Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Study on the Changes in Microvessel Density in Hepatocellular Carcinoma Following Transcatheter Arterial Chemoembolization

To study the changes in intratumoral microvessel density (MVD) in hepatocellular carcinoma (HCC) following transcatheter arterial chemoembolization (TACE), MVD in 42 HCC specimens histologically verified was studied by using immunohistochemical method. Of all the specimens, 20 were obtained from the patients treated with surgical resection alone, 22 from those with second stage surgical resection after TACE. The results showed that the MVD in HCC tissues was 53.4±21 9 in the TACE group and 27.6±9.2 in the single operating group, respectively, with the difference being significant between them ( P <0.001). It was suggested that TACE might contribute to angiogenesis of HCC, possibly due to anoxic stress and ischemia reperfusion injury.

Evaluation of hepatocellular carcinoma using contrast-enhanced ultrasonography:correlation with microvessel morphology

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is an important technique for depiction and assessment of tumor vascularity. This study aimed to explore the relationship between the morphological characteristics of tumor microvessels and enhancement patterns on CEUS in hepatocellular carcinoma (HCC). METHODS: Eighty patients with HCC underwent CEUS using SonoVue before hepatectomy. Contrast-enhanced ultrasonographic enhancement patterns and quantitative parameters were recorded. The tumor tissue sections were immunostained with human CD34 monoclonal antibody. The patients were classified into a point-line type group (n=36) and a loop-strip type group (n=44) according to microvessel morphology. The microvascular density (MVD) in the different types of microvessels was calculated. The relationship between enhancement patterns of HCC lesions and morphological characteristics of tumor microvessels was analyzed. RESULTS:TS: The mean MVD in HCC was 22.4 +/- 3.5 per 0.2 mm(2) in the point-line group, and 19.6 +/- 6.7 per 0.2 mm(2) in the loop-strip group, and there was no significant difference between them (t=0.948, P=0.354). In the portal vein phase, hypoenhancement was significantly more frequent in HCC (chi(2)=4.789, P=0.029) in the loop-strip group (40/44, 90.9%) than in the point-line group (26/36, 72.2%). The time to hypoenhancement in the loop-strip group (mean 64.84 +/- 26.16 seconds) was shorter than that in the point-line group (mean 78.39 +/- 28.72 seconds) (t=2.247, P=0.022). The time to hypoenhancement was correlated with MVD in the loop-strip group (r=-0.648, P=0.001). CONCLUSIONS: The enhancement patterns on CEUS are related to tumor microvascular morphology, and the type of microvascular morphology influences CEUS characterization. CEUS, an important noninvasive imaging technique, is used to evaluate microvascular morphology and angiogenesis, providing valuable information for antiangiogenic therapy in HCC. (Hepatobiliary Pancreat Dis Jut 2010; 9:605-610)

Dual-input two-compartment pharmacokinetic model of dynamic contrast-enhanced magnetic resonance imaging in hepatocellular carcinoma

AIM: To investigate the feasibility of a dual-input two-compartment tracer kinetic model for evaluating tumorous microvascular properties in advanced hepatocellular carcinoma(HCC). METHODS: From January 2014 to April 2015, we prospectively measured and analyzed pharmacokinetic parameters [transfer constant(K_(trans)), plasma flow(F_p), permeability surface area product(PS), efflux rate constant(k_(ep)), extravascular extracellular space volume ratio(V_e), blood plasma volume ratio(V_p), and hepatic perfusion index(HPI)] using dual-input two-compartment tracer kinetic models [a dual-input extended Tofts model and a dual-input 2-compartment exchange model(2CXM)] in 28 consecutive HCC patients. A well-known consensus that HCC is a hypervascular tumor supplied by the hepatic artery and the portal vein was used as a reference standard. A paired Student's t-test and a nonparametric paired Wilcoxon rank sum test were used to compare the equivalent pharmacokinetic parameters derived from the two models, and Pearson correlation analysis was also applied to observe the correlations among all equivalent parameters. The tumor size and pharmacokinetic parameters were tested by Pearson correlation analysis, while correlations among stage, tumor size and all pharmacokinetic parameters were assessed by Spearman correlation analysis. RESULTS: The F_p value was greater than the PS value(F_P = 1.07 m L/m L per minute, PS = 0.19 m L/m L per minute) in the dual-input 2CXM; HPI was 0.66 and 0.63 in the dual-input extended Tofts model and the dualinput 2CXM, respectively. There were no significant differences in the K_(ep), V_p, or HPI between the dual-input extended Tofts model and the dual-input 2CXM(P = 0.524, 0.569, and 0.622, respectively). All equivalent pharmacokinetic parameters, except for V_e, were correlated in the two dual-input two-compartment pharmacokinetic models; both Fp and PS in the dualinput 2CXM were correlated with K_(trans) derived from the dual-input extended Tofts model(P = 0.002, r = 0.566; P = 0.002, r = 0.570); K_(ep), V_p, and HPI between the two kinetic models were positively correlated(P = 0.001, r = 0.594; P = 0.0001, r = 0.686; P = 0.04, r = 0.391, respectively). In the dual input extended Tofts model, V_e was significantly less than that in the dual input 2CXM(P = 0.004), and no significant correlation was seen between the two tracer kinetic models(P = 0.156, r = 0.276). Neither tumor size nor tumor stage was significantly correlated with any of the pharmacokinetic parameters obtained from the two models(P > 0.05).CONCLUSION: A dual-input two-compartment pharmacokinetic model(a dual-input extended Tofts model and a dual-input 2CXM) can be used in assessing the microvascular physiopathological properties before the treatment of advanced HCC. The dual-input extended Tofts model may be more stable in measuring the V_e; however, the dual-input 2CXM may be more detailed and accurate in measuring microvascular permeability.

DCE-MRI和DWI检查在术前诊断脑胶质瘤病变恶性程度中的应用价值

目的探究利用磁共振动态造影技术预测术前脑胶质瘤参数与微血管密度(MVD)之间的关联。方法本次选取的研究对象为我院于2012年9月~2020年5月收治的76例脑胶质瘤患者。根据世界卫生组织(WHO)的分级和脑胶质瘤的恶性程度,将患者分为低级别胶质瘤(32例)和高级别胶质瘤(44例)。对不同分级患者的(Ktrans)容积转运参数、(Ve)血管外细胞外间隙容积比、(ADC)表观扩散系数以及MVD进行比较。经ROC分析,(Ktrans值、Ve、ADC、MVD)预测高级别脑胶质瘤的意义,整理(Ktrans值、Ve、ADC与MVD)的相关性。结果低级别脑胶质瘤患者Ktrans值、Ve、MVD与高级别脑胶质瘤患者及ACD对比后,前两者对比后者属于较高的,后两者对比是后者较高的。对ROC分析中,Ktrans值、Ve、ADC、MVD对于高级的曲线下面积是(0.746、0.812、0.682、0.668)。Ktrans值和Ve与MVD之间存在正相关关系,而ADC与MVD呈现负相关。结论DCE-MRI术前可用于诊断脑胶质瘤相关参数,并显示其与患者的微血管密度(MVD)以及病变恶性程度之间的关联,为手术方案制定和预后评估提供了可靠的参考依据。

Contrast ultrasound in hepatocellular carcinoma at a tertiary liver center: First Indian experience

AIM: To assess the role of contrast enhanced ultrasonography in evaluation of hepatocellular carcinoma (HCC) at the first Indian tertiary liver center. METHODS: Retrospective analysis of contrast enhanced ultrasound (CEUS) examinations over 24 mo for diagnosis, surveillance, characterization and follow up of 50 patients in the context of HCC was performed. The source and indication of referrals, change in referral rate, accuracy and usefulness of CEUS in a tertiary liver center equipped with a 64 slice dual energy computer tomography (CT) and 3 tesla magnetic resonance imaging (MRI) were studied. Sonovue (BR1, Bracco, Italy, a second generation contrast agent) was used for contrast US studies. Contrast enhanced CT/MRI or both were performed in all patients. The findings were taken as a baseline reference and correlation was done with respect to contrast US. Contrast enhanced MRI was performed using hepatocyte specific gadobenate dimeglumine (Gd-BOPTA). Iomeron (400 mg; w/v) was used for dynamic CT examinations. RESULTS: About 20 (40%) of the examinations were referred from clinicians for characterization of a mass from previous imaging. About 15 (30%) were performed for surveillance in chronic liver disease; 5 (10%) examinations were performed for monitoring lesions after radiofrequency ablation (RFA); 3 (6%) were post trans-arterial chemoembolization (TACE) assessments and 3 (6%) were patients with h/o iodinated contrast allergy. About 2(4%) were performed on hemodynamically unstable patients in the intensive care with raised alpha fetoprotein and 2(4%) patients were claustrophobic. The number of patients referred from clinicians steadily increased from 12 in the first 12 mo of the study to 38 in the last 12 mo. CEUS was able to diagnose 88% of positive cases of HCC as per reference standards. In the surveillance group, specificity was 53.3% vs 100% by CT/MRI. Post RFA and TACE specificity of lesion characterization by CEUS was 100% in single/large mass assessment, similar to CT/MRI. For non HCC lesions such as regenerative and dysplastic nodules, the specificity was 50% vs 90% by CT/MRI. The positive role of CEUS in imaging spectrum of HCC included a provisional urgent diagnosis of an incidentally detected mass. It further led to a decrease in time for further management. A confident diagnosis on CEUS was possible in cases of characterization of an indeterminate mass, in situations where the patient was unfit for CT/MRI, was allergic to iodinated contrast or had claustrophobia, etc.CEUS was also cost effective, radiation free and an easy modality for monitoring post RFA or TACE lesions. CONCLUSION: CEUS is a valuable augmentation to the practice of ultrasonography, and an irreplaceable modality for confounding cases and interpretation of indeterminate lesions in imaging of HCC.

CEUS、CE-MRI在肝细胞癌经TACE和微波消融介入治疗后随访中的应用分析

目的探究对比超声造影(CEUS)、对比增强磁共振成像(CE-MRI)在肝细胞癌经动脉化疗栓塞(TACE)和微波消融介入治疗后随访中的应用。方法回顾性选取2019年8月至2022年5月在重庆市綦江区人民医院进行治疗的肝细胞癌患者102例(156个病灶),所有患者均接受TACE或微波消融介入治疗,治疗后均进行CEUS、CE-MRI检查,并以数字减影血管造影(DSA)检查结果为金标准,对复发患者和非复发患者的检查结果进行分析,探究上述两种检查方法对患者预后评估的准确性,随访期为1年。结果DSA检查结果:102例肝细胞癌患者术后1年内38例(52个病灶)患者存在复发情况,64例(104个病灶)患者未发生复发情况。复发组与未复发组患者在门静脉增强、延迟性增强、瘤周强化及廓清时间方面比较差异均有统计学意义(P<0.05),但两组在动脉期增强、始增时间表、达峰时间方面比较差异均无统计学意义(P>0.05)。复发组患者治疗前及治疗后肿瘤体积均大于未复发组,治疗后的ADC值小于未复发组,差异均有统计学意义(P<0.05)。与术前瘤区相比较,术后肿瘤坏死区、碘油沉积区的ADC值均升高,差异均有统计学意义(P<0.05),但肿瘤复发区与术前瘤区的ADC值比较差异无统计学意义(P>0.05)。38例复发组患者共56个病灶进行CEUS及CE-MRI检查,在患者术前术后病灶体长短径及评估中,二者评估结果比较差异无统计学意义(P>0.05),对患者术后残留活性病灶数进行检查,CE-MRI的检出率高于CEUS,差异有统计学意义(P<0.05)。经DSA检查,确诊复发的38例患者经CEUS、CE-MRI检查确诊为复发的分别为29、34例;未复发的64例患者中经CEUS、CE-MRI检查确诊为未复发的分别为62、63例。CE-MRI检查与DSA检查结果一致性检验Kappa值为0.893,高于CEUS检查与DSA检查结果一致性检验Kappa值(0.760)(P<0.05)。以DSA检查结果为金标准,患者经CEUS检查复发的准确率、敏感度、特异度、阳性预测值、阴性预测值分别为89.22%、87.32%、93.55%、96.88%、76.32%;经CE-MRI检查复发的准确率、敏感度、特异度、阳性预测值、阴性预测值分别为95.10%、94.03%、97.14%、98.44%、89.47%。结论肝细胞癌患者行TACE和微波消融介入治疗后,以DSA为金标准,应用CEUS、CE-MRI对患者复发情况评估时,CE-MRI一致性高于CEUS。

Usefulness of contrast enhanced ultrasound in monitoring therapeutic response after hepatocellular carcinoma treatment

In the last years, the development in the oncology field has been huge and rapid. In particular, the evaluation of response to anti-tumour treatments has been being object of intense research, producing significant changes. Response assessment after therapy in solid neoplasias has always used radiological imaging techniques, with tumour size reduction representing a presumed therapeutic efficacy. However, with the introduction of anti-angiogenetic drugs the evaluation of tumour size has become unsuitable because some tumours, under treatment, show only tumour perfusion changes rather than lesion shrinkage. Between different imaging techniques with contrast-enhancement, contrastenhanced ultrasound(CEUS) and, in particular, dynamic CEUS have arisen as a promising and non-invasive device for monitoring cancer treatments. Moreover, the introduction of perfusion software has even more refined the technique since it is able to provide quantitative parameters related to blood flow and blood volume that can be associated with tumour response and clinical outcome such as the progression free survival and the overall survival. Here, we give an overview of the current status of CEUS in monitoring hepatocellular carcinoma response to different kind of treatments.

DCE-MRI联合CT增强扫描在肝细胞癌TACE治疗效果评估中的价值

目的 探究磁共振动态对比增强(DCE-MRI)联合电子计算机断层扫描(CT)增强扫描在肝细胞癌经导管肝动脉化疗栓塞术(TACE)治疗后病灶残留或复发中评估效果。方法 将淮安市第一人民医院2020年4月—2023年1月收治的89例肝细胞癌患者纳入研究,TACE治疗后1~2个月以数字减影血管造影为金标准,同时行DCE-MRI、CT增强扫描检查,分析DCE-MRI、CT增强扫描结果单一及联合对肝细胞癌TACE治疗后病灶残留或复发的评估效能。结果 数字减影血管造影检查结果显示,89例患者中共检出肝癌病灶116个,经TACE治疗后病灶残留或复发74个,完全灭活病灶42个。DCE-MRI、增强CT分别检出病灶残留或复发76个、77个,完全灭活病灶40个、39个。ROC分析得出,DCE-MRI、增强CT单一及联合诊断病灶残留或复发的灵敏度分别为90.48%、85.71%、92.86%,特异度分别为97.30%、95.95%、97.30%,曲线下面积(AUC)分别为0.939、0.908、0.951。DCE-MRI、增强CT单一及联合诊断原发性肝细胞TACE治疗后病灶残留或复发与数字减影血管造影诊断结果的Kappa值分别为0.887、0.829、0.906。结论 DCE-MRI联合CT增强扫描可用于评估肝细胞癌TACE治疗后病灶残留或复发,且效能良好。

DCE-MRI对宫颈癌患者病灶组织分化程度及微血管密度的评估价值

目的探讨动态增强磁共振成像(DCE-MRI)对宫颈癌患者病灶组织分化程度及微血管密度(MVD)的评估价值。方法选取2020年6月至2023年3月该院收治的宫颈癌患者65例作为宫颈癌组,均完善DCE-MRI检查,另选取2021年1月至2023年3月因子宫内膜或膀胱类疾病(膀胱结石、膀胱憩室、膀胱炎症)在该院进行DCE-MRI检查的65例健康宫颈患者作为对照组,以病理检查为金标准,分析DCE-MRI对宫颈癌的诊断效能。采用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接法检测两组MVD并进行比较;记录两组DCE-MRI定量参数[容量转移常数(Ktrans)、回流速率常数(Kep)、容积分数(Ve值)及表观扩散系数(ADC)]。根据组织分化程度将宫颈癌组分为低分化组(12例)、中分化组(27例)、高分化组(26例),比较不同组织分化程度宫颈癌患者DCE-MRI定量参数水平。采用Pearson相关分析Ktrans、Kep、Ve值与MVD的相关性,采用Spearman相关分析Ktrans、Kep、Ve值与组织分化程度的相关性。结果DCE-MRI诊断宫颈癌的准确度为86.15%(112/130),灵敏度为83.08%,特异度为89.23%,阳性预测值为88.52%,阴性预测值为84.06%,Kappa值为0.723。宫颈癌组Ktrans、Kep、Ve值及MVD明显高于对照组,ADC明显低于对照组,差异均有统计学意义(P<0.05)。低分化组的Ktrans、Kep、Ve值明显高于中分化组及高分化组,ADC明显低于中分化组及高分化组,差异均有统计学意义(P<0.05)。相较于中分化组,高分化组的Ktrans、Kep、Ve值更低,ADC更高,差异均有统计学意义(P<0.05)。Ktrans、Kep、Ve值与组织分化程度均呈负相关,与MVD呈正相关(P<0.05);ADC与组织分化程度呈正相关,与MVD呈负相关(P<0.05)。结论DCE-MRI对宫颈癌的诊断价值较高,且其定量参数与宫颈癌患者病灶组织分化程度及MVD密切相关,应用DCE-MRI定量参数可较好地评估宫颈癌患者病灶组织分化程度及MVD变化。

DCE-MRI功能成像参数鉴别原发性肝细胞肝癌分化程度的效能探讨

目的探讨动态增强磁共振成像(DCE-MRI)参数对原发性肝细胞肝癌(HCC)分化程度的鉴别效能。方法回顾性分析2021年1月—2023年1月本院收治的186例原发性HCC患者的临床资料,根据患者病理学诊断结果将其分为中分化组、高分化组和低分化组。比较三组患者DCE-MRI功能成像参数[容积转移常数(Ktrans)、运动速率常数(Kep)、血管外细胞外容积分数(Ve)];采用Pearson法分析原发性HCC分化程度与Ktrans、Kep、Ve的关系;绘制受试者工作特征(ROC)曲线分析DCE-MRI功能成像参数对原发性HCC分化程度的鉴别价值。结果经临床病理学鉴别,186例原发性HCC患者中低分化58例、中分化53例、高分化75例。中、低分化组Ktrans、Kep、Ve值均高于高分化组(P<0.05),低分化组高于中分化组(P<0.05);Ktrans、Kep、Ve均原发性HCC患者分化程度呈负相关(r=-0.657,-0.682,-0.623,P<0.05);Ktrans、Kep、Ve联合鉴别原发性HCC低分化的特异度、曲线下面积分别为90.63%、0.934,均高于单独鉴别(P<0.05),联合鉴别的灵敏度为84.48%,与单独鉴别比较差异无统计学意义(P>0.05)。结论DCE-MRI功能成像参数可有效鉴别原发性HCC分化程度,具有较好的应用价值。

基于术前DCE-MRI特征的肝癌患者术后MVI风险模型效能分析

目的探讨基于术前动态对比增强MRI(DCE-MRI)特征建立的风险模型在早期预测肝细胞癌存在微血管侵犯(MVI)效能。方法纳入我院在2020年1月—2022年4月收治的接受手术治疗的肝细胞肝癌(HCC)患者242例,收集患者临床实验室资料,于术前2周对所有患者进行DCE-MRI扫描,分析患者DCE-MRI的定量指标和定性指标。术后根据HCC是否存在微血管侵犯分为MVI组和对照组,对比两组患者临床实验室资料,分析影响HCC出现MVI的因素;将所有患者按7∶3比例分为训练集170例和测试集72例,基于训练集的数据采用R软件建立列线图模型,在测试集中验证模型效能。结果训练集170例患者中共出现70例MVI,据此分组后对比两组临床资料显示,MVsI组K trans、K ep、V e、V p指标明显高于对照组,MVI组肿瘤边缘不规则、肝胆期瘤周低信号比例高于对照组(P<0.05);多因素Logistics回归分析显示,K trans、V e、K ep、V p、肿瘤边缘不规则、肝胆期瘤周低信号是HCC出现MVI的独立相关因素(P<0.05);通过构建列线图预测模型,结果显示模型预测HCC出现MIV风险的一致性指数(C-index)为0.948。外部验证显示敏感性为88.00%,特异性为96.36%。结论K trans、V e、K ep、V p、肿瘤边缘不规则、肝胆期瘤周低信号是HCC存在MVI的独立相关因素;基于术前DCE-MRI特征建立的风险模型在早期预测HCC出现MVI方面具有良好的预测效能。

Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver

AIM: The expression pattern of endoglin (CD105) in hepatocellular carcinoma (HCC) has not been reported so far. We hypothesized that CD105 could differentially highlight a subset of microvessels in HCC, and intratumoral microvessel density (IMVD) by CD105 immunostaining (IMVD-CD105) could provide better prognostic information than IMVD by CD34 immunostaining (IMVD-CD34).METHODS: Paraffin blocks of tumor and adjacent nontumorous liver tissues from 86 patients who underwent curative resection of HCC were used for this study. Serial sections were stained for CD105 and CD34, respectively,to highlight the microvessels. IMVD was counted according to a standard protocol.RESULTS: In the HCC tissues, CD105 was either negatively or positively stained only in a subset of microvessels. In contrast, CD34 showed positive and more extensive microvessel staining in all cases examined. However, in the adjacent non-tumorous liver sections, CD105 showed a diffuse pattern of microvessel staining in 20 of 86 cases,while CD34 showed negative or only focal staining of the sinusoids around portal area. Correlation with clinicopathological data demonstrated that lower scores of IMVD-CD105 were found in larger sized tumors [mean 41.4/0.74 mm2 (＞5 cm tumor) vs 65.9/0.74 mm2(≤ 5 cm tumor), P = 0.043] and more aggressive tumors,as indicated by venous infiltration [36.8/0.74 mm2 (present)vs 64.2/0.74 mm2 (absent), P = 0.020], microsatellite nodules [35.1/0.74 mm2 (present) vs 65.9/0.74 mm2(absent), P = 0.012], and advanced TNM tumor stage [38.8/0.74 mm2 (stage 3 or 4) vs 68.3/0.74 mm2 (stage 1or 2), P = 0.014]. No prognostic significance was observed when median values were used as cut-off points using either IMVD-CD105 or IMVD-CD34. However, the presence of the diffuse pattern of CD105 expression in the adjacent non-tumorous liver tissues predicted a poorer disease-free survival (median 8.6 vs 21.5 mo, P = 0.026).CONCLUSION: Our data demonstrate that a lower IMVDCD105 is associated with larger and more aggressive tumors. In this study, IMVD-CD105 did not provide significant prognostic information. However, active angiogenesis as highlighted by diffuse CD105 staining of the microvessels in the adjacent non-tumorous liver tissues is predictive of early recurrence.

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma(HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcomedrug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients

Sorafenib is an effective anti-angiogenic treatment forhepatocellular carcinoma(HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients,avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume(viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume,density or perfusion. Perfusion computed tomography and Dynamic ContrastEnhanced-UltraS ound can measure the vascularization of HCC lesions and help predict tumor response to antiangiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable,reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue,allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.

Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma

BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy.

MSCT与MRI动态增强扫描对HCC与IHPCC的鉴别价值

目的 探讨多层螺旋CT(MSCT)与MRI动态增强扫描对HCC与肝内周围型胆管细胞癌(IHPCC)的鉴别价值。方法 纳入76例原发性肝癌患者,均行MSCT与MRI动态增强扫描检查。结果 经病理检查,76例原发性肝癌患者中,共有52例HCC,24例IHPCC。HCC患者MSCT诊断结果符合率为84.62%(44/52),IHPCC患者MSCT诊断结果符合率为54.17%(13/24),总符合率为75.00%(57/76);HCC患者MRI诊断符合率为92.31%(48/52),IHPCC患者MRI诊断符合率为66.67%(16/24),总符合率为84.21%(64/76);MSCT联合MRI诊断,Kappa=0.882,P<0.05,联合诊断准确率为96.05%(73/76)。结论 MSCT、MRI均可用于HCC与IHPCC患者鉴别诊断,二者联合诊断效果更佳。

肝细胞癌MRI动态增强表现的血供基础研究

目的 明确肝细胞癌MRI动态增强表现的微血管基础。方法 用二乙基亚硝胺长期小剂量灌喂大鼠诱发肝细胞癌 ,于不同时间行MRI动态增强扫描 ,并且在相应部位取材做病理、电镜及MVD测定。结果 41个结节做MRI动态增强扫描 ,绘制时间 信号强度曲线 ,可见曲线形态与肿瘤MVD有关 ,快速上升型曲线肿瘤的MVD值高 ,缓慢上升型曲线肿瘤的MVD值低。结论 MRI动态增强扫描可以客观的反映肿瘤的血供情况 ,有助于临床进一步治疗。

乳腺疾病动态增强MRI半定量参数与微血管密度的相关性

目的探讨乳腺良恶性病灶动态增强MRI半定量参数与病灶微血管密度(MVD)的相关性。方法44例乳腺病人经病理证实分为良恶性两组,经过MRI动态增强后计算时间-信号曲线半定量参数,并对所有病灶进行免疫组化CD34染色计数微血管密度进行评分,评价两者的相关性。结果乳腺癌24例,乳腺良性病灶20例,恶性组的早期强化率(Ee)、最大强化率(Emax)、最大强化速率(Vmax)、最大相对强化斜率(Eslop)及最大排泄率(Ewash)与微血管密度有明显正相关性(r=0.632,0.783,0.651,0.792,0.723,P<0.01),达峰时间(Tmax)与微血管密度呈明显的负相关(r=-0.785,P<0.01),而良性组中仅有早期强化率(Ee)、早期强化速率(Ve)、最大强化率(Emax)与微血管密度有明显正相关性(r=0.728,0.708,0.850,P<0.01)。结论MRT1动态增强是无创检测肿瘤微血管改变有效诊断方式,其强化参数与微血管密度具有明显的相关性。

肝细胞癌综合治疗后复发的小肝癌患者MRI平扫和动态增强各序列图像表现分析

目的分析肝细胞癌(HCC)综合治疗后复发的小肝癌(s HCC)患者磁共振(MRI)图像表现,提高对复发s HCC的认识。方法回顾分析本院36例HCC综合治疗后复发的s HCC患者,共44个病灶,均行MRI平扫和动态增强扫描,其中16例患者在3～6月后复查MRI,分析病灶图像特征。测量典型"快进快出"强化方式癌灶(A组)与非典型强化方式癌灶(B组)的长径和表观弥散系数(ADC)值,并比较两组差异。结果 MRI平扫T2压脂序列显示高信号癌灶39个(88. 64%),T1压脂序列显示低信号癌灶37个(84. 09%),弥散加权成像显示高信号癌灶41个(93. 18%),双回波序列显示含脂质成分癌灶4个(9. 09%)。MRI动态增强序列显示典型"快进快出"强化方式癌灶30个(68. 18%),非典型强化方式癌灶14个(31. 82%),延迟期出现"假包膜"征象癌灶12个(27. 27%)。A组癌灶长径大于B组,ADC值低于B组(P均<0. 05)。结论结合MRI平扫和动态增强各序列,有利于s HCC癌灶的检出,是诊断HCC综合治疗后复发的s HCC的重要方法。