The Intraocular Cytokine Profile and Therapeutic Response in Persistent Neovascular Age-Related Macular Degeneration

Citation: Rezar-Dreindl S, Sacu S, Eibenberger K, et al. The intraocular cytokine profile and therapeutic response in persistent neovascular agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2016;57:4144-4150. DOI:10.1167/iovs.16-19772 PURPOSE. To investigate the course of inflammatory and angiogenic cytokines in the aqueous humor of patients with persistent/recurrent neovascular age-related macular degeneration (nAMD) under ranibizumab monotherapy (IVM) or ranibizumab plus dexamethasone combination treatment. METHODS. In this 12-month prospective study, 40 eyes with nAMD were treated with either IVM or combined treatment with ranibizumab plus intravitreal dexamethasone implant (IVC). Patients in the IVM group were treated following an ''as needed'' treatment regimen; patients in the IVC group received ranibizumab and a dexamethasone implant at baseline and were retreated with ranibizumab. At baseline and at each time of retreatment aqueous humor samples were taken. RESULTS. Before treatment, levels of macrophage chemoattractant protein (MCP)-1, monokine induced by c interferon (MIG), and lipocalin-2/ neutrophil gelatinase-associated lipocalin (NGAL) were elevated in nAMD patients compared to healthy controls (P ¼ 0.024; P ¼ 0.04; P ¼ 0.01). In contrast, tumor necrosis factor a, IL-12p70, and secreted protein acidic and rich in cysteine (SPARC) concentrations were lower (P ¼ 0.001; P ¼ 0.008; P ¼ 0.03), while vascular endothelial growth factor (VEGF) was not altered (45 6 6/51 6 12 pg/mL nAMD/ control group; P ¼ 0.6). During IVC, levels of VEGF, MIG, platelet-derived growth factor (PDGF)-AA, and transforming growth factor b1 (P ¼ 0.005; P ¼ 0.011; P ¼ 0.008; P ¼ 0.013) were reduced. Ranibizumab monotherapy did not influence the course of any inflammatory/ angiogenic cytokine. Interleukin 6 and PDGF-AA levels correlated with central retinal thickness changes (P ¼ 0.007; P ¼ 0.022). Over the 12-month period visual function was maintained with no significant differences during or between both treatment groups. CONCLUSIONS. Inflammatory proteins are involved in the pathogenesis of chronic macular edema due to AMD and are associated with disease activity. During combined treatment, levels of inflammatory and angiogenic cytokines decreased over a 12-month period with no superiority in functional outcome

Variations in end-of-life care practices in older critically ill patients with COVID-19 in Europe

BACKGROUND: Previous studies reported regional differences in end-of-life care (EoLC) for critically ill patients in Europe. OBJECTIVES: The purpose of this post-hoc analysis of the prospective multi-centre COVIP study was to investigate variations in EoLC practices among older patients in intensive care units during the coronavirus disease 2019 pandemic. METHODS: A total of 3105 critically ill patients aged 70 years and older were enrolled in this study (Central Europe: n = 1573; Northern Europe: n = 821; Southern Europe: n = 711). Generalised estimation equations were used to calculate adjusted odds ratios (aOR) to population averages. Data were adjusted for patient-specific variables (demographic, disease-specific) and health economic data (GDP, health expenditure per capita). The primary outcome was any treatment limitation, and 90-day-mortality was a secondary outcome. RESULTS: The frequency of the primary endpoint (treatment limitation) was highest in Northern Europe (48%), intermediate in Central Europe (39%), and lowest in Southern Europe (24%). The likelihood for treatment limitations was lower in Southern than in Central Europe (aOR 0.39; 95%CI 0.21-0.73; p = 0.004), even after multivariable adjustment, whereas no statistically significant differences were observed between Northern and Central Europe (aOR 0.57; 95%CI 0.27-1.22; p = 0.15). After multivariable adjustment, no statistically relevant mortality differences were found between Northern and Central Europe (aOR 1.29; 95%CI 0.80-2.09; p = 0.30) or between Southern and Central Europe (aOR 1.07; 95%CI 0.66-1.73; p = 0.78). CONCLUSION: This study shows a north-to-south gradient in rates of treatment limitation in Europe, highlighting the heterogeneity of EoLC practices across countries. However, mortality rates were not affected by these results. This article is protected by copyright. All rights reserved.publishersversionepub_ahead_of_prin

A retrospective cohort study comparing differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in European tax-based healthcare systems (THS) versus social health insurance systems.

In Europe, tax-based healthcare systems (THS) and social health insurance systems (SHI) coexist. We examined differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in intensive care units in a THS or SHI. Retrospective cohort study. 2406 (THS n = 886; SHI n = 1520) critically ill ≥ 70 years patients in 129 ICUs. Generalized estimation equations with robust standard errors were chosen to create population average adjusted odds ratios (aOR). Data were adjusted for patient-specific variables, organ support and health economic data. The primary outcome was 30-day-mortality. Numerical differences between SHI and THS in SOFA scores (6 ± 3 vs. 5 ± 3; p = 0.002) were observed, but clinical frailty scores were similar (> 4; 17% vs. 14%; p = 0.09). Higher rates of renal replacement therapy (18% vs. 11%; p < 0.001) were found in SHI (aOR 0.61 95%CI 0.40-0.92; p = 0.02). No differences regarding intubation rates (68% vs. 70%; p = 0.33), vasopressor use (67% vs. 67%; p = 0.90) and 30-day-mortality rates (47% vs. 50%; p = 0.16) were found. Mortality remained similar between both systems after multivariable adjustment and sensitivity analyses. The retrospective character of this study. Baseline risk and mortality rates were similar between SHI and THS. The type of health care system does not appear to have played a role in the intensive care treatment of critically ill patients ≥ 70 years with COVID-19 in Europe

Total thyroidectomy (Tx) versus thionamides (antithyroid drugs) in patients with moderate-to-severe Graves ophthalmopathy a 1-year follow-up : study protocol for a randomized controlled trial

Background Graves disease (GD) is characterized by thyrotoxicosis and goiter and arises through circulating autoantibodies that bind to, and stimulate, the thyroid hormone receptor (TSHR). A temporal relation between the onset of hyperthyroidism and the onset of ophthalmopathy, a common extrathyroidal manifestation, has been demonstrated. Graves ophthalmopathy (GO) is typically characterized by an inflammation and expansion of the extraocular muscles and an increase in retroorbital fat. There are currently three forms of therapies offered for hyperthyroidism caused by Graves disease: antithyroid drugs (ATD) (thionamides), radioiodine ablation (RAI) and thyroidectomy (Tx). To date, there is no clear recommendation on the treatment of Graves disease and GO, mainly due to the individuality of the disease in each patient. The aim of the study is to examine the difference in the outcome of GO in patients with moderate-to-severe GO who receive Tx versus further ATD after suffering their first relapse of GO, or in which GO stays the same following the initial decrease in ATD therapy after 6 months. Methods/Design This prospective randomized clinical trial with observer-blinded analysis will analyze 60 patients with moderate-to-severe GO who receive Tx versus ATD without surgery. Main outcome variables include: muscle index measurements via ultrasound and thyroid antibody levels. Additional outcome variables include: Clinical Activity Score (CAScore), NOSPECS score, superonasal index measurements via ultrasound, and quality of life score. Discussion This study should allow for better therapeutic choices in patients with moderate-to-severe GO. In addition, it should demonstrate whether the outcome of GO in patients with moderate-to-severe GO is better in those who receive early Tx versus further ATD. Furthermore, this study will aim to establish a standard glucocorticoid scheme before and after Tx in patients with moderate-to-severe EO. Trial registration Eudra-CT: 2015003515-38; Medical University of Vienna Protocol Record 1839/2015. Date of Ethics Committee approval: 19 January 2017. Registered on 27 January 2017.(VLID)468223

Comparison of SD-Optical Coherence Tomography Angiography and Indocyanine Green Angiography in Type 1 and 2 Neovascular Age-related Macular Degeneration

Purpose: The purpose of this study is to compare the ability of spectral domain optical coherence tomography angiography (SD-OCTA) and indocyanine green angiography (ICGA) to detect and measure lesion area in patients with type 1 and 2 choroidal neovascularization (CNV). Methods: Types 1 and 2 neovascular AMD (nAMD) were included in this prospective and observational case series. ETDRS best-corrected visual acuity (BCVA), ophthalmic examination with funduscopy, OCTA (AngioVue), fluorescein angiography (FA), ICGA, and OCT (Spectralis) were performed. CNV measurements were done manually by two experienced graders using the systems' innate region selection tools. Results: Forty eyes of 39 consecutive patients with nAMD were included. Mean age was 77 6.4 years, ETDRS BCVA was 67 13 letters, and 11 eyes were treatment naïve. Nineteen CNV lesions were classified as type 1 and 21 as type 2. ICGA was able to identify CNV in all eyes. By contrast, OCTA detected CNV in 95% of type 1 and 86% of type 2 nAMD eyes. Mean overall CNV area (CNV-A) was 2.8 2.7 mm2 in ICGA and 2.1 2.7 mm2 in OCTA. Both lesion types CNV-A appeared significantly smaller in OCTA compared with ICGA (P < 0.01). Bland-Altman plot revealed a mean difference (bias) between OCTA and ICGA CNV-A of 0.76 1.74 mm2. Intraclass correlation coefficient (ICC) for CNV-A was 0.91 and 0.93 for ICGA and OCTA, respectively. ICGA CNV-A in the four OCTA-negative eyes (median 4.7 mm2) was not significantly different from the 36 OCTA-positive eyes (median 1.7 mm2). Conclusions: Type 1 and 2 CNV-A were significantly smaller in OCTA than in ICGA. OCTA was generally less successful in detecting CNV than ICGA in patients who were included into this study based on FA and OCT. However, OCTA detected all type 1 lesions except for one, indicating that the SD-OCTA signal is limited by detection limits of blood flow velocity rather than lesion type. Further efforts are needed pushing the limits of lowest detectable and fastest distinguishable flow until OCTA can deliver realistic qualitative and quantitative imaging of type 1 and 2 CNV for diagnosis and monitoring.(VLID)467265

A retrospective cohort study comparing differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in European tax-based healthcare systems (THS) versus social health insurance systems

In Europe, tax-based healthcare systems (THS) and social health insurance systems (SHI) coexist. We examined differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in intensive care units in a THS or SHI. Retrospective cohort study. 2406 (THS n = 886; SHI n = 1520) critically ill ≥ 70 years patients in 129 ICUs. Generalized estimation equations with robust standard errors were chosen to create population average adjusted odds ratios (aOR). Data were adjusted for patient-specific variables, organ support and health economic data. The primary outcome was 30-day-mortality. Numerical differences between SHI and THS in SOFA scores (6 ± 3 vs. 5 ± 3; p = 0.002) were observed, but clinical frailty scores were similar (> 4; 17% vs. 14%; p = 0.09). Higher rates of renal replacement therapy (18% vs. 11%; p < 0.001) were found in SHI (aOR 0.61 95%CI 0.40–0.92; p = 0.02). No differences regarding intubation rates (68% vs. 70%; p = 0.33), vasopressor use (67% vs. 67%; p = 0.90) and 30-day-mortality rates (47% vs. 50%; p = 0.16) were found. Mortality remained similar between both systems after multivariable adjustment and sensitivity analyses. The retrospective character of this study. Baseline risk and mortality rates were similar between SHI and THS. The type of health care system does not appear to have played a role in the intensive care treatment of critically ill patients ≥ 70 years with COVID-19 in Europe

Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas