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Canine mammary gland tumor (CMT) is one of the most important tumors in intact female dogs, and due its similarity to human breast cancer (BC), it is considered a model in comparative oncology. A subset of mammary gland tumors can show aggressive behavior, and a recurrent histological finding is the presence of vasculogenic mimicry (VM). VM is a process in which highly aggressive cancer cells fuse, forming fluid-conducting channels without endothelial cells. Although, VM has been described in canine inflammatory carcinoma, no previous studies have investigated the prognostic and predictive significance of VM in CMT. Thus, this research aimed to investigate the prognostic significance of VM in vivo and the capacity of sorafenib to inhibit VM in vitro. VM was identified in situ in formalin-fixed paraffin-embedded CMT samples (n = 248) using CD31/PAS double staining. VM was identified in 33% of tumors (82/248). The presence of VM was more strongly related to tumor grade than to histological subtype. Patients with positive VM experienced shorter survival times than dogs without VM (P < 0.0001). Due to the importance of the VEGF-A/VEGFR-2 autocrine feed-forward loop in epithelial tumors, we investigated the association between VEGF-A and VEGFR-2 expression by neoplastic tumor cells and the associations of VEGF-A or VEGFR-2 expression with VM. Among the VM-positive samples, all (n = 82) showed high scores (3 or 4) for VEGF-A and VEGFR-2, indicating that VM was a common finding in tumors overexpressing VEGF-A and VEGFR-2. Thus, we cultured two CMT primary cell lines with VM abilities (CM9 and CM60) in vitro and evaluated the anti-tumoral effect of sorafenib. The CM9 cell line showed a half maximal inhibitory concentration (IC50) of 2.61 µM, and the CM60 cell line showed an IC50 of 1.34 µM. We performed a VM assay in vitro and treated each cell line with an IC50 dose of sorafenib, which was able to inhibit VM in vitro. Overall, our results indicated that VM was a prognostic factor for dogs bearing CMT and that sorafenib had an inhibitory effect on VM in CMT cancer cells in vitro.
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Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management.
Assuntos
Antineoplásicos/efeitos adversos , Imunoterapia/efeitos adversos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Qualidade de Vida , Dermatopatias/prevenção & controle , Consenso , Dermatologia , Gerenciamento Clínico , Humanos , Neoplasias/patologia , Dermatopatias/induzido quimicamente , Sociedades Médicas , VenereologiaRESUMO
Cancer is often complicated by venous thromboembolism (VTE), a common and potentially fatal complication associated with poor prognosis in these patients. An increased incidence of VTE is being observed due to the advanced age of cancer patients, the thrombogenic effect of novel drugs and advances in the diagnosis of related complications. In this review, we look at five different risk groups of cancer patients with an increased probability of developing VTE, including hospitalized patients undergoing chemotherapy, patients undergoing a surgical procedure, ambulatory patients undergoing chemotherapy, patients with a central venous access and patients receiving antiangiogenic drugs or anticoagulant therapy due to previous chronic diseases. The aim of this review is to summarize the most important clinical evidence reported to date on the suitability of primary thromboprophylaxis to cancer patients. Recommendations have drawn up for each group based on current evidence and guidelines to facilitate decision-making in clinical practice.
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Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Humanos , PrognósticoRESUMO
Angiogenesis is a driving force of a tumor's development. Targeting this process is an attractive option, as this is a feature shared by most of the solid tumors. A lot of antiangiogenic drugs have been developed following this path, including bevacizumab, sorafenib, sunitinib, vandetanib, ramucirumab, motesanib and many others. The latest drug of this class to be approved for patients with non-small cell lung cancer (NSCLC) was nintedanib, a triple angiokinase inhibitor. This molecule targets vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways, avoiding the tumor's switch to normal escape mechanisms. The pharmacokinetic, pharmacodynamic and toxicity profiles of nintedanib have been tested in several studies. These trials revealed it to be very interesting, as this agent did not lead to the classical adverse events of other tyrosine kinase inhibitors. A phase III clinical trial that recently concluded provided us with relevant information in patients with NSCLC of adenocarcinoma histology. Here we present a short overview of the tumor angiogenesis pathways and antiangiogenic drugs. In particular, we will focus on nintedanib, from the preclinical studies to the latest phase III clinical trial that allowed this new agent to be approved by the European Medicines Agency as a second-line treatment option in association with docetaxel for NSCLC patients with adenocarcinoma histology.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/efeitos adversos , Indóis/farmacologia , Neoplasias Pulmonares/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologiaRESUMO
AIM: To evaluate histopathological retinal and renal response after one single dose of intravitreous injection of antiangiogenic drugs ranibizumab and bevacizumab in rats. METHODS: Experimental study in 60d of life adults Wistar rats. Ten animals were included. Group 1 included 5 animals that were injected with 1 µL ranibizumab 1.25 mg in the right eye and with 1 µL of balanced salt solution (BSS) in the left eye, as control; Group 2 included 5 animals that were injected with 1 µL of bevacizumab in the right eye and with 1 µL of BSS in the fellow eye. All injections were performed with Hamilton syringes. After 15d of the interventions, all animals were sacrificed in CO2 chamber. Both eyes were enucleated and one kidney was removed, fixed and embedded in paraffin for histopathological analysis by optic microscopy. For statistical purposes the initial expected abnormal histopathological responses were defined as 0%. RESULTS: Atypical histopathological retinal response was detected in 2 eyes injected with ranibizumab (40%) as well as in 2 control eyes in group 1. Same was detected in 1 eye injected with bevacizumab (20%) as well as in 1 control eye, in group 2. The noted atypical findings were lymphocytes and eosinophils in the vitreous posterior cavity and mild retinal inflammatory reaction with ganglion cell layer edema but without clinical significance. No atypical histopathological renal response was detected. CONCLUSION: Unexpected atypical histopathological retinal response without clinical significance was observed in 3 eyes injected with antiangiogenic drugs (2 in group 1 and 1 in group 2) as well as in 3 control eyes (2 in group 1 and 1 in group 2). No atypical renal response was detected suggesting no extra ocular involvement of the intravitreous injected antiangiogenic drugs.
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Se realizó una revisión sobre el tratamiento de la neovascularización coroidea en la miopía degenerativa. Se consultaron fundamentalmente artículos científicos de revistas publicados e indexados en las bases de datos PubMED y Cochrane, así como textos básicos que abordan este tema. No se encontraron certezas del beneficio de la fotocoagulación con láser de las lesiones neovasculares en esta entidad, mientras que la terapia fotodinámica parece brindar estabilidad de la lesión y mejoría visual, al menos a los 3 años de seguimiento. El uso de antiangiogénicos intravítreos tiene los mejores resultados en la actualidad respecto a la inactivación de la lesión y la recuperación visual pero no hay ensayos clínicos controlados que avalen su beneficio a largo plazo. Otras opciones de tratamiento se encuentran en investigación y desarrollo. No se ha concebido el protocolo ideal para tratar las membranas neovasculares miópicas
A literature review on the treatment of the choroidal neovascularization in the degenerative myopia was made. Published scientific articles of journals indexed in Pubmed and Cochrane databases, as well as basic texts that deal with this topic. No evidences of the benefits of the laser photocoagulation for neovascular lesions were found, whereas the photodynamic therapy seems to offer stability of the lesion and visual improvement after three years of follow-up. The use of intravitreous antiangiogenic drugs has currently achieved the best results in terms of lesion inactivation and visual recovery, but there are no controlled clinical trials that support their long-term benefits. Other treatment options are under research and development. The ideal protocol of treatment of neovascular myopic membranes has not yet been devised
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Humanos , Inibidores da Angiogênese/uso terapêutico , Miopia Degenerativa/complicações , Neovascularização de Coroide/patologia , Neovascularização de Coroide/terapiaRESUMO
PURPOSE: To evaluate the use of subconjunctival bevacizumab on corneal neovascularization in an experimental rabbit model for its effect on vessel extension, inflammation, and corneal epithelialization. METHODS: In this prospective, randomized, blinded, experimental study, 20 rabbits were submitted to a chemical trauma with sodium hydroxide and subsequently divided into two groups. The experimental group received a subconjunctival injection of bevacizumab (0.15 m; 3.75 mg), and the control group received an injection of 0.15 ml saline solution. After 14 days, two blinded digital photograph analyses were conducted to evaluate the inflammation/diameter of the vessels according to pre-established criteria. A histopathological analysis of the cornea evaluated the state of the epithelium and the number of polymorphonuclear cells. RESULTS: A concordance analysis using Kappa's statistic showed a satisfactory level of agreement between the two blinded digital photography analyses. The neovascular vessel length was greater in the control group (p<0.01) than in the study group. However, the histopathological examination revealed no statistically significant differences between the groups in terms of the state of the epithelium and the number of polymorphonuclear cells. CONCLUSIONS: Subconjunctival bevacizumab inhibited neovascularization in the rabbit cornea. However, this drug was not effective at reducing inflammation. The drug did not induce persistent corneal epithelial defects.