The Kallikrein Panel for prostate cancer screening: its economic impact.

BACKGROUND: Current diagnostic testing for prostate cancer results in numerous unnecessary biopsy procedures and creates a substantial financial burden. A statistical prediction model for prostate cancer has been developed, based on four Kallikrein markers in blood. This systematic review and meta-analysis examines the aggregated results from published studies of the Kallikrein Panel. METHODS: Literature searches to identify relevant studies were conducted. A meta-analysis of the results was performed using inverse variance, mean difference with corresponding 95% confidence intervals (CI). The results of the meta-analysis were used to assess the Kallikrein Panel's effect on healthcare costs. RESULTS: The Kallikrein Panel has been evaluated in more than 8,500 patients (2,780 with prostate cancer and 598 with high grade prostate cancer). Meta-analysis demonstrates a statistically significant improvement of 8-10% in predictive accuracy. In addition, 48% to 56% of current prostate biopsies could be avoided. Use of the Kallikrein Panel could result in annual US savings approaching $1 billion. CONCLUSIONS: The Kallikrein Panel has the potential to improve patient outcomes and reduce costs. The panel provides significantly improved specificity. Because the Kallikrein Panel has been studied in a range of clinical settings, it is a test that could be readily and widely used in practice.

Prostate biopsy in response to a change in nadir prostate specific antigen of 0.4 ng/ml after treatment with 5α-reductase inhibitors markedly enhances the detection rate of prostate cancer.

PURPOSE: We examined the effect of 5α-reductase inhibitor therapy on prostate cancer detection in men with persistently increased or fluctuating prostate specific antigen and prior negative prostate cancer biopsy. MATERIALS AND METHODS: A total of 276 men with prostate specific antigen greater than 4 ng/ml (208) or a prostate specific antigen velocity change of 0.75 ng/ml (68) and a normal digital rectal examination who had previously undergone biopsy a minimum of 2 times with prostate cancer not detected were given 5 mg finasteride (154) or dutasteride (122) daily. In phase 1, 97 patients had prostate specific antigen measured at 6 and 12 months with repeat transrectal ultrasonography and biopsy (12 cores) performed at 1 year. In phase 2, 179 patients underwent biopsy triggered by a change in nadir prostate specific antigen of more than 0.4 ng/ml. RESULTS: In phase 1 at 1 year prostate specific antigen had decreased by 2.4 ng/ml (-46.7%), and prostate volume had decreased 7.1 ml (-17.9%). Prostate cancer was detected in 27 of 97 (27.8%) patients and the mean minimum prostate specific antigen velocity from a nadir of 0.4 ng/ml was 0.6 ng/ml. In phase 2, 48 of 179 (26.8%) men underwent repeat biopsy at a mean of 14.6 months. Of these 48 men 26 (54.1%) were found to have prostate cancer. Of the 26 men in whom prostate cancer was detected 20 (76.9%) were found to have Gleason score 7 or greater disease. CONCLUSIONS: The magnitude of change in serum prostate specific antigen after 5α-reductase inhibitor therapy may be useful in diagnosing prostate cancer in patients with persistently increased or fluctuating prostate specific antigen and prior negative prostate biopsy.

Visual cues as a surrogate for tactile feedback during robotic-assisted laparoscopic prostatectomy: posterolateral margin rates in 1340 consecutive patients.

OBJECTIVE: To analyse consecutive cases of robotic-assisted laparoscopic prostatectomy (RALP), present the incidence of nerve-sparing-related positive surgical margins (SM+), include visual cues that might assist in smoothly changing to the robotic platform, and discuss the scientific rationale for 'intersensory integration' which might explain the 'reverse Braille' phenomenon, i.e. the ability to feel when vision is greatly enhanced, as the lack of tactile feedback during RALP is often cited as a disadvantage of robotic surgery, interfering with a surgeon's ability to make intraoperative oncological decisions. PATIENTS AND METHODS: Data from 1340 consecutive patients undergoing RALP from one institution were analysed and trends for positive posterolateral SM+ (PLSM+) were correlated with oncological variables before and after RALP. A sample of patient slides were reviewed by a extramural pathologist. Multivariate regression modelling was used to compare the projected rates of PLSM+ vs the actual rate, given the effect of a conscious effort to use visual cues. Finally, video recordings of the procedure were systematically reviewed and correlated with anatomical and histopathological images in an integrated session involving the surgeon and the pathology team. RESULTS: The incidence of PLSM+ was 2.1%, which gradually declined to 1.0% in the last 100 patients. The reduction in PLSM+ occurred despite an increased rate of high-risk tumours operated on during this period. Forecasting analysis showed that the actual PLSM+ rate declined by half in the most recent 1000 patients, due to an integrated effort involving the use of visual cues during surgery. The following visual cues were considered important; appreciation of periprostatic (lateral prostatic) fascial compartments; colour and texture of the tissue; periprostatic veins as a landmark for athermal dissection; signs of inflammation; and a freely separating bloodless plane showing loose shiny areolar tissue. CONCLUSION: Adapting to the robotic platform is easy and there is no compromise of the oncological safety of this procedure. Experienced surgeons can use visual cues to assist during nerve-sparing RALP and achieve low PLSM+ rates.

PCPT: Evidence that finasteride reduces risk of most frequently detected intermediate- and high-grade (Gleason score 6 and 7) cancer.

OBJECTIVES: To determine the effect of finasteride relative to placebo on prostate cancer (PCa) risk at each individual Gleason score in the Prostate Cancer Prevention Trial using a post hoc generalization of a prespecified, exploratory, biopsy sampling density-adjusted analysis. METHODS: The Prostate Cancer Prevention Trial enrolled 18 882 men aged >or=55 years with a prostate-specific antigen level of <3.0 ng/mL and normal digital rectal examination findings, and randomized them to finasteride 5 mg daily or placebo. PCa data from evaluable biopsies obtained within 7 years plus

Antagonism of BMP4 signaling disrupts smooth muscle investment of the ureter and ureteropelvic junction.

PURPOSE: Congenital ureteropelvic junction obstruction has been associated with aberrant ureteral smooth muscle organization. Recent evidence has shown that BMP4 may be involved in ureteral morphogenesis. We determined whether the disruption of BMP4 signaling results in abnormal smooth muscle investment of the ureter and ureteropelvic junction. MATERIALS AND METHODS: We used a Cre mediated Bmp4 knockout system to conditionally excise the Bmp4 gene in developing mouse embryos. Kidney rudiments were isolated from embryos at varying gestational ages from WT and conditional knockout mice. Metanephric kidney explants were cultured in the presence or absence of the BMP antagonist Noggin. Agarose beads pre-incubated with Gremlin, another BMP antagonist, were used for localized disruption of BMP signaling. Frozen sections and whole metanephric explants were then analyzed by immunofluorescence. RESULTS: Bmp4 gene excision resulted in a dose dependent loss of ureteral smooth muscle. Antagonism of BMP signaling inhibited ureteral smooth muscle investment in a dose dependent manner and was paralleled by a dose dependent decrease in the immediate downstream targets of BMP signaling, phosphorylated Smad1, 5 and 8. Localized antagonism of BMP resulted in the focal disruption of ureteral smooth muscle investment. CONCLUSIONS: We report that decreased BMP signaling, whether by the loss of BMP4 in vivo or direct antagonism in vitro, results in a gradual reduction of the normal, well organized coat of smooth muscle surrounding the ureter. Our results also suggest that this occurs via a direct Smad dependent pathway. This raises the possibility that abnormalities in BMP4 signaling may have a role in the development of congenital ureteropelvic junction obstruction.

Cutaneous renocolic fistula associated with diverticulitis.

We report a case of a cutaneous renocolic fistula in a patient with staghorn calculus and diverticulitis. The most common origins of renocolic fistula are primary renal diseases including xanthogranulomatous pyelonephritis, trauma, malignancy or tuberculosis. While diverticulitis has rarely been associated with renocolic fistula, previous instances of fistulae have been noted in patients with simultaneous kidney disease. Inflammation resulting from kidney disease may place patients with colonic diverticulitis at higher risk for developing renocolic or cutaneous renocolic fistulas.

Negative influence of changing biopsy practice patterns on the predictive value of prostate-specific antigen for cancer detection on prostate biopsy.

BACKGROUND: A correlation between prostate specific antigen (PSA) level and positive prostate biopsy rate was established in an era when biopsy practice patterns were different from what they are today. We evaluated if changes in biopsy practice patterns have affected the ability of PSA to predict cancer detection on prostate biopsy in the current era. METHODS: Of 3634 prostate biopsies performed from 1993-2005, 1607 met criteria for analysis. Biopsy data were divided into 3 time-cohorts (1993-1997, 1998-2001, and 2002-2005) to assess for practice patterns shifts and correlation between PSA and biopsy results. RESULTS: Significant changes in biopsy practice patterns included an increase in biopsy cores and more frequent use of PSA 2.5-3.99 ng/mL as a biopsy indication. In men with normal DRE, a moderate correlation between PSA and positive biopsy rate did exist from 1993-1997, but was subsequently lost. On multivariate analysis, PSA was not a significant predictor of biopsy result in men with normal DRE. CONCLUSIONS: Early in the PSA era, the predictive power of PSA depended on multiple factors: high prevalence of disease, higher prevalence of high-grade disease, and low likelihood of prostate cancer diagnosis in men with low PSA. Now, beyond the culling effect of increased biopsy incidence and with shifted biopsy practice patterns, the correlation between PSA and biopsy result is lost in men with normal DRE. Diagnosing a higher proportion of tumors in men with a PSA between 2.0-4.0 ng/mL has negatively influenced the predictive value of PSA for cancer detection.

Cancer control and the preservation of neurovascular tissue: how to meet competing goals during robotic radical prostatectomy.

OBJECTIVE: To present early functional and oncological data for the athermal trizonal nerve-sparing technique of robotic radical prostatectomy (RP), that addresses the concerns about deviations from the principles of open RP and revisits the anatomical foundations of this surgery from the robotic perspective. PATIENTS AND METHODS: The study involved close collaboration between the Cornell Institute of Robotic Surgery in New York, USA, and the Institute of Urology at the University of Innsbruck in Austria. The cadaveric studies and standardization of the athermal technique were conducted at Innsbruck, and the technique was used in 215 patients in New York. RESULTS: The athermal technique addresses concerns about the use of thermal energy and bulldog clamps during nerve sparing, and emphasizes the importance of the trizonal neural architecture. We analysed the surgical outcomes of 215 consecutive patients from January 2005. The operative duration was 120-240 min and the mean blood loss was 150 mL. In patients potent before RP the potency rate at 1 year after bilateral nerve-sparing was 87%. The overall surgical margin rate was 6.5% and positive margin rates for organ-confined cancer were 4.7%. CONCLUSION: We describe the athermal technique of robotic RP and introduce the concept of trizonal nerve preservation. The immediate oncological and sexual outcomes were encouraging.

Adeno-associated viral vector transduction of green fluorescent protein in kidney: effect of unilateral ureteric obstruction.

OBJECTIVE: To evaluate adeno-associated virus (AAV) mediated renal gene transfer, by examining the localization and time course of gene expression in the kidneys of mice with unilateral ureteric obstruction (UUO) and controls. AAV is a replication-defective virus that has the potential to deliver genes into the kidney to improve renal damage after UUO. MATERIALS AND METHODS: An AAV vector carrying a green fluorescent protein (GFP) reporter gene (rAAV-GFP) was used. In control mice, GFP expression was evaluated at 4, 7, 14 and 28 days after intrapelvic injection of rAAV or phosphate-buffered saline (PBS). In mice with UUO, the left ureter was obstructed, and 24 h later either rAAV or PBS was injected; GFP expression was evaluated 4, 7 and 14 days later by direct fluorescence. RESULTS: In the control mice, at least 7 days was required to detect GFP expression, whereas after UUO, GFP expression was already evident at 4 days after injection. GFP was localized mainly to the medullary tubules. CONCLUSIONS: This study shows successful transduction of GFP into mouse kidney using an AAV vector; GFP was expressed sooner in UUO kidneys than in the controls. These results show the feasibility of using AAV to transduce GFP into the obstructed kidney, and suggest that it might be useful in transducing therapeutically active agents.

Nerve advancement with end-to-end reconstruction after partial neurovascular bundle resection:a feasibility study.

BACKGROUND AND PURPOSE: It is clear that some patients with prostate cancer require a total or partial neurovascular bundle (NVB) resection for oncologic safety to be guaranteed. Nerve grafting is an alternative for these patients to maintain erectile function; however, we report on a feasible option where the NVB is released, and both terminal nerve fibers are approximated; this is the "nerve advancement technique (NAT)." PATIENTS AND METHODS: Since 2005, a total of 215 men aged 48 to 70 years (mean 59 years) with a Sexual Health Inventory for Men (SHIM) score of 22 have undergone robotic radical prostatectomy for cancer. We selected prospectively seven men to have NAT performed because of clinical high-risk criteria (serum prostate specific antigen [PSA] concentration >20 mg/dL, Gleason score = 8, and stage cT(2c) or higher), intraoperative criteria (difficulty separating the tissues around the prostate), and evidence of extracapsular extension (ECE) on magnetic resonance imaging. We performed unilateral partial resection, nerve advancement, and, finally, end-to-end anastomosis in six patients, whereas in one patient, we did a bilateral partial excision. We analyzed the results in terms of oncologic safety (positive surgical margins and PSA) and SHIM score after 18 months of follow-up. RESULTS: Pathologic examination revealed stage T3 disease in six patients; one had a positive surgical margin. Two patients are receiving salvage radiotherapy for PSA relapse, and five continue to have undetectable PSA concentrations after a median follow-up of 20 months. Five of the seven men recovered erectile potency with or without a phosphodiesterase inhibitor, and their median SHIM score is 18. CONCLUSIONS: We are encouraged by the initial results of NAT. The procedure may be an alternative for men who require extensive NVB dissection. However, further experience, longer follow-up, and independent trials are necessary.

Pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma.

OBJECTIVES: To determine the pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC). METHODS: From 1993 to 2003, 82 patients without a history of bladder cancer underwent nephroureterectomy or segmental distal ureterectomy for UUT-TCC. We reviewed the pathologic features of the subsequent bladder tumors, including stage, grade, and progression to cystectomy in these patients at a median follow-up of 44.1 months. RESULTS: A total of 36 (44%) of 82 patients developed bladder tumors after definitive therapy for UUT-TCC at a mean interval of 13.9 months. The mean number of bladder tumors diagnosed per patient in the follow-up interval was 2.1 (range 1 to 6), for a total of 74 bladder tumors. Of the 74 bladder tumors, 71 (96%) were superficial (Stage Ta, Tis, T1), 49 of these superficial tumors (69%) being low grade (grade 1 and 2) and 22 (31%) high grade (grade 3). Three patients had high-grade, muscle-invasive disease, and all progressed to cystectomy during follow-up. A greater than 75% concordance was found in pathologic grade between the UUT lesion and subsequent bladder tumors. The stage of the UUT malignancy, however, did not correlate with subsequent bladder tumor pathologic findings. CONCLUSIONS: Bladder tumors developed in 44% of patients after treatment of UUT-TCC. Of these bladder tumors, over 60% were superficial, low-grade lesions, yielding a similar pathologic distribution to that of bladder cancer de novo. The grade, but not the stage, of the UUT tumors correlated with the pathologic findings of subsequent bladder tumor recurrence. Aggressive surveillance with cystoscopy and urinary cytology after surgical management of UUT-TCC is imperative.

Renal cell carcinoma sub-typing by histopathology and fluorescence in situ hybridization on a needle-biopsy specimen.

OBJECTIVE: To determine the subtype of renal cell carcinoma (RCC) on needle-core biopsies of renal masses using histopathology and fluorescence in situ hybridization (FISH), and to evaluate the use of interphase FISH to augment the accuracy of needle-core biopsies. PATIENTS AND METHODS: Histology correlates with prognosis in RCC but, historically, biopsies are inaccurate for histological subtype. As histological subtypes of RCC have distinct cytogenetic abnormalities (loss of 3p in clear cell, trisomy 7 or 17 in papillary and widespread chromosomal losses in chromophobe), we hypothesized that FISH would improve the accuracy of biopsies. Forty patients with renal masses underwent nephrectomy, yielding 42 tumours. Needle-core biopsies were taken of the mass immediately after surgery. Interphase FISH was performed on one core for chromosomes 3, 7, 10, 13, 17, and 21 and the locus 3p25-26. Histopathology was performed on a second core. Results were compared in a 'blinded' fashion with final pathology. RESULTS: In all, 36 of 42 masses were RCC or oncocytoma. Histopathology of the biopsy correctly identified the tumour subtype in 27 (75%), while four (11%) were incorrectly classified and five (14%) were inadequate for diagnosis. With the addition of FISH, 31 (86%) were correctly subtyped, while two (6%) were incorrect and three (8%) were inadequate. In cases with adequate tissue, histology alone was 87% accurate, while the combined method was 94% accurate. CONCLUSION: Needle-core biopsy of renal tumours provides adequate material for evaluation of histological subtype. Adding FISH to histopathology might improve the accuracy of kidney tumour biopsies, providing important prognostic information that can guide management decisions.

Renal artery embolization: clinical indications and experience from over 100 cases.

OBJECTIVE: To review current indications and techniques for renal artery embolization (RAE) and more specifically to review cases of RAE before nephrectomy for treating patients with a large renal mass. PATIENTS AND METHODS: All RAEs done at our institution between May 1993 and December 2005 were reviewed. Patients were identified using a database assembled by the Division of Cardiovascular Interventional Radiology. Indications, techniques and RAE-related complications were then obtained from a retrospective review of medical records. Additional data for patients undergoing preoperative infarction were acquired, including estimated blood loss (EBL), transfusion requirement, pathological size, subtype, grade, stage, and level of tumour thrombus if present. RESULTS: In all, there were 121 RAEs, 69 in males and 52 in females (mean age 57.6 years, range 11-89). Metallic microcoils were the most often used embolization agent, followed by acrylic microspheres (embospheres), polyvinyl alcohol particles, absolute ethanol, and Gelfoam (Pharmacia & Upjohn, USA). The most common indication for RAE was infarction before nephrectomy (54.5%). Other indications included symptomatic angiomyolipomas, palliation of unresectable renal cancer, haemorrhage, perinephric bleeding in end-stage renal disease, vascular lesions, malignant hypertension, and sequelae of end-stage renal disease. RAE-associated complications including coil migration, incomplete embolization, and groin haematoma (in 5.0%). Symptoms of post-infarction syndrome were common, with 74.4% of patients having flank pain, nausea, or vomiting; the vast majority of these symptoms were mild and self-limited. In patients having nephrectomy after RAE the median (range) interval from RAE was 2 (0-78) days. The mean tumour size was 11.2 (3.5-25) cm and 46% of patients had tumour thrombus present in either the renal vein or inferior vena cava (IVC). The mean (median) overall EBL in patients having nephrectomy after RAE was 1048 (725) mL. The mean transfusion requirement over the course of hospitalization was 3.9 units of packed red blood cells. CONCLUSIONS: RAE is a safe and effective therapeutic tool for many urological, renal and vascular conditions. Its use has increased at our institution due to improved techniques, embolization materials, and our increasing use of RAE as an adjuvant procedure for patients requiring nephrectomy with or without IVC thrombectomy. There are many potential operative advantages for patients having RAE before surgery, with minimal morbidity. It is likely that the lack of prospective randomized trials is the primary reason why it is underutilized in the preoperative setting.

The proximal neurovascular plate and the tri-zonal neural architecture around the prostate gland: importance in the athermal robotic technique of nerve-sparing prostatectomy.

OBJECTIVE: To review the neural architecture around the prostate gland, as it is relevant for nerve-sparing robotic prostatectomy, including in particular the anatomy of the proximal neurovascular tissue, the neurovascular bundle (NVB), and accessory neural pathways (ANPs). MATERIALS AND METHODS: The aims of this study were achieved in collaboration between the Cornell Institute of Robotic Surgery, New York, NY, USA and the Institute of Urology at the University of Innsbruck, Austria. The broad steps were: (i) anatomical studies of 10 fresh and two fixed male cadavers; and (ii) collection of videotape and still image data from 200 men undergoing radical prostatectomy by the athermal robotic technique at the Cornell Institute. RESULTS: From a surgical standpoint there was a tri-zonal neural architecture including the proximal neurovascular plate (PNP), the predominant NVB (PNB) and ANPs. The PNP was a mean (range) of 5 (3-10) mm lateral to the seminal vesicles, was 3 (2-7) mm thick, 7 (5-25) mm wide and 9 (4-30) mm long. It was within 6 (4-15) mm of the bladder neck, 5 (2-7) mm of the endopelvic fascia and overlapped 5 (0-7) mm of the proximal prostate. The PNB varied in shape and size from the proximal to distal end, was thickest at the base and most variable near the apex. In eight of 12 cases, there was a medial extension behind the prostate, which converged medially at the apex in four cases. ANPs were noted within the layers of levator fascia and/or lateral pelvic fascia on the anterolateral aspect in five cases and in three on the posterior aspect of the prostate. In nine cadavers, the proximal third of the prostate was covered by the PNP where these ANPs were most prominent. The ANPs formed a plexus on the posterolateral aspect of the apex in four cases. CONCLUSION: We have created an anatomical map of neurovascular tissue relevant to robotic prostatectomy. A tri-zonal neural architecture is described which has helped in standardizing the steps of robotic prostatectomy.

Victor Fray Marshall: twentieth century renaissance urologist.

PURPOSE: Victor Fray Marshall (1913 to 2001) contributed to advancements in a variety of fields within urology, including incontinence, oncology, stone disease and pediatrics. MATERIALS AND METHODS: We reviewed historical records from the New York Hospital archives as well as the original publications of Marshall. Personal experiences of former residents and others were recounted. RESULTS: While Marshall may be most recognized for Marshall-Marchetti-Krantz vesicourethral suspension, designed to correct stress urinary incontinence, he was among the earliest advocates of surgical extirpation for bladder cancer and helped introduce the use of urinary cytology for the diagnosis of urothelial malignancy. At the same time Marshall contributed to the development of ureteroscopy for stone disease. His contributions to pediatric urology include the description of a nonrefluxing ureteral re-implantation technique for the surgical correction of reflux as well as his investigation of the embryology and surgical repair of bladder exstrophy. CONCLUSIONS: The contributions of Victor Marshall to urology are notable in breadth and significance.

A population-based study of renal cell carcinoma and prostate cancer in the same patients.

OBJECTIVE: To investigate the incidence of prostate cancer in men with renal cell carcinoma (RCC) and the incidence of RCC in men with prostate cancer. METHODS: We evaluated the database of the Surveillance, Epidemiology and End Results Program of the National Cancer Institute from 1973 to 1996, to calculate the incidence of RCC in men with prostate cancer and the incidence of prostate cancer in men with RCC. The standardized incidence ratio (SIR, observed/expected) was calculated for each of the scenarios of interest, as well as for RCC and prostate cancer in men with other common malignancies. Lung/bronchus cancer, colon/rectal cancer, and non-Hodgkin lymphoma were selected for the control scenarios because they are the most common non-urological cancers among men in the USA. RESULTS: There was a higher incidence of RCC in men with prostate cancer (SIR 1.25, P < 0.01). RCC incidence was also higher in men with each of the other malignancies. Prostate cancer incidence was higher in men with RCC (SIR 1.42, P < 0.001), but was not significantly elevated for any of the control scenarios. CONCLUSIONS: The incidence of RCC is higher in men with each of the index cancers, whereas that for prostate cancer was higher only in men with RCC. A common aetiological factor is possible. However, it is also possible that detection bias explains these findings. Serial imaging might increase the detection of RCC among patients with a variety of index malignancies. Patients with RCC who are followed by a urologist might be screened more rigorously for prostate cancer than patients with other primary malignancies, leading to increased detection in these men.