Rajesh Shinghal

Gene Expression Patterns in Renal Cell Carcinoma Assessed by Complementary DNA Microarray

Renal cell carcinoma comprises several histological types with different clinical behavior. Accurate pathological characterization is important in the clinical management of these tumors. We describe gene expression profiles in 41 renal tumors determined by using DNA microarrays containing 22,648 unique cDNAs representing 17,083 different UniGene Clusters, including 7230 characterized human genes. Differences in the patterns of gene expression among the different tumor types were readily apparent; hierarchical cluster analysis of the tumor samples segregated histologically distinct tumor types solely based on their gene expression patterns. Conventional renal cell carcinomas with clear cells showed a highly distinctive pattern of gene expression. Papillary carcinomas formed a tightly clustered group, as did tumors arising from the distal nephron and the normal kidney samples. Surprisingly, conventional renal cell carcinomas with granular cytoplasm were heterogeneous, and did not resemble any of the conventional carcinomas with clear cytoplasm in their pattern of gene expression. Characterization of renal cell carcinomas based on gene expression patterns provides a revised classification of these tumors and has the potential to supply significant biological and clinical insights.

Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] exerts anti-proliferative, differentiating and apoptotic effects on prostatic cells. These activities, in addition to epidemiologic findings that link Vitamin D to prostate cancer risk, support the use of 1,25(OH)(2)D(3) for prevention or therapy of prostate cancer. The molecular mechanisms by which 1,25(OH)(2)D(3) exerts antitumor effects on prostatic cells are not well-defined. In addition, there is heterogeneity among the responses of various prostate cell lines and primary cultures to 1,25(OH)(2)D(3) with regard to growth inhibition, differentiation and apoptosis. To understand the basis of these differential responses and to develop a better model of Vitamin D action in the prostate, we performed cDNA microarray analyses of primary cultures of normal and malignant human prostatic epithelial cells, treated with 50 nM of 1,25(OH)(2)D(3) for 6 and 24 h. CYP24 (25-hydroxyvitamin D(3)-24-hydroxylase) was the most highly upregulated gene. Significant and early upregulation of dual specificity phosphatase 10 (DUSP10), validated in five additional primary cultures, points to inhibition of members of the mitogen-activated protein kinase (MAPK) superfamily as a key event mediating activity of 1,25(OH)(2)D(3) in prostatic epithelial cells. The functions of other regulated genes suggest protection by 1,25(OH)(2)D(3) from oxidative stress. Overall, these results provide new insights into the molecular basis of antitumor activities of Vitamin D in prostate cells.

Tracking Intraoperative Fluoroscopy Utilization Reduces Radiation Exposure During Ureteroscopy

PURPOSE Recent studies have demonstrated deleterious effects of ionizing radiation from diagnostic and therapeutic imaging procedures. One of the barriers to minimizing patient exposure is physician awareness. We prospectively studied whether providing surgeons with feedback on their fluoroscopy utilization would affect intraoperative fluoroscopy times. MATERIALS AND METHODS In 2007, we prospectively began to track fluoroscopy usage for all urology cases. Nine months later, surgeons started to receive periodic reports with their mean fluoroscopy time compared with their peers. We reviewed all ureteroscopic cases for nephrolithiasis from the date tracking began (2006-2010, n = 311). Using the initial 9-month period as a control, we studied the effect of providing feedback on mean fluoroscopy times in subsequent periods and analyzed patient factors that may affect radiation exposure. RESULTS Mean fluoroscopy times for unilateral ureteroscopy decreased by 24% after surgeons received feedback (2.74-2.08 minutes, p = 0.002). On multivariate analysis, factors that independently predicted decreased fluoroscopy times included female sex (p = 0.02), stones in the distal ureter (p = 0.04), and if the surgeon had received feedback (p = 0.0004). Factors that increased fluoroscopy times included the presence of hydronephrosis (p = 0.001), use of a ureteral access sheath (p = 0.04), ureteral balloon dilation (p = 0.0001), and placement of a postoperative stent (p = 0.002). CONCLUSIONS Providing surgeons with feedback on their fluoroscopy usage reduces patient and surgeon radiation exposure. Implementing such a tracking system requires minimal changes to existing operating room staff workflow. Further study is warranted to study the impact of this program on other procedures that utilize fluoroscopy in urology and other specialties.

Limitations of transperineal ultrasound-guided prostate biopsies

OBJECTIVES Screening and diagnosing prostate cancer in men who have undergone abdominoperineal resection (APR) poses a diagnostic challenge. Transperineal ultrasound is an effective imaging technique, but the sensitivity of transperineal needle biopsy under ultrasound guidance has not been evaluated. We compared the results of transrectal ultrasound-guided (TRUS) biopsies and transperineal ultrasound-guided (TPUS) biopsies obtained from patients with known prostate cancer, to evaluate the accuracy of TPUS prostate biopsies. METHODS Twenty patients with prostate cancer diagnosed by TRUS-guided biopsies were studied. Immediately before radical prostatectomy, TPUS was performed in the lithotomy position and six TPUS-guided biopsies were obtained. Routine sextant TRUS-guided biopsies were then obtained. Finally, radical retropubic prostatectomy was performed and the results of both biopsy sets were compared with the pathologic features of the surgical specimen. RESULTS All 20 prostates contained adenocarcinoma. The prostate was well visualized with TPUS and TRUS in all cases. TPUS-guided biopsies detected cancer in only 2 of the 20 specimens, yielding a sensitivity of 10%. On the same specimens, TRUS-guided biopsies were positive in 13 of 20 cases, a sensitivity of 65%. Cancers detected by TPUS-guided biopsies tended to have a higher volume, higher Gleason grade, and higher prostate-specific antigen level than those not detected by TPUS-guided biopsies. CONCLUSIONS TPUS-guided sextant biopsies are less accurate than TRUS-guided sextant biopsies in detecting prostate cancer, even in the hands of experienced ultrasonographers. The limitations of TPUS-guided needle biopsies emphasize the importance of screening for prostate cancer before APR.

Biochemical recurrence without PSA progression characterizes a subset of patients after radical prostatectomy

OBJECTIVES To characterize a subset of patients with biochemical recurrence after radical prostatectomy but with little, if any, subsequent rise in serum prostate-specific antigen (PSA) and no clinical progression during long-term follow-up. METHODS Of a series of 600 patients, 158 with biochemical recurrence after radical prostatectomy were examined. We identified a subset with measurable serum PSA levels during long-term follow-up, but with very low PSA velocity and no clinical recurrence. Serum PSA was measured with the ultrasensitive TOSOH assay with a PSA recurrence defined as a serum PSA of 0.07 ng/mL or greater. RESULTS We identified 14 patients (8.8% of biochemical recurrences) with a detectable serum PSA level after radical prostatectomy yet without clinical or PSA progression at a mean follow-up after radical prostatectomy of 10.3 years. The mean time to PSA recurrence was 5.8 years, and the mean PSA velocity after recurrence was 0.028 ng/mL/yr. No clinical or pathologic features were found that could be used to identify this subset of patients. CONCLUSIONS A subset of patients with biochemical recurrence after radical prostatectomy will not exhibit a progressive rise in serum PSA or clinical progression at 10 years follow-up. This suggests that serum PSA kinetics should be observed after biochemical recurrence before adjuvant hormonal therapy or radiotherapy.

The Performance of Prostate Specific Antigen, Prostate Specific Antigen Density and Transition Zone Density in the Era of Extended Biopsy Schemes

PURPOSE Prostate specific antigen, prostate specific antigen density and transition zone density have been previously identified as prostate cancer detection tools. Recent studies suggest that prostate specific antigen may be increasingly accurate for detecting clinically significant high grade prostate cancer (Gleason grade 7 or greater). We defined the performance of these measures in a referral based population undergoing an extended prostate biopsy scheme. MATERIALS AND METHODS We retrospectively reviewed prospectively collected data on 1,708 men referred for prostate needle biopsy. All participants were men who had not undergone biopsy in the past. From these data ROC curves were constructed for prostate specific antigen, prostate specific antigen density and transition zone density for the presence of cancer, high grade (Gleason 3 + 4 or greater) and high volume (50% or greater of cores positive) disease. RESULTS Prostate specific antigen density had a statistically higher AUC than prostate specific antigen for detecting all prostate cancers (0.737 vs 0.633, p <0.001) as well as high grade (0.766 vs 0.673, p <0.001) and high volume (0.843 vs 0.755, p <0.001) disease. Additionally, prostate specific antigen and prostate specific antigen density performed better for detecting high grade and high volume disease compared to overall prostate cancer detection. The performance of transition zone density was similar to that of prostate specific antigen density. CONCLUSIONS Prostate specific antigen and prostate specific antigen density show improved performance characteristics for detecting clinically significant high grade and high volume prostate cancer in referral populations undergoing extended scheme prostate needle biopsy. Prostate specific antigen density shows better performance characteristics than prostate specific antigen. No advantage was seen when using transition zone density over prostate specific antigen density.

Decreasing Use of Luteinizing Hormone-Releasing Hormone Agonists in the United States is Independent of Reimbursement Changes: A Medicare and Veterans Health Administration Claims Analysis

PURPOSE Luteinizing hormone-releasing hormone agonists are the most common form of androgen deprivation therapy in men with prostate cancer. Limited data exist regarding physician decision-making in prescribing luteinizing hormone-releasing hormone agonists. We present an analysis of luteinizing hormone-releasing hormone agonist use trends based on a time matched comparison of data from Medicare and the Veterans Health Administration, a health care system unaffected by recent changes in Medicare reimbursement implemented by the Medicare Modernization Act in 2004. MATERIALS AND METHODS Medicare claims and payment data were obtained from the Centers for Medicare and Medicaid Services from 2003 to 2007 for luteinizing hormone-releasing hormone agonists and for simple orchiectomy. The Veterans Health Administration Pharmacy Benefits Management database was queried for the annual number of prescriptions for luteinizing hormone-releasing hormone agonists during the same period. RESULTS After implementation of the Medicare Prescription Drug, Improvement and Modernization Act in 2004 the reimbursement of luteinizing hormone-releasing hormone agonists in the Medicare population decreased by 54.8% and annual claims decreased by 25.1% from 2004 to 2007. During the same period luteinizing hormone-releasing hormone agonist use decreased by 16.8% in the Veterans Health Administration population. There was no compensatory increase in the use of simple orchiectomy for androgen deprivation therapy during the study period. CONCLUSIONS Use of luteinizing hormone-releasing hormone agonists has decreased in the Medicare and Veterans Health Administration populations since 2004 without a compensatory increase in the use of alternative forms of androgen deprivation therapy. The shift in practice patterns is likely due to a decrease in Medicare reimbursement for these drugs, an increase in the use of intermittent therapy and increased recognition of the adverse effects associated with androgen deprivation therapy.

Comparison of Holding Strength of Suture Anchors on Human Renal Capsule

INTRODUCTION The use of surgical clips as suture anchors has made laparoscopic partial nephrectomy (LPN) technically simpler by eliminating the need for intracorporeal knot tying. However, the holding strength of these clips has not been analyzed in the human kidney. Therefore, the safety of utilizing suture anchors is unknown as the potential for clip slippage or renal capsular tears during LPN could result in postoperative complications including hemorrhage and urinoma formation. With the above in mind, we sought to compare the ability of Lapra-Ty clips and Hem-o-lok clips to function as suture anchors on human renal capsule. METHODS Fresh human cadaveric kidneys with intact renal capsules were obtained. A Lapra-Ty clip (Ethicon, Cincinnati, OH) or a Hem-o-lok clip (Weck, Raleigh, NC) was secured to a no. 1 Vicryl suture (Ethicon) with and without a knot, as is typically utilized during the performance of LPN. The suture was then placed through the renal capsule and parenchyma and attached to an Imada Mechanical Force Tester (Imada, Northbrook, IL). The amount of force required both to violate the renal capsule and to dislodge the clip was recorded separately. RESULTS Six Lapra-Ty clips and six Hem-o-lok clips were tested. The mean force in newtons required to violate the renal capsule for the Lapra-Ty group was 7.33 N and for the Hem-o-lok group was 22.08 N (p < 0.001). The mean force required to dislodge the clip from the suture for the Lapra-Ty group was 9.0 N and for the Hem-o-lok group was 3.4 N (p < 0.001). When two Hem-o-lok clips were placed on the suture in series, the mean force required to dislodge the clips was 10.6 N. CONCLUSION When compared with Lapra-Ty clips, using two Hem-o-lok clips may provide a more secure and cost-effective method to anchor sutures on human renal capsule when performing LPN.

PREVENTION OF PROSTATE CANCER

Strategies for reducing the occurrence of prostate cancers will be critical in limiting the morbidity and mortality of this disease. The long latency period of prostate tumors and improved understanding of prostate carcinogenesis suggest opportunities for effective preventive measures. Because androgen is integral to prostatic carcinogenesis, several preventive strategies under investigation target the androgen axis. Epidemiologic and basic studies implicate dietary factors in prostate cancer development and suggest that altering diet may influence prostate cancer risk and progression. Many of the micronutrients with preventive potential have antioxidant properties; cellular defenses against oxidative stresses are likely to be crucial in reducing prostate carcinogenesis. This article summarizes the current status and opportunities in prostate cancer prevention.

Cavoatrial tumor thrombus excision without circulatory arrest.

INTRODUCTION Traditional methods of cavoatrial thrombus excision use deep hypothermic circulatory arrest with significant associated morbidity and mortality. We describe a novel technique that avoids circulatory arrest, yet provides a bloodless field for tumor excision. TECHNICAL CONSIDERATIONS A 59-year-old woman presented with a left renal mass and tumor thrombus with extension into the right atrium. After left radical nephrectomy, an aortic occlusion balloon was placed in the abdominal aorta at the level of the diaphragm, limiting flow in the inferior vena cava for tumor excision and maintaining both cerebral and spinal cord perfusion during cardiopulmonary bypass. Tumor excision was successfully performed using this technique with minimal postoperative morbidity in the patient described. She remained free of recurrence at 9 months of follow-up. CONCLUSIONS Cavoatrial tumor thrombus excision can be successfully performed without deep hypothermic circulatory arrest.