Augmented Reality-Assisted CT-Guided Puncture: A Phantom Study.

PURPOSE: To investigate the feasibility of a novel augmented reality system for CT-guided liver interventions and to compare it with free-hand interventions in a phantom setting. METHODS AND MATERIALS: A newly developed augmented reality interface was used, with projection of CT-imaging in multiplanar reconstruction and live rendering of the needle position, a bull`s eye view of the needle trajectory and a visualization of the distance to the target. Punctures were performed on a custom-made abdominal phantom by three interventional radiologists with different levels of expertise. Time and needle placement accuracy were measured. Two-tailed Wilcoxon signed rank test (p < 0.05) was performed to evaluate intraparticipant difference. RESULTS: Intraparticipant puncture times were significantly shorter for each operator in the augmented reality condition (< 0.001 for the resident, < 0.001 for the junior staff member and 0.027 for the senior staff member). The junior staff member had an improvement in accuracy of 1 mm using augmented reality (p 0.026); the other two participants showed no significant improvement regarding accuracy. CONCLUSION: In this small series, it appears that the novel augmented reality system may improve the speed of CT-guided punctures in the phantom model compared to the free-hand procedure while maintaining a similar accuracy.

An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner's lesions.

PURPOSE: The primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner's lesions (HL). METHODS: In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0-10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL-) were compared. RESULTS: In total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of -1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL-. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL- (R = 0.04 [95% CI -0.16, 0.29]). CONCLUSION: ASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL- suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes. TRIAL REGISTRATION: EudraCT number 2011-004555-39, date of registration: 2012-05-07.

Relationship between mean volume voided and incontinence in children with overactive bladder treated with solifenacin: post hoc analysis of a phase 3 randomised clinical trial.

This post hoc Poisson regression analysis investigated the relationship between mean volume voided and incontinence episodes/24 h after fixed frequency adjustment in children with overactive bladder from the LION study, a phase 3, double-blind, randomised, placebo-controlled, sequential, dose-titration solifenacin trial. Patients were aged 5-< 12 years with ≥ 4 episodes of daytime incontinence during a 7-day pre-baseline diary period. The dependent variable was the mean number of incontinence episodes/24 h at the end of study. Explanatory variables included treatment, mean number of incontinence episodes/24 h at baseline, and change from baseline to end of study in mean volume voided. Statistical significance and goodness of fit were analysed using the Pearson's chi-square test. A negative estimate was found between the dependent variable 'incontinence' and both mean volume voided and daytime maximum volume voided/micturition (an increase in mean volume voided or daytime maximum volume voided/micturition would lead to a reduction in incontinence; P = 0.0014 and P = 0.0317, respectively). The model was a good fit to the data in both analyses with a Pearson's chi-square goodness-of-fit criteria of 0.8.Conclusion: Increase in mean volume voided was significantly correlated to reduction in incontinence episodes/24 h in children with overactive bladder treated with solifenacin.This study is registered at ClinicalTrials.gov : NCT01565707. What is known: • Mean volume voided per micturition is used as an indicator of treatment efficacy, with increases noted as number of incontinence episodes (and micturition frequency) decrease. • The relationship between mean volume voided and incontinence episodes is not clearly understood. What is new: • Increase in mean volume voided significantly correlated to reduction in incontinence in solifenacin-treated children with overactive bladder (Poisson regression model analysis). • Compared with placebo, solifenacin-treated children had a lower predicted number of incontinence episodes/24 h.

Long-term efficacy and safety of solifenacin in pediatric patients aged 6 months to 18 years with neurogenic detrusor overactivity: results from two phase 3 prospective open-label studies.

INTRODUCTION: The standard recommended treatment for neurogenic detrusor overactivity (NDO) is clean intermittent catheterization combined with an antimuscarinic agent. However, the adverse systemic side-effects of oxybutynin, the most widely used agent, are of concern. OBJECTIVE: To evaluate the efficacy and safety of solifenacin in pediatric patients with NDO, aged 6 months-<5 years and 5-<18 years. STUDY DESIGN: Two open-label, baseline-controlled, phase 3 studies were conducted in pediatric patients with NDO. Patients were treated with sequential doses of solifenacin oral suspension (pediatric equivalent doses 2.5-10 mg) for 12 weeks to determine each patient's optimal dose, followed by a fixed dose ≥40-week treatment period. Primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC) after 24 weeks. Secondary endpoints included bladder compliance, bladder volume until first detrusor contraction (>15 cmH2O), number of overactive detrusor contractions (>15 cmH2O), maximum catheterized volume (MCV)/24 h, and incontinence episodes/24 h. Safety parameters were treatment-emergent adverse events (TEAEs), serious adverse events, laboratory variables, vital signs, electrocardiograms, and ocular accommodation and cognitive function assessments. RESULTS: After 24 weeks, MCC had significantly increased compared with baseline in patients aged 6 months -<5 years and 5-<18 years (37.0 ml and 57.2 ml, respectively; P < 0.001; Fig.). Improvement was also observed after 52 weeks' treatment. Significant changes were observed from baseline to week 24 in all secondary endpoints in both age groups: increase in bladder compliance, increase in bladder volume to first detrusor contraction as a percentage of expected bladder capacity, reduction in the number of overactive detrusor contractions, increase in MCV, and decreased incontinence episodes. TEAEs were mostly mild or moderate, and there were no new drug-related TEAEs compared with adult studies. Age-related improvements were noted in ocular accommodation and cognitive function. DISCUSSION: These long-term multicenter investigations demonstrated the efficacy and safety of solifenacin in pediatric patients with NDO. The observed increases in MCC were clinically relevant and demonstrated that an increase in fluid volume can be accommodated in the bladder prior to reaching intravesical pressures that endanger kidney function and/or are associated with leakage or discomfort. Solifenacin was well tolerated with low incidences of constipation and dry mouth (typically associated with antimuscarinics), central nervous system-related side-effects, and facial flushing. CONCLUSION: Solifenacin was effective and well tolerated in pediatric patients with NDO, aged 6 months-<18 years, suggesting that it is a viable alternative to oxybutynin, the current standard of care. STUDIES ARE REGISTERED AT CLINICALTRIALS.GOV: NCT01981954 and NCT01565694.

The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model-based pediatric dose estimation.

INTRODUCTION: Mirabegron, a selective ß3-adrenoreceptor agonist, is a well-established alternative to antimuscarinics in adults with overactive bladder (OAB) symptoms and is under development for use in pediatric patients. Understanding drug pharmacokinetics (PK) in pediatric patients is needed to determine appropriate dosing. Conducting these studies is ethically complex, particularly as regulatory guidance requires that PK is assessed in pediatric patients with a therapeutic need for the drug. It is also vital to evaluate the safety/tolerability and palatability/acceptability of pediatric formulations. PURPOSE: The purpose of the study was to characterize the PK of mirabegron in pediatric patients with neurogenic detrusor overactivity or idiopathic OAB, to provide a basis for a weight-based dosing algorithm, and to evaluate the safety, tolerability, and palatability/acceptability of the formulations. MATERIALS AND METHODS: A preliminary population PK model constructed from adult data with allometric scaling was used to predict single weight-adjusted mirabegron doses. This was developed to achieve exposures in pediatric patients in two phase 1 studies that were consistent with steady state in adults following once-daily 25 mg ('low dose') and 50 mg ('high dose') dosing. In study 1, adolescents (12-<18 years) and children (5-<12 years) received a single tablet under fed or fasted conditions. In study 2, children (3-<12 years) received a single oral suspension dose under fed conditions. The PK data were used to assess the predictive value of the preliminary PK model and to update it to analyze mirabegron PK in pediatric patients. The safety/tolerability and palatability/acceptability of the formulations were evaluated. RESULTS: Forty-three patients comprised six study cohorts: adolescents, low-dose tablets, fed (n = 7); children, low-dose tablets, fed (n = 7); adolescents, high-dose tablets, fed (n = 8); children, high-dose tablets, fed (n = 6); children, high-dose tablets, fasted (n = 6); and children, high-dose oral suspension, fed (n = 9). The population PK model-based doses for tablets and oral suspension achieved exposures that were typically consistent with steady state in adults. The final population PK model was used to describe the PK for mirabegron in pediatric patients (Table). Both formulations were well tolerated, and there were no reports of bad taste or swallowing difficulties for the tablets, although some found the oral suspension unpleasant. CONCLUSIONS: The single, weight-adjusted pediatric mirabegron doses were successfully predicted by population PK modeling to achieve drug exposures comparable with steady state in adults. The finalized PK model used to characterize the pediatric PK of mirabegron will be utilized to develop a weight-based dosing algorithm. The single mirabegron doses were well tolerated.

Measurement of ischaemia-reperfusion in patients with intermittent claudication using NMR-based metabonomics.

Intermittent claudication has proved to be a good in vivo model for ischaemia-reperfusion. For assessment of ischaemia-reperfusion damage, the known biochemical markers all have disadvantages with respect to sensitivity and interference with other physiological events. In this work, we studied the metabolic effects of ischaemia-reperfusion in patients with intermittent claudication, and the effects of vitamin C and E intervention, using both traditional biochemical measurements and 1H-NMR-based metabonomics on urine and plasma. The 1H-NMR spectra were subjected to multivariate modelling using principal components discriminant analysis, and the observed clusters were validated using joint deployment of univariate analysis of variance and Tukey-Kramer honestly significant difference (HSD) testing. The study involved 14 patients with intermittent claudication and three healthy volunteers, who were monitored during a walking test, before and after a vitamin C/E intervention, and after a washout period. The effect of exercise was only observable for a limited number of biochemical markers, whereas 1H NMR revealed an effect in line with anaerobic ATP production via glycolysis in exercising (ischaemic) muscle of the claudicants. Thus, the beneficial effect of vitamins C and E in claudicants was more pronounced when observed by metabonomics than by traditional biochemical markers. The main effect was more rapid recovery from exercise to resting state metabolism. Furthermore, after intervention, claudicants tended to have lower concentrations of lactate and glucose and several other citric acid cycle metabolites, whereas acetoacetate was increased. The observed metabolic changes in the plasma suggest that intake of vitamin C/E leads to increased muscle oxidative metabolism.

Carcinoid tumours of the testis.

OBJECTIVE: To review previous reports of carcinoid (an endocrine tumour mostly of the gastrointestinal tract) tumours of the testis. METHODS: Carcinoid tumours of the testis are rare and can be divided into primary carcinoid (group 1), testicular metastasis from another location (group 2) and carcinoid within a testicular teratoma (group 3). A case of testicular carcinoid within our clinic prompted us to review previous reports; all the cases found were assessed for patient and tumour characteristics, diagnostic tools used, treatment and prognosis. RESULTS: In all, 62 cases were assessed and divided into groups 1 (44 patients), 2 (six) and 3 (12), respectively. Seven patients in group 1 developed metastases. A wide variety of diagnostic tools was used to search for other tumour sites. All patients were treated with orchidectomy. Three patients with a primary carcinoid were treated with adjuvant chemotherapy (two) or radiotherapy (one), with unknown results. All but one of the nine patients who died were known to have metastasis, either from a primary testicular carcinoid or testicular metastases from an intestinal carcinoid. CONCLUSION: When a testicular carcinoid tumour is discovered, other tumour sites should be excluded. The most useful diagnostic tools for this purpose seem to be urinary 5-hydroxyindoleacetic acid measurement, somatostatin receptor scintigraphy, computed tomography and video-capsule endoscopy. Localized testicular carcinoid tumours have an excellent prognosis after orchidectomy.

Current opinions in horseshoe kidney transplantation.

Currently, horseshoe kidneys are also being considered for transplantation due to the shortage of organs. They can be transplanted en bloc or after division of the renal isthmus. However, because of their low incidence, horseshoe kidneys are rarely transplanted. The considerable variation in vascular anatomy of the horseshoe kidney add to both the frequency of primary non-function and the technical difficulty of the transplantation. In the study reported here, the surgical members of the European Society for Organ Transplantation were asked for their opinions regarding the techniques and results of horseshoe kidney transplantation. Most surgeons advised explanting the horseshoe kidney en bloc. The decision to transplant en bloc or after division of the renal isthmus depended on the morphology of the renal isthmus, the number and position of renal vessels and/or the anatomy of the urinary collecting system. Most surgeons thought that the results of horseshoe kidney transplantation were equal to those of normal kidneys.