正电子发射断层（PET）显像在脑胶质瘤放射治疗中的临床与实验研究
|
摘要
目的脑肿瘤是危害人类健康的常见疾病,发病率及死亡率均较高。原发性脑肿瘤中以胶质瘤为主,放射治疗是胶质瘤治疗的重要辅助手段,正确鉴别放疗后肿瘤复发和放射性损伤直接影响疗效和患者预后是临床关心的重要问题。目前计算机断层扫描(CT)和核磁共振成像(MRI)是用于鉴别脑肿瘤放射性损伤和复发的常规方法,能够对多数病变做出正确诊断,但放射性损伤有复杂的演变过程,在某个时期内的MRI影像表现易与肿瘤复发混淆,因此常规影像学检查并不能完全鉴别肿瘤复发和放射性损伤。正电子发射断层显像(Positron Emission Tomography, PET)及PET/CT作为一种功能代谢显像技术,借助多种示踪剂可以从不同角度体现病变组织的生理生化改变,反映肿瘤的生物学特性,已越来越多地用于脑肿瘤的术前分级、评价疗效、鉴别肿瘤放疗后的复发与坏死以及判断患者预后等方面。最常用的示踪剂为18F-氟代脱氧葡萄糖(2-[18F] fluoro-2-deoxy-D-glucose, FDG),对肿瘤复发与坏死的鉴别有较高的价值。目前的研究进展是,利用多种不同的示踪剂反映肿瘤的特征,应用多种示踪剂联合显像为临床提供更可靠的信息。本研究分为临床部分和动物实验部分。临床部分通过对一组可疑脑肿瘤放疗后复发患者的FDG、11C-蛋氨酸(methi onine, MET)及1’C-胆碱(choline, CHO) PET/CT检查进行回顾性分析,探讨多种示踪剂PET/CT显像在脑肿瘤放疗后复发和坏死鉴别诊断中单独和联合应用的价值。动物实验部分建立大鼠异位C6胶质瘤模型并给予放射治疗,在放疗前、后不同时期分别行FDG、MET、CHO和11C-乙酸盐(acetate, ACE) PET/CT显像,观察多种不同示踪剂的影像学表现与变化,并用免疫组化、RT-PCR及Western blot等方法观察大鼠C6胶质瘤在放疗前后病理学以及分子生物学方面的变化,探讨多种示踪剂PET显像的主要影响机制。资料和方法一、临床部分：选取2005年9月至2009年9月间,临床可疑脑肿瘤放疗后复发并于我院行PET/CT检查的患者38例,其中24例行MET和FDGPET/CT检查,14例行CHO和FDG PET/CT检查。38例患者中1例患者同时伴随有复发和放射性损伤,因此共39个病变纳入本研究,通过病理证实28个,临床及影像学随访证实(>6个月)证实11个。对所有患者的PET/CT行视觉和半定量分析。①视觉分析：病灶的示踪剂浓集程度高于周围正常脑组织或对侧相应部位时为阳性；病灶的示踪剂浓集程度低于或等于周围脑组织或对侧相应部位时为阴性。②半定量分析：测量计算病灶与对侧相应部位白质的SUV比值(T/WM)。将PET视觉分析结果与病理或临床随访结果进行对照,分别计算FDG与MET、CHOPET对脑肿瘤放射治疗后复发和坏死鉴别诊断的灵敏度、特异度和准确度。对脑肿瘤放疗后复发和坏死的各种示踪剂的T/WM进行比较。
二、动物实验部分：
1.C6细胞在高糖DMEM培养基(Dulbecco's modified Eagle's medium)中,37℃,5%CO2,饱和湿度条件下培养皿中单层培养。肿瘤细胞呈对数生长期时收集细胞悬液,调整细胞浓度至1×108/ml。
2.SD大鼠185只,雄性,4-5周龄,体重180-200mg。乙醚麻醉后,抽取细胞悬液0.2ml,种植于大鼠右侧腹股沟皮下。肿瘤细胞接种2周后,大鼠右侧腹股沟皮下处结节≥1cm时为肿瘤模型成功建立。模型成功后,随机分为2组,对照组和放射治疗组。
3.大鼠C6胶质瘤模型放射治疗：德国Siemens Primus直线加速器,6MV-X射线照射,剂量率2Gy/min,单次照射,总剂量12Gy。照射野为肿瘤边缘外放1.5cm,源皮距(source to skin distance, SSD)100cm。
4. PET/CT显像：对照组大鼠分为两组：B1组,接种C6细胞后2周即进行PET/CT显像；B2组,接种C6细胞后3周PET/CT显像。放疗组大鼠分为两组：R1组,放疗后48h内显像；R2组,放疗后1周显像(即接种C6细胞后3周)。B1,B2,R1,R2四组大鼠进行PET/CT显像时,每组内每只大鼠均只随机接受一种11C标记的示踪剂,并于同天行18F-FDG PET/CT显像。
5. PET/CT显像处理：图像数据传入Xeleris工作站,得到大鼠C6胶质瘤的CT、PET及PET/CT融合图像,测量肿瘤体积、SUVmax及T/M。测量肿瘤最大标准摄取值(maximal standardized uptake value, SUVmax)及对侧脊柱旁肌肉的平均标准摄取值(mean standardized uptake value, SUVmean),计算二者比值(tumor-to-muscle, T/M)。
6.标本处理：荷瘤大鼠完成全部PET检查后,无痛处死。取出肿瘤组织标本,立即分为两部分,一部分置入10%中性福尔马林溶液固定,石蜡包埋；另外一部分迅速液氮冷冻后-70℃保存。
7.病理学方法：石蜡切片HE染色,计数细胞密度,免疫组化染色评价葡萄糖转运蛋白1(Glucose transporter1， GLUT1)、 CD98.血管内皮生长因子(vascular endothelial factor, VEGF)、缺氧诱导因子-1α(hypoxia induible factor-1α, HIF-1α)、p53、微血管密度(microvessel density, MVD)、Ki67标记指数(Ki67labeling index, Ki67LI), TUNEL原位凋亡检测法(Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, TUNEL)。
8.分子生物学方法：用RT-PCR方法检测4F2hc、LAT1、VEGF、p53及HIF-1α mRNA表达水平。用Western blot法检测GLUT1、CD98、VEGF及p53蛋白表达水平。对上述实验室指标组间差异进行单因素方差分析,并将其与PET显像T/M做相关性分析。
结果一、临床部分：39个病变中肿瘤复发为28个,放射性损伤11个。视觉分析：FDG PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为85.7%、81.8%和84.2%; MET PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为94.4%、87.5%和96%; CHO PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为90%、75%和86%。半定量分析：在脑肿瘤复发和放射性损伤中FDG T/WM分别是2.53±1.11,1.40±0.57,二者有统计学差异(P=0.003)；在脑肿瘤复发和放射性损伤中MET T/WM分别是4.44±1.16,1.57±0.73,二者有明显差异(P=0.000)；在脑肿瘤复发和放射性损伤中CHO T/WM分别为14.70±8.60、7.69±1.89,P=0.033,有明显的统计学差异。联合MET与FDG PET/CT显像,对脑肿瘤放疗后复发和坏死的准确度可达到96%；联合CHO与FDG PET/CT显像,对脑肿瘤放疗后复发和坏死的准确度可提高到92.8%。
二、动物实验部分：
1.185只实验大鼠,3只未成瘤,种瘤成功率为97.7%。成瘤鼠中5只在放疗过程中或PET/CT显像时因麻醉意外死亡,最后共有177只实验鼠(占95.7%)纳入本研究。
2.B1、R1、R2及B2组各组肿瘤的大小分别是8.61±6.57cm3、7.80±7.31cm3、5.21±5.48cm3及8.88±6.16cm3。R2组与B1组、B2组间肿瘤大小差异具有统计学意义(p=0.014,p=0.008)。
3.各组大鼠C6胶质瘤均有不同程度的示踪剂摄取,B1组,FDG SUVmax及FDG T/M均明显高于MET、CHO及ACE(P<0.05)；R1组,FDG SUVmax明显高于ACE、MET和CHO (P<0.05), CHOSUVmax明显低于MET和ACE (P<0.05), FDG T/M明显高于其他三种示踪剂(P<0.05)；R2组,FDG SUVmax明显高于ACE、MET和CHO(P<0.05),FDGT/M明显高于ACE、MET和CHO(P<0.05),CHO T/M高于MET和ACE(P=0.01、P=0.00)。B2组,FDG SUVmax及FDGT/M均高于其他三种示踪剂(P<0.05)。
4.同一示踪剂的SUVmax、T/M的组间比较结果：FDG SUVmax及T/M,均是R2组低于B1、B2组(P<0.05); CHO SUVmax R1组低于其他三组,T/M R2组高于其他三组；ACE SUVmax、T/M,R2组低于B1、B2组;MET SUVmax B1组高于R2和B2组,T/M R2组低于B1组。
5.C6胶质瘤FDG T/M与肿瘤体积之间存在正相关关系(r=0.592,P=0.000),其余各参数与肿瘤体积之间不具有相关性。
6.HE染色：B1组C6细胞异型性明显,有病理核分裂像；R1组C6细胞活性欠佳,可见炎细胞浸润；R2组细胞大量坏死崩解,伴有反应性肉芽组织增生B2组与B1组相似,仅坏死略增加。
7.B1、R1、R2和B2组的C6胶质瘤细胞密度均数分别是715.7,633.9,355.6和760.6,R2组显著低于其他三组。肿瘤细胞密度与FDG、ACE PET/CT显像T/M呈正相关,与MET及CHO T/M没有相关性。
8.免疫组化结果：GLUT-1及CD98阳性细胞均是R2组明显低于B1和B2组；VEGF及HIF-1α阳性细胞,R1组显著升高,R2组明显降低；p53阳性细胞,R1组明显升高；Ki67LI及MVD均是R2组显著低于对照组；R1组及R2组TUNEL凋亡指数显著高于对照组。
9. RT-PCR结果：R2组4F2hcmRNA、LAT mRNA表达水平及VEGF mRNA均显著降低,低于其他三组；放疗后R1组及R2组HIF-1α mRNA明显升高；R1组p53mRNA表达水平升高。
10. Western blot结果：R2组GLUT-1及CD98蛋白水平显著下降；R1组VEGF及p53蛋白表达水平升高,显著高于对照组。
11. GLUT-1蛋白表达水平与FDGT/M呈明显正相关关系；
12.放疗前胶质瘤MET T/M与CD98蛋白表达量、Ki67LI、MVD存在明显正相关关系；放疗后肿瘤MET PET/CT显像可以反映肿瘤放射治疗后的急性乏氧水平；
13.对照组内Ki67LI、MVD是放疗前肿瘤CHO PET显像的主要影响因素,放射治疗后肿瘤对CHO的摄取程度与Ki67LI、p53及HIF-1α表达量没有明显相关关系。放疗后R1与R2组间,VEGF及MVD与C6胶质瘤CHO PET显像T/M存在明显正相关关系。
14. Ki67LI、MVD、VEGF、p53及HIF-1α表达量与各组C6胶质瘤ACE PET显像T/M均没有明显相关关系,表明ACE PET显像肿瘤对ACE摄取程度与Ki67LI、MVD、VEGF、p53及HIF-1α表达量没有明显的相关性,肿瘤ACE PET显像不能反映肿瘤细胞增殖水平、肿瘤内新生血管情况以及乏氧情况。
结论
1.18F-FDG、11C-MET和11C-CHO PET/CT在鉴别脑肿瘤复发和放射性坏死方面有较高的灵敏性、特异性和准确性；MET PET/CT在鉴别脑肿瘤复发和放射性坏死方面的准确性最高；FDG联合MET或CHO PET/CT,可提高脑肿瘤复发和坏死鉴别诊断的准确性。
2.大鼠异位C6/SD胶质瘤模型易于制作,成功率较高,适于形态和功能影像学研究。本研究显示,大鼠C6胶质瘤模型适于观察放疗前后的PET/CT显像变化,在放疗后1周即可利用PET/CT评价早期放疗疗效。
3.本研究显示,在评价大鼠异位C6胶质瘤早期放疗疗效方面11C-MET、11C-ACE、18F-FDGPET均较敏感；11C-CHO存在假阳性的可能；11C-ACE在C6胶质瘤放疗前、后不同时期PET/CT显像中的价值与11C-MET相比没有显著差异,优于11C-CHO。
4.肿瘤体积、细胞密度及葡萄糖转运体是胶质瘤FDG PET/CT显像的主要影响因素。
5.肿瘤细胞氨基酸转运载体表达数量、细胞增殖活性及血管生成是放疗前C6胶质瘤MET PET/CT显像的主要影响因素；放疗后C6胶质瘤MET PET/CT显像不能反映肿瘤增殖活性及血管生成情况；放疗后早期C6胶质瘤MET T/M与HIF-1α存在弱的负相关关系,在一定程度上MET PET/CT显像能反映肿瘤放射治疗后乏氧水平。
6.放疗前C6胶质瘤CHO PET显像主要受肿瘤增殖活性及血管生成情况影响,放疗后CHO PET显像肿瘤对CHO的摄取水平主要受血流灌注的影响。
7. ACE PET/CT显像中肿瘤摄取ACE的水平不受肿瘤体积、细胞增殖活性、肿瘤内新生血管、乏氧等情况的影响,肿瘤细胞密度对ACE PET/CT显像有轻度影响。
Objective Malignant gliomas are the most common primary brain tumor. Post-operative radiotherapy has been recommened as standard therapy for patients with malignant glioma. On routine follow-up MR images, the differentiation of recurrent tumor from radiation injury in subject previously resected and irradiated glioma is problematic, although both the lesions can be associated with more specific characteristics, such as the former with corpus callosum involvement or multiple enhancement. As a most widely used tracer,18F-flurdeoxyglucose positron emission tomography (18F-FDG PET) imaging is playing an increasingly important role in the diagnosis, grading, prognosis, response to the therapy, and differentiation recurrent from radiation injury of brain glioms. But FDG PET has some limits in clinical application. There are two parts in the study, including clinical and experimental researching of PET imaging in brain glioma and C6glioma model.
(1)The aim of the study is to investigate the usefulness of FDG PET/CT for differentiation of brain glioma necrosis and recurrence after radiotherapy, in comparison with "C-methionine (MET) and "C-choline (CHO).(2)To determine the accuracy of multiple tracers PET in evaluating radiotherapy of rat C6glioma model.
(3)The change of rat C6gliomas in the histopathology and molecular biology before and after radiotherapy was observed. To correlate the change with multiple radiotracers PET, using HE, Immunohistochemistry, RT-PCR and Western blot and test the affected mechanism of multiple radiotracers PET.
Materials and Methods (1)From Sep.2005to Sep.2009, thirty-eight patients with suspected brain gliomas recurrence after radiotherapy referred to our hospital were examined with CHO, MET, and FDG PET/CT and find39lesions. Twenty-four patients accepted MET and FDG PET/CT, fourteen patients accepted CHO and FDG PET/CT. The diagnosis of28patients was confirmed by histopathology after surgery or biopsy, whereas that of the other11patients was made by imaging or clinical follow (>6months). PET results were evaluated by visual and semiquantitative analysis.①For visual analysis, the positive diagnosis was made when the FDG accumulation of lesions was more obvious than the adjacent or contralateral normal white matter. On the contrary, the negative diagnosis was made.②For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal white matter (T/N) ratio were calculated. The PET results were compared with histopathology or clinical diagnosis. The sensitivity, specificity and accuracy of FDG and MET, CHO PET/CT for differentiation of brain glioma necrosis and recurrence were calculated. The T/WM of brain glioma necrosis and recurrence on FDG and MET, CHO PET/CT were compared.
(2)2.1The C6rat glioma cells were maintained in Dulbecco's modified Eagle medium (DMEM). The cells were cultured monolayerly at37℃in a5%CO2and100%humidity incubator. For injection, the cells were harvested at phase of growing logarithmically, washed3times with phosphate-buffered saline, and counted cells.
2.2One hundred and eighty-five male SD rats weighing180-200g and aged4-5weeks were used in this study. The rats were anesthetized with inhalation of aether. Then,1×108/ml cell suspensions were implanted subcutaneously into the right inguinal area.
2.3Two weeks after C6cells implanted, it was considered successful that the diameter of nodules in the right inguinal subcutaneous area was larger than1cm.2.4Radiation treatment:6MV X-ray produced by Siemens Primus accelerator was used to treat SD rats with tumor. The dose rate was2Gy/min and standard SSD (source to skin distance, SSD) radiation was used. The total dose of single fraction irradiation was12Gy. The radiation fields cover the tumor adding1.5cm margin and0.5cm thickness tissue equivalent was used.
2.5After C6glioma model successfully established, the rats were randomly classed into2groups:control group and radiotherapy group. The control group did not accept radiotherapy and was randomly classed into2groups:Bl, accepted PET/CT examination2weeks after C6cells implanted; B2, accepted PET/CT examination3weeks after C6cells implanted. The radiotherapy group was randomly classed into2groups:R1, accepted PET/CT examination24hours after radiotherapy; R2, accepted PET/CT examination1weeks after radiotherapy (3weeks after C6cells implanted). The every rat in all groups only accepted randomly one11C-tracer PET examination, and accepted FDG PET examination in the same day. 2.6PET was performed by use of a GE Discovery LS PET/CT scanner. The tail vein was used for administration of11C tracers and FDG11C tracers PET was performed5minutes after intravenously injection of0.2mCi radiotracers. FDG PET was performed2h after11C tracers'administration and1h after0.1mCi FDG administration. The data were transmitted to Xeleris workstation. CT, PET and PET-CT fusion images were obtained. The tumors SUVmax, size, and the SUVmean of contralateral muscle beside the spine were calculated. The T/M of tumors and muscle was calculated.
(3)3.1The experimental animals and PET examination were identical to Part Two.3.2The animals were euthanized after examination. The tumors were extirpated by surgery and divided into two groups. One part was fixed with10%formalin and embedded in paraffin. The other was preserved in the liquid nitrogen at-70℃.3.3The sections were stained with hematoxylin and eosin to assess the cellular density. The sections were immunostained for Glucose transporter1(GLUT1), CD98, VEGF, HIF-la, p53,microvessel density (MVD), Ki67LI. C6gliomas apoptosis before and after radiotherapy was assessed using Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL).3.4The expression of4F2hc, LAT, VEGF, p53and HIF-la mRNA were tested using RT-PCR.
3.5The expression of GLUT1, CD98, VEGF and p53protein was tested using Western blot.
3.6The parameters mentioned above were compared using ANOVA and correlated with PET T/M.
Results (1) There were28patients with recurrent tumors and11with radiation necrosis.①For visual analysis, the sensitivity, specificity and accuracy of FDG PET/CT for differentiation of brain glioma necrosis and recurrence were85.7%,81.8%and84.2%, respectively. MET PET/CT were94.4%,87.5%and96%, respectively. CHO PET/CT was90%,75%and86%, respectively.②For semiquantitative analysis, FDG_T/WM of brain glioma necrosis and recurrence were2.71±2.21,1.59±0.97,P=0.048; MET_T/WM of brain glioma necrosis and recurrence were4.25±1.88,1.48±0.81, P=0.001; CHO_T/WM of brain glioma necrosis and recurrence were15.33±13.35,7.44±1.77, P=0.038. The accuracy of combination FDG with MET or CHO PET/CT for differentiation of brain glioma necrosis and recurrence were96%and92.8%, respectively.(2)2.1Of the185rats,3did not have C6glioma, the rate of successful generation of a C6glioma was97.7%. But5rats died during radiotherapy or PET/CT examination.177rats were enrolled in this study at last.
2.2The mean size of tumors of B1, R1, R2and B2group were8.61±6.57cm3,7.80±7.31cm3,5.21±5.48cm3and8.88±6.16cm3, respectively. The difference of tumors size between R2and R1was not statistically significant (P=0.556). There was statistical significance between B1and B2(P=0.014, P=0.008).
2.3All rat C6gliomas accumulated radiotracers obviously but differently. The SUVmax of FDG, ACE, MET and CHO in B1group was10.81±5.65,3.63±0.75,.63±1.20and1.50±0.42. FDG SUVmax was higher than the other radiotracers (P=0.00). The T/M of FDG, ACE, MET and CHO in B1group was8.52±4.67,1.67±0.40,2.10±0.80and1.70±0.53. The FDG T/M higher than the other radiotracers (P=0.00).
The SUVmax of FDG, ACE, MET and CHO in R1group was7.91±5.50,4.12±3.26,3.05±0.86and0.67±0.39.FDG SUVmax was higher than the other radiotracers (P<0.05). CHO SUVmax was lower than MET and ACE (P<0.05). The T/M of FDG, ACE, MET and CHO in R1group was7.98±4.38,1.47±0.33,1.59±0.38and1.75±0.73. The FDG T/M was higher than the other radiotracers(P=.00)。
The SUVmax of FDG, ACE, MET and CHO in R2group was6.35±3.25,2.64±0.90,2.63±0.59and2.74±0.81. FDG SUVmax was higher than ACE, MET and CHO (P=0.00). The T/M of FDG, ACE, MET and CHO in R2group was5.06±3.21,1.32±0.34,1.40±0.32and2.36±0.93. FDG T/M was higher than ACE, MET and CHO (P=0.00). CHO T/M was higher than ACE and MET(P=0.01、P=0.00). The SUVmax of FDG, ACE, MET and CHO in B2group was10.05±3.20,2.64±0.68,2.86±0.76and2.14±0.51. FDG SUVmax was higher than the other radiotracers (P=0.00). The T/M of FDG, ACE, MET and CHO in B2group was8.17±4.28,1.62±0.34,1.61±0.44and1.81±0.54. The FDG T/M was higher than the other radiotracers (P=0.00). Among B1, R1, R2and B2, the FDG SUVmax and T/M of R2group were lower than B1and B2group (P<0.05). The CHO SUVmax of R1group was lower than the other3groups. The T/M of R2group was higher than the other3groups. The ACE SUVmax and T/M of R2was lower than B1and B2. The MET SUVmax of B1was higher than R2and B2, and the MET T/M of R2was lower than B1.2.4There was a positive correlation between FDG T/M and tumor size and cell density. No significant correlation was found between the other parameters and tumor size.
(3)3.1In B1, R1, R2and B2groups, the GLUT1expression was0.231±0.1,0.149±0.07,0.026±0.01,0.209±0.19, respectively. The CD98expression was0.29±0.05,0.20±0.15,0.06±0.01,0.26±0.07, respectively. The4F2hcmRNA expression was2.93±0.12,2.27±0.21,0.26±0.05,2.58±0.28, respectively. The LAT mRNA expression was2.67±0.31,2.14±0.29,0.39±0.05,2.45±0.23, respectively. The HIF-1α mRNA expression was3.13±0.21,0.95±0.45,0.61±0.34,2.63±0.56, respectively. The VEGF mRNA expression was1.25±0.04,1.15±0.12,0.46±0.06,1.15±0.24, respectively. The VEGF expression was0.29±0.12,0.17±0.06,0.04±0.01,0.26±0.14, respectively. The p53mRNA expression was0.96±0.21,3.84±0.67,1.31±0.23,1.50±0.45, respectively. The p53protein expression was0.041±0.02,0.242±0.10,0.084±0.03,0.057±0.01, respectively.
3.2FDG T/M positively correlated with GLUT1. There were no correlation between FDG T/M and p53, VEGF, and HIF-1α.
3.3MET T/M positively correlated with CD98, Ki67LI, and MVD before the radiotherapy of tumor.
3.4CHO T/M positively correlated with Ki67LI, and MVD before the radiotherapy of tumor.
3.5No correlation could be found between ACE T/M and VEGF, HIF-1α. p53, Ki67LI, MVD.
Conclusions
1. The sensitivity, specificity and accuracy of FDG and MET, CHO PET/CT for detection of brain gliomas recurrence were high. The false positive and negative also exit in FDG and CHO PET/CT for differentiation of brain glioma necrosis and recurrence. MET PET/CT was superior to FDG and CHO in differentiation between the recurrent and necrosis. FDG PET/CT combined with MET or CHO can evaluate the metabolism of brain gliomas in multiple aspects. Multiple tracers PET/CT can improve the accuracy of differentiation of brain glioma necrosis and recurrence.
2. Rat ectopic C6glioma model could be established easily, the successful rate was above90%. And the tumor grew rapidly and could be above2cm after2weeks. Rat C6glioma model could be used in morphologic and functional imaging study.
3.11C-MET,11C-ACE and18F-FDG PET could sensitively evaluate the effect of radiotherapy, but "C-CHO PET had some false positive.18F-FDG PET was superior to11C radiotracer PET in demonstrating the C6gliomas in the same group.11C-ACE PET was superior to11C-CHO.
4. Uptake of18F-FDG PET/CT significantly correlated with tumor size, cell density and GLUT-1.
5. Uptake of11C-MET PET/CT significantly correlated with tumor CD98, Ki67LI and MVD before the radiotherapy of tumor and no correlation with Ki67LI and MVD.
6. Uptake of " C-CHO PET/CT can reflect Ki67LI and MVD before the radiotherapy of tumor; Uptake of " C-CHO PET/CT correlated with tumor VEGF and MVD and could reflect tumor angiogenesis.
7."C-ACE PET/CT T/M could not reflect tumor angiogenesis, Ki67LI, HIF-1α; Uptake of ACE PET/CT correlated with tumor cell density. FDG, MET, CHO and ACE PET/CT could not reflect apoptosis of tumor.
二、动物实验部分：
1.C6细胞在高糖DMEM培养基(Dulbecco's modified Eagle's medium)中,37℃,5%CO2,饱和湿度条件下培养皿中单层培养。肿瘤细胞呈对数生长期时收集细胞悬液,调整细胞浓度至1×108/ml。
2.SD大鼠185只,雄性,4-5周龄,体重180-200mg。乙醚麻醉后,抽取细胞悬液0.2ml,种植于大鼠右侧腹股沟皮下。肿瘤细胞接种2周后,大鼠右侧腹股沟皮下处结节≥1cm时为肿瘤模型成功建立。模型成功后,随机分为2组,对照组和放射治疗组。
3.大鼠C6胶质瘤模型放射治疗：德国Siemens Primus直线加速器,6MV-X射线照射,剂量率2Gy/min,单次照射,总剂量12Gy。照射野为肿瘤边缘外放1.5cm,源皮距(source to skin distance, SSD)100cm。
4. PET/CT显像：对照组大鼠分为两组：B1组,接种C6细胞后2周即进行PET/CT显像；B2组,接种C6细胞后3周PET/CT显像。放疗组大鼠分为两组：R1组,放疗后48h内显像；R2组,放疗后1周显像(即接种C6细胞后3周)。B1,B2,R1,R2四组大鼠进行PET/CT显像时,每组内每只大鼠均只随机接受一种11C标记的示踪剂,并于同天行18F-FDG PET/CT显像。
5. PET/CT显像处理：图像数据传入Xeleris工作站,得到大鼠C6胶质瘤的CT、PET及PET/CT融合图像,测量肿瘤体积、SUVmax及T/M。测量肿瘤最大标准摄取值(maximal standardized uptake value, SUVmax)及对侧脊柱旁肌肉的平均标准摄取值(mean standardized uptake value, SUVmean),计算二者比值(tumor-to-muscle, T/M)。
6.标本处理：荷瘤大鼠完成全部PET检查后,无痛处死。取出肿瘤组织标本,立即分为两部分,一部分置入10%中性福尔马林溶液固定,石蜡包埋；另外一部分迅速液氮冷冻后-70℃保存。
7.病理学方法：石蜡切片HE染色,计数细胞密度,免疫组化染色评价葡萄糖转运蛋白1(Glucose transporter1， GLUT1)、 CD98.血管内皮生长因子(vascular endothelial factor, VEGF)、缺氧诱导因子-1α(hypoxia induible factor-1α, HIF-1α)、p53、微血管密度(microvessel density, MVD)、Ki67标记指数(Ki67labeling index, Ki67LI), TUNEL原位凋亡检测法(Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, TUNEL)。
8.分子生物学方法：用RT-PCR方法检测4F2hc、LAT1、VEGF、p53及HIF-1α mRNA表达水平。用Western blot法检测GLUT1、CD98、VEGF及p53蛋白表达水平。对上述实验室指标组间差异进行单因素方差分析,并将其与PET显像T/M做相关性分析。
结果一、临床部分：39个病变中肿瘤复发为28个,放射性损伤11个。视觉分析：FDG PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为85.7%、81.8%和84.2%; MET PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为94.4%、87.5%和96%; CHO PET/CT鉴别脑肿瘤放疗后复发和坏死的灵敏度、特异度及准确度分别为90%、75%和86%。半定量分析：在脑肿瘤复发和放射性损伤中FDG T/WM分别是2.53±1.11,1.40±0.57,二者有统计学差异(P=0.003)；在脑肿瘤复发和放射性损伤中MET T/WM分别是4.44±1.16,1.57±0.73,二者有明显差异(P=0.000)；在脑肿瘤复发和放射性损伤中CHO T/WM分别为14.70±8.60、7.69±1.89,P=0.033,有明显的统计学差异。联合MET与FDG PET/CT显像,对脑肿瘤放疗后复发和坏死的准确度可达到96%；联合CHO与FDG PET/CT显像,对脑肿瘤放疗后复发和坏死的准确度可提高到92.8%。
二、动物实验部分：
1.185只实验大鼠,3只未成瘤,种瘤成功率为97.7%。成瘤鼠中5只在放疗过程中或PET/CT显像时因麻醉意外死亡,最后共有177只实验鼠(占95.7%)纳入本研究。
2.B1、R1、R2及B2组各组肿瘤的大小分别是8.61±6.57cm3、7.80±7.31cm3、5.21±5.48cm3及8.88±6.16cm3。R2组与B1组、B2组间肿瘤大小差异具有统计学意义(p=0.014,p=0.008)。
3.各组大鼠C6胶质瘤均有不同程度的示踪剂摄取,B1组,FDG SUVmax及FDG T/M均明显高于MET、CHO及ACE(P<0.05)；R1组,FDG SUVmax明显高于ACE、MET和CHO (P<0.05), CHOSUVmax明显低于MET和ACE (P<0.05), FDG T/M明显高于其他三种示踪剂(P<0.05)；R2组,FDG SUVmax明显高于ACE、MET和CHO(P<0.05),FDGT/M明显高于ACE、MET和CHO(P<0.05),CHO T/M高于MET和ACE(P=0.01、P=0.00)。B2组,FDG SUVmax及FDGT/M均高于其他三种示踪剂(P<0.05)。
4.同一示踪剂的SUVmax、T/M的组间比较结果：FDG SUVmax及T/M,均是R2组低于B1、B2组(P<0.05); CHO SUVmax R1组低于其他三组,T/M R2组高于其他三组；ACE SUVmax、T/M,R2组低于B1、B2组;MET SUVmax B1组高于R2和B2组,T/M R2组低于B1组。
5.C6胶质瘤FDG T/M与肿瘤体积之间存在正相关关系(r=0.592,P=0.000),其余各参数与肿瘤体积之间不具有相关性。
6.HE染色：B1组C6细胞异型性明显,有病理核分裂像；R1组C6细胞活性欠佳,可见炎细胞浸润；R2组细胞大量坏死崩解,伴有反应性肉芽组织增生B2组与B1组相似,仅坏死略增加。
7.B1、R1、R2和B2组的C6胶质瘤细胞密度均数分别是715.7,633.9,355.6和760.6,R2组显著低于其他三组。肿瘤细胞密度与FDG、ACE PET/CT显像T/M呈正相关,与MET及CHO T/M没有相关性。
8.免疫组化结果：GLUT-1及CD98阳性细胞均是R2组明显低于B1和B2组；VEGF及HIF-1α阳性细胞,R1组显著升高,R2组明显降低；p53阳性细胞,R1组明显升高；Ki67LI及MVD均是R2组显著低于对照组；R1组及R2组TUNEL凋亡指数显著高于对照组。
9. RT-PCR结果：R2组4F2hcmRNA、LAT mRNA表达水平及VEGF mRNA均显著降低,低于其他三组；放疗后R1组及R2组HIF-1α mRNA明显升高；R1组p53mRNA表达水平升高。
10. Western blot结果：R2组GLUT-1及CD98蛋白水平显著下降；R1组VEGF及p53蛋白表达水平升高,显著高于对照组。
11. GLUT-1蛋白表达水平与FDGT/M呈明显正相关关系；
12.放疗前胶质瘤MET T/M与CD98蛋白表达量、Ki67LI、MVD存在明显正相关关系；放疗后肿瘤MET PET/CT显像可以反映肿瘤放射治疗后的急性乏氧水平；
13.对照组内Ki67LI、MVD是放疗前肿瘤CHO PET显像的主要影响因素,放射治疗后肿瘤对CHO的摄取程度与Ki67LI、p53及HIF-1α表达量没有明显相关关系。放疗后R1与R2组间,VEGF及MVD与C6胶质瘤CHO PET显像T/M存在明显正相关关系。
14. Ki67LI、MVD、VEGF、p53及HIF-1α表达量与各组C6胶质瘤ACE PET显像T/M均没有明显相关关系,表明ACE PET显像肿瘤对ACE摄取程度与Ki67LI、MVD、VEGF、p53及HIF-1α表达量没有明显的相关性,肿瘤ACE PET显像不能反映肿瘤细胞增殖水平、肿瘤内新生血管情况以及乏氧情况。
结论
1.18F-FDG、11C-MET和11C-CHO PET/CT在鉴别脑肿瘤复发和放射性坏死方面有较高的灵敏性、特异性和准确性；MET PET/CT在鉴别脑肿瘤复发和放射性坏死方面的准确性最高；FDG联合MET或CHO PET/CT,可提高脑肿瘤复发和坏死鉴别诊断的准确性。
2.大鼠异位C6/SD胶质瘤模型易于制作,成功率较高,适于形态和功能影像学研究。本研究显示,大鼠C6胶质瘤模型适于观察放疗前后的PET/CT显像变化,在放疗后1周即可利用PET/CT评价早期放疗疗效。
3.本研究显示,在评价大鼠异位C6胶质瘤早期放疗疗效方面11C-MET、11C-ACE、18F-FDGPET均较敏感；11C-CHO存在假阳性的可能；11C-ACE在C6胶质瘤放疗前、后不同时期PET/CT显像中的价值与11C-MET相比没有显著差异,优于11C-CHO。
4.肿瘤体积、细胞密度及葡萄糖转运体是胶质瘤FDG PET/CT显像的主要影响因素。
5.肿瘤细胞氨基酸转运载体表达数量、细胞增殖活性及血管生成是放疗前C6胶质瘤MET PET/CT显像的主要影响因素；放疗后C6胶质瘤MET PET/CT显像不能反映肿瘤增殖活性及血管生成情况；放疗后早期C6胶质瘤MET T/M与HIF-1α存在弱的负相关关系,在一定程度上MET PET/CT显像能反映肿瘤放射治疗后乏氧水平。
6.放疗前C6胶质瘤CHO PET显像主要受肿瘤增殖活性及血管生成情况影响,放疗后CHO PET显像肿瘤对CHO的摄取水平主要受血流灌注的影响。
7. ACE PET/CT显像中肿瘤摄取ACE的水平不受肿瘤体积、细胞增殖活性、肿瘤内新生血管、乏氧等情况的影响,肿瘤细胞密度对ACE PET/CT显像有轻度影响。
Objective Malignant gliomas are the most common primary brain tumor. Post-operative radiotherapy has been recommened as standard therapy for patients with malignant glioma. On routine follow-up MR images, the differentiation of recurrent tumor from radiation injury in subject previously resected and irradiated glioma is problematic, although both the lesions can be associated with more specific characteristics, such as the former with corpus callosum involvement or multiple enhancement. As a most widely used tracer,18F-flurdeoxyglucose positron emission tomography (18F-FDG PET) imaging is playing an increasingly important role in the diagnosis, grading, prognosis, response to the therapy, and differentiation recurrent from radiation injury of brain glioms. But FDG PET has some limits in clinical application. There are two parts in the study, including clinical and experimental researching of PET imaging in brain glioma and C6glioma model.
(1)The aim of the study is to investigate the usefulness of FDG PET/CT for differentiation of brain glioma necrosis and recurrence after radiotherapy, in comparison with "C-methionine (MET) and "C-choline (CHO).(2)To determine the accuracy of multiple tracers PET in evaluating radiotherapy of rat C6glioma model.
(3)The change of rat C6gliomas in the histopathology and molecular biology before and after radiotherapy was observed. To correlate the change with multiple radiotracers PET, using HE, Immunohistochemistry, RT-PCR and Western blot and test the affected mechanism of multiple radiotracers PET.
Materials and Methods (1)From Sep.2005to Sep.2009, thirty-eight patients with suspected brain gliomas recurrence after radiotherapy referred to our hospital were examined with CHO, MET, and FDG PET/CT and find39lesions. Twenty-four patients accepted MET and FDG PET/CT, fourteen patients accepted CHO and FDG PET/CT. The diagnosis of28patients was confirmed by histopathology after surgery or biopsy, whereas that of the other11patients was made by imaging or clinical follow (>6months). PET results were evaluated by visual and semiquantitative analysis.①For visual analysis, the positive diagnosis was made when the FDG accumulation of lesions was more obvious than the adjacent or contralateral normal white matter. On the contrary, the negative diagnosis was made.②For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal white matter (T/N) ratio were calculated. The PET results were compared with histopathology or clinical diagnosis. The sensitivity, specificity and accuracy of FDG and MET, CHO PET/CT for differentiation of brain glioma necrosis and recurrence were calculated. The T/WM of brain glioma necrosis and recurrence on FDG and MET, CHO PET/CT were compared.
(2)2.1The C6rat glioma cells were maintained in Dulbecco's modified Eagle medium (DMEM). The cells were cultured monolayerly at37℃in a5%CO2and100%humidity incubator. For injection, the cells were harvested at phase of growing logarithmically, washed3times with phosphate-buffered saline, and counted cells.
2.2One hundred and eighty-five male SD rats weighing180-200g and aged4-5weeks were used in this study. The rats were anesthetized with inhalation of aether. Then,1×108/ml cell suspensions were implanted subcutaneously into the right inguinal area.
2.3Two weeks after C6cells implanted, it was considered successful that the diameter of nodules in the right inguinal subcutaneous area was larger than1cm.2.4Radiation treatment:6MV X-ray produced by Siemens Primus accelerator was used to treat SD rats with tumor. The dose rate was2Gy/min and standard SSD (source to skin distance, SSD) radiation was used. The total dose of single fraction irradiation was12Gy. The radiation fields cover the tumor adding1.5cm margin and0.5cm thickness tissue equivalent was used.
2.5After C6glioma model successfully established, the rats were randomly classed into2groups:control group and radiotherapy group. The control group did not accept radiotherapy and was randomly classed into2groups:Bl, accepted PET/CT examination2weeks after C6cells implanted; B2, accepted PET/CT examination3weeks after C6cells implanted. The radiotherapy group was randomly classed into2groups:R1, accepted PET/CT examination24hours after radiotherapy; R2, accepted PET/CT examination1weeks after radiotherapy (3weeks after C6cells implanted). The every rat in all groups only accepted randomly one11C-tracer PET examination, and accepted FDG PET examination in the same day. 2.6PET was performed by use of a GE Discovery LS PET/CT scanner. The tail vein was used for administration of11C tracers and FDG11C tracers PET was performed5minutes after intravenously injection of0.2mCi radiotracers. FDG PET was performed2h after11C tracers'administration and1h after0.1mCi FDG administration. The data were transmitted to Xeleris workstation. CT, PET and PET-CT fusion images were obtained. The tumors SUVmax, size, and the SUVmean of contralateral muscle beside the spine were calculated. The T/M of tumors and muscle was calculated.
(3)3.1The experimental animals and PET examination were identical to Part Two.3.2The animals were euthanized after examination. The tumors were extirpated by surgery and divided into two groups. One part was fixed with10%formalin and embedded in paraffin. The other was preserved in the liquid nitrogen at-70℃.3.3The sections were stained with hematoxylin and eosin to assess the cellular density. The sections were immunostained for Glucose transporter1(GLUT1), CD98, VEGF, HIF-la, p53,microvessel density (MVD), Ki67LI. C6gliomas apoptosis before and after radiotherapy was assessed using Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL).3.4The expression of4F2hc, LAT, VEGF, p53and HIF-la mRNA were tested using RT-PCR.
3.5The expression of GLUT1, CD98, VEGF and p53protein was tested using Western blot.
3.6The parameters mentioned above were compared using ANOVA and correlated with PET T/M.
Results (1) There were28patients with recurrent tumors and11with radiation necrosis.①For visual analysis, the sensitivity, specificity and accuracy of FDG PET/CT for differentiation of brain glioma necrosis and recurrence were85.7%,81.8%and84.2%, respectively. MET PET/CT were94.4%,87.5%and96%, respectively. CHO PET/CT was90%,75%and86%, respectively.②For semiquantitative analysis, FDG_T/WM of brain glioma necrosis and recurrence were2.71±2.21,1.59±0.97,P=0.048; MET_T/WM of brain glioma necrosis and recurrence were4.25±1.88,1.48±0.81, P=0.001; CHO_T/WM of brain glioma necrosis and recurrence were15.33±13.35,7.44±1.77, P=0.038. The accuracy of combination FDG with MET or CHO PET/CT for differentiation of brain glioma necrosis and recurrence were96%and92.8%, respectively.(2)2.1Of the185rats,3did not have C6glioma, the rate of successful generation of a C6glioma was97.7%. But5rats died during radiotherapy or PET/CT examination.177rats were enrolled in this study at last.
2.2The mean size of tumors of B1, R1, R2and B2group were8.61±6.57cm3,7.80±7.31cm3,5.21±5.48cm3and8.88±6.16cm3, respectively. The difference of tumors size between R2and R1was not statistically significant (P=0.556). There was statistical significance between B1and B2(P=0.014, P=0.008).
2.3All rat C6gliomas accumulated radiotracers obviously but differently. The SUVmax of FDG, ACE, MET and CHO in B1group was10.81±5.65,3.63±0.75,.63±1.20and1.50±0.42. FDG SUVmax was higher than the other radiotracers (P=0.00). The T/M of FDG, ACE, MET and CHO in B1group was8.52±4.67,1.67±0.40,2.10±0.80and1.70±0.53. The FDG T/M higher than the other radiotracers (P=0.00).
The SUVmax of FDG, ACE, MET and CHO in R1group was7.91±5.50,4.12±3.26,3.05±0.86and0.67±0.39.FDG SUVmax was higher than the other radiotracers (P<0.05). CHO SUVmax was lower than MET and ACE (P<0.05). The T/M of FDG, ACE, MET and CHO in R1group was7.98±4.38,1.47±0.33,1.59±0.38and1.75±0.73. The FDG T/M was higher than the other radiotracers(P=.00)。
The SUVmax of FDG, ACE, MET and CHO in R2group was6.35±3.25,2.64±0.90,2.63±0.59and2.74±0.81. FDG SUVmax was higher than ACE, MET and CHO (P=0.00). The T/M of FDG, ACE, MET and CHO in R2group was5.06±3.21,1.32±0.34,1.40±0.32and2.36±0.93. FDG T/M was higher than ACE, MET and CHO (P=0.00). CHO T/M was higher than ACE and MET(P=0.01、P=0.00). The SUVmax of FDG, ACE, MET and CHO in B2group was10.05±3.20,2.64±0.68,2.86±0.76and2.14±0.51. FDG SUVmax was higher than the other radiotracers (P=0.00). The T/M of FDG, ACE, MET and CHO in B2group was8.17±4.28,1.62±0.34,1.61±0.44and1.81±0.54. The FDG T/M was higher than the other radiotracers (P=0.00). Among B1, R1, R2and B2, the FDG SUVmax and T/M of R2group were lower than B1and B2group (P<0.05). The CHO SUVmax of R1group was lower than the other3groups. The T/M of R2group was higher than the other3groups. The ACE SUVmax and T/M of R2was lower than B1and B2. The MET SUVmax of B1was higher than R2and B2, and the MET T/M of R2was lower than B1.2.4There was a positive correlation between FDG T/M and tumor size and cell density. No significant correlation was found between the other parameters and tumor size.
(3)3.1In B1, R1, R2and B2groups, the GLUT1expression was0.231±0.1,0.149±0.07,0.026±0.01,0.209±0.19, respectively. The CD98expression was0.29±0.05,0.20±0.15,0.06±0.01,0.26±0.07, respectively. The4F2hcmRNA expression was2.93±0.12,2.27±0.21,0.26±0.05,2.58±0.28, respectively. The LAT mRNA expression was2.67±0.31,2.14±0.29,0.39±0.05,2.45±0.23, respectively. The HIF-1α mRNA expression was3.13±0.21,0.95±0.45,0.61±0.34,2.63±0.56, respectively. The VEGF mRNA expression was1.25±0.04,1.15±0.12,0.46±0.06,1.15±0.24, respectively. The VEGF expression was0.29±0.12,0.17±0.06,0.04±0.01,0.26±0.14, respectively. The p53mRNA expression was0.96±0.21,3.84±0.67,1.31±0.23,1.50±0.45, respectively. The p53protein expression was0.041±0.02,0.242±0.10,0.084±0.03,0.057±0.01, respectively.
3.2FDG T/M positively correlated with GLUT1. There were no correlation between FDG T/M and p53, VEGF, and HIF-1α.
3.3MET T/M positively correlated with CD98, Ki67LI, and MVD before the radiotherapy of tumor.
3.4CHO T/M positively correlated with Ki67LI, and MVD before the radiotherapy of tumor.
3.5No correlation could be found between ACE T/M and VEGF, HIF-1α. p53, Ki67LI, MVD.
Conclusions
1. The sensitivity, specificity and accuracy of FDG and MET, CHO PET/CT for detection of brain gliomas recurrence were high. The false positive and negative also exit in FDG and CHO PET/CT for differentiation of brain glioma necrosis and recurrence. MET PET/CT was superior to FDG and CHO in differentiation between the recurrent and necrosis. FDG PET/CT combined with MET or CHO can evaluate the metabolism of brain gliomas in multiple aspects. Multiple tracers PET/CT can improve the accuracy of differentiation of brain glioma necrosis and recurrence.
2. Rat ectopic C6glioma model could be established easily, the successful rate was above90%. And the tumor grew rapidly and could be above2cm after2weeks. Rat C6glioma model could be used in morphologic and functional imaging study.
3.11C-MET,11C-ACE and18F-FDG PET could sensitively evaluate the effect of radiotherapy, but "C-CHO PET had some false positive.18F-FDG PET was superior to11C radiotracer PET in demonstrating the C6gliomas in the same group.11C-ACE PET was superior to11C-CHO.
4. Uptake of18F-FDG PET/CT significantly correlated with tumor size, cell density and GLUT-1.
5. Uptake of11C-MET PET/CT significantly correlated with tumor CD98, Ki67LI and MVD before the radiotherapy of tumor and no correlation with Ki67LI and MVD.
6. Uptake of " C-CHO PET/CT can reflect Ki67LI and MVD before the radiotherapy of tumor; Uptake of " C-CHO PET/CT correlated with tumor VEGF and MVD and could reflect tumor angiogenesis.
7."C-ACE PET/CT T/M could not reflect tumor angiogenesis, Ki67LI, HIF-1α; Uptake of ACE PET/CT correlated with tumor cell density. FDG, MET, CHO and ACE PET/CT could not reflect apoptosis of tumor.
引文
[1]Buchpiguel CA, Alavi JB, Alavi A, et al. PET versus SPECT in distinguishing radiation necrosis from tumor recurrence in the brain [J]. J Nucl Med,1995, 36(1):159-164.
[2]Meyer PT, Schreckenberger M, Spetzger U, et al. Comparison of visual and ROI-based brain tumor grading using 18F-FDG PET:ROC analysises [J]. Eur J Nucl Med,2000,28(2):165-174.
[3]Chen W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[4]Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury [J]. J Nucl Med,2000,41(11):1861-1867.
[5]Tsuyuguchi N, Sunada I, Iwai Y, et al. Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery:is a differential diagnosis possible? [J] J Neurosurg,2003, 98(5):1056-1064.
[6]Braga FJHN, Flamen P, Van Calenbergn F. 11C-methionine (MET) and 18F-FDG PET for the evaluation of suspected recurrent brain tumours (SRBT) [J]. Eur J Nucl Med,2000,27(8):1145.
[7]Ogawa T, Inugami A, Hatazawa J, et al. Clinical positron emission tomography for brain tumors:comparison of fludeoxyglucose F18 and L-methyl-"C-methionine[J]. AJNR,1996,17(2):345-353.
[8]DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers [J]. J Nucl Med,2001, 42(12):1805-1814.
[9]Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET:comparison with 18F-FDG [J]. J Nucl Med,2005,46(6): 945-952.
[10]Hatakeyama T, Kawai N, Nishiyama Y, et al. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET [J]. Eur J Nucl Med Imaging,2008, 35(6):2009-2017.
[11]Pan MH, Huang SC, Liao YP, et al. FLT-PET Imaging of Radiation Responses in Murine Tumors [J]. Mol Imaging Biol,2008,10(6):325-334.
[12]Murayama C, Harada N, Kakiuchi T, er al. Evaluation of D-18F-FMT,18F-FDG, L-"C-MET, and 18F-FLT for monitor response of tumors to radiotherapy [J]. J Nucl Med,2009,50(2):290-295.
[13]Tsuchida T, Takeuchi H, Okazawa H, et al. Grading of brain glioma with 1-11C-acetate PET:comparison with 18F-FDG PET [J]. Nucl Med Biol,2008, 35(2):171-176.
[14]Liu RS, Chang CP, Chu LS, et al. PET imaging of brain astrocytoma with-11C acetate [J]. Eur J Nucl Med Mol Imaging,2006,33(4):420-7.
[15]Yamamoto Y, Nishiyarna Y, Kimura N, et al. "C-Acetate PET in the Evaluation of Brain Glioma:Comparison with "C-Methionine and 18F-FDG-PET [J]. Mol imaging Biol,2008,10(5):281-287.
[16]Van WA, Cobben DC, Suurmeijer AJ, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model [J]. J Nucl Med, 2004,45(4):695-700.
[17]Klein LJ, Visser FC, Knaapen P, et al. Carbon-11 acetate as a tracer of myocardial oxygen consumption [J]. Eur J Nucl Med,2001,28(5):651-668.
[18]Vavere AL, Kridel SJ, Wheeler FB, et al. 1-11C-Acetate as a PET Radiopbarmaceutical for Imaging Fatty Acid Synthase Expression in Prostate Cancer[J]. J Nucl Med,2008,49(2):327-334.
[19]Park JW, Kim JH, Kim SK, et al. A prospective evaluation of 18F-FDG and "C-Acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma [J]. J Nucl Med,2008,49(12):1912-1921.
[20]Ponde DE, Dence CS, Oyama N, et al. F-fluoroacetate:a potential acetate analog for prostate tumor imaging-in vivo evaluation of F-fluoroacetate versus 11C-acetate [J]. J Nucl Med,2007,48(3):420-428.
[21]Yoshii Y, Waki A, Furukawa T, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase:implications for the mechanism of acetate PET [J]. Nucl Med Biol,2009,36(7):771-777.
[22]Wyss MT, Weber B, Treyer V, et al. Stimulation-induced increases of astrocytic oxidative metabolism in rats and humans investigated with 1-11C-acetate [J]. Journal of Cerebral Blood Flow & Metabolism,2009,29(1):44-56.
[23]Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors [J]. Neuroimag Clin N Am,2003(4),13:717-739.
[24]Nanni C, Rubello D, Al-Nahhas A, et al. Clinical PET in oncology:not only FDG [J]. Nucl Med Commun,2006,27(9):685-688.
[25]Fei BW, Wang HS, Wu CY, et al. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy [J]. J Nucl Med,2010,51(1):130-138.
[26]Kato T, Shinoda J, Nakayama N, et al. Metabolic Assessment of Gliomas Using 11C-Methionine, [18F] Fluorodeoxyglucose, and 11C-Choline Positron-Emission Tomography [J].Am J Neuroradiol,2008,29(6):1176-1182.
[27]王建交,李青松,詹奇,等.大鼠C6胶质瘤模型构建及生长特性的研究[J].中国康复理论与实践,2009,15(8)：742-745.
[28]Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology:the C6,9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas [J]. J Neurooncol,2009, 94(4):299-312.
[29]李明,冯华,李飞,等.大鼠C6脑胶质瘤模型的病理特征与MRI的观察[J].中华神经外科杂志,2005,21(5)：278-282.
[30]林健,王伟民,徐如祥,等9L/Fischer344与C6/Wistar两种大鼠脑胶质瘤模型的比较研究[J].中华神经医学杂志,2005,49(5)：445448.
[31]Braganhol E, Huppes D, Bernardi A, et al. A comparative study of ectonucleotidase and P2 receptor mRNA profiles in C6 cell line cultures and C6 ex vivo glioma model [J]. Cell Tissue Res,2009,335(11):331-340.
[32]Lee JW, Kang KW, Park KS, et al.18F-FDG PET in the assessment of tumor grade and prediction of tumor recurrence in intracranial meningioma [J]. Eur J Nucl Med Imaging,2009,36(8):1574-1582.
[33]Shinoura N, Nishijima M, Hara T, et al. Brain tumor:detection with C-11 choline PET [J]. Radiology,1997,202(2):497-503.
[34]Hara T, Kosaka N, Suzuki T, et al. Uptake rates of 18F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis:a positron emission tomography study [J]. Chest,2003,124(3):893-901.
[35]Liu Q, Peng ZM, Liu QW, et al.The role of "C-choline positron emission tomography computed tomography and video mediastinoscopy in the evaluation of diseases of middle mediastinum [J]. Chin Med J,2006,119(8):634-639.
[36]Tian M, Zhang H, Oriuchi N, et al. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors [J]. Eur J Nucl Med Mol Imaging,2004,31(8):1064-1072.
[37]Shiraki N, Hara M, Ogino H, et al. False-positive and true-negative hilar and mediastinal lymph nodes on FDG-PET-radiologicalpathological correlation [J]. Ann Nucl Med,2004,18(1):23-28.
[38]Gulyas B, Nyary I, Borbely K. FDG, MET or CHO? The quest for the optimal PET tracer for glioma imaging continues [J]. Nature Clinical Practice Neurology, 2008,4(9):470-471.
[39]Wyss MT, Spaeth N, Biollaz G, et al. Uptake of 18F-Fluorocholine,18F-FET, and FDG in C6 gliomas and correlation with 131I-SIP(L19), a marker of angiogenesis [J]. J Nucl Med,2007,48(4):608-614.
[40]Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic Accuracy of 11C-Methionine PET for Differentiation of Recurrent Brain Tumors from radiation necrosis after radiotherapy [J]. J Nucl Med,2008,49(5):694-699.
[41]Okubo S, Zhen HN, Kawai N, et al. Correlation of L-methyl-11C-methionine(MET) uptake with L-type amino acid transporter 1 in human gliomas [J]. J Neurooncol,2010,90(1):117-125.
[42]Kanai Y, Segawa H, Miyamoto K, et al. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98) [J]. J Biol Chem,1998,273(37):23629-23632.
[43]Nawashiro H, Otani N, Uozumi Y, et al. High expression of L-type amino acid transporter 1 in infiltrating glioma cells [J]. Brain Tumor Pathol,2005, 22(8):89-91.
[44]王全师,吴湖炳,王明芳,等.11C-蛋氨酸PET/CT显像在脑胶质瘤中的初步应用[J].中华核医学杂志,2005,25(5)：286-288.
[45]蔡莉,高硕,李彦生,等18F-FDG与11C-MET PET显像在神经上皮性肿瘤 术前分级中的价值及与Ki67相关性的比较[J].中华核医学杂志,2006,26(1)：8-12.
[46]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.
[47]Brown RS, Leung JY, Kison PV, et al. Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer [J]. J Nucl Med,1999, 40(4):556-565.
[48]Chung JK, Lee YJ, Kim C, et al. Mechanism related to [18F]fluorodeoxyglucose uptake of human colon cancers transplanted in nude mice [J]. J Nucl Med,1999, 40(2):339-346.
[49]李方成,余进,陶宗玉,等.不同速率生长的胶质瘤细胞的葡萄糖代谢状态研究[J].中华实验外科杂志,2004,21(3)：365-366.
[50]Nagamatsu S, Nakamihi Y, Inoue N, et al. Rat C6 glioma cell growth is related to glucose transport and metabolism. [J]. Biochem J,1996,319(part 2):477-482
[51]Maher F, Vannucci SJ, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glioma [J]. Glia,1997,21(2)2-21
[52]Campbell WA, Sah DE, Medina MM, et al. TA1/LAT1-1/CD98 light chain and system L activity, but not 4f2/CD98 heavy chain, respond to arginine availability in rat hepatic cells [J]. J Biolog Chem,2000,275(8):5347-5354
[53]Okamoto Y, Sakata M, Ogura K, et al. Expression and regulation of 4F2hc and hLAT1 in human trophoblasts [J]. Am J Physiol Cell Physiol,2002, 282(1):C196-C204.
[54]Kracht LW, Friese M, Herholz K, et al. Mehtyl-[11C]-1-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma [J]. Eur J Nucl Med Mol Imaging,2003,30(6):868-873.
[55]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with18F-FDG uptake and Prognostic impact in lung adenocarcinomas [J]. J Nucl Med,2006, 47(3):419-425.
[56]Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat:implications for separation of radiation necrosis from tumor recurrence [J]. J Nucl Med,2004,45(11):1931-1938.
[57]Lund EL, Hog A, Olsen MW, et al. Differential regulation of VEGF, HIF-1α and angiopoietin-1,-2 and-4 by hypoxia and ionizing radiation in human glioblastoma [J]. Int J Cancer,2004,108(6):833-838.
[58]Semenza GL. HIF-1:Mediator of physiological and pathophysiological responses to hypoxia [J]. Appl Physiol,2000,88(4):1474-1480.
[59]关丽明,赵明芳,徐克,等.大鼠C6脑胶质瘤VEGF,MMP-2,MMP-9表达与其MRI相关性的实验研究[J].中国临床医学影像杂志,2006,17(6)：311-313.
[60]蔡莉,张川,李彦生,等.人脑胶质瘤18F-FDG摄取与乏氧诱导因子-1α表达及微血管密度的相关性[J].中华核医学杂志,2010,30(1)：10-14.
[61]Kaur B, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible factor pathway in glioma growth and angiogenesis [J]. Neuro Oncol,2005, 7(2):134-53.
[62]Miles KA, Williams RE. Warburg revisited:imaging tumour blood flow and metabolism [J]. Cancer Imaging,2008,8(3):81-86.
[63]Zhao SJ, Kuge Y, Mochizuki T, et al. Biologic correlates of intra-tumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-Ⅱ in experimental tumor[J]. J Nucl Med,2005, 46(4):675-682.
[64]Kudo T, Ueda M, Kuge Y, et al. Imaging of HIF-1-Active Tumor Hypoxia using a protein effectively delivered to and specifically stabilized in HIF-1-active tumor cells [J]. J Nucl Med,2009,50(6):942-949.
[65]Okada J, Yoshikawa k, Itami M, et al. Positron emission tomography using fluorine-8-fluorodeoxyglucose in malignant lymphoma:a comparison with proliferative activity [J]. J Nucl Med,1992,33(3):325-329.
[66]Buck AC, Schirrmeister HH, Guhlmann CA, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis:does in vivo FDG uptake correlate with proliferative activity? [J] J Nucl Med,2001,42(5):721-725.
[67]Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C] choline does not correlate with cell proliferation in human prostate cancer [J]. Eur J Nucl Med Mol Imaging,2005,32(6):668-673.
[68]Mameda M, Higashi T, Kitaichi M, et al.[18F]FDG Uptake and PCNA, Glut-1, and Hexokinase-Ⅱ Expressions in Cancers and Inflammatory Lesions of the Lung [J]. Neoplasia,2005,7(4):369-379.
[69]Al-Saeedi F, Welch AE, Smith TA. [methyl-3H]Choline incorporation into MCF7 tumour cells:correlation with proliferation [J]. Eur J Nucl Med Mol Imaging,2005,32(6):660-667.
[70]赵庆秋,赵文清,周立霞,等.大鼠脑胶质瘤伽玛刀治疗对细胞凋亡和Caspase-3-. Fas表达的影响[J].中华放射医学与防护杂志,2003,23(4)：282-283.
[71]Hustinx R, Pourdehnad M, Kaschten B,et al. PET imaging for differentiating recurrent brain tumor from radiation necrosis [J]. Radiol Clin North Am,2005, 43(l):35-47.
[72]Marik J, Ogasawara A, McNulty MB, et al. PET of glial metabolism using 2-18F-Fluoroacetate [J]. J Nucl Med,2009,50(6):982-990.
[1].Mullins ME, Barest GD, Schaefer PW, et al. Radiation necrosis versus glioma recurrence:conventional MR imaging clues to diagnosis [J]. Am J Neuroradiol, 2005,26(8):1967-1972.
[2]Barajas RF, Chang JS, Segal MR, et al. Differentiation of Recurrent Glioblastoma Multiforme from Radiation Necrosis after External Beam Radiation Therapy with Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging [J]. Radiology,2009,253(11):486-498.
[3]Langleben DD, Segall GM.PET in differentiation of recurrent brain tumor from radiation injury [J]. J Nucl Med,2000,41(11):1861-1867.
[4]Braga FJHN, Flamen P, Van Calenbergn F. 11C-methionine (MET) and 18F-FDG PET for the evaluation of suspected recurrent brain tumours(SRBT)[J]. Eur J Nucl Med,2000,27(8):1145.
[5]Chao ST, Suh JH, Raja S, et al. The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereolaclic radiosurgery [J]. Int J Cancer,2001,96(3):191-197.
[6]Chen W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[7]Ohtani T, Kurihara H, Ishiguchi S, et al. Brain tumour imaging with carbon-11 choline:comparison with FDG PET and gadolinium-enhanced MR imaging [J]. Eur J Nucl Med,2001,28(11):1664-1670.
[8]Murayama C, Harada N, Kakiuchi T, er al. Evaluation of D-18F-FMT,18F-FDG, L-11C-MET, and 18F-FLT for monitor response of tumors to radiotherapy [J]. J Nucl Med,2009,50(2):290-295.
[9]Kato T, Shinoda J, Nakayama N, et al. Metabolic Assessment of Gliomas Using 11C-Melhionine, [18F] Fluorodeoxyglucose, and 11C-Choline Positron-Emission Tomography [J].Am J Neuroradiol,2008,29(6):1176-1182.
[10]Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and F-FDG in acute cerebral radiation injury in the rat:implications for separation of radiation necrosis from tumor recurrence [J]. J Nucl Med,2004,45(11):1931-1938.
[11]Mameda M, Higashi T, Kitaichi M, et al. [18F] FDG Uptake and PCNA, Glut-1, and Hexokinase-Ⅱ Expressions in Cancers and Inflammatory Lesions of the Lung[J].NeopIasia,2005,7(4):369-379.
[12]Hustinx R, Pourdenad M, Kaschten B, et al. PET imaging for differentiating recurrent brain tumor from radiation necrosis [J]. Radiol Clin N Am,2005, 43(1):35-47.
[13]Lee WJ, Kang KW, Park SH, et al. 18F-FDG PET in the assessment of tumor grade and prediction of tumor recurrence in intracranial meningioma [J]. Eur Nucl Med Mol Imaging,2009,36(4):1574-1582.
[14]Buchpiguel CA, Alavi JB, Alavi A, et al. PET versus SPECT in distinguishing radiation necrosis from tumor recurrence in the brain [J]. J Nucl Med,1995, 36(1):159-164.
[15]Meyer PT, Schreckenberger M, Spetzger U, et al. Comparison of visual and ROJ-bascd brain tumor grading using 18F-FDG PET:ROC analysises [J]. Eur J Nucl Med,2000,28(2):165-174.
[16]Chcn W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[17]Tsuyuguchi N, Sunada I, Iwai Y, et al. Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery:is a differential diagnosis possible? [J] J Neurosurg,2003, 98(5):1056-1064.
[18]Okubo S, Zhen HN, Kawai N, et al. Correlation of L-methyl-11C-methionine(MET) uptake with L-type amino acid transporter 1 in human gliomas [J]. J Neurooncol,2010,90(1):117-125.
[19]Nawashiro H, Otani N, Uozumi Y, et al.High expression of L-type amino acid transporter 1 in infiltrating glioma cells [J]. Brain Tumor Pathol,2005, 22(8):89-91.
[20]Kracht LW, Friese M, Herholz K, et al. Mehtyl-[11C]-1-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma. Eur J Nucl Med Mol Imaging,2003,30(6):868-873.
[21]Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic Accuracy of 11 C-Methionine PET for Differentiation of Recurrent Brain Tumors from radiation necrosis after radiotherapy [J]. J Nucl Med,2008,49(5):694-699.
[22]Popped G, Gotz C, Rachinger W, et al. Value of O-(2-[18F]fluoroethyl)-Ltyrosine PET for the diagnosis of recurrent glioma [J]. Eur J Nucl Med Mol Imaging,2004, 31(11):1464-1470.
[23]Wyss MT, Spaeth N, Biollaz G, et al. Uptake of 18F-Fluorocholine,18F-FET, and FDG in C6 gliomas and correlation with 131I-SIP(L19), a marker of angiogenesis [J]. J Nucl Med,2007,48(4):608-614.
[24]Floeth FW, Pauleit D, Sabel M, et al. I8F-FET PET Differentiation of Ring-Enhancing Brain Lesions [J]. J Nucl Med,2006,47(5):776-782.
[25]Pauleit D, Stoffels G, Bachofner A, et al. Comparison of 18F-FET and 18F-FDG PET in brain tumors [J]. Nucl Med Biol,2009,36(5):779-787.
[26]Hara T. 11C-choline and 2-deoxy-2-[18F]fluoro-d-glucose in tumor imaging with positron emission tomography [J]. Mol Imag Biol,2002,4(4):267-273.
[27]Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer [J]. Eur J Nucl Med Imaging,2005,32(6):668-673.
[28]Gulyas B, Nyary I, Borbely K. FDG, MET or CHO? The quest for the optimal PET tracer for glioma imaging continues [J]. Nature Clinical Practice Neurology, 2008,4(9):470-471.
[29]DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers [J]. J Nucl Med,2001, 42(12):1805-1814.
[30]Fci BW, Wang HS, Wu CY, et al. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy [J]. J Nucl Med,2010,51(1):130-138.
[31]Tian M, Zhang H, Oriuchi N, et al. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors [J]. Eur J Nucl Med Mol Imaging,2004,31(8):1064-1072.
[32]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.
[33]Liu Q, Peng ZM, Liu QW, et al. The role of 11C-choline positron emission tomographycomputed tomography and videomediastinoscopy in the evaluation of diseases of middle mediastinum [J]. Chin Med J,2006,119(8):634-639.
[34]Hara T, Kosaka N, Suzuki T, et al. Uptake rates of F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis:a positron emission tomography study [J]. Chest,2003,124(3):893-901.
[35]Shiraki N, Hara M, Ogino H, et al. False-positive and true-negative hilar and mediastinal lymph nodes on FDG-PET-radiologicalpathological correlation [J]. Ann Nucl Med,2004,18(1):23-28.
[36]Shinoura N, Nishijima M, Hara T, et al. Brain tumors:detection with C-11 choline PET [J]. Radiology,1997,202(2):197-503.
[37]Hara T, Kosaka N, Shinoura N, et al. PET imaging of brain tumor with [melhyl-11C]choline [J]. J Nucl Med,1997,38(6):842-847.
[38]Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors [J]. Neuroimag Clin N Am,2003(4),13:717-739.
[39]Zhang X, Chen W. Differentiation of recurrent astrocytoma from radiation necrosis:a pilot studywith 13N-NH3 PET [J]. J Neurooncol,2007,82 (3):305-311.
[40]Hatakeyama T, Kawai N, Nishiyama Y, et al. "C-methionine (MET) and 18F-fluorothymidine (FLT) PET [J]. Eur J Nucl Med Imaging,2008, 35(6):2009-2017.
[41]Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET:comparison witli 18F-FDG [J]. J Nucl Med,2005, 46(6):945-952.
[42]Buck AK, Halter G, Schirrmeister H, et al. Imaging proliferation in lung tumors with PET:18F-FLT versus 18F-FDG [J]. J Nucl Med,2003,44(9):1426-1431.
[43]Pan MH, Huang SC, Liao YP, et al.FLT-PET Imaging of Radiation Responses in Murine Tumors [J]. Mol Imaging Biol,2008,10(6):325-334
[44]Van Waarde A, Cobben DC, Suurmeijcr AJ, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model [J]. J Nucl Med,2004,45(4):695-700.
[45]Klein LJ, Visser FC, Knaapen P, et al. Carbon-11 acetate as a tracer of myocardial oxygen consumption [J]. Eur J Nucl Med,2001,28(5):651-668.
[46]Vavere AL, Kridel SJ, Wheeler FB, et al. 1-11C-Acetate as a PET Radiopharmaceutical for Imaging Fatty Acid Synthase Expression in Prostate Cancer [J]. J Nucl Med,2008,49(2):327-334.
[47]Park JW, Kim JH, Kim SK, et al. A prospective evaluation of 18F-FDG and 11C-Acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma [J]. J Nucl Med,2008,49(12):1912-1921.
[48]Ponde DE, Dence CS, Oyama N, et al.18F-fluoroacetate:a potential acetate analog for prostate tumor imaging-in vivo evaluation of F-fluoroacetate versus 11C-acetate [J]. J Nucl Med,2007,48(3):420-428.
[49]Yoshii Y, Waki A, Furukawa T, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase:implications for the mechanism of acetate PET [J]. Nucl Med Biol,2009,36(7):771-777.
[50]Wyss MT, Weber B, Treyer V, et al. Stimulation-induced increases of astrocytic oxidative metabolism in rats and humans investigated with 1-11C-acetate [J]. Journal of Cerebral Blood Flow & Metabolism,2009,29(1):44-56.
[51]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.
[2]Meyer PT, Schreckenberger M, Spetzger U, et al. Comparison of visual and ROI-based brain tumor grading using 18F-FDG PET:ROC analysises [J]. Eur J Nucl Med,2000,28(2):165-174.
[3]Chen W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[4]Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury [J]. J Nucl Med,2000,41(11):1861-1867.
[5]Tsuyuguchi N, Sunada I, Iwai Y, et al. Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery:is a differential diagnosis possible? [J] J Neurosurg,2003, 98(5):1056-1064.
[6]Braga FJHN, Flamen P, Van Calenbergn F. 11C-methionine (MET) and 18F-FDG PET for the evaluation of suspected recurrent brain tumours (SRBT) [J]. Eur J Nucl Med,2000,27(8):1145.
[7]Ogawa T, Inugami A, Hatazawa J, et al. Clinical positron emission tomography for brain tumors:comparison of fludeoxyglucose F18 and L-methyl-"C-methionine[J]. AJNR,1996,17(2):345-353.
[8]DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers [J]. J Nucl Med,2001, 42(12):1805-1814.
[9]Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET:comparison with 18F-FDG [J]. J Nucl Med,2005,46(6): 945-952.
[10]Hatakeyama T, Kawai N, Nishiyama Y, et al. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET [J]. Eur J Nucl Med Imaging,2008, 35(6):2009-2017.
[11]Pan MH, Huang SC, Liao YP, et al. FLT-PET Imaging of Radiation Responses in Murine Tumors [J]. Mol Imaging Biol,2008,10(6):325-334.
[12]Murayama C, Harada N, Kakiuchi T, er al. Evaluation of D-18F-FMT,18F-FDG, L-"C-MET, and 18F-FLT for monitor response of tumors to radiotherapy [J]. J Nucl Med,2009,50(2):290-295.
[13]Tsuchida T, Takeuchi H, Okazawa H, et al. Grading of brain glioma with 1-11C-acetate PET:comparison with 18F-FDG PET [J]. Nucl Med Biol,2008, 35(2):171-176.
[14]Liu RS, Chang CP, Chu LS, et al. PET imaging of brain astrocytoma with-11C acetate [J]. Eur J Nucl Med Mol Imaging,2006,33(4):420-7.
[15]Yamamoto Y, Nishiyarna Y, Kimura N, et al. "C-Acetate PET in the Evaluation of Brain Glioma:Comparison with "C-Methionine and 18F-FDG-PET [J]. Mol imaging Biol,2008,10(5):281-287.
[16]Van WA, Cobben DC, Suurmeijer AJ, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model [J]. J Nucl Med, 2004,45(4):695-700.
[17]Klein LJ, Visser FC, Knaapen P, et al. Carbon-11 acetate as a tracer of myocardial oxygen consumption [J]. Eur J Nucl Med,2001,28(5):651-668.
[18]Vavere AL, Kridel SJ, Wheeler FB, et al. 1-11C-Acetate as a PET Radiopbarmaceutical for Imaging Fatty Acid Synthase Expression in Prostate Cancer[J]. J Nucl Med,2008,49(2):327-334.
[19]Park JW, Kim JH, Kim SK, et al. A prospective evaluation of 18F-FDG and "C-Acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma [J]. J Nucl Med,2008,49(12):1912-1921.
[20]Ponde DE, Dence CS, Oyama N, et al. F-fluoroacetate:a potential acetate analog for prostate tumor imaging-in vivo evaluation of F-fluoroacetate versus 11C-acetate [J]. J Nucl Med,2007,48(3):420-428.
[21]Yoshii Y, Waki A, Furukawa T, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase:implications for the mechanism of acetate PET [J]. Nucl Med Biol,2009,36(7):771-777.
[22]Wyss MT, Weber B, Treyer V, et al. Stimulation-induced increases of astrocytic oxidative metabolism in rats and humans investigated with 1-11C-acetate [J]. Journal of Cerebral Blood Flow & Metabolism,2009,29(1):44-56.
[23]Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors [J]. Neuroimag Clin N Am,2003(4),13:717-739.
[24]Nanni C, Rubello D, Al-Nahhas A, et al. Clinical PET in oncology:not only FDG [J]. Nucl Med Commun,2006,27(9):685-688.
[25]Fei BW, Wang HS, Wu CY, et al. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy [J]. J Nucl Med,2010,51(1):130-138.
[26]Kato T, Shinoda J, Nakayama N, et al. Metabolic Assessment of Gliomas Using 11C-Methionine, [18F] Fluorodeoxyglucose, and 11C-Choline Positron-Emission Tomography [J].Am J Neuroradiol,2008,29(6):1176-1182.
[27]王建交,李青松,詹奇,等.大鼠C6胶质瘤模型构建及生长特性的研究[J].中国康复理论与实践,2009,15(8)：742-745.
[28]Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology:the C6,9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas [J]. J Neurooncol,2009, 94(4):299-312.
[29]李明,冯华,李飞,等.大鼠C6脑胶质瘤模型的病理特征与MRI的观察[J].中华神经外科杂志,2005,21(5)：278-282.
[30]林健,王伟民,徐如祥,等9L/Fischer344与C6/Wistar两种大鼠脑胶质瘤模型的比较研究[J].中华神经医学杂志,2005,49(5)：445448.
[31]Braganhol E, Huppes D, Bernardi A, et al. A comparative study of ectonucleotidase and P2 receptor mRNA profiles in C6 cell line cultures and C6 ex vivo glioma model [J]. Cell Tissue Res,2009,335(11):331-340.
[32]Lee JW, Kang KW, Park KS, et al.18F-FDG PET in the assessment of tumor grade and prediction of tumor recurrence in intracranial meningioma [J]. Eur J Nucl Med Imaging,2009,36(8):1574-1582.
[33]Shinoura N, Nishijima M, Hara T, et al. Brain tumor:detection with C-11 choline PET [J]. Radiology,1997,202(2):497-503.
[34]Hara T, Kosaka N, Suzuki T, et al. Uptake rates of 18F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis:a positron emission tomography study [J]. Chest,2003,124(3):893-901.
[35]Liu Q, Peng ZM, Liu QW, et al.The role of "C-choline positron emission tomography computed tomography and video mediastinoscopy in the evaluation of diseases of middle mediastinum [J]. Chin Med J,2006,119(8):634-639.
[36]Tian M, Zhang H, Oriuchi N, et al. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors [J]. Eur J Nucl Med Mol Imaging,2004,31(8):1064-1072.
[37]Shiraki N, Hara M, Ogino H, et al. False-positive and true-negative hilar and mediastinal lymph nodes on FDG-PET-radiologicalpathological correlation [J]. Ann Nucl Med,2004,18(1):23-28.
[38]Gulyas B, Nyary I, Borbely K. FDG, MET or CHO? The quest for the optimal PET tracer for glioma imaging continues [J]. Nature Clinical Practice Neurology, 2008,4(9):470-471.
[39]Wyss MT, Spaeth N, Biollaz G, et al. Uptake of 18F-Fluorocholine,18F-FET, and FDG in C6 gliomas and correlation with 131I-SIP(L19), a marker of angiogenesis [J]. J Nucl Med,2007,48(4):608-614.
[40]Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic Accuracy of 11C-Methionine PET for Differentiation of Recurrent Brain Tumors from radiation necrosis after radiotherapy [J]. J Nucl Med,2008,49(5):694-699.
[41]Okubo S, Zhen HN, Kawai N, et al. Correlation of L-methyl-11C-methionine(MET) uptake with L-type amino acid transporter 1 in human gliomas [J]. J Neurooncol,2010,90(1):117-125.
[42]Kanai Y, Segawa H, Miyamoto K, et al. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98) [J]. J Biol Chem,1998,273(37):23629-23632.
[43]Nawashiro H, Otani N, Uozumi Y, et al. High expression of L-type amino acid transporter 1 in infiltrating glioma cells [J]. Brain Tumor Pathol,2005, 22(8):89-91.
[44]王全师,吴湖炳,王明芳,等.11C-蛋氨酸PET/CT显像在脑胶质瘤中的初步应用[J].中华核医学杂志,2005,25(5)：286-288.
[45]蔡莉,高硕,李彦生,等18F-FDG与11C-MET PET显像在神经上皮性肿瘤 术前分级中的价值及与Ki67相关性的比较[J].中华核医学杂志,2006,26(1)：8-12.
[46]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.
[47]Brown RS, Leung JY, Kison PV, et al. Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer [J]. J Nucl Med,1999, 40(4):556-565.
[48]Chung JK, Lee YJ, Kim C, et al. Mechanism related to [18F]fluorodeoxyglucose uptake of human colon cancers transplanted in nude mice [J]. J Nucl Med,1999, 40(2):339-346.
[49]李方成,余进,陶宗玉,等.不同速率生长的胶质瘤细胞的葡萄糖代谢状态研究[J].中华实验外科杂志,2004,21(3)：365-366.
[50]Nagamatsu S, Nakamihi Y, Inoue N, et al. Rat C6 glioma cell growth is related to glucose transport and metabolism. [J]. Biochem J,1996,319(part 2):477-482
[51]Maher F, Vannucci SJ, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glioma [J]. Glia,1997,21(2)2-21
[52]Campbell WA, Sah DE, Medina MM, et al. TA1/LAT1-1/CD98 light chain and system L activity, but not 4f2/CD98 heavy chain, respond to arginine availability in rat hepatic cells [J]. J Biolog Chem,2000,275(8):5347-5354
[53]Okamoto Y, Sakata M, Ogura K, et al. Expression and regulation of 4F2hc and hLAT1 in human trophoblasts [J]. Am J Physiol Cell Physiol,2002, 282(1):C196-C204.
[54]Kracht LW, Friese M, Herholz K, et al. Mehtyl-[11C]-1-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma [J]. Eur J Nucl Med Mol Imaging,2003,30(6):868-873.
[55]Guo J, Higashi K, Ueda Y, et al. Microvessel density:correlation with18F-FDG uptake and Prognostic impact in lung adenocarcinomas [J]. J Nucl Med,2006, 47(3):419-425.
[56]Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat:implications for separation of radiation necrosis from tumor recurrence [J]. J Nucl Med,2004,45(11):1931-1938.
[57]Lund EL, Hog A, Olsen MW, et al. Differential regulation of VEGF, HIF-1α and angiopoietin-1,-2 and-4 by hypoxia and ionizing radiation in human glioblastoma [J]. Int J Cancer,2004,108(6):833-838.
[58]Semenza GL. HIF-1:Mediator of physiological and pathophysiological responses to hypoxia [J]. Appl Physiol,2000,88(4):1474-1480.
[59]关丽明,赵明芳,徐克,等.大鼠C6脑胶质瘤VEGF,MMP-2,MMP-9表达与其MRI相关性的实验研究[J].中国临床医学影像杂志,2006,17(6)：311-313.
[60]蔡莉,张川,李彦生,等.人脑胶质瘤18F-FDG摄取与乏氧诱导因子-1α表达及微血管密度的相关性[J].中华核医学杂志,2010,30(1)：10-14.
[61]Kaur B, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible factor pathway in glioma growth and angiogenesis [J]. Neuro Oncol,2005, 7(2):134-53.
[62]Miles KA, Williams RE. Warburg revisited:imaging tumour blood flow and metabolism [J]. Cancer Imaging,2008,8(3):81-86.
[63]Zhao SJ, Kuge Y, Mochizuki T, et al. Biologic correlates of intra-tumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-Ⅱ in experimental tumor[J]. J Nucl Med,2005, 46(4):675-682.
[64]Kudo T, Ueda M, Kuge Y, et al. Imaging of HIF-1-Active Tumor Hypoxia using a protein effectively delivered to and specifically stabilized in HIF-1-active tumor cells [J]. J Nucl Med,2009,50(6):942-949.
[65]Okada J, Yoshikawa k, Itami M, et al. Positron emission tomography using fluorine-8-fluorodeoxyglucose in malignant lymphoma:a comparison with proliferative activity [J]. J Nucl Med,1992,33(3):325-329.
[66]Buck AC, Schirrmeister HH, Guhlmann CA, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis:does in vivo FDG uptake correlate with proliferative activity? [J] J Nucl Med,2001,42(5):721-725.
[67]Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C] choline does not correlate with cell proliferation in human prostate cancer [J]. Eur J Nucl Med Mol Imaging,2005,32(6):668-673.
[68]Mameda M, Higashi T, Kitaichi M, et al.[18F]FDG Uptake and PCNA, Glut-1, and Hexokinase-Ⅱ Expressions in Cancers and Inflammatory Lesions of the Lung [J]. Neoplasia,2005,7(4):369-379.
[69]Al-Saeedi F, Welch AE, Smith TA. [methyl-3H]Choline incorporation into MCF7 tumour cells:correlation with proliferation [J]. Eur J Nucl Med Mol Imaging,2005,32(6):660-667.
[70]赵庆秋,赵文清,周立霞,等.大鼠脑胶质瘤伽玛刀治疗对细胞凋亡和Caspase-3-. Fas表达的影响[J].中华放射医学与防护杂志,2003,23(4)：282-283.
[71]Hustinx R, Pourdehnad M, Kaschten B,et al. PET imaging for differentiating recurrent brain tumor from radiation necrosis [J]. Radiol Clin North Am,2005, 43(l):35-47.
[72]Marik J, Ogasawara A, McNulty MB, et al. PET of glial metabolism using 2-18F-Fluoroacetate [J]. J Nucl Med,2009,50(6):982-990.
[1].Mullins ME, Barest GD, Schaefer PW, et al. Radiation necrosis versus glioma recurrence:conventional MR imaging clues to diagnosis [J]. Am J Neuroradiol, 2005,26(8):1967-1972.
[2]Barajas RF, Chang JS, Segal MR, et al. Differentiation of Recurrent Glioblastoma Multiforme from Radiation Necrosis after External Beam Radiation Therapy with Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging [J]. Radiology,2009,253(11):486-498.
[3]Langleben DD, Segall GM.PET in differentiation of recurrent brain tumor from radiation injury [J]. J Nucl Med,2000,41(11):1861-1867.
[4]Braga FJHN, Flamen P, Van Calenbergn F. 11C-methionine (MET) and 18F-FDG PET for the evaluation of suspected recurrent brain tumours(SRBT)[J]. Eur J Nucl Med,2000,27(8):1145.
[5]Chao ST, Suh JH, Raja S, et al. The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereolaclic radiosurgery [J]. Int J Cancer,2001,96(3):191-197.
[6]Chen W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[7]Ohtani T, Kurihara H, Ishiguchi S, et al. Brain tumour imaging with carbon-11 choline:comparison with FDG PET and gadolinium-enhanced MR imaging [J]. Eur J Nucl Med,2001,28(11):1664-1670.
[8]Murayama C, Harada N, Kakiuchi T, er al. Evaluation of D-18F-FMT,18F-FDG, L-11C-MET, and 18F-FLT for monitor response of tumors to radiotherapy [J]. J Nucl Med,2009,50(2):290-295.
[9]Kato T, Shinoda J, Nakayama N, et al. Metabolic Assessment of Gliomas Using 11C-Melhionine, [18F] Fluorodeoxyglucose, and 11C-Choline Positron-Emission Tomography [J].Am J Neuroradiol,2008,29(6):1176-1182.
[10]Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and F-FDG in acute cerebral radiation injury in the rat:implications for separation of radiation necrosis from tumor recurrence [J]. J Nucl Med,2004,45(11):1931-1938.
[11]Mameda M, Higashi T, Kitaichi M, et al. [18F] FDG Uptake and PCNA, Glut-1, and Hexokinase-Ⅱ Expressions in Cancers and Inflammatory Lesions of the Lung[J].NeopIasia,2005,7(4):369-379.
[12]Hustinx R, Pourdenad M, Kaschten B, et al. PET imaging for differentiating recurrent brain tumor from radiation necrosis [J]. Radiol Clin N Am,2005, 43(1):35-47.
[13]Lee WJ, Kang KW, Park SH, et al. 18F-FDG PET in the assessment of tumor grade and prediction of tumor recurrence in intracranial meningioma [J]. Eur Nucl Med Mol Imaging,2009,36(4):1574-1582.
[14]Buchpiguel CA, Alavi JB, Alavi A, et al. PET versus SPECT in distinguishing radiation necrosis from tumor recurrence in the brain [J]. J Nucl Med,1995, 36(1):159-164.
[15]Meyer PT, Schreckenberger M, Spetzger U, et al. Comparison of visual and ROJ-bascd brain tumor grading using 18F-FDG PET:ROC analysises [J]. Eur J Nucl Med,2000,28(2):165-174.
[16]Chcn W. Clinical Applications of PET in Brain Tumors [J]. J Nucl Med,2007, 48(9):1468-1481.
[17]Tsuyuguchi N, Sunada I, Iwai Y, et al. Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery:is a differential diagnosis possible? [J] J Neurosurg,2003, 98(5):1056-1064.
[18]Okubo S, Zhen HN, Kawai N, et al. Correlation of L-methyl-11C-methionine(MET) uptake with L-type amino acid transporter 1 in human gliomas [J]. J Neurooncol,2010,90(1):117-125.
[19]Nawashiro H, Otani N, Uozumi Y, et al.High expression of L-type amino acid transporter 1 in infiltrating glioma cells [J]. Brain Tumor Pathol,2005, 22(8):89-91.
[20]Kracht LW, Friese M, Herholz K, et al. Mehtyl-[11C]-1-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma. Eur J Nucl Med Mol Imaging,2003,30(6):868-873.
[21]Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic Accuracy of 11 C-Methionine PET for Differentiation of Recurrent Brain Tumors from radiation necrosis after radiotherapy [J]. J Nucl Med,2008,49(5):694-699.
[22]Popped G, Gotz C, Rachinger W, et al. Value of O-(2-[18F]fluoroethyl)-Ltyrosine PET for the diagnosis of recurrent glioma [J]. Eur J Nucl Med Mol Imaging,2004, 31(11):1464-1470.
[23]Wyss MT, Spaeth N, Biollaz G, et al. Uptake of 18F-Fluorocholine,18F-FET, and FDG in C6 gliomas and correlation with 131I-SIP(L19), a marker of angiogenesis [J]. J Nucl Med,2007,48(4):608-614.
[24]Floeth FW, Pauleit D, Sabel M, et al. I8F-FET PET Differentiation of Ring-Enhancing Brain Lesions [J]. J Nucl Med,2006,47(5):776-782.
[25]Pauleit D, Stoffels G, Bachofner A, et al. Comparison of 18F-FET and 18F-FDG PET in brain tumors [J]. Nucl Med Biol,2009,36(5):779-787.
[26]Hara T. 11C-choline and 2-deoxy-2-[18F]fluoro-d-glucose in tumor imaging with positron emission tomography [J]. Mol Imag Biol,2002,4(4):267-273.
[27]Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer [J]. Eur J Nucl Med Imaging,2005,32(6):668-673.
[28]Gulyas B, Nyary I, Borbely K. FDG, MET or CHO? The quest for the optimal PET tracer for glioma imaging continues [J]. Nature Clinical Practice Neurology, 2008,4(9):470-471.
[29]DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers [J]. J Nucl Med,2001, 42(12):1805-1814.
[30]Fci BW, Wang HS, Wu CY, et al. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy [J]. J Nucl Med,2010,51(1):130-138.
[31]Tian M, Zhang H, Oriuchi N, et al. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors [J]. Eur J Nucl Med Mol Imaging,2004,31(8):1064-1072.
[32]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.
[33]Liu Q, Peng ZM, Liu QW, et al. The role of 11C-choline positron emission tomographycomputed tomography and videomediastinoscopy in the evaluation of diseases of middle mediastinum [J]. Chin Med J,2006,119(8):634-639.
[34]Hara T, Kosaka N, Suzuki T, et al. Uptake rates of F-fluorodeoxyglucose and 11C-choline in lung cancer and pulmonary tuberculosis:a positron emission tomography study [J]. Chest,2003,124(3):893-901.
[35]Shiraki N, Hara M, Ogino H, et al. False-positive and true-negative hilar and mediastinal lymph nodes on FDG-PET-radiologicalpathological correlation [J]. Ann Nucl Med,2004,18(1):23-28.
[36]Shinoura N, Nishijima M, Hara T, et al. Brain tumors:detection with C-11 choline PET [J]. Radiology,1997,202(2):197-503.
[37]Hara T, Kosaka N, Shinoura N, et al. PET imaging of brain tumor with [melhyl-11C]choline [J]. J Nucl Med,1997,38(6):842-847.
[38]Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors [J]. Neuroimag Clin N Am,2003(4),13:717-739.
[39]Zhang X, Chen W. Differentiation of recurrent astrocytoma from radiation necrosis:a pilot studywith 13N-NH3 PET [J]. J Neurooncol,2007,82 (3):305-311.
[40]Hatakeyama T, Kawai N, Nishiyama Y, et al. "C-methionine (MET) and 18F-fluorothymidine (FLT) PET [J]. Eur J Nucl Med Imaging,2008, 35(6):2009-2017.
[41]Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET:comparison witli 18F-FDG [J]. J Nucl Med,2005, 46(6):945-952.
[42]Buck AK, Halter G, Schirrmeister H, et al. Imaging proliferation in lung tumors with PET:18F-FLT versus 18F-FDG [J]. J Nucl Med,2003,44(9):1426-1431.
[43]Pan MH, Huang SC, Liao YP, et al.FLT-PET Imaging of Radiation Responses in Murine Tumors [J]. Mol Imaging Biol,2008,10(6):325-334
[44]Van Waarde A, Cobben DC, Suurmeijcr AJ, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model [J]. J Nucl Med,2004,45(4):695-700.
[45]Klein LJ, Visser FC, Knaapen P, et al. Carbon-11 acetate as a tracer of myocardial oxygen consumption [J]. Eur J Nucl Med,2001,28(5):651-668.
[46]Vavere AL, Kridel SJ, Wheeler FB, et al. 1-11C-Acetate as a PET Radiopharmaceutical for Imaging Fatty Acid Synthase Expression in Prostate Cancer [J]. J Nucl Med,2008,49(2):327-334.
[47]Park JW, Kim JH, Kim SK, et al. A prospective evaluation of 18F-FDG and 11C-Acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma [J]. J Nucl Med,2008,49(12):1912-1921.
[48]Ponde DE, Dence CS, Oyama N, et al.18F-fluoroacetate:a potential acetate analog for prostate tumor imaging-in vivo evaluation of F-fluoroacetate versus 11C-acetate [J]. J Nucl Med,2007,48(3):420-428.
[49]Yoshii Y, Waki A, Furukawa T, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase:implications for the mechanism of acetate PET [J]. Nucl Med Biol,2009,36(7):771-777.
[50]Wyss MT, Weber B, Treyer V, et al. Stimulation-induced increases of astrocytic oxidative metabolism in rats and humans investigated with 1-11C-acetate [J]. Journal of Cerebral Blood Flow & Metabolism,2009,29(1):44-56.
[51]Yoshimoto M, Waki A, Obata A, et al. Radiolabeled choline as a proliferation marker:comparison with radiolabeled acetate [J]. Nucl Med Biol,2004, 31(7):859-865.