根皮苷可增强索拉非尼抑制肝癌细胞能量代谢及活力

目的：探讨根皮苷联合索拉非尼对肝癌细胞能量代谢与凋亡的影响。方法：将根皮苷5 μmol/L和（或）索拉非尼5 μmol/L作用于HepG2细胞48 h后,检测肝癌细胞活力、肝癌细胞葡萄糖摄取与细胞内ATP含量、caspase-3活力与凋亡细胞计数。结果：索拉非尼组肝癌细胞活力降低,与对照组差异有统计学意义（P<0.05）;索拉非尼与根皮苷联合组肝癌细胞活力进一步降低,与其他各组（对照组、索拉非尼组及根皮苷组）差异均有统计学意义（P<0.05）。根皮苷组葡萄糖摄取及ATP生成减少,与对照组差异有统计学意义（P<0.05）;索拉非尼与根皮苷联合组葡萄糖摄取及ATP生成进一步减少,与其他组差异均有统计学意义（P<0.05）。索拉非尼组与根皮苷组caspase-3活力与细胞凋亡较对照组增强（P<0.05）;索拉非尼与根皮苷联合组caspase-3活力与细胞凋亡进一步增强,与其他组差异均有统计学意义（P<0.05）。结论：根皮苷可以通过抑制肿瘤细胞ATP生成和促进肿瘤细胞凋亡来提高索拉非尼疗效。     

索拉非尼治疗肝细胞肝癌不良反应的护理

目的探讨索拉非尼治疗中晚期肝细胞肝癌的不良反应及护理措施。方法回顾性分析26例中晚期肝细胞肝癌患者服用索拉非尼期间出现的不良反应。结果 26例患者发生的不良反应有手足综合征(57.7%)、腹泻(53.8%)、高血压(50.0%)、皮疹(46.2%)、疲乏(46.2%)等,一般为1～2级,仅1例患者出现3级手足综合征,予减半量治疗,所有患者经护理干预后不良反应均有所好转。结论索拉非尼作为分子靶向治疗新药,服药期间应严密观察患者的不良反应,及时采取有效的护理干预,从而提高治疗疗效和患者的生活质量。     

基于细胞支架大鼠原位移植肝癌模型的制备

背景:超声引导下瘤细胞注射法已应用于制备大鼠原位移植肝癌模型,但成瘤率不高,且易形成腹腔种植.目的:实验拟采用细胞基质胶Matrigel包裹瘤细胞,超声引导下注射到大鼠肘内制各肝癌模型,以提高成瘤率,减少腹腔种植.设计、时间及地点:验证性实验,于2007-12/2008-03在福建医科大学药学院药理系动物实验室完成.材料:取Wistar大鼠20只,按随机数字表法分为瘤细胞悬液注射组和瘤细胞Matrigel注射组,每组10只.方法:取大鼠皮下移植的Walker-256肿瘤组织匀浆制备细胞悬液,在超声引导下注射到10只瘤细胞悬液组大鼠肝实质内,每只2×108个细胞.瘤细胞与Matrigel混合后,超声引导下注射到瘤细胞Matrigel组10只大鼠肝内.主要观察指标:定期超声监测大鼠肝脏移植肿瘤生长情况,移植后第21天麻醉处死动物进行人体解剖,取肿瘤行病理组织学检查.结果:瘤细胞Matrigel组10只大鼠有9只形成了肝脏移植肿瘤灶,仅1只大鼠发生腹腔种植.瘤细胞悬液组10只大鼠仅6只出现肝脏移植肿瘤灶,而发生腹腔种植达6只.大鼠原位移植肝癌病理切片显示典型的肿瘤组织形态学特征.结论:采用Matrigel作为细胞支架制各大鼠肝癌模型可提高成瘤率,明显降低腹腔种植的发生率,是一种较为理想的大鼠原位移植肝癌模型制备方法.     

Cerebellar stroke in a low cardiovascular risk patient associated with sorafenib treatment for fibrolamellar hepatocellular carcinoma

Sorafenib is the standard treatment of hepatocellular carcinoma (HCC). However, fibrolamellar HCC was not included in sorafenib trials. The case is a 26‐year‐old man with fibrolamellar HCC, who had a cerebrovascular accident (CVA) while being treated with sorafenib. This illustrates a probable relationship between use of sorafenib and CVA in low cardiovascular risk patients.     

甲苯磺酸索拉非尼治疗进展期肝细胞癌常见不良反应的护理观察

目的 观察甲苯磺酸索拉非尼治疗进展期肝细胞癌(HCC)的不良反应.方法 采用美国国立癌症研究所常见毒性分级标准观察不良反应发生情况,并对出现的不良反应采取针对性的护理措施.结果 最常见的不良反应为手足综合征(65.5％),最早出现的不良反应为腹泻;常见3级不良反应为手足综合征(15.5％)、肝损害(8.2％)、腹泻(4.5％)、高血压(3.6％)和出血(2.7％).4级不良反应有肝损伤(6.4％)、出血(4.5％)和腹泻(1.8％);采取针对性的护理措施可缓解药物不良反应.结论 对110例用药后产生的不良反应进行分级比较,并根据轻重程度给予不同的护理,可提高治疗效果.     

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC_0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m²/dose) or a pharmacokinetically guided dose targeting an AUC_0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sorafenib pharmacokinetics (PKs) show large interindividual variability given fixed doses (90 mg/m²/dose twice daily). This leads to a wide exposure range, particularly higher exposures, which can lead to hand foot skin reaction (HFSR), withheld doses, and therefore a possible lower antitumor efficacy.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PK and pharmacodynamic modeling and simulation approaches provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides evidence, through PK and pharmacodynamic simulations, that it is possible to decrease the variability of sorafenib exposure, increase the percentages of studies in a target range, and reduce the occurrence of HFSR.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials, including our prospective protocol in children with rare solid malignancies.     

Diabetes augments and inhaled nitric oxide prevents the adverse hemodynamic effects of transfusing syngeneic stored blood in mice

BACKGROUND: Stored red blood cells (RBCs) undergo progressive deleterious functional, biochemical, and structural changes. The mechanisms responsible for the adverse effects of transfusing stored RBCs remain incompletely elucidated. STUDY DESIGN AND METHODS: Awake wild‐type (WT) mice, WT mice fed a high‐fat diet (HFD‐fed WT) for 4 to 6 weeks, and diabetic (db/db) mice were transfused with syngeneic leukoreduced RBCs or supernatant with or without oxidation (10% of total blood volume) after storage for not more than 24 hours (FRBCs) or 2 weeks (SRBCs). Inhaled nitric oxide (NO) at 80 parts per million was administered to a group of mice transfused with SRBCs. Blood and tissue samples were collected 2 hours after transfusion to measure iron and cytokine levels. RESULTS: SRBCs had altered RBC morphology and a reduced P₅₀. Transfusion of SRBCs into WT or HFD‐fed WT mice did not produce systemic hemodynamic changes. In contrast, transfusion of SRBCs or supernatant from SRBCs into db/db mice induced systemic hypertension that was prevented by concurrent inhalation of NO. Infusion of washed SRBCs or oxidized SRBC supernatant into db/db mice did not induce hypertension. Two hours after SRBC transfusion, plasma hemoglobin (Hb), interleukin‐6, and serum iron levels were increased. CONCLUSION: Transfusion of syngeneic SRBCs or the supernatant from SRBCs produces systemic hypertension and vasoconstriction in db/db mice. It is likely that RBC storage, by causing in vitro hemolysis and posttransfusion hemoglobinemia, produces sustained NO scavenging and vasoconstriction in mice with endothelial dysfunction. Vasoconstriction is prevented by oxidizing the supernatant of SRBCs or breathing NO during SRBC transfusion.     

Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.     

Protective effects of fermented rice vinegar sediment (Kurozu moromimatsu) in a diethylnitrosamine-induced hepatocellular carcinoma animal model

Kurozu moromimatsu is the sediment of Kurozu, a jar-fermented Japanese black vinegar produced from unpolished rice. Here, we examined the protective effects of Kurozu moromimatsu in a diethylnitrosamine-induced model of hepatocellular carcinoma. Thirty-two F344 rats were divided into two groups; the control group received basal CE-2 diet, and the Kurozu moromimatsu group received CE-2 diet containing Kurozu moromimatsu. At 16 weeks after initial intraperitoneal administration of diethylnitrosamine (150 mg/kg/week), serum was collected from half the rats. These rats were sacrificed and the liver was resected for histological examination of hematoxylin-eosin-stained sections and assay of matrix metalloproteinase-2 and matrix metalloproteinase-9 levels in tumor tissues. Glutathione S-transferase placental form-positive foci were evaluated by immunostaining for glutathione S-transferase placental form. The remaining rats were maintained for evaluation of survival. There were no significant differences of serum transaminases, tumor necrosis factor-alpha, and also no marked hepatic histological differences, between the two groups. However, the size of hepatocellular carcinomas was greatly decreased and the levels of activated matrix metalloproteinase-2 and -9 were significantly reduced in the Kurozu moromimatsu group. Further, survival was significantly prolonged in the Kurozu moromimatsu group compared with the control. These results indicate that Kurozu moromimatsu inhibited the growth of hepatocellular carcinoma.     

肝癌肝移植术后患者服用索拉非尼不良反应的护理

目的探讨肝癌肝移植术后患者服用索拉非尼不良反应的临床观察要点与护理措施。方法回顾性分析2009年1月～2010年8月我院22例原发性肝癌患者行原位肝移植术后服用索拉非尼出现不良反应的情况及其护理措施。结果预防性服用索拉非尼的14例患者中,1例于术后2个月因出现不良反应不能耐受被迫停药后肝癌复发,行射频消融术;1例于术后10个月因坏死性胆管炎死亡;1例于术后8个月因下肢静脉血栓治疗无效死亡。治疗性服用的8例患者中,1例于术后6个月肝癌转移死亡,其他7例存活至今。其主要不良反应有手足综合征、皮疹、腹泻、乏力、高血压、肝功能异常和血小板减少。均为Ⅰ级或Ⅱ级,对症处理后治愈。结论索拉非尼对预防与治疗肝癌肝移植术后患者复发的疗效显著,但其不良反应较多。密切观察患者的不良反应,并及时采取相应的护理措施,是保证药物治疗效果的关键。     

Muscle-targeted interleukin-12 gene therapy of orthotopic hepatocellular carcinoma in mice using in vivo electrosonoporation

We developed a new potent nonviral gene transfer method into mouse muscles in vivo named "electrosonoporation." We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-gamma and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.     

Sorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma

ObjectiveTo compare the efficacy of sorafenib plus hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin to that of sorafenib alone in patients with advanced hepatocellular carcinoma (HCC).MethodsThis was a retrospective, single-center trial. Between April 3, 2017 and July 2, 2018, 104 patients with Child-Pugh A and advanced HCC received either 400 mg of sorafenib orally twice daily plus HAIC with oxaliplatin (oxaliplatin 85 mg/m², every 3 weeks via repetitive catheterization) (n = 46, soraOXA group) or 400 mg of only sorafenib orally twice daily (n = 58, sorafenib group). Overall survival, progression-free survival, objective response rate, and treatment-related adverse events were compared.ResultsThe median overall survival was 9.37 months (95% CI, 7.05–11.68) in the soraOXA group versus 4.8 months (95% CI, 2.98–6.62) in the sorafenib group (HR 0.46 [95% CI, 0.29–0.72]; P < 0.001). The soraOXA group also showed a higher objective response rate (16 [34.8%] vs 1 [1.7%]; P < 0.001) and a longer progression-free survival rate (5.5 months [95% CI, 2.32–8.68] vs 2.4 months [95% CI, 1.65–3.15], HR 0.54 [95% CI, 0.36–0.81], P = 0.003) than the sorafenib group. There was no significant difference in the overall incidence of any grade adverse events, grade 3/4 adverse events, serious adverse events, or incidence of treatment termination due to adverse events between the two groups.ConclusionCompared with sorafenib alone, sorafenib plus HAIC with oxaliplatin showed favorable treatment outcomes in patients with advanced HCC. The merits of this approach need to be established with a prospective trial.     

索拉菲尼联合肝动脉栓塞化疗和氩氦刀消融治疗晚期肝癌的效果观察

目的：对比索拉菲尼单药与联合应用肝动脉栓塞化疗术（ TACE）、经皮局部氩氦刀消融（PLCT）综合治疗失去手术机会的肝癌的治疗效果。方法回顾性分析64例无法手术切除的肝癌患者的临床资料,行索拉菲尼单药或索拉菲尼联合 TACE、PLCT 治疗。其中索拉菲尼单药治疗32例,联合介入和氩氦刀消融治疗32例,随访时间6～32个月,观察两组患者治疗效果和肿瘤进展时间。结果所有患者顺利完成治疗,无手术相关死亡及严重并发症。64例患者中,完全缓解（ CR）11例,部分缓解（PR）31例,稳定（SD）14例,进展（PD）8例,其中单药治疗组 CR 3例,PR 11例,SD 12例,PD 6例;联合介入和氩氦刀消融组 CR 8例,PR 20例,SD 2例,PD 2例,两组比较差异有统计学意义（χ^2=14.028,P=0.003）。中位肿瘤进展时间分别为20周和53周,两组比较差异有统计学意义（χ^2=14.773,P=0.000）。结论针对无法手术切除的肝癌,索拉菲尼联合 TACE 和 PLCT 治疗效果较好,可延长肿瘤进展时间。     

Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for “REnal Cell cancer treatment with Oral RAD001 given Daily”), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.     

索拉非尼联合经导管肝动脉化疗栓塞治疗中晚期肝癌的疗效分析

目的 观察索拉非尼联合经导管肝动脉化疗栓塞(TACE)治疗中晚期肝癌患者的临床疗效.方法 将150例中晚期肝癌患者分为单纯治疗组和联合介入组.比较2组治疗后的疗效,不良反应以及1、3、5年存活率.比较2组治疗前后血清磷脂酰肌醇聚糖3(GPC3)、转化生长因子结合蛋白2(LTBP2)表达情况.结果 联合介入组疗效优于单纯...     

Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in humans. Because the phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in more than 88% of GBM, new drugs which target this pathway, such as the mTOR inhibitor Everolimus, are currently in clinical trials. Early tumor response to molecularly targeted treatments remains challenging to assess non-invasively, because it is often associated with tumor stasis or slower tumor growth. Innovative neuroimaging methods are therefore critically needed to provide metabolic or functional information that is indicative of targeted therapeutic action at early time points during the course of treatment.In this study, we demonstrated for the first time that hyperpolarized (HP) ¹³C magnetic resonance spectroscopic imaging (MRSI) can be used on a clinical MR system to monitor early metabolic response of orthotopic GBM tumors to Everolimus treatment through measurement of the HP lactate-to-pyruvate ratios. The study was performed on a highly invasive non-enhancing orthotopic GBM tumor model in rats (GS-2 tumors), which replicates many fundamental features of human GBM tumors. Seven days after initiation of treatment there was a significant drop in the HP lactate-to-pyruvate ratio from the tumor tissue in treated animals relative to day 0 (67% ± 27% decrease). In the control group, no significant changes in the HP lactate-to-pyruvate ratios were observed. Importantly, at the 7 day time point, conventional MR imaging (MRI) was unable to detect a significant difference in tumor size between control and treated groups. Inhibition of tumor growth by conventional MRI was observed from day 15 of treatment. This implies that the decrease in the HP lactate-to-pyruvate ratio could be detected before any treatment-induced inhibition of tumor growth.Using immunohistochemical staining to further examine tumor response to treatment, we found that the decrease in the HP lactate-to-pyruvate ratio was associated with a drop in expression of lactate dehydrogenase, the enzyme that catalyzes pyruvate to lactate conversion. Also evident was decreased staining for carbonic anhydrase IX (CA-IX), an indicator of hypoxia-inducible factor 1α (HIF-1α) activity, which, in turn, regulates expression of lactate dehydrogenase.To our knowledge, this study is the first report of the use of HP ¹³C MRSI at a clinical field strength to monitor GBM response to molecularly targeted treatments. It highlights the potential of HP lactate-to-pyruvate ratio as an early biomarker of response, thereby supporting further investigation of this non-invasive imaging approach for eventual clinical application.     

基于影像学和血清学特征构建的列线图模型可较好预测原发性肝细胞癌的微血管浸润

目的 探讨术前基于影像学和血清学特征构建的列线图模型对肝癌微血管浸润(MVI)的预测价值。 方法 回顾性分析2015年1月~2020年12月于中山市人民医院接受切除或肝移植的548例肝细胞癌(HCC)患者的临床资料,最终纳入315例肝癌MVI患者,年龄53.2±11.5岁,肿瘤最大直径3.7~7.0 cm。收集患者临床及影像学资料并进行分析,采取单因素与多因素Logistic分析,筛查出能预测MVI的独立风险因素,构建预测HCC中MVI的列线图模型,利用ROC曲线、校准曲线和决策曲线对模型进行评估。 结果 MVI (+)患者的中位生存时间为13月(95%CI：8.1~17.9),1、3、5年无病生存率分别为50.6%、38.5%和30.9%(P < 0.05);MVI (-)患者的中位生存时间为47月(95%CI：32.7~61.3),1、3、5年无病生存率分别为77.9%、62.3%和38.8%(P < 0.05)。多因素Logistic回归分析显示,更大的肿瘤体积、突破肝外生长、缺乏或不完整假包膜、存在动脉期瘤周强化以及术前过高的球蛋白值是MVI (+)的独立危险因素(P < 0.05)。最终模型效能曲线下面积为0.895,95%CI为0.859-0.930,准确性为85.1%,敏感度为85.9%,特异性为84.1%。校准曲线显示预测概率与病理结果MVI (+)/MVI (-)概率有良好的一致性。决策曲线显示模型具有良好的临床应用价值。 结论 构建的列线图及预测模型能较好地术前预测MVI (+)的概率,可以根据MVI发生的风险调整HCC的治疗计划,以优化生存结果。     

Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Sorafenib, a tyrosine kinase inhibitor, was recently approved by the United States Food and Drug Administration for HCC. In this study, we established two sorafenib-resistant HCC cell lines from Huh7, a human HCC cell line, by long-term exposure of cells to sorafenib. Sorafenib induced significant apoptosis in Huh7 cells; however, Huh7-R1 and Huh7-R2 showed significant resistance to sorafenib-induced apoptosis at the clinical relevant concentrations (up to 10 μM). Thorough comparisons of the molecular changes between Huh7 and resistant cells showed that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway played a significant role in mediating acquired resistance to sorafenib in Huh7-R1 and Huh7-R2 cells. Phospho-Akt and p85 (a regulatory subunit of PI3K) were up-regulated, whereas tumor suppressor phosphatase and tensin homolog were down-regulated in these resistant cells. In addition, ectopic expression of constitutive Akt in Huh7 demonstrated similar resistance to sorafenib. The knockdown of Akt by RNA interference reversed resistance to sorafenib in Huh7-R1 cells, indicating the importance of Akt in drug sensitivity. Furthermore, the combination of 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one dihydrochloride (MK-2206), a novel allosteric Akt inhibitor, and sorafenib restored the sensitivity of resistant cells to sorafenib-induced apoptosis. In conclusion, activation of PI3K/Akt signaling pathway mediates acquired resistance to sorafenib in HCC, and the combination of sorafenib and MK-2206, an Akt inhibitor, overcomes the resistance at clinical achievable concentrations.     

Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3

The multiple kinase inhibitor dovitinib is currently under clinical investigation for hepatocellular carcinoma (HCC). Here, we investigated the mechanistic basis for the effects of dovitinib in HCCs. Dovitinib showed significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1, and Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, survivin, and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor reversed downregulation of p-STAT3 and apoptosis induced by dovitinib, and silencing of SHP-1 by RNA interference abolished the effects of dovitinib on p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase activity, indicating that dovitinib upregulates the activity of SHP-1 via direct interactions. In addition, dovitinib induced apoptosis in two sorafenib-resistant cell lines through inhibition of STAT3, and sorafenib-resistant cells showed significant activation of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 activity. In conclusion, dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1-mediated inhibition of STAT3.