Temsirolimus Inhibits Proliferation and Migration in Retinal Pigment Epithelial and Endothelial Cells via mTOR Inhibition and Decreases VEGF and PDGF Expression

Due to their high prevalence, retinal vascular diseases including age related macular degeneration (AMD),retinal vein occlusions (RVO),diabetic retinopathy (DR) and diabetic macular edema have been major therapeutic targets over the last years. The pathogenesis of these diseases is complex and yet not fully understood. However, increased proliferation, migration and angiogenesis are characteristic cellular features in almost every retinal vascular disease. The introduction of vascular endothelial growth factor (VEGF) binding intravitreal treatment strategies has led to great advances in the therapy of these diseases. While the predominant part of affected patients benefits from the specific binding of VEGF by administering an anti-VEGF antibody into the vitreous cavity, a small number of non-responders exist and alternative or additional therapeutic strategies should therefore be evaluated. The mammalian target of rapamycin (mTOR) is a central signaling pathway that eventually triggers up-regulation of cellular proliferation, migration and survival and has been identified to play a key role in angiogenesis. In the present study we were able to show that both retinal pigment epithelial (RPE) cells as wells as human umbilical vein endothelial cells (HUVEC) are inhibited in proliferating and migrating after treatment with temsirolimus in non-toxic concentrations. Previous studies suggest that the production of VEGF, platelet derived growth factor (PDGF) and other important cytokines is not only triggered by hypoxia but also by mTOR itself. Our results indicate that temsirolimus decreases VEGF and PDGF expression on RNA and protein levels significantly. We therefore believe that the mTOR inhibitor temsirolimus might be a promising drug in the future and it seems worthwhile to evaluate complementary therapeutic effects with anti-VEGF drugs for patients not profiting from mono anti-VEGF therapy alone

Subthreshold laser therapy with a standardized macular treatment pattern in chronic central serous chorioretinopathy

PURPOSE There is an ongoing controversial debate about the effectiveness of laser treatments in chronic central serous chorioretinopathy (cCSC). We performed a prospective non-randomized interventional study to learn about the effects of a subthreshold laser treatment (Topcon Endpoint Management™, Topcon Healthcare Inc., Tokyo, Japan) in patients with cCSC. METHODS Patients with cCSC and a minimum symptom duration of 4~months were included and treated with a standardized laser pattern covering the macular area. Retreatment was performed every 3~months if persistent subretinal fluid was observed. The primary endpoint was resolution of subretinal fluid at 6~months. Further outcome parameters included best corrected visual acuity, microperimetry, central macular and subfoveal choroidal thickness. RESULTS A total of 42 eyes of 39 patients were included. Mean patient age was 48 ± 10.6~years (range 25-67). Mean symptomatic time before inclusion into the study was 134 ± 133.4~weeks (16-518). Before inclusion, 78.6% of the patients had failed to resolve subretinal fluid under mineralocorticoid receptor antagonists and 14.3% had a recurrence after half-dose photodynamic therapy. Complete resolution of subretinal fluid was observed in 42.9% at 6~months and in 53.8% at 12~months after baseline. Central retinal thickness decreased from 398 ± 135~µm to 291 ± 68~µm (p < 0.001), subfoveal choroidal thickness changed slightly (430 ± 116~µm to 419 ± 113~µm, p = 0.026), microperimetry-derived macular function improved by 19.1 ± 4.7~dB to 21.3 ± 4.8~dB (p = 0.008) and mean BCVA improved by 4.9 ± 8.6 ETDRS letters (p < 0.001). CONCLUSION The results show that the investigated laser treatment is effective in reducing subretinal fluid and leads to an improvement of functional parameters

Anti-angiogenic properties of rapamycin on human retinal pericytes in an in vitro model of neovascular AMD via inhibition of the mTOR pathway

Purpose Choroidal neovascularizations (CNV) are partially stabilized through a coverage of pericytes leading to a partial anti-VEGF resistence. Drugs licensed for neovascular AMD (nAMD) do not take this mechanical and growth factor-driven CNV stability into account. The purpose of this work was to see if inhibiting the mammalian target of rapamycin (mTOR) may successfully block angiogenic cellular pathways in primary human retinal pericytes in an in vitro model of nAMD. Methods The mTOR inhibitor rapamycin was used to treat human retinal pericytes (HRP) at doses ranging from 0.005 to 15 g/ml. A modified metabolism-based XTT-Assay was used to assess toxicity and anti-proliferative effects. A scratch wound experiment showed the effects on migration. On Cultrex basement membrane gels, the influence of rapamycin on the development of endothelial cell capillary-like structures by human umbilical vein vascular endothelial cells (HUVEC) in the absence and presence of pericytes was investigated. Results Rapamycin showed no signs of toxicity within its range of solubility. The drug showed dose dependent anti-proliferative activity and inhibited migration into the scratch wound. Endothelial cell tube formation in a HUVEC monoculture was effectively inhibited at 45%. A co-culture of HUVEC with pericytes on Cultrex induced endothelial tube stabilization but was disrupted by the addition of rapamycin leading to degradation of 94% of the tubes. Conclusions Rapamycin allows for an efficient modulation of aspects of angiogenesis in pericytes via mTOR-modulation in vitro. Further studies are needed to elucidate whether rapamycin may have an impact on CNV in nAMD in vivo

Ranibizumab non-response in pachychoroid neovasculopathy: Effects of switching to aflibercept

Non-response to intravitreal ranibizumab represents a frequent problem in pachychoroid neovasculopathy (PNV). To investigate the effectivity of switching to aflibercept, the database of the Ludwig Maximilians University, Munich, was screened for patients fulfilling the following inclusion criteria: (i) diagnosis of PNV;(ii) inadequate response to >= 3 ranibizumab injections, in spite of monthly dosing, defined as persistence of subretinal-fluid four weeks after the last ranibizumab injection;(iii) resulting switch to aflibercept administered as three monthly injections. Primary outcome measure was percentage of eyes with a dry macula four weeks after the third aflibercept injection. Secondary outcome measures included changes in maximum subretinal fluid (SRF), central subfield thickness (CST) and subfoveal choroidal thickness (SFCT). In total, 14 eyes of 14 patients were included. Mean age was 64.1 +/- 7.5 (range: 51-78) years. Switching to aflibercept was performed after mean 8.4 +/- 4.1 (3-15) ranibizumab injections. While no eye (0%) achieved a dry macula status during ranibizumab treatment, switching to aflibercept achieved a dry macula status in eight eyes (57.1%) after three injections. While both ranibizumab and aflibercept showed an effect on CST (p=0.027, p=0.003), only aflibercept showed a significant effect on SRF (p=0.0009) and SFCT (p=0.044). In cases of PNV not responding to intravitreal ranibizumab, switching treatment to aflibercept induces a favorable short-term response resolving persistent fluid and achieving a dry macula. Further studies with longer follow-up are warranted

Intraocular Lens Power Calculation after Small Incision Lenticule Extraction

With more than 1.5 million Small Incision Lenticule Extraction (SMILE) procedures having already been performed worldwide in an ageing population, intraocular lens (IOL) power calculation in post-SMILE eyes will inevitably become a common challenge for ophthalmologists. Since no refractive outcomes of cataract surgery following SMILE have been published, there is a lack of empirical data for optimizing IOL power calculation. Using the ray tracing as the standard of reference - a purely physical method that obviates the need for any empirical optimization - we analyzed the agreement of various IOL power calculation formulas derived from the American Society of Cataract and Refractive Surgeons (ASCRS) post-keratorefractive surgery online calculator. In our study of 88 post-SMILE eyes, the Masket formula showed the smallest mean prediction error [-0.36 +/- 0.32 diopters (D)] and median absolute error (0.33D) and yielded the largest percentage of eyes within +/- 0.50D (70%) in reference to ray tracing. Non-inferior refractive prediction errors and +/- 0.50D accuracies were achieved by the Barrett True K, Barrett True K No History and the Potvin-Hill formula. Use of these formulas in conjunction with ray tracing is recommended until sufficient data for empirical optimization of IOL power calculation after SMILE is available

3D Heads-Up Display vs. Standard Operating Microscope Vitrectomy for Rhegmatogenous Retinal Detachment

Purpose: To assess the efficacy and outcomes of 23-gauge vitreoretinal surgery for rhegmatogenous retinal detachment using a three-dimensional heads-up display (3D HUD) surgical platform as compared to a standard operating microscope (SOM) setting. Design: Retrospective cohort study. Participants: One hundred and forty consecutive eyes of 140 patients with primary retinal detachment. Methods: All eyes underwent 23-gauge pars plana vitrectomy for primary retinal detachment using either a 3D HUD (NGENUITY;Alcon Inc., Fort Worth, Texas, USA;n = 70 eyes) or a SOM setting (n = 70 eyes);in cases of significant cataract, additional phacoemulsification with intraocular lens (IOL) implantation was performed. Minimum follow-up was 2 months. Main Outcome Measures: Primary retinal reattachment rate, rate of proliferative vitreoretinopathy (PVR), best-corrected visual acuity (BCVA), and duration of surgery. Results: There were 70 eyes each in the 3D HUD and the SOM group. Both groups did not differ concerning age (p = 0.70), extent of retinal detachment (p = 0.07), number of retinal tears (p = 0.40), macular involvement (p = 0.99), and preoperative BCVA (p = 0.99). Postoperatively, 3D HUD and SOM were comparable concerning the primary retinal reattachment rate (88.6 vs. 94.3%;p = 0.37), the development of postoperative PVR (12.9% vs. 7.1%;p = 0.40) and final BCVA (0.26 +/- 0.40 vs. 0.21 +/- 0.38 logMAR;p = 0.99). Duration of surgery was significantly longer in the 3D HUD group (66.2 +/- 16.5 vs. 61.2 +/- 17.1 min;p = 0.04), an effect which however vanished after a "learning curve" of the first 35 eyes (p = 0.49). Conclusions: On par results to a conventional operating microscope can be achieved with a 3D HUD setting when performing 23-gauge vitreoretinal surgery for rhegmatogenous retinal detachment, including the primary retinal reattachment rate, the incidence of postoperative PVR and final BCVA. However, duration of surgery might initially be slightly longer with 3D HUD, suggesting the effect of a learning curve

Impact of extreme (flat and steep) keratometry on the safety and efficacy of small incision lenticule extraction (SMILE)

Little is known about the connection between preoperative keratometry and postoperative results of myopic small-incision lenticule extraction (SMILE). To determine the influence of extreme (flat and steep) corneal keratometry on the safety and efficacy of SMILE, the databases of the Department of Ophthalmology, Ludwig-Maximilians-University Munich, Germany, and SMILE Eyes Linz, Austria, were screened for patients with steep and flat keratometry who had undergone SMILE. In this cross-sectional matched comparative cohort study, eyes with markedly flat (< 42.0 diopters; D) or steep (≥ 47.0D) preoperative corneal keratometry were matched to a cohort of eyes with regular keratometry (42.0-46.9D) by preoperative manifest refractive spherical equivalent and cylinder, age, corrected distance visual acuity and surgical SMILE parameters. The standardized graphs and terms for refractive surgery results were applied to compare the three groups. Changes in higher order aberrations (HOAs) were evaluated on Scheimpflug imaging. In total, 63 eyes (21 each) of 54 patients with a mean refractive spherical equivalent of - 5.21 ± 1.59 D were followed up for a mean of 9.2 ± 6.1 (minimum ≥ 3) months. Mean baseline keratometry was 41.3 ± 0.7D (flat), 45.5 ± 1.0D (regular) and 47.7 ± 0.6D (steep) (p < 0.0001). Compared to the regular group, the flat and the steep cornea group resulted in a non-inferior percentage of eyes within ± 0.50 D of target refraction (p = 0.20), uncorrected distance visual acuity (p = 0.95) and corrected distance visual acuity (p = 0.20). Flat corneas however experienced a stronger induction of spherical aberration (SA) compared to the steep group (p = 0.0005). In conclusion, non-inferior outcomes of SMILE can also be expected in eyes with steep (≥ 47D) or flat (< 42D) preoperative keratometry, while SMILE however induces more SA in eyes with a flat keratometry

Vanishing pachy-choroid in pachychoroid neovasculopathy under long-term anti-vascular endothelial growth factor therapy

BACKGROUND To investigate the diagnostic value of choroidal thickness in the definition of pachychoroid neovasculopathy (PNV), especially in eyes treated with anti-vascular endothelial growth factor (VEGF) therapy. METHODS Twenty-two consecutive eyes of 11 patients with uni- or bilateral PNV were analyzed. Anti-VEGF treatment was correlated with changes in choroidal thickness on enhanced depth imaging optical coherence tomography. RESULTS There were 14 eyes with PNV and 8 non-neovascular partner eyes. Mean age was 64.2 ± 4.0 (range: 60-72), total follow-up was 1.8 ± 0.4 (1-2) years. In PNV eyes, choroidal thickness at baseline was 400 ± 58 (269-485) μm. After two years and 13 anti-VEGF injections on average, a mean reduction of - 39 ± 10 (- 26 to - 56) % to final 241 ± 52 (162-327) μm was observed (p~ 0.13 for all comparisons). A significant correlation of choroidal thinning and anti-VEGF injection rate was observed at year one (r = - 0.79; R2~= 0.63; p~= 0.00073) and two (r = - 0.69; R2~= 0.48; p~= 0.019). While 85.7% of PNV eyes exceeded a pachychoroid threshold of ≥350 μm at baseline, this figure dropped to 21.4% at year one and 0% at year two. CONCLUSION In PNV, choroidal thickness significantly decreases with anti-VEGF therapy, resembling a \textquotedblvanishing pachy-choroid\textquotedbl, and thus does not represent a valid long-term diagnostic criterium, especially when differentiating PNV from nAMD