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Prevention

Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

^aDepartment of Medical Oncology and ^b Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy

Key Words. Epirubicin • Myocardial dysfunction • TDI • Inflammatory markers • Oxidative stress markers

Correspondence: Giovanni Mantovani, M.D., Cattedra e Divisione di Oncologia Medica, Università di Cagliari, Azienda Ospedaliero Universitaria di Cagliari, Strada Statale 554, Km 4.500, 09042 Monserrato (Cagliari), Italy: Telephone: 0039-070-5109-6253; Fax: 0039-070-5109-6253; e-mail: mantovan{at}medicina.unica.it

Received July 16, 2008; accepted for publication November 7, 2008; first published online in THE ONCOLOGIST Express on December 5, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

	ABSTRACT

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A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age ± standard deviation, 59 ± 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m². This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain () remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the E_m/A_m ratio declined at the 200-mg/m² cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m² cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m² dose, and IL-6 was persistently high at the 300- and 400-mg/m² doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m² dose, returned to within baseline values. A significant inverse correlation between SR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of SR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.

	INTRODUCTION

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Anthracycline antibiotics are potent antitumor agents used in a wide spectrum of malignancies in both the adjuvant and metastatic settings. The two most commonly used anthracyclines are doxorubicin and epirubicin, which, at similar doses, provide similar response rates; however, their toxicity profiles differ somewhat. The equimolar dose ratio of doxorubicin to epirubicin for cardiotoxicity is 1:1.7–2.0 [1]. A recent meta-analysis showed no evidence of a significant difference between epirubicin and doxorubicin in the occurrence of clinical heart failure [2]; however, there is some suggestion of a lower rate of this complication in patients treated with epirubicin [3].

Epirubicin is used in a wide range of solid and hematologic tumors such as breast cancer [4], sarcomas, lymphomas, and leukemias. Evidence that 10%–26% of patients administered cumulative anthracycline doses above those recommended (450 mg/m² for doxorubicin and 900 mg/m² for epirubicin) develop heart failure has compelled clinicians to set empirical dose limits above which the cardiotoxic risk is deemed unacceptable.

Therefore, the successful use of anthracyclines is limited by the risk of developing the known side effect of great interest and concern among oncologists and cardiologists, namely, chemotherapy-related cardiac dysfunction (CRCD), which directly involves the myocardium and is manifested by a decrease in left ventricular ejection fraction (LVEF) and which may progress to congestive heart failure [5]. CRCD became a relevant cancer-related chemotherapy issue in the early 1970s when anthracyclines were shown to produce cumulative dose-related cardiac dysfunction [6].

The anthracycline-associated abnormalities leading to cardiac dysfunction constitute an entity that should now be considered so-called type I CRCD. CRCD is a result of, at least in part, iron-based oxygen free radical–induced oxidative stress on cardiac muscle cells. Free radicals induce the peroxidation of myocyte membranes and subsequent influx of intracellular calcium. Mitochondria dysfunction has also been noted, and it correlates with morphologic changes seen in type I CRCD [7–9].

In fact, a major hypothesis regarding the pathophysiology of anthracycline-induced cardiotoxicity is that cardiac damage is caused by oxidative stress through the generation of reactive oxygen species (ROS) [10]. Moreover, it has been suggested that proinflammatory cytokines may contribute to the pathophysiology of epirubicin-induced cardiomyopathy [11].

Risk factors associated with a greater likelihood of type I CRCD have been identified and are commonly associated with increased left ventricular (LV) end diastolic pressure [12]. Currently, the most commonly used methods to detect anthracycline-induced cardiotoxicity are the evaluation of functional parameters including LVEF and fractional shortening by echocardiography (ECG) and radionuclide imaging. Unfortunately, impairment in these parameters is often detected only after considerable cell loss has taken place [13].

Therefore, biomarkers such as B-type natriuretic peptide (BNP) and troponins (I and T) have been recently used extensively to stratify patients into higher and lower risk categories. This practice is well established in the cardiology literature and was recently also reported in the oncology setting [14, 15]. In fact, an elevated troponin level during chemotherapy seems to correlate with a higher risk for the development of cardiac toxicity [14]. On the basis of these data, it was deemed necessary to incorporate biomarkers into the subsequent definitions of cardiac toxicity, especially when anthracyclines are used.

Tissue Doppler imaging (TDI) allows measurement of the diastolic and systolic velocities of the ventricular walls and of the mitral annulus. In the evaluation of LV diastolic performance, TDI is more reliable than conventional Doppler, because it is less influenced by loading conditions. TDI may also show changes in regional function that are not revealed by global LVEF, thus improving the reliability of the assessment of cardiac function changes during anthracycline therapy [16]. An ultrasound method of quantifying regional deformation based on principles derived from mechanical engineering called strain () and strain rate (SR) imaging was introduced recently. and SR may be more accurate than TDI velocities alone in detecting early changes in systolic function because they are less likely to be affected by translational motion. It has been shown that SR is a reliable index of LV contractility [17]. Thus, this newly developed technique may improve the evaluation of cardiac function changes during anthracycline therapy, enabling either the timely interruption of anthracycline-based therapy or, alternatively, the start of specific potentially cardioprotective treatment.

The aim of the present study was to detect early preclinical changes that are predictive of heart failure risk in a group of 31 epirubicin-treated patients with cancer at different sites by means of TDI and and SR imaging, and to correlate the TDI findings with inflammatory and oxidative stress markers that have been shown to play a major role in anthracycline-induced cardiac dysfunction. To highlight the preclinical dysfunction threshold that our technique was able to detect, all patients underwent a complete analysis of all variables 24 hours and 1 week after each 100 ± 20 mg/m² epirubicin dose. We prospectively evaluated the acute (24 hours and 1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. The follow-up started from the time of the last epirubicin administration.

	PATIENTS AND METHODS

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The study was a phase II, open, nonrandomized trial; it was approved by the Institutional Ethics Committee (Azienda Ospedaliero-Universitaria, University of Cagliari), and written informed consent was obtained from all subjects included. The study was performed in accordance with the Declaration of Helsinki.

Inclusion criteria were the following: age 18–70 years with a histologically confirmed diagnosis of cancer at any site, previously untreated, and a candidate to be treated with an epirubicin-based chemotherapy regimen according to international standardized protocols for each patient's specific tumor; an ECG LVEF value 55%; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 [18]; normal hepatic (transaminases 2x the upper limits of normal) and renal (creatinine 2.0 mg/dl) function; and no concomitant medications and medical conditions known to interfere with inflammatory and oxidative stress parameters. Patients with a history of cardiac disease, hypertension, and diabetes mellitus and/or those who had been previously treated with mediastinal irradiation were excluded from the study.

At enrollment, prior to starting chemotherapy treatment, all patients underwent a physical examination, a blood pressure measurement, a 12-lead ECG, and ECG analysis (conventional and TDI technique). In all subjects, a blood sample was obtained from venipuncture of the antecubital vein at 8 a.m., after overnight fasting. Blood samples were collected in tubes with a clot-activating factor and centrifuged immediately after collection, and serum was stored at –20°C until assayed. In each serum sample, levels of the proinflammatory cytokines interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), tumor necrosis factor (TNF)- and its soluble type 1 receptor (sTNF-R1), and IL-1β were analyzed. ROS and the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were assessed on fresh heparinized blood samples.

Instrumental and laboratory variables of the acute phase were assessed at baseline and 24 hours and 7 days after reaching an epirubicin dose of 100, 200, 300, and 400 mg/m². Reported doses of epirubicin are cumulative. The evaluations performed 7 days after each epirubicin dose were shown to be more sensitive than those performed after 24 hours in detecting changes in the variables, and therefore the latter are not reported. Late effects were assessed after 3, 6, 12, and 18 months of follow-up. The follow-up started from the time of the last epirubicin cumulative dose.

Conventional ECG and TDI
ECG images were recorded using a commercially available system equipped with TDI and and SR imaging (Toshiba APLIO CV ultrasound system-SSA 770A/CV; Toshiba Corp, Tochigi, Japan). LVEF was obtained from the apical four- and two-chamber views according to Simpson's rule and was considered abnormal at <55%. We performed a pulsed wave Doppler (PWD) examination of LV inflow from the four-chamber view with the sample volume placed between the mitral leaflet tips and early (E) and late (A) diastolic peak velocities; E deceleration time was measured and then the E/A ratio was derived [19]. We evaluated longitudinal function using pulsed TDI at the mitral annulus, placing the sample volume in the basal segment of the interventricular septum (IVS) from the apical four-chamber view: peak velocities in systole (Sm) and early (E_m) and late (A_m) diastole were measured. For more accurate measurements, TDI curves were obtained from raw data analysis. LV longitudinal function was evaluated from raw data; myocardial and SR were also quantified in the IVS. The same experienced echocardiographer, unaware of the patients' clinical status and therapeutic regimen, carried out all examinations. A simultaneous ECG tracing was also obtained. To reduce interobserver variability, all ECG data were randomly read by a second experienced observer, and an average value for each measurement was calculated. The reproducibility of TDI parameters in our laboratory has been previously documented [20].

Assessment of Biochemical Markers of Myocardial-Endothelial Damage
In our previous paper regarding the predictive value of TDI for early epirubicin-induced cardiac dysfunction, BNP as well as other biochemical markers of myocardial-endothelial damage (troponin I, creatine kinase-MB, and myoglobin) were assessed [21]. no significant changes were observed throughout the study and therefore we considered BNP to be a neither significant nor predictive biomarker of cardiac dysfunction. Thus, it was not assessed in the present study.

Assessment of Inflammatory and Oxidative Stress Markers
Serum levels of IL-6, sIL-6R, TNF-, sTNF-R1, and IL-1β were determined by enzyme-linked immunosorbent assay (Immunotech, Marseille, France). Results are expressed in pg/ml for IL-6, sIL-6R, TNF-, and IL-1β and in ng/ml for sTNF-R1. The detection limits for the assays used were: 3–1,000 pg/ml for IL-6, 4–2,000 pg/ml for sIL-6R, 5–1,000 pg/ml for TNF-, 1.2–47 ng/ml for sTNF-R1, and 1.5–250 pg/ml for IL-1β.

Blood levels of ROS were determined using the free oxygen radicals test (FORT). The radical species produced by the reaction, which are directly proportional to the quantity of lipid peroxides present in the sample, interact with an additive (phenylenediamine derivative) that forms a radical molecule detectable by spectrophotometry at 505 nm (Form CR 2000; Callegari, Parma, Italy). Results are expressed as FORT units, where 1 FORT unit corresponds to 0.26 mg/l of H₂O₂. The erythrocyte antioxidant enzymes GPx and SOD were measured by photometry using a commercially available kit (Ransod; Randox Lab, Crumlin, United Kingdom) and expressed as U/l and U/ml, respectively.

Statistical Analysis
Data are reported as mean ± standard deviation. Differences between values measured at baseline and at different epirubicin doses were assessed by Student's two-tailed t-test for paired data. Correlation between instrumental (SR peak) and laboratory variables was assessed by Pearson's t-test (or Spearman's t-test for nonparametric variables). Normal distribution was assessed by the Shapiro Wilks' test. Significant relationships were then examined by a multivariate linear regression analysis against the SR peak (dependent variable): p-values are considered significant when .05. The statistical analysis was performed using SPSS version 14 for Windows (SPSS, Inc., Chicago, IL).

	RESULTS

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Patients
Thirty-one patients were enrolled from May 2005 to December 2007. Their complete clinical characteristics are reported in Table 1. They were all candidates to be treated with an epirubicin-based chemotherapy regimen according to the international standardized protocols for their specific tumors. The regimens used and doses administered are reported in Table 2. All patients completed the planned treatment. Eighteen patients received a cumulative epirubicin dose of 400 mg/m² and the remaining patients received a cumulative epirubicin dose of 300 mg/m². Five patients died 6 ± 2 months after the end of the epirubicin administration, because of disease progression. Twenty-six patients were still alive in July 2008.

Overall, the treatment was well tolerated. The main toxicities observed were grade 3–4 neutropenia (four patients) at the higher cumulative epirubicin doses (300 mg/m² and 400 mg/m²), which required the administration of G-CSF and a few weeks postponement of the subsequent chemotherapy course; grade 3–4 anemia (two patients) at the 300-mg/m² cumulative epirubicin dose; and nausea (five patients) at the 200-mg/m² cumulative epirubicin dose. One patient with carcinoma of the endometrium suffered a massive pulmonary embolism 1 week after reaching the 300-mg/m² dose and was immediately treated with anticoagulant therapy (i.v. heparin followed by an oral anticoagulant). The patient had already completed epirubicin treatment and thereafter recovered. No correlation was found between grade of anemia/neutropenia and oxidative stress/inflammatory parameters. Moreover, TDI changes were not correlated with grade of anemia and/or neutropenia. As concomitant medication, patients received appropriate supportive therapy, such as antiemetic therapy, growth factors, and antidiarrheals, as required by chemotherapy-related symptoms. No patient underwent cardiologic therapy and in particular no patient received statins during treatment.

Conventional ECG
On ECG monitoring, we observed a normal ECG morphology in 19 patients (61.3%) throughout the treatment and during follow-up; in 12 patients (38.7%) we noticed nonspecific changes during the ventricular repolarization phase (diffuse negative or biphasic T waves) concomitant with the 300-mg/m² cumulative epirubicin dose, which persisted without complete ECG normalization during follow-up. These ECG changes were not associated with either concomitant TDI abnormalities or inflammatory/oxidative stress changes.

Conventional ECG and TDI
During epirubicin treatment, compared with baseline values, we observed diastolic dysfunction of the LV shown by a reduction in the E/A ratio measured by PWD in the transmitralic flow. These abnormalities became significant after the 300-mg/m² cumulative epirubicin dose (0.92 ± 0.05 versus 1.13 ± 0.14; p < .005) (Table 3). On the other hand, we did not observe any significant variation in LVEF at any stage of the study and throughout the follow-up (Table 3).

As for systolic function, the Sm wave showed a slow and progressive reduction that, in comparison with baseline, became significant only at the 18-month follow-up (6.18 ± 0.56 versus 7.15 ± 0.65; p < .05) (Table 3).

Noteworthy, from the raw data analysis, we observed an early reduction in the SR peak, which was significant after the 200-mg/m² cumulative epirubicin dose (1.45 ± 0.15 s^–1 versus 1.79 ± 0.06 s^–1; p < .001) (Fig. 1). This reduction persisted at a statistically significant level throughout treatment (after the 300-mg/m² and 400-mg/m² cumulative epirubicin doses) and throughout the follow-up, until 18 months (Fig. 1). On the other hand, the strain ( peak) remained unchanged during the whole treatment (after 200 mg/m², 20.75 ± 12.4; after 300 mg/m², 18 ± 6.8; after 400 mg/m², 21.05 ± 6.44), in comparison with baseline (20.89 ± 4.13), and during the entire follow-up (17.5 ± 9.3; p = .07 at 18 months).

View larger version (9K): [in this window] [in a new window]   Figure 1. Changes in strain rate peak over time. Abbreviations: FU, follow-up, M, months.

View this table: [in this window] [in a new window]   Table 5. Correlations between SR and the increase in both IL-6 and ROS (both calculated by subtracting the value after a 200-mg/m2 cumulative epirubicin dose from the baseline value)

	DISCUSSION

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As further evidence that LVEF cannot be considered a truly reliable marker of cardiac damage, Ewer and Lenihan [22], commenting on an article by Ganz et al. [23], who looked at late cardiac effects of adjuvant chemotherapy in breast cancer survivors treated on Southwest Oncology Group protocol S8897 and concluded that exposure to doxorubicin did not increase the likelihood of late adverse cardiac effects based on LVEF evaluation, stated "Here again, this demonstrates our inherent inability to see subtle changes in cardiac reserve when examining only LVEF measurements."

Overall, noninvasive methods able to assess myocardial damage before the appearance of LVEF abnormalities are currently completely lacking.

Thus, the main interesting features of our study are that we detected an early preclinical sign of myocardial dysfunction, we ascertained that this cardiac dysfunction persists after epirubicin interruption and is long lasting (at least 18 months), and we correlated these instrumental findings with biological signs of oxidative stress and inflammation, which play a very important role in inducing myocardial damage. Indeed, the results obtained in the present study not only confirm but are also far more significant than those previously reported by us of early myocardial dysfunction induced by epirubicin in subjects with no signs and symptoms of cardiovascular disease [21]: they represent a larger patient population (31 versus 16 cancer patients) studied for a long follow-up period (up to 18 months). LV function impairment, revealed by the SR peak on serial TDI, was evident immediately after a 200-mg/m² cumulative dose of epirubicin, a cumulative dose considered by oncologists as quite low and harmless [24]. At this dose, the TDI abnormality was paralleled by a significant increase in IL-6 and ROS, showing that the appearance of subclinical myocardial dysfunction and biological signs of oxidative stress and chronic inflammation are simultaneous. This reinforces the causative role, or at least the significant involvement, of these factors in inducing myocardial damage.

Unexpectedly, subtle cardiac abnormalities, evidenced by SR reduction, persisted throughout treatment and during follow-up (up to 18 months), and the Sm wave also showed a reduction, which became significant at 18 months, proving a further progression in the myocardial damage. At subsequent doses of epirubicin, IL-6 also was persistently significantly high, whereas during the follow-up (in contrast to the TDI findings) it returned to within baseline values. ROS, after the peak reached at the 200-mg/m² cumulative epirubicin dose, dropped to within the baseline range. Interestingly, contrary to current knowledge, our results showed that a measurable SR peak decline, regarded as the earliest sign of subclinical cardiotoxicity, appeared as early as after a 200-mg/m² cumulative epirubicin dose (so far regarded as insufficient to induce cardiac injury), paralleled by the E_m/A_m on TDI [24]. Moreover, systolic impairment preceded the signs of diastolic dysfunction, which was observed on conventional ECG only after administration of a 300-mg/m² cumulative epirubicin dose. More recently, it was shown that a "subcritical dose" (356–388 mg/m²) of doxorubicin accounted for LV diastolic dysfunction and that a 533-mg/m² cumulative doxorubicin dose may induce dilatative cardiomyopathy, with a clinical pattern of heart failure including systolic and diastolic dysfunction [25].

In addition to early detection of subclinical epirubicin-induced cardiac dysfunction, the present study shows that this dysfunction persists for a while after epirubicin interruption and that TDI abnormalities should be regarded not only as a transitory toxic effect of the drug but also as the beginning of chronic myocardial dysfunction. In fact, at the 18-month follow-up we found persistence of impaired longitudinal function evidenced by SR decline. Moreover, this finding was associated with the unprecedented appearance of significant Sm wave reduction on TDI. It should be taken into account that all the above-mentioned findings were reported in patients who had previously been persistently free from signs and symptoms of cardiovascular disease.

The few recent investigations that used the TDI technique to examine the short- and long-term effects of anthracycline chemotherapy both in adult and pediatric patients were partially limited by their study designs [16, 26, 27]. Thus, in the above-reported literature, too much time had elapsed between anthracycline administration and the assessment of ECG abnormalities after therapy interruption, and furthermore, these studies did not suggest any hypothesis or explanation of the mechanisms leading to myocardial dysfunction.

The cardiotoxic effect of epirubicin has been attributed to irreversible damage of heart cell mitochondria, which express a unique enzyme on their inner membrane that is able to reduce anthracyclines to their semiquinone derivatives. This specific cellular pathway results in severe oxidative stress, disruption of mitochondrial energetic machinery, and irreversible damage of mitochondrial DNA. The compromised regenerative capability of the organelles ultimately leads to apoptosis or necrosis of myocytes [10]. Moreover, ROS and nitric oxide species might interact to develop highly toxic products that negatively affect cellular calcium and iron homeostasis [28].

Our data support the most probable causal role of oxidative stress in the early functional impairment of cardiac contractility. Moreover, increasing evidence suggests a predictive role of inflammatory factors as clinically useful markers of cardiovascular morbidity and mortality [29]. Accordingly, the present study shows the independent predictive significance of the early change in IL-6 and ROS versus the SR change at a 200-mg/m² cumulative epirubicin dose and highlights the significance of their reciprocal inverse correlation.

Specific cytokines, such as IL-6 and TNF-, are sensitive systemic markers of tissue damage, predictive of the development of unstable cardiovascular diseases [30]. Moreover, a correlation between apoptosis of cardiomyocytes in the failing human heart and an increase in the plasma concentration of IL-6 and sIL-6R, as well as TNF- and sTNF-R1, has been found [31, 32].

In several of our previous studies, carried out on different populations of cancer patients, high levels of inflammatory cytokines and oxidative stress markers correlated with advanced stage of disease, poor ECOG performance status, and symptoms such as cachexia and fatigue [33–36], regardless of heart disease. Approximately half of the patients enrolled in the present study had early-stage cancer, and no patient had cardiovascular disease. Baseline values of inflammatory and oxidative stress markers were within the range of normal individuals, and therefore their subsequent changes could be attributable to chemotherapy, that is, epirubicin-based treatment, or, alternatively, to disease progression; however, the latter was not the case. In the present study, the sensitivity of inflammatory and oxidative stress parameters may be considered the counterpart of TDI measurements. In fact, the significant increase in IL-6 and sIL-6R at a cumulative epirubicin dose of 200 mg/m² appears as a biological equivalent of the TDI evidence of initial cell deterioration.

The slight and premature contractility dysfunction evidenced by TDI is probably attributable to an impairment in the intracellular processes of cardiomyocytes, as the association between SR peak reduction and high levels of circulating inflammatory and oxidative stress markers seems to suggest.

Throughout the follow-up period, the SR peak remained persistently declined whereas ROS and IL-6 levels returned to baseline values. These findings seem to suggest that the pathophysiologic changes detected early persisted not only during subsequent epirubicin treatment but even several months (18) after epirubicin interruption. This abnormality, possibly corresponding to chronic inotropic dysfunction, seems to be relatively independent from the biologic substrate of cardiac cell distress.

A partial limitation of the present study could be the relatively small number of patients. On the other hand, the need for sophisticated technology and laboratory data does not seem to be an obstacle because of their extensive and growing availability both on cardiology units and in oncology laboratories, often found in the same facility.

The possibility of using the above-reported techniques to safeguard patients against anthracycline-induced cardiotoxicity seems to be very promising.

	AUTHOR CONTRIBUTIONS

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Conception/design: Giovanni Mantovani, Giuseppe Mercuro

Admininistrative support: Giovanni Mantovani

Provision of study materials: Giovanni Mantovani, Clelia Madeddu, Elena Massa

Collection/assembly of data: Clelia Madeddu, Mariele Dessì, Elena Massa, Roberto Serpe, Giorgia Antoni, Christian Cadeddu, Alessandra Piras

Data analysis: Giovanni Mantovani, Clelia Madeddu, Mariele Dessì, Elena Massa, Roberto Serpe, Giorgia Antoni, Christian Cadeddu, Alessandra Piras, Giuseppe Mercuro

Manuscript writing: Giovanni Mantovani

Final approval of manuscript: Giovanni Mantovani, Clelia Madeddu, Mariele Dessì, Elena Massa, Roberto Serpe, Giorgia Antoni, Christian Cadeddu, Alessandra Piras, Giuseppe Mercuro

	ACKNOWLEDGMENTS

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The authors take full responsibility for the content of the paper but thank Ms. Anna Rita Succa for her assistance in editing the article.

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