Completion Of Anthracycline Therapy Research Articles

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Cardiac magnetic relaxometry versus ejection fraction in anthracycline-related cardiac changes: a systematic review and meta-analysis

PurposeThe purpose of this meta-analysis is to compare the magnitude of the changes in left ventricular ejection fraction (LVEF) and cardiac magnetic resonance (CMR) relaxometry techniques soon after the completion...

Cardiac magnetic resonance relaxometry compared to left ventricular ejection fraction in the identification of anthracycline related cardiac changes: a systematic review and meta-analysis

Abstract Background Anthracyclines are associated with cancer therapeutics related cardiac dysfunction (CTRCD). The identification of CTRCD currently uses a change in left ventricular ejection fraction (LVEF). Myocardial damage associated with anthracyclines include myocardial inflammation and oedema. This can be assessed using cardiac magnetic resonance (CMR) relaxometry techniques; T1 and T2 mapping and extracellular volume (ECV) fraction. Purpose In this meta-analysis, we compared the magnitude of the changes in LVEF and CMR relaxometry techniques wihtin a month of anthracycline therapy completion. Methods We performed a structured literature review as per the PRISMA guidelines across three databases (EMBASE, MEDLINE, and SCOPUS) for studies evaluating CMR relaxometry parameter at baseline and soon after completion of anthracycline therapy (3–5 months post baseline). CMR parameters pre and post anthracycline-based chemotherapy were abstracted. A random effects model was used to pool mean difference (MD) in LVEF and ECV given standardisation in imaging acquisition techniques. A random effects model was used to pool standardized mean difference (SMD) in LVEF, T1, T2 and ECV after anthracycline to adjust for variations in imaging techniques and comparison between techniques. Results A total of 174 patients were included from seven studies. 91% were female with a mean age of 55.6 years. The pooled MD in LVEF and ECV was −3.15% [95% CI −4.99, −1.31] and 1.61% [0.90, 2.32], respectively. The pooled SMD in LVEF, T1, T2 and ECV was −0.61 [−0.96, −0.25] 0.34 [0.04, 0.63], 0.67 [0.12,1.21], 0.6 [0.31, 0.89], respectively (Table 1). Conclusions T2 mapping, ECV and LVEF can identify early myocardial changes better than T1 mapping. These changes suggest there is marked oedema in the myocardial injury from anthracycline therapy. Whilst these findings support the role of CMR relaxometry in identifying CTRCD, further studies are required. Funding Acknowledgement Type of funding sources: None.

Valvular changes following anthracycline therapy: is it time to look beyond ejection fraction?

Abstract Background Advancements in early detection and treatment of breast cancer have improved survival, but with the costs of side effects, with cardiotoxicity being the most significant one. Anthracycline (ANT) is the most recognized therapy leading to cardiotoxicity, mainly manifested as left ventricle (LV) dysfunction. While the changes in LV ejection fraction (LVEF) are well studied, little is known about the effect of ANT on valvular function. We aimed to evaluate the change in valvular function following ANT therapy in patients diagnosed with breast cancer. Methods The study population is part of the Israel Cardio-Oncology Registry (ICOR). All patients performed serial echocardiography; before (T1), during (T2), at the end (T3), and following (T4) ANT therapy, assessing valvular changes. Exclusion criteria included age below 18 and baseline LVEF &amp;lt;55%. Results The study included 141 female patients diagnosed with breast cancer and treated with ANT with a mean age of 51±12 years (Table 1). During a median follow-up of 255 [IQR 214–313] days, from T1 to T4, we observed a significant increase in the portion of patients developing new mitral regurgitation (MR) (3.5% to 18.7%, p&amp;lt;0.0001), with a trend for developing moderate and above MR (0.7% to 3.3%, p=0.13). While a statistically significant reduction in mean LVEF (60.2%±1.5 to 59.2%±2.7, p=0.0004) and median LV global longitudinal strain (LV GLS) (−21.6% [−20.0 to −23.0] to −20.0% [−19.1 to −21.1], p&amp;lt;0.0001) was observed (Figure 1), the values remain within the normal range with no significant clinical change. In a multivariate binary logistic regression model, age (OR 1.06, 95% CI: 1.01–1.11) and trastuzumab therapy (OR 5.59, 95% CI: 1.95–16.6) were strong independent predictors for MR development, while medical history was not. Conclusions MR development following ANT exposure is frequent, increasingly after the completion of ANT therapy. The parallel reduction in LV function might imply a functional mechanism. Larger trials are needed to evaluate the MR prognostic clinical role in cancer patients. Funding Acknowledgement Type of funding sources: None.

Polymorphism rs4673 and plasma paraoxonase 1 level for prediction and early diagnosis of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12077 Background: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Despite their antitumor efficacy there is a risk of cardiotoxic manifestations that reduce the time and quality of life of patients. The purpose was to study the effectiveness of molecular genetic tests based on rs4673 CYBA genotyping (c.242C &gt; T) and measurement of plasma paraoxonase 1 (PON1) level in patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For rs4673 genotyping, DNA was extracted from the blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). The concentration of PON1 in blood plasma was measured at baseline and after 4 course of chemotherapy with anthracyclines using ELISA kits (Cloud-Clone Corp., China/USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AMC the frequency of the minor allele rs4673 (c.214C &gt; T CYBA) was 0.38, the frequency of genotypes C/C was 0.4, C/T - 0.43, and T/T - 0.17. The risk of AMC increased by 6.49 times in the presence of the rs4673 polymorphic allele (p = 0.002). The area under the ROC curve of the test based on rs4673 genotyping was 71.9%. The concentration of PON1 after the 4 courses of chemotherapy increased by 19.57% in the group of patients without cardiotoxic manifestations (p = 0.018) and in the group of patients with AMC by 20.23% (p = 0.007) as compared to the initial level. Besides, after 4 courses of chemotherapy the PON1 level was higher in patients with AMC by 25.08% (p = 0.026) than in patients without cardiovascular complications. The sensitivity of the test based on the measurement of the PON1 level in the blood plasma after 4 courses of chemotherapy was 100%, the specificity was 70.8% with a cut-off value of 2.9 ng/ml. Conclusions: This study has showed that genotyping of patients for the rs4673 polymorphism allows pre-stratification of the risk group white determination of the PON1 level in blood plasma after 4 courses of chemotherapy gives the opportunity to identify patients with AMC and promptly correct the chosen treatment.

SNP-SNP interactions and a 4-locus model for prediction the risk of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12076 Background: Numerous pharmacogenetic studies have identified genetic polymorphisms (SNPs) associated with an increased risk of anthracycline-mediated cardiotoxicity (AMC). The purpose was to search for SNP-SNP interactions associated with the risk of cardiotoxic manifestations caused by anthracycline therapy in breast cancer patients. Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer with normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For SNP genotyping of c.4544G &gt; A rs8187710 (ABCC2), c.1744C &gt; T rs11549465 ( HIF1A), g.22125504G &gt; C rs1333049 ( CDKN2A/ B) and c.214T &gt; C rs4673 ( CYBA). DNA was extracted from blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic anthracycline mediated cardiotoxicity (changes developed within a year after completion of anthracycline therapy). Using the multifactorial dimension reduction method. We obtained a 4-locus model of SNP-SNP interactions c.4544G &gt; A rs8187710 ( ABCC2) x g.22125504G &gt; C rs1333049 ( CDKN2A/B) x c.214T &gt; C rs4673 ( CYBA) x g.23708527G &gt; A rs28714259 which has high prognostic properties. The specificity of the test based on the 4-locus model was 68%, the sensitivity was 100%, and the overall accuracy was 71%. The results of the analysis of SNP-SNP interactions indicate the greatest contribution of rs4673 and rs28714259 to the predisposition to AMC. The first ones yet into antagonistic interactions with rs28714259, rs1333049 and rs11549465, the second with rs8187710, rs11549465 and rs4673. On the contrary rs11549465 and rs1333049 contribute to a synergistic effect. Conclusions: The 4-locus model discovered in this study can form the basis of prognostic tests that predict early the risks of developing AMC in cancer patients, which in the future allow to personalize and select the most optimal treatment regimen.

Rational and design of SATRACD study: detecting subclinical anthracycline therapy related cardiac dysfunction in low income country.

Anthracycline therapy-related cardiac dysfunction (ATRCD) is the most notorious adverse side-effect of chemotherapy. It has become a significant cardiovascular health concern for long-term cancer survivors. With the emerging concept of subclinical ATRCD and newer diagnostictools (Speckle Tracking Echocardiography (STE) and biomarkers), detecting anthracycline cardiac toxicity at an early stage has become an important step to prevent severe cardiac dysfunction and improve the cardiovascular outcome in cancer survivors. Despite the increasing population at risk in sub-Saharan Africa (SSA), there is no contemporary data in Uganda to address the burden, pathogenesis and risk factors of subclinical ATRCD. This big gap in knowledge has led to a lack of local guidelines for monitoring and management of ATRCD. SATRACD (Detecting Subclinical Anthracycline Therapy Related Cardiac Dysfunction In Low Income Country) study is an observational prospective cohort study. Three hundred and fifty-three anthracycline naïve cancer patients will be recruited at baseline. Patients are followed up on completion of anthracycline-based chemotherapy and at 6 months after completion of anthracycline therapy. Data on demographics, cancer profile and clinical presentation will be collected at baseline. Comprehensive cardiac assessment will be performed at each visit, including electrocardiogram, conventional echocardiography, STE, cardiac and oxidative stress markers. We will be able to determine the incidence of subclinical and clinical ATRCD at 6 months after completion of anthracycline therapy, determine whether hypertension is a major risk factor for ATRCD, evaluate the role of conventional echocardiography parameters, and biomarkers for detecting subclinical ATRCD. This SATRACD study will provide contemporary data on Ugandan cancer patients who have subclinical and clinical ATRCD, help in the development of local strategies to prevent and manage ATRCD, and improve cardiovascular outcome for Ugandan cancer survivors.

Polymorphisms rs4673 and rs28714259 as predictors of anthracycline-mediated cardiotoxicity in patients with breast cancer.

12005 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to study the frequency of rs4673 and rs28714259 and possible associations with the risk of cardiovascular changes in patients with breast cancer during anthracycline therapy (anthracycline-mediated cardiotoxicity — AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular changes, who were treated with anthracyclines at the National Medical Research Center of Oncology in 2019-2020. For genotyping of rs4673 and rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphisms was confirmed by Sanger sequencing on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients were diagnosed with signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AOC the allelic frequency of rs4673 (c.214T &gt; C CYBA) was 0.38, the frequency of genotypes C/C – 0.4, C/T – 0.43, and T/T – 0.17. In the same group, the frequency of the A allele rs28714259 was 0.07, the frequency of the G/G genotypes – 0.87, G/A – 0.13, and A/A – 0. The prevalence of genotypes T/T rs4673 and allele G rs28714259 in a cohort of Russian patients differed from the European population (p = 0.014 and p = 0.05, respectively). The risk of cardiovascular changes on the background of anthracycline therapy increased in the presence of the rs4673 polymorphic allele by 6.49 times, in the case of the G/A and A/A rs28714259 genotypes - by 3.27 times. The results of the ROC-analysis suggested high quality of the tests based on the dominant models rs4673 and rs28714259 (AUC was 71.9% and 76.3% correspondingly). Conclusions: In this study the prognostic efficiency of the genetic markers rs4673 and rs28714259 was shown for the prompt detection of the risks of AMC development in the management of cancer patients. However, population characteristics should be taken into consideration for risk assessment.

Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients from Southern Sri Lanka: An Echocardiographic Analysis.

Anthracycline-induced cardiotoxicity has never been investigated in Sri Lanka. Therefore, this study was conducted to determine the prevalence of anthracycline-induced cardiotoxicity in breast cancer patients using echocardiographic findings. A prospective cohort study was performed. All newly diagnosed breast cancer patients who were administered with anthracycline and cyclophosphamide (AC schedule) for the first time were enrolled in the study. In the hospital setting, anthracycline is administered only as a combination therapy, and only this combination was selected to limit the effect of other cardiotoxic chemotherapy agents. Records of echocardiography were obtained: one day before anthracycline chemotherapy (baseline), one day after the first chemotherapy dose, one day after the last chemotherapy dose, and six months after the completion of anthracycline chemotherapy. Following parameters were recorded from the echocardiography results: ejection fraction (EF, %), fractioning shortening (FS, %), posterior wall thickness, left ventricle (PWT, mm), the thickness of interventricular septum (IVS, mm), left ventricular end-diastolic diameter (LVEDD, mm), and left ventricular end-systolic diameter (LVESD, mm). Statistical analysis of the echocardiography results was performed using ANOVA at four stages. A p value <0.05 was considered significant. Subclinical cardiac dysfunction was defined as a fall of EF >10% during the follow-up echocardiography. There was no significant change (p > 0.05) between the baseline echocardiographic parameters and one day after the 1st anthracycline dose. However, significant differences (p < 0.05) were observed between the baseline echocardiographic parameters and one day after the last anthracycline dose and six months after the completion of anthracycline therapy with a gradual and progressive deterioration in functional parameters including EF, FS, PWT, and IVS over time. There were 65 patients out of 196 (33.16%) who developed subclinical cardiac dysfunction six months after the completion of anthracycline chemotherapy. The prevalence of subclinical anthracycline-induced cardiotoxicity was relatively higher in these patients. An equation was also developed based on left ventricular ejection fraction (LVEF) to predict the anthracycline-induced cardiotoxicity of a patient six months after the completion of anthracycline chemotherapy. We believe that this will help in the monitoring of patients who undergo anthracycline therapy for cardiotoxicity. It is recommended to carry out a long-term follow-up to detect early-onset chronic progressive cardiotoxicity in all patients who were treated with anthracycline therapy.

Circulating high-sensitivity troponin T and microRNAs as markers of myocardial damage during childhood leukaemia treatment.

We investigated whether plasma high-sensitivity cardiac troponin T (hs-cTnT) and circulating heart-associated microRNA (miRs) are increased in children with leukaemias during anthracycline-based chemotherapeutic treatment. In vitro human pluripotent stem cell (hPSC)-derived cardiomyocyte model showed that miR-1, miR-133a, miR-208a, miR-208b, and miR-499 are released from cells into culture medium in a time- and dose-dependent manner on doxorubicin exposure. Left ventricular (LV) myocardial deformation and circulating heart-associated miRs and plasma hs-cTnT during and after completion of chemotherapy were determined in 40 children with newly diagnosed acute leukaemia. Significant reduction of LV global longitudinal strain and strain rates were found within 1 week after completion of anthracycline therapy in the induction phase of treatment (all p < 0.05). Hs-cTnT level peaked and miR-1 increased significantly at this time point. Log-transformed hs-cTnT correlated negatively with LV global systolic longitudinal strain (r = -0.38, p < 0.001). Receiver operating characteristic analysis revealed that area under the curve for changes in plasma hs-cTnT from baseline and plasma miR-1 levels in detecting a reduction in ≥20% of global longitudinal strain were respectively 0.62 (95% CI 0.38-0.87) and 0.62 (95% CI 0.40-0.84). Plasma hs-cTnT and circulating miR-1 may be useful markers of myocardial damage during chemotherapy in children with leukaemias. Heart-associated miRNAs including miR-1, miR-133a, miR-208a, miR-208b,and miR-499 were increased in the culture medium upon exposure of hPSC-derived cardiomyocytes to doxorubicin. Only miR-1 increased significantly during anthracycline-based therapy in paediatric leukaemic patients. In paediatric leukaemic patients, plasma hs-cTnT and circulating level of miR-1 showed the most significant increase within 1 week after completion of anthracycline therapy in the induction treatment phase. The study provides the first evidence of progressive increase in circulating miR-1 and plasma hs-cTnT levels during the course of anthracycline-based therapy in children with leukaemias, with hs-cTnT level also associated with changes in LV myocardial deformation.

Utilization of Cardiac Surveillance Tests in Survivors of Breast Cancer and Lymphoma After Anthracycline-Based Chemotherapy.

The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74-0.85]; P<0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39-1.69] and odds ratio, 1.42 [95% CI, 1.3-1.53]; P<0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance. The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.

Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: the PRADA trial.

Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade. PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003). Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume.

Circulating Neuregulin During the Transition From Stage A to Stage B/C Heart Failure in a Breast Cancer Cohort

BackgroundBreast cancer (BC) treatments can cause heart failure (HF) in a subset of patients. ACC/AHA guidelines classify patients receiving cardiotoxic medications as stage A, a high-risk population for the development of HF. Circulating neuregulin (NRG) correlates with outcomes in stage C and D HF. We examined the levels of NRG in a BC cohort receiving cardiotoxic chemotherapy and its relationship with adverse cardiac effects during the transition from stage A to stage B or C HF. Methods and ResultsIn an ongoing prospective study, a planned interim analysis of 78 BC women receiving either anthracycline (AC) or trastuzumab (Tsz) was performed. Biometric data, cardiac risk factors, and NRG levels, were collected before chemotherapy and after completion of AC therapy and/or 3 months into Tsz therapy. Cardiac function was measured by left ventricular ejection fraction (LVEF) by echocardiography at the above time points and longitudinally as standard of care. The interim cohort was predominately white with stage II BC and a median age of 50 years. A reduction of >10 absolute percentage points in LVEF was observed in 21.4% of the cohort, representing a transition from stage A to stage B or C HF. A statistically significant drop in plasma NRG was observed in women treated with AC and/or Tsz (P < .001). Additionally, baseline NRG correlated with the maximal change in LVEF. ConclusionsMore than 20% of women experienced cardiac dysfunction, detected by decline in LVEF, and were reclassified as stage B or C HF. Plasma NRG levels were reduced after exposure to cardiotoxic chemotherapy, suggesting a loss in a cardioprotective growth factor. Higher baseline NRG levels were observed in those with the greatest decline in LVEF, supporting the continued investigation of NRG as a potential prognostic marker in early-stage HF.

Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults

Anthracycline therapy is limited by cardiotoxicity. Currently no diagnostic parameter is available allowing ubiquitous and reliable detection of preclinical anthracycline cardiomyopathy and prediction of prognosis. In 100 consecutive patients receiving anthracycline-based chemotherapy serial measurements of left ventricular systolic and diastolic function, Tei index (a Doppler echocardiographic parameter of global ventricular function), cardiac troponin T (cTnT) and NT-probrain natriuretic peptides (BNP) at baseline and during 1-year follow-up were performed. Mean ejection fraction (LVEF) significantly decreased immediately after completion of anthracycline therapy (mean dose 226.1 +/- 8.3 mg/m(2)) und further declined during follow-up (65.9 +/- 0.6% Vs. 61.6 +/- 0.7%; P < 0.001), while mean E/A ratio decreased after 6 months (P = 0.05). No patient presented with cardiac symptoms. The Tei index increased after therapy in the majority of patients (78.8%) compared with pre-therapy values indicating myocardial alteration in more patients than previously recognized. cTnT levels did not exceed the upper limit of the normal range in any patient. Seven patients had low-level elevations of cTnT. Only one of these patients developed a concomitant decrease in LVEF. Mean N-terminal-pro-BNP (NT-proBNP) levels did not significantly change after anthracycline administration. However, in 13 patients (15.3%) a marked, transient increase of NT-proBNP was obtained after the first anthracycline cycle without cardiac dysfunction presumably due to altered cardiac loading conditions during chemotherapy. Low to moderate doses of anthracyclines resulted in subclinical myocardial alteration in more patients than so far noticed. Clinical implications of increased Tei index remain to be determined in long-term. Our results do not support that assessment of cTnT or BNP levels may safely replace serial echocardiographic evaluation of systolic and diastolic function for the monitoring of anthracycline cardiotoxicity.

Treatment of Anthracycline-Resistant Breast Cancer

The anthracyclines are commonly used for the treatment of early stage and advanced stage breast cancer, but many patients develop resistance to therapy. The definition of anthracycline resistance varies considerably in the literature, but in most cases includes disease progression during or within 6–12 months after completion of anthracycline therapy. Some authors have distinguished true anthracycline resistance (defined as progression during anthracycline therapy) from anthracycline pretreatment (defined as progression after completion of therapy).

Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia.

Late anthrocycline cardiotoxicity after treatment for childhood cancer is common and often progressive. A safe anthracycline dose that will not result in late cardiac abnormalities has not been established due to the limited dose ranges used in existing studies. To determine the relationship between cumulative anthracycline dose and late cardiotoxicity, we performed echocardiograms on 189 survivors of childhood acute lymphoblastic leukemia a median of 8.1 years (range, 2.0 to 23.4) after completion of anthracycline therapy. Patients were treated according to protocols that used widely varying cumulative anthracycline doses, but comparable nonanthracycline chemotherapy. Patients were divided into four groups based on the city of treatment and cumulative anthracycline dose: Copenhagen, 0 to 23 mg/m2 (n = 32); Boston, 45 mg/m2 (n = 17); Copenhagen, 73 to 301 mg/m2 (n = 53); and Boston, 244 to 550 mg/m2 (n = 87). Left ventricular dimension and fractional shortening were adjusted for sex and age or body-surface area through use of a control population (n = 296), and then compared among the four groups. Mean left ventricular dimension was significantly increased in the high-dose Boston group (observed:predicted value, 4.57 cm:4.45 cm; P = .002) and significantly higher than in the two Copenhagen groups. In the three lower-dose groups, there was no significant increase in mean left ventricular dimension, and the groups were not significantly different from each other. Similarly, the mean left ventricular fractional shortening was significantly depressed in the high-dose Boston group (observed:predicted value, 29.0%:33.8%; P = .0001) and significantly lower than in the three lower-dose groups. Depressed left ventricular fractional shortening and left ventricular dilatation were uncommon years after treatment of childhood leukemia when cumulative anthracycline doses were < or = 300 mg/m2.

Langzeituntersuchung zur anthracyclininduzierten Kardiomyopathie bei Kindern und Jugendlichen

In order to detect changes in cardiac function, electrocardiographic, echocardiographic and radiologic studies were performed in 71 patients (age 1-26 yrs) who had been treated at the University Children's Hospital Berlin because of malignant diseases according to protocols of the DAL/GPO and had received anthracyclines (doxorubicin or daunorubicin) at cumulative doses up to 480 mg/m2 (median 280 mg/m2). Clinically overt cardiomyopathy was observed in one girl and required transient administration of digoxin. In 2 patients echocardiographic changes led to a reduction of the scheduled anthracycline doses. No patient died from congestive heart failure. During treatment, an increase in the cardiothoracic index was observed in 14 children, and in 16 the ECG showed pathological findings. A decrease in contractility to 25% or less as detected by ultrasound was seen in 15 patients. More than 50% of patients developed echocardiographical signs indicating an impairment of myocardial function. However, persistent changes were only found in 1 patient after discontinuation of treatment. Long-term echocardiographic follow-up studies for 4-48 months (median 14 months) after completion of anthracycline therapy were performed in 18 patients and the findings compared to matched-pair controls. The observed M-mode parameters were completely normal, and the ejection fractions calculated from the two-dimensional ultrasound investigations were in the normal range but slightly diminished compared to controls. Cardiac ultrasound is a non-invasive, reproducible and tolerable procedure for early detection of an anthracycline cardiomyopathy. In our patients, time of occurrence and the extent of pathological changes were not associated with the cumulative applied anthracycline doses.(ABSTRACT TRUNCATED AT 250 WORDS)