Five-alpha reductase inhibitors in men undergoing active surveillance for prostate cancer: impact on treatment and reclassification after 6 years follow-up.

OBJECTIVES: To evaluate the impact of 5-alpha reductase inhibitors (5-ARIs) on definitive treatment (DT) and pathological progression (PP) in patients on active surveillance (AS) for prostate cancer. METHODS: We identified 361 consecutive patients, from an IRB-approved database, on AS for prostate cancer with minimum 2 years follow-up. Patients were grouped into two cohorts, those using 5-ARIs (5-ARI; n = 119) or not using 5-ARIs (no 5-ARI; n = 242). Primary and secondary endpoints were treatment-free survival (TFS) and PP-free survival (PPFS), which were evaluated by Kaplan-Meier analysis. Univariate and multivariable cox regression analysis were used to identify predictors for PP and DT. A p value < 0.05 was considered statistically significant. RESULTS: Baseline characteristics and the prostate biopsy rate were similar between the two groups. Median (range) follow-up was 5.7 (2.0-17.2) years. Five-year and 10-year TFS was 92% and 59% for the 5-ARI group versus 80% and 51% for the no 5-ARI group (p = 0.005), respectively. Five-year and 10-year PPFS was 77% and 41% for the 5-ARI group versus 70% and 32% for the no 5-ARI group (p = 0.04), respectively. Independent predictors for treatment and PP were not taking 5-ARIs (p = 0.005; p = 0.02), entry PSA > 2.5 ng/mL (p = 0.03; p = 0.01) and Gleason pattern 4 on initial biopsy (p < 0.001; p < 0.001), respectively. The main limitation is the retrospective study design. CONCLUSIONS: 5-ARIs reduces reclassification and cross-over to treatment in men on active surveillance for prostate cancer. Further, taking 5-ARIs was an independent predictor for prostate cancer progression and definitive treatment.

Image-based monitoring of targeted biopsy-proven prostate cancer on active surveillance: 11-year experience.

PURPOSE: To report our 11-year experience of Active Surveillance (AS) program focusing on modern transrectal ultrasound (TRUS)-based monitoring of targeted biopsy-proven cancer lesion. METHODS: Consecutive patients on AS, who had targeted biopsy-proven lesion followed by at least a repeat surveillance biopsy and three times TRUS monitoring of the identical visible lesion, were included. Doppler grade of blood flow signal within the lesion was classified from grade 0 to 3. Biopsy-proven progression was defined as upgrade of Gleason score or 25% or greater increase in cancer core involvement. RESULTS: Fifty patients were included in this study. Clinical variables (median) included age (61 years), clinical stage (T1c, 42;T2, 8), PSA (4.6 ng/ml), and Gleason score (3 + 3, n = 41;3 + 4, n = 9). Of the 50 patients, 34 demonstrated pathological progression at a median follow-up of 4.4 years. In comparing between without (n = 16) and with (n = 34) pathological progression, there were significant differences in cancer core involvement at entry (p = 0.003), the major axis diameter (p = 0.001) and minor axis diameter (p = 0.001) of the visible lesion at entry, increase in the major axis diameter (p = 0.005) and minor axis diameter (p = 0.013), and upgrade of Doppler grade (p < 0.0001). In multivariate analysis for predicting pathological progression, the increase (≥25%) in diameter of biopsy-proven lesion (hazard ratio, 15.314; p = 0.023) and upgrade of Doppler grade (hazard ratio, 37.409; p = 0.019) were significant risk factors. CONCLUSIONS: Longitudinal monitoring of the TRUS-visible biopsy-proven cancer provides a new opportunity to perform per-lesion-based AS. The increase in diameter and upgrade of Doppler grade of the lesion were significant risk factors for biopsy-proven progression on AS.

Robotic transmural ablation of bladder tumors using high-intensity focused ultrasound: Experimental study.

OBJECTIVES: To evaluate the feasibility of robot-assisted laparoscopic high-intensity focused ultrasound for targeted, extravesical, transmural, full-thickness ablation of intact bladder wall and tumor. METHODS: In three fresh cadavers and one acute porcine model, the transperitoneal robotic approach was used to mobilize the bladder and create a midline cystotomy. "Mimic" bladder tumors (2 tumors/case) were created by robotically suturing a piece of striated muscle (2.5 × 2.5 cm) to the luminal, urothelial surface of the bladder wall. The cystotomy was suture-repaired and bladder distended with 250 mL saline. A laparoscopic high-intensity focused ultrasound probe was robotically placed extravesically in direct contact with the serosal surface of the bladder wall to image the "mimic" tumor. Targeted, transmural, full-thickness high-intensity focus ultrasound ablation of the "mimic" tumor and adjacent bladder was carried out under real-time ultrasound and robotic monitoring. Untreated areas of the bladder served as a comparison. Post-procedure, gross and microscopic examinations were carried out. RESULTS: Laparoscopic high-intensity focused ultrasound ablation was feasible for all "mimic" tumors (100%). Real-time ultrasound clearly visualized the "mimic" tumor. Simultaneous display of the pre-planning and real-time treatment ultrasound images confirmed targeting precision. Mean operative room times for ultrasound localization, laparoscopic high-intensity focused ultrasound probe coupling, high-intensity focus ultrasound ablation, and total procedure were 3, 5, 6 and 60 min, respectively. On necropsy, no thermal/mechanical injuries occurred to the untreated bladder wall, adjacent organs or ureters. Gross inspection distinguished the treated from untreated areas. Histopathology confirmed sharply demarcated thermal coagulative necrosis and shrinkage effects between the treated and untreated areas. CONCLUSIONS: Laparoscopic extravesical high-intensity focus ultrasound for transmural, full-thickness targeted ablation of intact bladder wall and tumor is feasible. This has implications for bladder-sparing surgery in select patients with solitary muscle-invasive bladder cancer.

Three-dimensional navigation system integrating position-tracking technology with a movable tablet display for percutaneous targeting.

OBJECTIVES: To assess the feasibility of a novel percutaneous navigation system (Translucent Medical, Inc., Santa Cruz, CA, USA) that integrates position-tracking technology with a movable tablet display. MATERIALS AND METHODS: A total of 18 fiducial markers, which served as the target centres for the virtual tumours (target fiducials), were implanted in the prostate and kidney of a fresh cadaver, and preoperative computed tomography (CT) was performed to allow three-dimensional model reconstruction of the surgical regions, which were registered on the body intra-operatively. The position of the movable tablet's display could be selected to obtain the best recognition of the interior anatomy. The system was used to navigate the puncture needle (with position-tracking sensor attached) using a colour-coded, predictive puncture-line. When the operator punctured the target fiducial, another fiducial, serving as the centre of the ablative treatment (treatment fiducial), was placed. Postoperative CT was performed to assess the digitized distance (representing the real distance) between the target and treatment fiducials to evaluate the accuracy of the procedure. RESULTS: The movable tablet display, with position-tracking sensor attached, enabled the surgeon to visualize the three-dimensional anatomy of the internal organs with the help of an overlaid puncture line for the puncture needle, which also had a position-tracking sensor attached. The mean (virtual) distance from the needle tip to the target (calculated using the computer workstation), was 2.5 mm. In an analysis of each digitalized axial component, the errors were significantly greater along the z-axis (P < 0.01), suggesting that the errors were caused by organ shift or deformation. CONCLUSION: This virtual navigation system, integrating a position-tracking sensor with a movable tablet display, is a promising advancement for facilitating percutaneous interventions. The movable display over the patient shows a preoperative three-dimensional image that is aligned to the patient. Moving the display moves the image, creating the feeling of looking through a window into the patient, resulting in instant perception and a direct, intuitive connection between the physician and the anatomy.

Trans-rectal ultrasound visibility of prostate lesions identified by magnetic resonance imaging increases accuracy of image-fusion targeted biopsies.

PURPOSE: To compare the diagnostic yield of targeted prostate biopsy using image-fusion of multi-parametric magnetic resonance (mp-MR) with real-time trans-rectal ultrasound (TRUS) for clinically significant lesions that are suspicious only on mp-MR versus lesions that are suspicious on both mp-MR and TRUS. METHODS: Pre-biopsy MRI and TRUS were each scaled on a 3-point score: highly suspicious, likely, and unlikely for clinically significant cancer (sPCa). Using an MR-TRUS elastic image-fusion system (Koelis), a 127 consecutive patients with a suspicious clinically significant index lesion on pre-biopsy mp-MR underwent systematic biopsies and MR/US-fusion targeted biopsies (01/2010-09/2013). Biopsy histological outcomes were retrospectively compared with MR suspicion level and TRUS-visibility of the MR-suspicious lesion. sPCa was defined as biopsy Gleason score ≥7 and/or maximum cancer core length ≥5 mm. RESULTS: Targeted biopsies outperformed systematic biopsies in overall cancer detection rate (61 vs. 41 %; p = 0.007), sPCa detection rate (43 vs. 23 %; p = 0.0013), cancer core length (7.5 vs. 3.9 mm; p = 0.0002), and cancer rate per core (56 vs. 12 %; p < 0.0001), respectively. Highly suspicious lesions on mp-MR correlated with higher positive biopsy rate (p < 0.0001), higher Gleason score (p = 0.018), and greater cancer core length (p < 0.0001). Highly suspicious lesions on TRUS in corresponding to MR-suspicious lesion had a higher biopsy yield (p < 0.0001) and higher sPCa detection rate (p < 0.0001). Since majority of MR-suspicious lesions were also suspicious on TRUS, TRUS-visibility allowed selection of the specific MR-visible lesion which should be targeted from among the multiple TRUS suspicious lesions in each prostate. CONCLUSIONS: MR-TRUS fusion-image-guided biopsies outperformed systematic biopsies. TRUS-visibility of a MR-suspicious lesion facilitates image-guided biopsies, resulting in higher detection of significant cancer.

Denonvilliers' space expansion by transperineal injection of hydrogel: implications for focal therapy of prostate cancer.

We developed and assessed a technique of: (i) expanding Denonvilliers' space by hydrogel (polyethylene glycol) during focal cryoabation; and (ii) temperature mapping to ensure protection of the rectal wall. In a fresh cadaver, 20 cc of hydrogel was injected transperineally into Denonvilliers' space under transrectal ultrasound guidance. Successful expansion of Denonvilliers' space was achieved with a range of 9-11 mm thickness covering the entire posterior prostate surface. Two freeze-thaw cycles were used to expand the iceball reaching the rectal wall as an end-point. Intraoperative transrectal ultrasound monitoring and temperature mapping in Denonvilliers' space by multiple thermocouples documented real-time iceball expansion up to 10 mm beyond the prostate, and safety in protecting the rectal wall from thermal injury. The lowest temperatures of the thermocouples with a distance of 0 mm, 5 mm and 10 mm from the prostate were: -35°C, -18°C and 0°C (P < 0.001), respectively. In gross and microscopic examination, the hydrogel mass measured 11 × 40 × 34 mm, which was identical to the intraoperative transrectal ultrasound measurements, there was no infiltration of the hydrogel into the rectal wall or prostate and no injury to the pelvic organs. In conclusion, the expansion of Denonvilliers' space by transperineal injection of hydrogel is feasible and a promising technique to facilitate energy-based focal therapy of prostate cancer.

Urothelial Tumors and Dual-Band Imaging: A New Concept in Confocal Laser Endomicroscopy.

OBJECTIVES: Confocal laser endomicroscopy (CLE) uses a low-energy laser light source to obtain microscopic histology images of bladder tissue exposed to a fluorescent dye. To evaluate the feasibility of using CLE with two fluorophores: fluorescein (FLUO) and hexylaminolevulinate (HAL) to determine histologic and cytologic bladder cancer criteria. METHODS: Patients eligible for HAL-photodynamic diagnosis-assisted transurethral resection of bladder tumor were included. The procedures were performed with the patient under regional or general anesthesia (60-90 minutes) after bladder instillation of HAL (50 mL, 8 mmol/L; Hexvix®; Ipsen, France). Resected tissue was examined ex vivo using CLE either with Cellvizio® system (CVI) single laser (488 nm) or with Cellvizio Dual system (CVII) double laser (488, 660 nm). RESULTS: Twenty-one patients were included, 12 examined by CVI and 9 by CVII. Sample examination on CVI after HAL-CLE-only histologic analysis was not possible because HAL is mostly cytoplasmic and gives poor details on cellular architecture. On the contrary, FLUO-CLE gives good extracellular architecture and not clear information of nucleocytoplasmic abnormality. Samples on CVII for seven out of nine patients clearly showed cytoplasm of suspect cells and nuclei. In real time, fluorescence observed on bandwidth (673-800 nm) with HAL and FLUO was associated with the presence of cancer, with a sensibility and specificity of 80% and 100%, respectively. CONCLUSIONS: Real-time cytodetection was feasible using two fluorophores (FLUO and HAL) and the new system of CVII. This technology was useful to observe cytoplasm, nuclei, and nucleocytoplasmic abnormality, but an improved system is necessary (to overcome the overlapping of fluorescence) to increase the specificity.

Robotic implantation of biodegradable regenerative urinary conduit: experimental study.

PURPOSE: To determine the feasibility and develop a robotic technique for intracorporeal implantation of a biodegradable tubular scaffold seeded with adipose-sourced smooth muscle cells (Neo-Urinary-Conduit) that, when implanted as a conduit for urinary diversion, facilitates regeneration of native-like neourinary tissue. MATERIALS AND METHODS: Robotic NUC implantation was performed in two fresh male cadavers. The greater omentum was widely detached from the greater curvature of the stomach, in preparation for final wrapping of the conduit. Bilateral ureters were mobilized for implantation. The NUC, with two precreated ureteral openings, was inserted into the abdomen. Bilateral, stented uretero-NUC anastomoses were created. The NUC was circumferentially wrapped with the predissected omentum, exteriorized through the abdominal wall, and maturated. RESULTS: Both procedures were successfully completed intracorporeally. Operative time for NUC implantation was 90 and 100 minutes, respectively. Examination of gross anatomy showed no injury to other organs. There was no omental kinking, rotation, eversion, or stripping from the NUC. Bilateral stents were confirmed to be in situ with the proximal coil in the kidney. Uretero-NUC anastomoses and omentum were tension free. The entire NUC, including its distal edge and posterior aspect, was circumferentially wrapped 360 degrees. CONCLUSION: We demonstrated the feasibility and developed a robotic technique for intracorporeal implantation of a biodegradable regenerative urinary conduit. This study serves as the foundation for the robotic surgical technique before the clinical application.

Magnetic resonance imaging-transectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients.

BACKGROUND: Prostate biopsies targeted by elastic fusion of magnetic resonance (MR) and three-dimensional (3D) transrectal ultrasound (TRUS) images may allow accurate identification of the index tumor (IT), defined as the lesion with the highest Gleason score or the largest volume or extraprostatic extension. OBJECTIVE: To determine the accuracy of MR-TRUS image-fusion biopsy in characterizing ITs, as confirmed by correlation with step-sectioned radical prostatectomy (RP) specimens. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 135 consecutive patients who sequentially underwent pre-biopsy MR, MR-TRUS image-fusion biopsy, and robotic RP at two centers between January 2010 and September 2013. INTERVENTION: Image-guided biopsies of MR-suspected IT lesions were performed with tracking via real-time 3D TRUS. The largest geographically distinct cancer focus (IT lesion) was independently registered on step-sectioned RP specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A validated schema comprising 27 regions of interest was used to identify the IT center location on MR images and in RP specimens, as well as the location of the midpoint of the biopsy trajectory, and variables were correlated. RESULTS AND LIMITATIONS: The concordance between IT location on biopsy and RP specimens was 95% (128/135). The coefficient for correlation between IT volume on MRI and histology was r=0.663 (p<0.001). The maximum cancer core length on biopsy was weakly correlated with RP tumor volume (r=0.466, p<0.001). The concordance of primary Gleason pattern between targeted biopsy and RP specimens was 90% (115/128; κ=0.76). The study limitations include retrospective evaluation of a selected patient population, which limits the generalizability of the results. CONCLUSION: Use of MR-TRUS image fusion to guide prostate biopsies reliably identified the location and primary Gleason pattern of the IT lesion in >90% of patients, but showed limited ability to predict cancer volume, as confirmed by step-sectioned RP specimens. PATIENT SUMMARY: Biopsies targeted using magnetic resonance images combined with real-time three-dimensional transrectal ultrasound allowed us to reliably identify the spatial location of the most important tumor in prostate cancer and characterize its aggressiveness.

Target ablation--image-guided therapy in prostate cancer.

INTRODUCTION: Current treatment options for prostate cancer, other than active surveillance, are limited to entire prostate gland destruction through removal (radical prostatectomy), radiation (external beam, brachytherapy, or a combination of both), or thermal ablation (cryoablation, high-intensity focused ultrasound, or radiofrequency). There has been a demand to develop ablative therapies that attempt to reduce treatment burden while retaining cancer control and avoiding the psychological morbidity associated with surveillance. MATERIALS AND METHODS: We reviewed the literature to concentrate on the practical aspects of focal therapy for Pca with the following key words: photodynamic therapy, HIFU, cryotherapy, focal laser ablation, electroporation, radiofrequency, external beam radiation, organ-sparing approach, focal therapy, prostate cancer. The aim of this article is to review these energy modalities' functional and oncologic results. RESULTS: Prostatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU and using thermal effect of light for FLA and activation of a photosensitizer by light for PDT, among others. Radiofrequency and microwave therapy have been tested in this field and demonstrated their usefulness. Electroporation is currently being developed on preclinical models. External beam radiation with microboost on neoplastic foci is under evaluation. HIFU and cryotherapy require the use of sophisticated and expensive machines. However, series published short term effective with low morbity, reversible therapy. CONCLUSION: Several energy modalities are being developed to achieve the trifecta of continence, potency, and oncologic efficiency. Comparison of the different focal approaches is complex owing to important heterogeneity of the trials. In the future, it seems likely that each technique will have its own selective indications.