Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer.

PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.

Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective patients.

BACKGROUND: Currently, there are multiple commercially available RNA-based biomarkers that are Medicare approved and suggested for use by the National Comprehensive Cancer Network guidelines. There is uncertainty as to which patients benefit from genomic testing and for whom these tests should be ordered. Here, we examined the correlation patterns of Decipher assay to understand the relationship between the Decipher and patient tumor characteristics. METHODS: De-identified Decipher test results (including Decipher risk scores and clinicopathologic data) from 2 342 consecutive radical prostatectomy (RP) patients tested between January and September 2015 were analyzed. For clinical testing, tumor specimen from the highest Gleason grade was sampled using a 1.5 mm tissue punch. Decipher scores were calculated based on a previously locked model. Correlations between Decipher score and clinicopathologic variables were computed using Spearman's rank correlation. Mixed-effect linear models were used to study the association of practice type and Decipher score. The significance level was 0.05 for all tests. RESULTS: Decipher score had a positive correlation with pathologic Gleason score (PGS; r=0.37, 95% confidence interval (CI) 0.34-0.41), pathologic T-stage (r=0.31, 95% CI 0.28-0.35), CAPRA-S (r=0.32, 95% CI 0.28-0.37) and patient age (r=0.09, 95% CI 0.05-0.13). Decipher reclassified 52%, 76% and 40% of patients in CAPRA-S low-, intermediate- and high-risk groups, respectively. We detected a 28% incidence of high-risk disease through the Decipher score in pT2 patients and 7% low risk in pT3b/pT4, PGS 8-10 patients. There was no significant difference in the Decipher score between patients from community centers and those from academic centers (P=0.82). CONCLUSIONS: Although Decipher correlated with baseline tumor characteristics for over 2 000 patients, there was significant reclassification of tumor aggressiveness as compared to clinical parameters alone. Utilization of the Decipher genomic classifier can have major implications in assessment of postoperative risk that may impact physician-patient decision making and ultimately patient management.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2-0.49 and ⩾0.5 ng ml(-1), respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Targeting cell cycle and hormone receptor pathways in cancer.

The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.

Costs of early adjuvant radiation therapy after radical prostatectomy: a decision analysis.

BACKGROUND: This analysis was carried out to evaluate the cost-effectiveness of adjuvant radiation therapy (ART) versus observation, using a decision analysis model based primarily upon the published results of the Southwest Oncology Group prospective trial (SWOG 8794). PATIENTS AND METHODS: A decision analysis model was designed to compare ART versus observation over a 10-year time horizon. Probabilities of treatment success, utilization of salvage treatments, and rates of adverse events were taken from published results of SWOG 8794. Cost inputs were based on 2010 Medicare reimbursement rates. Primary outcome measure was incremental cost per prostate-specific antigen (PSA) success (i.e. serum PSA level <0.4 ng/ml). RESULTS: ART results in a higher PSA success rate than observation with probability of 0.43 versus 0.22. The mean incremental cost per patient for ART versus observation was $6023. The mean incremental cost-effectiveness ratio was $26,983 over the 10-year period. CONCLUSIONS: ART appears cost effective compared with observation based upon this decision analysis model. Future research should consider more costly radiation therapy (RT) approaches, such as intensity-modulated RT, and should evaluate the cost-effectiveness of ART versus early salvage RT.

MITOSTATIN, a putative tumor suppressor on chromosome 12q24.1, is downregulated in human bladder and breast cancer.

Allelic deletions on human chromosome 12q24 are frequently reported in a variety of malignant neoplasms, indicating the presence of a tumor suppressor gene(s) in this chromosomal region. However, no reasonable candidate has been identified so far. In this study, we report the cloning and functional characterization of a novel mitochondrial protein with tumor suppressor activity, henceforth designated MITOSTATIN. Human MITOSTATIN was found within a 3.2-kb transcript, which encoded a approximately 62 kDa, ubiquitously expressed protein with little homology to any known protein. We found homozygous deletions and mutations of MITOSTATIN gene in approximately 5 and approximately 11% of various cancer-derived cells and solid tumors, respectively. When transiently overexpressed, MITOSTATIN inhibited colony formation, tumor cell growth and was proapoptotic, all features shared by established tumor suppressor genes. We discovered a specific link between MITOSTATIN overexpression and downregulation of Hsp27. Conversely, MITOSTATIN knockdown cells showed an increase in cell growth and cell survival rates. Finally, MITOSTATIN expression was significantly reduced in primary bladder and breast tumors, and its reduction was associated with advanced tumor stages. Our findings support the hypothesis that MITOSTATIN has many hallmarks of a classical tumor suppressor in solid tumors and may play an important role in cancer development and progression.

Molecular genetics of prostate cancer: clinical translational opportunities.

Prostate cancer (PC) development reflects a complex sequence of biologic and molecular events. Several inheritable and somatic genetic changes have been identified. The knowledge of the molecular basis of PC can improve our understanding of the causes of this common cancer and provide information on prognosis and treatment. To date, however, no molecular studies have yet yielded consistent information that is ready to be incorporated into clinical practice. We reviewed the current literature on the molecular biology of prostate cancer and analyzed different potential tumor markers according to the classical concepts of oncogenes, suppressor genes, and the more modern concepts of genes involved in detoxification or inflammatory pathways of cancer progression. This review aims to identify trends in PC research and suggests potential clinical applications for diagnosis, prognosis, prevention and treatment.

Molecular genetics of bladder cancer: targets for diagnosis and therapy.

Transitional cell carcinoma of the bladder is a common tumor. While most patients presenting superficial disease can be expected to do well following treatment, still many patients will return to our office with muscle invasive and metastatic disease. Survival in advanced bladder cancer is less than 50%. Tumors of similar histologic grade and stage have variable behavior, suggesting that genetic alterations must be present to explain the diverse behavior of bladder cancer. It is hoped that through the study of the subtle genetic alterations in bladder cancer, important prognostic and therapeutic targets can be exploited. Many new diagnostic tests and gene therapy approaches rely on the identification and targeting of these unique genetic alterations. A review of literature published on the molecular genetics of bladder cancer from 1970 to the present was conducted. A variety of molecular genetic alterations have been identified in bladder cancer. Oncogenes (H-ras, erbB-2, EGFR, MDM2, C-MYC, CCND1), tumor suppressor genes (p53, Rb, p21, p27/KIP1, p16, PTEN, STK15, FHIT, FEZ1/LZTS1, bc10), telomerase, and methylation have all been studied in bladder cancer. Several have proven to be potentially useful clinical targets in the prognosis and therapy of bladder cancer such as staining for p53 and gene therapy strategies such as p53 and fez1. Clinical trials targeting HER2/neu and the EGFR pathways are underway. The UroVysion bladder cancer assay relies on FISH to detect genetic alterations in this disease. Continuing identification of the molecular genetic alterations in bladder cancer will enhance future diagnostic and therapeutic approaches to bladder cancer. Capitalizing on these alterations will allow early detection, providing important prognostic information and unique targets for gene therapy and other therapeutic approaches.

Phase i study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer.

PURPOSE: Vaccinia virus is a DNA poxvirus previously used as a vaccine to eradicate smallpox. The virus has a high efficiency of infection, replicates in the cytoplasm without chromosomal integration and can transport a large amount of recombinant DNA without losing infectivity. Therefore, it is an excellent choice as a vector for gene delivery in vivo. Large quantities of vaccinia have been injected into dermal, subcutaneous and peripheral lymph node melanoma metastases without significant side effects, and with efficient infection of the tumor cells and recombinant gene transfection. To determine if vaccinia, when given intravesically, can effectively infect bladder mucosa and tumor with acceptable toxicity, we performed a phase I trial of intravesical vaccinia in patients with muscle invasive transitional cell carcinoma before radical cystectomy. MATERIALS AND METHODS: After documenting immune competence and demonstration of a major reaction after revaccination, patients received 3 increasing doses of intravesical Dryvax vaccinia virus (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) that was provided by the Centers for Disease Control. Approximately 24 hours after the third dose, cystectomy was performed and the tissue was examined microscopically. RESULTS: There were 4 patients who were treated. The 3 patients who received the highest doses (100 x 106 plaque forming units) had significant mucosal and submucosal inflammatory infiltration by lymphocytes, eosinophils, and plasma cells into tumor and normal tissue. Dendritic cells were recruited to the site after exposure to the vaccinia. Significant mucosal edema and vascular ectasia were seen. Tumor and normal urothelial cells showed evidence of viral infection, including enlarged vacuolated cells with cytoplasmic inclusions. There were no clinical or laboratory manifestations of vaccinia related toxicity except mild dysuria. Of the 4 patients 3 survived and were free of disease at 4-year followup. CONCLUSIONS: Our study demonstrates that vaccinia virus can be administered safely into the bladder with recruitment of lymphocytes and induction of a brisk local inflammatory response. To our knowledge, this is the first report of direct delivery of live virus into the human bladder. The role of wild type vaccinia as immunotherapy for bladder cancer warrants further study. Furthermore, these data support the exploration of recombinant vaccinia as a putative gene therapy vector for intravesical infection and transfection of bladder tumor cells with cytokine or other genes, an approach that our group pioneered and most recently studied in patients with superficial melanoma.

Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status.

OBJECTIVES: To investigate the diurnal variations in circulating tumor cells (CTCs) in metastatic carcinoma of the prostate (CAP) and to determine whether the change in CTCs correlated with disease progression. METHODS: Samples were prepared by immunomagnetic selection of cells from 7 mL of blood targeting the epithelial cell adhesion molecule and differential fluorescent labeling of the collected cells using a nucleic acid dye, antibodies directed against the common leukocyte (CD45), and cytokeratin antigens. Events that stained with the nucleic acid dye and expressed cytokeratin but lacked CD45 were defined as CTCs by multiparameter flow cytometry. RESULTS: Male controls (n = 22) exhibited 0.8 +/- 1.2 events per 7 mL blood compared with 5.9 +/- 4.7 in 10 samples from patients with localized CAP and 46.6 +/- 65.6 events in 10 samples from patients with metastatic CAP. Diurnal testing of 8 cases demonstrated stable levels of CTCs. Ten patients were serially analyzed during a 6-month period for serum prostate-specific antigen and CTCs. The correlation between the prostate-specific antigen level and CTC number was fair. Slow disease progression was found in 4 patients with low CTC numbers (3.0 +/- 3) but it was significantly higher than the control group (P <0.002). Rapid disease progression occurred in 6 patients who demonstrated high CTC numbers (68.5 +/- 71.9). Two patients received chemotherapy that caused substantial fluctuations in the CTCs with less pronounced changes in the prostate-specific antigen level. CONCLUSIONS: We conclude that the level of CTCs can be quantified in the circulation of patients with metastatic CAP and that the change in CTCs correlates with disease progression with no diurnal variations.

Ultrasound for prostate imaging and biopsy.

Transrectal ultrasound guided systemic sextant needle biopsy of the prostate has been the procedure of choice for the diagnosis of prostate cancer. Several shortcomings of this procedure have been recognized and there is concern that it may represent an inadequate sampling of the prostate. Refinements include modifications of biopsy location and an increase in the number of cores obtained. Enhanced ultrasound techniques may improve the accuracy of prostate biopsy. In addition, research continues to develop prognostic factors derived from the core biopsy that may enhance the prediction of tumor biology. This paper provides a basic review of transrectal ultrasound diagnosis of prostate cancer with emphasis on advances in this area.

Contrast-enhanced power Doppler imaging of normal and decreased blood flow in canine prostates.

The purpose of this study was to investigate if Sonazoid, a new ultrasound (US) contrast agent, can improve the delineation of areas with normal and decreased blood flow in the prostate. Sonazoid was administered in the dose range of 0.00625-0.0375 microL microbubbles/kg into five anaesthetised mongrel adult male dogs. Transrectal power Doppler imaging of the prostate was performed in 2-D and 3-D with a C9-5 end-fire probe, using an HDI 3000 scanner. An area of decreased blood flow was created by inducing tissue ablation with a CL60 laser system, to mimic an avascular lesion. A subjective assessment of the intraprostatic vessels and the prostate vascular architecture was performed, with and without Sonazoid, before and after inducing the abnormal site. Visibility of the prostate blood flow improved following Sonazoid injection (p < 0.001). A symmetric, radial vascular pattern was identified in the normal prostate prior to tissue ablation, but only on the enhanced images. After tissue ablation, a disturbance of the normal vascular pattern and identification of areas with lack of blood flow was possible, following Sonazoid injection. Furthermore, the location and size of these areas were verified in all dogs by gross histology examination. Sonazoid enhances the visibility of the prostate vascular architecture and improves, thereby the delineation of areas with normal and decreased blood flow.

Does hormonal therapy influence sexual function in men receiving 3D conformal radiation therapy for prostate cancer?

PURPOSE: We evaluated the effect of three-dimensional conformal radiation therapy (3D-CRT) with or without hormonal therapy (HT) on sexual function (SF) in prostate cancer patients whose SF was known before all treatment. METHODS AND MATERIALS: Between March 1996 and March 1999, 144 patients received 3D-CRT (median dose = 70.2 Gy, range 66.6-79.2 Gy) for prostate cancer and had pre- and post-therapy SF data. All SF data were obtained with the O'Leary Brief SF Inventory, a self-administered, multidimensional, validated instrument. We defined total sexual potency as erections firm enough for penetration during intercourse. Mean follow-up time was 21 months (SD +/- 11 months). The Wilcoxon signed-rank test was used to test for significance of the change from baseline. RESULTS: Before 3D-CRT, 87 (60%) of 144 men were totally potent as compared to only 47 (47%) of 101 at 1-year follow-up. Of the 60 men totally potent at baseline and followed for at least 1 year, 35 (58%) remained totally potent. These changes corresponded to a significant reduction in SF (p < 0.05). Patients who had 3D-CRT alone were more likely to be totally potent at 1 year than those receiving 3D-CRT with HT (56% vs. 31%, p = 0.012); however, they were also more likely to be potent at baseline (71% vs. 44%, p = 0.001). Although these two groups had a significant reduction in SF from baseline, their change was not significantly different from each other. CONCLUSION: These data indicate that 3D-CRT causes a significant reduction in total sexual potency as compared to pretreatment baseline. The addition of HT does not appear to increase the risk of sexual dysfunction.

Sildenafil citrate effectively reverses sexual dysfunction induced by three-dimensional conformal radiation therapy.

OBJECTIVES: We evaluated the response of sildenafil citrate in patients with prostate cancer treated with three-dimensional conformal radiation therapy (3DCRT) whose sexual function (SF) was known prior to therapy initiation. METHODS: From March 1996 to April 1999, 24 men with median age of 68 years (range 51 to 77) had 3DCRT for localized prostate cancer (median prescribed dose to the planning target volume of 70.2 Gy). These men started taking sildenafil for relief of sexual dysfunction at a median time of 1 year after completing 3DCRT. We used the self-administered O'Leary Brief Sexual Function Inventory to evaluate in series SF and overall satisfaction at three time points. These points were (a) before initiation of all therapies (3DCRT or hormonal treatment [HT]) for prostate cancer, (b) before starting sildenafil (50 mg or 100 mg) but after completion of all therapies, and (c) at least 2 months afterward. Rates of SF were based on the number of men responding to a given question. We tested for significance of these two interventions to change SF by applying the Wilcoxon sign rank test. RESULTS: Prior to all treatments, 20 (87%) of 23 men were sexually potent, with 8 (36%) of 22 fully potent (little or no difficulty for penetration at intercourse). After 3DCRT with or without HT and prior to sildenafil use, 13 (65%) of the 20 potent patients remained potent, with only 2 (11%) of 19 being fully potent. The use of sildenafil citrate resulted in 21 (91%) of 23 men being potent, with 7 (30%) being fully potent. In 16 men responding to the satisfaction question, 10 (63%) and 12 (75%) were mixed to very satisfied with their sex life before 3DCRT with or without HT and after sildenafil citrate use, respectively. This response corresponded to potency and satisfaction scores significantly decreasing and subsequently increasing on average by one unit after 3DCRT and sildenafil citrate use, respectively (P <0.05). CONCLUSIONS: In men receiving 3DCRT for prostate cancer, these data indicate that sildenafil citrate is effective for restoring SF and associated satisfaction back to baseline before treatment.

Imaging prostate cancer: current and future applications.

Various treatment options are available for adenocarcinoma of the prostate--the most common malignant neoplasm among men in the United States. To select an optimum management strategy, we must be able to identify an organ-confined disease (in which local therapy such as surgery or radiation may be beneficial) vs prostate cancer beyond the confines of the gland (for which other treatment approaches may be more appropriate). At present, no standard imaging modality can by itself reliably diagnose and/or stage adenocarcinoma of the prostate. Standard transrectal ultrasound, magnetic resonance imaging (MRI), computed tomography, bone scans, and plain x-ray are not sufficiently reliable when used alone. Fortunately, advances in imaging technology have led to the development of several promising modalities. These modalities include color and power Doppler ultrasonography, ultrasound contrast agents, intermittent and harmonic ultrasound imaging, MR contrast imaging, MRI with fat suppression, MRI spectroscopy, three-dimensional MRI spectroscopy, elastography, and radioimmunoscintigraphy. These newer imaging techniques appear to improve the yield of prostate cancer detection and staging, but are limited in availability and thus require further validation. This article reviews the status of current imaging modalities for prostate cancer and identifies emerging imaging technologies that may improve the diagnosis and staging of this disease.

Prostate cancer: contrast-enhanced us for detection.

PURPOSE: To assess the detection of prostate cancer with contrast material-enhanced transrectal sonography. MATERIALS AND METHODS: Sixty subjects were examined with conventional gray-scale, harmonic gray-scale, and power Doppler sonography. Evaluation was repeated during intravenous infusion of contrast agent. Gray-scale imaging was performed in continuous mode and with intermittent imaging by using interscan delay times of 0.5, 1.0, 2.0, and 5.0 seconds. Sextant biopsy sites were scored prospectively as benign or malignant at baseline imaging and again during enhanced transrectal sonography. RESULTS: Prostate cancer was present in 37 biopsy sites from 20 subjects. Baseline imaging demonstrated prostate cancer in 14 sites in 11 subjects. Enhanced transrectal sonography depicted prostate cancer in 24 sites in 15 subjects. Each of the five subjects in whom prostate cancer was missed had only a single biopsy core with positive findings (Gleason score < or = 6). In three of these five subjects, prostate cancer made up less than 10% of the core. The improvement in sensitivity from 38% (14 of 37 malignant foci) at baseline to 65% (24 of 37 malignant foci) with contrast enhancement was significant (P<.004, McNemar chi(2) test). Specificity was similar at baseline (267 [83%] of 323 malignant foci) and during enhanced transrectal sonography (257 [80%] of 323 malignant foci). Clustered receiver operating characteristic analysis demonstrated significant improvement in diagnostic accuracy during enhanced transrectal sonography (P =.027). CONCLUSION: Enhanced transrectal sonography improves sensitivity for the detection of malignant foci within the prostate without substantial loss of specificity. Low-volume tumors with a Gleason score of 6 or less may not be detected with enhanced transrectal sonography.

Comparison and clinical evaluation of hand-assist devices for hand-assisted laparoscopy.

Hand-assisted laparoscopic surgery (HALS) is being used increasingly in urologic laparoscopy, particularly for laparoscopic nephrectomy. Hand-assist devices (HADs) facilitate the intra-abdominal placement of the hand during laparoscopy. There are currently three HADs available in the United States: the Pneumo Sleeve, the Handport, and the Intromit. The performance of each HAD is assessed regarding usage options, maintenance of pneumoperitoneum, device failure, exchange of intra-abdominal hands, adaptation to obese patients, and specimen removal. The use of these devices is reviewed based on our experience in more than 100 cases of HALS.

Hand-assisted laparoscopic nephroureterectomy: description of technique.

PURPOSE: Traditional treatment of transitional cell carcinoma of the upper urinary tract (UTTCC) has been nephroureterectomy by open surgical techniques, often requiring two incisions. Our experience and technique for hand-assisted laparoscopic nephroureterectomy (HALNU) is reviewed. MATERIALS AND METHODS: Thirty-two patients had HALNU performed by one of three surgeons from August 1998 to October 2000. The distal ureter and bladder cuff was resected laparoscopically and sutured closed in 15 patients and resected by combined cystoscopic and laparoscopic approach in 17 patients. RESULTS: The indication for surgery was UTTCC for 29 patients and benign conditions in 2 patients. The mean operating time (including initial cystoscopy) was 372 minutes (281-530), and the mean blood loss was 541 cc (50-3500). The mean hospital stay was 5.5 days (3-12). There were no positive surgical margins, local recurrences, trocar site seeding, or wound seeding. CONCLUSIONS: HALNU is an effective minimally invasive approach for the treatment of UTTCC.

Prostate cancer: risk assessment and diagnostic approaches.

The successful treatment of prostate cancer relies on detection of the disease at its earliest stages. Although prostate-specific antigen (PSA)-based screening has been a significant advance in the early diagnosis of prostate cancer, identifying specific genetic alterations in a given family or patient will allow more appropriate screening for early disease. Mapping and identification of specific prostate cancer susceptibility genes is slowly becoming a reality. Other prostate cancer risks include a family history, race, and possibly serum markers such as insulin-like growth factor-I (IGF-I). Once a high-risk man is identified, transrectal ultrasound (TRUS)-guided biopsies are the standard to diagnose prostate cancer. Although TRUS is an advance over traditional digitally directed biopsies, it represents a random sampling of the prostate since most lesions cannot be visualized. Newer modalities such as ultrasound contrast agents, pattern recognition, and artificial neural networks (ANNs), applied to TRUS images, may improve diagnostic accuracy. If a man at risk for prostate cancer has undergone a negative TRUS biopsy, the decision for the need for additional biopsies is problematic. Use of PSA derivatives such as free and total PSA and the initial biopsy abnormalities such as atypia or high-grade prostatic intraepithelial neoplasia may define those patients in need of follow-up biopsy.

Therapeutic strategies for localized prostate cancer.

Prostate-specific antigen determinations for prostate cancer screening have led to a dramatic increase in the number of men who are diagnosed with organ-confined and therefore potentially curable prostate cancer. Advances in predicting outcomes with artificial neural networks may help to recommend one therapy over another. Less invasive forms of treatment, such as high-intensity focused ultrasound, may ultimately give patients additional options for treatment. Furthermore, attempts to better define the role of both neoadjuvant hormonal therapy and chemotherapy may give higher-risk patients better outcomes than with current treatments. These advances as well as continued research will likely lead to a day when more and more men with organ-confined disease will be cured.