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PURPOSE: To evaluate the structural and functional changes in eyes with neovascular age related macular degeneration (nAMD) in a real-world setting, using Treat and Extend protocol (T&E), comparing four antiangiogenic agents. METHODS: Prospective, observational, case series study performed in 131 patients with the exudative form of nAMD. Patients were randomly assigned into four groups according to the antiangiogenic agent. During the first year, all eyes received at least 3 monthly intravitreal injections of antiangiogenic agents, and afterwards, were submitted to the T&E. RESULTS: There was statistically significant difference (p < 0.05) between pre- and post-treatment in the best corrected visual acuity measurements by drug used. Patients who used aflibercept had significantly fewer injections than patients using the other drugs (mean = 9.03). No significant difference was observed between the drugs bevacizumab, ranibizumab and ziv-aflibercept. With regard to biomarkers, patients who used aflibercept and had lower baseline central retinal thickness, absence of hyperreflective foci and no subretinal hyperreflective material had the lowest number of injections. CONCLUSION: Results indicate that over 2 years, Intravitreal aflibercept on T&E provided better visual and anatomical improvements when compared to other drugs used in this study with significantly fewer injections.

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ABSTRACT Purpose: To evaluate early changes after the first antivascular endothelial growth factor injection for macular edema secondary to diabetic retinopathy and retinal vein occlusion and the relationship between longterm outcomes. Methods: The study enrolled patients who received anti-vascular endothelial growth factor injections for treatment-naive macular edema due to retinal vein occlusion and diabetic retinopathy. The central macular thickness was measured at baseline, post-injection day 1, week 2, and month 1, and at the last visit using spectral-domain optical coherence tomography. A good response was defined as a central macular thickness reduction of ≥10% on post-injection day 1. Patients were reassessed at the last visit with regard to treatment response on post-injection day 1 based on the favorable anatomic outcome defined as a central macular thickness <350 µm. Results: In total, 26 (44.8%) patients had macular edema-retinal vein occlusion and 32 (55.2%) had macular edema-diabetic retinopathy. The mean follow-up time was 24.0 (SD 8.5) months. A statistically significant decrease in the central macular thickness was observed in both patients with macular edema-retinal vein occlusion and macular edema-diabetic retinopathy after antivascular endothelial growth factor injection therapy (p<0.001 for both). All patients with macular edema-retinal vein occlusion were good responders at post-injection day 1. All nongood responders at post-injection day 1 belong to the macular edema-diabetic retinopathy group (n=16.50%). The rate of hyperreflective spots was higher in nongood responders than in good responders of the macular edema-diabetic retinopathy group (p=0.03). Of 42 (2.4%) total good responders, one had a central macular thickness >350 µm, whereas 5 (31.2%) of 16 total nongood responders had a central macular thickness >350 µm at the last visit (p=0.003). Conclusion: The longterm anatomical outcomes of macular edema secondary to retinal vein occlusion and diabetic retinopathy may be predicted by treatment response 1 day after antivascular endothelial growth factor injection.

RESUMO Objetivo: Avaliar as alterações precoces após a primeira injeção de anticorpos antifator de crescimento endotelial vascular (anti-VEGF) em casos de edema macular secundário à retinopatia diabética e oclusão da veia da retina e a relação entre essas alterações e o resultado a longo prazo. Métodos: Foram incluídos no estudo pacientes que receberam uma injeção de antifator de crescimento endotelial vascular para edema macular, virgem de tratamento e devido à oclusão da veia retiniana ou a retinopatia diabética. A espessura macular central foi medida no início do tratamento e no 1º dia, 2ª semana e 1º mês após a injeção, bem como na última visita, através de tomografia de coerência óptica de domínio espectral. Definiu-se uma "boa resposta" como uma redução ≥10% na espessura macular central no 1º dia após a injeção. Os pacientes foram reavaliados na última visita com relação à resposta ao tratamento no 1º dia após a injeção, com base em um resultado anatômico favorável, definido como uma espessura macular central <350 µm. Resultado: Foram registrados 26 (44,8%) pacientes com edema macular e oclusão da veia da retina e 32 (55,2%) com edema macular e retinopatia diabética. O tempo médio de acompanhamento foi de 24,0 meses (desvio-padrão de 8,5 meses). Foi observada uma diminuição estatisticamente significativa da espessura macular central após o tratamento antifator de crescimento endotelial vascular tanto em pacientes com edema macular e oclusão da veia retiniana quanto naqueles com edema macular e retinopatia diabética (p<0,001 para ambos). Todos os pacientes com edema macular e oclusão da veia retiniana responderam bem no 1º dia pós-injeção. Todos os que responderam mal no 1º dia pós-injeção pertenciam ao grupo com edema macular e retinopatia diabética (n=16,50%). A presença de manchas hiperrefletivas foi maior nos pacientes que responderam mal do que naqueles que tiveram boa resposta no grupo com edema macular e retinopatia diabética (p=0,03). Um dos 42 (2,4%) pacientes com boa resposta total teve espessura macular central >350 um, enquanto 5 (31,2%) do total de 16 pacientes com resposta ruim apresentaram espessura macular central >350 µm na última visita (p=0,003). Conclusão: O resultado anatômico de longo prazo do edema macular secundário à oclusão da veia retiniana e à retinopatia diabética pode ser previsto pela resposta ao tratamento no 1º dia após a injeção de antifator de crescimento endotelial vascular.

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ABSTRACT Purpose: Intravitreal antiangiogenic therapy is currently the most invasive ophthalmic procedure performed worldwide. This study aimed to describe the clinical and epidemiological profile of patients undergoing intravitreal antiangiogenic therapy in a tertiary referral hospital in Brazil. Methods: This cross-sectional, retrospective, and observational study analyzed medical records of patients who received intravitreal injections of antiangiogenic agents for the treatment of retinal diseases at the ophthalmology outpatient clinic in the Hospital das Clínicas at Unicamp between January and December 2020. Results: The study included 429 patients and 514 eyes. The study population was predominantly male (51.28%), white (80.89%), between 50 and 80 years old (mean age, 60.92 years), had complete or incomplete first-grade education (56.88%), and did not belong to the Regional Health Department of which Campinas is a part (78.55%). Bevacizumab was the most commonly used intravitreal injectable medicine (79.38%), pro re nata was the most commonly used treatment regimen (90.27%), and macular edema was the most prevalent pathology indicative of treatment (60.12%), with diabetes etiology accounting for 48.25%. The average number of injections per patient was 3.83, with the macular neovascularization group and the pro re nata group having the highest and lowest with five and three injections, respectively. Treatment adherence was associated with the patient's pathology, and the macular edema (52.24%) and macular neovascularization (49.48%) groups had the lowest adherence rates. Conclusions: This study evaluated the epidemiological and clinical profile of patients undergoing antiangiogenic therapy in a high-complexity public hospital, which is fundamental for a better understanding of the demand for ophthalmic reference service in Brazil, and the analysis of functional results and user adherence profile promotes optimization of indications and leverages the benefits of intravitreal therapy.

RESUMO Objetivo: A terapia antiangiogênica intravítrea revolucionou o tratamento de inúmeras patologias de relevância global, sendo atualmente o procedimento oftalmológico invasivo mais realizado no mundo. Objetiva-se no presente estudo descrever o perfil clínico e epidemiológico dos pacientes submetidos a terapia intravítrea com antiangiogênicos em hospital terciário de referência no Brasil. Métodos: Trata-se de um estudo transversal, retrospectivo e observacional que foi realizado através da análise de prontuários de pacientes submetidos a injeção intravítrea de antiangiogênicos para tratamento de doenças retinianas no ambulatório de oftalmologia do Hospital das Clínicas da Unicamp no período de janeiro a dezembro de 2020. Resultados: O estudo analisou 429 pacientes e 514 olhos. A maioria pertencia ao sexo masculino (51,28%), raça branca (80,89%), possuía entre 50-80 anos com idade média de 60,92 anos e escolaridade de 1º grau completo ou incompleto (56,88%) e não pertenciam (78,55%) a área de abrangência do Departamento Regional de Saúde do qual Campinas faz parte. O fármaco mais utilizado nas injeções intravítreas foi o bevacizumabe (79,38%), o principal regime de tratamento foi o pro re nata (90,27%) e a principal grupo de patologia indicativa de tratamento foi o edema macular (60,12%), sendo 48,25% desses de etiologia diabética. A média de injeções foi de 3,83/paciente, sendo o grupo de neovascularização macular o de maior mediana com 5 injeções/paciente e o esquema pro re nata o regime de tratamento com menor mediana, 3 injeções/paciente. A adesão ao tratamento associou-se a patologia do paciente, sendo as menores taxas de adesão as dos grupos com edema macular (52,24%) e neovascularização macular (49,48%). Conclusões: O presente estudo avaliou o perfil epidemiológico e clínico dos pacientes submetidos a terapia antiangiogênica em hospital público de alta complexidade, o que é fundamental para melhor conhecimento da demanda de serviço oftalmológico de referência no Brasil e possibilita, a partir da análise dos resultados funcionais e perfil de adesão dos usuários, otimizar as indicações e alavancar os benefícios de terapia intravítrea.

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ABSTRACT Purpose: To evaluate the effectiveness of in­­­travitreal bevacizumab injections following a single dexamethasone implant in the treatment of macular edema secondary to branch and central retinal vein occlusion. Methods: This was a prospective interventional non-comparative study, 44 eyes of patients with naïve macular edema related to branch and central retinal vein occlusion were treated with a dexamethasone implant. Patients were followed-up at four-week intervals from the second to the sixth month. If persistent or recurrent macular edema occurred during this period, the patient was treated with intravitreal bevacizumab injections on an as-needed basis. The outcome measures were best-corrected visual acuity and central macular thickness changes. Results: The mean best-corrected visual acuity changed from 0.97 ± 0.33 LogMAR at baseline to 0.54 ± 0.40 at the six-month post-implant examination (p<0.00001). Improvement ≥3 Snellen lines were seen in 20 eyes (45.54%). The mean central macular thickness at baseline was 670.25 ± 209.9 microns. This had decreased to 317.43 ± 112.68 microns at the six-month follow-up (p<0.00001). The mean number of intravitreal bevacizumab injections received in the six months post-implant was 2.32. The mean time from dexamethasone implant to first anti-VEGF injection was 3.45 months. Conclusions: Intravitreal bevacizumab injections following a single dexamethasone implant were found to improve best-corrected visual acuity and central macular thickness in patients with macular edema due to branch and central retinal vein occlusion at six months, with few intravitreal injections required.

RESUMO Objetivo: Avaliar a eficácia da combinação de in­jeções intravítreas de bevacizumabe em olhos com edema macular secundário à oclusão de ramo e da veia central da retina após um único implante de dexametasona. Métodos: Foi realizado um estudo prospectivo intervencionista não comparativo com 44 olhos de pacientes com edema macular relacionado à oclusão de ramo e veia central da retina, sem tratamento prévio e tratados com um único implante de dexametasona, que foram acompanhados em intervalos de quatro semanas do segundo ao sexto mês. Se fosse constatado edema macular persistente ou recorrente durante esse período, os pacientes eram tratados com injeções intravítreas de bevacizumabe em um regime ajustado conforme a necessidade. Foram estudadas a melhor acuidade visual corrigida e alterações da espessura macular central. Resultados: A média da melhor acuidade visual corrigida mudou de 0,97 ± 0,33 LogMAR iniciais para 0,54 ± 0,40 no exame de 6 meses (p<0,00001). Vinte olhos (45,54%) melhoraram 3 linhas de Snellen ou mais. A média da espessura macular central inicial foi de 670,25 ± 209,9 μm e diminuiu para 317,43 ± 112,68 μm na visita de 6 meses (p<0,00001). O número médio de injeções intravítreas de bevacizumabe em 6 meses foi de 2,32 e o tempo médio entre o implante de dexametasona e a primeira injeção de anti-VEGF foi de 3,45 meses. Conclusão: Injeções intravítreas de bevacizumabe após um único implante de dexametasona podem proporcionar um aumento da melhor acuidade visual corrigida e diminuição da espessura macular central aos 6 meses em pacientes com edema macular devido à oclusão de ramo e da veia central da retina, com poucas injeções intravítreas.

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Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and ß2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 µg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 µM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 µM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and ß2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.

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PURPOSE: The purpose of this study was to measure the anti-angiogenic effect of N-desulfated Re-N-acetylated, a chemically modified heparin (mHep). METHODS: In vitro assays (cell tube formation, viability, proliferation, and migration) with endothelial cells were performed after 24 h of treatment with mHep at 10, 100, and 1000 ng/mL or saline. In vivo tests were performed after laser-induced choroidal neovascularization (CNV) in rats, followed by an intravitreal injection (5 µL) of mHep (10, 100, 1000 ng/mL) or balanced salt solution. Immunofluorescence analysis of the CNV was performed after 14 days. RESULTS: mHep produced a statistically significant reduction in cell proliferation, tube formation, and migration, without cell viability changes when compared to saline. Mean measures of CNV area were 54.84 × 106 pixels/mm (± 12.41 × 106), 58.77 × 106 pixels/mm (± 17.52 × 106), and 59.42 × 106 pixels/mm (± 17.33 × 106) in groups 100, 1000, and 10,000 ng/mL, respectively, while in the control group, mean area was 72.23 × 106 (± 16.51 × 106). The P value was 0.0065. Perimeter analysis also demonstrated statistical significance (P = 0.0235) with the mean measure of 93.55 × 104, 94.23 × 104, and 102 × 104 in the 100 ng/mL, 1000 ng/mL, and control groups, respectively. CONCLUSIONS: These results suggest that mHep N-DRN is a potent anti-angiogenic, anti-proliferative, and anti-migratory compound with negligible anticoagulant or hemorrhagic action and no cytotoxicity for retina cells. This compound may serve as a candidate for treating choroidal neovascularization.

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O objetivo foi avaliar o nível de conhecimento dos discentes do último ano do curso de odontologia da Universidade de Pernambuco, acerca da etiológia e manejo da osteonecrose dos maxilares. Metodologia: Trata-se de um estudo transversal realizado com os alunos do 9° e 10° períodos, onde 45 alunos responderam voluntariamente, após firmarem o aceite do termo de Consentimento Livre e Esclarecido, questionário estruturado mediante informações básicas sobre drogas antirreabsortivas e antiangiogênicas, além do manejo de pacientes com osteonecrose dos maxilares. Resultados: Dos 45 discentes que aceitaram responder o questionário 22 (48,8%) eram do 9° período e 23 (51,11%) do 10° período; 82% relataram que não aprenderam sobre medicamentos antirreabsortivos e antiangiogênicos; 84,4% tiveram informações sobre a osteonecrose durante a formação acadêmica. Em relação à possibilidade terapêutica 43,6% indicaram o tratamento cirúrgico (desbridamento); 20,5% laser de baixa intensidade e antibiótico; 12,8% ressecção cirúrgica; 10,3% laser de baixa intensidade; 7,7% oxigenação hiperbárica; (5,12%) infusão de PRP (plasma rico em plaquetas). Conclusão: O atual padrão de conhecimento passado sobre a etiologia e manejo da osteonecrose dos maxilares, induzida por fármacos, não está dando o suporte necessário para a tomada de decisão ao término do processo formal de ensino e aprendizagem no curso de odontologia... (AU)

The objective was to evaluate the level of knowledge of the final-year dental students of the Universidade de Pernambuco about the etiology and management of osteonecrosis of the jaws. Methodology: This is a cross-sectional study carried out with students from the 9th and 10th periods. Informed Consent, a structured questionnaire with basic information about antiresorptive and antiangiogenic drugs, besides the management of patients with osteonecrosis of the jaws. Results: Of the 45 students who agreed to answer the questionnaire, 22 (48.8%) were from the 9th period and 23 (51.11%) from the 10th period; 82% reported that they did not learn about antiresorptive and antiangiogenic drugs; 84.4% had information about osteonecrosis during their academic training. Regarding the therapeutic possibility 43.6% indicated surgical treatment (debridement); 20.5% low intensity laser and antibiotic; 12.8% surgical resection; 10.3% low intensity laser; 7.7% hyperbaric oxygenation; (5.12%) infusion of PRP (platelet rich plasma). Conclusion: The current pattern of past knowledge on the etiology and management of drug-induced osteonecrosis of the jaws is not providing the necessary support for decision making at the end of the formal teaching and learning process in the dental course... (AU)

El objetivo es evaluar el nivel de conocimiento de los estudiantes del último año del curso de odontología de la Universidad de Pernambuco, sobre la etiología y el manejo de la osteonecrosis de los maxilares. Metodología: Se trata de un estudio transversal realizado con los estudiantes de los periodos 9° y 10°, en el que 45 estudiantes respondieron voluntariamente, tras firmar el término de Consentimiento Livre y Esclarecido, a un cuestionario estructurado mediante información básica sobre drogas antirreabsortivas y antiangiogénicas, además del manejo de pacientes con osteonecrosis de los maxilares. Resultados: De los 45 estudiantes que accedieron a contestar el cuestionario, 22 (48,8%) eran del 9º periodo y 23 (51,11%) del 10º periodo; el 82% informó de que no había aprendido sobre los fármacos antirresortivos y antiangiogénicos; el 84,4% tuvo información sobre la osteonecrosis durante su formación académica. En cuanto a la posibilidad terapéutica, el 43,6% indicó tratamiento quirúrgico (desbridamiento); el 20,5%, láser de baja intensidad y antibiótico; el 12,8%, resección quirúrgica; el 10,3%, láser de baja intensidad; el 7,7%, oxigenación hiperbárica; el 5,12%, infusión de PRP (plasma rico en plaquetas). Conclusión: El modelo actual de conocimientos previos sobre la etiología y el tratamiento de la osteonecrosis de los maxilares inducida por fármacos no está proporcionando el apoyo necesario para la toma de decisiones al final del proceso formal de enseñanza y aprendizaje en el curso de odontologia... (AU)

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INTRODUCTION: Despite the use of multimodality therapy, locally advanced rectal cancer (LARC) still presents high rates of disease recurrence. Fluoropyrimidine-based chemotherapy concurrently with radiation therapy (RT) remains the cornerstone of neoadjuvant therapy of LARC, and novel therapies are urgently needed in order to improve the clinical outcomes. AREAS COVERED: We aim to summarize data from completed and ongoing clinical trials addressing the role of biological therapies, including monoclonal antibodies, immune checkpoint inhibitors (ICIs), antibody-drug conjugates, bispecific antibodies, and gene therapies in the systemic therapy of rectal cancer. EXPERT OPINION: Deeper understanding of the molecular biology of colorectal cancer (CRC) has allowed meaningful advances in the systemic therapy of metastatic disease in the past few years. The larger applicability of biological therapy in CRC, including genome-guided targeted therapy, antiangiogenics, and immunotherapy, gives us optimism for the personalized management of rectal cancer. Microsatellite instability (MSI) tumors have demonstrated high sensitivity to ICIs, and preliminary findings in the neoadjuvant setting of rectal cancer are promising. To date, antiangiogenic and anti-EGFR therapies in LARC have not demonstrated the same benefit seen in metastatic disease. The outstanding results accomplished by biomarker-guided therapy in metastatic CRC will guide future developments of biological therapy in LARC.

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La osteonecrosis de los maxilares (ONM) secundaria al consumo de medicamentos antirresortivos y antiangiogénicos es una patología oral que afecta el funcionamiento del organismo de los seres humanos no sólo a nivel bucal, sino que disminuye su calidad de vida y aumenta su morbilidad. La ONM se define como la presencia de hueso necrótico expuesto que puede ser explorado mediante una fístula en el territorio maxilofacial, que se mantiene durante un periodo mínimo de ocho se- manas. Los fármacos antirresortivos y antiangiogénicos son indicados a pacientes que presentan patologías osteometabólicas, cáncer, entre otras, de ahí la importancia de mantener una estrecha relación entre médico tratante-odontólogo-paciente. El propósito de este artículo es establecer un protocolo de cuidado oral básico y definir las funciones del médico tratante, cirujano dentista y cirujano maxilofacial mediante una revisión bibliográfica con el fin de crear una propuesta preventiva para el tratamiento de estos pacientes (AU)

Medication-related osteonecrosis of the jaw (MRONJ), secondary to the consumption of antiresorptive and antiangiogenic drugs is an oral pathology that affects the functioning of the human body, not only at the oral level, but also decreasing their quality of life and increasing their morbidity. MRONJ is defined as the presence of exposed necrotic bone that can be explored through a fistula in the maxillofacial territory, which is maintained for a minimum period of eight weeks. Antiresorptive and antiangiogenic drugs are indicated for patients with osteometabolic pathologies, cancer, among others. For the same reasons, the importance of maintaining a close relationship between the treating physician, dentist and patient. The purpose of this article is to establish a clinical guide for basic oral care and define the functions of the treating physician, dental surgeon and maxillofacial surgeon through a bibliographic review; in order to create a preventive proposal for the treatment of these patients (AU)

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ABSTRACT Purpose: This study was conducted to evaluate visual function and changes in the central macular thickness of patients with unresponsive neovascular age-related macular degeneration who were switched from ranibizumab (Lucentis®) to aflibercept (Eylea®) treatment at 30 months. Methods: This retrospective study examined patients with neovascular age-related macular degeneration who were switched to aflibercept after ≥6 previous intravitreal ranibizumab injections at 4- to 8-week intervals. All patients were switched to intravitreal aflibercept (2.0 mg) and analyzed after 3 consecutive injections followed by a prore nata dosing regimen and after 30 months of treatment. Best corrected visual acuity, biomicroscopic examination, intraocular pressure, fundus examination, and central macular thickness were recorded at the start of treatment, before the transition to intravitreal aflibercept treatment, and at 6, 12, 18, 24, and 30 months of intravitreal aflibercept treatment. Results: A total of 33 eyes met the inclusion criteria. The median age of the patients was 73.57 ± 7.98 years, and 21 (61.8%) patients were males and 12 (35.3%) were females. Before the transition, the patients received a mean of 16.8 ± 8.8 ranibizumab injections (range 6-38).After the transition to intravitreal aflibercept treatment, the mean number of aflibercept injections was 9.09 ± 3.94. No significant differences were observed in best corrected visual acuity after the aflibercept switch in any of the months. The central macular thickness was significantly decreased at 6, 12, 18, and 30 months (p=0.01, p=0.03, p=0.05, p=0.05, p<0.001, respectively). Conclusion: Patients with neovascular age-related macular degeneration who were switched to intravitreal aflibercept treatment due to unresponsiveness to intravitreal ranibizumab exhibited a significant anatomic improvement in the retina, and although this state persisted, there was no significant functional gain.(AU)

RESUMO Objetivo: Avaliar, depois de 30 meses, a função visual e as alterações na espessura macular central de pacientes com degeneração macular relacionada à idade sem resposta terapêutica ao ranibizumabe (Lucentis®) que mudaram seu tratamento para o aflibercepte (Eylea®). Métodos: Realizou-se um estudo retrospectivo de pacientes com degeneração macular neovascular relacionada à idade que mudaram o tratamento para o aflibercepte após 6 ou mais injeções intravítreas de ranibizumabe a intervalos de 4-8 semanas. Todos os pacientes mudaram para o aflibercepte intravítreo (2,0 mg) e depois de 3 injeções consecutivas, seguidas de um regime de dosagem pro re nata, foram avaliados após 30 meses de tratamento. A melhor acuidade visual corrigida, o exame biomicroscópico, a pressão intraocular, a fundoscopia e a espessura macular central foram registrados no início do tratamento, antes da transição para o tratamento com aflibercepte intravítreo e aos 6, 12, 18, 24 e 30 meses de tratamento com o aflibercepte intravítreo. Resultados: Satisfizeram aos critérios de inclusão 33 olhos. A mediana da idade dos pacientes foi de 73,57 ± 7,98 anos. Dos pacientes, 21 (61,8%) eram homens e 12 (35,3%) eram mulheres. Antes da transição para o tratamento com o aflibercepte intravítreo, os pacientes receberam em média 16,8 ± 8,8 injeções de ranibizumabe (faixa 6-38).Depois da transição, o número médio de injeções de aflibercepte foi de 9,09 ± 3,94. Não houve diferenças significativas na melhor acuidade visual corrigida depois da mudança para o aflibercepte em qualquer das avaliações. Houve diminuição significativa da espessura macular central aos 6, 12, 18 e 30 meses (respectivamente, p=0,01, p=0,03, p=0,05, p=0,05 e p<0,001). Conclusão: Pacientes com degeneração macular neovascular relacionada à idade que mudaram seu tratamento para o aflibercepte intravítreo devido à falta de resposta ao ranibizumabe intravítreo, tiveram melhora anatômica significativa da retina; mas embora esse estado tenha persistido, não foi observado nenhum ganho funcional significativo.(AU)

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Squamous cell carcinoma of the anal canal (SCCA) is an HPV-related malignancy with rising incidence in the past few decades in the US, characterized by high rates of complete response to chemoradiotherapy with curative intent. However, in a long-term follow-up, a meaningful subgroup of patients with locally advanced disease presents disease recurrence, which demands treatments with high morbidity and important impact in the quality of life. In metastatic or unresectable disease, palliative chemotherapy is the standard of care, but it is still associated with a dismal prognosis. Novel agents are urgently needed in the systemic therapy of SCCA. From a translational standpoint, there are many hurdles to overcome, since PI3KCA mutation is the most frequent genetic abnormality and actionable mutations are rarely found in SCCA, as well as it is characterized by low tumor mutational burden and low rates of high-frequency microsatellite instability. But the latest studies of immunotherapeutic approaches have produced promising findings and this therapeutic strategy is the major path being followed in the ongoing clinical trials. The latest advances in the systemic therapy of SCCA have provided the framework for the conception of new clinical trials. Therefore, carboplatin plus paclitaxel have become the backbone for novel agents. Immune checkpoint inhibitors (ICIs), mainly anti-PD-1 monoclonal antibodies, such as retifanlimab, nivolumab, and atezolizumab have been studied in Phase III trials with chemotherapy in first-line therapy. Likewise, ICIs have been evaluated in locally advanced and refractory disease. Novel technologies, such as bispecific antibodies, and immunotherapeutic approaches, such as vaccines and adoptive T-cell therapies, have also been tested in ongoing clinical trials. Immunotherapy may bring practice-changing advances in the systemic therapy of SCCA in the next few years and it might play a larger role in the therapeutic management of this challenging disease.

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ABSTRACT Age-related macular degeneration is the leading cause of vision loss in elderly individuals, as well as a medical and socio-economic challenge. The treatment of dry age-related macular degeneration is based on vitamin supplementation. New treatment studies are focused on preventing the progression of degeneration and repopulating the atrophic macula. Recently, research on the treatment of neovascular age-related macular degeneration experienced a breakthrough with the advent of anti-vascular endothelial growth factor inhibitors. Nevertheless, despite the fact that ranibizumab, aflibercept, and bevacizumab are effective in reducing severe visual impairment, patients usually lose some vision over time. Therefore, the search for new therapies and diagnostic methods is fundamentally important. Current studies are focused on new anti-vascular endothelial growth factor drugs, nucleoside reverse transcriptase inhibitors, antibody against sphingosine-1-phosphate, anti-platelet-derived growth factor, gene therapy, and RNA interference. The results of ongoing clinical studies may improve the therapy of age-related macular degeneration.

RESUMO Degeneração macular relacionada à idade (DMRI) é a principal causa de perda de visão em pessoas idosas. É também um desafio médico e socioeconômico. O tratamento da degeneração macular relacionada à idade seca baseia-se na suplementação vitamínica. Novos tratamentos estão focados na prevenção da progressão da degeneração e tentativas de repovoar a mácula atrófica. A degeneração macular relacionada à idade neovascular experimentou um grande avanço com o advento dos inibidores do fator de crescimento endotelial anti-vascular (anti-VEGF); no entanto, apesar do ranibizumab, aflibercept e bevacizumab serem eficazes na redução do comprometimento visual grave, os pacientes geralmente per­dem visão ao longo do tempo. Portanto, a busca por novas terapias, tratamentos e diagnósticos é de fundamental importância. Os estudos estão focados em novos fármacos sobre fator de crescimento endotelial anti-vascular, inibidores nucleosideos da transcriptase reversa, anticorpos contra esfingosina-1-fosfato, fator de crescimento derivado de plaquetas, terapia genética e RNA de interferência. A terapia para degeneração macular relacionada à idade está prestes a melhorar como resultado desses estudos clínicos em andamento.

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ABSTRACT Purpose: To compare visual acuity, macular thickness, and the area of active neovascularization based on fluorescein angiography outcomes associated with standard single-spot panretinal photocoagulation in the Early Treatment Diabetic Retinopathy Study (ETDRS) pattern combined with intravitreal ranibizumab injection versus multiple-spot full scatter (PASCAL) panretinal photocoagulation combined with intravitreal ranibizumab injection versus intravitreal injection alone in patients with proliferative diabetic retinopathy. Methods: Patients with proliferative diabetic retinopathy and no prior laser treatment were randomly assigned to receive three different types of treatment. Panretinal photocoagulation in the ETDRS group was administered in two sessions (weeks 0 and 2), and panretinal photocoagulation in the PASCAL group was administered in one session (week 0). Intravitreal injection of ranibizumab was administered at the end of the first laser session in both the ETDRS and PASCAL groups and at week 0 in the intravitreal injection group. Comprehensive ophthalmic evaluations were performed at baseline and every 4 weeks through week 48. Results: Thirty patients (n=40 eyes) completed the 48-week study period. After treatment, best-corrected visual acuity was significantly (p<0.05) improved at all follow-up visits in the group receiving intravitreal injection alone, at all but week 4 in the ETDRS group, and at all but weeks 4 and 8 for the PASCAL group. A significant decrease in central subfield macular thickness was observed in the PASCAL group at weeks 4, 8, and 48; only at week 48 in the intravitreal injection group; and never in the ETDRS group. There was no significant difference among the three treatment groups with respect to change from baseline to week 48 in best-corrected visual acuity, central subfield macular thickness, or fluorescein leakage from active neovascularization in best-corrected visual acuity, central subfield macular thickness, or fluorescein leakage from active neovascularization. Conclusions: Intravitreal injection alone or combined with single- or multiple-spot panretinal photocoagulation yielded similar outcomes with respect to mean change in best-corrected visual acuity, central subfield macular thickness, and fluorescein leakage from active neovascularization at up to one-year of follow-up. All subjects provided written informed consent to participate (NCT02005432 in clinicaltrials.gov).

RESUMO Objetivo: Comparar as medidas de acuidade visual, espessura macular central e área de neovasos ativos na an­giofluoresceinografia submetidos a panfotocoagulação retiniana padrão ETDRS associado a injeção intravítrea de ranibizumabe versus panfotocoagulação padrão PASCAL associado a injeção intravítrea de ranibizumabe versus somente injeção intravítrea de ranibizumabe em pacientes com retinopatia diabética pro­liferativa. Métodos: Pacientes com retinopatia diabética proliferativa e virgens de tratamento, randomicamente divididos nas três diferentes terapias retinianas. Panfotocoagulação no grupo ETDRS em 2 sessões (semanas 0 e 2) e no grupo PASCAL, na semana 0. Injeção intravítrea de ranibizumabe realizado ao fim da primeira sessão de laser em ambos os grupos: ETDRS e PASCAL, e na semana 0 no grupo injeção intravítrea de ranibizumabe. Avaliações oftalmológicas, tomografia de coerência óptica e angiofluoesceinografia realizados na visita basal e a cada 4 semanas por 48 semanas. Resultados: Trinta pacientes (n=40 olhos) completaram as 48 semanas de seguimento. Após o tratamento, a acuidade visual melhorou significantemente em todas a visitas no grupo injeção intravítrea de ranibizumabe (p<0,05); em todas exceto na semana 4 no grupo ETDRS, em todas exceto nas semanas 4 e 8 no grupo PASCAL. Redução significativa na espessura do subcampo central foi evidenciada no grupo PASCAL nas semanas 4, 8 e 48; somente na semana 48 no grupo injeção intravítrea de ranibizumabe, e em nenhuma visita no grupo ETDRS. Redução também na área de neovasos ativos em todas as visitas em todos os grupos. Não houve diferença significante entre os três grupos com relação a mudança media na medidas de acuidade visual, espessura macular central ou área de neovasos ativos da visita inicial para a semana 48. Conclusões: Somente IVB ou este associado a panfotocoagulação ETDRS ou PASCAL, apresentaram efeitos semelhantes em relação a medidas de acuidade visual, espessura do subcampo central e área de neovasos ativos no decorrer de 48 semanas de seguimento.

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ABSTRACT BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is still the most prevalent type of osteonecrosis with clinical relevance. In Brazil, bisphosphonate use is high but there is a lack of epidemiological studies on BRONJ. OBJECTIVE: To determine the clinical profile of BRONJ in a Brazilian population through an integrative review. DESIGN AND SETTING: Integrative review of BRONJ in a Brazilian population. METHODS: Cases and clinical research on Brazilians with BRONJ between 2010 and 2019, indexed in PubMed/MEDLINE, Scopus, Web of Science and LILACS were reviewed. Age, sex, type and time of bisphosphonate intake, administration route, related diseases, region of the BRONJ, diagnostic criteria, staging, triggering factor and type of treatment were analyzed. RESULTS: Fifteen articles on 128 subjects were included. Most patients were women (82.03%); the mean age was 63 years. Intravenous zoledronic acid was mostly used (62.50%), for breast cancer treatment (46.87%). The main localization of BRONJ was the mandible (54.68%), associated mainly with tooth extractions (45.98%). The diagnostic criteria were clinical (100%) and radiographic (89.06%), mostly in stage II (68.08%). The surgical treatments were sequestrectomy (37.50%) and platelet-rich plasma (PRP) (36.71%). Microbial control was done using chlorhexidine (93.75%) and infection control using clindamycin (53.90%). CONCLUSIONS: BRONJ had higher prevalence in Brazilian women receiving treatment for breast cancer and osteoporosis. The mandible was the region most affected with a moderate stage of BRONJ, particularly when there were histories of tooth extraction and peri-implant surgery. Sequestrectomy with additional drugs and surgical therapy was the treatment most accomplished.

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Medication-related osteonecrosis of the jaw is a disease where there is necrotic bone exposed or that can be explored by means of a fistula in the maxillofacial region. It has been associated with the use Biphosphonates and denosumab for osteoporosis. Although its etiology is unclear, it may be related to a decrease in bone turnover produced by these drugs, rendering the bone more prone to generate cell necrosis during invasive dental procedures, especially in the posterior region of the jaw. There is no consensus about the prevention and treatment of this condition. The aim of this paper is to present a review of the literature with the main characteristics of osteonecrosis of the jaws associated with drugs, together with a proposal for prevention and treatment for these patients.

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To report a treatment of radiation retinopathy in a patient exposed to ionizing radiation for a period of 2 years. A 26-year-old female patient with no comorbidities diagnosed with myelodysplasia confirmed by bone marrow biopsy. She presented a complaint of bilateral progressive visual acuity reduction. At the ophthalmologic examination, she presented alterations suggestive of radiation retinopathy as well as macular thickness to optical coherence tomography (OCT) of over 500 µm. The patient underwent intravitreal injection (0.05 mL) of ranibizumab (Lucentis®) monthly in both eyes and follow-up through visual acuity and OCT examination. She presented reduction of macular edema as well as a slight improvement of visual acuity. In this case, the treatment of radiation retinopathy with intravitreal injection of ranibizumab (Lucentis) was relatively useful, with a slight improvement of visual acuity, due to the regression of macular edema, not being curative.

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BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is characterized by the development of bone necrosis in the jaws of patients receiving antiresorptive and/or antiangiogenic medications. No scientific reports have been published yet on bevacizumab-related osteonecrosis of the jaw (BeRONJ) when associated with dental implant placement and adjuvant ozone therapy. CASE PRESENTATION: A 54-year-old female patient with a history of metastatic breast cancer and bevacizumab use presented with a dental infection. Dental extraction followed immediately by dental implant placement was planned after suspension of the bevacizumab treatment. The patient presented with pain, drainage of purulent secretion, and bone exposure 5 weeks post-surgery. Complete healing was achieved at postoperative 7 months. CONCLUSIONS: The combination of adjuvant ozone therapy and surgical debridement was effective for the treatment of MRONJ; however, the risk of MRONJ may persist after the suspension of bevacizumab for 28 days.

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BACKGROUND: Anti-angiogenic regulators may have therapeutic implications for onset and progression of atherosclerosis. OBJECTIVES: To demonstrate histological changes secondary to the use of bevacizumab in the aorta of pigs after interruption of flow in the vasa vasorum. METHODS: Twelve pigs were divided into two groups. The intercostal arteries of the descending aorta were dissected and ligated and wrapped with a polyvinyl chloride membrane. The treatment group received an intravenous dose of bevacizumab. After 15 days, the animals were euthanized and the aorta removed. Histological slides were prepared for control and treatment groups and for non-manipulated areas and analyzed for degree of angiogenesis, injury, inflammation, and intimal thickening. Data were expressed as mean (SD) of scores and groups were compared using the Mann-Whitney test. The Poisson distribution was used to calculate 95% confidence intervals for mean scores, in order to determine effect statistics. RESULTS: Bevacizumab had adverse effects on all treated pigs. The analysis using a Scale of Magnitudes for Effect Statistics showed a trend toward a decrease in angiogenesis [0.58 (1.79/-0.63)] and injury [0.55 (1.76/-0.66)] and an increase in inflammation [0.67 (1.89/-0.55)] with threshold moderate effects. There was no difference in intimal thickening [0 (1.19/-1.19)]. CONCLUSIONS: The medication exhibited a trend toward reduced angiogenesis and injury, but no reduction in the inflammatory process or intimal thickening of the aortic wall. These findings are in disagreement with studies that correlate neovascularization with increased migration of inflammatory cells. Bevacizumab exhibited toxicity in the porcine model.

CONTEXTO: Agentes antiangiogênicos podem ter implicações terapêuticas na progressão e manifestação da aterosclerose. OBJETIVOS: Demonstrar a alteração histológica secundária ao uso de bevacizumabe na aorta descendente de suínos submetida à interrupção dos vasa vasorum. MÉTODOS: Em doze suínos, divididos em dois grupos, foi realizada dissecção da aorta torácica, além de ligadura das artérias intercostais e proteção com polivinil. O grupo tratamento recebeu dose endovenosa de bevacizumabe. Após 15 dias, os animais foram sacrificados para retirada da artéria e preparo das lâminas histológicas dos grupos tratamento, controle e áreas não manipuladas para análise quanto aos graus de angiogênese, injúria, inflamação e espessamento intimal. A análise estatística foi conduzida através da média e do desvio padrão dos escores. As comparações entre os grupos foram realizadas pelo teste de Mann-Whitney. A distribuição de Poisson calculou os intervalos de confiança de 95% para as médias, a fim de determinar o efeito estatístico. RESULTADOS: O bevacizumabe causou efeitos adversos em todos os suínos tratados. As variáveis analisadas através da Escala de Magnitude para Efeito Estatístico demonstraram tendência de redução da angiogênese [0,58 (1,79/-0,63)] e da injúria [0,55 (1,76/-0,66)] e aumento da inflamação [0,67 (1,89/-0,55)] no limite do moderado. Não ocorreu diferença no espessamento intimal [0 (1,19/-1,19)]. CONCLUSÕES: A medicação utilizada mostrou tendência de redução da angiogênese e da injúria, mas não reduziu o processo inflamatório ou o espessamento intimal da parede arterial. Esses achados contrariam estudos que correlacionam a neovascularização com o aumento da migração de células inflamatórias. O bevacizumabe mostrou toxicidade no modelo suíno.

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BACKGROUND: Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naïve chemotherapy-refractory advanced colorectal cancer. PATIENTS AND METHODS: This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8. RESULTS: Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade ≥3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months). CONCLUSION: These findings support the antitumor activity of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory mCRC. IMPLICATIONS FOR PRACTICE: The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naïve patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.

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BACKGROUND/PURPOSE: Age-related macular degeneration (AMD) is the leading cause of visual impairment in patients over 55 years. Currently, the most common therapies for neovascular AMD (nAMD) are intravitreal antiangiogenics. Studies suggest that genetic factors influence on antiangiogenics therapy outcomes. The purpose of this work was to establish the association between complement factor H (CFH) (Y402H), age-related maculopathy susceptibility 2 (ARMS2) (A69S), and high-temperature requirement factor A1 (HTRA1) (rs11200638) polymorphisms and the response to treatment with ranibizumab in patients with nAMD. METHODS: A cross-sectional study with 61 eyes with nAMD treated with ranibizumab was performed. Association between polymorphisms from CFH, ARMS2, and HTRA1 with the response to treatment was established. RESULTS: The mean age of patients was 76.6 (51-91) years. Only 37.7% of patients had a functional response and 26.2% had an anatomic response. TT polymorphism Y402H from CFH gene was associated with an increased likelihood of functional response to treatment. Otherwise, there was not a statistically significant association between anatomic and functional response to gene polymorphisms rs11200638 from HTRA1 and rs10490924 from ARMS 2. CONCLUSIONS: This study suggests that the response to intravitreal antiangiogenic therapy with ranibizumab was not associated to main polymorphisms from genes HTRA1 and ARMS2. However, it was found that the response to treatment differed according to CFH genotype, suggesting that further investigations are needed to establish if patients with the CC and TC genotype may need to be monitored more closely for disease recurrence than the TT genotype.