Three‐dimensional CT cavernosography: reconsidering venous ligation surgery on the basis of the modern technology

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Venous ligation surgery has been conducted as a symptomatic treatment, but the effective rate of this surgery was insufficient. We thought that one of the reasons for the low effective rate of this surgery was insufficient for the diagnostic modality. We confirmed that 3D cavernosography was, in comparison with conventional cavernosography, higher in diagnosis precision.

OBJECTIVE

• ? To examine the feasibility of three‐dimensional (3D) CT cavernosography in the diagnosis of corporal veno‐occlusive dysfunction.

PATIENTS AND METHODS

• ? The subjects were 55 patients who had failed to respond to phosphodiesterase type 5 inhibitors. We performed pharmacodynamic infusion cavernosometry and cavernosography, using 60 mg papaverine hydrochloride.
• ? Cavernosography was performed at 90 mmHg intracavernous pressure, using a multi‐slice CT scan system. The 3D images were reconstructed using aquarius net station , ver.2 computer software.
• ? For comparison with conventional cavernosography, maximum intensity projection (MIP) images were used. A flow of 20 mL/min or being more capable of maintaining 90 mmHg of intracavernous pressure indicated veno‐occlusive dysfunction.

RESULTS

• ? Forty‐five of the 55 patients were diagnosed with corporal veno‐occlusive dysfunction. 3D‐CT cavernosography revealed drainage veins in all 45 cases, including cavernous veins, dorsal veins, crural veins and other emissary veins.
• ? Compared with 3D‐CT cavernosography, observing cavernous veins and the proximal part of the deep dorsal veins using MIP imaging was especially difficult because the origins of the penile veins are often behind the pelvic bone or cavernous body.
• ? Of the patients who seemingly had leakage via the deep dorsal vein, 80.6% did not in fact have leakage via this vein, but had other leakages. The image resolution of 3D‐CT cavernosography was significantly higher than that of MIP.

CONCLUSION

• ? 3D‐CT cavernosography can provide high‐resolution images of venous drainage from any angle. We conclude that the images obtained by 3D‐CT cavernosography are very helpful for both the diagnosis of corporal veno‐occlusive dysfunction and the anatomical study of the human penile venous system.

     

Protective effect of annexin‐A1 against irreversible damage to cavernous tissue after cavernous nerve injury in the rat

Study Type – Aetiology (case control) Level of Evidence 3b What's known on the subject? and What does the study add? Penile rehabilitation is still controversial regarding good results. Our study shows a non‐invasive treatment option to recovery after cavernous nervous damage. The assessment of changes in the intracavernous pressure and karyometry demonstrates the protective effect of annexin‐A1 in an animal model of cavernous nerve injury. We found that annexin‐A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis.

OBJECTIVE

• ? To evaluate the protective effect of annexin‐A1 against irreversible damage to cavernous tissue after cavernous nerve injury.

PATIENTS AND METHODS

• ? Thirty Sprague‐Dawley male rats were divided into 3 groups; sham‐operated rats (n= 10), bilateral cavernous nerve injury treated intravenously with 100 µg/kg annexin‐A1 (n= 10), and a crush group of rats submitted to bilateral cavernous nerve injury and vehicle (n= 10). Groups were compared in respect to intracavernous pressure and karyometric parameters.

RESULTS

• ? After annexin‐A1 treatment, the maximum changes in intracavernous pressure responses were significantly higher in the annexin‐A1 group compared to the vehicle‐only group on the 7^th postoperative day (p‐value <0.05). Hematoxylin‐eosin staining showed that the percentage of cavernosal smooth muscle was higher in the annexin‐A1 group. Karyometry showed that the nuclear volume was greater in the annexin‐A1 group, as was the major/minor smooth muscle cell diameter ratio compared to the vehicle‐only group on the 7^th postoperative day (p‐value <0.05).

CONCLUSION

• ? This is the first report that, by assessing changes in the intracavernous pressure and karyometry, demonstrates the protective effect of annexin‐A1 in an animal model of cavernous nerve injury. We found that annexin‐A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis.

     

The penis in diabetes: structural analysis of connective tissue and smooth muscle alterations in a rabbit model

Study Type – Aetiology (case control) Level of Evidence 3b OBJECTIVE

• ? To assess the volumetric density of collagen, elastic system fibres and smooth muscle cells in the corpus cavernosum (CC), corpus spongiosum (CS) and tunica albuginea (TA) in the penis of diabetic rabbits.

MATERIALS AND METHODS

• ? Twenty‐six New Zealand white rabbits were used. Diabetes was induced at 8 weeks of age in 13 rabbits by i.v. injection of 100 mg/kg of alloxan. The remaining 13 rabbits served as a control group. After 10 weeks, the rabbits were killed using sodium thiopenthal.
• ? Midshaft penile fragments were obtained and processed by routine histological techniques. Stereological analysis of collagen, elastic system fibres and smooth muscle was performed in 5‐µm sections by using a M42 test grid system.
• ? Data were expressed as volumetric density (Vv; %). Collagen organization was evaluated by Picrosirius red staining under polarization.

RESULTS

• ? In the TA of diabetic rabbits, thickness increased by 88% (P < 0.001) with an enhanced collagen turnover. Moreover, the elastic fibre content was 34% higher (P < 0.001). In the CC of diabetics, collagen was diminished by 45% (P < 0.001) with a more organized collagen.
• ? The elastic fibres were decreased by 46% (P < 0.001). Diabetes induced a 11% increase in CS collagen (P < 0.024) with an enhanced collagen turnover.
• ? Smooth muscle in the CC of diabetic rabbits was increased by 40% (P < 0.001), whereas, in the CS, it was decreased by a similar amount (P < 0.001).

CONCLUSIONS

• ? Penile tissues were affected differently by diabetes, possibly as a result of cellular heterogeneity.
• ? These changes could have an impact on blood flow and tissue resistance, and therefore might adversely affect erection.

     

IL-23 gene therapy for mouse bladder tumour cell lines

OBJECTIVES

• ? To evaluate the antitumour effects of IL‐23 gene transfer into mouse bladder carcinoma (MBT2) cells.
• ? To investigate the mechanisms underlying the subsequent constitutive secrection of IL‐23 by the MBT2 cells

MATERIALS AND METHODS

• ? An expression vector containing IL‐23 gene was introduced into MBT2 cells by liposome‐mediated gene transfer, and secretion of IL‐23 was confirmed by ELISA.
• ? The in vivo antitumour effect of IL‐23‐secreting MBT2 cells (MBT2/IL‐23) was examined by injecting the cells into syngeneic C3H mice.
• ? A tumour vaccination study using mitomycin C (MMC)‐treated IL‐23‐secreting MBT2 cells was carried out, and the usefulness of in vivo CD25 depletion for an additional vaccine effect was also investigated.
• ? The mechanisms underlying the antitumour effects were investigated by antibody depletion of CD8 or CD4 T cells, or natural killer cells, and cells infiltrating the tumour sites in vivo were assessed using immunohistochemistry.

RESULTS

• ? Stable transformants transduced with MBT2/IL‐23 secreted IL‐23 into the culture supernatant.
• ? Genetically engineered IL‐23‐secreting MBT2 cells were rejected in syngeneic mice.
• ? MBT2/IL‐23‐vaccinated mice inhibited the tumour growth of parental MBT2 cells injected at a distant site and this vaccine effect was enhanced by combination with in vivo CD25 depletion by an antibody.
• ? The main effector cells for the direct antitumour effect of MBT2/IL‐23 were CD8 T cells, which was shown by in vivo depletion and immunohistochemical study.

CONCLUSIONS

• ? IL‐23‐secreting MBT2 cells were rejected in syngeneic mice by the activation of CD8 T cells.
• ? MMC‐treated MBT2/IL‐23 can have a tumour vaccine effect for parental MBT2 cells, and this effect was enhanced by combination with in vivo CD25 depletion.

     

Non-transecting anastomotic bulbar urethroplasty: a preliminary report

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Excision of a stricture and end‐to‐end anastomosis of the two ends is thought to be the best form of treatment for short strictures of the proximal bulbar urethra but involves transecting the main blood supply of the corpus spongiosum and the urethra. This is a preliminary report of achieving the same goal but without transecting the blood supply of the corpus spongiosum of the urethra.

OBJECTIVE

• ? To report our early experience with a novel approach to the excision and end‐to‐end anastomotic repair of bulbar urethral strictures.

PATIENTS AND METHODS

• ? A total of 22 patients underwent excision and end‐to‐end anastomosis of a proximal bulbar urethral stricture using a technique in which the corpus spongiosum is not transected, so as to maintain its blood supply intact.
• ? The range of follow‐up was 6–21 months and for 16 patients the follow up was ≥1year.

RESULTS

• ? At 1 year of follow‐up there was no evidence of a recurrent stricture on symptomatic assessment or uroflowmetry in the 16 patients.
• ? On urethrography one patient has a urethral calibre 80% of normal. In the other 15 the calibre is normal or greater than normal.

CONCLUSION

• ? The non‐transecting anastomotic bulbar urethroplasty technique used appears to give results that are as good as those of traditional anastomotic urethroplasty with less surgical trauma.

     

Microstructure and cytocompatibility of collagen matrices for urological tissue engineering

What's known on the subject? and What does the study add? The gold standard in the reconstruction of the defect urinary system is still the transplantation of autologous gastrointestinal segments although numerous different types of biomaterials (natural/synthetic) have been investigated as possible replacements. However, the ideal biomaterial is still not identified. In this study, we were able to identify the engineered collagen‐based OptiMaix® scaffolds as promising biomaterials for the reconstruction of the urinary tract.

OBJECTIVES

• ? To analyse the in vitro cytocompatibility of several engineered collagen‐based biomaterials for tissue engineering of the urinary tract.
• ? Tissue‐engineered implants for the reconstruction of the urinary tract are of major interest for urological researchers as well as clinicians. Although several materials have been investigated, the ideal replacement has still to be identified.

MATERIALS AND METHODS

• ? Several collagen matrices were tested.
• ? Electron microscopy was used to visualize the microstructure of the tested matrices.
• ? Examination of cell attachment and growth of primary porcine urothelial and smooth muscle cells were performed and cell phenotypes were analysed using immunohistochemical stains.
• ? Urea permeability was investigated using Ussing chamber experiments.

RESULTS

• ? The best cytocompatibility for both urinary tract‐specific cell types was obtained with OptiMaix® (Matricel GmbH, Herzogenrath, Germany) materials.
• ? Cell‐specific phenotypes were maintained during culture as shown by immunohistochemical staining.
• ? Furthermore, simultaneous cultivation of both cell types for 7 and 14 days significantly reduced urea permeability.

CONCLUSION

• ? These results show the potential of OptiMaix materials in tissue engineering approaches of urinary tract tissues.

     

Amelioration of diabetes-induced cavernosal fibrosis by antioxidant and anti-transforming growth factor-β1 therapies in inducible nitric oxide synthase-deficient mice

Study Type – Aetiology (case control) Level of Evidence 1b What's known on the subject? and What does the study add? The development of penile fibrosis in diabetes is associated with an increase in oxidative stress and the key pro‐fibrotic factor. TGFβ1 within the corpora. As a consequence, a putative compensatory expression of inducible nitric oxide synthase (iNOS) cause a steady output of nitric oxide and cGMP which act as endogenous antifibrotic agents by quenching oxidative stress and inhibiting collagen synthesis and myofibroblast formation. This study adds to the growing body of evidence that the use of antioxidant or antifibrotic therapies may be effective in preventing and possibly ameliorating penile corporal fibrosis and therefore improving erectile function in diabetes, by targeting different pathways involved in the chronic histological damage that underlies erectile dysfunction.

OBJECTIVE

• ? To investigate whether sustained long‐term separate treatments of diabetic inducible nitric oxide synthase knockout (iNOSKo) mice with allopurinol, an antioxidant inhibiting xanthine oxidoreductase, decorin, a transforming growth factor‐β1 (TGFβ1) ‐binding antagonist, and molsidomine, a long‐life nitric oxide donor, prevent the processes of diabetes‐induced cavernosal fibrosis.

MATERIALS AND METHODS

• ? Eight week old male iNOS knock out (iNOSKo) mice were made diabetic by injecting 150 mg/kg B.W Streptozotocin (1P) with were either left untreated or treated with the oral antioxidant allopurinol (40 mg/kg/day), or decoin (50 mg, 1P, twice), as an anti‐TGFβ1 agent (n = 8/group).
• ? Glycemia and oxidative stress markers were determined in blood and urine.
• ? Paraffin‐embedded tissue sections from the penile shaft were subjected to Masson trichrome staining for the smooth muscle (smc)/collagen ratio, and imunostaining for smc content, profibrotic factors, oxidative stress, cell replication and cell death markers followed by quantitative image analysis.

RESULTS

• ? Eight‐week treatment with either allopurinol or decorin counteracted the decrease in smooth muscle cells and the increase in apoptosis and local oxidative stress within the corpora tissue.
• ? Decorin but not allopurinol increased the smooth muscle cell/collagen ratio, whereas allopurinol but not decorin inhibited systemic oxidative stress.
• ? Molsidomine was effective in reducing both local and systemic oxidative stress, but did not prevent corporal fibrosis.

CONCLUSION

• ? Both allopurinol and decorin appear as promising approaches either as a single or a combined pharmacological modality for protecting the diabetic corpora from undergoing apoptosis and fibrosis although their functional effects still need to be defined.

     

Targeting castration‐induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model

What’s known on the subject? and What does the study add? Castration therapy has rather modest effects on cell death in tumours but can be enhanced by other treatments targeting tumour stroma and vasculature. This study shows that the prostate becomes hypoxic following castration and that targeting hypoxic cells during castration therapy potently enhances the effects of castration.

OBJECTIVE

• ? To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short‐ and long‐term therapeutic response.

MATERIAL AND METHODS

• ? We used the androgen‐sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients.
• ? Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

RESULTS

• ? Hypoxia was transiently up‐regulated after castration therapy and correlated with the induction of tumour cell apoptosis.
• ? When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

CONCLUSION

• ? The present study suggests that castration‐induced tumour hypoxia is a novel target for therapy.

     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

Enhanced S100 calcium‐binding protein P expression sensitizes human bladder cancer cells to cisplatin

What’s known on the subject? and What does the study add? So far, several molecules have been reported to be involved in cisplatin resistance. This study revealed that a decreased expression of S100P is implicated in cisplatin resistance. In addition, S100P overexpression rendered bladder cancer cells sensitive to cisplatin.

OBJECTIVE

• ? To investigate the role of S100 calcium‐binding protein P (S100P) in the gain of cis‐diamminedichloroplatinum (II) (cisplatin) resistance in bladder cancer, having previously found, with cDNA microarrays using two pairs of parental (T24, KK47) and their cisplatin‐resistant bladder cancer cell lines (T24/DDP10, KK47/DDP20), that S100P mRNA expression was significantly reduced in cisplatin‐resistant cells.

MATERIALS AND METHODS

• ? S100P mRNA and protein expression levels were investigated by northern and western blot analyses, respectively.
• ? Intracellular S100P localization was examined by immunocytochemistry and immunohistochemistry.
• ? S100P over‐expression, obtained by transfection with S100P expression plasmid, was used to investigate whether or not S100P affected cellular resistance to cisplatin.

RESULTS

• ? S100P mRNA showed increased expression by cisplatin stimulation in parental cell lines.
• ? On the other hand, S100P mRNA and protein expression levels were markedly reduced in cisplatin‐resistant cells.
• ? The over‐expression of S100P in resistant cells resulted in an increased sensitivity to cisplatin.

CONCLUSIONS

• ? In bladder cancer cells, S100P was expressed and localized mainly in the nucleus.
• ? S100P expression was also involved in cisplatin sensitivity.
• ? S100P might thus represent a molecular marker predicting cisplatin sensitivity and a molecular therapeutic target for cisplatin‐based chemotherapy.

     

Open non‐microsurgical,laparoscopic or open microsurgical varicocelectomy for male infertility: a meta‐analysis of randomized controlled trials

Study Type – Therapy (systematic review) Level of Evidence 1a What's known on the subject? and What does the study add? There are several surgical techniques for the treatment of varicocele in infertile men, including open non‐microsurgical, laparoscopic and microsurgical varicocelectomy. It is currently unclear, however, which is the most beneficial method for patients. The present meta‐analysis found that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.

OBJECTIVE

• ? To compare various techniques of open non‐microsurgical, laparoscopic or microsurgical varicocelectomy procedures to describe the best method for treating varicocele in infertile men.

PATIENTS AND METHODS

• ? We searched PubMed, Embase, the Cochrane Library, the Institute for Scientific Information (ISI) – Science Citation Index and the Chinese Biomedicine Literature Database up to June 2011. Only randomized controlled trials (RCTs) were included in the present study.
• ? The outcome measures assessed were pregnancy rate (primary), the incidence of recurrent varicocele, time to return to work, the incidence of postoperative hydrocele and operation duration (secondary).
• ? Two authors independently assessed the study quality and extracted data. All data were analysed using Review Manager (version 5.0).

RESULTS

• ? The present study included four randomized controlled trials comprising 1,015 patients in total.
• ? At the follow‐up endpoints, patients who had undergone microsurgery showed a significant advantage over those who had undergone open varicocelectomy in terms of pregnancy rate (odds ratio [OR]= 1.63, 95% confidence interval [CI]: 1.19–2.23].
• ? There was no significant difference between laparoscopic and open varicocelectomy (OR = 1.11, 95% CI: 0.65–1.88) or between microsurgery and laparoscopic varicocelectomy (OR = 1.37, 95% CI: 0.84–2.24).
• ? The incidences of recurrent varicocele and postoperative hydrocele were significantly lower after microsurgery than after laparoscopic or open varicocelectomy.
• ? The time to return to work after microsurgery and laparoscopic varicocelectomy was significantly shorter than that after open varicocelectomy.
• ? The operation duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy.

CONCLUSIONS

• ? Current evidence indicates that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.
• ? More high‐quality, multicentre, long‐term RCTs are required to verify the findings.

     

Organ‐preserving surgery for penile cancer: description of techniques and surgical outcomes

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Organ‐preserving surgeries for penile cancer have been described to reduce the morbidity associated with traditional operations. Patients derive better functional outcomes from penile‐preserving surgery, although local recurrence rates can be higher. Excellent results can be obtained at large‐volume centres. With close follow‐up, local recurrences can be identified and treated promptly (often with further local excision).

OBJECTIVE

• ? To describe the outcomes of organ‐preserving surgery for penile cancer at a UK tertiary referral centre.

PATIENTS AND METHODS

• ? Patients at Sunderland Hospital (UK) between 2001 and 2008 who had squamous cell tumours limited to the glans penis underwent penile‐preserving surgery including total glansectomy and glanuloplasty, partial glansectomy, glans relining and distal penectomy with glans reconstruction.
• ? Recurrence rates, cosmetic and functional outcomes were recorded.

RESULTS

• ? In all, 65 patients were identified with a median follow‐up of 40 months. Local recurrence was present in four patients (6%) despite 72% having intermediate or poorly differentiated tumours and 30% with T2 disease.
• ? Complications included partial graft loss (1.5%), graft contractures (4.5%) and meatal stenosis (7.5%).
• ? In all, 5% were deemed to have poor cosmetic outcome and 85% described good erections at 1 year after surgery.

CONCLUSION

• ? Penile‐preserving surgery can achieve good penile cancer control with minimal morbidity and reduced psychosexual side‐effects.

     

Single application of high‐intensity focused ultrasound as a first‐line therapy for clinically localized prostate cancer: 5‐year outcomes

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence. The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low‐risk disease, with rates of efficacy declining in intermediate‐ and high‐risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low‐risk disease.

OBJECTIVE

• ? To report cancer control results after a single application of high‐intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification.

PATIENTS AND METHODS

• ? In a retrospective single‐centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP‐TMS, France).
• ? Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands.
• ? Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to ≥0.5 ng/mL if PSA doubling time was ≤6 months. Kaplan–Meier analysis was performed for survival estimates.

RESULTS

• ? A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51–82) years, and 38, 34 and 28% of these patients were in the low‐, intermediate‐ and high‐risk groups, respectively.
• ? The median (range) follow‐up was 52.8 (0.2–79.8) months.
• ? At 5 years, overall and cancer‐specific survival rates were 86.3% and 98.4%, respectively.
• ? Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5‐year biochemical‐free survival rates were 84.8%, 64.9% and 54.9% (P < 0.01), and 5‐year disease‐free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively.

CONCLUSION

• ? Single‐session HIFU is recommended as a curative approach in elderly patients with low‐risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU.

     

Inhibition of sympathetic neuroeffector transmission in human corpus cavernosum

Study Type – Aetiology (case control) Level of Evidence 2b What's known on the subject? and What does the study add? In the present study the mechanisms regulating EFS‐evoked neurogenic contraction in the human corpus cavernosum (HCC) were investigated. Overall, our data adds to current knowledge that the NO‐independent heme dependent activation of sGC and the RhoA/Rho‐kinase signaling pathways play an important role in the regulation of neurogenic contractile activity in HCC tissue.

OBJECTIVE

• ? To investigate the mechanisms of adrenergically mediated smooth muscle contraction in the human corpus cavernosum (HCC) using an organ bath approach.

METHODS

• ? Human corpus cavernosum specimens were obtained from patients (aged 59–72 years) with erectile dysfunction (ED), undergoing penile prosthesis implantation surgery.
• ? Isolated HCC strips (1 × 1 × 6 mm) were suspended in tissue bath chambers for isometric tension recording.
• ? The effects of various drugs on neurogenic contractions evoked by electrical field stimulation (EFS) were investigated. The drugs included nitric oxide (NO) donors, phosphodiesterase 5 (PDE5) inhibitor, Rho kinase (ROCK) inhibitor, NO‐independent stimulator, L‐type Ca2+ channel blocker and α‐receptor antagonist.

RESULTS

• ? Pre‐incubation with the NO donor sodium nitroprusside (SNP; 10⁴ M) significantly reduced the initial peak increase in tension evoked by EFS (by 71%, P < 0.05). The PDE5 inhibitor sildenafil (10^?4 M) reduced the increase in tension by 69%, while a combination of sildenafil and ROCK inhibitor, fasudil, inhibited tension by 81%.
• ? The EFS‐induced contractile response at 80 Hz was decreased by 65% with fasudil and by 70% with isradipine (P < 0.001), while a combination of these drugs decreased the response by 88%. An NO‐independent stimulator soluble guanylate cyclase (sGC), BAY 41‐8543, significantly reduced the response (by 82%, P < 0.001) Phentolamine, an α‐receptor antagonist, nearly eliminated the contractile response (98%, P < 0.001).

CONCLUSIONS

• ? These data suggest that neurogenic contractions are mediated by an increase in Ca(2+) influx via L‐type voltage‐gated Ca(2+) channels and that an increase in Ca(2+) sensitivity is mediated by the ROCK pathway and the PDE5 enzyme system as well as by the inhibitory NO/sGC/cGMP pathway.
• ? The neurogenic contractile response in HCC is mediated by several intracellular pathways, including adrenergic receptors, Ca(2+) entry, Ca(2+) sensitization and activation of the PDE5 enzyme. The Rho‐kinase (ROCK) inhibitor fasudil, L‐type Ca(2+) channel antagonist isradipine, and PDE5 inhibitor sildenafil, as well as a NO‐independent stimulator of sGC, had similar inhibitory effects, suggesting parallel mechanisms in the HCC.

     

Population‐based comparative effectiveness of nephron‐sparing surgery vs ablation for small renal masses

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Case series of patients undergoing various forms of ablation show that it is technically feasible and possible for ablation to achieve short‐ and intermediate‐term cancer‐specific survival rates similar to those of controls undergoing partial nephrectomy. This is the first well‐powered study with a controlled design to compare effectiveness between partial nephrectomy and ablation.

OBJECTIVE

• ? To determine, in a population‐based cohort, if disease‐specific survival (DSS) was equivalent in patients undergoing ablation vs nephron‐sparing surgery (NSS) for clinical stage T1a renal cell carcinoma (RCC).

PATIENTS AND METHODS

• ? A retrospective cohort study was performed using patients from the Surveillance, Epidemiology and End Results cancer registry with RCC < 4 cm and no evidence of distant metastases, who underwent ablation or NSS.
• ? Kaplan–Meier and Cox regression analyses were performed to determine if treatment type was independently associated with DSS.

RESULTS

• ? Between 1998 and 2007, a total of 8818 incident cases of RCC were treated with either NSS (7704) or ablation (1114).
• ? The median (interquartile range) follow‐up was 2.8 (1.2–4.7) years in the NSS group and 1.6 (0.7–2.9) years in the ablation group, although 10% of each cohort were followed up beyond 5 years.
• ? After multivariable adjustment, ablation was associated with a twofold greater risk of kidney cancer death than NSS (hazard ratio 1.9, 95% confidence interval 1.1–3.3, P= 0.02).
• ? Age, gender, marital status and tumour size were also significantly associated with outcome.
• ? The predicted probability of DSS at 5 years was 98.3% with NSS and 96.6% with ablation.

CONCLUSION

• ? After controlling for age, gender, marital status and tumour size, the typical patient presenting with clinical stage T1a RCC, who undergoes ablation rather than NSS, has a twofold increase in the risk of kidney cancer death; however, at 5 years the absolute difference is small, and may only be realized by patients with long life expectancies.

     

Evans blue as a selective dye marker for white-light diagnosis of non-muscle-invasive bladder cancer: an in vitro study

What's known on the subject? and What does the study add? We found that Evans blue preferentially accumulate in spheroids prepared from urothelial cell carcinoma (UCC) cells as compared to spheroids composed of normal human urothelial (NHU) cells. The present findings could be important for future developments in clinical diagnostics for early bladder cancer detection staging and grading involving white light cystocopy.

OBJECTIVE

• ? To develop a diagnostic method relying on the preferential accumulation of a dye in non‐muscle‐invasive bladder cancer (NMIBC) that is visible in conjunction with white‐light cystoscopy (WLC).

MATERIALS AND METHODS

• ? We investigated in detail the permeation of Evans blue in urothelial cell carcinoma (UCC) spheroids prepared from T24, J82 and RT‐112 human cell lines and spheroids composed of normal human urothelial (NHU) cells.
• ? To gain more insight into the differential accumulation, all spheroids were investigated ultrastructurally using transmission electron microscopy (TEM).

RESULTS

• ? We found that, after exposure to Evans blue for 2 h, UCC spheroids accumulated dramatically more dye than spheroids composed of NHU cells.
• ? Using TEM it was found that the malignant spheroids contain similar ultrastructural characteristics, i.e. a wide intercellular space and a decreased number of desmosome‐like cell attachments, to those from clinical samples of non‐papillary carcinoma in situ of the bladder.

CONCLUSION

• ? We believe the present findings could be important for future developments in clinical diagnostics for early bladder cancer detection, staging and grading involving WLC.

     

Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre,randomized, double‐blind,placebo‐controlled trial

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side‐effect profile relative to currently available PDE5 inhibitors. As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well‐tolerated therapy for ED of broad‐spectrum aetiology and severity.

OBJECTIVE

• ? To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED).

PATIENTS AND METHODS

• ? The present study was a multicentre, randomized, double‐blind, placebo‐controlled, fix‐dosed phase three clinical trial involving 200 patients with ED.
• ? The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ).
• ? The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score.
• ? The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD ≥ 26), and response to the GAQ.

RESULTS

• ? Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF‐EFD score.
• ? There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ.
• ? Flushing was the most common treatment‐related adverse event.
• ? Most adverse events were transient and mild or moderate in severity.

CONCLUSION

• ? Avanafil is an effective and well‐tolerated therapy for ED of broad‐spectrum aetiology and severity.

     

Effects of Schisandra chinensis extract on the contractility of corpus cavernosal smooth muscle (CSM) and Ca2+ homeostasis in CSM cells

What's known on the subject? and What does the study add? Schisandra chinensis extract (SCE) has been known to have relaxative effects on penile smooth muscle. A recent study showed that SCE could enhance slidenafil citrate‐induced relaxation of penile corpus cavernosum. The current study investigated the mechanism of action of SCE and its constituents on corporal smooth muscle cells. And this study shows that SCE induced relaxation of CSM primarily through an endothelium independent pathway and the relaxation effects of SCE on corporal smooth muscle are, in part, due to the activation of K⁺ channels and inhibition of TRPC6 channels, resulting in decreased [Ca²⁺].

OBJECTIVE

• ? To evaluate the relaxant effects of Schisandra chinensis extract (SCE) on corporal tissue in the penis and to investigate the mechanism of action of SCE and its constituents on corporal smooth muscle (CSM) cells.

MATERIALS AND METHODS

• ? The fruit of SC was collected and extracted with ethanol. Six SC lignans (schisandrol A, schisandrol B, schisandrin A, schisandrin B, gomisin N, and schisandrin C) were isolated and purified, and the chemical structures were confirmed by ¹H‐nuclear magnetic resonance (NMR) and ¹³C‐NMR data.
• ? Isolated rabbit CSM strips were mounted in an organ‐bath system, and the effects of SCE were evaluated.
• ? To estimate the intracellular Ca²⁺ level ([Ca²⁺]_i), we used a Fura‐2 fluorescent technique, and a conventional whole‐cell patch‐clamp technique was used to measure the calcium‐sensitive K⁺ channels (K_Ca), inward rectifier K⁺ channels (K_IR), and canonical transient receptor potential cation channel 6 (TRPC6) currents.

RESULTS

• ? SCE induced concentration‐dependent relaxation in contracted CSM tissue, and the removal of the endothelium did not significantly affect their relaxation potencies.
• ? In CSM cells, extracellular application of SCE significantly increased whole‐cell K_Ca currents (117.4%) and K_IR currents (110.0%). These effects were completely abolished by charybdotoxin or BaCl₂.
• ? In contrast, carbachol‐induced TRPC6 channel activity was significantly inhibited (87.3%) by SCE in green fluorescent protein‐TRPC6 pcDNA transfected HEK 293 cells. [Ca²⁺]_i measurements showed that SCE effectively reduced basal [Ca²⁺]_i in both cell lines (CSM cells and A7r5 cells) and the [Arg8]‐vasopressin (AVP)‐induced [Ca²⁺]_i increase in A7r5 cells.
• ? Among the six SC lignans, schisandrin A and schisandrin B most effectively attenuated the AVP‐induced [Ca²⁺]_i increase.

CONCLUSIONS

• ? SCE induced relaxation of CSM that occurred primarily via an endothelium‐independent pathway.
• ? The relaxation effects of SCE on CSM were, in part, due to the activation of K⁺ channels and inhibition of TRPC6 channels, resulting in decreased [Ca²⁺]_i.

     

Is joint hypermobility associated with vesico‐ureteral reflux? An assessment of 50 patients

Study Type – Aetiology (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Recent studies have already shown associations between generalized joint hypermobility (GJH) and voiding and defecation dysfunction and/or slow transit constipation. Changes in extracellular matrix composition in vesico‐ureteric junction of vesico‐ureteral reflux (VUR) patients were also observed previously. This study is the first to assess joint mobility as a parameter for connective tissue composition in vesico‐ureteral reflux. We convincingly demonstrate that VUR patients have significantly more hypermobile joints compared to controls and this provides a new angle to the intriguing subjects of development of VUR and susceptibility to VUR.

OBJECTIVE

• ? To assess whether there is an increased prevalence of joint hypermobility in patients with vesico‐ureteric reflux (VUR).

MATERIALS AND METHODS

• ? We studied 50 patients with primary VUR and matched controls drawn from a reference population.
• ? Joint mobility was assessed using the Bulbena hypermobility score.

RESULTS

• ? We identified significantly more patients with VUR with generalized joint hypermobility than controls (24% vs 6.7%, P= 0.007).

CONCLUSION

• ? Our findings confirm our clinical observation of an increased rate of joint hypermobility in patients with VUR. We speculate that an altered composition of the connective tissue may contribute to the severity of the (pre‐existing) VUR phenotype.