Use Of Angiogenesis Inhibitors Research Articles

Angiogenesis in Breast Cancer: A Review

Breast cancer is the leading cause of cancer related deaths worldwide. The development of new blood vessel from preexisting vasculature is associated to the growth and metastasis of breast cancer. The present review aimed to highlight the mechanisms of angiogenesis and the progression of malignancy in breast cancer. Poor breast cancer prognosis correlate with increased micro-vascular density and factors that stimulate vascular growth. Inhibiting angiogenesis of this process reduce the oxygen and nutrient supply. Therefore, tumor angiogenesis is a strategic therapeutic target for preventing breast cancer. We suggest the use of angiogenesis inhibitors to be explored to interrupt the process of tumor development.

A Retrospective Study Comparing Olaparib and Bevacizumab as a Maintenance Therapy for Platinum-Sensitive Recurrent Ovarian Cancer: Impact on Recurrence-Free Survival in Japanese and Asian Populations.

The use of angiogenesis inhibitors and poly ADP-ribose polymerase inhibitors following multi-agent chemotherapy, including platinum-based agents, has become the standard treatment for platinum-sensitive recurrent ovarian cancer (PSROC). However, the optimal maintenance therapy and selection criteria for these patients remain unclear. Thus, this study aimed to optimize the treatment options and selection criteria for patients with PSROC. The clinical data of 51 patients with PSROC admitted to Nippon Medical School Chiba Hokusoh Hospital and Nippon Medical School Hospital were retrospectively collected. The log-rank test was used for the survival analysis, and Cox proportional hazard regression analysis was used for the multivariate survival analysis. Of the 51 patients, 17 received maintenance therapy with bevacizumab (Bev), and 34 received olaparib (Ola). Recurrence-free survival (RFS) was significantly prolonged in the Ola group (27 months; 95% confidence interval (CI), 19-NA months) compared with that in the Bev group (9 months; 95% CI, 5-22 months; p = 0.000103). The efficacy of Ola was independent of background factors, including response to previous chemotherapy, homologous recombination status, histological type, or laboratory data. Ola is superior to Bev as PSROC maintenance therapy, especially in Japanese and Asian populations.

Глаукома псевдофакичного глаза

Relevance. Currently, there is a steady increase in the age-associated eye diseases worldwide. First of all, this applies to such ocular diseases as age-related maculodegeneration (AMD), glaucoma and cataracts. Despite the development and standardization of surgical techniques, the widespread introduction of cataract phacoemulsification, appearance of many modifications of anti-glaucomatous surgery, and the active use of angiogenesis inhibitors used to treat AMD, these diseases continue to occupy a leading position in the causes of low vision and blindness. Purpose. To reveal the problem of the development of pseudophakic glaucoma in patients who underwent surgical treatment for cataracts. Material and methods.To complete this review, we searched for literature sources on the PubMed and Scopus abstract databases for the period up to 2021 inclusive. In total, 53 articles related to the topic of the review were selected. The beginning of publications on this topic dates back to 1963. Results. At risk are patients with pseudoexfoliative syndrome, high-grade myopia, traumatic, diabetic and uveal cataracts. Pseudophakic glaucoma can also be caused by intraoperative (iris damage, vitreous prolapse, implantation of an intraocular lens outside the capsular bag, incomplete viscoelastic washout) and postoperative complications (inflammatory process, hyphema, dislocation of the artificial lens, pupillary block or Ellingson syndrome). Conclusion. Pseudophakic glaucoma, although rare, is quite formidable, which can reduce result of cataract surgery. Key words: pseudophakic glaucoma, glaucoma, cataract, ophthalmohypertension, complications of phacoemulsification

Arterial hypertension and anticancer drug therapy: pathophysiological relationships and clinical significance

Arterial hypertension (AH) is one of the most common cardiovascular complications of anticancer drug therapy. In this review article, we consider the main groups of anticancer drugs that may cause the development of iatrogenic AH, the pathophysiological mechanisms of increased blood pressure, as well as the clinical significance of AH developed during treatment with cytostatics and targeted drugs in the practice of an oncologist and a cardiologist. It was found that AH is frequently associated with the use of angiogenesis inhibitors, as well as alkylating cytostatics, antimetabolites, taxanes, and proteasome inhibitors. In addition, erythropoietins, glucocorticosteroids, and non-steroidal anti-inflammatory drugs used as part of supportive therapy may contribute to an increase in blood pressure. Management of hypertension in cancer patients is an important part of antitumor treatment therapy whose implementation contributes to improving their quality of life. Research into various clinical and pathophysiological aspects of cardiovascular disorders in cancer patients is becoming increasingly relevant, which is indicated by the rapid development of cardio-oncology, a new interdisciplinary field of knowledge aimed at developing practical recommendations for the prevention, diagnosis, and treatment of cardiovascular toxicity caused by anticancer therapy.

Targeting Microenvironment of Melanoma and Head and Neck Cancers in Photodynamic Therapy.

Photodynamic therapy (PDT), in comparison to other skin cancers, is still far less effective for melanoma, due to the strong absorbance and the role of melanin in cytoprotection. The tumour microenvironment (TME) has a significant role in tumour progression, and the hypoxic TME is one of the main reasons for melanoma progression to metastasis and its resistance to PDT. Hypoxia is also a feature of solid tumours in the head and neck region that indicates negative prognosis. The aim of this study was to individuate and describe systematically the main strategies in targeting the TME, especially hypoxia, in PDT against melanoma and head and neck cancers (HNC), and assess the current success in their application. PubMed was used for searching, in MEDLINE and other databases, for the most recent publications on PDT against melanoma and HNC in combination with the TME targeting and hypoxia. In PDT for melanoma and HNC, it is very important to control hypoxia levels, and amongst the different approaches, oxygen self-supply systems are often applied. Vascular targeting is promising, but to improve it, optimal drug-light interval, and formulation to increase the accumulation of the photosensitiser in the tumour vasculature, have to be established. On the other side, the use of angiogenesis inhibitors, such as those interfering with VEGF signalling, is somewhat less successful than expected and needs to be further investigated. The combination of PDT with immunotherapy by using multifunctional nanoparticles continues to develop and seems to be the most promising for achieving a complete and lasting antitumour effect.

Angiogenesis Pathway in Kidney Renal Clear Cell Carcinoma and Its Prognostic Value for Cancer Risk Prediction.

Angiogenesis, a process highly regulated by pro-angiogenic and anti-angiogenic factors, is disrupted and dysregulated in cancer. Despite the increased clinical use of angiogenesis inhibitors in cancer therapy, most molecularly targeted drugs have been less effective than expected. Therefore, an in-depth exploration of the angiogenesis pathway is warranted. In this study, the expression of angiogenesis-related genes in various cancers was explored using The Cancer Genome Atlas datasets, whereupon it was found that most of them were protective genes in the patients with kidney renal clear cell carcinoma (KIRC). We divided the samples from the KIRC dataset into three clusters according to the mRNA expression levels of these genes, with the enrichment scores being in the order of Cluster 2 (upregulated expression) > Cluster 3 (normal expression) > Cluster 1 (downregulated expression). The survival curves plotted for the three clusters revealed that the patients in Cluster 2 had the highest overall survival rates. Via a sensitivity analysis of the drugs listed on the Genomics of Drug Sensitivity in Cancer database, we generated IC50 estimates for 12 commonly used molecularly targeted drugs for KIRC in the three clusters, which can provide a more personalized treatment plan for the patients according to angiogenesis-related gene expression. Subsequently, we investigated the correlation between the angiogenesis pathway and classical cancer-related genes as well as that between the angiogenesis score and immune cell infiltration. Finally, we used the least absolute shrinkage and selection operator (LASSO)–Cox regression analysis to construct a risk score model for predicting the survival of patients with KIRC. According to the areas under the receiver operating characteristic (ROC) curves, this new survival model based on the angiogenesis-related genes had high prognostic prediction value. Our results should provide new avenues for the clinical diagnosis and treatment of patients with KIRC.

Assessing tumor angiogenesis using dynamic contrast-enhanced integrated magnetic resonance-positron emission tomography in patients with non-small-cell lung cancer

BackgroundAngiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC.MethodsThis prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), reverse reflux rate constant (kep), volume transfer constant (Ktrans), blood plasma volume fraction (vp), extracellular extravascular volume fraction (ve), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC60). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously.ResultsSerum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p < 0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, Ktrans, and kep, showed strong linear correlations (p < 0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p < 0.001), and kep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm3 (p = 0.046), Ktrans > 200 10− 3/min (p = 0.069), and kep > 900 10− 3/min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival.ConclusionsThe present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.

Modeling the atrophy of retinal pigment epithelium

Purpose : to develop easy-to make and reproducible models of retinal pigment epithelium atrophy (RPE) and retinal degeneration using two types of solution (0.9 % sodium chloride and bevacizumab) and to evaluate these models using clinical instrumental and pathomorphological studies. Material and methods . To create the two models, we used 60 New Zealand albino rabbits divided into 2 groups of 30 animals each (30 eyes). In group 1, 0.01 ml of 0.9 % sodium chloride solution was delivered into the subretinal space at a distance of 1–1.5 mm downwards from the optic disc forming a subretinal bladder, whilst group 2 received 0.01 ml of bevacizumab solution which contained 0.025 mg of the drug. Optical coherence tomography (OCT) and fundus autofluorescence imaging were performed in live rabbits’ eyes before and after the procedure on the 2nd, 7th, 14th, 24th, and 30th day using Heidelberg Spectralis™ SD-OCT (Heidelberg Engineering, Germany). The enucleated eyes were histologically evaluated 14 and 30 days after RPE atrophy modeling. Results . Two easily reproducible experimental models of RPE atrophy have been developed. Clinical and morphological indications of RPE atrophy are described. Histological analysis revealed a more aggressive action of 0.9% sodium chloride solution on the retina and the choroid as compared with the model obtained with a similarly delivered subretinal angiogenesis inhibitor. Conclusion . The obtained experimental models may be useful in investigating various types of RPE atrophy, including those arising from the use of angiogenesis inhibitors.

Применение лазерной коагуляции сетчатки при болезни Илза

Eales’ disease is an idiopathic occlusive inflammatory vasculopathy resulting in peripheral retinal ischemia, neovascularization, recurrent hemophthalmos, and proliferative tissue formation. It is often complicated by tractional retinal detachment, secondary glaucoma, and central retinal vein occlusion. The management of patients with Eales’ disease includes mainly glucocorticosteroid therapy, the use of angiogenesis inhibitors, vitreoretinal surgery and laser photocoagulation. The clinical case reported demonstrates the potential of retinal laser photocoagulation for treatment of the Eales’ disease in the ischemic and proliferative stages. The results of retinal laser photocoagulation used as monotherapy demonstrate the clinical and functional indices improvement: enhanced visual acuity, stabilized central retinal sensitivity value, restored clarity to the ocular media, regression of neovascularization and macular edema in the patient’s eye being in the proliferative (3b) stage, and the process stabilization in the eye being in the ischemic (2a) stage of the disease.

Применение ингибиторов ангиогенеза в комплексном лечении неоваскулярной глаукомы

Применение ингибиторов ангиогенеза в комплексном лечении неоваскулярной глаукомы

A differentiated approach to analysis of retinal fluid and assessment of its effect on anti-VEGF therapy of neovascular age-related macular degeneration

Neovascular age-related macular degeneration (nAMD) causes rapid irreversible vision loss presenting a serious socio-economic problem. The recommended approach to the treatment of this pathology is the use of angiogenesis inhibitors (anti-VEGF drugs). Following the proactive principles when conducting anti-VEGF treatment helps achieve the maximum therapeutic efficacy. The evolution of diagnostic capabilities and the rising awareness of the pathogenetic features of nAMD have contributed to implementation of a more personalized approach of conducting intravitreal injections, bringing to light the necessity of determining the diagnostic criteria for repeated anti-VEGF injections. Currently, the discourse looks at the subject of OCT criteria that could act as sufficiently reliable biomarkers to help decide the change in frequency of intravitreal injections. A differentiated approach to defining the role of retinal fluid as a marker of disease activity depending on the compartment of its localization on the OCT images has not been fully determined and is of particular scientific and practical interest. The importance of correct interpretation and understanding of differences in the effects of various types of retinal fluid on the frequency of anti-VEGF injections will be discussed in this review.

Abstract 20: Inhibition of mutant EGFR in NSCLC promotes endothelin-1-mediated NSCLC disease progression and angiogenesis

Abstract Despite recent advances in the treatment of NSCLC targeting of EGFR kinase domain mutations with tyrosine kinase inhibitors (TKIs), work needs to be done to reduce morbidity and improve survival for NSCLC patients. In NSCLC, tumor angiogenesis has been identified as important therapeutic target in combination with EGFR TKIs. However, only small advancements have been made for the use of angiogenesis inhibitors in NSCLC and it remains elusive why the inhibition of VEGF-mediated neovascularization is not therapeutically efficacious. We present evidence that a subpopulation of NSCLC cells with the EGFR TKI-induced epithelial to mesenchymal transition (EMT) contributes to the attenuation of response to anti-VEGF/VEGFR therapy. One of the hallmarks of cancer is heterogeneity and we have previously demonstrated that tumor heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations gives rise to divergent resistance mechanisms in response to treatment. In vivo admix models are instructive in studying intratumoral heterogeneity and in elucidating therapeutic responses. While NSCLC cell with acquired EGFR TKI resistance and EMT phenotype did not exhibit growth advantage in vivo, a 50% epithelial EGFR TKI sensitive and 50% mesenchymal EGFR TKI resistant admix provided significant growth advantage in vivo assessed by caliper measurement. Moreover, the admix tumors are resistant to EGFR TKI treatment. Interestingly, short-term in vitro co-culture of epithelial and mesenchymal cells did not provide a proliferative/growth advantage. The preliminary result led us to hypothesize that the epithelial-mesenchymal admix helps to create a tumor-host niche that is suitable for EGFR TKI resistance. To this end, we utilized the Luminex multiplex assay system to quantify secreted growth factors, cytokines, and chemokines. We have discovered that epithelial EGFR TKI sensitive cells secrete a significant amount of VEGF-A and cells with acquired/transient EGFR TKI resistance with an EMT phenotype secrete substantial amount of endothelin-1 (EDN1). Using an in vitro tube formation assay, we showed that secreted VEGF-A and EDN1 in admix conditions work synergistically to promote angiogenesis. Ectopic overexpression of EDN1 in EGFR-mutated HCC827 cells and predominantly secreting VEGF-A conferred significant resistance to gefitinib in vivo compared to control HCC827 cells. Importantly, the increased HUVEC cell tube formation in conditioned media from admix cells rich in both VEGF-A and EDN1 was significantly attenuated by the dual inhibition of VEGFR and EDNRA. Notably, the exposure of HCC4006 cells to 100nM gefitinib for 72 hours alone promoted transition from predominately VEGF-A secretion to EDN1 secretion. This suggests that the therapeutic efficacy of combining EGFR inhibitor with VEGFR inhibitors in the treatment of EGFR mutation positive NSCLC should be significantly tempered. Citation Format: Stephen L. Ollosi, Margaret Soucheray, Jeffrey Becker, Ines Pulido, Annika Dalheim, Fatima Al-Shahrour, Wei Qui, Michael Nishimura, Julian Carretero, Simon Kaja, Takeshi Shimamura. Inhibition of mutant EGFR in NSCLC promotes endothelin-1-mediated NSCLC disease progression and angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 20.

Association between ramucirumab-related hypertension and response to treatment in patients with metastatic gastric cancer.

PurposeHypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway, such as ramucirumab. The aim of this study was to retrospectively evaluate if occurrence of HTN is correlated with response to second line treatment with ramucirumab+paclitaxel for metastatic gastric cancer.MethodsTreatment consisted of ramucirumab 8 mg/kg intravenously (iv) on days 1 and 15, plus paclitaxel 80 mg/m2 iv on days 1, 8, and 15 of a 28-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or withdrawal of consent.ResultsThirty-four patients were retrospectively evaluated. Among these, 6 (17.6%) developed grade 3 ramucirumab-induced HTN. These patients had a better outcome than those with lesser grades events, with a progression-free survival (PFS) of 7.8 months (95% CI 4.4-not reached) versus 4.2 months (95% CI 3.1-5.2) (p=0.001). overall survival (OS) was 11.9 months (95% CI 9.3-not reached) in the grade 3 HTN group, versus 7.2 months (95% CI 5.9-10.1).ConclusionsDespite the small number of patients and the retrospective nature of the data, our analysis showed that occurrence of ramucirumab-related HTN, in particular G3 HTN, predicts response to treatment with ramucirumab+paclitaxel in patients with metastatic gastric cancer.

Angiogenesis inhibitors and symptomatic anal ulcers in metastatic colorectal cancer patients

Background: Angiogenesis inhibitors are a standard first-line treatment for metastatic colorectal cancer. Anal canal pain is a common adverse event, but its cause has never been described. The aim of the study was to evaluate the association between the use of angiogenesis inhibitors and symptomatic anal ulcer development.Methods: This retrospective cohort study included all 601 consecutive metastatic colorectal cancer patients undergoing first line treatment from January 2010 to June 2016 at the Veneto Institute of Oncology. Details about patient characteristics, treatment and proctology reports were retrieved and compared. Vascularization of the anal canal was evaluated with contrast MRI.Results: Fifty out of 601 patients reported perianal complaints during treatment and underwent proctologic evaluation. Among those, 16 were found to have an anal ulcer. Symptomatic anal ulcers occurred only in patients receiving bevacizumab (4.2% vs. 0% with other regimens, p = .009). The peak incidence was 4–8 weeks after treatment start. Vascularization of anal canal was significantly lower in patients treated with bevacizumab (p = .03). Hypertension and hemorrhoids were associated with a lower risk of anal ulcer occurrence (p = .009 and p = .036). Pain intensity was severe. All attempts at symptomatic treatment only led to transient benefit. The absence of symptomatic ulcers was protective against earlier permanent discontinuation of treatment (HR = .22, 95%CI: 0.04–0.62).Conclusions: The development of symptomatic anal ulcers in patients receiving angiogenesis inhibitor is a common adverse event which can compromise the continuation of cancer therapy. We recommend an early proctologic evaluation in case of anal symptoms with the aim to prevent and timely manage such complication.

Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced HCC patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group.

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (−0.30, p=0.0008) in the responder group (−0.58, p=0.003) than in those with progressive disease (−0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment.

Abstract 4115: BNC420 is a novel VEGFR3 selective inhibitor, which unlike the pan-VEGFR inhibitor Sunitinib, suppresses lymphatic metastasis in a model of metastatic melanoma

Abstract The dissemination of cancer cells through the lymphatic system is a well-known route of metastasis. Studies have implicated the hypoxic tumor microenvironment as an instigator of tumor cell invasion and metastatic spread. The use of angiogenesis inhibitors targeting VEGFR2 has been reported in preclinical models to augment metastasis through increased hypoxia within the tumor microenvironment. We have sought to identify a selective VEGFR3 targeting compound that will inhibit metastatic spread through lymphatic dissemination without the concomitant hypoxia induced metastasis effect associated with VEGFR2 targeting. BNC420 is a novel small molecule inhibitor of VEGFR3 phosphorylation that displays significant selectivity over VEGFR2. In phosphorylation detection ELISA based assays BNC420 exhibited a 25 fold greater potency for VEGFR3 over VEGFR2 with IC50 of 30nM and 744nM respectively. We investigated the activity of BNC420 and the pan-VEGFR inhibitor Sunitinib in the B16F10 murine melanoma model. This model involves the intradermal administration of B16F10 melanoma cells in the mouse ear resulting in the formation of a primary lesion, metastatic satellite lesions (in-transit) and regional lymph node metastasis. While Sunitinib slowed the growth of the primary lesion, as expected, it did not inhibit the development of lymph node metastasis and appeared to enhance the development of in-transit satellite lesions by 38% compared to its corresponding vehicle control. In contrast, only 20% of animals treated with BNC420 exhibited in-transit lesions compared to 53% in the corresponding vehicle control. Furthermore, a 50% reduction in the number of metastasis to the draining lymph nodes was seen in BNC420 treated animals. The lymph node metastatic lesions were significantly smaller compared to control and in some instances only detected under microscopic examination. Melanoma lesions in animals treated with BNC420 were devoid of peritumoral lymphatic vessels. These results demonstrate that selective inhibition of VEGFR3 utilising the novel small molecule BNC420 effectively inhibits the development of both in-transit metastatic lesions and lymph node metastasis while being unencumbered by the pro-metastatic effects that can accompany VEGFR2 inhibition through the induction of tumor hypoxia. Citation Format: Annabell Leske, Tina Lavranos, Donna Beaumont, Chloe Brown, Darham Paul, Daniel Inglis, Michaela Scherer, Andrew Harvey, Gabriel Kremmidiotis. BNC420 is a novel VEGFR3 selective inhibitor, which unlike the pan-VEGFR inhibitor Sunitinib, suppresses lymphatic metastasis in a model of metastatic melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4115. doi:10.1158/1538-7445.AM2015-4115

Hypertension in patients with cancer.

There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non-steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality.

CN-14 * RETROSPECTIVE ANALYSIS OF ISCHEMIC CEREBRAL STROKES IN PATIENTS DIAGNOSED WITH A GLIOBLASTOMA DURING THE COURSE OF A BEVACIZUMAB TREATMENT

Bevacizumab is an anti-vascular endothelial growth factor approved in the treatment of recurrent glioblastoma. It prolongs progression-free survival, improes radiologic response and contributes to reduce the dose of dexamethasone required to control peritumoral edema. Arterial and venous thromboembolic events represent significant toxicities related to the use of angiogenesis inhibitors. Various mechanisms could be implicated in bevacizumab-related strokes, as cardioembolic, lacunar stroke related to hypertension, deep venous thrombosis passing through a patent foramen ovale, pro-coagulant effect of the underlying glioblastoma and radiation-induced damages on peritumoral vessels. The characterization of the risk factors and stroke mechanisms is primordial since bevacizumab is currently used in the treatment of glioblastoma and VEGF receptor tyrosine-kinase inhibitors are actually in clinical trials for malignant gliomas. The prevention and optimal treatment of strokes depend on a precise description of the pathophysiological mechanisms involved. This retrospective study is performed with the collaboration of Roche to evaluate in detail risk factors and stroke mechanisms in the population of patients diagnosed with a glioblastoma who presented an ischemic cerebral stroke during the course of a bevacizumab treatment. The impact of the stroke on the overall survival and the location of the infarct in relation to the tumor emplacement will also be evaluated. This project will be completed in time for the SNO meeting, since we received the official approval from Roche and the ethics committee of Princess Margaret Hospital.

Targeting Angiogenesis

ABSTRACT Blood vessels constitute the first organ in the embryo and form the largest network in the body, but sadly are often deadly. Angiogenesis is the process of generating new capillary blood vessels. Vasculogenesis is the term used for spontaneous bloodvessel formation, and intussusception is the term for new blood vessel formation by splitting off existing ones. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. It is also a fundamental step in the transition of tumors from a dormant state to a malignant one, leading to the use of angiogenesis inhibitors. Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature. Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. In this review, we will present an overview of the knowledge gained in studies related to the identification and characterization of different inhibitors and regulators of angiogenesis and also to highlight briefly the pathological and physiological angiogenesis. How to cite this article Kaur M. Targeting Angiogenesis. Int J Head Neck Surg 2014;5(2):78-86.

Glioma and glioblastoma - how much do we (not) know?

Cancer is a heterogeneous disease, which provides a broad field for investigation, while simultaneously reducing the chances for a universal treatment. Malignant gliomas are the most common type of primary brain tumors. The heterogeneity of gliomas regarding clinical presentation, pathology and response to treatment makes this type of tumor a challenging area of research. As the clinical symptoms may be unspecific (e.g., seizures and headaches) it is often difficult to diagnose a patient in the early stages of the disease. Thus far, there are no known genetic patterns of inheritance of this disease. Currently, the treatment of glioblastoma involves surgery, whenever possible, followed by radiation and chemotherapy. Experimental procedures, such as passive and active immunotherapy, use of angiogenesis inhibitors in combination with chemotherapeutics and gene/antibody therapy, are additional treatment options. However, as the brain is difficult to access due to the presence of the blood-brain barrier (BBB), none of the above-mentioned therapies have been successful in curing this disease. The lack of knowledge regarding the mechanisms underlying the development and progression of gliomas further adds to the difficulties. Currently, investigations are focused on the development of novel methods for improving the outcome of this disease. However, despite the extensive investigations, 88% of all glioblastoma multiforme (GBM) patients succumb to the disease within 3 years. GBM remains one of the most challenging malignancies worldwide.