索拉非尼联合免疫检查点抑制剂治疗TACE抵抗的中晚期肝癌的疗效及安全性

目的 探讨索拉非尼联合免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗经肝动脉化疗栓塞术（transcatheter arterial chemoembolization,TACE）抵抗的中晚期肝癌的疗效及安全性。方法 回顾性分析2017年1月至2021年3月期间在温州医科大学附属第五医院确诊为TACE抵抗的中晚期肝癌患者的资料,共54例,年龄28～82（56.1±11.8）岁,其中BCLC B期24例,C期30例;Child-Pugh A级34例,B级20例。根据治疗方法不同,分为对照组和联合组,对照组接受单一索拉非尼治疗（n=33）,联合组接受索拉非尼联合ICIs治疗（n=21）;比较两组患者的一般情况、肿瘤反应性、肿瘤无进展生存时间（progression-free survival,PFS）及不良反应的发生情况。结果 联合组（2例CR、11例PR、4例SD和4例PD）的肿瘤反应性明显优于对照组（2例CR、8例PR、10例SD、13例PD）（P=0.041）。联合组的中位PFS明显长于对照组（13.5个月 vs 6.8个月,P=0.010）;多因素分析显示Child-Pugh B级（HR 2.202,95%CI 1.059～4.581,P=0.035）、BCLC C期（HR 4.077,95%CI 1.902～8.742,P<0.001）、AFP≥400 ng/mL（HR 5.728,95%CI 2.227～14.729,P＜0.001）是TACE抵抗肝癌PFS的独立危险因素,索拉非尼联合ICIs（HR 0.180,95%CI 0.082～0.392,P<0.001）是肝癌患者的保护因素。联合组并发皮炎、腹泻的发生率明显多于对照组（P<0.05）。结论 索拉非尼联合ICIs治疗提高TACE抵抗中晚期肝癌的肿瘤反应性,延长患者PFS,是一种有效、安全的治疗方案。     

肝癌索拉非尼敏感性预测模型的构建及临床意义

目的：基于生物信息学方法构建并验证肝细胞癌(以下简称肝癌)对索拉非尼敏感性相关基因的预后风险模型,探究该模型对肝癌患者预后和对索拉非尼敏感性的预测能力。 方法：本研究对GSE109211数据集、TCGA-LIHC队列、ICGC-LIRI队列进行差异基因分析,通过交集筛选出肝癌索拉非尼敏感性相关基因。利用单因素Cox分析和LASSO回归构建预后风险模型并进行验证。通过GDSC数据库分析索拉非尼的IC50值并探索其与风险评分的关系。 结果：筛选出365个与索拉非尼敏感性相关的基因,富集分析显示存在与药物代谢相关的信号通路。单因素Cox回归分析出221个与预后相关的基因,通过LASSO回归构建了一个包含7个关键基因的预后风险模型,与低风险组相比,高风险组具有较短的生存时间。多因素Cox回归分析显示风险评分是独立的预后因素。通过对比高、低风险组患者的索拉非尼IC50值,发现高风险组的索拉非尼IC50值较低,提示高风险组对索拉非尼的治疗可能更敏感。 结论：基于索拉非尼敏感性相关基因构建的预后风险模型对肝癌患者预后具有良好的预测价值,并为评估肝癌患者的索拉非尼敏感性提供理论依据。     

A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of >/=12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA-response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.     

Two important factors affecting the prognosis of patients treated with sorafenib followed by regorafenib for advanced hepatocellular carcinoma

ObjectiveTo investigate the effects of hand–foot syndrome (HFS) and fatigue on disease progression and survival in patients treated with sorafenib followed by regorafenib for advanced hepatocellular carcinoma.MethodsA retrospective analysis of patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from 1 October 2018 to 31 October 2021 was performed, and clinical and pathological data and follow-up results were obtained. Patients were divided into groups according to the severity of HFS and fatigue. Survival analysis among the groups was performed using the Kaplan–Meier method, continuous variables were analyzed using the t-test, and factors associated with survival were evaluated using multivariate Cox regression analysis.ResultsThe study included 150 men and 23 women with a mean age of 60.77 years (range: 40–85 years). The median overall survival (OS), progression-free survival (PFS), and time to tumor progression (TTP) increased with increasing severity of HFS. Conversely, the median OS, PFS, and TTP decreased with increasing severity of fatigueConclusionHFS and fatigue were independent risk factors affecting TTP, PFS, and OS among patients treated with sorafenib followed by regorafenib for advanced hepatocellular carcinoma.     

多靶点抗肿瘤新药索拉非尼的药理作用及临床研究进展

索拉非尼(sorafenib)是一种口服多激酶抑制剂,为一新的多靶点抗肿瘤药,能抑制肿瘤血管形成及肿瘤细胞增殖。临床研究表明,索拉非尼能有效治疗肾细胞癌晚期患者,并延长其无疾病进展期和总生存期,索拉非尼对其他癌症的作用也正在研究中。索拉非尼的常见不良反应有皮疹、手足综合征、高血压及腹泻等。     

索拉非尼固体脂质纳米粒冻干粉制备及体外释药特性研究

 目的 制备索拉非尼固体脂质纳米粒,并考察其理化性质及体外释药特性。方法 采用乳化蒸发-低温固化法制备索拉非尼固体脂质纳米粒,透射电镜观察形态,激光粒度仪测定粒径和Zeta电位,葡聚糖凝胶法和HPLC测定其包封率,透析法考察其体外释药特性,冷冻干燥法制备索拉非尼固体脂质纳米粒冻干粉,差示扫描量热分析其物相状态。结果 制得索拉非尼固体脂质纳米粒为类球形实体,粒径分布比较均匀,平均粒径为(108.2±7.0) nm,多分散指数为（0.250±0.022）,Zeta电位为(-16.4±0.7) mV;测得3批样品的平均包封率为(73.49±1.87)%;体外释放符合Weibull模型;等体积15%甘露醇作冻干保护剂效果较好;DSC分析证明纳米粒已形成。结论 乳化蒸发-低温固化法适用于索拉非尼固体脂质纳米粒的制备,所制纳米粒各项物理指标稳定,具有明显缓释作用。     

姜黄素与索拉非尼联合对人肾癌细胞株786-O增殖抑制作用的体外研究

目的：研究姜黄素和索拉非尼联合应用对人肾癌786-O 细胞株增殖的影响。方法采用 MTT 法观察姜黄素和索拉非尼对人肾癌细胞786-O 细胞株的抑制作用。结果姜黄素及索拉非尼能抑制人肾癌786-O 细胞株的增殖,并呈浓度及时间依赖性,两者作用人肾癌786-O 细胞株48 h 的半数抑制浓度（ IC50）分别为29.2μmol/ L、6.5μmol/ L。姜黄素6.25μmol/ L、12.5μmol/ L、25μmol/ L、50μmol/ L 与索拉非尼1.5μmol/ L、3μmol/ L、6μmol/ L、12μmol/ L、联合24 h、48 h、72 h 的抑制率显著高于单用索拉非尼、姜黄素组（ P ﹤0.05）。结论姜黄素在体外对人肾癌786-O 细胞株的增殖有明显的抑制作用,能提高索拉非尼对人肾癌786-O 细胞株的敏感性。     

吲哚脲类化合物的设计合成及其体外抗肿瘤活性研究

目的以索拉非尼为先导物,设计并合成一系列吲哚脲类化合物,并对其体外抗肿瘤活性进行初步评价。方法以5-硝基吲哚-2-甲酸为起始原料,采用BOP法合成酰胺,再将硝基还原成胺基,最后与异氰酸酯缩合,共3步反应制备目标化合物;采用MTT法评价目标化合物对4种肿瘤细胞株(MX-1、A375、HepG2、Ketr3)的生长抑制作用。结果与结论合成了28个吲哚脲类新化合物,其结构经1H-NMR和HR-MS确证。体外活性结果表明,与索拉非尼相比多数化合物选择性地作用于MX-1细胞株,显示出较强的抑制肿瘤细胞增殖的活性。其中含甲基哌啶的化合物26、30和31抑制MX-1和A375细胞生长的作用显著强于索拉非尼。尤其是化合物31抑制A375细胞增殖的作用是索拉非尼的10倍,对HepG2的抑制活性与索拉非尼相当,IC50值均达到微摩尔级水平,值得进一步研究。     

Tumor-treating fields in combination with sorafenib restrain the proliferation of liver cancer in vitro

Liver cancer is a common malignancy worldwide, with a poor prognosis and a high recurrence rate despite the available treatment methodologies. Tumor-treating fields (TTFields) have shown good preclinical and clinical results for improving the prognosis of patients with glioblastoma and malignant pleural mesothelioma. However, there is minimal evidence for the effect of TTFields on other cancer types. Thus, the present study aimed to investigate the therapeutic efficacy of TTFields in an in vitro model, and to further elucidate the underlying mechanisms. In the present study, two hepatocellular carcinoma (HCC) cell lines (Hep3B and HepG2) were treated with TTFields (intensity, 1.0 V/cm; frequency, 150 kHz) in order to determine the potential antitumor effects of this approach. TTFields significantly inhibited the proliferation and viability of HCC cell lines, as measured using Trypan blue and MTT assays, as well as colony formation in three-dimensional cultures. The TTFields also significantly inhibited the migration and invasion of HCC cells in Transwell chamber and wound-healing assays. Moreover, TTFields enhanced the production of reactive oxygen species in the cells and increased the proportion of apoptotic cells, as evidenced by increased caspase-3 activity, as well as PARP cleavage in western blotting experiments. All of these effects were increased following the application of TTFields in combination with the multi-kinase inhibitor sorafenib, which demonstrated a synergistic effect. Thus, to the best of our knowledge, these results demonstrate for the first time the potential of TTFields in improving the sensitivity of HCC cells to sorafenib, which may lay the foundation for future clinical trials for this combination treatment strategy.     

索拉非尼联合伊匹单抗对肝癌抑制作用的实验研究

目的 探讨索拉非尼联合伊匹单抗对肝癌的抑制作用.方法 设置索拉非尼组、伊匹单抗组及联合组,分别加入不同浓度的索拉非尼(5、10、15、20μmol/L)、伊匹单抗(5、10、15、20μmol/L)及两药联合(10μmol/L索拉非尼+10μmol/L伊匹单抗)处理肝癌HepG2细胞.采用CCK-8法检测细胞活力,流式...