Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour

BackgroundPreclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.Material and methodsTwo dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.ResultsTwo D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.ConclusionDoxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.     

右丙亚胺用于乳腺癌术后化疗所致患者心肌损害的有效性和安全性

目的 探讨右丙亚胺对乳腺癌患者采用蒽环类化疗时心肌的保护作用.方法 选择乳腺癌术后接受CAF(环磷酰胺+阿霉素+5-氟尿嘧啶)方案和TE(多西他赛+表柔比星)方案化疗的患者98例.按照随机数字法将患者分为试验组和对照组各49例.对照组及实验组均采用CAF方案和TE方案化疗,试验组在给予阿霉素或表柔比星30 min前给予右丙亚胺(奥诺先)静脉滴注(右丙亚胺:阿霉素或表柔比星=10:1),30 min内滴完.结果 与治疗前比较,试验组治疗12个月以后出现血清BNP升高,对照组治疗6个月以后出现升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清BNP低于对照组,差异有统计学意义(P<0.05).与治疗前比较,2组患者治疗6个月以后血清cTnT升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清cTnT低于对照组,差异有统计学意义(P<0.05).试验组患者治疗后血清CK-MB与治疗前差异无统计学意义(P>0.05);对照组治疗12个月以后升高,差异有统计学意义(P<0.05).试验组治疗期间,LVEF与治疗前差异无统计学意义(P>0.05);对照组治疗6个月以后LVEF下降,差异有统计学意义(P<0.05);治疗6个月以后,对照组LVEF低于观察组,差异有统计学意义(P<0.05).2组患者不良反应发生情况差异无统计学意义(P>0.05).结论 右丙亚胺用于乳腺癌术后化疗可以明显减轻蒽环类药物的心脏毒性,保护心肌细胞,且不增加化疗的不良反应,提高患者化疗药物耐受性.     

Cardiotoxicity of anthracycline (ANT) treatment in children with malignant tumors

Objective: To investigate the cardiotoxicity indexes in children with malignant tumors after the administration of anthracycline (ANT) chemotherapy.

Materials and Methods: Data from 131 children with malignant tumors who were treated using ANT chemotherapy at our hospital from January 2011 to December 2015 were collected to analyze the serologic indexes (such as N-terminal pro-brain natriuretic peptide [NT-proBNP] and isoenzyme of creatine kinase [CK-MB]) and changes in corrected QT interval(QT-c) and left ventricular ejection fraction (LVEF) before and after treatment with different ANT cumulative doses.

Results: General clinical data revealed that 2 of the 131 children developed clinical cardiotoxicity. The ANT cumulative dose range was 12–697 mg/m². All patients were divided into three groups according to the ANT cumulative dose: group 1 (<100 mg/m²), 2 (≥100 and <200 mg/m²), and 3 (≥200 mg/m²). Although NT-proBNP and LVEF among the three groups differed significantly after chemotherapy (p = 0.022 and 0.035, respectively), no significance was noted for CK-MB and QT-c among the three groups after chemotherapy (p = 0.190 and p = 0.084, respectively). Multiple linear regression analysis revealed that the ANT cumulative dose had the most significant impact on NT-proBNP (standardized coefficient 0.423, p = 0). Pearson correlation analysis revealed that ANT cumulative dose was positively correlated with NT-proBNP post-treatment (correlation coefficient 0.423), but LVEF was negatively correlated with NT-proBNP after chemotherapy (correlation coefficient ?0.542).

Conclusions: NT-proBNP showed significant changes when the ANT dose was >200 mg/m². Post-treatment serum NT-proBNP was linearly correlated with ANT cumulative dose, hence strictly controlling the ANT cumulative dose and monitoring serum NT-proBNP may have certain clinical significance in predicting cardiotoxicity.     

蒽环类药物对肿瘤患者左心功能影响的组织多普勒评价

目的探讨组织多普勒技术(TDI)在评价蒽环类药物(ATC)对肿瘤患者左心功能早期损害的临床应用价值。方法测定并比较26例肿瘤患者ATC化疗前和化疗后6个月的常规超声心动图参数及TDI参数。结果TDI显示ATC化疗后二尖瓣环的收缩期运动速度峰值(Sm)及舒张早期运动速度峰值(Em)较化疗前明显降低(P<0.05),心房收缩期运动速度峰值(Am)较化疗前明显升高(P<0.01),Em/Am较化疗前明显降低(P<0.01),但舒张早期左室充盈峰速度(E)、心房收缩期左室充盈峰速度(A)、E/A、E峰减速时间(DT)、左室等容舒张时间(IVRT)及射血分数(EF)、短轴缩短率(FS)等常规心功能指标化疗前后差异无显著性(P>0.05)。结论TDI技术能更早、更敏感地评价ATC对肿瘤患者左室功能损害。     

心肌背向散射积分参数评价蒽环类抗肿瘤药心脏毒性的临床研究

目的 :探讨背向散射积分参数分析技术在评价蒽环类抗肿瘤药 (ATC)心脏毒性方面的应用价值。方法 :应用 HP Sonos550 0型超声诊断仪及其配置的背向散射联机分析软件测定 83例接受 ATC化疗的肿瘤患者及 50例正常对照组心肌背向散射积分参数 :心肌背向散射积分均值 (IBS) ;背向散射积分的心动周期变化幅度 (CVIB) ;心肌校正的背向散射积分均值 (IBS% )和背向散射积分周期变异率 (CVIB% )。结果 :ATC化疗组与对照组心肌 IBS均呈周期性变化 ,但 ATC化疗组变化幅度明显减低 ;ATC化疗组心肌 IBS%较对照组明显增高 (P<0 .0 5) ,CVIB和 CVIB%则较对照组明显减低 (P<0 .0 5,P<0 .0 1) ;ATC化疗组中 3 0例 (3 6.1% )患者出现左心室舒张功能指标异常 ,其中 E/A明显低于对照组。但左心室收缩功能参数和室间隔 (IVS)及左室后壁 (L VPW)的室壁增厚率 (Δ T% )在 ATC化疗组和对照组之间无显著性差异 ;IBS参数与 ATC累积剂量、距首次化疗时间、心功能参数及相应节段的室壁增厚率均无显著相关性。结论 :ATC化疗组患者心肌组织背向散射积分参数与对照组显著不同 ,背向散射积分参数测定可作为评价 ATC早期心脏毒性的手段之一。     

蒽环类药物累积剂量与校正后QT间期关系的研究

目的：研究蒽环类药物累积剂量与其校正后QT间期（QTc)的关系。方法：回顾性分析48例患者初次化疗前及应用蒽环类药物化疗后12导联同步心电图，测量QTc，以Bazett公式计算出QTc，结果：蒽环类药物累积剂量＜200mg/m^2者，1／37QTc延长，在蒽环类药物累积剂量≥200mg/m^2者，5／11QTc延长（P＜0．05），结论：随蒽环类药物累积剂量增加，QTc延长发生率增加。     

Menogaril, an Anthracycline Compound with a Novel Mechanism of Action: Cellular Pharmacology

Menogaril, an anthracycline compound possessing a significant antitumor activity after both po and iv administration, has been introduced into clinical trials. However, its mechanism of action has not been clarified yet. This study revealed that its cytotoxicity correlated very well with the inhibition of macromolecular synthesis, indicating the involvement of interaction with DNA. The spectrophotometric study showed a weaker binding of this compound to calf thymus DNA when compared to that of doxorubicin (adriamycin). Despite the lower binding affinity of menogaril to DNA, pronounced DNA cleavage was observed in an intact cell system, indicating that the character of the interaction with DNA is different from intercalation. In contrast to doxorubicin, menogaril is extensively localized in the cytoplasm. The cytoplasmic localization prompted us to study its effect on cytoskeleton proteins. It was found that menogaril inhibited the initial polymerization rate of tubulin, indicating a possible contribution of this process to the overall cytotoxicity of menogaril.     

新的蒽环类抗生素80334B,C和F的研究 Ⅱ.发酵、分离、理化特性、生物学活性和化学结构的测定

襄樊假孢囊放线菌(Actinosporangium xiangfanensis SIPI 80334 nov.sp)产生三个新的蔥环类抗肿瘤抗生素80334 B,C和F。本文报告这三个新抗生素的发酵,分离和精制、理化特性、抗菌和抗肿瘤等生物学活性以及化学结构的测定。     

Cardiomyopathy Induced by Anthracycline-Derivates

ABSTRACT. Two cases of anthracycline-induced congestive heart failure are described. Serial assessment of cardiac function during treatment showed early deterioration of the systolic time intervals of the left ventricle (LSTI) before congestive cardiomyopathy could be demonstrated by echocardiography. We recommend that the cardiac function should be assessed regularly during anthracycline therapy by systolic time intervals and echocardiography to reveal early signs of cardiotoxic effect and that anthracycline therapy should be stopped when LSTI is 0.45 or when it has increased more than 50 % compared to pretreatment values