Is Erectile Dysfunction an Example of Abnormal Endothelial Function?

Erectile dysfunction (ED) affects approximately half of men during middle age. Erectile dysfunction is often an early symptom of systemic vascular disease, which may precipitate significant cardiac events. The pathophysiology of ED and cardiovascular disease is closely linked. Endothelial dysfunction occurs at an early stage in ED and cardiovascular disease (CVD). In normal conditions, nitric oxide dependent and independent mechanisms regulate penile vascular tone ensuring an appropriate balance of vasoconstriction and vasodilatation. A normal endothelium is responsible for mediating the effect of pro-erectile mediators derived from the endothelium and is critical in normal erectile function. Endothelial dysfunction disrupts the homeostatic mechanisms responsible for regulation of smooth muscle contraction and penile vascular tone. Reduced bioavailability of nitric oxide (NO) occurs as a response to endothelial damage. Phosphodiesterases further degrade levels of cyclic guanosine monophosphate (cGMP) and impair smooth muscle relaxation and erectile function. A number of endothelium derived NO independent mediators of erectile function have been described and are known to contribute to ED in the presence of endothelial damage. This review provides an up to date analysis of the role of the endothelium in ED describing the pathways involved and how these represent current and potential therapeutic targets.

'Phaco-ECP': combined endoscopic cyclophotocoagulation and cataract surgery to augment medical control of glaucoma.

OBJECTIVES: Does phaco-ECP reduce intraocular pressure? Is phaco-ECP safe? DESIGN: Retrospective case note review of all patients undergoing phaco-ECP between June 2008 and June 2009. All glaucoma subtypes were included. SETTING: Single District General Hospital Ophthalmology Department within the UK. PARTICIPANTS: 58 participants case notes reviewed. Mean age 79.0 years (SD ±9.8). INTERVENTIONS: All patients received combined cataract surgery and endoscopic cyclophotocoagulation. OUTCOME MEASURES: Follow-up was 1 day, 1 week, 1, 3, 6, 12, 18 and 24 months for intraocular pressure (IOP) measurement. Number of medications, visual acuity and presence of complications were also assessed. RESULTS: Of the 58 cases performed, 56 case notes (97%) were available for analysis. Mean age 79.0 years (SD ±9.8). Mean pre-procedural IOP was 21.54 mm Hg (95% CI 19.86 to 23.22, n=56). Mean IOP was 14.43 mm Hg (95% CI 13.65 to 15.21, n=53) at 18 months and 14.44 mm Hg (95% CI 13.63 to 15.25, n=41) at 24 months. The mean drop from baseline to 18 and 24 months was 7.1 mm Hg. Statistically significant decrease in IOP was demonstrated at all time points (p<0.001). Mean medication usage was 1.97 agents (95% CI 1.69 to 2.25) at baseline, 1.96 agents (95% CI 1.70 to 2.22) at 18 months and 2.07 agents (95% CI 1.76 to 2.38) at 24 months. No statistically significant change throughout. CONCLUSIONS: This study confirms the safety of phaco-ECP. In this case series, the IOP-lowering effect was significant at all time points; however, the effect of cataract surgery alone was not controlled. A randomised controlled trial is required to draw efficacy conclusions. The authors proposed endoscopic cyclophotocoagulation's main role is to optimise control of low-risk glaucoma of low-risk patients at the time of cataract surgery. However, the authors do not propose that phaco-ECP is a substitute for filtration surgery in high-risk eyes or when low target pressures (<14 mm Hg) are indicated.

Spatiotemporal monitoring of high-intensity focused ultrasound therapy with passive acoustic mapping.

PURPOSE: To demonstrate feasibility of monitoring high-intensity focused ultrasound (HIFU) treatment with passive acoustic mapping of broadband and harmonic emissions reconstructed from filtered-channel radiofrequency data in ex vivo bovine tissue. MATERIALS AND METHODS: Both passive acoustic emissions and B-mode images were recorded with a diagnostic ultrasound machine during 180 HIFU exposures of five freshly excised, degassed bovine livers. Tissue was exposed to peak rarefactional pressures between 3.6 and 8.0 MPa for 2, 5, or 10 seconds. The B-mode images were analyzed for hyperechoic activity, and threshold levels were determined for the harmonic (1.17 mJ) and broadband (0.0137 mJ) components of the passively reconstructed source energy to predict tissue ablation. Both imaging methods were compared with tissue lesions after exposure to determine their spatial accuracy and their capability to help predict presence of ablated tissue. Performance of both methods as detectors was compared (matched-pair test design). RESULTS: Passive mapping successfully aided prediction of the presence of tissue ablation more often than did conventional hyperechoic images (49 of 58 [84%] vs 31 of 58 [53%], P < .001). At 5.4-6.3-MPa exposures, sensitivity, specificity, negative predictive value, and positive predictive value of the two methods, respectively, were 15 of 20 versus five of 21 (P = .006), eight of nine versus eight of nine (P = .72), 15 of 16 versus five of six (P = .53), and eight of 13 versus eight of 24 (P = .011). Across HIFU exposure amplitude ranges, passive acoustic mapping also aided correct prediction of the visually detected location of ablation following tissue sectioning in 42 of 45 exposures for which the harmonic and broadband threshold levels for tissue ablation were exceeded. Early cavitation activity indicated the focal position within the tissue before irreversible tissue damage occurred. CONCLUSION: Passive acoustic mapping significantly outperformed the conventional hyperecho technique as an ultrasound-based HIFU monitoring method, as both a detector of lesion occurrence and a method of mapping the position of ablated tissue.

Laparoscopic high-intensity focused ultrasound for renal tumours: a proof of concept study.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence What's known on the subject? and What does the study add? Renal cancer is increasingly diagnosed when tumours are small and asymptomatic, during routine abdominal imaging. Whilst surgery is an effective and potentially curative option, it carries a significant risk of complications. Recent work suggests that thermally ablative therapies (RFA, cryotherapy, HIFU) may be suitable minimally invasive treatment options in selected patients. The success of extracorporeal HIFU has been limited by the abdominal wall and rib-cage limiting energy delivery. For this study, a purpose-built laparoscopic HIFU probe was designed to allow direct application of the transducer to the tumour surface, thus facilitating tumour destruction. Successful and accurate tumour destruction was demonstrated, paving the way for further clinical trials, subject to device modifications. OBJECTIVE: • To test and establish clinical proof of concept for a laparoscopic high-intensity focused ultrasound (HIFU) device that facilitates delivery of ultrasound by direct application of a probe to the tumour surface. PATIENTS AND METHODS: • Twelve patients with renal tumours were treated with laparoscopic HIFU using a newly designed probe inserted via an 18-mm laparoscopic port. • HIFU treatment was targeted at a pre-defined proportion of the tumour and immediate laparoscopic partial or radical nephrectomy was then performed. RESULTS: • No tumour ablation was seen in the first five patients which made modifications in the treatment protocol necessary. After this, definite histological evidence of ablation was seen in the remaining seven patients. • The ablated zones were within the targeted area in all patients and no intra-lesional skipping was seen. • Subcapsular skipping was seen at the probe-tumour interface in two patients with viable tumour cells seen at microscopy. • One patient did not undergo surgical extirpation; subsequent biopsy revealed no viable tumour cells. • There were no intraoperative or postoperative complications directly related to HIFU therapy and patients have reached a mean (range) follow-up of 15 (8-24) months with no evidence of metastatic disease or late complications. CONCLUSIONS: • Tumour ablation with laparoscopic HIFU is feasible. • Homogenous ablation can be achieved with no vital tissue within the targeted zone. • The technique is associated with low morbidity and may have a role in the definitive management of small tumours.

Nuclear localization of factor inhibitor hypoxia-inducible factor in prostate cancer is associated with poor prognosis.

PURPOSE: We determined the role of factor inhibiting hypoxia-inducible factor-1 in prostate cancer specimens. MATERIALS AND METHODS: A tissue microarray of 152 prostate cancers was constructed and stained for factor inhibiting hypoxia-inducible factor-1, hypoxia-inducible factor-1α and 2α, and glucose transporter 1 as a prototypical downstream target of hypoxia-inducible factor-1α. Correlation analysis was done between these variables, and between factor inhibiting hypoxia-inducible factor-1, and clinical and pathological variables, including prostate specific antigen as a surrogate of recurrence. RESULTS: Factor inhibiting hypoxia-inducible factor-1 was expressed in the cytoplasm and/or the nucleus in 86.5% of tumors, including exclusive cytoplasmic expression in 51.3% and exclusive nuclear expression in 5.3%. Any nuclear and exclusive expression of factor inhibiting hypoxia-inducible factor was associated with poor prognosis on univariate analysis (p = 0.007 and 0.042, respectively). On multivariate analysis men with nuclear expression in tumors were twice as likely to experience recurrence (p = 0.034). CONCLUSIONS: Factor inhibiting hypoxia-inducible factor-1 is widely expressed in prostate tumors. Its differential subcellular expression suggests that regulation of its expression is an important factor in the activity of the hypoxia-inducible factor pathway. Its modulation may help treat hypoxia-inducible factor driven aggressive prostate cancer.

Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up.

OBJECTIVE: To determine whether primary extracorporeal high-intensity focused ultrasound (HIFU) is safe, feasible and effective for managing small renal tumours. PATIENTS AND METHODS: Although surgery currently remains the standard treatment for localized renal cell carcinoma (RCC), the increasing incidence of small renal cancers has led to a shift towards nephron-sparing surgery, with associated morbidity in 20-25% of cases, and minimally invasive ablative therapies present an alternative management. HIFU results in 'trackless' homogenous tissue ablation and when administered via an extracorporeal device, is entirely noninvasive. The study comprised 17 patients (mean tumour size 2.5 cm) with radiologically suspicious renal tumours who underwent extracorporeal HIFU using the Model-JC System (Chongqing HAIFU™, China), under general anaesthesia with one overnight hospital stay. Real-time diagnostic ultrasonography was used for targeting and monitoring. Patients were followed with a clinical review and gadolinium-enhanced magnetic resonance imaging at 12 days and every 6 months for a mean of 36 months. The outcomes measures were patient morbidity and oncological efficacy of HIFU treatment. RESULTS: Of the 17 patients, 15 were treated according to protocol; two procedures were abandoned due to intervening bowel. There were no major complications related to HIFU. Radiological evidence of ablation was apparent at 12 days in seven of the 15 patients. Before the 6-month follow-up one patient had surgery due to persisting central enhancement. Fourteen patients were evaluated at the 6-month follow-up; eight tumours had involuted (mean 12% decrease in tumour area). Four patients had irregular enhancement on imaging and had alternative therapies. Ten patients remain on follow-up at a mean (range) of 36 (14-55) months after HIFU (mean 30% decrease in tumour area). There was central loss of enhancement in all. CONCLUSIONS: Renal HIFU achieves stable lesions in two-thirds of patients, with minimal morbidity, and might be appropriate in selected cases. Further trials with accurate histological follow-up are essential to fully evaluate this novel technique.