Cezar Iliescu

Cardiotoxicity of the cancer therapeutic agent imatinib mesylate

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Cardiovascular Health of Patients With Cancer and Cancer Survivors : A Roadmap to the Next Level

Many existing and emerging cancer therapies have a significant effect on the cardiovascular health of patients with cancer and cancer survivors. This paper examines current aspects of interdisciplinary cardio-oncology clinical care delivery and education in the United States and outlines how these data provide a platform for future development of the field. We present the results of the nationwide survey on cardio-oncology services, practices, and opinions, conducted among chiefs of cardiology and program directors, which demonstrate ranges of clinical activities and identify significant interest for increased educational opportunities and expert training of cardiovascular physicians in this field. The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology. We discuss potential solutions to unmet needs through interdisciplinary collaboration and the active roles of professional societies and other stakeholders.

Vascular Toxicities of Cancer Therapies The Old and the New – An Evolving Avenue

Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

Incidence, predictors, and impact on survival of left ventricular systolic dysfunction and recovery in advanced cancer patients

Although left ventricular (LV) dysfunction occurs not uncommonly in the course of cancer therapy, little is known about its natural history and prognostic impact on patients. To investigate the incidence, predictors, and impact on survival of LV systolic dysfunction and recovery during cancer therapy, we conducted a retrospective cohort observational study over 1 year at the University of Texas MD Anderson Cancer Center. We enrolled patients with a decrease in ejection fraction by echocardiography to <50% while undergoing cancer therapy from January 2009 to December 2009. We collected and analyzed their chart data. Of 7,648 patients with echocardiograms in 2009, 366 (4.8%) had ejection fraction <50% and 104 met study criteria. LV systolic dysfunction was associated with cardiotoxic therapy in 53 patients (51%). Recovery occurred in 57 patients (55%) and was independently predicted by younger age, smaller left atrial volume index, and lower B-type natriuretic peptide. At last follow-up, 69 patients (66%) were dead, and 35 (34%) were alive. There was a 20% advantage in 2-year survival among patients with LV systolic recovery compared with those without (95% confidence interval 4% to 41%, p = 0.02). In this retrospective study, LV systolic dysfunction recovery occurred in over half of the patients, appeared independent of cardiotoxic etiology, and associated with a 20% survival benefit at 2 years. Multivariable predictors of recovery are younger age, a small left atrial volume index, and lower B-type natriuretic peptide.

SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista)

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

Outcomes of Cancer Patients Undergoing Percutaneous Pericardiocentesis for Pericardial Effusion

BACKGROUND Pericardial effusion (PE) is common in cancer patients, but the optimal therapeutic approach is not well defined. Percutaneous pericardiocentesis is less invasive than surgery, but its long-term effectiveness and safety have not been well documented. OBJECTIVES The goal of this study was to evaluate outcomes of cancer patients undergoing percutaneous pericardiocentesis for PE and assess the procedures safety in patients with thrombocytopenia. METHODS Cancer patients who underwent percutaneous pericardiocentesis for PE between November 2009 and October 2014 at the MD Anderson Cancer Center were included. Procedure-related complications, effusion recurrence rate, and overall survival were analyzed. RESULTS Of 1,645 cancer patients referred for PE, 212 (13%) underwent percutaneous pericardiocentesis. The procedure was successful in 99% of the cases, and there were no procedure-related deaths. Four patients had major procedure-related bleeding that did not vary by platelet count <50,000/μl or ≥50,000/μl (p = 0.1281). Patients with catheter drainage for 3 to 5 days had the lowest recurrence rate (10%). Median overall survival was 143 days; older age (i.e., >65 years), lung cancer, platelet count <20,000/μl, and malignant pericardial fluid were independently associated with poor prognosis. Lung cancer patients with proven malignant effusions had a significantly shorter median 1-year survival compared with those with nonmalignant effusions (16.2% vs. 49.0%, respectively; log-rank test p = 0.0101). A similar difference in 1-year survival was not observed in patients with breast cancer (40.2% vs. 40.0%; log-rank test p = 0.4170). CONCLUSIONS Percutaneous pericardiocentesis with extended catheter drainage was safe and effective as the primary treatment for PE in cancer patients, including in those with thrombocytopenia. Malignant PE significantly shortened the survival outcome of patients with lung cancer but not those with breast cancer.

SCAI Expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologıa interve: Management of Cancer Patients in the Cath Lab

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

Cancer as a Risk Factor for Cardiovascular Disease

Improvements in early diagnosis and cancer treatments have contributed to high survival rates for many cancer patients. However, these patients often die of cardiovascular disease rather than recurrence of their cancer. Heart disease manifesting after cancer may be due to several mechanisms: shared cardiovascular risks between cancer and cardiovascular disease, inflammatory states associated with malignancies, and/or cardiotoxic effects of cancer therapy. Cancer treatment increases the risk of cardiovascular diseases directly by damaging critical structures of the heart or indirectly by promoting accelerated atherosclerosis. Estimating cardiovascular risk by using advanced imaging and monitoring of the cardiac biomarkers can be used for early detection and treatment of subclinical cardiac injury. Better knowledge of these early and late cardiac effects in cancer patients will enable adoption of both primary and secondary prevention measures of long-term treatment complications in cancer survivors.

SCAI expert consensus statement—executive summary evaluation, management, and special considerations of cardio‐oncology patients in the cardiac catheterization laboratory

In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

Outcome of acute limb ischemia in cancer patients

The optimal management strategy for acute limb ischemia (ALI) in patients with a concomitant malignancy is not well established. A very high mortality rate (83–100%) at 1 year has been reported in those who are treated surgically. Accordingly, a conservative management approach has been suggested as the main therapeutic modality. Our aim was to evaluate the survival outcomes of cancer patients treated for ALI at our cancer center. Cancer patients treated for ALI at the MD Anderson Cancer Center from 2001 to 2011 were included in this study. Overall survival and amputation-free survival rates were calculated. A total of 74 cancer patients with concomitant ALI were included in the study. Surgery was the most common therapy (36 patients; 49%). Percutaneous catheter-based interventions were used in 21 patients (28%). Eighteen patients (24%) received anticoagulation therapy only, and six patients (8%) received no therapy. The 30-day, 6-month, and 1-year overall survival rates were 80% (95% confidence interval [CI], 69% to 87%), 59% (95% CI, 47% to 69%), and 48% (95% CI, 36% to 59%), respectively. Eight patients (11%) underwent amputation. The 1-year amputation-free survival rate was 47% (95% CI, 35% to 58%). In conclusion, we did not find an invasive approach for the treatment of ALI in cancer patients to be associated with the very high mortality rates previously reported. In our opinion, the indications for surgery or catheter-based intervention in these patients should not differ from patients without cancer.