Intravitreal bevacizumab plus propranolol for neovascular age-related macular degeneration (the BEVALOL study): a phase I clinical trial.

BACKGROUND: Given the persistently large public health impact of neovascular age-related macular degeneration (nARMD) despite many years of anti-VEGF therapy as the first-line treatment and the demonstrated ability of b-blockers to reduce neovascularization, a synergistic effect between an anti-VEGF agent and an intravitreal beta-blocker is important to investigate in the quest for therapeutic alternatives that maximize efficacy and/or reduce costs. The main purpose of this study is to investigate the safety of a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) to treat nARMD. METHODS: Prospective phase I clinical trial that included patients with nARMD. Comprehensive ophthalmic evaluation was performed at baseline and included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), biomicroscopy of the anterior and posterior segments, binocular indirect ophthalmoscopy, color fundus photography, spectral domain optical coherence tomography (OCT), OCT angiography (OCT-A), fluorescein angiography (Spectralis, Heidelberg), and full-field electroretinography (ERG). All eyes were treated with a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) within 1 week of baseline evaluation. The patients were reexamined at weeks 4, 8 and 12, and clinical evaluation and SD-OCT were performed at all follow-up visits. Additional injections of combination bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) were administered at weeks 4 and 8. At the final study evaluation (week 12), color fundus photography, OCT-A, fluorescein angiography, and full-field ERG were repeated. RESULTS: Eleven patients (11 eyes) completed all study visits of the 12 week study. Full field ERG b-waves did not show significant (p < 0.05) changes at week 12 compared to baseline. During the 12 week follow-up period, none of the study eyes developed intraocular inflammation, endophthalmitis or intraocular pressure elevation more than 4 mmHg over baseline. Mean ± SE BCVA (logMAR) was 0.79 ± 0.09 at baseline and was significantly (p < 0.05) improved to 0.61 ± 0.10 at week 4; 0.53 ± 0.10 at week 8; and 0.51 ± 0.09 at week 12. Mean ± SE central subfield thickness (CST) (µm) was 462 ± 45 at baseline and was significantly (p < 0.05) lower at 4, 8 and 12 weeks (385 ± 37; 356 ± 29 and 341 ± 24, respectively). CONCLUSIONS: In this 12 week trial of a combination of intravitreal bevacizumab and propranolol for treatment of nARMD, no adverse events or signals of ocular toxicity were observed. Further studies using this combination therapy are warranted. Trial Registration Project registered in Plataforma Brasil with CAAE number 28108920.0.0000.5440 and approved in ethics committee of Clinics Hospital of Ribeirao Preto Medicine School of São Paulo University-Ribeirão Preto, São Paulo, Brazil (appreciation number 3.999.989 gave the approval).

Comparing the postoperative refractive predictability of Pentacam HR and IOLMaster 500 after a multifocal intraocular lens implantation / Comparação da previsibilidade refrativa pós-operatória do Pentacam HR e IOLMaster 500 após implante de lentes intraoculares multifocais

ABSTRACT Purpose: To compare the postoperative refractive predictability of IOLMaster 500 and Pentacam HR on the basis of keratometry and anterior chamber depth values in eyes with an indication for multifocal intraocular lens (IOL) implantation. Methods: This was a retrospective study conducted on 118 eyes treated with phacoemulsification and multifocal intraocular lens implantation. Only the eyes that achieved emmetropia in the dynamic refraction performed on postoperative day 30 were included. Haigis' formula was used in each case to calculate the intraocular lens power, and the intraocular lens with the target refraction closest to emmetropia was implanted. Four lens calculation scenarios were tested by combining keratometry and anterior chamber depth measurements obtained using the two devices. Results: IOLMaster 500 and Pentacam HR differed with regard to mean keratometry (D 0.07 ± 0.03 D; p=0.0065) and anterior chamber depth (D 0.08 ± 0.01 mm; p<0.001). In the analysis of covariance, the following differences were obtained using the Haigis' formula when confronted with the biometric values obtained by inserting keratometry and anterior chamber depth values, respectively: Penta/IOL x IOL/Penta (0.13 ± 0.03; p<0.0001); Penta/Penta × IOL/Penta (0.13 ± 0.03; p<0.0001); Penta/IOL × IOL/IOL (0.11 ± 0.03; p=0.001); Penta/Penta × IOL/IOL (0.11 ± 0.03; p=0.002); IOL/IOL × IOL/Penta (0.02 ± 0.03; p=0.865); and Penta/IOL × Penta/Penta (0.002 ± 0.03; p=0.99). The difference was smaller when measuring the anterior chamber depth using the IOLMaster 500, regardless of which device was used to measure keratometry. Conclusions: Pentacam HR significantly differed from IOLMaster 500 when calculating keratometry. As regards the anterior chamber depth, the two devices were equally accurate.

RESUMO Objetivo: Comparar a previsibilidade refrativa pós-operatória do IOLMaster 500 e Pentacam HR com base nos valores de ceratometria e profundidade de câmara anterior nos olhos com indicação de implante de lentes intraoculares multifocais. Métodos: Estudo retrospectivo realizado em 118 olhos tratados com facoemulsificação e implante de lentes intraoculares multifocal. Apenas os olhos que atingiram a emetropia na refração dinâmica no 30º dia pós-operatório foram incluídos. A fórmula de Haigis foi usada em cada caso para calcular o poder das lentes intraoculares, e a lente intraocular com a refração alvo mais próxima da emetropia foi implantada. Cenários de cálculo de quatro lentes foram testados pela combinação de medidas de ceratometria e profundidade de câmara anterior obtidas usando os dois dispositivos. Resultados: IOLMaster 500 e Pentacam HR diferiram quanto à média de ceratometria (D 0,07 ± 0,03 D; p=0,0065) e profundidade de câmara anterior (D 0,08 ± 0,01 mm; p<0,001). Na análise da covariância, as seguintes diferenças foram obtidas usando a fórmula de Haigis quando confrontadas com os valores biométricos obtidos pela inserção dos valores de ceratometria e profundidade de câmara anterior, respectivamente: Penta/IOL x IOL/Penta (0,13 ± 0,03; p<0,0001); Penta/Penta x IOL/Penta (0,13 ± 0,03; p<0,0001); Penta/IOL x IOL/IOL (0,11 ± 0,03; p=0,001); Penta/Penta x IOL/IOL (0,11 ± 0,03; p=0,002); IOL/IOL x IOL/Penta (0,02 ± 0,03; p=0,865); Penta/IOL x Penta/Penta (0,002 ± 0,03; p=0,99). A diferença foi menor ao medir a profundidade da câmara anterior usando o IOLMaster 500, independentemente de qual dispositivo foi usado para medir a ceratometria. Conclusões: O Pentacam HR diferiu significativamente do IOLMaster 500 no cálculo de ceratometria. Quanto à profundidade da câmara anterior, os dois dispositivos foram igualmente precisos.

Comparing the postoperative refractive predictability of Pentacam HR and IOLMaster 500 after a multifocal intraocular lens implantation.

PURPOSE: To compare the postoperative refractive predictability of IOLMaster 500 and Pentacam HR on the basis of keratometry and anterior chamber depth values in eyes with an indication for multifocal intraocular lens (IOL) implantation. METHODS: This was a retrospective study conducted on 118 eyes treated with phacoemulsification and multifocal intraocular lens implantation. Only the eyes that achieved emmetropia in the dynamic refraction performed on postoperative day 30 were included. Haigis' formula was used in each case to calculate the intraocular lens power, and the intraocular lens with the target refraction closest to emmetropia was implanted. Four lens calculation scenarios were tested by combining keratometry and anterior chamber depth measurements obtained using the two devices. RESULTS: IOLMaster 500 and Pentacam HR differed with regard to mean keratometry (D 0.07 ± 0.03 D; p=0.0065) and anterior chamber depth (D 0.08 ± 0.01 mm; p<0.001). In the analysis of covariance, the following differences were obtained using the Haigis' formula when confronted with the biometric values obtained by inserting keratometry and anterior chamber depth values, respectively: Penta/IOL x IOL/Penta (0.13 ± 0.03; p<0.0001); Penta/Penta × IOL/Penta (0.13 ± 0.03; p<0.0001); Penta/IOL × IOL/IOL (0.11 ± 0.03; p=0.001); Penta/Penta × IOL/IOL (0.11 ± 0.03; p=0.002); IOL/IOL × IOL/Penta (0.02 ± 0.03; p=0.865); and Penta/IOL × Penta/Penta (0.002 ± 0.03; p=0.99). The difference was smaller when measuring the anterior chamber depth using the IOLMaster 500, regardless of which device was used to measure keratometry. CONCLUSIONS: Pentacam HR significantly differed from IOLMaster 500 when calculating keratometry. As regards the anterior chamber depth, the two devices were equally accurate.

The Impact of Computed Tomography on Decision Making in Tibial Plateau Fractures.

Schatzker introduced one of the most used classification systems for tibial plateau fractures, based on plain radiographs. Computed tomography brought to attention the importance of coronal plane-oriented fractures. The goal of our study was to determine if the addition of computed tomography would affect the decision making of surgeons who usually use the Schatzker classification to assess tibial plateau fractures. Image studies of 70 patients who sustained tibial plateau fractures were uploaded to a dedicated homepage. Every patient was linked to a folder which contained two radiographic projections (anteroposterior and lateral), three interactive videos of computed tomography (axial, sagittal, and coronal), and eight pictures depicting tridimensional reconstructions of the tibial plateau. Ten attending orthopaedic surgeons, who were blinded to the cases, were granted access to the homepage and assessed each set of images in two different rounds, separated to each other by an interval of 2 weeks. Each case was evaluated in three steps, where surgeons had access, respectively to radiographs, two-dimensional videos of computed tomography, and three-dimensional reconstruction images. After every step, surgeons were asked to present how would they classify the case using the Schatzker system and which surgical approaches would be appropriate. We evaluated the inter- and intraobserver reliability of the Schatzker classification using the Kappa concordance coefficient, as well as the impact of computed tomography in the decision making regarding the surgical approach for each case, by using the chi-square test and likelihood ratio. The interobserver concordance kappa coefficients after each assessment step were, respectively, 0.58, 0.62, and 0.64. For the intraobserver analysis, the coefficients were, respectively, 0.76, 0.75, and 0.78. Computed tomography changed the surgical approach selection for the types II, V, and VI of Schatzker (p < 0.01). The addition of computed tomography scans to plain radiographs improved the interobserver reliability of Schatzker classification. Computed tomography had a statistically significant impact in the selection of surgical approaches for the lateral tibial plateau.

Panretinal photocoagulation versus intravitreal injection retreatment pain in high-risk proliferative diabetic retinopathy.

PURPOSE: To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy. METHODS: Prospective study including patients with high-risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group) or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group). In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2), and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-µm additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection). Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums). RESULTS: Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (±SEM) was 4.7 ± 2.1 and was significantly lower (p<0.0001) than mean panretinal photocoagulation pain (60.8 ± 7.8). Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5. CONCLUSION: In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment was performed with an intravitreal injection in comparison with retinal photocoagulation. Further larger studies are necessary to confirm our preliminary findings.

Panretinal photocoagulation versus intravitreal injection retreatment pain in high-risk proliferative diabetic retinopathy / Dor em panfotocogulação retiniana versus injeção intravítrea em pacientes com retinopatia diabética proliferativa de alto risco

PURPOSE: To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy. METHODS: Prospective study including patients with high-risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group) or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group). In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2), and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-µm additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection). Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums). RESULTS: Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (±SEM) was 4.7 ± 2.1 and was significantly lower (p<0.0001) than mean panretinal photocoagulation pain (60.8 ± 7.8). Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5. CONCLUSION: In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment was performed with an intravitreal injection in comparison with retinal photocoagulation. Further larger studies are necessary to confirm our preliminary findings.

OBJETIVO: Comparar a dor relacionada à injeção intravítrea e panfotocoagulação no tratamento de pacientes com retinopatia diabética proliferativa de alto risco. MÉTODOS: Estudo prospectivo incluindo pacientes com retinopatia diabética proliferativa de alto risco e nenhum tratamento a laser prévio aleatoriamente designados para receber panfotocoagulação retiniana (grupo PRP) ou panfotocoagulação e ranibizumabe intravítreo (grupo PRPplus). Em todos os pacientes, a panfotocoagulação foi administrada em duas sessões (semanas 0 e 2), e ranibizumabe intravítreo foi administrado no final da primeira sessão de laser no grupo PRPplus. Retratamento foi realizado nas semanas 16 e 32 se neovasos ativos fossem detectados na angiofluoresceinografia, utilizando ranibizumabe intravítreo no grupo PRPplus e laser adicional grupo PRP. Após o fim do retratamento, uma Escala Analógica Visual de 100-unidades foi utilizada para a estimativa da pontuação da dor. O paciente foi questionado sobre a intensidade da dor durante todo o procedimento (sessão de fotocoagulação de retina ou injeção intravítrea de ranibizumabe). A comparação dos índices de dor foi realizada utilizando um teste não-paramétrico (Wilcoxon rank sums). RESULTADOS: Dezessete pacientes do grupo PRPplus e 14 do grupo PRP foram avaliados para os índices de dor. Não houve diferenças significativas entre os dois grupos quanto ao sexo, hemoglobina glicosilada e duração da doença. A média de dor da injeção intravítrea (±SEM) foi 4,7 ± 2,1, significativamente menor (p<0,0001) do que a dor média da panfotocoagulação (60,8 ± 7,8). Doze dos 17 pacientes do grupo PRPplus referiram pontuação de intensidade da dor zero, enquanto que o índice mínimo no grupo PRP foi encontrado em um paciente com 10,5. CONCLUSÃO: Em pacientes com retinopatia diabética proliferativa de alto risco que necessitaram de retratamento por neovasos persistentes, houve mais conforto para o paciente quando o retratamento foi realizado com uma injeção intravítrea em comparação com fotocoagulação da retina. Estudos posteriores são necessários para confirmar nossos achados preliminares.

Capsulorhexis rescue after peripheral radial tear-out: quick-pull technique.

UNLABELLED: We describe a technique to rescue the continuous curvilinear capsulorhexis (CCC) in cases in which complete radial tears make it impossible to use normal traction forceps. A circumferential path and rapid movement are applied in the plane of the anterior capsule in the direction of the center pupil. This technique was used in 50 cases. In 47, the CCC could be completed; in 3, it could not and surgery was continued with low-parameter phacoemulsification. No other intraoperative complications occurred. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells / Possíveis mecanismos de recuperação da função da retina com uso de terapia celular com células tronco derivadas da medula óssea

Bone marrow has been proposed as a potential source of stem cells for regenerative medicine. In the eye, degeneration of neural cells in the retina is a hallmark of such widespread ocular diseases as age-related macular degeneration (AMD) and retinitis pigmentosa. Bone marrow is an ideal tissue for studying stem cells mainly because of its accessibility. Furthermore, there are a number of well-defined mouse models and cell surface markers that allow effective study of hematopoiesis in healthy and injured mice. Because of these characteristics and the experience of bone marrow transplantation in the treatment of hematological disease such as leukemia, bone marrow-derived stem cells have also become a major tool in regenerative medicine. Those cells may be able to restore the retina function through different mechanisms: A) cellular differentiation, B) paracrine effect, and C) retinal pigment epithelium repair. In this review, we described these possible mechanisms of recovery of retinal function with the use of cell therapy with bone marrow-derived stem cells.

As células tronco derivadas da medula óssea têm sido propostas como uma fonte em potencial de células para medicina regenerativa. No olho, a degeneração de células neurais da retina são a marca de doenças difusas, como a degeneração macular relacionada com a idade (DMRI) e a retinose pigmentar. A medula óssea é um tecido ideal para estudar as células tronco por causa da sua acessibilidade. Devido a estas características e a experiência do transplante de medula óssea no tratamento de doenças hematológicas, como as leucemias, as célulastronco derivadas da medula óssea têm se tornado a maior ferramenta na medicina regenerativa. Essas células podem ser capazes de restaurar a função da retina através dos seguintes mecanismos: A) diferenciação celular; B) efeito parácrino; C) reparo do epitélio pigmentado da retina. Nesta revisão nós descrevemos os possíveis mecanismos de recuperação da função da retina com uso de terapia celular com células tronco derivadas da medula óssea.

Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells.

Bone marrow has been proposed as a potential source of stem cells for regenerative medicine. In the eye, degeneration of neural cells in the retina is a hallmark of such widespread ocular diseases as age-related macular degeneration (AMD) and retinitis pigmentosa. Bone marrow is an ideal tissue for studying stem cells mainly because of its accessibility. Furthermore, there are a number of well-defined mouse models and cell surface markers that allow effective study of hematopoiesis in healthy and injured mice. Because of these characteristics and the experience of bone marrow transplantation in the treatment of hematological disease such as leukemia, bone marrow-derived stem cells have also become a major tool in regenerative medicine. Those cells may be able to restore the retina function through different mechanisms: A) cellular differentiation, B) paracrine effect, and C) retinal pigment epithelium repair. In this review, we described these possible mechanisms of recovery of retinal function with the use of cell therapy with bone marrow-derived stem cells.