Urine detection of survivin and diagnosis of bladder cancer.

CONTEXT: Dysregulation of apoptosis may favor onset and progression of cancer and influence response to therapy. Survivin is an inhibitor of apoptosis that is selectively overexpressed in common human cancers, but not in normal tissues, and that correlates with aggressive disease and unfavorable outcomes. OBJECTIVE: To investigate the potential suitability of survivin detection in urine as a novel predictive/prognostic molecular marker of bladder cancer. DESIGN, SETTING, AND PATIENTS: Survey of urine specimens from 5 groups: healthy volunteers (n = 17) and patients with nonneoplastic urinary tract disease (n = 30), genitourinary cancer (n = 30), new-onset or recurrent bladder cancer (n = 46), or treated bladder cancer (n = 35), recruited from 2 New England urology clinics. MAIN OUTCOME MEASURES: Detectable survivin levels, analyzed by a novel detection system and confirmed by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR), in urine samples of the 5 participant groups. RESULTS: Survivin was detected in the urine samples of all 46 patients with new or recurrent bladder cancer using a novel detection system (31 of 31) and RT-PCR (15 of 15) methods. Survivin was not detected in the urine samples of 32 of 35 patients treated for bladder cancer and having negative cystoscopy results. None of the healthy volunteers or patients with prostate, kidney, vaginal, or cervical cancer had detectable survivin in urine samples. Of the 30 patients with nonneoplastic urinary tract disease, survivin was detected in 3 patients who had bladder abnormalities noted using cystoscopy and in 1 patient with an increased prostate-specific antigen level. Patients with low-grade bladder cancer had significantly lower urine survivin levels than patients with carcinoma in situ (P =.002). CONCLUSIONS: Highly sensitive and specific determination of urine survivin appears to provide a simple, noninvasive diagnostic test to identify patients with new or recurrent bladder cancer.

Geographic variation in patient surveillance after radical prostatectomy.

BACKGROUND: Prostate cancer is often diagnosed early enough in its clinical course to permit radical prostatectomy to be done with curative intent, yet many patients experience tumor recurrence. Most patients receive postoperative surveillance, but the intensity of testing varies appreciably. We sought to evaluate the influence of geographic location on the variability of surveillance intensity. METHODS: Questionnaires pertaining to postoperative surveillance were mailed to 4467 members of the American Urological Association (AUA). Practice pattern variation was assessed among 24 large metropolitan statistical areas, among nine United States census regions, and by health maintenance organization penetration rate. RESULTS: Of 4467 urologists surveyed, 1416 (32%) responded and 1050 (24%) responses were evaluable. Correlation analysis showed that mean follow-up intensity across modalities surveyed was highly correlated across tumor, node, metastasis (TNM) stages and years postsurgery. We found no significant main effects attributable to metropolitan statistical area, United States (US) census region, or health maintenance organization (HMO) penetration rate for commonly used surveillance modalities: serum prostate-specific antigen (PSA), office visit, and urinalysis. For infrequently used modalities, there were minimal effects on testing intensity of US census region, metropolitan statistical area, and HMO penetration rate. Few two-way and three-way interactions were significant. CONCLUSIONS: The utilization of commonly used surveillance modalities by urologists caring for patients after radical prostatectomy is not affected by metropolitan statistical area, US census region, or HMO penetration rate.

How tumor stage affects american urologists' surveillance strategies after prostate cancer surgery.

The factors which influence decision-making among urologists are not well understood. We evaluated how tumor stage in patients subjected to potentially curative surgery for carcinoma of the prostate affects the self-reported follow-up strategies employed by practicing United States urologists. Standardized patient profiles and a detailed questionnaire based on these profiles were mailed to 4,467 randomly selected members of the American Urological Association (AUA), comprising 3,205 US and 1,262 non-US urologists. The effect of TNM stage on the surveillance strategies chosen by respondents was analyzed by repeated-measures ANOVA. There were 1, 050 respondents who provided evaluable data of whom 760 were from the US. The three most commonly used surveillance modalities by urologists were office visit, serum PSA level, and urinalysis. Nine of the 11 most commonly requested modalities were ordered significantly (p<0.001) more frequently with increasing TNM stage. This effect persisted through 10 years of follow-up, but the differences across stage were tiny. Fifty-five percent of US respondents do not modify their strategies at all according to the patient's TNM stage. Most American AUA members performing surveillance after potentially curative radical prostatectomy for otherwise healthy patients use the same follow-up strategies irrespective of TNM stage. These data permit the rational design of a randomized clinical trial of two alternate follow-up plans. The two trial arms would employ office visits, blood tests, and urinalyses at different frequencies based on current actual practice patterns; there would be no imaging tests in either arm.

The age of the urologist affects the postoperative care of prostate carcinoma patients.

BACKGROUND: Strategies utilized by urologists in managing prostate carcinoma patients after radical prostatectomy vary appreciably. The reason for this is unclear. The authors investigated the effect of practitioner age on management strategies. METHODS: From among the total of 12,500 American Urological Association (AUA) members, 4467 were randomly selected to receive a custom-designed survey about their care of prostate carcinoma patients after radical prostatectomy. Respondents were asked to describe their follow-up practices for patients treated with curative intent, their motivations regarding postoperative surveillance, their methods of evaluating a postoperative increase in serum prostate specific antigen (PSA) level, and their choices of treatment for patients with recurrent prostate carcinoma. RESULTS: One thousand fifty responses were analyzed. There was a statistically significant influence of practitioner age on the management of at-risk patients, but it was quite small. The typical workup for an elevated postoperative serum PSA level also varied significantly according to practitioner age; older urologists ordered more serum prostatic acid phosphatase levels and computed tomography scans of the abdomen and pelvis, whereas younger urologists ordered more bone scans. The treatment of recurrent prostate carcinoma did not vary significantly according to urologist age. The opinions of older urologists regarding the survival benefits of postoperative surveillance were considerably different from the opinions of their younger colleagues. CONCLUSIONS: The results of this study suggest that urologist age accounts for some of the variation in the postoperative management of prostate carcinoma patients. Differences in beliefs regarding the benefits of surveillance may be partially responsible for this. Persuasive clinical research will probably be required to increase the uniformity of practice in this important area.

A prospective randomized comparison of three blood conservation strategies for radical prostatectomy.

BACKGROUND: Preoperative autologous blood donation is a standard of care for elective surgical procedures requiring transfusion. The authors evaluated the efficacy of alternative blood-conservation strategies including preoperative recombinant human erythropoietin (rHuEPO) therapy and acute normovolemic hemodilution (ANH) in radical retropubic prostatectomy patients. METHODS: Seventy-nine patients were prospectively randomized to preoperative autologous donation (3 U autologous blood); rHuEPO plus ANH (preoperative subcutaneous administration of 600 U/kg rHuEPO at 21 and 14 days before surgery and 300 U/kg on day of surgery followed by ANH in the operating room); or ANH (blinded, placebo injections per the rHuEPO regimen listed previously). Transfusion outcomes, perioperative hematocrit levels, postoperative outcomes, and blood-conservation costs were compared among the three groups. RESULTS: Baseline hematocrit levels were similar in all groups (43%+/-2%). On the day of surgery hematocrit decreased to 34% +/-4% in the preoperative autologous donation group (P < 0.001), increased to 47%+/-2% in the rHuEPO plus ANH group (P < 0.001), and remained unchanged at 43%+/-2% in the ANH group. Allogeneic blood exposure was similar in all groups. The rHuEPO plus ANH group had significantly higher hematocrit levels compared with the other groups throughout the hospitalization (P < 0.001). Average transfusion costs were significantly lower for ANH ($194+/-$192) compared with preoperative autologous donation ($690+/-$128; P < 0.001) or rHuEPO plus ANH ($1,393+/-$204, P < 0.001). CONCLUSIONS: All three blood-conservation strategies resulted in similar allogeneic blood exposure rates, but ANH was the least costly technique. Preoperative rHuEPO plus ANH prevented postoperative anemia but resulted in the highest transfusion costs.

Current followup strategies after radical prostatectomy: a survey of American Urological Association urologists.

PURPOSE: Followup care of men who have undergone potentially curative surgical treatment for prostate cancer varies widely among clinicians. To determine current practice patterns we mailed a custom designed questionnaire to American and nonAmerican urologists who were American Urological Association (AUA) members. MATERIALS AND METHODS: Surveys were mailed to a random sample of the approximately 12,000 AUA members, comprising 3,205 Americans and 1,262 nonAmericans. Evaluable surveys were returned by 760 American (24%) and 290 nonAmerican (23%) urologists. Our analysis is based on these 1,050 responses. RESULTS: In generally healthy patients after radical prostatectomy for stages T1 to 2NOMO and T3a to cNOMO prostate cancer the most frequently recommended followup diagnostic tests included office visit with digital rectal examination, serum prostate specific antigen (PSA) and urinalysis. Although there is appreciable variation in the frequency of use of these methods, respondents generally recommended office visit with digital rectal examination, serum PSA and urinalysis every 3 months in year 1, every 6 months in years 2 to 5 and annually thereafter. Other tests, such as serum prostatic acid phosphatase, bone scan, and abdominal and pelvic computerized tomography and magnetic resonance imaging, are rarely recommended. CONCLUSIONS: Our survey provides information regarding current followup strategies recommended by AUA urologists after radical prostatectomy for stages T1 to 2NOMO and T3a to cNOMO disease. Office visits and digital rectal examination, urinalysis and PSA measurement are the main tools that urologists currently use. Although optimal strategy remains unknown, these data permit the rational design of clinical trials of alternate followup strategies based on actual current practice to answer this important question.

Evaluation and management of men whose radical prostatectomies failed: results of an international survey.

OBJECTIVES: To determine how urologists evaluate and treat men who develop recurrent prostate cancer after radical prostatectomy. METHODS: Surveys were mailed to 4467 American Urological Association members comprising 3205 U.S. and 1262 non-U.S. urologists randomly selected from a total membership of approximately 12,000. One thousand four hundred sixteen were returned and 1050 (760 U.S. and 290 non-U.S.) surveys were evaluable. RESULTS: To evaluate men with an elevated or rising prostate-specific antigen (PSA) level more than 1 year after radical prostatectomy, 98% of respondents use digital rectal examination, 68% use bone scan, 54% use transrectal ultrasound with biopsy, 36% use abdominal or pelvic computed tomography scan, 31% use transrectal ultrasound without biopsy, 25% use prostatic acid phosphatase, 11% use monoclonal antibody scan, and 5% use abdominal or pelvic magnetic resonance imaging. Respondents evaluate men with an elevated or rising PSA within 1 year of radical prostatectomy similarly. To treat documented local recurrence, 81% of respondents recommend radiation therapy, 7% recommend orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonists, 6% recommend observation only, and 5% recommend combined androgen ablation. To treat documented distant recurrence, 50% recommend combined androgen ablation, 42% recommend orchiectomy or LHRH agonists, and 7% recommend observation only. To treat PSA-only recurrence, 54% recommend observation only, 16% recommend combined androgen ablation, 15% recommend orchiectomy or LHRH agonists, and 13% recommend radiation therapy. CONCLUSIONS: The evaluation of men whose radical prostatectomy failed varies among urologists and does not depend on time of recurrence. Radiation therapy is used by most urologists to treat local recurrence. Hormonal manipulation is used by more than 90% of urologists to treat distant recurrence. More than 50% of urologists recommend observation for men with biochemical-only recurrence.

Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy.

UNLABELLED: Predonation of autologous blood (PAD) is a standard of care for patients undergoing radical prostatectomy, but recent studies have shown that PAD is not cost-effective. Acute normovolemic hemodilution (ANH) is an alternative autologous blood procurement technique that is much less costly than PAD. We compared the efficacy and costs of ANH alone to ANH combined with PAD. Two hundred-fifty patients who predonated fewer than 3 units of autologous blood before radical prostatectomy underwent ANH to a target hematocrit of 28%. Perioperative hematocrit levels, transfusion outcomes and costs, and postoperative outcomes were compared for patients who predonated 0, 1, or 2 units of blood before surgery. A computer model was used to estimate the savings in red blood cells (RBC) associated with each autologous intervention. ANH alone resulted in a 21% allogeneic transfusion rate and contributed a mean net savings of 112 mL RBC in blood conservation (equivalent to 0.6 unit of blood). The addition of 1 or 2 units of PAD reduced allogeneic exposure rates to 6% or 0%, respectively. Overall, patients who predonated blood had a mean net loss of 198 mL of RBC (equivalent to 1 blood unit), due to both an absence in compensatory erythropoiesis and to the wastage of 60% of the blood units donated. Patients who underwent ANH alone had a 60% reduction in mean total transfusion costs ($103 +/- $102) compared with patients who predeposited 2 units of autologous blood in addition to ANH ($269 +/- $11, P < 0.05). We conclude that ANH can replace PAD as an autologous blood option because it is less costly and equally effective. A combination of ANH and PAD can further decrease allogeneic blood exposure, but it increases transfusion costs and wastage. IMPLICATIONS: A patient's own blood can be obtained for use in surgery by predonation or acute normovolemic hemodilution on the day of surgery. Both blood collection techniques decrease the need for blood bank transfusions, but acute normovolemic hemodilution is less expensive and more convenient for patients.

Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis.

OBJECTIVE: To determine the long-term outcome of men with carcinoma of the penis with clinically negative lymph nodes undergoing a modification of the standard inguinal lymphadenectomy. PATIENTS AND METHODS: The study included nine men (mean age 56.2 years, range 41-72) with squamous cell carcinoma of the penis who underwent a modified inguinal lymphadenectomy. RESULTS: Of the nine patients, three had histologically positive lymph nodes; none of the patients with positive or negative nodes had evidence of recurrent disease. All patients were alive within a follow-up of 13-108 months (mean 67.5). Early post-operative complications occurred in two patients with skin-flap necrosis, one with prolonged lymphatic drainage and one with a delayed groin lymphocele and cellulitis. CONCLUSION: The modified inguinal lymphadenectomy is a reasonable alternative to surveillance and may accurately identify men with positive nodes. Long-term survival and low morbidity seem to justify this approach in men with squamous cell carcinoma of the penis and clinically negative inguinal lymph nodes.

Pediatric endopyelotomy: the Washington University experience.

PURPOSE: Endopyelotomy has gained acceptance as minimally invasive therapy for ureteropelvic junction obstruction in adults. Its role in the treatment of pediatric ureteropelvic junction obstruction remains controversial. We report our experience with antegrade endopyelotomy for treating pediatric ureteropelvic junction obstruction. MATERIALS AND METHODS: A total of 17 patients 3 months to 17 years old underwent endopyelotomy as primary treatment for ureteropelvic junction obstruction (8) and after failed open pyeloplasty with secondary endopyelotomy performed a mean of 12 weeks after open pyeloplasty (9). Standard antegrade percutaneous techniques were used. Electrosurgical incision of the ureteropelvic junction at a posterolateral orientation was done in each case. Internal ureteral stents remained in place for 4 to 6 weeks postoperatively. RESULTS: In 5 of the 8 patients (62%) treated primarily the outcome was successful at a mean followup of 38 months (range 25 to 53). Failures occurred at 6 weeks, 3 months. In all 9 patients treated secondarily outcomes were successful at a mean followup of 59 months (range 16 to 110). CONCLUSIONS: Endopyelotomy as primary treatment of pediatric ureteropelvic junction obstruction remains controversial but it may be appropriate in select cases. On the other hand, endopyelotomy is safe and effective for pediatric patients in whom open pyeloplasty fails.

Paracrine stimulation of preadipocyte-enriched cell cultures by mature adipocytes.

We developed a double-chamber system in which to examine the effects of mature adipocytes on the growth and differentiation of preadipocytes and other cells in the adipose tissue. In the present study we found that mature adipocytes from both lean and obese subjects release a factor that stimulates the growth of preadipocyte-enriched and dedifferentiated adipocyte-enriched cell cultures. This growth stimulation was dependent on both time of exposure to mature cells and the number of mature cells in the coculture. Proliferation of the preadipocyte-enriched (n = 4) and dedifferentiated adipocyte-enriched cultures (n = 5) in the presence of mature adipocytes from obese subjects [body mass index (BMI) > 35] was 4.1- and 2.9-fold more (P < 0.05) than that in the presence of adipocytes from lean subjects (BMI < or = 25). There was no difference in the growth of cultures enriched in preadipocytes or dedifferentiated adipocytes from lean or obese subjects in the absence of mature adipocytes. These observations demonstrate that mature adipocytes from obese patients stimulate the growth of preadipocyte-enriched cultures to a greater extent than those from lean individuals.

Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia.

We tested the hypothesis that liver protein kinase C (PKC) is increased in non-insulin-dependent diabetes mellitus (NIDDM). To this end we examined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls. PKC isozymes alpha, beta, epsilon and zeta were detected by immunoblotting in both the cytosol and membrane fractions. Isozymes gamma and delta were not detected. There was a significant increase in immunodetectable PKC-alpha (twofold), -epsilon (threefold), and -zeta (twofold) in the membrane fraction isolated from obese subjects with NIDDM compared with the lean controls. In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next sought an animal model where this observation could be studied further. The Zucker diabetic fatty rat offered such a model system. Immunodetectable membrane PKC-alpha, -beta, -epsilon, and -zeta were significantly increased when compared with both the lean and obese controls. The increase in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane. Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity. Further, phlorizin treatment did not improve insulin receptor autophosphorylation nor did the treatment lower liver diacylglycerol. We conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKC-mediated phosphorylation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM.

Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.

Obese (ob) gene expression in abdominal subcutaneous adipocytes from lean and obese humans was examined. The full coding region of the ob gene was isolated from a human adipocyte cDNA library. Translation of the insert confirmed the reported amino acid sequence. There was no difference in the sequence of an reverse transcription PCR product of the coding region from five lean and five obese subjects. The nonsense mutation in the ob mouse which results in the conversion of arginine 105 to a stop codon was not present in human obesity. In all 10 human cDNAs, arginine 105 was encoded by CGG, consequently two nucleotide substitutions would be required to result in a stop codon. To compare the amount of ob gene expression in lean and obese individuals, radiolabed primer was used in the PCR reaction with beta-actin as a control. There was 72% more ob gene expression (P < 0.01) in eight obese subjects (body mass index, BMI = 42.8 +/- 2.7) compared to eight lean controls (BMI = 22.4 +/- 0.8). Regression analysis indicated a positive correlation between BMI and the amount of ob message (P < 0.005). There was no difference in the amount of beta-actin expression in the two groups. These results provide evidence that ob gene expression is increased in human obesity; furthermore, the mutations present in the mouse ob gene were not detected in the human mRNA population.

Ureteropelvic junction obstruction in infants mimicking ureterovesical junction obstruction on sonography.

We present two infants with ureteropelvic junction obstruction with very large renal pelves, which extended to the level of the urinary bladder. In both cases, the distal aspect of the renal pelvis simulated a dilated distal ureter, leading to the incorrect sonographic diagnosis of ureterovesical junction obstruction. Awareness of this potential pitfall on sonography is important when imaging infants with prenatal diagnosis of hydronephrosis.

Laparoscopic nephroureterectomy in the child: initial case report.

Laparoscopy in the pediatric population is beginning to be used for major therapeutic procedures. We report the completion of a laparoscopic nephroureterectomy and bladder diverticulectomy in a 6-year-old child.

A new technique for biopsy of human abdominal fat under local anaesthesia with Lidocaine.

The objectives of this study were to develop a new technique to safety, reliably, and in a cosmetically acceptable way, obtain more than 5.0 g of abdominal subcutaneous fat in out-patients, and to investigate whether inhibitory effects of a local anaesthetic on adipose tissue function in vitro are sufficient argument against the use of infiltrative local anaesthesia during fat biopsy to obtain samples for metabolic studies. Measurements were obtained to compare glucose transport and lipolysis response to insulin in adipocytes isolated from subcutaneous abdominal fat obtained: (i) during elective surgery in eight women and four men (BMI 25.8 +/- 3.1 kg/m2); and (ii) from five male and three female out-patients (BMI 25.8 +/- 3.1 kg/m2) by the described novel technique performed under local anaesthesia with Lidocaine. The effects of acute and 11-day exposure to Lidocaine in vitro on adipocyte lipolysis and glucose transport response to insulin, and the growth potential were determined. In vivo exposure of the tissue samples to local anaesthetic by the novel technique had no apparent effect on isolated adipocyte responses to insulin by stimulation of glucose transport or by inhibitor- or adrenaline-stimulated lipolysis; the results were not different to those for adipocytes isolated from fat obtained during elective abdominal surgeries. Lidocaine added in vitro potently inhibited glucose transport and lipolysis in adipocytes, and cell attachment and growth in primary 'ceiling' culture; this effect persisted only as long as Lidocaine was present. After washing, adipocytes fully regained their function and growth regardless of the exposure period, as short as 30 min or as long as 11 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and pathological extent of prostate cancer in men with prostate specific antigen levels of 2.9 to 4.0 ng./ml.

Various authors have recommended different values for the upper limit of normal for the monoclonal prostate specific antigen (PSA) assay (for example 4.0 ng./ml. or less by the manufacturer Hybritech or 2.8 ng./ml. or less by others). To our knowledge, no studies have examined the prevalence and pathological extent of prostate cancer detectable by needle biopsy in ambulatory volunteers with PSA levels in the range of 2.9 to 4.0 ng./ml. We evaluated 121 volunteers by rectal examination and transrectal ultrasonography with PSA levels in that range. We performed ultrasound-directed needle biopsy of the prostate if abnormal findings were present on either examination. The prevalence of detectable prostate cancer in this group was 7.2% (8 of 111). All 8 patients had pathologically organ confined cancer, and only 2 had suspicious findings on rectal examination but all had abnormal or suspicious ultrasound findings. We believe that the 7.2% yield from ultrasonography and biopsy in patients with a PSA level of 2.9 to 4.0 ng./ml. is too low to justify further invasive evaluation. Rather, we recommend careful followup and monitoring of these patients with serial PSA measurements and rectal examination, and advise performance of ultrasonography and biopsy if the rectal examination becomes suspicious for cancer or the PSA level increases above 4.0 ng./ml.