cTnT早期诊断蒽环类药物心脏毒性的实验研究

目的:研究血清肌钙蛋白T(cT-nT)浓度是否可以成为蒽环类药物心脏毒性早期诊断指标。方法:新西兰雄性兔44只,随机分为对照组(8只)和实验组(36只)。对照组新西兰兔注射等体积的生理盐水;实验组新西兰兔静脉注射多柔比星2 mg/(kg.次),1次/周,根据实验周数不同,实验组分为1周组(8只)、2周组(8只)、4周组(9只)和8周组(11只)。经胸超声心动图测量左室射血分数(LVEF)和左室短轴缩短分数(FS)以及E峰和A峰比值。血清GPBB浓度测量采用ELISA方法。心肌光镜Billingham评分和电镜检查评价多柔比星心脏毒性。结果:8周组新西兰兔LVEF、FS和E/A值均下降,P<0.05。与对照组相比,4周组新西兰兔血清cTnT浓度明显升高,P<0.05;8周组新西兰兔血清cTnT浓度显著高于其他组,P<0.05。光镜下4周组新西兰兔心肌损害比对照组严重,P<0.05;8周组新西兰兔心肌损害最严重,P<0.05。电镜下线粒体水肿和断裂可见于2周组、4周组和8周组,心肌损伤程度与多柔比星累积剂量有关。相关分析提示,血清cTnT浓度与多柔比星累积剂量(r=0.887,P<0.001)及血清cTnT浓度与...     

NT-proBNP与CVP对蒽环类药物致心脏毒性的早期监测应用的临床意义

目的:探讨N末端原脑利钠肽前体（NT-proBNP）与中心静脉压（CVP）对蒽环类药物所致心脏毒性的早期监测及其临床意义。方法:对我院乳腺癌术后应用蒽环类化疗药物化疗的女性患者80例,在化疗前、第1、2、3个疗程结束及全程化疗结束后5个时间点,使用免疫荧光法定量测定患者血浆NT-proBNP浓度,同时对患者行深静脉穿刺置管CVP测定并记录结果。结果:NT-proBNP在第1、2、3个疗程结束及全程化疗结束时其水平与化疗前比较均有统计学意义（均P<0.05）,CVP在化疗结束时与化疗前比较有统计学意义（P<0.05）。结论:NT-proBNP联合CVP对在乳腺癌患者中应用蒽环类药物化疗致心脏毒性的早期监测有必要,加强其检测可对保护心脏功能以及判断预后有重要意义。     

T1、T2 mapping成像技术评价蒽环类药物所致心脏毒性的研究进展

随着现代医疗手段的进步,肿瘤患者的生存期逐渐延长,癌症患者的远期生存质量越来越得到重视.蒽环类抗肿瘤药物应用于临床已达半世纪之久,在血液系统肿瘤及乳腺癌的治疗上目前仍然有着不可取代的地位.然而其所导致的心脏毒性亦对肿瘤患者的远期生存构成严重威胁.心脏磁共振(cardiac magnetic resonance,CMR)...     

二维与三维超声心动图斑点追踪技术检测乳腺癌蒽环类药物心脏毒性的可行性研究

目的:探讨二维与三维斑点追踪技术以及实时三维超声心动图在早期检测蒽环类药物所致心脏毒性中的价值,并评估其可行性.方法:对乳腺癌患者于蒽环类药物化疗前、化疗第3周期及化疗结束后行超声心动图检查,以3D LVEF结果为评价标准,统计分析各参数在评估心脏毒性中的临床价值.结果:共92例乳腺癌患者纳入研究.常规超声心动图以及2...     

炙甘草汤预防蒽环类药物心脏毒性的临床观察

目的：研究炙甘草汤改善含蒽环类方案化疗的乳腺癌患者心脏毒性的临床效果。方法：收集40例接受含蒽环类方案化疗的乳腺癌患者的病案资料,根据随机数字表法,将患者随机分为单纯组和联合治疗组,记录并比较两组患者化疗前和随后第2、4、6周期治疗后的 LVEF、BNP、CK - MB、cTnT、心电图等的变化。结果：所有患者均未出现充血性心力衰竭（ CHF）。两组患者,随着治疗周期的延长,LVEF 呈下降趋势（P ﹤0.05）,cTnT、BNP 及 CK - MB 呈上升趋势（P ﹤0.05）。结论：炙甘草汤能有效改善蒽环类药物化疗所致的心脏毒性,且未观察到毒副反应增加。     

Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients

Background:

The aim of this study was to assess the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting late cardiotoxicity in patients treated with not-high-dose chemotherapy (NHDC), and to compare the predictive value of NT-proBNP and cardiac troponin I (cTnI).

Methods:

In 71 patients undergoing NHDC with anthracyclines, NT-proBNP and cTnI levels were measured before and 24 h after each NHDC cycle. Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up.

Results:

During NHDC, only NT-proBNP showed abnormal values. According to NT-proBNP behaviour, patients were divided into two groups: group A (n=50) with normal (n=23) or transiently elevated NT-proBNP levels (n=27), and group B (n=21) with persistently elevated NT-proBNP levels. At follow-up, LV impairment was significantly worse in group B than in group A. %Δ (baseline–peak) NT-proBNP was predictive of LV impairment at 3-, 6- and 12-month follow-up, with a cutoff of 36%.

Conclusion:

Serial measurements of NT-proBNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity.     

Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.

BACKGROUND: The aim of this systematic review was to summarise and appraise the published evidence with regard to the frequency and risk factors of subclinical cardiotoxicity in apparently healthy survivors of childhood cancer after anthracycline therapy. PATIENTS AND METHODS: A search was made in Medline for studies published between 1966 and May 2001 that included >50 children and reported on the frequency of measures of subclinical cardiotoxicity. Information about the studies was abstracted by two reviewers and a validity score was calculated for each study. RESULTS: The reported frequency of subclinical cardiotoxicity varied between 0% and 57% in the 25 studies included. Differences in outcome definitions of subclinical cardiotoxicity and differences in study patients with respect to the dose of anthracycline seemed to explain part of the wide variance of the frequency of subclinical cardiotoxicity. Fourteen of the 25 studies showed serious methodological limitations. CONCLUSIONS: The reported frequency of subclinical cardiotoxicity shows a wide variation. Well designed studies with accurate and precise outcome measurements in well described groups of patients, after a sufficiently long follow-up period, are needed to obtain more insight into the frequency and importance of risk factors, and the clinical consequences of anthracycline-related subclinical cardiotoxicity.     

Genome‐wide association study of genetic variants related to anthracycline‐induced cardiotoxicity in early breast cancer

We performed a genome‐wide association study to investigate the association between single nucleotide polymorphisms and anthracycline‐induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m²‐300 mg/m²) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty‐seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m² [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23‐4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11‐5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E?06), rs11894115 (MPP4, P = 4.71E?06), rs58328254 (RPL7, P = 6.09E?06), and rs117299725 (PRUNE2, P = 8.53E?06), although none of these variants reached the Bonferroni‐corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E?07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.     

新药心脏毒性体外检测方法的建立

目的： 建立适合于药物心脏毒性评价的人心肌细胞模型,并采用此模型评价新药中化合物潜在的心脏毒性。方法： 选用浓度为0.33、1、3 μmol/mL的他莫昔芬（Tamoxifen）和浓度为0.11、0.33、1 μmol/mL的氟哌利多（Droperidol）分别与人心肌细胞孵育48 h。给药后1、2、3、6、9、12、18、24、30、36、42和48 h采用实时细胞分析法和高内涵细胞成像技术监测心肌细胞搏动的频率、振幅、规律性及线粒体膜电位等指标在给药前后的变化,建立人心肌细胞体外心脏毒性评价模型。应用此模型评价化合物他莫昔芬和氟哌利多的心脏毒性。结果： 他莫昔芬和氟哌利多与人心肌细胞共同孵育后,3 μmol/mL的他莫昔芬在处理3 h时使人源性心肌细胞场电位时程（FPD）和人源性心肌细胞收缩频率降为0,18 h后恢复,其他浓度与对照组基本一致;心肌细胞FPD和心肌细胞收缩频率对氟哌利多均具有浓度依赖性,浓度越高FPD （Max）数值越大而收缩频率数值越小,24 h后进行全换液,换液后各浓度处理的心肌细胞均可恢复。结论： 利用人心肌细胞可以建立一种可行的体外心脏毒性评价模型,结合实时细胞分析法以及高内涵细胞成像技术可评价药物的心脏毒性。     

Q-T间期离散度联合肌钙蛋白I检测早期诊断乳腺癌蒽环类化疗所致心脏毒性的价值

目的:探讨Q-T间期离散度（QTd）联合肌钙蛋白I（cTnI）在蒽环类化疗药所致心脏毒性早期检测中的应用价值。方法:回顾性分析我医院2019年01月至2020年06月用蒽环类药物完成化疗的97例乳腺癌患者的临床资料。以左心射血分数（LVEF）下降幅度及充血性心衰症状为参考标准将纳入患者分为观察组（心脏毒性组）与对照组（非心脏毒性组）,统计其QTd、cTnI水平,用SPSS 25.0分析软件进行数据处理。结果:入组的97例患者中18人发生心脏毒性,发生率18.6%。化疗前对照组与观察组QTd、cTnI基线水平无明显统计学差异(P＞0.05);各化疗周期后QTd、cTnI水平均较基线水平明显升高（P＜0.05）;相同化疗周期观察组QTd、cTnI水平明显高于对照组（P＜0.05）。QTd、cTnI的ROC曲线下面积（AUC）分别为0.877、0.871,敏感性分别为85.4%、82.6%,特异性分别为96.5%、93.4%,联合应用时AUC为0.876,敏感性与特异性分别为84.0%、97.3%。结论:QTd、cTnI检测均可作为无创性评估蒽环类化疗药所致心脏毒性发生的前瞻性方法之一;QTd、cTnI联合应用具有更高的诊断价值。     

Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients.

BACKGROUND: With increasing doses the highly tumoricidal anthracycline drugs cause heart damage. Based on empirical drug limitations about 10-15% of patients will develop congestive heart failure (CHF) with a mortality of -50% within 2 years on digitalo-diuretic therapy alone. To avoid CHF there is a consensus recommendation that cardiac function should be monitored in close connection with anthracycline administration. As no prospective studies in a larger series have been performed, these recommendations are based on retrospective data on small numbers of patients. PATIENTS AND METHODS: In a prospective, blinded observational study 120 patients with advanced breast cancer were followed before, during, and a median 3 years after treatment with epirubicin. They had 604 serial radionuclide measurements of left ventricular ejection fraction (LVEF) that were stored without calculations except in patients who developed a well-defined CHF. RESULTS: Anthracycline cardiotoxicity was closely correlated with the cumulative dose, with a great variability in individual susceptibility and a dramatic increase with advancing age. With a delayed onset of 3 months or more, epirubicin induced a threatening, slowly progressive deterioration of cardiac function continuing years after treatment. An actuarial estimation of 59% of the patients experienced a 25% relative reduction in LVEF 3 years after 850-1000 mg/m2 of epirubicin and 20% had deteriorated into a CHF. The patients did not spontaneously regain cardiac function whereas continued therapy with a circadian angiotensin-converting enzyme inhibitor for more than 3 months caused a remarkably potent and long-lasting recovery. CONCLUSIONS: Due to the displaced cardiotoxic manifestation, functional monitoring in close connection with anthracycline administration appears to be a poorly effective method while later monitoring is essential. Current monitoring recommendations should therefore be revised.     

Cardiac imaging techniques for the assessment of immune checkpoint inhibitor-induced cardiotoxicity and their potential clinical applications

Immune checkpoint inhibitors (ICIs) have encouraged a paradigm shift in the clinical management of patients with cancer. Despite the dramatically improved tumor response and patient prognosis, ICIs have been associated with ICI-related myocarditis, which has a high fatality rate. Cardiac imaging plays a critical role in the assessment of cardiac injury. Echocardiography, cardiac magnetic resonance imaging, and targeted tracer-based cardiac molecular imaging techniques alone or in combination reflect pathophysiology and depict different aspects of lesions at different clinical stages, i.e., they have potentially complementary value. Imaging techniques for identifying ICI-induced cardiotoxicity at the early stage may reduce the incidence of adverse cardiovascular events. Particularly in planned ICI therapy among patients with cancer, improved monitoring approaches to identify patients who are at the highest risk of ICI-related myocarditis may help in refining clinical decisions, allowing treatment to be more accurately targeted toward patients who are most likely to benefit. In this study, we systematically reviewed the studies on cardiac imaging techniques for assessing ICI-induced cardiotoxicity. We elaborated about the potential applications of cardiac imaging techniques for the optimized management of patients with ICI-related myocarditis, including risk stratification, diagnosis, and prognosis.     

Sequential equilibrium gated radionuclide angiocardiography for the detection of doxorubicin cardiotoxicity

Right and left ventricular ejection fractions (RVEF and LVEF) were studied at rest, during exercise, and in the immediate post-exercise period (recovery) in 23 patients treated with doxorubicin. Ejection fractions were determined using equilibrium gated radionuclide angiography and non-interactive computer processing. Two effects of doxorubicin emerged: (1) The LVEF at rest and the maximal LVEF reached during the stress test decreased as a function of the cumulative dose expressed in mg/m2. (2) When two measurements were performed before and after an interval dose of less than 100 mg/m2, the resting and maximal LVEF showed an increase, but at higher interval doses, those values showed a decrease. In general, the effect of an incremental dose was not a function of the cumulative dose. No significant changes were detected in RVEF, and LVEF at standardized exercise levels did not correlate with cumulative doses or change as a function of interval dosage.     

Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review.

BACKGROUND: Anthracyclines are essential for the treatment of the children with cancer. We performed a systematic review to evaluate the existing evidence of the frequency and risk factors of anthracycline-induced clinical heart failure (A-CHF) in children. DESIGN: Medline was searched for articles reporting the frequency of A-CHF, published from 1966 to December 2000. Information about study features, risk factors and frequency were abstracted, and a validity score was given for each study. The potential predictive factors of A-CHF were analysed both within and across the studies. RESULTS: The frequency of A-CHF in children was estimated in 30 studies described in 25 articles. All studies have serious methodological limitations. The frequency varied between 0% and 16%. In the analysis across the studies the type of anthracyclines and the maximal dose in 1 week explain a considerable part of the variation of the frequency of A-CHF. CONCLUSIONS: Doxorubicin and a dose above 45 mg/m2 within 1 week seemed to increase the frequency of A-CHF. Well designed and executed studies are needed to accurately estimate the frequency of A-CHF and reliably assess the importance of potential risk factors.     

血清cTnI联合BNP检测在乳腺癌化疗相关心脏毒性早期预测中的应用价值

目的:探究血清高敏心肌肌钙蛋白(cTnI)联合脑利钠肽(BNP)检测在乳腺癌化疗相关心脏毒性早期预测中的应用价值.方法:选择2015年12月至2016年12月本院收治的乳腺癌患者125例,所有患者均采用DA方案进行化疗,化疗前1天,每次化疗周期结束后第2天清晨采集静脉血液,收集血清,化学发光法检测血清cTnI、BNP水...     

Cardiotoxicity of anticancer treatments: Epidemiology,detection, and management

Answer questions and earn CME/CNE Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost. Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evident years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious cardiac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction, such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer treatment may be associated with other cardiac events, such as severe treatment‐induced hypertension and vasospastic and thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life‐threatening. Early and late effects of chest radiation can lead to radiation‐induced heart disease, including pericardial disease, myocardial fibrosis, cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline of cardio‐oncology has developed in response to the combined decision making necessary to optimize the care of cancer patients, whether they are receiving active treatment or are long‐term survivors. Strategies to prevent or mitigate cardiovascular damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascular issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA Cancer J Clin 2016;66:309‐325. © 2016 American Cancer Society .     

Aberrant promoter methylation can be useful as a marker of recurrent disease in patients with cervical intraepithelial neoplasia grade III

INTRODUCTION: Although studies of risk factor profiles have been conducted to identify biological markers to predict the natural history of cervical intraepithelial neoplasia (CIN) grade III, there is not sufficient information to support the routine clinical use of any biomarker. OBJECTIVES: The purpose of this study was to examine aberrant promoter methylation, which is implicated in cancer development and progression, in CIN III lesions in order to identify markers associated with more aggressive biological behavior that could be used to recognize women who are at higher risk of recurrence. PATIENTS AND METHODS: We used methylation-specific polymerase chain reaction to analyze promoter hypermethylation of 8 genes (p16, RARbeta, GSTP1, MGMT, p14, TIMP3, E-cad and DAPk) in 33 uterine cervix cones with CIN III that were also submitted to human papillomavirus (HPV) genotyping. All 33 patients in this study had been clinically followed after conization with Papanicolaou smears, colposcopy, and biopsy when indicated, every 6 months during 5 years. RESULTS: Of the 33 patients, 12 (36%) underwent immediate hysterectomy after conization for having compromised cone margins, 14 (43%) have not relapsed, and 7 (21%) presented CIN relapse. The frequency of HPV infection in this group was 97% and no significant difference between the groups was observed. HPV of high oncogenic risk was present in 29 (87.9%) cases; HPV 16 was the most frequent (69.7%), while HPV 18 was found in 33.3%; however, it was associated with HPV 16 in 15.1%. Concomitant infection by HPV 6/11 was detected in 21.2% (15.1% with HPV 16 and 6.1 with HPV 18). 85.7% (6/7) of patients with recurrence had HPV 18 vs 0% (0/14) of patients without recurrence (P = 0.0001). At least 1 of the 8 genes was found hypermethylated in all samples. Concomitant hypermethylation of several genes was frequently found. However, CIN relapse was only seen in the cases with hypermethylation of 3 or more of the 8 genes studied (P = 0.0039). CONCLUSION: We suggest that aberrant promoter methylation may play a role and may serve as a useful biomarker in the recurrence of CIN.     

Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.

BACKGROUND: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. RESULTS: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. CONCLUSIONS: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.