Cardiovascular Damage Induced by Anti-VEGF Therapy

Vascular endothelial growth factor (VEGF) plays an important role in maintaining the regular homeostasis of vascular walls. VEGF binds its receptor (VEGFR) promoting the regular survival and function of endothelial cells. Anti-VEGF and anti-VEGFR drugs inhibit the action of VEGF and VEGFR. These drugs can cause cardiovascular toxic effects such as arterial hypertension, thromboembolism, myocardial ischemia and heart failure. The monoclonal antibody bevacizumab and tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, regorafenib, axitinib, cabozantinib, ponatinib) are the main inhibitors of VEGF, VEGFR and other tyrosine kinases. In this chapter we will illustrate the cardiovascular …

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Abstract: The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to…

Metastatic site location influences the diagnostic accuracy of ctDNA EGFR- mutation testing in NSCLC patients: a pooled analysis

Background: Recent studies evaluated the diagnostic accuracy of circulating tumor DNA (ctDNA) analysis in the detection of epidermal growth factor receptor (EGFR) mutations from plasma of NSCLC patients, overall showing a high concordance as compared to standard tissue genotyping. However it is less clear if the location of metastatic site may influence the ability to identify EGFR mutations. Objective: This pooled analysis aims to evaluate the association between the metastatic site location and the sensitivity of ctDNA analysis in detecting EGFR mutations in NSCLC patients. Methods: Data from all published studies, evaluating the sensitivity of plasma-based EGFRmutation testing, stratifi…

Role of curcumin in idiopathic pulmonary arterial hypertension treatment: A new therapeutic possibility

The idiopathic pulmonary arterial hypertension is a complex disease that mainly affects pulmonary arterial circulation. This undergoes a remodeling with subsequent reduction of flow in the small pulmonary arteries. Because of this damage an increased vascular resistance gradually develops, and over time it carries out in heart failure. The inflammatory process is a key element in this condition, mediated by various cytokines. The inflammatory signal induces activation of NF-κB, and prompts TGF-β-related signaling pathway. Clinical evolution leads to progressive debilitation, greatly affecting the patient quality of life. The actual therapeutic approaches, are few and expensive, and include …

Immunotherapy for recurrent ovarian cancer: a further piece of the puzzle or a striking strategy?

Introduction: Treatment of ovarian cancer has been long standardized with the inclusion of surgery and chemotherapy based on platinum and taxanes, this strategy reaching high remission rates. However, when this treatment fails, further options are available with little benefit. Since ovarian cancer has specific immunologic features, actually immunotherapy is under evalua- 15 tion to overcome treatment failure in patients experiencing recurrence. Areas covered: Immunogenicity of ovarian cancer and its relationship with clinical outcomes is briefly reviewed. The kinds of immunotherapeutic strategies are summarized. The clinical trials investigating immunotherapy in recurrent ovarian cancer pa…

Stable microvascular angina: instrumental evaluation of coronary microvascular dysfunction with coronary angiography and myocardial scintigraphy

Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors.

Many new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEK-inhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on …

Targeted Therapies in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the main causes of death in patients affected by chronic liver diseases. The awareness of the biomolecular mechanisms underlying the complex carcinogenic process led to the development of targeted molecules, which are able to block this process. Sorafenib is a tyrosine-kinase inhibitor, and currently, it is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of HCC. However, some studies have demonstrated the efficacy of single drug therapies or combination therapies. They showed an improvement with regard to overall survival, time to progression, and progression-free survival, although these therapies were not free …

KRAS and BRAF as prognostic biomarkers in patients undergoing surgical resection of colorectal cancer liver metastasis: A systematic review and meta-analysis.

3565Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of li...

What links BRAF to the heart function? new insights from the cardiotoxicity of BRAF inhibitors in cancer treatment

The RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolonga…

Epithelial-to-mesenchymal transition in the context of epidermal growth factor receptor inhibition in non-small-cell lung cancer

The identification of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) has led to the development of targeted drugs. Tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) target lung tumours bearing EGFR-activating mutations. This new therapeutic strategy has greatly improved tumour response rates. However, drug resistance invariably occurs during TKI-based treatment. Epithelial-to-mesenchymal transition (EMT) is one of the resistance mechanisms identified in EGFR-mutated NSCLC treated with TKIs. In this review we gather together the most important findings on this phenomenon in relation to cancer stem cells and cancer epigenetics. We…

E26The effects of LIPUS on ctDNA release in the medium of NSCLC cell lines

Low Intensity Pulsed Ultrasound (LIPUS) application has been shown to have an encouraging effect in inducing a transient pore formation through cellular membranes. This permeability condition has been demonstrated to be useful in enhancing gene and drug delivery. Nowadays, in the management of NSCLC patients, the use of liquid biopsy has entered the clinical practice. One of the main limits in the analysis of circulating tumor DNA is the low concentration rate of nucleic acids in body fluids. Ultrasound stimulation (US) has been recently demonstrated to be effective for the release of specific circulating tumor biomarkers in many mouse models. We demonstrated the role of US in inducing the …

The prognostic role of KRAS and BRAF in patients undergoing surgical resection of colorectal cancer liver metastasis: a systematic review and meta-analysis

Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of liver metastasis (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Materials and Methods: Data from all published studies reporting survival outcomes (RFS and/or OS) of CRC patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status were collected by sear…

Targeted Therapies in Hepatocellular Carcinoma

Abstract: The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients a…

The effects of LIPUS on ctDNA release in the medium of NSCLC cell lines

Cardiovascular Toxicity in Cancer Patients Treated with Tyrosine Kinase Inhibitors: A Real-World Single-Center Experience

<b><i>Background:</i></b> Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. <b><i>Methods:</i></b> A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with…

The prognostic role of KRAS and BRAF in patients undergoing surgical resection of colorectal cancer liver metastasis: a systematic review and meta-analysis

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

Cardiotoxicity induced by chemotherapeutic agents and radiotherapy is a growing problem. In recent years, an increasing number of new drugs with targeted action have been designed. These molecules, such as monoclonal antibodies and tyrosine kinase inhibitors, can cause different type of toxicities compared to traditional chemotherapy. However, they can also cause cardiac complications such as heart failure, arterial hypertension, QT interval prolongation and arrhythmias. Currently, a field of intense research is the vascular toxicity induced by new biologic drugs, particularly those which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) and other tyrosine kinases.…

Cardiotoxic Effects of Anti-VEGFR Tyrosine Kinase Inhibitors

Angiogenesis is a key moment in tumor development and proliferation. Until recently oncologists did not know the mechanisms that were behind this phenomenon, but following the discoveries of Folkman and coworkers, they have gradually created and developed a series of drugs that act against angiogenesis by interacting with molecules belonging to the vascular endothelial growth factor (VEGFs) class and its receptors (VEGFRs) giving rise to anticancer effects. Tyrosine kinase inhibitors (TKIs) are a major class of these new anticancer agents, demonstrating high antitumor activity in a variety of "orphan" neoplasms (such as hepatocellular carcinoma, kidney cancer, sarcomas, etc.). The mechanism…

Cardiovascular Damage in Clinical Trials

The Cardio-oncology field has grown considerably in the last two decades. The remarkable increase in the number of molecules used in oncology has brought with it a huge set of cardiovascular adverse events. For this reason, it is necessary to intervene on the early stages of drug development. This is what the Food and Drug Administration aims to do. This purpose can be achieved through a more careful analysis of the adverse event, development of guidelines, and identification of objective parameters that could guide the researcher in defining precisely the adverse event. It is also necessary to use additional methods not yet used in clinical trials that can allow an early detection of adver…

Chronic atrial fibrillation in presence of aortic stenosis in a patient with polysplenia syndrome.

We report a rare case of “situs viscerum ambiguous” with polysplenia syndrome, in a 69 year old female patient with aortic stenosis and chronic atrial fibrillation. The presenting symptom was dyspnoea on moderate exertion and an ECG showed supra ventricular arrhythmia. Patients trans-thoracic echocardiogram revealed a dilated left atrium, reduced ejection fraction, mild tricuspid regurgitation, moderate-severe pulmonary hypertension and severe aortic stenosis. The patient was successfully treated with a replacement of her aortic valve and ascending aorta.

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Abstract: Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs i…

LncRNA H19, HOTAIR and MALAT1 as prognostic molecular biomarkers in GIST

Immuno-targeted combinations in oncogene-addicted non-small cell lung cancer

The identification of tumor “oncogenic drivers” and the subsequent development of targeted therapy represented a milestone in the treatment of lung cancer over the last years. Tumor genotyping has been incorporated into therapeutic decision making of advanced non-small cell lung cancer (NSCLC) since has become clear that individuals with actionable molecular alterations receiving a matched targeted agent certainly live longer and better. The recent understanding of biological mechanisms underlying cancer immune evasion has allowed the development of a new class of immunomodulatory agents which are able to reactivate host immune-response, offering the potential for long-term disease control …