospitalization time for injuries managed non-operatively versus those that underwent surgical exploration. The nonoperative group had fewer intensive care days and significantly lower transfusion requirements with few effects on renal function. Despite the presence of a grade 5 injury, if contrast is reaching the distal ureter of the affected kidney and bleeding is not life-threatening, initial non-operative management with close follow-up is appropriate for these patients. Mydlo et al. reported on 5 patients who were managed expectantly after presumed penile fracture (Mydlo et al., 2001.) One patient had mild curvature that did not require treatment. Although a non-operative approach is not recommended as the primary treatment, many patients appear to do well with this manner of treatment.
Andrich and Mundy from London studied the aftereffects of urethral injury in 20 patients who were asymptomatic after anastomotic repair of urethral injury associated with pelvic fracture. Their findings suggest that avulsion of the membranous urethra from the bulbar urethra occurs as the mechanism rather than shearing through the membranous urethra (Andrich & Mundy, 2001.) Corriere (2000) reported a series of 63, one-stage bulboprostatic urethroplasty procedures for posterior urethral rupture with long term follow-up. Of patients who were potent, 52% remained potent postoperatively and 72% voided normally, whereas 8% had urge incontinence and two patients had moderate stress incontinence requiring treatment. 32% of patients required treatment for strictures.
Urologic Oncology: Prostate
Etiology and Natural history
Both environment and genetics have an apparent role in causation of prostate cancer. The relative contribution of these two factors may be analyzed in twin studies. An analysis of a twin cohort from Sweden, Denmark and Finland suggested that hereditary factors are more important in prostate cancer than in other cancers. It was estimated that 42% of the risk of prostate cancer may be attributable to genetic factors (Lichtenstein et al., 2000.) The value of detection of prostate cancer by PSA screening has been questioned by some as having limited value. A study from Sweden indicated that the 15-year cancer specific survival of men with PSA less than 10 ng/mL was only 50%, calculated from the time of PSA sampling(Hugosson et al., 2000.) Another study from California analyzed the mean time to death from prostate cancer for men with T1-2 and nonmetastatic T2-3 disease. They demonstrated a steep increase in mortality at 16 years after diagnosis (Horan & McGehee, 2000.) The role of “watchful waiting” in management of prostate cancer was further explored in a study of patients from Denmark with clinically localized disease who were managed with initial noncurative intent (Brasso et al., 2000.) They found that the diagnosis of prostate cancer accounted for a significant need for hospital care in the years after diagnosis. When evaluating quality of life, the need for medical care in this group of patients must be considered. The clinical outcome of patients more than 70 years of age at the time of diagnosis was reported from Stanford. The men who were older had more aggressive tumors, perhaps because these tumors had grown longer than for younger men (Sung et al., 2000.) Although several medical groups have proposed providing information before PSA screening, little data exist on evaluation of how this information affects patient’s choices. An illustrated informational pamphlet did not change patient’s choices regarding screening in a recent study from Milwaukee (Schapira & VanRuiswyk, 2000.)
Appropriate use of prostate-specific antigen (PSA) testing for early detection and diagnosis of prostate cancer was formulated in a “best practice policy” statement by the American Urological Association (Carroll et al., 2001.) They published recommendations of regular screening of men over age 50 (African-American men or those with a family history over age 40-45) using PSA and digital rectal examination. Cut-points for biopsy are based on age-specific PSA evaluations, and screening is only recommended for men with a life expectancy of more than 10 years. The use of PSA for staging and follow-up of patients after definitive treatment of prostate cancer was published in an accompanying article that serves as a worthwhile reference (Carroll et al., 2001.) Now that standard approaches for PSA screening has been proposed, Ross et al., based on a Monte Carlo simulation based on a Markov model, recommended PSA testing at ages 40 and 45, followed by biennial testing after age 50. This approach prevented the same number of deaths with fewer tests and less PSA tests & biopsies (Ross et al., 2000.) Derivative evaluations of PSA and PSA subtypes continue to clarify the roles of these tests. A prospective evaluation of complexed PSA versus free/total PSA measurements for the diagnosis of prostate cancer showed similar value of these two tests, with the complexed PSA measurement having better receiver operating curve characteristics than total PSA (Mitchell et al., 2001.) A novel histologic marker for prostate cancer, increased prostatic lysophosphatidylcholine acyltransferase activity, was evaluated by a group from Arkansas (Faas et al., 2001.) The measurement of this enzyme level in blood as a potential tumor marker has not yet been investigated. Clinical management of premalignant lesions of the prostate (high grade PIN) management guidelines were proposed in a literature review by the WHO Collaborative Project and Consensus Conference (Haggman et al., 2000.) It was recommended that further evaluation of these lesions only be performed in patients who are suitable for treatment with curative intent, that patients found to have high grade PIN should have prompt repeat biopsy whether PSA and/or rectal exam are normal or not. Patients with PIN who have a repeat negative biopsy after a diagnosis of PIN should be reevaluated in 1 year. The presence of low-grade PIN is of no clinical significance and should not be commented upon in pathologic evaluations. The pattern of rebiopsy should include both the site of prior high grade PIN & adjacent sites as well as a general sextant pattern of the prostate (Park et al., 2001.) The rate of cancer detection in this series was 51% after initial identification of PIN. Another study from Austria also confirmed that the presence of PIN is an independent predictor of cancer. Total PSA and percent free PSA are not necessary to identify patients for repeat biopsy (Horninger et al., 2001.) Several diseases, including prostate cancer, have been shown to have improved 5-year survival in recent studies. Welch et al. (2000) reported that changes in 5-year survival over time may not reflect improved survival from cancer treatment, especially when changing patterns of diagnosis are ongoing. The value of prostate cancer screening was reported for the Tyrol region of Austria, where an improved rate of organ-confined disease was seen after initiation of PSA-based screening (Horninger et al., 2000.) The rate of organ-confined tumors increased from 29% in 1993 to 66% in 1997. Subsequent data from this region have suggested a decrease in prostate cancer mortality associated with screening, beginning approximately 8 years after its introduction.
Treatment with intravesical BCG for transitional cell carcinoma will typically result in a 2-fold increase in PSA, as seen in a recent study for 75% of patients. The effect on PSA is self-limited and will resolve within 3 months. Development of nodules may also occur and are usually associated with benign disease. Followup PSA 3 months after BCG therapy is recommended (Leibovici et al., 2000.) The role of imaging studies after diagnosis of clinically localized prostate cancer was evaluated in a population-based analysis of 3,690 patients (Albertsen et al., 2000.) This group found that bone scan, MRI and CT scan had a low yield, especially when the Gleason score was 6 or less. For all men with a PSA of 4 to 20 ng/mL, the positive yield of bone scan and CT was 5% and 12%, respectively. Optimal imaging protocols for patients with early prostate cancer are yet to be developed.
Radical retropubic prostatectomy has been performed on more than ten thousand men a year between 1989 and 1995. A nationwide sample of American hospitals examined the relationship of hospital surgical volume to complications. Mortality and length of stay as well as hospital charges were lower in high volume centers, although overall in-hospital mortality was relatively low (0.25%) (Ellison et al., 2000.) One of the most interesting changes in radical prostatectomy technique is the recent demonstration of the effectiveness of a laparscopic approach to prostatectomy. Vallancien et al. initially reported on a cohort of 120 patients who underwent laparoscopic prostatectomy at Mountsouris in France. They demonstrated a progressive decrease in complications and operative time in this series of cases (Guillonneau & Vallancien, 2000.) The same authors have subsequently reported on a series of 260 consecutive cases at this center. Operating time was approximately 3 hours for the last 120 cases with a transfusion rate <1% and conversion rate of 0%. Minimal postoperative pain and removal of the urethral catheter at 3 days were apparent advantages of this technique (Guillonneau & Vallancien, 2000.) Guillonneau et al. also reported robotic-assisted laparoscopic pelvic lymph node dissection for locally advanced prostate cancer in ten patients (Guillonneau et al., 2001.) A similar number of lymph nodes was removed with this technique, relative to that of open surgical node dissection, with a shorter operative time for the laparoscopic technique. A series of 20 patients undergoing radical prostatectomy with a laparoscopic approach was also reported with similar short-term results to that expected with open surgery (Jacob et al., 2000.)
The role of bladder neck preservation during radical prostatectomy was reported on by Poon et al. (2000) who found that bladder neck preservation did not affect return of urinary control. Other investigators have shown a marginally higher positive margin rate with preservation of this structure, at least in pathologically more advanced tumors (Marcovich et al., 2000.) The risk of detection of lymph node metastases is vanishingly low in most men found to have localized prostate cancer now. A retrospective study of men with favorable tumor characteristics were retrospectively analyzed in a report from the Cleveland Clinic. They found no difference in biochemical relapse if the patients had lymph node dissection or no lymph node dissection (Fergany et al., 2000.) A review of the use of neoadjuvant hormonal therapy for radical prostatectomy series confirmed the impression that lower surgical margin rates in these series has not been translated into improved disease-free survival. Therefore, there is no support for this practice (Scolieri et al., 2000.) Four year follow-up of a study from Europe confirmed the absence of benefit for neoadjuvant hormonal therapy before radical prostatectomy (Schulman et al., 2000.) Not surprisingly, 93% of urologists recommend prostatectomy, whereas 72% of radiation oncologists consider surgery and radiation equal treatments for men with clinically localized tumors and a life expectancy over 10 years (Fowler et al., 2000.)
Although seminal vesicle invasion is usually an unfavorable prognostic factor, a retrospective review from Hopkins suggested that some men with seminal vesicle invasion do not have a poor prognosis. Patients with Gleason score 5 or 6 and seminal vesicle involvement did well long-term, as long as margins were negative (Epstein et al., 2000.) Biochemical PSA progression after prostatectomy is variably defined in different series. A study from San Diego and the Mayo Clinic reported that the PSA cut point of 0.4 ng/ml was most effective at defining PSA progression after radical prostatectomy (Amling et al., 2001.) The presence of perineural invasion on biopsy has been suggested as a strong indicator of capsular penetration. A study from Boston confirmed that resection of the neurovascular bundle on the side corresponding to perineural invasion on biopsy may decrease the positive surgical margin rate (D’Amico et al., 2001.) A Cox proportional hazards model on a large data base of pT2 and pT3 patients was used to create a scoring algorithm for risk of recurrence after prostatectomy (Blute et al., 2001.) Since the patients in this data set were treated from 1990-1993, it is not clear how predictive this model would be for patients diagnosed one decade later in the PSA era of detection.
Prospective evaluation of erectile dysfunction was performed using a small subset of 2,956 patients diagnosed with prostate cancer and treated with radical prostatectomy, radiation or watchful waiting. Very few men treated with prostatectomy (10%) or radiation (15%) had post-treatment erectile function (Siegel et al., 2001.) These results are not consistent with that obtained and reported by centers of excellence for prostate cancer surgical treatment. Rabbani et al. (2000) reported similar results in preservation of sexual function after radical prostatectomy to that previously reported by centers of excellence in this technique. Return of erectile function adequate for sexual activity took up to 40 months to be realized and correlated with age and number of neurovascular bundles preserved. The use of a nerve stimulator during radical prostatectomy has been proposed as a method of identifying cavernous nerves intraoperatively to improve postoperative sexual functioning. A study from Nashville suggested that intraoperative Cavermap device stimulation results do not allow precise anatomical localization of the cavernous nerves (Holzbeierlein et al., 2001.) The authors suggest significant background related to anesthesia, surgical manipulation or other undefined factors limiting the value of this device. Walsh (2000) reported that review of intraoperative videotapes allowed introspection into minor alterations in surgical techniques that may affect sexual function postoperatively. A study of pelvic floor re-education after radical prostatectomy suggested only a limited benefit to these exercises as an aid to minimizing the duration and extent of urinary leakage after radical prostatectomy (Van Kampen et al., 2000.) Use of preoperative epoetin alpha in men undergoing radical retropubic prostatectomy was reported from NYU (Rosenblum et al., 2000.) The authors used 600 IU/kg at two weeks and one week prior to radical prostatectomy. The safety of this treatment was shown with increases of an average of 2.9% in hematocrit levels preoperatively.
The role of radiotherapy after isolated biochemical recurrence following prostatectomy was reported in a series of 166 consecutive patients from Mayo Clinic followed for a median of 52 months (Pisansky et al., 2000.) These authors reported a 46% biochemical NED rate 5 years after salvage radiation. Seminal vesicle invasion, tumor grade and pre-radiation PSA were independent factors associated with relapse. One in 6 patients had a chronic complication from treatment. Patients treated for prostate cancer with primary radiation therapy were found to have a statistically significant increase in the risk of development of a second malignancy compared to those patients treated with surgery but no radiation (Brenner et al., 2000.) Second tumors most commonly involved carcnimoas of the bladder, rectum and lung as well as sarcomas in the treatment field.
Modern prostate brachytherapy has had a resurgence of interest in the past several years, based in large part on the excellent results reported by Ragde et al. from Seattle. The authors have recently reported a 10-year followup of patients after brachytherapy (Ragde et al., 2000.) The proportion of men who were treated with brachytherapy alone was small (67 patients), and the overall disease-free rate was only 70%. This is low because many men had very well differentiated tumors (Gleason’s sum score 2-5), and no patients had Gleason score 7 or above. Comparable results for surgery would be expected above 90% (Polascik et al., 1998.) Radiation techniques using external beam now involves 3-dimensional conformal treatment with dose escalation. Whereas prior treatment involved only 65 cGy, it is now clear that optimal results include 75-80 cGy to the prostate with trials at higher doses (Hanks et al., 2000.) A study from Georgia reported that 35% of men treated with external beam radiation combined with seed implantation had “bounces” of their PSA, defined as an increase of 0.1 ng/ml or more (Critz et al., 2000.) Median time to PSA bounce was 18 months and median bounce height was 0.4 ng/ml. These authors felt that the “bounce” had no prognostic significance. Stone et al. (2000) reported that 11% of patients with brachytherapy had positive biopsies, with 16% of patients treated by neoadjuvant hormonal therapy followed by brachytherapy. PSA, Gleason score and isotope used did not predict outcome of the biopsy. Given that no men after prostatectomy have cancer remaining in the prostate gland inside a patient, it is hard to argue that brachytherapy will have the same treatment outcomes as surgery.
Use of 6 months of neoadjuvant hormonal therapy prior to 3-dimensional radiation thaerapy was analyzed in a retrospective study published in JAMA. The authors found that intermediate and high-risk patients had better 5-year PSA outcomes when treated for 2 months before and 4 months after radiation therapy. Erectile function after radioactive seed implantation was noted to decrease progressively at 3 and 6 years after treatment, in an actuarial analysis of men from New York (Stock et al., 2001.) Of men potent before treatment, 36% and 70% had declines in sexual function at 3 and 6 years, although many of these men were still able to have sexual activity.
Hormonal therapy/Advanced disease
Hormonal therapy is the standard approach for men with advanced or symptomatic prostate cancer. Isolated elevations of PSA in men after failed local therapy or advanced asymptomatic cancer have been treated in select cases. Herr & O’Sullivan (2000) reported significant impairment in physical and emotional health of patients treated if asymptomatic. Interestingly, the symptoms of fatigue, loss of energy, emotional distress and lower overall quality of life was lower in treated men, especially men treated with combined androgen blockade. A meta-analysis of randomized trial comparing maximal androgen blockade versus monotherapy with GnRH agonist or castration demonstrated no difference in survival rates with either treatment (Prostate Cancer Trialist’s Collaborative group, 2000.) These observations support the practice of antiandrogens only during the first month of GnRH agonist therapy. Not surprisingly, the use of combined androgen blockade or GnRH agonist alone was confirmed to be much more expensive than surgical castration (Mariani et al., 2001.) Lack of patient acceptance of surgery is capitalized upon by U.S. drug marketing to dramatically increase the cost of prostate cancer treatment. Hormonal therapy accounts for over one-half of all HCFA costs for treatment of prostate cancer. GnRH agonists increase testosterone, PSA levels and disease symptomatology in the first weeks of treatment before castrate levels of testosterone are achieved. A GnRH antagonist has been introduced recently that will promptly achieve castrate testosterone levels in 75% of patients within the first week of treatment (Tomera et al., 2001.) Abarelix is given in monthly shots and does not result in LH, testosterone or PSA levels.
Use of antiandrogens as monotherapy resulted in preservation of sexual function for only 20% of treated men (Schroder et al., 2000.) Given the significant side effects with this form of treatment (i.e., gynecomastia) antiandrogen monotherapy is of limited value. Use of intermittent androgen suppression has been proposed in uncontrolled trials with limited data. A study of 43 patients who were treated for 18 or more months until PSA levels reached a nadir below 4 ng/ml (or stable levels) were then taken off treatment and treatment was restarted if symptoms occurred from cancer progression or PSA reached 20 ng/ml. In the first cycle off treatment, patients stayed off treatment for only 6 months, with 4 months off treatment in the second cycle. The duration off treatment is little more than that required for testosterone levels to return to baseline levels. The value of intermittent androgen therapy appears little, as return of sexual activity did not occur during treatment “breaks.” It has been understood for several years that osteoporosis occurs during androgen deprivation. Daniell et al. (2000) reported that 2.4% of bone loss was lost in the first year after initiation of hormonal therapy with 7.6% in the second year. Average bone mineral density loss was 1.4 to 2.6% per year in years 3-8 of uninterrupted androgen deprivation. Bone loss was increased in men who were obese, younger than 75 years or without regular exercise. The use of stilbesterol and hydrocortisone as second line treatment for men with androgen-independent prostate cancer growth was studied by Farrugia et al. (2000.) They reported response in 83% of patients, remarkably similar to that reported for the herbal medication combination, PC-SPES. It appears that much of the activity of PC-SPES is attributable to the estrogenic activity of the phytoestrogenic soy protein in this compound. The use of rye bran and soy protein for prostate cancer prevention have been suggested by others. Its use was supported by an in vitro observations in human LNCaP prostate adenocarcinoma cell line (Bylund et al., 2000.)
Advanced prostate cancer may cause ureteral obstruction as a pre-terminal event. A study from Greece supported the safety of percutaneous urinary diversion in these patients (Pappas et al., 2000.) However, survival was <8 months after diversion and many of these patients will have very poor quality of life during this time period. An observational approach to these patients with informed consent and discussion among family members may be an alternative approach. The phenomenon of low PSA, metastatic, androgen-independent prostate cancer was presented by Sella et al. (2000.) These patients usually have small cell cancer (87%) with or without adenocarcinoma. Some patients have anaplastic tumors. Involvement of liver, lymph nodes and lung was common as well as pelvic masses and lytic bone metastates. Each patient had elevation of at least one of these tumor markers: CEA, CA19-9, CA15-3, or CA 125. Knowledge of this condition is important, as patients may be treated with cisplatin-based chemotherapy.
Urologic Oncology: Renal Tumors
Tsui et al. (2000) validated the revised 1997 TNM staging criteria for renal cell carcinoma, reporting 5-year cancer specific survival of 91%, 74%, 67%, and 32% for TNM stages I, II, III and IV lesions, respectively. The natural history of small renal tumors (avg. 2.9 cm diameter) was reported by Rendon et al. (2000) in a series of patients who averaged 69 years of age. Two of 13 tumors grew rapidly, caused symptoms and were removed. The remainder of tumors grew by an average of 1.3 cc per year. These data support initial expectant management of small renal tumors in the frail or elderly. A study of more than 350,000 Swedish men reported in the New England Journal of Medicine demonstrated a relationship between renal cell carcinoma and higher body mass index as well hypertension (Chow et al., 2000.) Whether weight control would lower the risk is unknown.
The role of partial nephrectomy for small renal cell tumors was supported by results from Cleveland Clinic and Memorial Sloan-Kettering Cancer Center. Lee et al. (2000)demonstrated similar perioperative morbidity and outcome with radical or partial nephrectomy. Fergany et al. (2000) reported 10-year followup of 107 patients with localized sporadic renal cell carcniomas, many of whom had renal insufficiency preoperatively. Cancer-specific survival was 88% at 5 years and 73% at 10 years. These results were not affected by tumor stage, symptoms, tumor laterality or tumor size. The need for adrenalectomy during nephrectomy was reported by Tsui et al. from UCLA (Tsui et al., 2000) who showed that the negative value of CT scan for predicting absence of adrenal involvement was better than 99%. Positive findings on CT are less specific but should lead to consideration of adrenalectomy.
A comparative trial of 47 laparoscopic nephrectomies for renal cell carcinoma were compared in a contemporary series with open radical nephrectomies. Laparoscopy resulted in less blood loss, shorter hospital stay, analgesic requirement and shorter convalescence with fewer overall complications. A report on the frequency of metastatic renal cell cancer after laparoscopic morcellation in N0 M0 patients demonstrated a 5% metastasis rate, including a renal fossa recurrence and a laparoscopic port recurrence (Fentie et al., 2000.) These findings are of concern for a tumor that can only be effectively treated with surgery.
Management of isolated renal cell metastases to bone in patients with solitary metastases, intractable pain, impending or present pathologic fracture was reported in the Journal of Urology (Kollender et al., 2000.) Postoperative pain was significantly reduced in 91% of paitents with 89% having good or excellent functional results. This group of patients was highly selected before treatment. Another study from the Mayo Clinic confirmed the potential to perform excision of isolated renal fossa recurrences after nephrectomy (Itano et al., 2000.) The 5-year survival rate with surgical resection was 51% compared to 18% with adjuvant medical therapy and only 13% with observation in this retrospective study. Although surgical treatment is possible in a limited number of these patients, it is often a major intervention requiring removal of contiguous organs in many cases. The later after initial surgery, the better the prognosis of patients treated for solitary recurrences in most series. A multicenter randomized trial of adjuvant interferon a2b for stages II and III renal cell carcinoma was reported by Pizzocaro et al. (2001.) The results of this study demonstrated no benefit in 5-year overall and event-free survival for treated patients.
New treatment approaches
Novel approaches to management of localized renal tumors with radiofrequency ablation or embolization and ablation were reported by Hall et al. (2001) and Walther et al. (2000.) The NIH group demonstrated antitumor effect in 10 of 11 renal cell tumors. The remaining tumor had treatment effect of only 35% of the cancer.
Urologic Oncology: Testis Tumors
An article in the journal Cancer reported a 6- to 10-fold increase in the risk of developing a testicular tumor in the sons of fathers found to have a germ cell tumor (Hans & Peschel, 2000.) Although these results are based on a literature survey, the observations could lead to genetic analysis that could provide insight into genetic predisposition for developing testicular cancer and lead to earlier diagnosis. A comprehensive review of carcinoma-in-situ of the testis (more accurately refered to as intratubular germ cell neoplasia) was presented by Rorth et al (2000.) They noted that CIS invariably progresses to invasive tumor, so orchiectomy or radiation therapy is warranted. Chemotherapy will suppress but does not eradicate disease in many patients. Although risk groups include subfertile men, those with a history of cryptorchidism, atrophic testes, ambiguous genitalia and history of contralateral germ cell tumors, guidelines for biopsy are not well delineated.
The presence of elevated tumor markers in patients with germ cell tumors generally reflect active disease in these patients and warrant aggressive treatment. A series of 6 patients with modestly elevated, constant or spontaneously normalized tumor markers were noted to remain in remission in a report from Memorial Hospital (Morris & Bosl, 2000.) Careful repeat evaluation may be warranted with subsequent close surveillance in selected patients to avoid unnecessary chemotherapy.
Lymph node dissection
Rassweiler et al. (2000) reported on 34 attempted laparoscopic lymph node dissections performed for low-stage testis tumors. All complications (5) were noted in the first 10 cases, suggesting a rapid but potentially dangerous learning curve for this procedure. A comparison of primary RPLND compared to initial treatment with chemotherapy for clinical stage II A/B NSGCT was analyzed in a prospective multicenter trial from Germany and Austria (Weissbach et al., 2000.) They found that more patients had relapse after chemotherapy (11%) than primary RPLND (7%) and that 33% of chemotherapy patients required subsequent RPLND. Secondary RPLND was associated with a higher complication rate, suggesting that primary RPLND may be a better approach for these patients.
Fertility after treatment
Spermatogenic function was analyzed in two studies of men after orchiectomy or 2 cycles of chemotherapy for germ cell tumor. In 60 patients managed with surveillance, sperm counts improved in the first year after orchiectomy, especially when the FSH was initially normal. One year after orchiectomy, ¾ of these men had sperm concentration above 10 million sperm/cc (Jacobsen et al., 2001.) Of 59 patients with stage I NSGCT treated with chemotherapy, no significant effects of adjuvant chemotherapy on fertility or sexual activity were identified (Bohlen et al., 2001.)
Urologic Oncology: Transitional Cell Tumors
Evaluation and prognostic factors
Survivin, a protein inhibitor of apoptosis, was measured in the urine of patients with transitional cell carcinoma of the bladder in a 2001 study reported in JAMA (Smith et al., 2001.) Urinary survivin levels were highly specific and sensitive in predicting the presence of tumors in this small study of 46 patients. Prior studies have shown that detection of human complement factor H related protein [BTA test] (Raitanen et al., 2001) has a role in patients at risk for recurrent bladder cancer. Sanchez-Carbayo et al. (2001) also reported on the urinary tests CYFRA 21-1 and NMP22 for patients at risk for bladder cancer recurrence. Although all of these tests are more sensitive for detection of recurrent bladder tumors than cytology, the clinical value of such urinary screening tests appears limited as they cannot remove cystoscopic evaluation in the follow-up of patients with bladder cancer. Other tumor markers evaluated on histologic study of transitional cell carcinoma of the bladder included E-cadherin (Byrne et al, 2001), bcl-2, p53 and Ki-67 index (Wu et al., 2000), p53 and muscularis mucosae invasion (Bernardini et al. 2001) and p21, p53, Ki67 and pRb as well as mitotic frequency (Holmang et al., 2001.) In most studies, p53 overexpression and depth of invasion have correlated with tumor progression. The Ki-67 labeling index appears to be an independent predictor of tumor recurrence, as has loss of E-cadherin immunoreactivity.
Recurrent TA, T1 and CIS treatment with maintenance BCG was reported in a large randomized multi-institutional study by SWOG (Lamm et al., 2000.) This study showed an improvement in recurrence-free survival in the 3-week maintenance arm compared to no maintenance. Maintenance appeared to be beneficial for select patients with Ta and T1 disease as well as those with CIS. No difference in 5-year survival was detected.
Invasive bladder cancer
The mechanisms of prostatic stromal invasion in patients with bladder cancer was investigated at Memorial Hospital (Donat et al., 2001.) They found that tumors at the bladder neck may directly invade prostatic stroma without extravesical or intraurethral spread. Such patterns of spread are not easily detected with standard clinical biopsies.
A contemporary series of 300 patients treated with cystectomy for bladder cancer was also reported from Memorial (Dalbagni et al., 2001.) The authors proposed categorizing lesions into organ-confined and nonorgan-confined lesions, with no observed differences in survival among patients with pT3 to pT4a tumors, nor among histological subtypes. Herr & Donat (2001) reported on 84 patients with grossly node positive disease who had pelvic lymph node dissection and radical cystectomy with a 24% overall survival rate. Survival was better for T2 tumors (32%) than for patients with stage T3 disease. The effect of perioperative MVAC on relapse after cystectomy for patients with muscle-invasive bladder cancer was reported from Columbia (Ennis et al., 2000.) They showed that low risk patients had excellent disease control with cystectomy alone, and perioperative chemotherapy affected pelvic failure but not metastatic disease. The preservation of urethral sensitivity distal to the membranous urethra after cystectomy and ileal bladder substitution was common and appeared to be an important factor in achieving continence after these procedures (Hugonnet et al., 2001.)
Upper tract transitional cell carcinoma (TCC)
Ureteroscopic management of 23 patients with upper tract tumors was reported by Chen & Bagley (2000.) With 35 month mean follow-up, all patients were alive withough evidence of disease progression. However, the patients treated were mostly low- and intermediate-grade lesions who were followed very aggressively by an expert endourologist. It is not clear if this is the optimal management for all patients with upper tract transitional cell tumors.
Laparoscopic surgery has continued to evolve as a primary treatment approach for a number of conditions. In addition to the extensive work that has been published in the area of laparoscopic donor nephrectomy and prostatectomy, investigators have explored early release from the hospital after laparoscopic adrenalectomy. Indy Gill and associates reported on 9 patients who underwent “outpatient laparoscopic adrenalectomy” at the Cleveland Clinic (Gill et al., 2000.) Almost all patients had aldosteronomas and the average tumor size was 2 cm. Only one complication developed, a local abscess treated two weeks postoperatively. Hand assisted laparoscopic and open surgical live donor nephrectomy were compared in another study (Wolf et al., 2000.) The laparscopic approach was found to be safe and effective, with progressively decreased operative time in the hand-assisted approach within the first 10 cases, suggesting a short learning curve.
Renal artery stenosis
The diagnosis of renal artery stenosis (RAS) was the subject of a new article and a review published this year in the New England Journal of Medicine (Radermacher et al., 2001; Safian et al., 2001.) Although diagnosis of RAS has moved from invasive renal vein renin measurements and arteriography to captopril scanning, the role of Doppler ultrasonography in diagnosis has recently been proposed. In these studies, if the renal resistant index is greater than 80, then there is little improvement in glomerular filtration rate, blood pressure or kidney survival after revascularization or angioplasty. The review by Safian et al has a clear discussion of renal arterial disease, renovascular hypertension and ischemic nephropathy.
A study published in the New England Journal of Medicine evaluated the use of the antioxidant acetylcysteine along with hydration as a means of avoiding contrast-induced nephrotoxicity. The authors found a significant benefit to both of these interventions (Tepel et al., 2000.) Although cyclooxygenase-2 inhibitors have fewer side effects than other non-steroidal anti-inflammatory drugs, their effect on renal function is less well elucidated. Swan et al. (2000) found that those with decreased renal function, patients after nephrectomy, and those with intrinsic renal disease may still have a deleterious effect associated with short-term use of cox-2 inhibitors, similar to that seen with other NSAIDs.
The rare condition of placenta percreta with bladder invasion was described in a report by Abbas et al. (2000.) Presenting symptoms included severe hematuria or prepartum hemorrhage with shock. Hysterectomy, bladder wall resection & repair as well as bilateral internal iliac artery ligation were required in both cases and fetal death occurred in both cases. Knowledge of this rare life-threatening condition is necessary to be aware of its existence.
A study of the relationship between cancer and thromboembolism was reported from the Danish cancer registry by Sorenson et al. (2000.) They found that 44% of 668 patients with venous thromboembolism had metastatic disease compared to 35% with controls. Having a vascular event was associated with a dramatically lower 1 year survival, which was related to more advanced cancer rather than a complication of venous thromboembolism. A series of 13 patients with squamous cell cancer of the penis and iliac metastases were reported by Lopes et al. (2000.) Although this clinical presentation has previously been considered pre-terminal, 5 of 13 patients were free of cancer at 56 months follow-up. Four of the five survivors had only one lymph node involved.
Adrenal lesions & imaging
The role of dynamic CT scans for adrenal imaging was reviewed by Pena et al. (2000) in Radiology. They found that 98% of masses were correctly characterized as benign or malignant if >50% washout was present, but malignant lesions had <50% washout. Of the malignant lesions, almost all were metastatic, but there were no adrenocortical carcinomas imaged. One study that confirmed the limitations of IVP studies was reported by Corrigan et al. (2000.) They found that approximately one-quarter of all new bladder tumors were diagnosed on IVP before cystoscopy; however, multiple tumors were always undetected and large tumors were often overlooked. The value of a “full bladder” film on IVP is limited.
Female sexual dysfunction
As with interstitial cystitis and chronic pelvic pain/prostatitis, the study of female sexual dysfunction is in its infancy. A significant step forward in making advances in this condition resulted from an interdisciplinary consensus conference panel of 19 experts from 5 countries, supported by the American Foundation for Urologic Diseases (Basson et al., 2000.) A new diagnostic and classification system based on physiological as well as psychological pathophysiologies was described, with a personal distress criterion for most diagnostic categories. Hopefully, this poorly understood syndrome will benefit from additional description as a step toward better treatment.
Advances in immunosuppression have dramatically improved transplant survival rates. A new class of immunosuppressants have recently been introduced. Sirolimus is the first of these agents that act to inhibit cytokine-driven cell proliferation and maturation. Its action is thought to be synergistic to previously applied immunosuppressants (Podbielski & Scheonberg, 2001.)
An interesting overview of how patients use the internet was published by Hellawell et al. (2000.) The authors of this paper, based on a questionnaire of patients at urologic outpatient and prostate cancer clinics suggest that 1 in 4 to 1 in 5 patients had used the internet to obtain medical information about their urological problems. The web sites were then reviewed and felt to provide conventional and good quality information.
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