BACKGROUND: Many different ocular diseases produce a common symptom of macular edema - a leakage of fluid into the retina. In addition to the presence of this structural aberration, functionally, the retina’s capacity to effectively conduct electrochemical signals will be impaired. The impediment can be demonstrated by a decreased electrical response measured via electroretinography (ERG) and visualized as a waveform with quantifiable amplitude. Macular edema and its associated effects on retinal structure and function are resultant of abnormal blood vessel growth, or angiogenesis. The process of angiogenesis involves a pathway of multiple growth factors and signaling molecules, including vascular endothelial growth factor (VEGF). Modern day treatments to help resolve macular edema target VEGF in order to inhibit pathological angiogenesis; two such anti-VEGF medications are aflibercept, or Eylea, and bevacizumab, also known as Avastin. This retrospective cohort study aims to compare the outcomes of patients treated with either Avastin or Eylea, and to observe what structural or functional changes occur in each sample. METHODS: This study included twelve eyes of 8 eligible patients that were injected with intravitreal Avastin for diabetic macular edema (DME), clinically significant macular edema (CSME), proliferative diabetic retinopathy, or non-proliferative diabetic retinopathy (NPDR), and had resolved macular edema. Five eyes of 6 eligible patients that were injected with intravitreal Eylea for NPDR, neovascular age-related macular degeneration (AMD), cystoid macular edema (CME), central retinal vein occlusion (CRVO), or DME, and had resolved edema were also included in the study. Patient data was randomly screened and collected via the MDIntelleSys (MDI) electronic medical record system at Fromer Eye Centers, New York. No personally identifiable information was collected in this study. The parameters used for comparison of the two anti-VEGF medications were the length of treatment, frequency of injection, change in ERG magnitude between subsequent scans, and net change in ERG magnitude between the baseline scan and the most recent scan obtained during the period of the study. The means of each parameter were determined to be the best measure of central tendency to summarize the data. Welch’s t-tests were conducted at a significance level of α= 0.05 between the parameters of each group to determine the significance of the differences in the means obtained. RESULTS: There was no significant difference found between the mean number of injections, time until recovery, change in magnitude, and net change in magnitude for both Avastin-treated patients and those treated with Eylea. CONCLUSION: The results of this study support the conclusion that both aflibercept and bevacizumab are comparably effective anti-VEGF treatments, in both relieving macular edema and restoring function in retinal cells. The similar outcomes observed in each treatment group offer insight into the versatility of anti-VEGF treatment and provide physicians with the flexibility of pursuing alternative medication options for their patients. Further study into the structural and functional effects of various anti-VEGF medications is needed to account for variables such as age, sex, race, or other possibly confounding factors. An inclusion of other quantifiable data such as visual acuity would also benefit this investigation. Furthermore, this study is limited by its focus solely on anti-VEGF medication; this subject of discussion would benefit from an experimental comparison between anti-VEGF treatments and other allopathic interventions. Recent studies have suggested alternatives to anti-VEGF altogether such as intravitreal triamcinolone acetonide and intravitreal steroids like dexamethasone, marketed as Ozurdex.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20975号 / 医博第4321号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 鈴木 茂彦, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

INTRODUÇÃO: A degeneração macular relacionada à idade (DMRI) é a principal causa de perda de visão irreversível e cegueira mundialmente. A perda da visão central interfere nas atividades de vida diária, como o reconhecimento facial, leitura e escrita, direção de veículos automotores e em atividades funcionais e de lazer. Esta perda de visão relaciona-se também com o desencadeamento de quadros de ansiedade e depressão. Este estudo avaliou a qualidade de vida visual em pacientes com degeneração macular relacionada à idade neovascular por meio do questionário de função visual 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). MÉTODOS: Estudo clínico observacional de 87 pacientes de ambos os sexos, com idade >= 50 anos e com o diagnóstico de DMRI neovascular unilateral ou bilateral. Todos os pacientes responderam ao questionário de função visual NEI VFQ- 25 no final do tratamento em regime Tratar e Estender ou PrONTO, com as drogas antiangiogênicas ranibizumabe ou aflibercepte. RESULTADOS: A idade dos pacientes foi a variável que menos influenciou a qualidade de vida visual dos pacientes. O gênero teve uma influência um pouco maior que a idade, no entanto, a lateralidade da doença demonstrou maior influência na qualidade de vida visual, comparada ao gênero e idade dos pacientes e foi significante para oito dos 12 domínios do questionário de função visual NEI VFQ-25. Os pacientes com acometimento bilateral tiveram pontuações mais baixas que os com doença unilateral em todos os domínios do questionário. A acuidade visual corrigida (AVc) foi a variável que apresentou o maior número de domínios com valores significantes e, portanto, foi a variável que mais se correlacionou com a qualidade de vida visual. A AVc do melhor olho (MO) foi significante para a maioria dos domínios relacionados com a visão, ao contrário do pior olho (PO) que não foi significante para nenhum domínio do questionário. CONCLUSÃO: Todas as variáveis testadas afetaram a qualidade de vida visual dos pacientes, onde a lateralidade teve uma maior influência, seguida pela idade e sexo dos pacientes. Na tomada de decisão para o tratamento de pacientes com DMRI neovascular, pelo menos para esta população, a manutenção da AVc do MO >= 0,5 (escala decimal de Snellen) foi essencial para a manutenção de boa qualidade de vida visual, independente da AVc do PO, que não teve efeito significante em nenhum domínio do questionário de função visual NEI VFQ-25 / INTRODUCTION: The neovascular age-related macular degeneration (AMD) is the main cause of irreversible loss of vision and blindness woldwide. The loss of the central visual field interferes on daily activities such as facial recognition, reading and writing, driving as well as functional and leasure activities. This loss of vision may also increases anxiety and depression for this age group. To evaluate the impact of neovascular AMD on the visual quality of life of patients using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). METHODS: This was an observational clinical, with 87 patients of both genders, with age >= 50 years and a clinical diagnosis of unilateral or bilateral neovascular age related macular degeneration. All patients answered the visual functioning questionaire NEI VFQ-25 at the end of the treatment with the Treat and Extend or PrONTO regimen using antiangiogenic drugs ranibizumab or aflibercept. RESULTS: The age of patients was the variable with the lower influence on the quality of life of the patients. Gender had an influence slightly higher then the age, however, the laterality of the disease had the highest influence on the quality of life, compared with age and gender, and was significant for 8 of the 12 domains of the visual functioning questionaire NEI VFQ-25. The patients with bilateral age-related macular degeneration had lower scores than patients with unilateral disease for all domains of the questionaire. Visual acuity was the variable with the higher number of domains with significant values, and therefore the variable with the higher correlation with the quality of life. The visual acuity of the best eye (BE) was significant for most of the vision related domains, in opposition the the visual acuity of the worst eye (WE) which was not significant for any domain of the questionaire. CONCLUSION: All variables tested affected the visual quality of life, where the laterality of the disease had the highest influence, followed by the age and gender of the patients. The decision process for the treatment of patients with neovascular AMD, at least for this population, keeping the visual acuity of the BE >= 0,5 (Snellen\'s decimal scale) was essential to maintain a long term quality of life, despite the visual acuity of the worst eye, that had no significant effect on any domain of the visual functioning quaestionaire NEI VFQ-25

Le VEGF est une cible validée pour le traitement du cancer colorectal métastatique avec le bevacizumab (Avastin) et l’aflibercept (Zaltrap) qui sont approuvés en première ligne et seconde ligne de traitement. Malgré les efforts intenses, il n’existe pas de biomarqueurs prédictifs pour identifier les patients qui pourraient répondre ou non aux therapies anti-VEGF. Récemment, différents sous-groupes de cancers colorectaux ont été identifies se basant sur l’expression de genes, incluant le groupe CMS4, un sous-groupe de phénotype mésenchymateux, angiogénique et de mauvais prognostic. Nous voulons établir si le phenotype mésenchymateux est prédictif pour la réponse aux agents anti-VEGF. Les cellules de cancer colorectal ont été étudiées in vitro et in vivo pour l’expression des marqueurs épithéliaux (E-cadherine, gamma-catenine, cytokeratine 18) et mésenchymateux (vimentine, N-cadherine, fibronectine) par qRT-PCR and western-blot et leur distribution par E-cadherine et beta-catenine pour immunocytochimie. Cinq modèles de cancer colorectal ont été rangés selon un phénotype épithélial prononcé (HT-29 et DLD-1), intermédiaire (HCT-116) à mésenchymateux (HCT-116/5-FU, LS174T) et les capacités d’inhibition de la croissance par le bevacizumab et l’aflibercept ont été établi. La sécrétion de VEGF a été déterminé par ELISA et la densité microvasculaire a été caractérisé par immunohistochimie quantitative. Le phénotype mésenchymateux est associé à une grande densité vasculaire mais pas aux ligands VEGF. Deux modèles de xénogreffes (DLD-1, HCT-116/5-FU) sont sensibles au bevacizumab et à l’aflibercept, deux modèles sont plus sensibles à l’aflibercept qu’au bevacizumab et un modèle est résistant aux deux molécules. L’aflibercept est plus efficace que le bevacizumab sur l’ensemble des modèles. Le phénotype mésenchymateux n’est pas prédictif pour la réponse aux agents ciblant le VEGF, ni positivement, ni négativement. / VEGF is a validated target for treatment of metastatic colorectal cancer (mCRC) with bevacizumab (avastin) and aflibercept (zaltrap) being approved for first and second line treatment, respectively. Despite intense efforts, no predictive biomarkers are available to identify patients likely to respond, or not, to VEGF-targeted therapies. Recently, different subtypes of CRC have been identified based on gene expression analysis including CMS4, a molecular subgroup with a mesenchymal phenotype, prominent angiogenesis and poor prognosis. We here wish to establish if the mesenchymal phenotype is predictive for the response to VEGF-targeted agents. CRC cell lines were examined for expression of epithelial (E-cadherin, gamma-catenin, cytokeratin 18) and mesenchymal (vimentin, N-cadherin, fibronectin) markers in vitro and in vivo by qRT-PCR and Western blot analysis and for the cellular distribution of E-cadherin and beta-catenin by ICC. Five CRC models were selected ranging from pronounced epithelial (HT-29, DLD-1), intermediate (HCT-116) to mesenchymal (HCT-116/5-FU, LS174T) and the tumor growth inhibitory activity of bevacizumab and aflibercept was established. VEGF-secretion was determined by ELISA and the microvascular density was characterized by quantitative IHC analysis. The mesenchymal phenotype was associated with higher microvascular density, but not with the expression of VEGF ligands. Two CRC xenograft models (DLD-1, HCT-116/5-FU) were sensitive to both bevacizumab and aflibercept, two models were more sensitive to aflibercept, compared to bevacizumab (HT-29, HCT-116), and one model (LS174T) was resistant to both agents. Aflibercept was more potent than bevacizumab in all CRC models. The mesenchymal phenotype was not predictive for the response to VEGF-targeted agents, neither positively nor negatively.

INTRODUÇÃO: A degeneração macular relacionada à idade (DMRI) é a principal causa de perda de visão irreversível e cegueira mundialmente. A perda da visão central interfere nas atividades de vida diária, como o reconhecimento facial, leitura e escrita, direção de veículos automotores e em atividades funcionais e de lazer. Esta perda de visão relaciona-se também com o desencadeamento de quadros de ansiedade e depressão. Este estudo avaliou a qualidade de vida visual em pacientes com degeneração macular relacionada à idade neovascular por meio do questionário de função visual 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). MÉTODOS: Estudo clínico observacional de 87 pacientes de ambos os sexos, com idade >= 50 anos e com o diagnóstico de DMRI neovascular unilateral ou bilateral. Todos os pacientes responderam ao questionário de função visual NEI VFQ- 25 no final do tratamento em regime Tratar e Estender ou PrONTO, com as drogas antiangiogênicas ranibizumabe ou aflibercepte. RESULTADOS: A idade dos pacientes foi a variável que menos influenciou a qualidade de vida visual dos pacientes. O gênero teve uma influência um pouco maior que a idade, no entanto, a lateralidade da doença demonstrou maior influência na qualidade de vida visual, comparada ao gênero e idade dos pacientes e foi significante para oito dos 12 domínios do questionário de função visual NEI VFQ-25. Os pacientes com acometimento bilateral tiveram pontuações mais baixas que os com doença unilateral em todos os domínios do questionário. A acuidade visual corrigida (AVc) foi a variável que apresentou o maior número de domínios com valores significantes e, portanto, foi a variável que mais se correlacionou com a qualidade de vida visual. A AVc do melhor olho (MO) foi significante para a maioria dos domínios relacionados com a visão, ao contrário do pior olho (PO) que não foi significante para nenhum domínio do questionário. CONCLUSÃO: Todas as variáveis testadas afetaram a qualidade de vida visual dos pacientes, onde a lateralidade teve uma maior influência, seguida pela idade e sexo dos pacientes. Na tomada de decisão para o tratamento de pacientes com DMRI neovascular, pelo menos para esta população, a manutenção da AVc do MO >= 0,5 (escala decimal de Snellen) foi essencial para a manutenção de boa qualidade de vida visual, independente da AVc do PO, que não teve efeito significante em nenhum domínio do questionário de função visual NEI VFQ-25 / INTRODUCTION: The neovascular age-related macular degeneration (AMD) is the main cause of irreversible loss of vision and blindness woldwide. The loss of the central visual field interferes on daily activities such as facial recognition, reading and writing, driving as well as functional and leasure activities. This loss of vision may also increases anxiety and depression for this age group. To evaluate the impact of neovascular AMD on the visual quality of life of patients using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). METHODS: This was an observational clinical, with 87 patients of both genders, with age >= 50 years and a clinical diagnosis of unilateral or bilateral neovascular age related macular degeneration. All patients answered the visual functioning questionaire NEI VFQ-25 at the end of the treatment with the Treat and Extend or PrONTO regimen using antiangiogenic drugs ranibizumab or aflibercept. RESULTS: The age of patients was the variable with the lower influence on the quality of life of the patients. Gender had an influence slightly higher then the age, however, the laterality of the disease had the highest influence on the quality of life, compared with age and gender, and was significant for 8 of the 12 domains of the visual functioning questionaire NEI VFQ-25. The patients with bilateral age-related macular degeneration had lower scores than patients with unilateral disease for all domains of the questionaire. Visual acuity was the variable with the higher number of domains with significant values, and therefore the variable with the higher correlation with the quality of life. The visual acuity of the best eye (BE) was significant for most of the vision related domains, in opposition the the visual acuity of the worst eye (WE) which was not significant for any domain of the questionaire. CONCLUSION: All variables tested affected the visual quality of life, where the laterality of the disease had the highest influence, followed by the age and gender of the patients. The decision process for the treatment of patients with neovascular AMD, at least for this population, keeping the visual acuity of the BE >= 0,5 (Snellen\'s decimal scale) was essential to maintain a long term quality of life, despite the visual acuity of the worst eye, that had no significant effect on any domain of the visual functioning quaestionaire NEI VFQ-25

Retinale Venenverschlüsse kann man in Astvenenverschlüsse und Zentralvenenverschlüsse unterteilen. Beide Erkrankungen werden primär mit intravitrealen Injektionen behandelt, wie den Anti-VEGF-Antikörpern oder dexametasonhaltigen Implantaten. Ziel dieser Arbeit ist die Evaluation der Therapiewirksamkeit von Anti-VEGF- Injektionen bei Patienten mit geringem Visus von ≤ 0,2 bei Behandlungsbeginn anhand von OCT und Visus von 150 Patienten im Behandlungsverlauf von bis zu zwölf Monaten. Die Gruppe der Patienten mit Baseline-Visus >0,2 stellt dabei die Vergleichsgruppe dar. In der Patientengruppe A mit Visus ≤ 0,2 bei ZVV stellte sich ein Visusanstieg von 0,10 auf 0,20 ± 0,18 nach zwölf Monaten ein. Im Patientenkollektiv B mit Visus >0,2 und ZVV stellte sich eine Visusbesserung von 0,43 auf 0,61 ± 0,27 ein. In der Patientengruppe A mit Visus ≤ 0,2 bei VAV stellte sich ein Visusanstieg von 0,11 auf 0,27 ± 0,07 nach zwölf Monaten ein. Im Patientenkollektiv mit Visus > 0,2 und VAV stellte sich eine Visusbesserung von 0,52 auf 0,68 ± 0,18 ein. Damit ist bei allen Gruppen eine signifikante Visusverbesserung nachweisbar, wobei es ersichtlich ist, dass der bessere initiale Visus auch einen besseren Endvisus determiniert. Bei der Patientengruppe mit Anfangsvisus ≤ 0,2 konnte signifikant eine größere absolute Netzhautdickenabnahme bei stets höherer Netzhautdicke als in der Referenzgruppe nachgewiesen werden.:Inhaltsverzeichnis 1 Einleitung..........................................................................................................................1 1.1 Netzhautanatomie.....................................................................................................1 1.1.1 Blutversorgung der Netzhaut...............................................................................2 1.1.2 Venenverschlüsse der Retina..............................................................................3 1.2 Makulaödem..............................................................................................................7 1.3 Der molekulare Signalweg beim Makulaödem......................................................8 1.4 Diagnostik................................................................................................................10 1.4.1 Symptome.........................................................................................................10 1.4.2 Sehschärfenprüfung..........................................................................................10 1.4.3 .Ophthalmoskopie..............................................................................................11 1.4.4 Bildgebende Diagnostik.....................................................................................12 1.4.4.1 Fluoreszeinangiographie............................................................................12 1.4.4.2 Optische Kohärenz-Tomografie.................................................................13 1.5 Therapie der Venenverschlüsse............................................................................15 1.5.1 Intravitreale Injektionen.....................................................................................15 1.5.1.1 VEGF-Antikörper........................................................................................16 Bevacizumab.....................................................................................................17 Ranibizumab......................................................................................................17 Aflibercept..........................................................................................................17 1.5.1.2 Therapieschemata von intravitrealen Anti-VEGF-Injektionen....................18 1.5.1.3 Kortikosteroide...........................................................................................19 1.5.2 Laserkoagulation...............................................................................................20 Fokale Laserkoagulation....................................................................................20 Periphere Laserkoagulation...............................................................................21 1.6 Prognose.................................................................................................................21 2 Arbeitshypothese und Fragestellung..........................................................................23 3 Materialien und Methoden.............................................................................................24 3.1 Behandlungsablauf................................................................................................24 3.2 Patientenkollektiv und Statistik............................................................................26 4 Ergebnisse......................................................................................................................27 4.1 Patientenkollektiv...................................................................................................27 Demografie des Patientenkollektivs...................................................................30 4.2 Art der Behandlung................................................................................................35 4.3 Laserkoagulation....................................................................................................40 4.4 Patientengruppe Lucentis und ZVV......................................................................41 4.5 Patientengruppe Lucentis und VAV......................................................................49 5 Diskussion......................................................................................................................54 6 Zusammenfassung der Arbeit......................................................................................59

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States in people who are 50 and older. The safety and efficacy of aflibercept for the treatment of late stage neovascular AMD (NAMD) has been demonstrated by clinical trials among several populations; however, it is unclear whether all NAMD patients respond in the same manner as was studied in the clinical trials. The purpose of this study was to examine if populations of patients treated with aflibercept for the treatment of NAMD were significantly different from one another in terms of health characteristics, treatment regimens, and treatment outcomes. The burden of treatment theory was used to guide this study. Data collected from electronic medical records were used to investigate NAMD characteristics 199 patients from 3 private, retinal practices in the United States. Data were analyzed using one-way ANOVA, 2, Spearman's correlation, and point-biserial correlation tests. The results of this study showed the specific retinal practice populations of NAMD patients treated with aflibercept were generally similar with respect to selected health characteristics, treatment regimens, and treatment outcomes. By using the information reported from this research, public health initiatives can be developed that focus on the need for early detection of AMD to capture changes that represent NAMD and move to early treatment for better outcomes. The positive social change that could result from this research is that retinal specialists may gain insight into the use and outcomes of aflibercept treatment.