高强度聚焦超声（HIFU）治疗肝癌的剂量学研究及联合氩氦刀治疗的临床研究

发布时间：2018-03-05 14:14

本文选题：高强度聚焦超声（HIFU）　切入点：癌　出处：《郑州大学》2014年博士论文　论文类型：学位论文

【摘要】：第一部分高强度聚焦超声（HIFU）治疗肝癌的剂量学研究目的通过SCT评估HIFU消融肝癌的结果，在有效性与安全性的基础上，总结HIFU消融肝癌的剂量学数据，建立剂量模型，以预测治疗一定体积肝癌所需要的超声剂量，为HIFU治疗肝癌的治疗计划系统（TPS）的制定和优化提供剂量学基础。方法 1.研究对象 2009年12月至2013年6月，郑州大学第一附属医院肝胆胰外科收治的行HIFU治疗的122例肝癌患者，其中男88例，女34例，年龄24~78岁，平均53.82±10.44岁。纳入标准：（1）原发性肝癌诊断依据卫生部颁布的“原发性肝癌诊疗规范(2011年版)”肝癌诊断标准，包括慢性肝病背景（肝硬化或HBV/HCV感染）、影像学检查（CT或/和MRI）、血清AFP水平；（2）HIFU治疗之前未经过其它治疗；（3）无远处转移，无下腔静脉癌栓；（4）失去手术机会的晚期肝癌或不愿意接受手术治疗的原发性肝癌患者；（5）无严重心、肺、肾等重要脏器疾病，能够耐受全身麻醉；（6）了解HIFU治疗过程及可能风险，愿意接受HIFU治疗。排除标准（1）转移性肝癌；（2）弥漫型原发性肝癌；（3）严重心、脑血管疾病（不稳定性心绞痛、半年内有心肌梗塞、心律失常需用药物控制者、严重高血压及心力衰竭、近期有大范围的脑梗塞、脑出血者）；（4）未控制的糖尿病患者。 2.研究设备重庆海扶技术有限公司生产的JC200型聚焦超声肿瘤治疗系统。该系统由计算机系统控制的治疗头、定位监视装置、治疗运动控制装置、超声功率源、治疗床及脱气水装置等组成。治疗参数:治疗探头频率0.96MHz，焦距134mm，治疗焦域1.5～10mm，治疗声功率200～400W，扫描速度3mm/s，焦域声强4000～15000W/cm2，层距5mm。 GE LightSpeed CT成像系统。120KV，Auto-mA（240~700mA）；进床速度为39.37mm/r，螺距为0.984：1；层厚为5mm，转速为0.8s/r。高压注射器采用了美国瑞达双筒注射器，造影剂采用非粒子型对比剂如欧乃派克（300mgI/mL），经肘静脉注射，造影剂用量为80~100mL，注射流速4.0mL/s。扫描时相：动脉期延迟25~30s，门静脉期延迟60~65s，延迟期延迟90~180s。 3.研究方法 3.1影像学评估所有患者术前均行SCT和超声检查，以明确肿瘤的性质、形态、部位、数目以及与周围组织和脏器的毗邻关系。肿瘤体积计算方法：SCT或超声测量靶肿瘤的三维径线：长径（D1）、前后径（D2）和横径（D3），根据椭圆体计算公式计算靶肿瘤的体积。计算公式：V=0.5233×D1×D2×D3 肝癌血供评估：选择肝癌最大截面为研究层面，根据CT多期扫描的动脉期肝癌的强化面积占最大截面积的百分比将肝癌血供分为4级：（1）0级：肿瘤基本不强化或仅在肿瘤周边有环形强化，强化面积＜25%；（2）Ⅰ级：肿瘤以不强化为主，其不强化的背景内夹杂有强化区，25%"f强化面积50%；（3）Ⅱ级：肿瘤不均匀强化，其强化背景内夹杂有低密度或等密度区，50%"f强化面积90%；（4）Ⅲ级：肿瘤均匀强化，强化面积≥90%。通过SCT影像学测量腹壁厚度，肋间宽度，肿瘤距肝脏边缘距离等参数。3.2HIFU消融治疗 3.2.1治疗前准备①对于小肝癌或多发肝癌，术前进行模拟定位，以便更好地制定治疗计划，同时帮助病人消除治疗的恐惧感，配合治疗。 ②术前备皮、术区清洗、呼吸功能训练，并留置胃管尿管。 ③肿瘤靠近肝脏脏面并且为外生型者应进行严格的肠道准备。④所有患者术前均不行肋骨切除术。 3.2.2手术过程所有患者均采用全身麻醉，局部皮肤行脱脂脱气，对于靠近肝顶部的肿瘤，预计声通道通过肺组织，需行“人工胸水”。根据肿瘤的部位，采用右侧卧位或俯卧位（通常右半肝及左内叶肿瘤采用右侧卧位，左外叶肿瘤采用俯卧位）。在超声实时监控下确定肿瘤的部位、形态、数目、大小和与邻近组织的关系。按5mm的层距将肿瘤分为多个不同的连续层面，由深到浅适形治疗各个层面内癌组织，直至完全覆盖预定靶区。如遇肋骨阻挡，应进行呼吸控制，即在治疗过程中暂停呼吸机，采用手动挤压呼吸球囊，使肺扩张并保持1~2分钟，从而使膈肌下移、肝脏下移，原先被肋骨阻挡的肿瘤组织下降至肋间隙。扫描方式采用点、线结合的方式，治疗过程中通过实时监控超声影像图，根据治疗时靶区组织的灰阶变化来评价HIFU的治疗效果，靶区出现团块状高回声改变或整体灰度明显增加是HIFU治疗有效的确切证据。 3.2.3观察指标 ①治疗剂量参数：治疗时间、辐照时间、治疗功率；②安全性指标：不良反应。 3.3治疗后影像学评估治疗后1月内行SCT复查，测量消融区体积（non-perfused volume，NPV）和肿瘤消融率。公式：体积消融率（non-perfused volume ratio，NPVR）=无灌注区体积/靶肿瘤体积×100％。体积消融率≥50%为临床有效。 3.4治疗后并发症评价统计并发症发生情况，并发症严重程度评价依据国际介入放射治疗协会制定的SIR分类法。 3.5剂量学分析方法剂量用能效因子（energy effect factor, EEF）表示：EEF=η. Pt/V (J/mm3)η表示聚焦系数（=0.7），P为声功率（W），t为照射时间，V为无灌注区体积（NPV）（mm3），EEF为消融单位体积肿瘤所需能量。 3.6统计学分析采用SPSS17.0统计软件进行统计分析。结果 1．消融结果 122例病人，接受HIFU消融治疗，治疗时间平均2.76±1.34小时，，实际消融时间平均2301.98±1225.15秒，肿瘤的平均直径57.67±32.73mm，肿瘤体积217.41±361.8cm3，平均肿瘤体积消融率为73.73%±22.37%。 2.并发症和副反应术后常见并发症为发热、转氨酶升高、治疗区域疼痛、局部软组织肿胀，治疗区皮肤麻木，右侧胸腔积液等。2例患者出现肋骨骨折，1例患者出现皮肤Ⅲ度烧伤。1例患者出现结肠穿孔。按照SIR分级系统分级，19.83%为SIR A级并发症，79.59%为SIR B级并发症，0.58%为SIR D级并发症。 3.剂量学研究结果腹壁厚度与EEF之间缺乏相关性，而肿瘤距肝脏边缘的距离、肋间隙宽度、肿瘤直径以及肿瘤血供分级均与EEF具有线性相关关系。结论 1. HIFU对肝癌是一种安全有效的治疗方法。 2.能效因子（EEF）能够直接反映HIFU治疗肝癌量效关系，可作为HIFU治疗肝癌剂量学研究的量化指标。 3.肝癌距肝脏边缘的距离、肋间隙宽度、肿瘤的直径、血供分级与EEF具有线性相关关系。 4.肝癌HIFU消融的预测回归模型为：y=-56.096+21.029X1+1.165X2-0.502X3。注：X1=肝癌的血供分级+1（1,2,3,4）X2=肝癌距肝脏边缘的距离（肝癌中心部位作为测量点mm）X3=肝癌直径（平均直径mm）。第二部分高强度聚焦超声与氩氦刀联合治疗富血供肝癌的临床研究目的 1.通过比较高强度聚焦超声（HIFU）与氩氦刀治疗不同大小、不同血供丰富程度肝癌的疗效差异，为临床治疗肝癌选择合适的局部治疗方案提供实验依据。 2.采用HIFU联合氩氦刀的方法对于富血供大肝癌进行消融，评价其疗效，并与单独HIFU组及氩氦刀治疗组做对比，探讨HIFU联合氩氦刀治疗富血供大肝癌的有效性及可行性。方法 1.选取2011年6月至2013年6月郑州大学第一附属医院肝胆胰外科收治的原发性肝癌患者120例，其中男79例，女41例，患者年龄28-76岁，平均53.70±9.82岁。所有病例均经螺旋CT或MRI结合AFP证实为原发性肝细胞癌，并且均为无法行外科手术切除或者患者本人拒绝接受手术治疗。将患者随机分为2组，分别接受HIFU治疗及氩氦刀治疗，每组各60例。将每组按肿瘤直径分为3个亚组（小癌型：瘤体直径3cm；结节型：3cm"f瘤体直径5cm；块状型：5cm"f瘤体直径10cm）；多发肿瘤按最大肿瘤直径进行分组。按肿瘤的血供丰富程度用术前增强SCT进行评估同样分为4个亚组，分组方法详见第一部分摘要。所有患者均在治疗后1月内接受SCT影像学评估，计算肝癌的体积消融率。在各亚组层面比较HIFU和氩氦刀的的疗效。 2.取2009年12月~2013年6月郑州大学第一附属医院肝胆胰外科收治的富血供大肝癌20例（直径5cm，肿瘤血供Ⅱ、Ⅲ级）行联合HIFU及氩氦刀治疗，其中12例先行HIFU治疗，经SCT或超声复查后证实仍有残留组织，2周后行氩氦刀治疗。另有8例先行氩氦刀治疗，经SCT或超声证实有残余肿瘤组织后再行HIFU治疗。该组患者男14例，女6例，年龄59.32±12.34岁，瘤径5.0~10cm。对照组为同期单独行HIFU治疗的富血供大肝癌30例，及单独行氩氦刀治疗的富血供大肝癌30例。比较三组治疗方式的有效性及安全性。结果 1.HIFU和氩氦刀的整体疗效比较，两组消融率无明显差异(P0.05)。按肿瘤直径分成亚组，瘤体直径3cm组以及3cm"f瘤体直径5cm组有效率HIFU与氩氦刀治疗无明显差异(P0.05)，但瘤体直径≥5cm组，氩氦刀效果优于HIFU（P0.05）。根据血供丰富程度分成亚组，在乏血供组（0~Ⅰ级血供）HIFU与氩氦刀疗效无显著性差异（P0.05），但在富血供组（Ⅱ~Ⅲ级血供），氩氦刀疗效优于HIFU（P0.05）。 2.并发症方面，HIFU组无严重并发症，多数并发症经对症处理后好转或观察即可。氩氦刀治疗组有1例出现冷休克，并最终肾功能衰竭。 3.三组比较，在肿瘤体积消融率方面，联合组(75%)优于HIFU组(30%)(P0.05),但和氩氦刀组(56.67%)比较，差异无统计学意义（P0.05）；在症状改善方面，三组无统计学差异(联合组58%，HIFU组50%，氩氦刀组48%，P0.05)；在AFP下降方面，联合组(76.47%)优于HIFU组(43.48%)及氩氦刀组(44.00%)(P0.05)。联合治疗组未出现严重并发症。结论 1. HIFU和氩氦刀对于直径5cm的肝癌均为有效治疗手段，对于富血供的大肝癌，HIFU及氩氦刀治疗效果均下降，氩氦刀优于HIFU。 2. HIFU和氩氦刀均是安全的治疗手段，氩氦刀治疗肝癌需注意并预防冷休克、腹腔出血等严重并发症的发生。 3. HIFU联合氩氦刀治疗肝癌效果优于单纯HIFU治疗或氩氦刀冷冻治疗，HIFU联合氩氦刀对于富血供大肝癌是一种有效、安全的治疗方式。
[Abstract]:The dosimetry study of high intensity focused ultrasound (HIFU) in the treatment of liver cancer
objective
Through the SCT evaluation of HIFU ablation of hepatocellular carcinoma results in efficacy and safety, summarize the dosimetry data HIFU ablation of liver cancer, a model to predict the treatment dose, ultrasonic dose volume needed for liver cancer, treatment planning system HIFU for the treatment of hepatocellular carcinoma (TPS) to develop and provide basis for optimizing dosimetry.
Method
1. research objects
From December 2009 to June 2013, 122 cases of liver cancer treated by HIFU were enrolled in the First Affiliated Hospital of Zhengzhou University, including 88 males and 34 females, aged 24~78 years, with an average age of 53.82 + 10.44 years.
Inclusion criteria: (1) primary liver cancer diagnosis according to the Ministry of health promulgated the "standard of diagnosis and treatment of primary liver cancer (2011 Edition)" liver cancer diagnostic criteria, including the background of chronic liver disease (cirrhosis or HBV/HCV infection), imaging (CT or MRI), the serum level of AFP (2) HIFU before treatment; without other treatment; (3) no distant metastasis, no tumor thrombus in the inferior vena cava; (4) unresectable liver cancer or are not willing to accept the surgical treatment of primary liver cancer patients; (5) no serious heart, lung disease, kidney and other organs, able to withstand general anesthesia; (6) understand the HIFU treatment process and the possible risk, willing to accept HIFU treatment.
Exclusion criteria (1) metastatic hepatocellular carcinoma; (2) diffuse hepatocellular carcinoma; (3) serious heart cerebrovascular disease (unstable angina, 6 months after myocardial infarction, arrhythmia with drug control, severe hypertension and heart failure, the recent massive cerebral infarction, cerebral hemorrhage); (4) diabetic patients without control.
2. research equipment
The JC200 focused ultrasound tumor treatment system produced by Chongqing Haifu Technology Co., Ltd.
The treatment head of a computer control system, positioning monitoring device, control device for motor, ultrasonic power source, composition and water treatment bed degassing device. The treatment parameters: the treatment probe frequency 0.96MHz, focal length of 134mm, treatment of focal region of 1.5 ~ 10mm, 200 ~ 400W for sound power, scanning speed 3mm/s, focal intensity 4000 ~ 15000W/cm2, from the 5mm. layer
GE LightSpeed CT.120KV imaging system, Auto-mA (240~700mA); bed velocity is 39.37mm/r, pitch 0.984:1; layer thickness is 5mm, the speed of 0.8s/r. high pressure syringe Rita double syringe, contrast agent using particle contrast agent (300mgI/ mL), such as Omnipaque through elbow vein injection, contrast agent dosage 80~100mL injection velocity 4.0mL/s. scan time of arterial phase delay 25~30s, portal venous phase delay 60~65s delay time delay 90~180s.
3. research methods
3.1 imaging evaluation
All patients were examined by SCT and ultrasound before operation to determine the nature, morphology, location, number, and adjacent relationship with the surrounding tissues and organs.
The volume of tumor was calculated by SCT or ultrasound to measure the three-dimensional diameter of target tumor: long diameter (D1), anteroposterior diameter (D2) and transverse diameter (D3). The volume of target tumor was calculated according to the calculation formula of ellipsoid. The formula is: V=0.5233 * D1 * D2 * D3.
The evaluation for the liver blood: choose the maximum section of liver cancer as the research level, to strengthen the area according to the CT scan of the arterial liver percentage of the maximum cross-sectional area of the blood supply of liver cancer is divided into 4 levels: (1) 0: tumor basic no enhancement or only in the periphery of tumors with ring enhancement, enhanced area is less than 25%; (2) level I: to strengthen the tumor, its inclusion in the background of the reinforcement strengthening area, 25% "f enhancement area of 50%; (3) II: tumor inhomogeneous enhancement, the enhancement of background with low density or density, 50% f reinforcement
Area of 90%; (4) class III: tumor enhancement and enhancement area is larger than 90%. by SCT imaging measurement of abdominal wall thickness, rib width, distance from the edge of liver tumor ablation parameters such as.3.2HIFU
Pre - 3.2.1 preparation (1) for small or multiple hepatocellular carcinoma (HCC) or multiple hepatocellular carcinoma (HCC) before operation, in order to make the treatment plan better.
At the same time, help the patients to eliminate the fear of treatment, combined with treatment.
The preoperative skin preparation, preoperative cleaning, respiratory function training and indwelling gastric tube catheter.
(3) the tumor is close to the liver and should be prepared for the exogenic type. (4) all patients do not have ribs before operation.
The 3.2.2 procedure in all patients under general anesthesia, local skin degreasing for near the top of the degassing, liver tumor, lung tissue through the acoustic channel is expected, the need for "artificial hydrothorax." according to the location of the tumor, the right lateral decubitus or prone position (usually the right liver and left lobe tumor in the right lateral decubitus, left lateral lobe tumor with prone position). To determine the location of the tumor, ultrasound in real-time monitoring the number, shape, size and relationship with surrounding tissues. According to the 5mm layer from the tumor will be divided into a number of different continuous level, from deep to shallow conformal treatment of cancer organizations in various levels, until completely covering a predetermined the target area. If the ribs should be blocked, breath control, suspended mechanical ventilation in the treatment process, using manual extrusion breathing balloon, the lung expansion and keep 1~2 minutes, so that the diaphragm moves down, liver depression, had previously been rib bone block of tumor tissue under To the rib clearance. Scan mode using point line combination, in the course of treatment by real-time monitoring of ultrasonic images, HIFU treatment evaluation according to the gray-scale changes of target tissue to the treatment effect, appeared in the target region mass shaped high echo change or overall gray increased significantly for HIFU evidence effectively.
3.2.3 observation index
(1) treatment dose parameters: treatment time, irradiation time, treatment power, and safety index: adverse reaction.
3.3 after treatment, imaging evaluation of January underwent SCT re examination after treatment, measurement of ablation zone volume (non-perfused volume, NPV) and the tumor ablation rate. The formula: Volume ablation rate (non-perfused volume ratio, NPVR) = non perfusion volume / target tumor volume x 100%. volume ablation rate greater than 50% is clinically effective.
Evaluation of complications after 3.4 treatment
The incidence of complications was statistically analyzed, and the severity of the complications was evaluated according to the SIR classification established by the International Association for interventional radiology treatment.
3.5 methods of dosimetric analysis using dose efficiency factor (energy effect factor EEF) said: EEF= Pt/V (J/mm3). ETA ETA said focusing factor (=0.7), P (W), sound power t irradiation time, V volume perfusion area (NPV) (mm3) EEF, the energy required for ablation the unit volume of the tumor.
3.6 statistical analysis was carried out by SPSS17.0 statistical software.
Result
1. result of ablation
122 patients were treated with HIFU ablation, the average time of treatment was 2.76 + 1.34 hours, the actual ablation time was 2301.98 + 1225.15 seconds, the average diameter of the tumor was 57.67 + 32.73mm, the tumor volume was 217.41 + 361.8cm3, and the average tumor volume ablation rate was 73.73% + 22.37%..
2. complications and side effects
The postoperative complications included fever, elevated transaminases, regional pain treatment, local soft tissue swelling, numbness of skin in the treatment area, right pleural effusion.2 patients with rib fractures, 1 cases of patients with skin burns.1 patients with colonic perforation. According to SIR classification system for SIR grade, 19.83% grade 79.59% complications. SIR B 0.58% SIR D for complications and complications.
3. research results of dosimetry
There was no correlation between the thickness of abdominal wall and EEF, but the distance from tumor to the liver edge, the width of rib space, the diameter of tumor and the classification of tumor blood supply all had a linear correlation with EEF.
1. HIFU is a safe and effective treatment for liver cancer.
The 2. energy efficiency factor (EEF) can directly reflect the dose effect relationship of HIFU in the treatment of liver cancer, and can be used as a quantitative indicator of dosimetry for the treatment of liver cancer by HIFU.
3. the distance from the liver to the edge of the liver, the width of the intercostal space, the diameter of the tumor, the classification of blood supply and the EEF
Linear correlation.
4., the predictive regression model of HIFU ablation for liver cancer is: y=-56.096+21.029X1+1.165X2-0.502X3. note: X1= blood supply grading +1 (1,2,3,4) X2=, liver cancer distance from the liver edge (the center of liver cancer as the measurement point mm), the diameter of X3= liver cancer (mean diameter mm).
Clinical study on the combination of second parts of high intensity focused ultrasound and argon helium knife in the treatment of liver cancer with rich blood supply
1., by comparing the therapeutic effects of high intensity focused ultrasound (HIFU) and argon helium knife on different sizes and blood supply levels, we can provide experimental evidence for selecting suitable local treatment for liver cancer.
2., we used HIFU combined with argon helium knife to evaluate the efficacy of ablation for hepatocellular carcinoma with large blood supply and evaluate its efficacy. Compared with group HIFU and argon helium knife therapy, we explored the feasibility and effectiveness of HIFU combined with argon helium knife in the treatment of large hepatocellular carcinoma with rich blood supply.
1. were selected and hepatobiliary surgery the First Affiliated Hospital of Zhengzhou University from June 2011 to June 2013, 120 cases of primary liver cancer patients, 79 were male, 41 were female, with average age of 28-76 years, 53.70 + 9.82 years. All cases were confirmed by spiral CT or MRI combined with AFP confirmed primary liver cell carcinoma, and as to surgical excision or patient refused to accept surgical treatment. The patients were randomly divided into 2 groups, were treated with HIFU and cryoablation therapy, 60 cases in each group. Each group according to the diameter of the tumor was divided into 3 subgroups (small cancer type: tumor diameter 3cm; node type: 3cm the diameter of tumor f 5cm; massive type: 5cm "f tumor diameter 10cm); multiple tumors were grouped according to the maximum diameter of the tumor. According to tumor blood supply by preoperative enhanced SCT assessment is also divided into 4 sub groups, in the first part the grouping method. All the patients were cured After January, the SCT imaging assessment was performed to calculate the volume ablation rate of liver cancer. The therapeutic effects of HIFU and argon helium were compared in each subgroup.
2. December 2009 ~2013 year in June of hepatobiliary surgery the First Affiliated Hospital of Zhengzhou University, the rich blood supply of large hepatocellular carcinoma in 20 cases (diameter 5cm, the blood supply of the tumor II, III) treated with HIFU and cryoablation, first HIFU treatment in 12 cases, by SCT or ultrasound examination confirmed that there is still residual tissue, 2 weeks after treatment of argon helium knife. Another 8 cases of the first treatment of argon helium knife by SCT or ultrasound confirmed residual tumor after HIFU treatment. The patients were male 14 cases, female 6 cases, age 59.32 + 12.34 years, tumor diameter 5.0~10cm. control group for the same period alone HIFU rich blood supply of large hepatocellular carcinoma in 30 cases, and a separate line of argon helium cryoablation of hypervascular large hepatocellular carcinoma in 30 cases. The efficacy and safety of treatment were compared between the three groups.
Result
Comparison of the overall effect of 1.HIFU and argon helium knife, two groups of ablation rate had no significant difference (P0.05). Divided into sub groups according to tumor diameter, tumor diameter had no significant difference between group 3cm and 3cm with HIFU and f efficiency of argon helium knife diameter of tumor in 5cm group (P0.05), but the diameter of tumor was more than 5cm group, argon helium knife is better than HIFU (P0.05). According to the blood supply into subgroups in hypovascular group (0~ grade of blood supply) there was no significant difference between the efficacy of HIFU and argon helium knife (P0.05), but in the rich blood supply (group II or III blood supply), argon helium knife the curative effect is better than that of HIFU (P0.05).
2., there were no serious complications in HIFU group. Most of the complications were improved or observed after symptomatic treatment. 1 cases suffered from cold shock and eventually renal failure in argon helium therapy group.
Comparison of 3. groups in three, the volume of tumor ablation rate, the combined group (75%) than that of HIFU group (30%) (P0.05), but the cryoablation group (56.67%), the difference was not statistically significant (P0.05); improvement in symptoms, no significant difference between three groups (group 58%, HIFU group 50% argon helium knife, group 48%, P0.05); the decline in AFP, the combined group (76.47%) than that of HIFU group (43.48%) and cryoablation group (44%) (P0.05). The combined treatment group had no serious complications.
conclusion
1. HIFU and argon helium knife are effective treatments for hepatocellular carcinoma with diameter of 5cm. For blood rich large hepatocellular carcinoma, the effect of HIFU and argon helium knife is decreased, and argon helium knife is better than HIFU..
2. HIFU and argon helium knife are all safe treatment methods. Argon helium knife should pay attention to the treatment of liver cancer and prevent severe complications such as cold shock and abdominal bleeding.
The effect of 3. HIFU combined with argon helium knife in the treatment of liver cancer is better than that of HIFU alone.

【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R735.7

【参考文献】