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.

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.

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.

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.

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.

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.

Combination therapy for the pharmacological management of benign prostatic hyperplasia: rationale and treatment options.

The management of symptomatic benign prostatic hyperplasia (BPH) continues to evolve, with new techniques and forms of medical management being introduced and traditional surgical techniques being used less frequently. Medical management of BPH has evolved from nonspecific alpha-adrenoceptor antagonists to uroselective alpha-adrenoceptor antagonists and 5-alpha reductase inhibitors. Traditionally, alpha-adrenoceptor antagonists have been used for relief of lower urinary tract symptoms (LUTS) as a result of BPH and are known for their quick onset of action. 5-alpha Reductase inhibitors have proven useful for the prevention of BPH progression as measured by prostate volume, disease progression, incidence of acute urinary retention and the need for subsequent BPH-related surgery. Recent studies have shown that the combination of an alpha-adrenoceptor antagonist and a 5-alpha reductase inhibitor has significantly better efficacy than either drug alone or placebo. Currently, alpha-adrenoceptor antagonists are used in the acute setting or for short-term relief of LUTS. The combination of an alpha-adrenoceptor antagonist and a 5-alpha reductase inhibitor is used for the longer term management of BPH symptoms and to prevent progression of BPH and perhaps avoid surgical intervention.

Diseases of the adrenal gland.

It is fortunate that the ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytic methodology to measure the appropriate adrenocortical and medullary hormonal production and the radiologic techniques for localization are superb. The management of these adrenal disorders usually using a laparoscopic approach following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this is a true success story with the evolution of these different techniques over the past 50 years.

The impact of technological advances on the evolution of 3D conformal brachytherapy for early prostate cancer.

Permanent implantation of I-125 and Pd-103 seeds is one of the widely used treatment options for the early stage prostate cancer with minimum normal tissue complications and long-term local control of the tumor. This is possible because of several technological advances made in the past decade to better understand the procedural aspects of implantations with the desired clinical outcome and with acceptable morbidities. In addition, with the widespread use of PSA testing, more widely disseminated information about prostate cancer and increased patient awareness, over 70% of patients are diagnosed early with localized disease and therefore are candidates for definitive local therapy. Delineation of soft tissue structures including the prostate, rectum, urethra and bladder has become more accurate with the use of imaging modalities including Ultrasound and MRI, with or without the CT. A re-evaluation of the dosimetric parameters of the radioactive sources has lead to a more precise estimate of the dose delivered to the prostate and the associated critical normal structures. Technological improvements in the post implant dosimetry have helped to understand the factors, which makes an implant a "good implant" or a "poor implant". Intraoperative treatment planning with on line dosimetry is emerging as one of the best approaches for prostate brachytherapy. In addition, better software is now available producing dose-volume histograms with 3D target and normal tissue reconstruction. The combination of seed implant followed by IMRT would provide scope for differentially boosting the regions under-dosed because of uncontrollable and unexpected reasons during the implant and unsuspected micro extensions of the tumor.

Abnormal selective cytology results predict recurrence of upper-tract transitional-cell carcinoma treated with ureteroscopic laser ablation.

BACKGROUND AND PURPOSE: Endoscopic management of transitional-cell carcinoma (TCC) of the upper urinary tract remains associated with a significant rate of recurrence. We evaluated the impact of selective upper-tract cytology findings on tumor recurrence and renal salvage rate after ureteroscopic laser tumor ablation. PATIENTS AND METHODS: From 1993 though 2003, 38 patients with upper-tract TCC underwent ureteroscopic laser tumor ablation. Cytology specimens were collected from the upper urinary tract prior to ablation. "Abnormal cytology" was defined as the presence of malignant or atypical cells. Patients with abnormal cytology results were compared with patients with those having negative findings for tumor recurrence and renal salvage rates using the X (2) test. RESULTS: Of the 38 patients, 26 (68.4%) experienced at least one recurrence at a mean follow-up of 37.2 months. Pretreatment upper-tract cytology results were available in 34 of these patients: 17 (50%) were negative, and 17 were abnormal. Sixteen of the patients (94.1%) with abnormal cytology results had tumor recurrence after ablation, compared with 8 of the 17 (47.1%) with negative cytology findings (P = 0.0026). Twelve patients (31.5%) underwent nephroureterectomy during follow-up: 8 of the 17 (47.1%) with abnormal cytology, and 4 of the 17 (23.5%) with negative cytology (P = 0.15). CONCLUSION: Abnormal selective cytology results were associated with a significantly higher rate of tumor recurrence and a trend toward increased renal loss in patients with upper-tract TCC treated with ureteroscopic ablation. These findings suggest a prognostic value for upper-tract cytology analysis in patients undergoing endoscopic therapy.

Liposome-mediated gene therapy in the kidney.

Gene therapy directed to the kidney has been attempted to improve renal disorders such as inherited kidney diseases and common renal diseases that cause interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Viral and non-viral vectors have been tried and been modulated to obtain sufficient transgene expression. However, gene delivery to the kidney is usually difficult because of characteristics of renal cell biology. Among non-viral vectors, the liposome system is a promising procedure for kidney-targeted gene therapy. Using cationic liposome, tubular cells were effectively transduced by retrograde injection of liposome/cDNA complex. Although transgene expression was reportedly modest using cationic liposomes, this method improved renal disease models such as carbonic anhydrase II deficiency and unilateral ureteral obstruction. In contrast, HVJ-liposome system is an effective transfection method to glomerular cells using intra-renal arterial infusion and improved glomerular disease models such as glomerulonephritis and glomerulosclerosis. In addition, intra-renal pelvic injection of DNA by HVJ-liposome system showed transgene expression in interstitial fibroblasts. In kidney-targeted gene therapy, liposome-mediated gene transfer is an attractive method because of its simplicity and reduced toxicity. In spite of modest transgene expression, several renal disease models were successfully modulated by liposome system. Although one limitation of liposome-mediated gene delivery is the duration of transgene expression, the liposome/cDNA complex can be repeatedly administered due to the absence of an immune response.

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