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ABSTRACT: To investigate whether magnetic resonance imaging (MRI) findings, when converted into a scoring system, can predict the biochemical recurrence of prostate cancer after radical prostatectomy (RP).
Between January 2000 and October 2004, 610 patients with biopsy-confirmed prostate cancer had MRI before RP, with whole-mount step-sectioning of the pathology sample. MRI findings were retrospectively scored on a seven-point scale based on Tumour-Node-Mestastasis staging (1, no tumour seen, to 7, lymph node metastasis). MRI scores were added to published 5- and 10-year clinical preoperative nomograms for predicting recurrence. The predictive accuracy of MRI was quantified as the differences in bootstrap-corrected concordance indices of the models with and without MRI.
As of August 2007, 64 (10.5%) patients had a biochemical recurrence. MRI scores were associated with recurrence (P < 0.001) with hazard ratios of 1.76 and 1.81 in the 5- and 10-year models, respectively. Actual recurrence rates by MRI score were: 1, 0%; 2, 4.5%; 3, 9%; 4, 24.1%; 5, 33.3%; 6, 69.2%; 7, 100%. When MRI was added, the concordance indices of the 5- and 10-year models increased, from 0.762 to 0.776 (P = 0.081) and 0.773 to 0.788 (P = 0.107), respectively; the improvement was not significant.
The MRI scoring system devised was a strong predictor of biochemical recurrence after RP. Although MRI did not provide added prognostic value to standard clinical nomograms, in centres where MRI is used routinely, it might increase the confidence of the clinician in assessing the risk of recurrence by contributing supporting data.
BJU International 02/2009; 104(3):315-20. · 2.84 Impact Factor
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ABSTRACT: Radical prostatectomy (RP) is associated with erectile dysfunction (ED). A single, placebo-controlled, human study has assessed the effects of regular sildenafil use after RP and demonstrated an increased chance of preservation of preoperative erectile function. Aim. This study was undertaken to define the effects of such a regimen in an animal model.
Using the cavernous nerve (CN) crush injury model, animals were divided into a number of groups: no CN injury (sham), bilateral CN injury exposed to either no sildenafil (control) or sildenafil at two doses (10 and 20 mg/kg) subcutaneously daily for three different durations (3, 10, 28 days).
At these time points, CN electrical stimulation was used to assess erectile function by mean intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio. For the structural analyses, whole rat penes were harvested. Staining for Masson's trichrome was utilized to calculate the smooth muscle-collagen ratio. Immunohistochemical antibody staining was performed for endothelial (CD31 and eNOS) and neural (GAP43, NGF, and nNOS) factors and immunoblotting was performed to analyze the AKT/eNOS pathway. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay was used for the assessment of apoptotic indices and the CN architecture was evaluated by transmission electron microscopy (TEM).
Erectile function was improved with sildenafil in a time- and dose-dependent fashion with maximization of erectile function recovery occurring with daily 20 mg/kg at the 28-day time point. Sildenafil use resulted in smooth muscle-collagen ratio protection and CD31 and eNOS expression preservation. Sildenafil reduced apoptotic indices significantly compared with control. Animals exposed to sildenafil had increased phosphorylation of akt and eNOS. Tem demonstrated distinct differences in architecture between control and sildenafil groups toward an increased amount of myelinized nerve fibers.
Sildenafil use in the CN crush injury model preserves erectile function that appears to be mediated predominantly through preservation of smooth muscle content and endothelial function as well as through reduction in apoptosis.
Journal of Sexual Medicine 06/2008; 5(5):1126-36. · 3.55 Impact Factor
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ABSTRACT: The immunophilin-ligand FK506 has been shown to ameliorate erectile function and preserve cavernous nerve (CN) architecture in short-term-studies using rat models of CN injury.
The aim of this series was to ascertain the optimal dose and timing of FK506 administration in this animal model.
Rats underwent bilateral CN crush and were treated with FK506 at different time points. There were control (C) and sham groups for each time point. Based on preliminary experiments, the CN-crush rats had no treatment (C) or either FK506 1 mg/kg (BL) or 3.2 mg/kg (BH) for 3 days prior to and the day of CN crush (PRE), on the day of and for 3 days following CN crush (POST) and for 3 days pre-, on the day of, and 3 days post-CN crush (PP).
All animals had measurement of intracavernosal pressure/mean arterial blood pressure (ICP/MAP) ratios at 28 days post-CN crush. Structural analysis was conducted in the POST groups. Penile tissue was assessed for apoptosis with terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay and immunohistochemically for neural factors (growth associated protein 43 [GAP43], nerve growth factor [NGF], and neural nitric oxide synthase [nNOS]). The CN architecture was examined by transmission electron microscopy (TEM).
Sham animals had an ICP/MAP ratio of 70%. Only the BH-POST group revealed an improved ICP/MAP ratio compared with C (50 +/- 9% vs. 32 +/- 8%, P < 0.01). nNOS staining was significantly restored reaching sham levels in BL-POST and BH-POST groups vs. C (P < 0.05). NGF and GAP43 staining displayed no significant differences between C and treatment groups (P < 0.05). Apoptosis was significantly reduced in BL-POST and BH-POST groups compared with C (16 +/- 4%, 21 +/- 9%, and 63 +/- 7%, P < 0.001). TEM exhibited preservation of CN architecture for BH-POST compared with C.
These results suggest that short-term treatment with doses of FK506 higher than previously utilized preserves erectile function in the rat CN-injury model. Pretreatment appears to offer no advantage. However, FK506 administration just prior to CN injury and for a short-time post-injury achieves the best functional and structural preservation outcomes.
Journal of Sexual Medicine 06/2008; 5(6):1334-44. · 3.55 Impact Factor
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ABSTRACT: Only minimal literature exists on consequences of shock wave therapy (SWT) on erectile function in treatment of Peyronie's disease (PD). This study was undertaken to define SWT impact at varied energy/dose levels at different time points on functional and structural changes in erectile tissue.
In 45 rats 2000 shock waves (sw) at 2 BAR were applied to the penis weekly sorted by one, two, and three sessions (high-dose/energy level, HD-1, HD-2, HD-3). Each group was followed for 1, 7, or 28 d before measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Fifteen control animals (C1, C7, C28) underwent anesthesia alone. Another 15 animals were exposed to three SWT sessions applying 1000 sw at 1 BAR and analyzed identically (low-dose/energy level, LD-3-1, -7, -28). Terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling assay was used to define the apoptotic index (AI) and Masson's trichrome (MT) staining was prepared to evaluate smooth muscle-to-collagen ratios.
ICP/MAP ratios for all C groups displayed a mean of 64%. All SWT groups demonstrated significantly reduced ICP/MAP ratios compared to their corresponding C groups (p<0.05). The LD-3 groups showed a trend toward improved ICP/MAP ratios. LD-3-28 demonstrated significant recovery compared to HD-3-28 (55+/-8% vs. 41+/-10%, p=0.004), but remained reduced compared to C28 (63+/-5%, p=0.03). No statistical differences were seen for MT staining in SWT groups compared to C (p>0.05). AIs for the LD-3 groups were significantly lower compared to the HD-3 groups (p<0.001), but all AIs were significantly increased compared to C groups (p<0.01).
Overall, at both energy/dose levels, SWT resulted in a time- and treatment-dependent reduction of ICP/MAP ratios, which might be mediated partly through apoptosis and collagenization of corporal smooth muscle.
European Urology 04/2008; 53(3):635-42. · 8.49 Impact Factor
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ABSTRACT: Cavernosal oxygenation appears to be important for preservation of erectile tissue health. Hyperbaric oxygen therapy (HBOT) has been shown to improve tissue oxygenation and has neuromodulatory effects.
This study was designed to define the effects of HBOT on erectile function (EF) and cavernosal tissue in the rat cavernous nerve (CN) injury model.
Four groups of Sprague-Dawley rats were studied: rats with bilateral CN crush, HBOT treated (Crush+/HBOT+); bilateral CN-crush/no HBOT (C+/H-); no crush/no HBOT (C-/H-); and no crush/HBOT (C-/H+). HBOT was delivered daily for 90 minutes at three atmospheres for 10 days commencing the day of CN crush.
Ten days after CN injury, the animals underwent CN stimulation measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios. Corporal tissue was harvested pre-sacrifice, and immunohistochemically stained for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), and cluster of differentiation molecule (CD31). Histologic analysis was performed for Masson's trichrome to assess the smooth muscle-collagen ratio. Terminal deoxynucleotidyl transferase Biotin-dUTP Nick End Labeling assay was used to define apoptotic indices (AIs).
The C+/H- group had significantly lower ICP/MAP ratios compared with C-/H- rats, (31% vs. 70%, P < 0.001). C+/H+ rats had significantly higher ICP/MAP ratio recovery compared with the C+/H- group (55% vs. 31%, P = 0.005). NGF and eNOS staining densities were higher in C+/H+ rats compared with C+/H- rats (P < 0.05 and P < 0.001, respectively). No difference was seen in CD31 expression. Staining density for MT displayed a trend toward higher smooth muscle preservation after HBOT. AIs were significantly increased by HBOT (P < 0.05).
HBOT following a CN injury improved EF preservation in this model, supporting the cavernosal oxygenation concept as protective mechanism for EF. The effects appear to be mediated via preservation of neurotrophic and endothelial factor expression.
Journal of Sexual Medicine 03/2008; 5(3):562-70. · 3.55 Impact Factor
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ABSTRACT: "Dry lab" facilities are integral to laparoscopy training, but access is often limited due to the high costs of video-laparoscopy equipment. We assessed the effectiveness of a cheap and simple training model compared to conventional video-laparoscopy for basic training using a randomised, blinded study.
Thirty-six third-year medical students without previous surgical skills were randomised into two groups: group A students were taught basic laparoscopy skills using a conventional video-laparoscopy pelvic trainer and group B students were taught similar techniques using a cardboard box with a cut-out top to allow light and visualisation. Participants in group B had one eye obscured to reduce their stereoscopic vision. After eight sessions of training amounting to 24h, the two groups were assessed by a blinded adjudicator on set tasks using both the video-laparoscopy pelvic trainer and the cardboard box. Accuracy, timing and depth perception were assessed and the results compared.
There was no significant difference in performance scores or times between the two groups in any of the parameters when tested on the cardboard box. However, when assessed on the video trainer, the cardboard box-trained group had significantly faster times with equivalent scores in the majority of tasks.
For basic laparoscopic training the cardboard box, costing nothing, is a simple and effective alternative, which can be used in conjunction with sophisticated video-laparoscopy equipment costing thousands of dollars.
European Urology 01/2007; 50(6):1285-90; 1290-1. · 8.49 Impact Factor
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ABSTRACT: Patients with high grade (Gleason score 8 to 10) prostate cancer on biopsy are at high risk for cancer recurrence after local treatment, such as radiation therapy and radical prostatectomy. We examined long-term outcomes in patients with high grade prostate cancer on biopsy who were treated with radical prostatectomy alone. We also investigated the impact on outcomes of changes in the radical prostatectomy Gleason score.
Of 5,662 patients who underwent radical prostatectomy during 20 years 238 had a biopsy Gleason score of 8 to 10. We analyzed the rate of biochemical recurrence in this subgroup according to the Gleason grade of cancer in the radical prostatectomy specimen.
Ten-year biochemical recurrence-free probability in the cohort was 39%. However, 45% of patients (95% CI 38 to 51%) with Gleason score 8 to 10 cancer on biopsy had a Gleason score of 7 or less in the radical prostatectomy specimen. These patients had a 10-year biochemical recurrence-free probability of 56% compared to 27% in those with a final Gleason score that remained 8 to 10 (p = 0.0004). On multivariate analysis neither prostate specific antigen nor biopsy features, including total number of cores, number of cores with cancer and percent of cancer in the cores, was a significant predictor of downgrading. However, clinical stage and biopsy Gleason score were significant with 58% of cT1c and 51% of biopsy Gleason score 8 cancers downgraded. Almost 65% of cT1c Gleason score 8 cancers were downgraded compared to 11% of cT3 Gleason score 9 cancers.
Patients diagnosed with poorly differentiated prostate cancer (Gleason score 8 to 10) on biopsy do not uniformly have a poor prognosis. Of the patients 39% remain free of cancer recurrence 10 years after radical prostatectomy. Of these cancers 45% have a lower Gleason score in the radical prostatectomy specimen and a correspondingly more favorable long-term outcome. Predictors of downgrading are lower clinical stage (cT1c) and Gleason score 8 in the biopsy specimen.
The Journal of Urology 10/2006; 176(3):991-5. · 3.75 Impact Factor
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ABSTRACT: The rat model of cavernous nerve (CN) injury has been developed in an effort to define the functional and structural consequences of neural trauma in the corpus cavernosum. However, there is no universally accepted method of inducing nerve injury in this model, with neurotomy and crush models being used currently. To address this issue, we induced CN injury using various techniques in an effort to compare the hemodynamic sequelae of these injuries.
Twenty-five adult male Sprague-Dawley rats were divided into five groups: (1) control: laparotomy only; (2) exposure: laparotomy and exposure of cavernous nerves bilaterally without nerve manipulation; (3) neurotomy; bilateral neurotomy; (4) bulldog crush: bilateral nerve crush with bulldog vascular clamp; and (5) hemostat nerve crush: bilateral nerve crush with a hemostat. Ten days later, a second operation was performed during which systemic mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured in response to CN stimulation proximal to the site of injury. Hemodynamic endpoints assessed included ICP/MAP ratio, rate of tumescence, and rate of detumescence.
The ICP/MAP ratio (mean +/- 95% confidence interval) in the control group was 70 +/- 4%. ICP/MAP ratios were significantly reduced in all CN injury groups compared with control group: exposure: 41 +/- 10% (P < 0.001); neurotomy: 35 +/- 15% (P < 0.001); bulldog crush: 39 +/- 13% (P < 0.001); hemostat crush: 31 +/- 9% (P < 0.0001). No significant difference existed in ICP/MAP ratios between the injury groups. Of note, the exposure group also demonstrated significant functional alterations. The rates of tumescence and detumescence were significantly reduced in all groups compared with the control group.
No significant difference in the magnitude and consistency of hemodynamic alterations has been demonstrated in all CN injury models assessed in this study.
Journal of Sexual Medicine 02/2006; 3(1):77-83. · 3.55 Impact Factor
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ABSTRACT: To measure expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in the prostates of men after transurethral resection of the prostate (TURP) following 2 weeks of treatment with finasteride.
Sixty-four men scheduled to undergo TURP were randomized to receive 5 mg of finasteride or placebo daily for 2 weeks before surgery. Sections of prostatic urothelium were stained for VEGF expression and for CD31 to assess MVD. Ten consecutive, non-overlapping high-power fields were analysed in a blinded fashion.
In all, 31 men received finasteride and 33 placebo; the groups were similar in patient age, resected prostate weight, preoperative catheterization, prostate-specific antigen level, aspirin use, spinal anaesthesia and postoperative diagnosis of prostate cancer. The mean (95% confidence interval) MVD was significantly lower in the finasteride group (60, 55-65) than in the placebo group (71, 64-78; P < 0.01). Similarly, the mean expression of VEGF was significantly lower in the finasteride group (47, 43-52 vs 61, 54-67; P < 0.001)
Finasteride inhibits angiogenic growth factors leading to reduced vascularity, and this is the basis of its action in reducing haematuria of prostatic origin. The present study shows that finasteride influences the prostatic microvasculature after only 2 weeks exposure.
BJU International 12/2005; 96(9):1319-22. · 2.84 Impact Factor
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ABSTRACT: Bleeding associated with transurethral prostate resection can often be significant and lead to increased morbidity and occasionally mortality. It has been shown that finasteride decreases bleeding in patients with hematuria of prostatic origin. We hypothesized that bleeding in patients undergoing transurethral prostate resection could be decreased by giving finasteride for 2 weeks before surgery.
A total 70 patients scheduled to undergo elective transurethral prostate resection were randomized to receive 5 mg. finasteride daily or placebo for 2 weeks before surgery. Serum hemoglobin was measured before and after surgery, and the following day. The volume of irrigation fluid used and its hemoglobin concentration as well as resected prostate weight were recorded.
Of the 68 patients who underwent transurethral prostate resection 2 were withdrawn before surgery, and so 32 received finasteride and 36 received placebo. There was significantly less mean blood loss in irrigation fluid in the finasteride group than in the control group (43.6 versus 69.3 gm. hemoglobin, p = 0.011). The mean difference was more significant when blood loss per gm. resected prostate was calculated (2.65 versus 4.65 gm. hemoglobin per gm. prostate, p < 0.01).
This study shows that finasteride given for 2 weeks preoperatively decreases bleeding in patients undergoing transurethral prostate resection. Further study is required to determine the optimal timing and dose duration to minimize blood loss and identify how relevant such a decrease in bleeding is in clinical practice.
The Journal of Urology 11/2002; 168(5):2024-6. · 3.75 Impact Factor
