Marc Colombel

Prostate Cancer Diagnosis: Multiparametric MR-targeted Biopsy with Cognitive and Transrectal US–MR Fusion Guidance versus Systematic Biopsy—Prospective Multicenter Study

PURPOSE To compare biopsy performance of two approaches for multiparametric magnetic resonance (MR)-targeted biopsy (TB) with that of extended systematic biopsy (SB) in prostate cancer (PCa) detection. MATERIALS AND METHODS This institutional review board-approved multicenter prospective study (May 2009 to January 2011) included 95 patients with informed consent who were suspected of having PCa, with a suspicious abnormality (target) at prebiopsy MR. Patients underwent 12-core SB and four-core TB with transrectal ultrasonographic (US) guidance, with two cores aimed visually (cognitive TB [TB-COG]) and two cores aimed using transrectal US-MR fusion software (fusion-guided TB [TB-FUS]). SB and TB positivity for cancer and sampling quality (mean longest core cancer length, Gleason score) were compared. Clinically significant PCa was any 3 mm or greater core cancer length or any greater than 3 Gleason pattern for SB or any cancer length for TB. Statistical analysis included t test, paired χ(2) test, and κ statistic. Primary end point (core cancer length) was calculated (paired t test). RESULTS Among 95 patients (median age, 65 years; mean prostate-specific antigen level, 10.05 ng/mL [10.05 μg/L]), positivity rate for PCa was 59% (n = 56) for SB and 69% (n = 66) for TB (P = .033); rate for clinically significant PCa was 52% (n = 49) for SB and 67% (n = 64) for TB (P = .0011). Cancer was diagnosed through TB in 16 patients (17%) with negative SB results. Mean longest core cancer lengths were 4.6 mm for SB and 7.3 mm for TB (P < .0001). In 12 of 51 (24%) MR imaging targets with positive SB and TB results, TB led to Gleason score upgrading. In 79 MR imaging targets, positivity for cancer was 47% (n = 37) with TB-COG and 53% (n = 42) with TB-FUS (P = .16). Neither technique was superior for Gleason score assessment. CONCLUSION Prebiopsy MR imaging combined with transrectal US-guided TB increases biopsy performance in detecting PCa, especially clinically significant PCa. No significant difference was observed between TB-FUS and TB-COG for TB guidance.

A Review of Current Guidelines and Best Practice Recommendations for the Management of Nonmuscle Invasive Bladder Cancer by the International Bladder Cancer Group

PURPOSE Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. MATERIALS AND METHODS An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. RESULTS Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. CONCLUSIONS Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.

Increased Immunodetection of Acidic Fibroblast Growth Factor in Bladder Cancer, Detectable in Urine

Acidic fibroblast growth factor is a regulatory peptide involved in cell proliferation, differentiation and motility. We used a polyclonal antiserum raised against purified native bovine acidic fibroblast growth factor, with no cross-reactivity for basic fibroblast growth factor to detect acidic fibroblast growth factor in tissue extracts and urine samples by means of a competitive enzyme immunoassay. Histochemical analysis was also performed on 10 specimens of normal urothelium and 50 of bladder cancer. Acidic fibroblast growth factor immunoreactive material was found in normal urothelium (1.77 +/- 2 ng./gm. tissue) and was increased more than 10-fold in patients with transitional cell carcinoma of the bladder (20.36 +/- 12 ng./gm. tissue). Immunohistochemical analysis localized immunoreactivity in the epithelial compartment of bladder tumors. Acidic fibroblast growth factor was assayed in urine from 579 individuals comprising a control group (114) and patients with benign prostatic hypertrophy (133), carcinoma of the prostate (96) or transitional cell carcinoma of the bladder (236). There was a significant difference in the frequency of urinary acidic fibroblast growth factor detection among the patients with invasive transitional cell carcinoma, the control group (p < 0.001) and the patients with prostatic disease (p < 0.01). The sensitivity was 72% and the specificity was 91%. Furthermore, the frequency of acidic fibroblast growth factor detection by enzyme immunoassay in the urine and the intensity of immunostaining was correlated with the stage of the disease. These data strongly suggest that acidic fibroblast growth factor is a potential marker for bladder tumors that may be of use in the noninvasive followup of patients with bladder cancer. We present a simple and reliable enzyme immunoassay for the detection of acidic fibroblast growth factor in voided urine that might be useful to quantitate this marker.

Whole-gland Ablation of Localized Prostate Cancer with High-intensity Focused Ultrasound: Oncologic Outcomes and Morbidity in 1002 Patients

BACKGROUND High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa). OBJECTIVE The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study. DESIGN, SETTING, AND PARTICIPANTS Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence. INTERVENTION Whole-gland prostate ablation with transrectal HIFU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2-13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression. RESULTS AND LIMITATIONS A total of 1002 patients were included. The median nadir prostate-specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA ≤0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients. CONCLUSIONS HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity.

Evaluation of T2-weighted and dynamic contrast-enhanced MRI in localizing prostate cancer before repeat biopsy

We assessed the accuracy of T2-weighted (T2w) and dynamic contrast-enhanced (DCE) 1.5-T magnetic resonance imaging (MRI) in localizing prostate cancer before transrectal ultrasound-guided repeat biopsy. Ninety-three patients with abnormal PSA level and negative prostate biopsy underwent T2w and DCE prostate MRI using pelvic coil before repeat biopsy. T2w and DCE images were interpreted using visual criteria only. MR results were correlated with repeat biopsy findings in ten prostate sectors. Repeat biopsy found prostate cancer in 23 patients (24.7%) and 44 sectors (6.6%). At per patient analysis, the sensitivity, specificity, positive and negative predictive values were 47.8%, 44.3%, 20.4% and 79.5% for T2w imaging and 82.6%, 20%, 24.4% and 93.3% for DCE imaging. When all suspicious areas (on T2w or DCE imaging) were taken into account, a sensitivity of 82.6% and a negative predictive value of 100% could be achieved. At per sector analysis, DCE imaging was significantly less specific (83.5% vs. 89.7%, p < 0.002) than T2w imaging; it was more sensitive (52.4% vs. 32.1%), but the difference was hardly significant (p = 0.09). T2w and DCE MRI using pelvic coil and visual diagnostic criteria can guide prostate repeat biopsy, with a good sensitivity and NPV.

Regulation of Apoptosis in the Prostate Gland by Androgenic Steroids.

The prostate gland requires androgenic steroids for its appropriate embryological formation and postpubertal growth and, once at adult size, remains dependent on a continuous supply of androgens for its vitality and function. A reduction of the levels of circulating androgens will rapidly induce apoptosis of the cells of the prostate, leading to extensive glandular regression. Studies of rodent models of prostate response to castration have shown that there are some remarkable changes in the gene activity of prostate epithelial cells leading up to apoptosis. There is now evidence for a critical cell signaling pathway, regulated by c-fos expression, necessary for castration-induced apoptosis, as well as evidence that this signaling initiates an abrupt and transient alteration in the synthesis of fas antigen, p53, bax and bcl-2 proteins in the androgen receptor-expressing prostate epithelial cells, the cellular compartment that appears to be the most affected by castration. However, more recent studies suggest that these castration-induced effects on the prostate epithelial cells might be, at least in part, an indirect response to a critical reduction in blood flow to the prostate gland that precedes the onset of epithelial cell apoptosis. The castration effects on blood flow to the prostate gland seem to be related to vascular degeneration associated with apoptosis of a subset of prostate endothelial cells.

Conservative management of upper urinary tract tumours

PURPOSE We determined the immediate and long-term results of endoscopic management of upper tract transitional cell in regard to rates of tumor recurrence and preservation of renal function. MATERIALS AND METHODS From January 1990 to July 1999, 61 patients (mean age 66.2 years) underwent endoscopic management of upper tract cell carcinoma. Of the patients 20 (32%) had a solitary kidney. Tumors were resected in a one time procedure by ureteroscopy only in 31.5%, by percutaneous nephroscopy in 29% or both in 8%; multiple treatment was necessary in 31.5% of cases using percutaneous nephroscopy only. RESULTS Immediate nephrectomy was done in six cases for high grade (three patients), insufficient local control (two cases) or patients choices (one case). There were six cases of benign tumors excluded from survival Kaplan Meier analysis. With a mean follow-up of 39.9 months, the rate of kidney preservation, recurrence free rate, global survival and specific survival rates were, respectively, 81%, 68%, 77%, and 84%. CONCLUSIONS Nephron sparing percutaneous management of upper tract cell carcinoma is applicable in a significant number of patients with a filling defect of upper urinary tract TCC. In carefully selected patients the results are at least comparable to other forms of management of tumor control and preservation of renal function.

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase

Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 μM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.

Conservative Management of Upper Urinary Tract Tumors

Abstract Purpose: We determined the immediate and long-term results of endoscopic management of upper tract transitional cell in regard to rates of tumor recurrence and preservation of renal function. Materials and Methods: From January 1990 to July 1999, 61 patients (mean age 66.2 years) underwent endoscopic management of upper tract cell carcinoma. Of the patients 20 (32%) had a solitary kidney. Tumors were resected in a one time procedure by ureteroscopy only in 31.5%, by percutaneous nephroscopy in 29% or both in 8%; multiple treatment was necessary in 31.5% of cases using percutaneous nephroscopy only. Results: Immediate nephrectomy was done in six cases for high grade (three patients), insufficient local control (two cases) or patient’s choices (one case). There were six cases of benign tumors excluded from survival Kaplan Meier analysis. With a mean follow-up of 39.9 months, the rate of kidney preservation, recurrence free rate, global survival and specific survival rates were, respectively, 81%, 68%, 77%, and 84%. Conclusions: Nephron sparing percutaneous management of upper tract cell carcinoma is applicable in a significant number of patients with a filling defect of upper urinary tract TCC. In carefully selected patients the results are at least comparable to other forms of management of tumor control and preservation of renal function.

Results of pyeloureterostomy after ureterovesical anastomosis complications in renal transplantation

OBJECTIVES The most frequent urologic complications after renal transplantation involve the ureterovesical anastomosis (ie, leakage, stenosis, and reflux), with a frequency of 1% to 30% in different series. We present the results of pyeloureterostomy using the recipients ureter. METHODS From 1988 to 1996, 570 cadaveric renal grafts were performed at our institution. A Lich Gregoir ureterovesical anastomosis was used in every case. Complications involving the anastomosis occurred in 19 cases (3.3%), with 10 stenoses (1.7%), 6 cases of leakage (1.1%), and 3 of reflux (0.5%). The mean donor age was 36.2 years, and the mean duration of cold ischemia was 29.4 hours. The mean recipient age was 41.3 years. Corrective surgery was performed 0.09 years (range 0.01 to 0.22) after transplantation for leakage, 1.13 years (range 0.14 to 5.11) for stenosis, and 5.55 years (range 0.51 to 9.71) for reflux. The recipients ureter was stented with a ureteral catheter before median laparotomy, except in 3 cases of early leakage (less than 3 days). The recipients ureter was cut, without the need for ipsilateral nephrectomy, and sutured to the graft pelvis. A nephroureterostomia stent (Gil Vernet stent) (12 cases) or a double J ureteral stent (7 cases) was used for urinary drainage. RESULTS One graft was lost on day 1 through renal vein thrombosis. Percutaneous nephrostomy was performed on day 2 to clear an obstruction of the double J ureteral stent in one case, and a double J ureteral stent was inserted on day 2 because the nephrouretrostomia stent was incorrectly positioned in another case. Pyelographic controls on day 15 were normal in every case. The mean follow-up was 2.25 years (range 0.24 to 6.1) (2.9 years for leakage, 2.08 years for stenosis, and 1.44 years for reflux). One patient died with a functional graft 3 years after surgery. One graft was lost 4 years after surgery through chronic rejection. There were no complications affecting the ipsilateral kidney. No further ureteral complications occurred after surgery. The mean creatinine level 3 years after surgery was 1.59 mg/dL. CONCLUSIONS Pyeloureterostomy is a safe and permanent treatment for complications of ureterovesical anastomosis and gives excellent results. The technique requires stenting of the recipients ureter and graft drainage with a nephroureterostomia stent or a double J ureteral stent.