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Generating scientific evidence from clinical trials for the treatment of rare diseases is associated with particular challenges. Standard clinical trial methodology is hardly ever appropriate in the rare disease setting, so innovative approaches need to be developed, evaluated and established. Among the various innovative methodologies introduced two approaches are discussed in more detail: the influence of randomised treatment allocation and the integration of external control information, both with respect to the level of evidence. The evaluation of the impact of randomised treatment allocation is guided by a structured approach which can be used to inform the design in the planning phase of a trial and select an appropriate randomisation procedure. Moreover, after the conduct of the trial the magnitude of actual bias can be estimated, and both a bias-adjusted treatment effect and a bias-adjusted test can be derived to put the level of reachable evidence into context. Adding external control data to randomised clinical trials appears charming with respect to small numbers of available patients but raises the question of how this can be achieved without compromising on the quality of evidence. One approach that seems promising in this respect is to check after a determined proportion of the total sample size whether the addition of external control data appears justified without compromising the pre-specified level of evidence. New approaches need to be accepted by all stakeholders. Their strengths and weaknesses in terms of reachable evidence need to be evaluated and presented in a such a way that they are comprehensible for patients, clinicians, industry, regulatory and HTA bodies.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.

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Patients’ need to improve outcomes and to reduce the number of complications triggers the development of new materials and surgery concepts. Currently, there are many implants and fixation systems dedicated for intraperitoneal onlay mesh procedure. The aim of this study was to compare two different mesh/fixation system concepts (PH: Physiomesh/Securestrap and VS: Ventralight ST/SorbaFix) for laparoscopic ventral hernia repair with respect to pain. A single-center, prospective, randomized study was designed to include 50 patients per group with a planned interim analysis for safety after 25 patients. The endpoints were pain occurrences and intensity, which was measured with the visual analogue scale 7 days, 30 days, 3 months and 6 months after surgery. The safety parameters included the number of recurrences and postoperative complications. During the interim analysis, the study was stopped due to safety reasons. We observed five (20 %) recurrences in the PH group in first 6 months and none in the VS group. We observed a significantly higher pain rate in the PH group after 3 months (p< 0.0001) and no difference after 7 days (p= 0. 7019). The pain intensity decreased significantly over time (p< 0.0001) and was significantly higher in the PH group (p< 0.0001). Although this clinical trial was terminated prior to the preplanned recruitment goal, the obtained results from the enrolled patients indicate that the PH system associated with significantly greater hernia recurrences and postoperative pain compared with the VS system. This confirms the superiority of the elastic mesh concept, which may be a safer and more efficacious option for laparoscopic ventral hernia repairs.

Until today, there have been no conventional imaging methods available to visualize surgical mesh implants and related complications. In a new approach, we incorporated iron particles into polymer-based implants and visualized them by magnetic resonance imaging (MRI).

Purpose To evaluate the concurrent rate of expression of c-Kit and its ligand stem cell factor (SCF) in uveal melanoma in respect to the further clinical course and the correlation of these markers.Methods Paraffin sections from 35 primary uveal melanomas were evaluated immunohistochemically for the expression of c-Kit and SCF. Sixteen cases developed systemic metastasis during the follow-up (median: 5 years after diagnosis). The patients who did not develop metastasis (n=19) had a mean follow-up of 10.6 (9–13) years. Radiation was performed in 6 patients.Results c-Kit and SCF were expressed in all patients who did or did not develop metastasis in the further clinical course. A mean SCF expression of 77.2% (range 52.7%-97.5%) of tumors that did not develop systemic metastasis and 30.1 % (range 2.9%-61.5%) of tumors with systemic metastasis were evident. Uveal melanomas revealing an increased SCF expression were found to develop no metastasis more frequently (p<0.0001; hazard ratio (HR)=0.963, 95% confidence interval (CI) 0.945–0.981). A mean c-Kit expression of 58.01% (range 5.9%-97.9%) in the group who did not develop metastasis and 48.9% (range 5.0%-95.9%) in the group with systemic metastasis were observed. c-Kit expression was not associated with increased rates of metastasis formation (p=0.7329; HR=0.997, 95% CI 0.982–1.013). The correlation between SCF and c-Kit is weak (0.39; 95% CI 0.06–0.63).Conclusions c-Kit expression was not found to be associated with metastasis formation. A high SCF expression of primary choroidal melanomas was significantly associated with a lower incidence of systemic metastasis, which indicated SCF as a benign prognostic factor in the further clinical course.

OBJECTIVE To assess long-term functional and morphological changes after macular translocation in patients with exudative age-related macular degeneration. METHODS Evaluation of a noncomparative cohort study of 90 patients with a follow-up of 14 to 79 months (mean, 38.2 months). RESULTS Visual acuity increased by 3 or more lines in 15 patients, remained stable in 35 patients, and deteriorated in 40 patients at final examination. Pigment epithelium atrophy extending to the new fovea was detected in 44 patients; in 25 patients this new atrophy was associated with loss of visual function. CONCLUSIONS Long-term follow-up of macular translocation with 360° retinotomy showed stabilization or improvement in half of the patients. Progressive atrophy of the pigment epithelium represented one major limiting factor of the beneficial effect of the treatment. Macular translocation may be an option for cases of exudative age-related macular degeneration that are not eligible for or do not respond to alternative treatments.Arch Ophthalmol. 2007;125(10):1367-1372--

Proliferative vitreoretinopathy (PVR) is the most important reason for blindness following retinal detachment. Presently, vitreous tamponades such as gas or silicone oil cannot contact the lower part of the retina. A heavier-than-water tamponade displaces the inflammatory and PVR-stimulating environment from the inferior area of the retina. The Heavy Silicone Oil versus Standard Silicone Oil Study (HSO Study) is designed to answer the question of whether a heavier-than-water tamponade improves the prognosis of eyes with PVR of the lower retina.

Statement of Problem.Internal discoloration may occur with the intraoral use of resin-based restoration materials. Water storage and light exposure influence the color properties of microfilled and hybrid composites. Purpose.The purpose of this study was to determine color and translucency changes in a hybrid and a microfilled composite after light exposure with and without water storage. Material and Methods.A hybrid (Tetric) and a microfilled composite (Silux Plus) were subjected to artificial daylight with and without water storage. Tristimulus Yxy values were determined colorimetrically against a black or a white background. Differences from baseline were calculated as ΔE*abfor up to 1 month. After 1 month, ΔL*, Δa*, Δb*, and the contrast ratio ΔC were calculated. Data were analyzed with 2-way analysis of variance (P<.05). Results.The ΔEab*increased over time for wet and dry stored specimens of both materials. Wet storage for 1 month resulted in significantly higher ΔEab*and ΔC but lower Δb*than dry storage. The Δa*was significantly higher for Tetric compared with Silux Plus. Both materials showed negative ΔL*values under both storage conditions without significant differences between materials or storage conditions. Conclusion.The results of this in vitro study suggest that resin-based restoration materials undergo measurable changes due to daylight exposure. Increased changes occurred under the influence of water storage. (J Prosthet Dent 2002;87:264-70.)

Meyer JMA, Buecker A, Spuentrup E, et al. Improved in-stent magnetic resonance angiography with high flip angle excitation. Invest Radiol 2001;36677–681.

Abstract. Background: In patients with more complex rhegmatogenous retinal detachments (RRD) not complicated by proliferative vitreoretinopathy (PVR), the most appropriate operating method is controversial, and different surgeons use different techniques. The Scleral Buckling Versus Primary Vitrectomy in Rhegmatogenous Retinal Detachments Study (SPR Study) is designed to compare primary vitrectomy and scleral buckling techniques in these patients. Methods: The SPR Study is a multicentre, randomised, controlled clinical trial stratified by lens status. Patients with RRD which is not complicated by PVR grade B or C and which cannot be treated with a single meridional sponge are randomised to either scleral buckling or pars plana vitrectomy as first surgical intervention. Four hundred consecutive patients are to be recruited per subtrial (phakic and aphakic/pseudophakic patients), and followed up for 1 year. The primary endpoint (functional outcome) is the change in visual acuity. Secondary endpoints (anatomical outcome) include postoperative PVR, retinal reattachment and the number of reoperations necessary to achieve retinal reattachment. Twenty-seven institutions (49 surgeons) in six European countries have been recruited for participation in the study. Conclusion: The SPR Study is the first randomised prospective clinical trial to compare scleral buckling and primary vitrectomy in patients with RRD. The results of this study should enable vitreoretinal surgeons to improve the surgical therapy of patients with the more complicated manifestations of RRD.

Abstract: · Background. The assessment of the cup of the optic disc in follow-up of glaucomatous optic nerve heads depends on the variability of the cup area over time. We examined the variability of topographic measurements depending on scan focus settings and evaluated the long-term fluctuations of the normalised rim/disc area ratio quotient of normal subjects for 1 year. · Methods. Part 1. Evaluation of the influence of scan focus and corneal curvature on the number of pixels per millimetre in one emmetropic volunteer. The scan focus was varied using contact lenses of different refraction. Part 2. HRT examinations of the optic nerve head of five eyes of five volunteers were repeatedly recorded during a 12-month period. The contour line from the first mean topographic image was transferred into the following seven mean topographic images of each subject. · Results. Part 1. The size of pixels depends on the adjusted scan focus for mean corneal curvature radius between 6 and 9 mm. However, after image to image scaling the size of pixels is nearly independent to the scan focus. Part 2. We found the highest variation of normalised rim/disc area ratio for the location of the temporal horizontal sectors, followed by the temporal inferior and the temporal superior sectors. Variation was smallest in the nasal sectors. Mean fluctuation of the normalised rim/disc area ratio quotient of the 95th percentile was 0.09 following image to image scaling compared to 0.16 when using individual image scaling. · Conclusion. Scan focus variation during HRT follow-up examinations can influence optic disc parameters, especially when image to image scaling has not been performed. A confidence area of an individual optic disc could now be calculated. These confidence bands could help to distinguish more easily between progress of glaucomatous optic nerve head damage and physiological intertopographic variation of optic cup measurements. A decrease of more than 43% in the fluctuations of the normalised rim/disc area ratio could be achieved using image to image scaling techniques. For that reason follow-up of glaucomatous optic nerve heads should only be performed using this software application.

Biochemical changes in the vitreous in different vitreoretinal disorders have not yet been thoroughly studied. Using enzyme-linked immunosorbent analysis (ELISA), we established mean values and 95% confidence intervals for six proteins of physiologic human vitreous: albumin (293 ± 18 mg/l), transferrin (73.7 ±6.6 mg/l), immunoglobulin G (IgG), (33,5 ± 3 mg/l), α1-antitrypsin (14.1 ± 2.9 mg/l), α1-acid glycoprotein (4 ±0.7 mg/l), and lactoferrin (< 50 μg/l). These six proteins were also determined in vitreous aspirates from patients with idiopathic proliferative vitreoretinopathy (n= 10), traumatic proliferative vitreoretinopathy (n= 10),and proliferative diabetic retinopathy (n= 15). The pattern of protein levels varied widely within each of the disorders. An analysis of absolute protein levels showed significant differences in total protein and α1-antitrypsin levels between controls and pathologic vitreous samples. We observed differences in transferrin between controls and proliferative diabetic retinopathy (PDR), and differences in α1-acid glycoprotein between controls and both types of proliferative vitreoretinopathy (PVR). The single disorders themselves could not be differentiated by any of the proteins. When the relative contribution of single proteins to total vitreal protein was compared, albumin was lower in all three disorders than in controls. Transferrin was lower in traumatic PVR than in controls, in PDR, or in idiopathic PVR. Our results indicate that the three vitreoretinal disorders studied are characterized by a breakdown of blood-ocular barriers.

• Background: The assessment of the cup of the optic disc depends, among other criteria, on the disc area. A small cup in a small optic disc can indicate an advanced glaucomatous lesion, while on the other hand a large cup in a large optic disc can be normal. Therefore, a cumulative normalised rim/disc area ratio curve could help to distinguish between glaucomatous and normal optic cups. The aim of our study was to calculate and to evaluate such a cumulative normalised rim/disc area ratio curve. • Methods: Heidelberg Retina Tomograph examinations of the optic nerve head of 100 randomly selected eyes of 100 normal subjects were evaluated. We calculated the disc area-adjusted normalised rim/disc area ratio in sectors of 10°. The 95th, 90th and 50th percentiles of each of the 36 sectors were displayed in descending order. • Results: In relation to the normal percentile curves, it is possible to display an individual normalised rim/disc area ratio curve. We obtained such curves for a normal optic disc, optic nerve heads with moderate and advanced lesions and a small optic disc with glaucomatous damage. • Conclusion: We present a new display mode for the results of Heidelberg Retina Tomograph optic nerve head examination, which may be helpful for easy and reliable assessment of the local, diffuse and combined components of glaucomatous optic nerve head damage depending on optic disc size.

Because diabetes mellitus leads to vascular dysfunction, we examined the microvascular endothelial and smooth muscle function in long-term diabetes and a possible influence of fosinopril treatment (10 mg/kg). We investigated isolated perfused mesenteric beds of diabetic rats (4 groups: control, control + fosinopril, diabetes, diabetes + fosinopril; diabetes of 6-month duration, induced by streptozotocin, STC) were investigated using computer-assisted microvideoangiometry. Vascular diameter of four different vascular regions [classified as conductive (G1, 303 ± 6.5 μm and G2, 239 ± 6.3 μm) and resistance (G3, 192 ± 4.5 μm and G4, 124 ± 2.6 μm) vessel generations; resting conditions, control group] were increased in diabetes by 20%. However, the endothelium-dependent relaxation in response to 1 μMacetylcholine (ACh) was reduced from 38-44% to 20-25% (diabetes mellitus) with maximal impairment in G4 vessels. This could be significantly antagonized by fosinopril treatment. Similarly, vasodilation in response to 1 μMglyceroltrinitrate (GTN) was reduced from 50-58 to 20-30%, but was partially prevented by fosinopril (32-38%), whereas potassium chloride (KCl)-induced vasoconstriction did not show differences between the groups. Inhibition of nitric oxide (NO) synthesis by 3 μML-NG-nitro arginine (L-NNA) resulted in a slight vasoconstriction of all vessels (12-25%), with maximum response in G3/G4. This was not altered by disease or treatment. We conclude that (a) long-term diabetes leads to endothelial and smooth muscle dysfunction with reduced capability of vasodilation and either an impairment of NO release or a reduced smooth muscle responsiveness to and (b) a predominant impairment of NO-dependent regulation in small resistance vessels, and (c) that fosinopril treatment can at least partially prevent this vascular dysfunction.

The assessment of the cup of the optic disc depends, among other criteria, on the disc area. A small cup in a small optic disc can indicate an advanced glaucomatous lesion, on the other hand a large cup in a large optic disc can be normal. Therefore, an individual normalised rim/disc area ratio line together with the curves of 50th percentile and the 95th percentile of normal could help to better distinguish between glaucomatous and normal optic cups. The aim of our study was to calculate and to evaluate such a normalised rim/disc area ratio line. Heidelberg Retina Tomograph examinations of the optic nerve head of 100 randomly selected eyes of 100 normal subjects were evaluated. We calculated the disc area adjusted rim/disc area ratio in sectors of 10 degree. The 95th percentile and the 50th percentile of each of the 36 sectors were calculated. Based on these normal percentile lines it was possible to display an individual normalised rim/disc area ratio line in the topographic images of an individual optic disc examination. Here we demonstrated examples of a normal optic disc, optic nerve heads with moderate and advanced lesions and a small optic disc with glaucomatous damage. We present a new display mode of the results of Heidelberg Retina Tomograph optic nerve head examination, which may be helpful for an easy and reliable assessment of glaucomatous optic nerve head damage only looking at topographic images.

We describe the long-term results after treatment of 68 eyes showing advanced stages of proliferative vitreoretinopathy with vitrectomy, daunomycin perfusion, and silicone-oil injection. Six reoperations were performed. After 18 months, 73% of the eyes showed no signs of retinal detachment and 89% had a visual acuity of > 20/800. These results are better than those reported in previously published studies. Whether this improvement was due to the daunomycin treatment or to more aggressive surgical techniques such as retinotomies remains to be answered by a randomized trial.

No relevant conflicts of interest to declare.

Abstract 2247