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1.
Urologe A ; 59(2): 149-154, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32076796

RESUMO

In view of a considerable risk of recurrence especially in patients with a high-risk profile after organ-sparing surgery or nephrectomy, adjuvant treatment seems to make sense in renal cell carcinoma. After the failed attempts using older immunotherapeutics or vaccination therapies, new hope was put in the panel of targeted VEGF/R inhibitors. But the results from these studies published so far are also disappointing. In this context the instruments for selecting the best suitable patients for adjuvant trials have to be discussed. It remains to be seen whether using the same selection criteria as in ongoing trials with checkpoint inhibitors will show better results.


Assuntos
Carcinoma de Células Renais/terapia , Quimioterapia Adjuvante/métodos , Neoplasias Renais/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia , Nefrectomia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
2.
Nat Commun ; 11(1): 694, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019921

RESUMO

Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.


Assuntos
Doenças Retinianas/tratamento farmacológico , Sunitinibe/administração & dosagem , Animais , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coelhos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Doenças Retinianas/genética , Doenças Retinianas/metabolismo , Sunitinibe/química , Sunitinibe/farmacocinética , Suínos , Porco Miniatura , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Cancer Treat Rev ; 84: 101966, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32044644

RESUMO

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.


Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Anilidas/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/farmacologia , Axitinibe/uso terapêutico , Interações Medicamentosas , Humanos , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico
4.
Expert Opin Drug Saf ; 19(2): 223-228, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31698959

RESUMO

Objectives: Recent studies have shown an increase risk of cardiovascular and hematological adverse events associated with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). The authors hypothesize that the original studies may have produced exaggerated results because of the small baseline risks involved.Methods: A meta-analysis that included 71 trials, 8 different VEGFR-TKIs, and 11 adverse events were re-analyzed. The outcome of interest was re-defined as the complementary outcome (i.e. remaining free of an adverse event). The inverse variance heterogeneity model was used to pool the effect size.Results: VEGFR-TKIs decreased the risk of remaining free of hypertension by 7% (RR 0.93; 95%CI:0.88-0.97). Specific VEGFR-TKIs; pazopanib, regorafenib, and nintedanib were associated with a decrease risk of remaining free of an arterial thrombotic event (RR 0.96; 95%CI:0.93-0.99), thrombocytopenia (RR 0.91; 95%CI:0.89-0.93), and bleeding (RR 0.96; 95%CI:0.93-0.99) respectively. VEGFR-TKIs were not associated with the thrombotic event, myocardial infarction, stroke, venous thrombotic event, pulmonary embolism, left ventricular dysfunction, or QTc interval prolongation.Conclusion: VEGFR-TKIs are associated with a small increase in the risk of patients developing hypertension, arterial thrombotic events, thrombocytopenia, and bleeding. Previous studies overestimated the actual risk associated with VEGFR-TKIs by analyzing the outcome with the lower baseline risk.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Hematológicas/epidemiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Doenças Cardiovasculares/etiologia , Doenças Hematológicas/etiologia , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
5.
Medicine (Baltimore) ; 98(50): e18089, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852067

RESUMO

RATIONAL: The growing population of young cancer survivors and a trend toward postponing pregnancy until later years in life are leading to a deeper attention towards understanding treatment-induced sequelae, and, in particular, the effects of cancer and/or treatment on fertility. Nowadays, the infertility risks potentially associated with molecular targeted therapies are not established, and clinical reports are sparse. Moreover, the increasing use of molecular targeted drugs in the adjuvant setting and in diseases with better prognosis makes preservation of fertility a major topic in current research. PATIENT'S CONCERNS: Here, we report the case of an 18-year-old woman, with a 3-cm superficial lump of the right breast, who had no remarkable family or medical history. Menarche had occurred at the age of 14 years, with normal regular periods. DIAGNOSIS: High-grade angiosarcoma, with metastatic progression and multiple relapse, was diagnosed. INTERVENTIONS: After diagnosis, right radical mastectomy was carried out with no evidence of residual disease. No adjuvant treatment was delivered. Lymph node metastasis were found later and chemotherapy with doxorubicin 25 mg/m/day and ifosfamide 1 g/m/day (both on days 1-3) every 21 days was administered. During treatment, the patient reported menstrual irregularities but no amenorrhea. Due to further local relapse a few years later, the patient was treated for progressive metastatic disease with gemcitabine 1000 mg/m on days 1 and 8 every 21 days for 6 cycles, and underwent surgery, followed by pegylated liposomal doxorubicin, 50 mg/m on day 1 every 28 days. After further disease progression 5 years after first diagnosis, pazopanib was administered at a dose of 800 mg daily for 10 months. OUTCOMES: The patient experienced a transient ovarian insufficiency possibly due to pazopanib. Since amenorrhea developed within 2 months from the initiation of pazopanib treatment and menses returned regularly only after discontinuation of the treatment itself. LESSONS: This is the first case report that strongly suggests a correlation between pazopanib exposure and development of ovarian insufficiency. Our case tantalizes to inspire additional preclinical and clinical research on the true incidence, possible dose dependence, and reversibility of pazopanib (and other TKIs) -induced ovarian failure.


Assuntos
Neoplasias da Mama/terapia , Hemangiossarcoma/terapia , Insuficiência Ovariana Primária/induzido quimicamente , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Adolescente , Terapia Combinada , Endossonografia/métodos , Feminino , Humanos , Mastectomia , Insuficiência Ovariana Primária/diagnóstico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Vagina
6.
Cancer Treat Rev ; 81: 101912, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715423

RESUMO

Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mutação , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptor TIE-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas ras/genética
7.
Rom J Ophthalmol ; 63(3): 281-286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687633

RESUMO

Objective: To describe the chronological features of choroidal neovascular membrane (CNV) development subsequent to accidental firing of diode laser into the eye of a young female during hair epilation. Methods: Descriptive case report. Results: The patient presented one week after the laser injury to a local ophthalmologist complaining of RE (right eye) blurred central vision. Snellen's visual acuity (VA) was 6/ 7.5. Optical coherence tomography (OCT) showed focal disruption of the ellipsoid and the interdigitation zones. Four weeks later, she presented with worsening symptoms and RE VA 6/ 15. Funduscopy revealed a perifoveal grayish lesion with adjacent retinal hemorrhage, which, on fluorescein angiography, was leaking, compatible with CNV. OCT showed a dome-shaped sub-retinal pigment epithelium lesion with extension into the subretinal space and little subretinal fluid. The patient was treated with one intravitreal bevacizumab injection. There was rapid regression of the CNV and improvement of VA to 6/ 7.5 at one-month visit and to 6/ 6 at 6-month visit. Conclusion: All the laser procedures should be conducted with intensive care for both the patient and the laser surgeon since inadvertent effects are constantly being reported due to lack of adherence to safety measures.


Assuntos
Neovascularização de Coroide/etiologia , Remoção de Cabelo/efeitos adversos , Terapia a Laser/efeitos adversos , Acuidade Visual , Adulto , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Neovascularização de Coroide/diagnóstico , Feminino , Remoção de Cabelo/métodos , Humanos , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica
8.
Jpn J Ophthalmol ; 63(5): 389-395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31376050

RESUMO

PURPOSE: To determine the association of age-related maculopathy susceptibility 2 (ARMS2) gene polymorphisms with the 12-month outcomes of intravitreal aflibercept combined with photodynamic therapy (IVA+PDT) in polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: Interventional cohort study. METHODS: This was a retrospective study of 48 consecutive treatment-naïve PCV patients. The patients underwent IVA+PDT as the initial therapy and were followed up for more than 12 months under a pro re nata regimen. The single nucleotide polymorphism (SNP) at rs10490924 in the ARMS2 gene was genotyped using the TaqMan assay. The clinical characteristics and outcomes of IVA+PDT were compared among the 3 genotypes at rs10490924. Multivariate regression analysis was performed to evaluate the influence of the clinical cofactors on the association of rs10490924 with the visual outcome at 12 months after the first IVA+PDT. RESULTS: No significant difference was found in the baseline characteristics among the 3 genotypes (n = 9, 23, and 16 for the GG, GT, and TT genotypes, respectively). All the patients, regardless of genotype, showed a significant improvement in vision, central retinal thickness, and subfoveal choroidal thickness at all time points measured after the initial IVA+PDT. The number of treatments was significantly smaller in the patients with the GG genotype than in those with the GT or the TT genotype. On multivariate logistic regression analysis, the number of the T allele at rs10490924 was significantly associated with the chance of retreatment after the initial IVA+PDT. CONCLUSION: The presence of the G allele at rs10490924 in the ARMS2 gene is likely associated with a lower chance of retreatment after IVA+PDT in patients with PCV.


Assuntos
Doenças da Coroide/tratamento farmacológico , Corioide/irrigação sanguínea , Predisposição Genética para Doença , Degeneração Macular/etiologia , Fotoquimioterapia/métodos , Pólipos/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Alelos , Doenças da Coroide/complicações , Doenças da Coroide/diagnóstico , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Variação Genética , Humanos , Injeções Intravítreas , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Masculino , Polimorfismo de Nucleotídeo Único , Pólipos/complicações , Pólipos/diagnóstico , Proteínas/genética , Proteínas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Acuidade Visual
9.
Graefes Arch Clin Exp Ophthalmol ; 257(9): 1897-1913, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327036

RESUMO

PURPOSE: Putative roles of long non-coding RNAs (lncRNAs) as indicators for diabetic retinopathy (DR) and associated complications are beginning to emerge. We aimed to evaluate a panel of circulating hyperglycemia-related lncRNAs: RNCR2, NEAT2, CDKN2B-AS1, and PVT1 in type 2 diabetes patients with/without DR and to correlate their levels with the clinical characteristics and response to aflibercept intravitreal injection in terms of visual acuity (VA) improvement, central macular thickness (CMT) decline, and macular edema resolution after 4 weeks of the initial injection. METHODS: Pre-treatment plasma relative expression levels of the specified lncRNAs were quantified in 130 consecutive patients with diabetes (75 and 55 with/without DR, respectively) and 108 controls using quantitative real-time PCR. RESULTS: One month after aflibercept injection, significant reductions in CMT and VA were observed in DR cohorts. The four lncRNAs were over-expressed in DM compared with those in controls. However, downregulated baseline plasma levels of RNCR2 and NEAT2 were observed in glycemic-controlled DR patients. None of the lncRNAs showed a correlation with the severity of retinopathy or drug response. CONCLUSION: Though circulating levels of the analyzed lncRNAs did not show an association with DR progression or aflibercept therapy response, the expression pattern demonstrated good diagnostic performance in differentiating DM from controls and DR.


Assuntos
Retinopatia Diabética/sangue , RNA Longo não Codificante/sangue , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA/genética , RNA Longo não Codificante/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Retina/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento , Acuidade Visual
10.
Semin Ophthalmol ; 34(6): 420-435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314638

RESUMO

Background: Age-related macular degeneration is the leading cause of blindness in adults over the age of 50 in the United States of America. Neovascular age-related macular degeneration (nAMD) is sight-threatening, but can be treated by three currently utilized, intravitreally administered drugs: aflibercept, bevacizumab, and ranibizumab. Ziv-aflibercept is an analogue of aflibercept, containing the same active molecule in a different buffer solution, and its recent availability has prompted numerous pre-clinical and clinical trials addressing its viability for intraocular use, summarized herein. Results: Trial outcomes demonstrate that ziv-aflibercept has a similar safety profile to other indicated drugs with effective maintenance or improvement of best-corrected visual acuity (BCVA) and reduction of retinal fluid or central foveal thickness (CFT). Clinical trials of ziv-aflibercept in other neovascular disorders such as diabetic macular edema (DME) and retinal vein occlusion (RVO) have shown similar results. Conclusion: Further prospective, randomized studies of ziv-aflibercept are needed, particularly in eyes with nAMD.


Assuntos
Degeneração Macular/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Relação Dose-Resposta a Droga , Humanos , Injeções Intravítreas , Macula Lutea/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica , Resultado do Tratamento
11.
Arterioscler Thromb Vasc Biol ; 39(8): 1652-1666, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31294623

RESUMO

OBJECTIVE: We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A-positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti-VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. CONCLUSIONS: VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Elastase Pancreática/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Quimiotaxia/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Camundongos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sunitinibe/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Graefes Arch Clin Exp Ophthalmol ; 257(10): 2119-2125, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286206

RESUMO

PURPOSE: To analyze and compare loss to follow-up (LTFU) rates between patients with diabetic retinopathy (DR) and those with neovascular age-related macular degeneration (nAMD) in patients, receiving treatment with anti-vascular endothelial growth factor (VEGF), under universal health coverage. METHODS: We retrospectively analyzed the relevant data of 1264 patients receiving anti-VEGF therapy, in this cohort study. The observation period ranged from September 01, 2015 to December 31, 2018. Intervals between each procedure and the subsequent follow-up examination were measured. Demographic data, visual acuity (VA), the type of transport for treatment access, and distance between the residence and clinic were evaluated as risk factors for LTFU. RESULTS: We collected data for 841 patients with nAMD (age, 81.0 (± 8.1 years)) and 423 patients with DR (age, 67.7 (± 12.1 years)). The rate of LTFU, for at least 6 months, was 28.8% and 2.9% for patients with DR and nAMD, respectively (p < 0.001). In the DR group, 18.9% patients were lost to follow-up exceeding > 12 months. Multivariate regression analysis showed that advanced age, lack of mobility, and need for assisted transport, poor final VA despite treatment, and decrease in vision during the observational period were independent risk factors for LTFU exceeding 12 months (p < 0.05). CONCLUSIONS: We found a high long-term LTFU rate for patients with DR, despite treatment under universal health coverage. Considering the risk of disease progression, particularly in patients with chronic DR, strategies for better compliance and adherence to therapy should be considered for optimized patient care.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Cobertura do Seguro , Degeneração Macular/tratamento farmacológico , Cooperação do Paciente , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/economia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Macula Lutea/patologia , Degeneração Macular/diagnóstico , Degeneração Macular/economia , Masculino , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento
13.
Graefes Arch Clin Exp Ophthalmol ; 257(9): 1889-1895, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31256237

RESUMO

PURPOSE: To compare treatment efficacy of anti-VEGF medications following pro re nata (PRN, "as needed", monthly injections only in case of active disease) or treat and extend (T&E, progressive extension of treatment intervals up to 12 weeks depending on the clinical findings) treatment protocols in real-world conditions. METHODS: Retrospective, observational study. Patients diagnosed with age-related macular degeneration and without pre-treatment undergoing routine anti-VEGF treatment in one eye clinic in Switzerland were included. Treatment was performed according to local practices, using ranibizumab or aflibercept, and following T&E or PRN regimens. Changes in logMAR and injection intervals (time between two injections) for specific treatment periods were evaluated descriptively and using mixed models. RESULTS: In total, 1071 patients with 1332 treated eyes (ranibizumab/PRN 722, ranibizumab/T&E 191, aflibercept/T&E 419) were included in the analyses. At baseline, logMAR (mean ± SD) was similar in both ranibizumab treatment groups (PRN 0.63 ± 0.43, T&E 0.57 ± 0.42). In the ranibizumab/PRN group, logMAR was about 0.1 lower for all time intervals in the initial and maintenance phases in comparison with baseline, indicating an improvement in VA. By comparison, logMAR improved more strongly in the ranibizumab/T&E group (16 to < 22 months, - 0.19 [- 0.23-0.15]) in comparison with baseline. Comparing ranibizumab/T&E vs. aflibercept/T&E groups, improvements in logMAR were similar over time. In the maintenance phase, the rate of patients with a clinically relevant improvement in visual acuity (> 0.2 logMAR) was higher in both T&E groups compared with the ranibizumab/PRN group. Injection intervals in the maintenance phase in ranibizumab/T&E group gradually expanded over time; whereas in the aflibercept/T&E group, injection intervals remained relatively stable. CONCLUSIONS: Ranibizumab used according to T&E protocol yielded a stronger improvement in logMAR, compared with PRN protocol with longer injection intervals than aflibercept/T&E. This large real-world data assessment supports previous data on the superiority of T&E treatment.


Assuntos
Macula Lutea/patologia , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Degeneração Macular Exsudativa/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento , Degeneração Macular Exsudativa/diagnóstico
14.
Medicine (Baltimore) ; 98(23): e15806, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169681

RESUMO

BACKGROUND: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have been developed for targeted therapies in non-small-cell lung cancer (NSCLC); moreover, some drug-related toxic reactions among cancer patients have been reported. A meta-analysis of randomized controlled trials (RCTs) to definite the incidence and the risk of grade ≥3 adverse events (AEs), serious and fatal AEs (SAEs and FAEs), with VEGFR-TKIs in advanced/metastatic NSCLC patients was performed. METHODS: A comprehensive literature search was conducted for the clinical trials published up to December 2017. Qualified studies allotted patients with advanced/metastatic NSCLC to receive either chemotherapy alone or in combination with VEGFR-TKIs. Data were extracted by 2 authors. RESULTS: Eighteen RCTs of VEGFR-TKIs plus chemotherapy, involving 8461 advanced NSCLC patients were included. The proportion of patients with grade ≥3 AEs was increased with the addition of VEGFR-TKIs (relative risk, 1.35; 95% confidence interval [CI] 1.19-1.52; incidence, 68.1% vs 50.1%; P < .001). The most common grade ≥3 AEs was neutropenia (24.9% vs 15.4%, P < .001). Addition of VEGFR-TKIs was also related to the increased risk of SAEs (relative risk, 1.34; 95% CI 1.14-1.56; incidence, 37.8% vs 27.9%; P < .001) and FAEs (relative risk, 2.16, 95% CI 1.47-3.19; incidence, 3.4% vs 1.8%). Subgroup analysis suggested there was no difference in the rates of SAEs and FAEs in the second-line settings. No evidence of bias was found between the literatures. The study was registered with PROSPERO (CRD42018099654). CONCLUSIONS: In comparison with chemotherapy alone, the addition of VEGFR-TKIs in advanced NSCLC patients was related to the increased risk of grades ≥3 AEs, SAEs, and FAEs, especially in the first-line settings. Physicians should be aware of some specific grade ≥3 adverse effect, especially haematologic adverse events, and it is also necessary to monitor cancer patients receiving VEGFR-TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Ophthalmologica ; 242(4): 239-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163436

RESUMO

INTRODUCTION: Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (nAMD). Untreated, the lesions are thought to be aggressive and lead to a poor visual outcome. Despite some limitations, studies reporting the treatment of RAP lesions with the intravitreal anti-VEGF drugs ranibizumab and bevacizumab have demonstrated variable but generally favourable responses. More recently, aflibercept has been licensed for the treatment of nAMD and may offer some advantages over other agents. We present the visual and anatomical outcomes at 96 weeks of patients with RAP lesions who were treated with intravitreal aflibercept, according to the pivotal VIEW study nAMD treatment protocol. METHODS: This is a prospective study of treatment-naïve patients with Reading Centre-graded RAP lesions. The patients received aflibercept every 8 weeks, after 3 initial monthly injections, up to and including week 48. During weeks 52-96, patients received injections at least every 12 weeks, with monthly evaluations for interim injections if they fulfilled the retreatment criteria. At each visit, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) central macular thickness (CMT) were measured. RESULTS: Forty-six patients reached study completion at week 96. Mean BCVA had improved by 6.0 (standard deviation [SD] 7.9) and 4.8 (SD 7.4) ETDRS letters at 52 (p = 0.003) and 96 (p = 0.02) weeks, respectively, from a baseline of 57.3 (SD 12.0) letters. At 52- and 96-week time points, 45/46 (98%) and 41/46 (89%) of patients, respectively, had maintained their vision (<15 letters of BCVA lost). At the 96-week time point, 13/46 (28%) of patients had gained ≥15 letters and also demonstrated a mean reduction in CMT of 162 µm (SD 106) (p = <0.0001), with 72% of maculae being fluid-free. Using univariate analysis, we found no significant difference between any of the visual outcome measures in this study and the pivotal VIEW study; the mean number of injections required and change in CMT were also similar. CONCLUSIONS: In this study, we present the 96-week results, of the largest series to date, of patients treated prospectively with aflibercept for RAP using the VIEW protocol. We show that they benefited from treatment to a degree similar to those with type 1 and 2 nAMD.


Assuntos
Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Retina/patologia , Perfurações Retinianas/tratamento farmacológico , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Masculino , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Perfurações Retinianas/diagnóstico , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento
16.
Indian J Ophthalmol ; 67(7): 1193-1194, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31238461

RESUMO

We report a rare case of deep anterior lamellar keratoplasty (DALK) neovascularization managed with combination of subconjunctival bevacizumab and argon laser photocoagulation. A 24 year old male underwent Deep anterior lamellar keratoplasty for corneal stromal opacity following presumed viral keratitis. Deep corneal neovascularization was observed postoperatively which was successfully managed using a combination of subconjunctival bevacizumab and argon laser photocoagulation within one week of DALK. The neovascularization resolved by 3 months and at 2 years follow up, patient maintained good visual acuity of 6/12 Snellen's without recurrence of vascularization. A combination of bevacizumab and argon laser may be an effective approach to manage neovascularisation in the immediate postoperative phase (Post DALK) and improve graft survival.


Assuntos
Bevacizumab/administração & dosagem , Neovascularização da Córnea/terapia , Ceratite/cirurgia , Ceratoplastia Penetrante/efeitos adversos , Terapia a Laser/métodos , Lasers de Excimer/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Túnica Conjuntiva , Neovascularização da Córnea/etiologia , Sobrevivência de Enxerto , Humanos , Injeções , Masculino , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
17.
Future Oncol ; 15(20): 2337-2348, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31184937

RESUMO

Von Hippel-Lindau (VHL), a tumor suppressor gene, is frequently inactivated in renal cell carcinoma (RCC). It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC. Resistance to VEGFR therapy eventually occurs, in part due to activation of alternative signaling pathways like AXL and MET. Cabozantinib is a potent inhibitor of VEGF, AXL and MET receptors providing rationale for its use in RCC. Cabozantinib has been approved for use in the first- and second-line setting in patients with advanced RCC. This manuscript reviews the preclinical data, pharmacology, clinical efficacy and safety of the use of cabozantinib in RCC.


Assuntos
Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Administração Oral , Anilidas/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Proteína Supressora de Tumor Von Hippel-Lindau/genética
18.
Korean J Ophthalmol ; 33(3): 259-266, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31179657

RESUMO

PURPOSE: To evaluate the changes in visual acuity (VA) and central macular thickness (CMT) after intravitreal dexamethasone (IVD) implantation in intravitreal bevacizumab (IVB) treatment-resistant cases with pseudophakic cystoid macular edema (PCME). METHODS: This study included 10 PCME cases who underwent uneventful phacoemulsification and intraocular lens implantation with similar methods and six PCME cases referred to our hospital for treatment of low VA after cataract surgery. Due to the persistence of PCME, both topical steroid and anti-inflammatory medication were administered first, followed by IVB injection. IVD implantation was performed for all IVB treatment-resistant cases. VA and CMT values were compared before and at three months after the first IVD implantation. RESULTS: The mean VA values before and at 3 months after the first IVD implantation were 0.69 ± 0.19 logarithm of the minimum angle of resolution (logMAR) (1.50 to 0.10 logMAR) and 0.26 ± 0.07 logMAR (1.00 to 0.00 logMAR), respectively (p < 0.001). The mean CMT was 476.13 ± 135.13 mm (314 to 750 mm) and 294.06 ± 15.26 mm (222 to 480 mm), respectively (p < 0.001). The mean number of implanted IVD was 1.44 ± 0.89 (1 to 4) and the mean follow-up time was 7.4 ± 4.6 months (6 to 24 months). After IVD implantation therapy, the mean VA and CMT values were 0.19 ± 0.05 logMAR (0.70 to 0.00 logMAR) and 268.38 ± 31.35 mm (217 to 351 mm), respectively. CONCLUSIONS: To the best of our knowledge, this is the first report to show the efficacy of IVD implantation even after repeated IVB injections in treatment-resistant PCME. IVD implantation is both a safe and effective method for decreasing PCME after both uneventful and complicated cataract surgery.


Assuntos
Bevacizumab/administração & dosagem , Dexametasona/administração & dosagem , Resistência a Medicamentos , Macula Lutea/patologia , Edema Macular/tratamento farmacológico , Pseudofacia/complicações , Acuidade Visual , Idoso , Inibidores da Angiogênese/administração & dosagem , Implantes de Medicamento , Feminino , Glucocorticoides/administração & dosagem , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Facoemulsificação , Pseudofacia/diagnóstico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica
19.
Neurology ; 93(2): e143-e148, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167931

RESUMO

OBJECTIVE: To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer. METHODS: Published data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment. RESULTS: Thirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13-2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09-2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01-1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06-1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09-1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control. CONCLUSIONS: VEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.


Assuntos
Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Humanos
20.
Expert Rev Clin Pharmacol ; 12(8): 713-721, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177854

RESUMO

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect. Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed. Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Benzofuranos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
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