Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

RGD peptide inhibits tumor growth by affecting angiogenesis related signaling pathway of laryngeal cancer stem cells / El péptido RGD inhibe el crecimiento tumoral al afectar la vía de señalización relacionada con la angiogénesis de las células madre del cáncer de laringe

SUMMARY: This study is to investigate the role and mechanism of RGD peptide in laryngeal cancer stem cells (CSCs). Laryngeal cancer CD133+Hep-2 CSCs were sorted by flow cytometry. RGD peptide was co-cultured with sorted laryngeal CSCs. Cell proliferation was detected with CCK-8 assay. The mRNA levels of VEGF/VEGFR2/STAT 3/HIF-1α were detected with RT-PCR. The proteins of VEGF/ VEGFR2/STAT 3/HIF-1α were detected with Western blot. The sorted CSCs were inoculated into nude mice. Tumor volume was measured. Integrin αvβ3 expression in tumor tissues was analyzed with immunohistochemistry. The results showed that the ratio of CD133+ CSCs to the total number of cells was 1.34±0.87 %, while CD133-non-tumor stem cells accounted for 95.0±5.76 %. The sorted cancer stem cells grew well. The RGD peptide significantly inhibited the proliferation of CD133+Hep-2 laryngeal CSCs in a dose-dependent manner. The RGD peptide significantly inhibited the mRNA of VEGFR2, STAT3 and HIF-1α in laryngeal CSCs in a concentration-dependent manner. Consistently, the RGD peptide significantly inhibited the protein expression of VEGFR2, STAT3 and HIF-1α in laryngeal CSCs in a dose-dependent manner. At the same time, in vivo tumor experiments showed that the RGD peptide significantly inhibited tumor volume but not the body weight. Furthermore, RGD peptide significantly inhibited the expression of tumor angiogenesis-related protein integrin αvβ3. Our findings demonstrate that RGD peptide inhibits tumor cell proliferation and tumor growth. The underlying mechanism may that RGD inhibits tumor angiogenesis-related signaling pathways, thus affecting the tumor angiogenesis, and decreasing the progression of human laryngeal CSCs.

Este estudio se realizó para investigar el papel y el mecanismo del péptido RGD en las células madre del cáncer de laringe (CSC). Las CSC CD133+Hep-2 de cáncer de laringe se clasificaron mediante citometría de flujo. El péptido RGD se cocultivó con CSC laríngeas clasificadas. La proliferación celular se detectó con el ensayo CCK-8. Los niveles de ARNm de VEGF/VEGFR2/ STAT 3/HIF-1α se detectaron con RT-PCR. Las proteínas de VEGF/ VEGFR2/STAT 3/HIF-1α se detectaron con Western blot. Las CSC clasificadas se inocularon en ratones nudos. Se midió el volumen del tumor. La expresión de integrina αvβ3 en tejidos tumorales se analizó con inmunohistoquímica. Los resultados mostraron que la proporción de CSC CD133+ con respecto al número total de células fue de 1,34 ± 0,87 %, mientras que las células madre no tumorales CD133 representaron el 95,0 ± 5,76 %. Las células madre cancerosas clasificadas crecieron bien. El péptido RGD inhibió significativamente la proliferación de CSC laríngeas CD133+Hep-2 de una manera dependiente de la dosis. El péptido RGD inhibió significativamente el ARNm de VEGFR2, STAT3 y HIF-1α en CSC laríngeas de manera dependiente de la concentración. De manera consistente, el péptido RGD inhibió significativamente la expresión proteica de VEGFR2, STAT3 y HIF-1α en CSC laríngeas, de manera dependiente de la dosis. Al mismo tiempo, los experimentos con tumores in vivo mostraron que el péptido RGD inhibía significativamente el volumen del tumor pero no el peso corporal. Además, el péptido RGD inhibió significativamente la expresión de la proteína integrina αvβ3 relacionada con la angiogénesis tumoral. Nuestros hallazgos demuestran que el péptido RGD inhibe la proliferación de células tumorales y el crecimiento tumoral. El mecanismo subyacente puede ser que RGD inhiba las vías de señalización relacionadas con la angiogénesis tumoral, afectando así la angiogénesis tumoral y disminuyendo la progresión de las CSC laríngeas humanas.

Changes in the ganglion cell complex thickness after anti-VEGF treatment for diabetic macular edema / Alterações na espessura do complexo de células ganglionares após tratamento anti-VEGF para edema macular diabético

ABSTRACT Purpose: To assess tomographic ganglion cell complex changes in patients with diabetic macular edema treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). Methods: We analyzed data from 35 eyes of 35 previously untreated patients in whom diabetic macular edema improved after three loading doses of anti-VEGF injection and who did not receive repeated injections. We recorded spectral domain-optical coherence tomography assessments of ganglion cell complex and central macular thickness at baseline and monthly for three months, and on the sixth and ninth month after treatment. We compared the results with those of the unaffected eyes in the same patients and with those in a control group of patients with diabetic macular edema who were untreated. Results: The mean age of the patients in the treatment group was 60 ± 4.38 years. The foveal thicknesses measured using optical coherence tomography decreased significantly from baseline to the third month post-injection (p<0.05). The mean ganglion cell complex thickness was 115.08 ± 16.72 µm before the first injection and 101.05 ± 12.67 µm after the third injection (p<0.05). The mean ganglion cell complex was 110.04 ± 15.07 µm on the sixth month (p>0.05) and 113.12 ± 11.15 µm on the ninth month (p>0.05). We found a significant difference between the patients and the control group in terms of mean ganglion cell complex thickness on the second- and third-months post-injection (p<0.05). Conclusion: Our study showed that the ganglion cell complex thickness in patients with diabetic macular edema decreased after the anti-VEGF injections. We cannot ascertain whether the ganglion cell complex thickness decreases were due to effects of the anti-VEGF agents or to the natural disease course.

RESUMO Objetivo: Avaliar as alterações do complexo tomográfico das células ganglionares em pacientes com edema macular diabético tratados com injeções intravítreas do fator de crescimento endotelial anti-vascular (anti-VEGF). Métodos: Analisamos dados de 35 olhos de 35 pacientes previamente não tratados nos quais o edema macular diabético melhorou após três doses de injeção de anti-VEGF e que não receberam injeções repetidas. Registramos avaliações da tomografia de coerência óptica de domínio espectral do complexo de células ganglionares e da espessura macular central na linha de base e mensalmente por três meses e, também no sexto e nono mês após o tratamento. Comparamos os resultados com os olhos não afetados nos mesmos pacientes e com os de um grupo controle de pacientes com edema macular diabético que não foram tratados. Resultados: A média da idade dos pacientes no grupo de tratamento foi de 60 ± 4,38 anos. As espessuras foveais medidas pela tomografia de coerência óptica diminuiram significativamente desde o início até o terceiro mês após a injeção (p<0,05). A espessura média do complexo de células ganglionares foi de 115,08 ± 16,72 µm antes da primeira injeção e 101,05 ± 12,67 µm após a terceira injeção (p<0,05). A média do complexo de célula ganglionar foi de 110,04 ± 15,07 µm no sexto mês (p>0,05) e 113,12 ± 11,15 µm no nono mês (p>0,05). Encontramos uma diferença significativa entre os pacientes e o grupo controle quanto à média da espessura do complexo de células ganglionares no segundo e terceiro meses após a injeção (p<0,05). Conclusão: Nosso estudo mostrou que a espessura do complexo de células ganglionares em pacientes com edema macular diabético diminuiu após as injeções de anti-VEGF. Não podemos determinar se a diminuição da espessura do complexo de células ganglionares ocorreu devido aos efeitos dos agentes anti-VEGF ou ao curso natural da doença.

Standard treatment with bevacizumab as targeted therapy in cervical cancer

ABSTRACT Metastatic, recurrent, or persistent disease in cervical cancer has a poor prognosis. Historically, this group of patients has had limited treatment options, even with the best cytotoxic treatments (platinum-based chemotherapy [CT] doublets). Therefore, investigating new medications that help improve the patient's quality of life and survival has been essential. Angiogenesis has been shown to play a critical role in tumor cell growth and survival. Bevacizumab is a recombinant humanized monoclonal G1 immunoglobulin targeted against vascular endothelial growth factor. The combination of CT and bevacizumab is associated with an increase in overall survival as well as in progression-free survival and response rates.

Optical coherence tomography angiography findings in patients with branch retinal vein occlusion treated with Anti-VEGF / Achados de angiografia por tomografia de coerência óptica em pacientes com oclusão de ramo da veia retiniana tratada com anti-VEGF

ABSTRACT Purpose: To investigate retinal microvasculature changes in patients treated with anti-VEGF for macular edema secondary to branch retinal vein occlusion. Methods: We examined 38 eyes of 19 patients for the study. We measured superficial and deep capillary plexus vessel densities (%), foveal avascular zone areas (mm2), and central macular thicknesses. Results: Parafoveal superficial and deep capillary plexus values were significantly lower in eyes with branch retinal vein occlusion than in fellow eyes (p<0.001). We found a significant increase in parafoveal deep capillary plexus values after the anti-VEGF treatment (p=0.032). The mean foveal avascular zone was larger in eyes with branch retinal vein occlusion than in control eyes (p<0.001). The mean central macular thickness was significantly higher in eyes with branch retinal vein occlusion than in controls, and we observed a significant decrease in central macular thickness after anti-VEGF treatment (<0.001). In addition, the cystic structures in the deep capillary plexus regressed. Conclusion: Optical coherence tomography angiography enables qualitative and quantitative evaluations during follow-up of patients treated for branch retinal vein occlusion.

RESUMO Objetivo: Investigar as alterações na microvascu latura da retina em pacientes tratados com anti-VEGF para ede ma macular secundário à oclusão de ramo da veia retiniana. Métodos: Foram examinados 38 olhos de 19 pacientes para o estudo. Medimos as densidades dos vasos do plexo capilar superficial e profunda (%), áreas da zona avascular foveal (mm2) e espessura macular central. Resultados: Os valores do plexo capilar superficial e profundo parafoveal foram significativamente menores nos olhos com oclusão de ramo da veia retiniana do que nos outros olhos (p<0,001). Encontramos um aumento significativo nos valores de plexo capilar profundo parafoveal após o tratamento com anti-VEGF (p=0,032). A zona avascular foveal média foi maior nos olhos com oclusão de ramo da veia retiniana do que nos olhos controle (p<0,001). A espessura macular central média foi significativamente maior nos olhos com oclusão de ramo da veia retiniana do que nos controles, e observamos uma diminuição significativa na espessura macular central após o tratamento com anti-VEGF (< 0,001). Além disso, as estruturas císticas no plexo capilar profundo regrediram. Conclusão: A angiotomografia de coerência óptica permite avaliações qualitativas e quantitativas durante o acompanhamento de pacientes tratados por oclusão de ramo da veia retiniana.

Retinopatía del prematuro: actualización en detección y tratamiento / Retinopathy of the premature: update in screening and treatment

Resumen: La Retinopatía del Prematuro (RDP) es una alteración proliferativa de los vasos sanguíneos de la retina inmadura, que afecta principalmente a los recién nacidos de muy bajo peso (RNMBP) y de menor edad gestacional. El objetivo de esta revisión es describir a qué niño se debe efectuar la detección de esta enfermedad y analizar los recientes avances en su tratamiento. La detección de RDP está dirigida principalmente a los RNMBP y a < de 32 semanas de edad gestacional, pero también se ha propuesto un criterio según edad postmenstrual. Además de la fotocoagulación con láser, tratamiento estándar en la actualidad, se han desarrollado nuevas terapias, como los agentes anti factor de crecimiento vas cular endotelial (VEGF), que se han utilizado exitosamente en la retinopatía umbral, especialmente localizada en zona I, con menos efectos adversos y mejores resultados oculares a futuro. que la fo tocoagulación con láser. En los últimos años, se han realizado ensayos clínicos con propranolol oral como tratamiento de la RDP, principalmente en la etapa pre-umbral (etapa 2 o 3 en zona II ó III). Este bloqueador beta-adrenérgico puede prevenir la progresión de la retinopatía en RNMBP de etapa pre- umbral a umbral y/o evitar la necesidad de terapias invasivas, como la fotocoagulación con láser o la administración intravítrea de agentes anti-VEGF. La fotocoagulación con láser continúa siendo el tra tamiento de elección en la RDP. Los agentes anti-VEGF y el propranolol oral, evitarían la progresión de esta patología de etapa pre-umbral a umbral, y podrían complementar el tratamiento de la RDP.

Abstract: Retinopathy of Prematurity (ROP) is a proliferative disorder of the blood vessels of the immature retina, which affects mainly very-low-birth-weight infants (VLBW). The objective of this review is to describe to which infant the screening examination of this disease should be performed and to analy ze the recent advances in the treatment of this disease, which have emerged in the last decade. The detection of this disease is mainly focused on VLBW infants and newborns < 32 weeks of gestational age. In addition to laser photocoagulation, standard treatment today, new therapies have appeared, such as the anti-VEGF agents, which have been successfully used in the threshold ROP, especially located in zone I. This therapy is less harmful than laser photocoagulation and with better ocular results in the future. In recent years, oral propranolol has been used as a treatment for ROP in clinical trials, mainly in the pre-threshold stage (stage 2 or 3 in zone II or III). This drug is a beta-adrenergic blocker that can prevent the progression of retinopathy in pre-threshold to threshold stage and/or avoid the need for invasive therapies, such as laser photocoagulation or intravitreal administration of anti-VEGF agents. Laser photocoagulation continues to be the standard treatment for ROP. New treatments have emerged for ROP, such as anti-VEGF agents and oral propranolol, which could pre vent the progression of this disease from the pre-threshold to the threshold stage.

Treat and extend comparado con pro re nata en degeneración macular asociada a la edad neovascular / Treat and extend compared to pro re nata regimen in neovascular age-related macular degeneration

INTRODUCCIÓN: La degeneración macular asociada a la edad es la principal causa de ceguera en personas mayores en el mundo. El tratamiento más eficaz consiste en inyecciones intravítreas de fármacos anti factor del crecimiento vascular endotelial (anti-VEGF). Sin embargo, no existe consenso sobre su frecuencia de administración, siendo pro re nata y treat and extend los protocolos más utilizados, pero existe controversia sobre su efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta análisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos dos revisiones sistemáticas que en conjunto incluyeron dos estudios primarios, ambos observacionales. Concluimos que no es posible establecer con claridad si el protocolo treat and extend en comparación a pro re nata es superior en términos de ganancia visual, disminución del grosor de la retina, número de inyecciones ni en el desarrollo de efectos adversos serios a los 12 meses, debido a que la certeza de la evidencia existente es muy baja.

INTRODUCTION: Age-related macular degeneration is the leading cause of blindness in older people in the world. One of the most effective treat-ments consists of injection intravitreal of anti-endothelial vascular growth factor (anti-VEGF) drugs. However, there is no con-sensus on their frequency of administration, being the treat and extend and the pro re nata the most commonly used regimens, but there is still controversy regarding their effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews that together included two primary studies, both observational studies. We concluded that we are uncertain whether the treat and extend regimen is superior in terms of visual gain, decrease in retinal thickness, number of injections and serious adverse effects at 12 months in comparison with the pro re nata regimen, because the certainty of the existing evidence has been assessed as very low.

Acute bilateral Irvine-Gass Syndrome following uneventful cataract surgery in a patient without systemic risk factors / Síndrome de Irvine-Gass aguda bilateral após cirurgia de catarata sem complicações em paciente sem fatores de risco sistêmicos

Abstract We herein report a patient without risk factors who presented acute bilateral Irvine-Gass syndrome after uneventful phacoemulsification. The novelty of our case lies on the fact that the patient presented acute bilateral Irvine-Gass syndrome without a predisposing systemic disease. Even though Cystoid Macular Edema (CME) was somehow expected in the first eye because of the ocular history of trauma, prophylactic measures were not strong enough to avoid its development. Furthermore, those measures could not avoid developing CME in the second eye. A 44-years-old male who underwent cataract surgery in both eyes presented bilateral Irvine-Gass syndrome. Despite prophylactic measures, both eyes developed CME after uneventful cataract surgery. Regular treatment options could not solve the situation and intravitreal Anti-VEGF injections were needed. Bilateral cases of Irvine-Gass Syndrome are rare and generally associated with systemic risk factors. Patients who developed CME following their first cataract surgery should be counseled about the risks of developing the condition following surgery on the contralateral eye. On top of that, aggressive prophylactic measures should be encouraged to prevent CME in these cases.

Resumo Relatamos aqui um paciente sem fatores de risco que apresentou síndrome de Irvine-Gass bilateral aguda após facoemulsificação sem intercorrências. A novidade do nosso caso reside no fato de o paciente apresentar síndrome de Irvine-Gass bilateral aguda sem doença sistêmica predisponente. Embora o Edema Macular Cistoide (EMC) fosse de alguma forma esperado no primeiro olho por causa do histórico ocular de trauma, as medidas profiláticas não foram suficientemente fortes para evitar seu desenvolvimento. Além disso, essas medidas não puderam evitar o desenvolvimento de EMC no segundo olho. Homem de 44 anos submetido a cirurgia de catarata em ambos os olhos apresentou síndrome de Irvine-Gass bilateral. Apesar das medidas profiláticas, ambos os olhos desenvolveram EMC após a cirurgia de catarata sem intercorrências. As opções de tratamento regular não conseguiram resolver a situação e foram necessárias injeções intravítreas de Anti-VEGF. Casos de Síndrome de Irvine-Gass bilateral são raros e geralmente associados a fatores de risco sistêmicos. Os pacientes que desenvolveram EMC após a primeira cirurgia de catarata devem ser avisados sobre os riscos de desenvolver a doença após a cirurgia no olho contralateral. Além disso, medidas profiláticas agressivas devem ser incentivadas para evitar a EMC nesses casos.

Comparative study between intravitreal ranibizumab and triamcinolone treatment of diabetic macular edema as regard to optical coherence tomography changes and visual acuity / Estudo comparativo entre o tratamento intravítreo com ranibizumabe e triancinolona do edema macular diabético quanto às alterações na tomografia de coerência óptica e na acuidade visual

Abstract Objectives: To compare the effect of intravitreal Ranibizumab (0.3mg) and Triamicinolone (4mg) on different parameters in spectral domain OCT and their relation to visual acuity of patients with diabetic macular edema. Methods: This study is designed as a prospective randomized study. Patients were randomly divided into 2 groups receiving either Pro re nata intravitreal Ranibizumab (0.3mg) or Triamicinolone acetonide (4mg), to whom Spectral Domain OCT was done as well as best corrected Log MAR visual acuity. Results: 40 patients were included in this study. Comparison and correlation of mean BCVA and mean CMT among and within treatment groups of our study revealed strong and significant relationship between both parameters and showing equal effect of both treatment types regarding them with the consideration that Triamicinolone acetonide treated group (Group B) showed statistically significant lower CMT compared to Ranibizumab treated group (Group A) at three and six months. Also both showed equal effectivity regarding improvement of the photoreceptors integrity and in turn the improvement of the BCVA. Meanwhile the association of CMT and IS/OS integrity was found to be significant only at six months in both groups (p =0.009 in Group A; p =0.031 in Group B). The fading initial effect of a single ranibizumab injection on macular edema can be augmented by following that one injection with two injections of the loading dose. Triamicinolone effect after single injection began to fade at 3 months. Conclusion: Both treatment types had good effect on reduction of CMT and improvement of BCVA and the IS/OS junction with difference in sustainability of their effects due to difference in their pharmacokinetics and need for repeated injections.

Resumo Objetivos: Comparar o efeito do ranibizumabe intravítreo (0,3mg) e triacmicinolona (4mg) em diferentes parâmetros do domínio espectral da OCT e sua relação com a acuidade visual de pacientes com edema macular diabético. Métodos: Este estudo foi concebido como um estudo prospectivo randomizado. Os pacientes foram divididos aleatoriamente em 2 grupos que receberam Ranibizumab Pro rata intravitreal (0,3mg) ou acetonido de Triamicinolona (4mg), a quem foi realizada a Spectral Domain OCT, bem como a melhor acuidade visual de Log MAR corrigida. Resultados: Quarenta pacientes foram incluídos neste estudo. A comparação e a correlação da acuidade visual média e CMT média entre e dentro de grupos de tratamento do nosso estudo revelaram uma relação forte e significativa entre ambos os parâmetros e mostrando um efeito igual de ambos os tipos de tratamento, considerando que o grupo tratado com acetonido Triamicinolona (Grupo B) apresentou significância estatística. menor CMT comparado ao grupo tratado com Ranibizumab (Grupo A) aos três e seis meses. Também ambos mostraram igual efetividade em relação à melhoria da integridade dos fotorreceptores e, por sua vez, a melhora do BCVA. Enquanto isso, a associação de CMT e IS / OS integridade foi significativa apenas aos seis meses em ambos os grupos (p = 0,009 no Grupo A; p = 0,031 no Grupo B). O efeito inicial enfraquecido de uma única injeção de ranibizumabe no edema macular pode ser aumentado seguindo-se aquela injeção com duas injeções da dose de ataque. O efeito triamicinolona após injeção única começou a diminuir aos 3 meses. Conclusão: Ambos os tipos de tratamento tiveram bom efeito na redução da CMT e melhora do BCVA e da junção IS / OS com a diferença na sustentabilidade de seus efeitos devido à diferença em sua farmacocinética e necessidade de injeções repetidas.

Effectiveness of monthly and fortnightly anti-VEGF treatments for age-related macular degeneration / Efetividade de tratamentos anti-VEGF mensais e quinzenais para a degeneração macular relacionada à idade

ABSTRACT Purpose: To study the efficacy and safety of treatments with ranibizumab and bevacizumab for exudative age-related macular degeneration. Methods: A parallel randomized clinical trial was conducted to compare the efficacy and safety of three regimens (bevacizumab every month, bevacizumab every 2 weeks, and ranibizumab every month), followed by as-needed retreatments, for 1 year, in previously untreated individuals with age-related macular degeneration. The primary outcome was change in visual acuity and in central macular thickness after 1 year of follow-up. Subjects were assigned randomly to one of the three groups in a 1:1:1 ratio, and investigators and examiners were blinded to the randomization results. Results: We included 15 patients in each group. After 1 year of follow-up, we found statistically significant improvements in visual acuity and central macular thickness reduction in all groups. However, we found no statistically significant differences between the three groups. Conclusions: The bi-weekly follow-up was effective and we found no significant differences in efficacy or safety between the treatments with ranibizumab and bevacizumab.

RESUMO Objetivo: Estudar a eficácia e segurança dos tratamentos com ranibizumabe e bevacizumabe para a degeneração macular relacionada à idade exsudativa. Métodos: Ensaio clínico paralelo randomizado foi conduzido para comparar a eficácia e segurança de três regimes (bevacizumabe a cada mês, bevacizumabe a cada 2 semanas e ranibizumabe todos os meses), seguidos por retratamentos conforme necessidade, durante 1 ano, em indivíduos previamente não tratados com degeneração macular relacionada à idade. O desfecho primário foi alteração na acuidade visual e na espessura macular central após um ano de seguimento. Os indivíduos foram designados aleatoriamente para um dos 3 grupos em uma proporção de 1:1:1, e os investigadores e examinadores foram mascarados para os resultados da randomização. Resultados: Foram incluídos 15 pacientes em cada grupo. Após um ano de seguimento, encontramos melhorias estatisticamente significativas na acuidade visual e na redução da espessura macular central em todos os grupos. No entanto, não encontramos diferenças estatisticamente significativas entre os 3 grupos. Conclusões: O seguimento quinzenal foi eficaz e não encontramos diferenças significativas na eficácia ou segurança entre os tratamentos com bevacizumabe e ranibizumabe.

Lopinavir and curcumin directly alters BAX/BCL2 and VEFG165b mRNA levels to suppress human squamous cervical carcinoma cell growth / Lopinavir y curcumina alteran directamente los niveles de ARNm de BAX/ BCL 2 y VEFG165 para suprimir el crecimiento de células de carcinoma cervical escamoso humano

Following the success of the highly active antiretroviral therapy, the potential of multidrug combination regimen for the management of cancer is intensely researched. The anticancer effects of curcumin on some human cell lines have been documented. Lopinavir is a FDA approved protease inhibitor with known apoptotic activities. Dysregulated apoptosis is important for the initiation of cancer while angiogenesis is required for cancer growth and development, this study therefore investigated the effects of the combination of lopinavir and curcumin on cell viability, apoptosis and the mRNA expression levels of key apoptotic and angiogenic genes; BAX, BCL2 and VEGF165b in two human cervical cell lines; human squamous cell carcinoma cells - uterine cervix (HCS-2) and transformed normal human cervical cells (NCE16IIA). The two human cervical cell lines were treated with physiologically relevant concentrations of the agents for 120 h following which BAX, BCL2 and VEGF165b mRNA expression were determined by Real Time qPCR. The Acridine Orange staining for the morphological evaluation of apoptotic cells was also performed. The combination of lopinavir and curcumin up-regulated pro-apoptotic BAX and antiangiogenic VEGF165b but down-regulated the mRNA levels of anti-apoptotic BCL2 mRNA in the human squamous cell carcinoma (HCS-2) cells only. The fold changes were statistically significant. Micrographs from Acridine Orange staining showed characteristic evidence of apoptosis in the human squamous cell carcinoma (HCS-2) cells only. The findings reported here suggest that the combination of curcumin and the FDA approved drug-lopinavir modulate the apoptotic and angiogenic pathway towards the inhibition of cervical cancer.

Tras el éxito de la terapia antirretroviral altamente activa, se investiga intensamente el potencial del régimen de combinación de múltiples fármacos para el tratamiento del cáncer. Se han documentado los efectos anticancerígenos de la curcumina en algunas líneas celulares humanas. Lopinavir es un inhibidor de proteasa aprobado por la FDA con actividades apoptóticas conocidas. La apoptosis disrregulada es importante para el inicio del cáncer, mientras que la angiogénesis es necesaria para el crecimiento y desarrollo del cáncer. Por lo tanto, este estudio investigó los efectos de la combinación de lopinavir y curcumina sobre la viabilidad celular, la apoptosis y los niveles de expresión del ARNm de genes apoptóticos y angiogénicos clave: BAX, BCL2 y VEGF165b en dos líneas celulares cervicales humanas; células de carcinoma de células escamosas humanas: cérvix uterino (HCS-2) y células cervicales humanas transformadas (NCE16IIA). Las dos líneas celulares cervicales humanas se trataron con concentraciones fisiológicamente relevantes de los agentes durante 120 horas, después de lo cual la expresión de ARNm de BAX, BCL2 y VEGF165b se determinó mediante qPCR en tiempo real. También se realizó la tinción con naranja de acridina para la evaluación morfológica de células apoptóticas. La combinación de lopinavir y curcumina reguló incrementando BAX proapoptósicos y VEGF165b antiangiogénicos, pero reguló a la baja los niveles de ARNm del BCL2 antiapoptótico en células de carcinoma de células escamosas humanas (HCS-2) únicamente. Los cambios en el pliegue fueron estadísticamente significativos. Las micrografías de la tinción con naranja de acridina mostraron evidencia característica de apoptosis solo en las células del carcinoma de células escamosas humanas (HCS-2). Los hallazgos reportados aquí sugieren que la combinación de curcumina y el fármaco aprobado por la FDA lopinavir modulan la vía apoptótica y angiogénica hacia la inhibición del cáncer cervical.

Perfil epidemiológico das aplicações intravítreas de Ranibizumab / Epidemiological profile of Ranibizumab intravitreal applications

Resumo Objetivo: O objetivo desse trabalho é avaliar o perfil de aplicações intravítreas do Ranibizumab em uma população de adultos atendidos no Instituto Benjamin Constant, no ano de 2015, levando em consideração o efeito sobre a acuidade visual e a espessura macular após tratamento. O objetivo secundário é apresentar as principais indicações desse tipo tratamento no serviço de olhos acima citado. Métodos: Foi realizado um estudo retrospectivo seccional, em indivíduos acima de 20 anos entre os meses de março a agosto de 2015, para analisar a acuidade visual e espessura foveal pré e pós tratamento. A dose do anti-VEGF utilizada foi de 0,05ml por aplicação com intervalo de quatro semanas entre elas. A aferição da acuidade visual assim como o OCT pós tratamento foram realizados em torno de trinta dias após a última aplicação. As análises estatísticas foram feitas com uso do software SPSS versão 21 e o nível de significância estatística foi de 95% com um valor de p <0,05. Resultado: O estudo mostrou que a principal afecção relacionada a esse tratamento foi a retinopatia diabética não proliferativa associada ao edema macular (32,8%). Após o tratamento indicado com Ranibizumab, houve uma melhora da acuidade visual média de 0,70 para 0,59 (logMAR) e uma regressão da espessura macular, visto no OCT, de 408,1µm para 337,2 µm (valor de p <0,05). Conclusão: Pode-se concluir portanto, que o tratamento com Ranibizumab na população estudada contribuiu para uma melhor qualidade de vida dos pacientes, pois a maioria dele apresentou uma melhora estatisticamente significativa na acuidade visual após as aplicações.

Abstract The objective of this work is to evaluate the profile of intravitreal applications of Ranibizumab in a population of adults attended at the Benjamin Constant Institute in the year of 2015, taking into account the effect on visual acuity and macular thickness after the treatment. The secondary objective is to present the main indications of this type of treatment in the eye care mentioned above. A retrospective cross-sectional study was performed in individuals over 20 years of age between March and August of 2015 to analyze visual acuity and foveal thickness before and after treatment. The dose of anti-VEGF used was 0.05 ml per application with an interval of four weeks between them. Visual acuity assessment as well as OCT post treatment were performed around 30 days after the last application. Statistical analyses were performed using SPSS software version 21 and the level of statistical significance was of 95% with a value of p <0.05. The study showed that the main condition related to this treatment was non-proliferative diabetic retinopathy associated with macular edema (32.8%). After treatment indicated with Ranibizumab, there was an improvement in the average visual acuity from 0.70 to 0.59 (logMAR) and a regression of the macular thickness, seen in the OCT, from 408.1μm to 337.2μm (p < 0.05). It can be concluded, therefore, that treatment with Ranibizumab in the studied population contributed to a better quality of life of the patients, since most of them presented a statistically significant improvement in the visual acuity after the applications.

Efficacy of targeted therapy for advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials

ABSTRACT We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect comparison, to provide an optimal treatment among these agents. A systematic search of Medline, Scopus, Cochrane Library and Clinical Trials unpublished was performed up to Jan 1, 2015 to identify eligible randomized trials. Outcomes of interest assessing a targeted agent included progression free survival (PFS), overall survival (OS) and objective response rate (ORR). Thirty eligible randomized controlled studies, total twentyfourth trails (5110 cases and 4626 controls) were identified. Compared with placebo and IFN-α, single vascular epithelial growth factor (receptor) tyrosine kinase inhibitor and mammalian target of rapamycin agent (VEGF(r)-TKI & mTOR inhibitor) were associated with improved PFS, improved OS and higher ORR, respectively. Comparing sorafenib combination vs sorafenib, there was no significant difference with regard to PFS and OS, but with a higher ORR. Comparing single or combination VEGF(r)-TKI & mTOR inhibitor vs BEV + IFN-α, there was no significant difference with regard to PFS, OS, or ORR. Our network ITC meta-analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib. Our data suggest that targeted therapy with VEGF(r)-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS, OS and higher ORR compared to placebo and IFN-α. In summary, here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting.

Which dose of bevacizumab is more effective for the treatment of aggressive posterior retinopathy of prematurity: lower or higher dose? / Qual a dose de bevacizumab no tratamento da retinopatia da prematuridade posterior agressiva: menor ou maior dose?

ABSTRACT Purpose: To compare 0.5 mg and 0.625 mg of bevacizumab for treating aggressive posterior retinopathy of prematurity (AP-ROP). Methods: The medical records of patients with AP-ROP who were administered intravitreal bevacizumab (IVB) as a primary treatment at a university clinic were evaluated retrospectively. Five eyes of three patients (Group 1) who received 0.625 mg/0.025 ml IVB and 10 eyes of another five patients (Group 2) who received 0.5 mg/0.02 ml IVB were evaluated. Laser photocoagulation was used as additional treatment after relapses. Anatomic results and complications were evaluated in both groups. Results: We evaluated 15 eyes of eight patients (four girls and four boys) with a flat demarcation line at posterior zone 2 and plus disease or stage-3 disease in this study. The mean gestational age of the three babies in Group 1 was 26 ± 1 weeks and the mean birth weight was 835.33 ± 48.01 g. The corresponding values were 25.2 ± 1.6 weeks and 724 ± 139.03 g, respectively, for the five babies in Group 2. Retinal vascularization was completed at a mean postmenstrual duration of 53.6 ± 1.5 weeks without additional treatment in the five eyes in Group 1. Laser photocoagulation for relapse was administered to five of the 10 eyes in Group 2. Retinal vascularization was completed at a mean postmenstrual duration of 47.6 ± 1.5 weeks in the remaining five eyes. None of the patients developed complications such as cataract, glaucoma, retinal tear, retinal or vitreous hemorrhage, or retinal detachment. Conclusion: Although lower IVB doses in the treatment of AP-ROP are expected to be safer in terms of local and systemic side effects in premature infants, these patients may require additional treatment with IVB or laser photocoagulation.

RESUMO Objetivo: Comparar doses de 0,5 mg e 0,625 mg de bevacizumab no tratamento da retinopatia da prematuridade posterior agressiva (ROP-PA). Métodos: os registros médicos de pacientes com ROP-PA que receberam bevacizumab intravítreo (IVB) como tratamento primário em uma clínica universitária foram avaliados retrospectivamente. Houve 5 olhos de 3 casos (Grupo 1) que receberam 0,625 mg/0,025 ml de IVB e 10 olhos de outros 5 casos (Grupo 2) que receberam 0,5 mg/0,02 ml de IVB. A fotocoagulação com laser foi utilizada como tratamento adicional para casos de recidiva. Os resultados e complicações anatômicas foram avaliados em ambos os grupos. Resultados: Incluímos os 15 olhos de 8 pacientes (4 meninas e 4 meninos) com linha de demarcação plana na zona posterior 2 e doença "plus" (dilatação e tortuosidade vascular) neste estudo. A idade gestacional média dos três bebês no Grupo 1 foi de 26 ± 1 semana e o peso médio ao nascer foi de 835,33 ± 48,01 g, enquanto esses valores foram de 25,2 ± 1,6 semanas e 724 ± 139,03 g, respectivamente, para os cinco bebês do Grupo 2. A vascularização da retina foi completada com uma duração média pós-menstrual de 53,6 ± 1,5 semanas sem tratamento adicional nos cinco olhos no Grupo 1. A fotocoagulação a laser foi administrada devido à recaída em 5 dos 10 olhos do Grupo 2. A vascularização da retina foi completada em média de 47,6 ± 1,5 semanas do período pós-menstrual nos cinco olhos restantes. Nenhum dos casos desenvolveu complicações, como catarata, glaucoma, rasgo da retina, hemorragia retiniana ou vítrea ou descolamento da retina. Conclusão: Embora as doses mais baixas de IVB no tratamento de ROP-PA sejam mais seguras em termos de efeitos colaterais locais e sistêmicos em prematuros, esses pacientes podem precisar de tratamento adicional com IVB ou fotocoagulação a laser.

Preoperative treatment with 5α-reductase inhibitors and the risk of hemorrhagic events in patients undergoing transurethral resection of the prostate - A population-based cohort study

OBJECTIVES: To assess the associations between preoperative treatment with 5-alpha reductase inhibitors and the risks of blood transfusion during transurethral resection of the prostate and blood clot evacuation or emergency department visits for hematuria within 1 month after surgery. METHODS: We used data from the Taiwan National Health Insurance Research Database in this population-based cohort study. A total of 3,126 patients who underwent first-time transurethral resection of the prostate from 2004 to 2013 were identified. Adjusted odds ratios estimated by multiple logistic regression models were used to assess the independent effects of the preoperative use of 5-alpha reductase inhibitors on the risks of perioperative hemorrhagic events after adjustment for potential confounders. RESULTS: Two hundred and ninety-seven (9.4%) patients were treated with 5-alpha reductase inhibitors for <3 months, and 65 (2.1%) patients were treated for ≥3 months prior to undergoing transurethral resection of the prostate. The blood transfusion rates for patients who were not treated with 5-alpha reductase inhibitors (controls), patients who were treated with 5-alpha reductase inhibitors for <3 months, and patients who were treated with 5-alpha reductase inhibitors ≥3 months were 9.5%, 8.8%, and 3.1%, respectively. 5-alpha reductase inhibitors tended to decrease the risk of blood transfusion; however, this association was not statistically significant (adjusted odds ratio=0.14, 95% confidence interval: 0.02-1.01). Age ≥80 years, coagulopathy, and a resected prostate tissue weight >50 g were associated with significantly higher risks of blood transfusion than other parameters. CONCLUSIONS: This nationwide study did not show that significant associations exist between 5-alpha reductase inhibitor use before transurethral resection of the prostate and the risks of blood transfusion and blood clot evacuation or emergency visits for hematuria.

Choroidal neovascularization silent on optical coherence tomography: report of two cases / Neovascularização de coroide silente a tomografia de coerência ótica: relato de dois casos

ABSTRACT Herein, we report two cases of vision loss after successful cataract surgery, associated with drusenoid retinal pigment epithelial detachment without features of choroidal neovascularization on optical coherence tomography along with angiographic examinations suggestive of choroidal neovascularization in which anatomical and functional improvements were achieved with intravitreal injections of anti-vascular endothelial growth factor.

RESUMO Relatamos dois casos de baixa visual após cirurgia bem sucedida de catarata, associada a descolamento drusenóide do epitélio pigmentar da retina (DPED) sem achados de neovascularização de coroide a tomografia de coerência óptica OCT (CNV silente ao OCT) e com exames angiográficos sugestivos de neovascularização da coroide (CNV), nos quais melhoras anatômicas e funcionais foram obtidas com aplicações intravítreas de anti-VEGF.

Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report / Bevacizumab como tratamiento para telangiectasia hemorrágica hereditaria en niños: Reporte de caso

Abstract Case description: Five-year-old female patient with hereditary hemorrhagic telangiectasia. Clinical Findings: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. Treatment and Outcome: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. Clinical Relevance: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome.

Resumen Descripción del caso: Paciente de cinco años de sexo femenino con telangiectasia hemorrágica hereditaria. Hallazgos Clínicos: Deterioro de la función cardiopulmonar con mayores requerimientos de oxígeno secundario a shunt pulmonar arteriovenoso, epistaxis. Tratamiento y resultado: La paciente fue tratada con el anticuerpo monoclonal bevacizumab, que inhibe el factor de crecimiento endotelial vascular, con buen resultado clínico. Relevancia clínica: La telangiectasia hemorrágica hereditaria es un trastorno autosómico dominante caracterizado por malformaciones arteriovenosas en diferentes órganos, lo que hace que sus presentaciones clínicas varíen. Las opciones terapéuticas sistémicas para la enfermedad generalizada son limitadas. El anticuerpo monoclonal bevacizumab, parece ser una buena opción en este trastorno. Aunque se ha reportado como exitoso en la población adulta, su uso en población pediátrica aún no ha sido reportado. Aquí se informa el uso de bevacizumab en una paciente de 5 años de edad con telangiectasia hemorrágica hereditaria, mostrando beneficios clínicos y buen resultado.