Clinical application of NMP22 in the management of transitional cell carcinoma of the bladder.

The combination of a noninvasive, quantitative immunoassay, NMP22, with voided urinary cytology prior to cystoscopy was evaluated in patients with urothelial transitional cell carcinoma. Fifty-six patients with a history of transitional cell carcinoma were evaluated. Voided urine was obtained for NMP22 and cytology prior to cystoscopy. One hundred and twenty-three NMP22 assays, 124 cytologies, and 124 cystoscopies were performed. The type of anesthesia used for cystoscopic evaluation was determined by the NMP22 value in 30 patients. Cystoscopy results were considered positive on biopsy-confirmed malignancy. The reference value used for NMP22 was 10.0 U/ml. NMP22, cytology, and the combination of NMP22 and cytology were compared to cystoscopy and to pathologic grading and staging. Thirty-four recurrent transitional cell carcinoma episodes occurred; 22 were low-grade (I-II), and 12 were high-grade (III-IV). Twenty-seven were stage Ta; four were T1; and three were T3b or 4. Within this group, NMP22 detected low- and high-grade tumors equally, as compared to cytology, which was sensitive only to high-grade tumors. Nineteen patients were NMP22-negative and underwent cystoscopy under topical anesthesia; 17 were tumor-free. Eleven patients were NMP22-positive and had anesthesia, and all had visible lesions, which were subjected to biopsy and were resected. Six lesions were tumors, five were inflammatory. Overall sensitivity of combined NMP22 and cytology was 70%; specificity was 72%; positive predictive value was 54%; and negative predictive value was 77%. An accurate assessment of the risk of a bladder cancer can be obtained with NMP22, cytology, and cystoscopy in patients with a history of bladder cancer. NMP22 values can be used to determine the level of anesthesia for cystoscopy in patients with a history of bladder cancer.

Blood-based RT-PCR assays of MN/CA9 or PSMA: clinical application in renal cancer patients.

OBJECTIVES: To report a survey of blood-based RNAs obtained from common groups of control and renal cancer patients for expression of both MN/CA9 and prostate-specific membrane antigen (PSMA) messenger RNAs. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) assays for MN/CA9 and PSMA were performed on RNAs extracted from 81 blood samples (59 patients with renal cancer, 7 with benign tumors, and 15 control volunteers). The results of these assays were statistically analyzed to determine whether a positive result (individually or combined) correlates with any tumor characteristics. RESULTS: Neither MN/CA9 nor PSMA amplification products were detected in the RNAs from peripheral blood samples of the 15 control volunteers and from the 7 patients with benign renal tumor (sensitivity 100%). MN/CA9 alone was detected in 11 (19%) of 59 samples and PSMA alone in 12 (20%) of 59 samples from patients with renal cancer. PSMA positivity was significantly correlated with vascular invasion of the primary tumor. Expression of one or both of these molecular tumor markers was detected in 21 (36%) of 59 renal cancer patients. When combined, the results of the MN/CA9 and PSMA RT-PCR tests were found to be highly associated with vascular invasion in nephrectomy specimens (sensitivity 67%, specificity 77%, odds ratio = 6.89, P = 0.002). CONCLUSIONS: Combination of RT-PCR assays for MN/CA9 and PSMA provides a sensitive blood test for molecular detection of clear cell carcinoma of the kidney and its potential for vascular invasion. Further testing of this assay will be required to evaluate its efficacy in the diagnosis, screening, and follow-up of patients with kidney cancer.

Detection of prostate-specific membrane antigen expressing cells in blood obtained from renal cancer patients: a potential biomarker of vascular invasion.

Originally, prostate-specific membrane antigen (PSMA) was described in benign and malignant prostate cells. On the basis of recent reports that this antigen also is expressed in normal renal proximal tubular cells and in the neovascular endothelium associated with renal carcinoma, we used a nested reverse transcriptase-polymerase chain reaction assay to evaluate whether PSMA-expressing cells might be present in specimens of peripheral blood obtained from renal cancer patients, benign renal tumor patients, and healthy volunteers. Our reverse transcriptase-polymerase chain reaction PSMA assay had a sensitivity of detecting 1 lymph node prostate cancer (LNCaP) per 10(7) lymphocytes. None of the 20 non-renal cancer controls were positive for PSMA mRNA, whereas 11 of 50 patients (22%) with diagnosed renal cancer were positive. Despite a comparative increase of PSMA positivity with stage, no statistical correlation was found. However, 44% of PSMA-positive patients had tumor size greater than 12 cm, versus only 9% in patients negative for PSMA (P = .03), and 67% of positive PSMA patients were found to have vascular invasion versus only 16% of patients negative for PSMA (P = .006; odds ratio, 10.8). This preliminary study suggests the possibility that PSMA expression in peripheral blood might be a useful biomarker for detecting or monitoring the progression of renal cancer in patients.

Renal cell carcinoma: should radical nephrectomy be performed in the presence of metastatic disease?

Metastatic renal cell carcinoma is associated with an unfavorable prognosis and the treatment options are limited. Adjunctive radical nephrectomy, performed either before or after the administration of systemic immunotherapy, has been proposed as a means of improving outcome. The role of nephrectomy for patients with metastatic disease remains controversial. This article reviews the role of nephrectomy in metastatic renal cell carcinoma and the optimal timing for surgery relative to immunotherapy.

The detection of renal carcinoma cells in the peripheral blood with an enhanced reverse transcriptase-polymerase chain reaction assay for MN/CA9.

BACKGROUND: Using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay, the authors previously determined the expression of MN/CA9 mRNA in renal cell carcinoma (RCC) and its absence in benign renal tissue. In the current study, the utility of an enhanced RT-PCR assay in the detection of renal carcinoma cells in the peripheral blood was assessed. METHODS: An enhanced MN/CA9 RT-PCR assay was applied to peripheral blood samples from a total of 96 patients. Forty-two patients had renal tumors, including 5 with benign renal lesions, 28 with localized RCC, and 9 with metastatic RCC. Fifty-four control patients without renal tumors were similarly tested. Pathologic staging for patients with localized cancer was T1N0M0 for 5, T2N0M0 for 9, and T3N0M0 for 14 patients. RESULTS: Cells expressing MN/CA9 were detected in 1 of 54 controls (1.8%) and in 18 of 37 cancer patients (49%). Thirteen of twenty eight patients (46%) with localized RCC and 5 of 9 (56%) with metastatic disease tested positive with the assay. No patient with a benign renal tumor exhibited MN/CA9 expression. All blood test results for patients with clear cell RCC were noted to be positive. No correlation was noted between MN/CA9 results and age, gender, or tumor grade. The differences in MN/CA9 results according to T classification were not statistically significant. CONCLUSIONS: The enhanced RT-PCR assay for MN/CA9 is a highly specific technique for detecting circulating renal carcinoma cells in the peripheral blood, and it may prove useful in the diagnosis and monitoring of RCC.

Radiologic follow-up of patients with T1-3a,b,c or T4N+M0 renal cell carcinoma after radical nephrectomy.

OBJECTIVES: To determine the pattern of disease recurrence after radical nephrectomy in patients with node-positive renal cell carcinoma (RCC) in order to design a schedule for subsequent radiologic evaluation. METHODS: We reviewed the postoperative radiologic studies of 45 patients with T1-3a,b,c or T4N+M0 RCC enrolled in a prospective trial of adjuvant autolymphocyte therapy (ALT) after radical nephrectomy for node-positive disease. Chest radiograph and abdominal computed tomography (CT) were performed quarterly, and bone scan and head CT were performed every 6 months until disease recurrence, or earlier if clinically indicated. Time from surgery to recurrence and sites of recurrence were analyzed. RESULTS: Twenty-nine patients (64%) had disease progression, with a mean time to progression of 14.9 months. Mean follow-up of patients without progression was 39 months. The sites of recurrence were retroperitoneal lymph nodes (n=14), lung (n=11), liver (n=5), bone (n=5), mediastinal lymph nodes (n=4), renal fossa (n=3), pelvis (n=2), brain (n=2), contralateral kidney (n=1), retrocecum (n=1), and skin (n=1). Fourteen patients had recurrence at more than one site. Of the patients whose disease progressed, 59% did so by 12 months, 83% by 24 months, and 93% by 36 months. Mean time to progression in the ALT group was delayed compared with the observation group, but the sites of disease recurrence were not different between the two groups. Abdominal CT alone detected recurrent lesions in 79% of patients with progression, and the combination of abdominal CT and chest radiograph detected lesions in 100% of patients with progression. CONCLUSIONS: Abdominal CT with chest radiograph detects recurrence in all patients with T1-3a,b,c or T4N+M0 RCC whose disease progresses, and more than 90% of recurrences occur within the first 3 years after surgery. We recommend abdominal CT and chest radiograph every 6 months for at least 3 years and yearly thereafter in this high-risk group of patients.

Eccrine sweat gland carcinoma of the scrotum with associated extramammary Paget's disease.

Sweat gland carcinomas are rare tumors which have not previously been reported as arising from the scrotum. We present the first known case of primary eccrine sweat gland carcinoma of the scrotum in association with extramammary Paget's disease (EPD) and review the presentation and management of these tumors. Sweat gland carcinomas frequently coexist with EPD and this association provides insight into the histogenesis of EPD, which is presently unknown. Sweat gland carcinoma should be included in the differential diagnosis of cutaneous scrotal tumors and carefully ruled out pathologically if the diagnosis of EPD alone is made.

Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma.

MN is a novel cell surface antigen originally detected in human HeLa cells. Although it is also expressed in normal gastric mucosa, this antigen was previously found to be expressed in cells with a malignant phenotype in certain tissues of the female genital tract (cervix and ovary). Using an oligonucleotide primer set specific for MN-complimentary DNA, we performed reverse transcription-PCR assays on RNAs extracted from human cell lines and tissues to evaluate whether this marker might be expressed at other sites. RNA libraries extracted from normal human heart, lung, kidney, prostate, peripheral blood, brain, placenta, and muscle were negative for MN expression. RNAs extracted from liver and pancreatic tissue were positive for MN expression. Three of six renal cancer cell lines tested revealed MN expression. In addition, 12 of 17 samples of human renal cell carcinoma tissue tested positive for MN, all 12 of which were clear cell adenocarcinomas. This survey identified a unique association of MN expression with renal cell cancers, especially those of the clear cell variety, suggesting that MN is a potential marker for the diagnosis, staging, and therapeutic monitoring of renal cell carcinoma in humans.

Epidermal growth factor suppresses renal tubular apoptosis following ureteral obstruction.

OBJECTIVES: Acute unilateral ureteral obstruction (UUO) results in ipsilateral hydronephrosis characterized by a decrease in epidermal growth factor (EGF) mRNA expression and EGF protein levels in the distal renal tubules. UUO results in programmed cell death with increases in the characteristic markers of apoptosis. To suppress the apoptotic response during UUO, recombinant EGF was administered during renal obstruction and the ensuing molecular and histologic changes were studied. METHODS: Mature Sprague-Dawley rats underwent left ureteral obstruction and the kidneys were harvested at 24, 48, and 72 hours. Markers of apoptosis included DNA laddering pattern on agarose gel electrophoresis, in situ gap labeling of fragmented DNA for quantitative apoptotic body determination, polyadenylated mRNA expression of SGP-2, and in situ hybridization for sulfated glycoprotein-2 (SGP-2) mRNA. Studies were repeated in rats following administration of 10, 20, and 40 micrograms of subcutaneous recombinant EGF on a daily basis after UUO. RESULTS: Subcutaneous injection of EGF into unilaterally obstructed rats promotes renal tubular epithelial cell regeneration, as demonstrated by increased cortical mitotic activity. Systemic EGF supplementation in these unilaterally obstructed rats also resulted in a decrease in the intensity of the DNA laddering pattern associated with renal tubular apoptosis. An in situ labeling procedure to identify apoptotic nuclei in the ureterally obstructed kidneys revealed a 50% reduction in apoptosis after EGF administration. Northern blot analysis and in situ hybridization for SGP-2 mRNA or clustering gene product also revealed a decreased expression in the obstructed and EGF-treated renal parenchyma. CONCLUSIONS: These data suggest that EGF, apart from its known role as a mitogenic substance for renal tubular epithelial cells, is also a critical in vivo renal cell survival factor for the developmentally mature kidney.

Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma.

OBJECTIVES: We assessed the frequency of bone metastases, their association with serum alkaline phosphatase (AP), and prognostic capabilities of AP in patients with renal cell carcinoma (RCC), using bone scan as the reference standard for diagnosis. METHODS: We conducted a retrospective review of patients with metastatic RCC treated with either autologous ex vivo activated T-lymphocytes and cimetidine (ALT) or cimetidine alone. RESULTS: Twenty-eight of 90 patients (31%) had evidence of bone metastases by bone scan. With 100 mg/ dL as the upper limit of normal, 11 of 28 (39%) patients with bone metastases had normal AP levels. Of these 11 patients, 8 had bone pain. Of the 3 asymptomatic patients with bone metastasis and normal AP levels, only 1 had bone as the only site of metastasis and would have been incorrectly staged without the scan. Patients with bone metastases had a significantly shorter median survival than those without bone metastases (13.8 versus 25.3 months; P < 0.05). Among patients without bone metastases who had elevated AP levels, those treated with ALT had significantly longer median survivals than those treated with cimetidine alone (27.6 versus 14.5 months; P < 0.05). Overall, patients treated with ALT had a significantly longer median survival than the ones treated only with cimetidine (21 versus 8.5 months; P < 0.05). Overall, the median survival for patients with elevated AP levels (10 months) was not significantly different from that of those with normal AP levels (13 months). CONCLUSIONS: In a high-risk group of patients with metastatic RCC, 31% had bone metastases. Elevated AP levels, the presence of bone pain, or the presence of other metastases correctly predicted bone metastasis in all but 1 patient. A bone scan may safely be omitted in patients with RCC, normal AP levels, and no bone pain. However, AP elevation itself had little prognostic capability in these patients.

Transurethral electrovaporization of bladder cancer.

OBJECTIVES: To describe the use of transurethral electrovaporization in the treatment of large superficial bladder tumors. METHODS: The records of 9 consecutive patients with large superficial bladder tumors treated by transurethral electrovaporization were retrospectively reviewed. All patients underwent vaporization of superficial tumor with either a grooved or smooth rollerball electrode. Tumor characteristics, blood loss, operative time, and length of hospital stay were recorded. RESULTS: A total of 12 bladder tumors were treated in 9 patients. The mean tumor size was 4.3 cm in diameter and the mean operative time was 80 minutes with a range of 60 to 100 minutes. No complications were noted and only 1 patient required a transfusion. The mean fall in hematocrit was 0.7%. CONCLUSIONS: Transurethral electrovaporization represents a new application of electrosurgery that is safe and effective in the treatment of large superficial bladder tumors.

Transperineal prostate needle biopsy guided by transurethral ultrasound in patients without a rectum.

OBJECTIVES: Patients with elevated prostate-specific antigen (PSA) and no access to the rectum present a diagnostic challenge to the urologist. This study was undertaken to determine the efficacy of transperineal prostate biopsy using transurethral ultrasound guidance for the detection of prostate cancer. METHODS: Five men status post either total colectomy or abdominoperineal resection (age range: 58 to 73 years, mean age 65.8 years) were referred to us for the evaluation of an elevated PSA (range: 5.6 to 21.4 ng/dL, mean 16.1 ng/dL). Seven procedures were performed utilizing transurethral ultrasound to guide transperineal prostate biopsies in these men. RESULTS: Biopsy results revealed benign prostatic hyperplasia in 4 procedures and prostate cancer in 3 procedures. CONCLUSIONS: Transurethral ultrasound enables the practitioner to perform accurate sonographic assessment and precise biopsy of the prostate in such patients.

Idiopathic renal infarction.

We describe the course of acute renal infarction, without a demonstrable cause, in an otherwise healthy young male. Renal function was not compromised, and the infarct failed to progress. Literature on relevant diagnostic and therapeutic modalities is reviewed.

High incidence of asymptomatic brain lesions in metastatic renal cell carcinoma.

The metastatic pattern of renal cell carcinoma has been well established. Studies have revealed a relatively high incidence of spread to lung, liver, bone and brain. A retrospective review of the records of ninety patients with metastatic renal cell carcinoma showed seven to have evidence of brain metastases. Six of the seven were asymptomatic at time of diagnosis. This study shows a significant incidence of asymptomatic brain metastases in patients with metastatic renal cell carcinoma. Subsequent to our chart review, an additional two patients have presented to our institution with asymptomatic brain lesions from metastatic renal cell carcinoma.

Renal hemangiopericytoma. Case report and review of the literature.

Hemangiopericytoma (HPC) is an uncommon tumor which was first described in 1942. There are no unique radiological or clinical identifiers that can reliably aid in preoperative diagnosis. Surgery is the only reliable therapy as both chemotherapy and radiotherapy have proven ineffective in several series. The outcome is difficult to predict; the only reliable predictor is the presence or absence of metastasis. We report on a 63-year-old female with a large left renal HPC.

Oliguria during laparoscopic surgery.

Oliguria is infrequently viewed as a complication of laparoscopic surgery. The rate of urine output in six healthy patients undergoing laparoscopic surgery was measured during the period of CO2 pneumoperitoneum and for several hours after desufflation. The average hourly urine output during insufflation was 0.30 +/- 0.14 mL/kg despite an average hourly intravenous infusion rate of lactated Ringer's solution of 13.0 +/- 4.0 mL/kg. After release of pneumoperitoneum, urine output increased 467% to 1.7 +/- 1.1 mL/kg per hour. Patients remained hemodynamically unchanged perioperatively. Preoperative and postoperative blood urea nitrogen and creatinine concentrations did not significantly differ. We discuss the potential etiologic factors in the development of oliguria in the setting of the increased intra-abdominal pressure of pneumoperitoneum and the implications of this acute but reversible renal dysfunction.

Renal tubular apoptosis after partial ureteral obstruction.

Partial ureteral obstruction in the weanling rat leads to hydronephrosis of the ipsilateral kidney and renal cell deletion through the process of programmed cell death known as apoptosis. The apoptotic response following partial ureteral obstruction in weanling Sprague-Dawley rats was studied using the traditional markers of apoptosis, including deoxyribonucleic acid (DNA) laddering pattern on agarose gel electrophoresis, in situ gap labeling of fragmented DNA for quantitative apoptotic body determination, polyadenylated messenger ribonucleic acid (mRNA) expression of sulfated glycoprotein-2, and polyadenylated mRNA expression of epidermal growth factor and transforming growth factor-beta. Partial ureteral obstruction resulted in a progressive increase in the intensity of DNA fragmentation associated with apoptosis during the initial 3 weeks. Quantitative apoptotic body counting revealed a 3-fold increase by week 3 of partial obstruction. This increase represented a level of apoptosis, which is 65% of that observed in complete ureteral obstruction. By week 2 of partial obstruction there was a 13-fold increase in the expression of sulfated glycoprotein-2 mRNA, as well as changes in the growth factor environment characterized by a decline in the constitutive expression of epidermal growth factor mRNA and an increase in the expression of transforming growth factor-beta mRNA. These altered levels represent changes in expression comparable to those observed during the apoptotic response following complete ureteral obstruction, although the time course is delayed by 2 to 3 weeks.