磁共振成像在淋巴系统疾病中的应用及新型淋巴特异性造影剂的研究

发布时间：2018-06-12 19:37

本文选题：淋巴水肿 + 磁共振成像　；参考：《上海交通大学》2014年博士论文

【摘要】：第一部分常规磁共振成像在淋巴系统相关疾病诊断中的应用目的：（1）探讨常规磁共振成像在继发性淋巴水肿诊断中的价值并评估其参数在淋巴水肿早期诊断以及分期中的应用价值。（2）探讨DWI和FDG-PET（CT）在评估和预测直肠患者接受NCRT治疗后病理反应诊断的准确性。方法：（1）对72名妇科术后继发单侧下肢淋巴水肿患者以及22名妇科术后无明显肢体水肿出现的患者进行T1WI、T2WI、T2脂肪抑制序列以及磁共振水成像序列扫描，分析下肢淋巴水肿分期与患侧大、小腿的直径（TT）、相应肌肉直径（MT）、皮下软组织厚度（STT）、患侧与正常侧大小腿直径差值（DTT）、肌肉直径差值（DMT）、皮下软组织厚度差值（DSTT）间的相关性。（2）通过数据库文件检索和筛选，最终入组33文献并进行meta-analysis，评价指标包括敏感性、特异性、PPV以及NPV等。结果：（1）淋巴水肿在常规磁共振图像上表现有：真皮增厚；皮下组织增厚；网格状改变；蜂窝状改变；淋巴水肿基本不引起肌肉组织信号的改变。T2脂肪抑制序列可以消除脂肪信号干扰，因此T2脂肪抑制序列更有利于显示淋巴水肿。磁共振水成像可以显示呈囊样、串珠样扩张的淋巴管、皮下积液程度和范围以及水肿肢体的皮下网格状改变。T2脂肪抑制序列参数中，患侧大、小腿的TT、STT以及DTT、SDTT与淋巴水肿分期相关，但是MT则没有相关性，其中小腿DSTT以及大腿DTT与淋巴水肿分期的相关性最好。患侧小腿STT、DTT、DSTT以及大腿DTT在淋巴水肿不同分期间比较具有统计学差异（p值均小于0.05），其他参数没有统计学差异。根据ROC曲线分析，小腿皮下软组织厚度差值DSTT是评价淋巴水肿分期的最佳参数指标。（2）研究发现DWI敏感性和NPV高于PET或FDG PET-CT(p＜0.05)，而二者的特异性和PPV没有差异（p＞0.05）。本研究没有发现阈值效应。元回归分析表明DW-MRI及FDG PET (CT)盲法研究是诊断准确性最重要的影响因素。结论：本次研究表明常规磁共振成像可以用于辅助淋巴水肿的临床诊断；小腿皮下软组织厚度差值可以作为淋巴水肿患者早期诊断和水肿分期的指标，帮助临床选择最佳的治疗时机和治疗方案。DWI在评估直肠癌患者接受NCRT治疗的病理反应方面优于FDG PET (CT)。第二部分磁共振淋巴造影在淋巴水肿相关疾病诊断中应用价值目的：探讨磁共振淋巴造影成像在妇科肿瘤术后继发下肢淋巴水肿以及腹股沟区淋巴管瘘诊断中的应用价值。方法：（1）对80名妇科肿瘤术后继发下肢淋巴水肿患者进行磁共振淋巴造影成像，，计数和测量患侧大、小腿淋巴管数目、淋巴管最大径并与正常侧进行比较，同时统计分析不同淋巴水肿分期间淋巴管数目及最大径有无差别。（2）对23名腹股沟区淋巴管瘘患者行磁共振淋巴造影成像检查，评估其显示淋巴管瘘成功率以及与淋巴结显像差别，同时以瘘持续时间为据将病人分成2组后比较分析冠状面淋巴管瘘的最大截面积、引流淋巴管的数目及最大径间的差异。结果：（1）妇科肿瘤术后继发淋巴水肿患侧小腿淋巴管数目多于正常侧（p＜0.01）；而大腿患侧、正常侧淋巴管数目比较无显著性差异（p＞0.05）；患侧小腿淋巴管数目以及最大径与患侧大腿比较，均有显著性差异（p＜0.01）。患侧小腿淋巴管最大径于淋巴水肿各分期组间比较发现，1期VS.2期以及2期VS.3期均无统计学差异，1期VS.3期有统计学差异。患侧大腿各分期内淋巴管最大径比较无统计学差异（p＞0.05）。患侧小腿淋巴管数目淋巴水肿各分期组间比较发现，1期VS.2期无统计学差异，2期VS.3期以及1期VS.3期有统计学差异（p值均小于0.05）。患侧大腿各分期内淋巴管数目中位数比较无统计学差异（p＞0.05）。所有水肿侧下肢一共发现淋巴反流56处。（2）淋巴管瘘患者MRL图像表现为造影剂外溢呈高信号，显示成功率为22/23；18名淋巴瘘患者所在位置较表浅，另4名患者瘘位于深筋膜-肌间隙；淋巴管瘘SNR较腹股沟区淋巴结高，两者有统计学差异（p＜0.05），淋巴管瘘信号强度SI上升速度较腹股沟区淋巴结慢，二者间有统计学差异（p＜0.05）；瘘持续时间≤8周的患者瘘冠状面最大截面积、引流淋巴管数目以及最大径均小于瘘持续时间＞8周的患者，以上比较均有统计差异（p＜0.05）。22名患者于磁共振检查后完成手术治疗，随访未见瘘复发。结论：（1）磁共振淋巴造影MRL可以显示妇科肿瘤术后继发下肢淋巴水肿患者的外周淋巴系统的解剖学和形态学特征，为临床诊断和水肿分期提供帮助，此外本研究还发现继发性淋巴水肿患侧小腿的形态学改变较大腿更明显。（2）磁共振淋巴造影MRL可以成为临床诊断淋巴管瘘的可靠的影像学检查方法，帮助临床诊断、术前评估以及手术方案的制定；此外淋巴管瘘可能随时间推移加重病情，保守治疗无效时应尽快手术治疗。第三部分新型淋巴特异性造影剂HA-Gd-DTPA复合物的研究目的：通过适当的方法，制备出新型淋巴特异性磁共振大分子阳性造影剂HA-Gd-DTPA复合物，通过磁共振淋巴造影显像探索和评估其显示正常淋巴系统以及良恶性淋巴结鉴别诊断方面的能力。方法：（1）以透明质酸纳、二乙三胺五乙酸以及硝酸钆为主要原料通过化学桥接、螯合等制备出HA-Gd-DTPA复合物，并对该造影剂的理化性质进行检测，通过MMT法考察其细胞毒性，用小鼠实验考察其活体毒性并得到其半数致死量。（2）以小分子造影剂马根维显作为对照，通过对正常新西兰大白兔进行磁共振淋巴造影，评估HA-Gd-DTPA复合物显示正常淋巴系统的能力。（3）用完全福氏佐剂和VX-2肿瘤瘤株分别制备淋巴结炎症和肿瘤转移模型，以马根维显为对照，考察HA-Gd-DTPA复合物鉴别良恶性淋巴结的能力。结果：（1）新制备的HA-Gd-DPTA复合物结构稳定；水合粒径平均为350纳米，分子量为100000道尔顿；钆离子浓度为0.02±0.005mol/L；其弛豫性强于等浓度的马根维显，并且具有良好的生物安全性。（2）正常动物磁共振淋巴造影成像显示，HA-Gd-DTPA复合物组（A组）乆窝淋巴结信号强度达到峰值的时间（6.27±0.82）较马根维显组即B组（4.19±0.27）更长，两者间有显著性差异（p＜0.01）；A组乆窝淋巴结增强后到达峰值时，SNRmax=41.14±5.52，CNRmax=33.22±5.34，E%max=（375.55±55.72）%；B组乆窝淋巴结增强后到达峰值时，SNRmax=37.78±6.21，CNRmax=29.48±5.78，E%max=（345.50±42.80）%；A组乆窝淋巴结增强后信号下降斜率L=0.85±0.20，B组乆窝淋巴结增强后信号下降斜率L=1.02±0.15；A、B组间SNR、CNR、E%以及下降斜率比较均有统计学差异。（3）在HA-Gd-DTPA磁共振增强造影图像上，肿瘤转移性淋巴结表现为斑片状、斑点状高信号，而炎性淋巴结呈均匀高信号且随时间变化不大，二者强化形态存在明显差异；肿瘤转移性淋巴结强化到达峰值的时间较炎症淋巴结长（p＜0.05），而且峰值信噪比SNR也低于炎症淋巴结（p＜0.05）。对照病理，HA-Gd-DTPA复合物检出炎性和肿瘤转移性淋巴结多于马根维显，而且其敏感性和特异性更高。结论：成功制备出新型亲淋巴大分子磁共振阳性造影剂HA-Gd-DTPA复合物，该造影剂安全性好、分子结构稳定，弛豫性好，磁共振淋巴造影显像表明其显示正常淋巴系统优于小分子磁共振造影剂马根维显，并可用于炎症和肿瘤转移性淋巴结的鉴别。
[Abstract]:The first part is the application of conventional magnetic resonance imaging in the diagnosis of lymphatic system related diseases.
Objective: (1) to evaluate the value of conventional magnetic resonance imaging (MRI) in the diagnosis of secondary lymphedema and to evaluate the value of its parameters in the early diagnosis and staging of lymphedema.
(2) to explore the accuracy of DWI and FDG-PET (CT) in evaluating and predicting the pathological response of rectal patients receiving NCRT treatment.
Methods: (1) 72 patients with secondary unilateral lower extremity lymphedema after gynecologic surgery and 22 patients with no apparent edema after gynecologic operation were scanned by T1WI, T2WI, T2 fat suppression sequence and magnetic resonance water imaging sequence, and the lower extremity lymphedema staging, the diameter of the leg (TT), the corresponding muscle diameter (MT), and subcutaneous soft group were analyzed. The correlation between thickness (STT), diameter difference between the affected side and the normal side (DTT), the difference of muscle diameter (DMT), and the difference of subcutaneous soft tissue thickness (DSTT).
(2) through the search and screening of database files, we finally entered into 33 documents and carried out meta-analysis. The evaluation indexes included sensitivity, specificity, PPV and NPV.
Results: (1) lymphedema was shown in conventional MRI images: the thickening of the dermis, the thickening of the subcutaneous tissue, the change of the meshes, the changes in the honeycomb shape, and the changes in the signal of the muscle tissue in the lymphedema. The.T2 fat suppression sequence could eliminate the interference of the fat signal, so the T2 fat suppression sequence was more beneficial to the display of lymphedema. Magnetic resonance hydrography can show cystic, bead like dilated lymphatics, subcutaneous fluid degree and scope, and subcutaneous meshes of the edema limb changes in the.T2 fat suppression sequence parameters, large affected side, TT, STT, DTT, SDTT of the calf, and lymphedema staging, but MT has no correlation, including the leg DSTT and thigh DTT and drenching. The correlation of the STT, DTT, DSTT and thigh DTT in the affected leg was statistically different (P value was less than 0.05), and the other parameters were not statistically different. According to the ROC curve, the difference of subcutaneous soft tissue thickness of the calf DSTT was the best parameter for evaluating the stage of lymphedema.
(2) the study found that the sensitivity of DWI and NPV were higher than that of PET or FDG PET-CT (P < 0.05), but the specificity and PPV of the two were not different (P > 0.05). The threshold effect was not found in this study. The regression analysis of the DW-MRI and FDG PET (CT) was the most important factor in the accuracy of diagnosis.
Conclusion: This study shows that conventional MRI can be used to assist the clinical diagnosis of lymphedema, and the difference of subcutaneous soft tissue thickness can be used as an indicator of early diagnosis and edema staging of patients with lymphedema, and helps to select the best time for treatment and treatment of.DWI in the evaluation of NCRT treatment for patients with rectal cancer. The pathological reaction is better than FDG PET (CT).
The second part is the value of magnetic resonance lymphography in the diagnosis of lymphedema related diseases.
Objective: To evaluate the diagnostic value of magnetic resonance lymphography (MRI) in the diagnosis of lymphedema secondary to lower extremity lymphedema after gynecological tumor operation.
Methods: (1) magnetic resonance lymphography was performed on 80 patients with secondary lower extremity lymphedema after gynecologic tumor surgery. The number of the affected side, the number of the calf lymphatics, the maximum diameter of the lymphatics were compared with the normal side, and the number and the maximum diameter of the lymphedema in the different stages of the lymphedema were statistically analyzed.
(2) 23 patients with inguinal lymphangitic fistula were examined by magnetic resonance imaging (MRI) to assess the success rate of Lymphangio fistula and the difference between lymph node imaging and lymph node imaging. At the same time, the patients were divided into 2 groups according to the duration of fistula. The maximum cross section of the coronary Lymphangio fistula, the number of drainage lymphatics and the difference between the maximum diameter were compared.
Results: (1) the number of calf lymphatics in secondary lymphedema after gynecologic tumor was more than that of normal side (P < 0.01), while there was no significant difference in the number of normal lateral lymphatic vessels in the affected side of the thigh (P > 0.05), and the number of calf lymphatics and the maximum diameter of the affected side were significantly different from that of the affected side (P < 0.01). There was no statistical difference between the 1 stage VS.2 stage and the 2 phase VS.3 stage, and there was no statistical difference between the 1 stage VS.3 stages and the maximum diameter of the lymphatic vessels in the affected side thighs (P > 0.05). There was no statistical difference between the 1 stages of the 1 stage of the lymphoid swelling of the affected leg. The difference, the 2 phase VS.3 and the 1 phase VS.3 period were statistically different (P values were all less than 0.05). The median number of lymphatic vessels in the affected side thighs was not statistically significant (P > 0.05). All the lower extremities were found to be 56 of the lymphatic reflux.
(2) the MRL image of the Lymphangio fistula patients showed that the contrast agent was high signal and the success rate was 22/23; the location of the 18 lympho fistula patients was shallow, and the other 4 patients were located in the deep fascia muscle space; the lymphatic fistula SNR was higher than the inguinal lymph node, and the two were statistically different (P < 0.05), and the signal intensity of lymphatic fistula was higher than that of SI. The lymph nodes in the inguinal region were slow, and there was a statistical difference between the two (P < 0.05); the maximum section area of the coronary artery in patients with fistula duration less than 8 weeks, the number of drainage lymphatics and the maximum diameter were less than the duration of the fistula duration > 8 weeks. The above comparison had statistical differences (P < 0.05).22 patients completed the surgical treatment after magnetic resonance examination, followed up. There was no recurrence of fistula.
Conclusions: (1) magnetic resonance lymphography MRL can show the anatomical and morphological features of the peripheral lymphatic system of the patients with secondary lower extremities after gynecologic tumor surgery, providing help for clinical diagnosis and edema staging. Furthermore, this study also found that the morphological changes of the side leg of secondary lymphedema are more obvious than those of the thighs.
(2) magnetic resonance lymphography MRL can be a reliable imaging method for clinical diagnosis of Lymphangio fistula. It helps clinical diagnosis, preoperative assessment and the formulation of surgical procedures; in addition, Lymphangio fistula may aggravate the condition with time, and the treatment should be done quickly when the conservative treatment is invalid.
The third part is the study of a novel lymphatic specific contrast agent HA-Gd-DTPA complex.
Objective: to prepare a new type of lymphoid magnetic resonance macromolecule positive contrast agent HA-Gd-DTPA complex by means of appropriate methods, and to explore and evaluate its ability to display the normal lymphatic system and the differential diagnosis of benign and malignant lymph nodes through magnetic resonance lymphography.
Methods: (1) the HA-Gd-DTPA complex was prepared by chemical bridging and chelating with hyaluronic acid, two B, three amine five acetic acid and gadolinium nitrate. The physicochemical properties of the contrast agent were detected, the cytotoxicity was examined by MMT, and the living toxicity was investigated in mice and half of the lethal dose was obtained.
(2) the ability of HA-Gd-DTPA complex to display normal lymphatic system was evaluated by magnetic resonance lymphography of normal New Zealand white rabbits by using a small molecular contrast agent, Ma root.
(3) the model of lymphadenitis and tumor metastasis was prepared by full Fu's adjuvant and VX-2 tumor tumor strain respectively. The ability of the HA-Gd-DTPA complex to identify the benign and malignant lymph nodes was investigated by the contrast of the HA-Gd-DTPA complex.
Results: (1) the structure of the newly prepared HA-Gd-DPTA complex is stable, the average diameter of the hydrated particles is 350 nanometers, the molecular weight is 100000 Dalton, the gadolinium ion concentration is 0.02 + 0.005mol/L, and the relaxation is stronger than the equal concentration of Ma gage, and it has good biological safety.
(2) the magnetic resonance lymphography of normal animals showed that the time of the signal intensity of the lymph node in the HA-Gd-DTPA complex group (A group) reached the peak value (6.27 + 0.82), which was longer than that in group B (4.19 + 0.27), which was significantly different (P < 0.01). When the lymph nodes in the A group reached the peak, SNRmax=41.14 + 5.52, CNRmax=33.22 + 5 .34, E%max= (375.55 + 55.72)%, SNRmax=37.78 + 6.21, CNRmax=29.48 5.78, E%max= (345.50 + 42.80)%, A in group A and L=0.85 + 0.20 after enhanced lymph node enhancement in A group, and L=1.02 + 0.15 in B group. There were statistical differences.
(3) on the HA-Gd-DTPA MRI enhanced imaging, the metastatic lymph nodes were flaky and high signal, while the inflammatory lymph nodes were homogeneous high signal and changed little with time, and the enhanced morphology of the two groups was significantly different, and the time of tumor metastatic lymph node to peak was longer than that of the inflammatory lymph nodes (P < 0.05). The peak signal to noise ratio (SNR) was also lower than that of the inflammatory lymph nodes (P < 0.05). The HA-Gd-DTPA complex detected inflammatory and metastatic lymph nodes more than that of Ma, and had higher sensitivity and specificity than that of the inflammatory lymph nodes (P < 0.05).
Conclusion: a new type of lymphoid macromolecule magnetic resonance positive contrast agent HA-Gd-DTPA complex is successfully prepared. The contrast agent has good safety, stable molecular structure and good relaxation. Magnetic resonance lymphography shows that the normal lymphatic lymphography shows that the normal lymphatic system is superior to the small molecular magnetic resonance contrast agent MA root, and can be used in inflammation and metastatic lymph nodes. The identification of the knot.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R445.2;R551.2

【参考文献】