Vertical bone augmentation and regular implants versus short implants in the vertically deficient posterior mandible:a systematic review and meta-analysis of randomized studies

Item does not contain fulltextThe aim of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the outcomes of short dental implants (≤7mm) versus vertical bone augmentation followed by regular dental implants (>7mm) in the deficient posterior mandible. In total, eight RCTs (six using interpositional sandwich grafting and two using a guided bone regeneration technique) were reported in 17 articles at different time points. In the meta-analysis of the sandwich group, the relative risk (RR) for implant loss at 1year was in favour of short implants (RR 0.41, P=0.02), while no significant difference was found at 3 years (RR 0.65, P=0.43), 5 years (RR 1.08, P=0.86), or 8 years (RR 1.53, P=0.52). The risk of complications was in favour of short implants (RR 0.34, P=0.0002), as was the mean difference in marginal bone resorption after 1 year (-0.09mm, P=0.17), 3 years (-0.32mm, P<0.00001), 5 years (-0.65mm, P<0.00001), and 8 years (-0.88, P<0.00001). The mean residual osseointegration length of the implants was between 2.94mm and 4.44mm in the short implants group and between 7.97mm and 8.62mm in the regular implants group after 5 years. In conclusion, in the deficient atrophic posterior mandible, short implants and regular implants demonstrate comparable outcomes within the first 5 years. Patients who are fit for surgery should be informed about the risks and benefits of both options

Biocompatibility of bone graft substitutes: effects on survival and proliferation of porcine multilineage stem cells in vitro

Bone graft substitutes (BGS) are widely used in clinical practice. For stem cellbased approaches to bone tissue engineering BGS need to show sufficient biocompatibility in the in vitro setting. This study was designed to demonstrate the influence of six different BGS on the proliferation and metabolic activity of porcine mesenchymal multilineage stem cells (pMSC) in vitro. Bone-marrow derived pMSC were cultivated for 24 hours with the eluates of six different BGS. The eluates were generated by incubating the BGS three times in succession for 24 hours with a culture medium and collecting the supernatants. pMSC vitality and proliferation in the presence of eluates from the first, second, and third incubation were assessed by WST-test quantification of metabolically active cells. Culture of pMSC with eluates in all cases resulted in decreased cell numbers in an eluate concentration-dependent manner. At least a 65% loss of cells compared to controls (culture medium without eluates) could be observed in the presence of undiluted eluates. The negative influence of eluates varied significantly among BGS. In all cases, second and third eluates were less potent in their negative effects on cellular vitality/proliferation. In conclusion, the BGS examined here should be submitted to thorough preincubation before in vitro use for cell-based constructs to maximize cell viability for the tissue engineering of bone. (Folia Morphol 2011; 70, 3: 154&#8211;160

Two techniques for the preparation of cell-scaffold constructs suitable for sinus augmentation: steps into clinical application.

The objective of this clinical trial was the analysis of 2 methods for engineering of autologous bone grafts for maxillary sinus augmentation with secondary implant placement. Group 1 (8 patients, 12 sinuses): cells of mandibular periosteum were cultured in a good manufacturing practice laboratory (2 weeks) with autologous serum and then transferred onto a collagen matrix. After another week, these composites were transplanted into the sinuses. In group 2A (2 patients, 3 sinuses), cells of maxillary bone were cultivated with autologous serum for 2 weeks, seeded onto natural bone mineral (NBM, diameter [Ø] = 8 mm) blocks, and cultivated for another 1.5 months. These composites were transplanted into the sinuses. Group 2B (control, 3 patients, 5 sinuses) received NBM blocks alone. In the course of implant placement 6 (group 1) and 8 (group 2) months later, core biopsy were taken. Clinical follow-up period was 1 to 2.5 years in group 1 and approximately 7 years in groups 2A and 2B. New vital bone was found in all cases at median densities of 38\% (n = 12) in group 1, 32\% in group 2A (n = 3), and 25\% in group 2B (n = 5). Differences between group 1 and 2B as well as 2A and 2B were statistically significant ( p = 0.025). No adverse effects were seen. All methods described were capable of creating new bone tissue with sufficient stability for successful implant placement

Spectrally resolved autofluorescence imaging in posterior uveitis.

Clinical discrimination of posterior uveitis entities remains a challenge. This exploratory, cross-sectional study investigated the green (GEFC) and red emission fluorescent components (REFC) of retinal and choroidal lesions in posterior uveitis to facilitate discrimination of the different entities. Eyes were imaged by color fundus photography, spectrally resolved fundus autofluorescence (Color-FAF) and optical coherence tomography. Retinal/choroidal lesions' intensities of GEFC (500-560 nm) and REFC (560-700 nm) were determined, and intensity-normalized Color-FAF images were compared for birdshot chorioretinopathy, ocular sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and punctate inner choroidopathy (PIC). Multivariable regression analyses were performed to reveal possible confounders. 76 eyes of 45 patients were included with a total of 845 lesions. Mean GEFC/REFC ratios were 0.82 ± 0.10, 0.92 ± 0.11, 0.86 ± 0.10, and 1.09 ± 0.19 for birdshot chorioretinopathy, sarcoidosis, APMPPE, and PIC lesions, respectively, and were significantly different in repeated measures ANOVA (p < 0.0001). Non-pigmented retinal/choroidal lesions, macular neovascularizations, and fundus areas of choroidal thinning featured predominantly GEFC, and pigmented retinal lesions predominantly REFC. Color-FAF imaging revealed involvement of both, short- and long-wavelength emission fluorophores in posterior uveitis. The GEFC/REFC ratio of retinal and choroidal lesions was significantly different between distinct subgroups. Hence, this novel imaging biomarker could aid diagnosis and differentiation of posterior uveitis entities

Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions

The slow progression of early AMD stages to advanced AMD requires the use of surrogate endpoints in clinical trials. The use of combined endpoints may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite endpoints as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite endpoints used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite endpoint categories were: Combined structural and functional endpoints, combined structural endpoints, combined functional endpoints and combined multi-categorical endpoints. The majority of the studies included binary composite endpoints. There was a lack of sensitivity analyses of different endpoints against accepted outcomes (i.e. progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined endpoints in clinical studies of early stages of AMD exists and no surrogate endpoints have been accepted for AMD progression

Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after &gt;5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. Patients and methods: In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. Results: In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). Conclusion: Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC

Heterogeneity of patient-reported outcome measures in clinical research

Background The use of patient-reported outcome measures (PROMs) in clinical research increases and use of heterogeneous instruments reflects how well diverse traits are captured by a medical specialty. In order to reflect the heterogeneity of current PROM use in ophthalmology, we reviewed the available literature. Methods The medical literature database Web of Science was searched for the most cited articles in clinical ophthalmology. Titles, abstracts and full text articles were reviewed for the use of PROMs and a list of the 100 most cited articles using PROMs was obtained and stratified by year of publication. Results A total of 1,996 articles were screened. Seventy-seven out of the 100 articles identified included one PROM, and the average number of instruments was 1.5 ± 1.1. The most widely used PROMs were the National Eye Institute Visual Function Questionnaire (33%), the Ocular Surface Disease Index (14%) and the Medical Outcomes Study Short Form (13%). A simulation analysis suggested that the distribution of PROM use in ophthalmology study did not significantly differ from a power law distribution. Twenty-two percent and fifteen percent of articles did not reference and did not specify the PROM used, respectively. This rate decreased in the more recently published articles (p = 0.041). Conclusions Our data suggest that the heterogeneity of PROMs applied in ophthalmology studies is low. The selection of PROMs for clinical studies should be done carefully, depending on the research goal

Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma

Background: Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). Methods: Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10&nbsp;mg/kg every 2&nbsp;weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. Results: Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse. Conclusions: Patients with OR by 7 or 13&nbsp;weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance

Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention-MACUSTAR.

BACKGROUND: There is an unmet need for treatment options in intermediate age-related macular degeneration (iAMD). However, for any new interventions to be tested in clinical trials, novel currently unavailable clinical endpoints need to be developed. Thus, the MACUSTAR study aims to develop and evaluate functional, structural, and patient-reported candidate endpoints for use in future iAMD trials. METHODS: The protocol describes a low-interventional clinical multicenter study employing a novel two-part design. The cross-sectional part (total duration, 1 month) and the longitudinal part (total duration, 36 months) include participants with iAMD and control groups with early/late/no AMD. The cross-sectional part's primary objective is a technical evaluation of functional, structural, and patient-reported candidate outcomes. The longitudinal part's primary objective is to assess the prognostic power of changes in functional, structural, and patient-reported outcomes for progression from iAMD to late AMD. All data will be used to support a biomarker qualification procedure by regulatory authorities. DISCUSSION: The MACUSTAR study characterizes and evaluates much needed novel functional, structural, and patient-reported endpoints for future clinical trials in iAMD and will improve our understanding of the natural history and prognostic markers of this condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017

Development and validation of novel clinical endpoints in intermediate age-related macular degeneration in MACUSTAR

Background Currently, no validated clinical endpoints for treatment studies exist for intermediate age-related macular degeneration (iAMD). Objective The European MACUSTAR study aims to develop and clinically validate adequate clinical endpoints for future treatment studies in iAMD and to identify early determinants of disease progression to late stage AMD. Material and methods The MACUSTAR study protocol was developed by an international consortium of researchers from academia, the pharmaceutical industry and medical device companies. The MACUSTAR project is funded by the Innovative Medicines Initiative 2 (IMI2) of the European Union. Results The MACUSTAR study consists of a cross-sectional and a longitudinal investigation. A total of 750 subjects with early, intermediate and late AMD as well as control subjects with no signs of AMD will be included with a follow-up period of 3 years. Overall, 20 European study centers are involved. Conclusion The MACUSTAR project will generate large high-quality datasets, which will allow clinical validation of novel endpoints for future interventional trials in iAMD. The aim is that these endpoints will be accepted as suitable for medication approval studies by the regulatory authorities and that understanding of the disease process will be improved