~（18）F-FDG PET-CT显像在乳腺癌复发和转移诊断中的应用
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摘要
目的:通过螺旋CT、PET和PET-CT对诊断乳腺癌复发和转移的对比研究,探讨~(18)F-FDG PET-CT显像在乳腺癌复发和转移诊断中的应用价值。
材料与方法:收集2003年11月至2006年3月间,临床疑乳腺癌术后复发或转移患者37例(均为女性,年龄37 ~ 68岁,平均51±6.3岁)。37例均采用GE Discovery LS PET-CT行~(18)F-脱氧葡萄糖(~(18)F-FDG)PET-CT显像,图像经迭代重建后传至工作站(GE Entegra)进行图像融合。局部延迟显像于注射后2.5 ~ 3h进行双时相显像。2次显像条件一致。37例患者在PET-CT之前或之后1月内进行了多层螺旋CT扫描。经二位有经验的核医学医师和1位放射学医师分别对PET、CT及融合图像进行分析评价。螺旋CT诊断腋窝淋巴结转移的标准是:淋巴结长径(L)大于10mm或短径(S)大于5mm;淋巴结长短径比率(L/S)小于或等于2,即L/S≤2;淋巴结周围脂肪密度增高模糊。远处区域淋巴结最小径≥8mm,如果淋巴结成串或呈环状增强,则不必强调大小。当符合以上标准时,该淋巴结记录为阳性(淋巴结有转移),不符合标准时记录为阴性(淋巴结无转移)。PET-CT图像分析采用两种方法对图像进行分析:(1)目测法:根据放射性浓聚程度,将病灶分为两种类型:病灶的~(18)F-FDG摄取量高于正常周围组织为阳性;~(18)F-FDG摄取量与周围组织相近或其摄取量低于周围组织或无摄取为阴性。(2)半定量分析法:在~(18)F-FDG浓聚的病灶部位设感兴趣区(region of interest,ROI),由计算机程序自动计算病灶部位的最大标准摄取值(SUVmax)和平均标准摄取值(SUVmean),以SUVmean≥2.5为阳性,SUVmean<2.5为阴性。双时相显像以延迟显像SUV值增加(ΔSUV%=(SUV_(延迟)-SUV_(早期))/(SUV_(早期))×100%)大于10%判断为增高阳性。最后通过融合图像进行具体诊断、准确定位。
将PET-CT、螺旋CT及PET对乳腺癌复发及转移病灶的检出结果分别与近期组织病理检查、活检或细胞学检查,和临床随访(4 ~ 29个月)结果进行对照。
采用x~2检验和四格表资料的精确概率法,计算P值,统计学检验结果均以P<0.05作为有显著性差异的判断标准。
结果:经组织病理学、活检或细胞学检查,和临床随访,37例患者中,27例乳腺癌患者诊断为术后复发和/或转移,余10例未见乳腺癌复发及转移。
1. PET-CT,CT和PET在乳腺癌术后复发和/或转移诊断的中比较
PET-CT:28例患者PET-CT显像为阳性,其中26例最终确诊为真阳性,2例诊断为假阳性。18F-FDG PET-CT检出乳腺癌术后复发和/或转移的灵敏度为96.30%(26/27例),特异性为80.00%(8/10例),准确性为.91.89%(34/37例),阳性预测值为92.86%(26/28例),阴性预测值为88.89%(8/9例)。
螺旋CT:27例经确诊为术后乳腺癌复发和/或转移的患者中,17例CT诊断为阳性,10例CT诊断为阴性;10例经确诊为术后未见复发和/或转移的患者中,7例为CT诊断为阴性,3例CT诊断为阳性。螺旋CT对乳腺癌术后复发和/或转移诊断的灵敏度为62.96%(17/27例),特异性为70.00%(7/10例),准确性为64.86%(24/37例),阳性预测值为85.00%(17/20例),阴性预测值为41.18%(7/17例)。
PET:27例经确诊为术后乳腺癌复发和/或转移的患者中,21例PET诊断为阳性,6例PET诊断为阴性;10例经确诊为术后未见复发和/或转移的患者中,6例PET诊断为阴性,4例PET诊断为阳性。PET诊断乳腺癌术后复发和/或转移的灵敏度为77.76%(21/27例),特异性为60.00%(6/10例),准确性为72.97%(27/37例),阳性预测值为84.00%(21/25例),阴性预测值为50.00%(6/12例)。
CT与PET-CT对乳腺癌术后复发和/或转移定性诊断的灵敏度之间、准确性之间和阴性预测值差异有显著意义,P<0.05,即PET-CT对乳腺癌术后复发和/或转移诊断的灵敏度、准确性和阴性预测值明显较CT高。CT、PET-CT对乳腺癌术后复发和/或转移定性诊断的特异性之间和阳性预测值之间差异不存在显著意义,P>0.05,即CT与PET-CT对乳腺癌术后复发和/或转移定性诊断的特异性和阳性预测值相当。
PET与PET-CT在诊断乳腺癌复发和/或转移定性方面的灵敏度之间、特异性之间、阳性预测值之间和阴性预测值之间差异无明显意义,P>0.05,即PET与PET-CT对乳腺癌术后复发和/或转移定性诊断的灵敏度、特异性、阳性预测值和阴性预测值相当。在PET和PET-CT对乳腺癌术后复发和/或转移诊断的准确性之间差异有明显意义,P<0.05,即PET-CT的准确性高于PET。
2. PET-CT和CT在乳腺癌术后淋巴转移诊断的比较
37例患者行螺旋CT局部检查共检出淋巴结55枚,其中37枚CT诊断为阳性,18枚为阴性;经组织病理学、活检或细胞学检查,和临床随访诊断,有33枚被确诊为阳性,22枚为阴性。行PET-CT全身检查患者共检出淋巴结64枚,其中44枚PET-CT显像为阳性,20枚为阴性;经组织病理学、活检或细胞学检查,和临床随访诊断,有39枚被确诊为阳性,25枚为阴性。
CT对淋巴结转移定性诊断的灵敏度、特异性、准确性、阳性预测值及阴性预测值分别为81.82%(27/33例)、54.55%(12/22例)、70.91%(39/55例)、72.97%(27/37例)、66.67%(12/18例);PET-CT对淋巴结转移定性诊断的灵敏度、特异性、准确性、阳性预测值及阴性预测值,分别为97.44%(38/39例)、76.00%(19/25例)、89.06%(57/64例)、86.36%(38/44例)及95.00%(19/20例)。
CT与PET-CT对乳腺癌术后淋巴结转移定性诊断的灵敏度之间、准确性之间及阴性预测值之间的差异有显著意义,P<0.05,即PET-CT显像在乳腺癌术后诊断淋巴结转移阳性时明显较CT准确;CT、PET-CT对淋巴结转移定性的特异性之间及阳性预测值之间的差异无明显意义,P>0.05,即CT与PET-CT对乳腺癌术后淋巴结转移的特异性和阳性预测值相当。PET-CT对短径小于5mm的淋巴结检测准确性优于螺旋CT。对于短径大于5mm的淋巴结的检测,CT与PET-CT检测的结果基本一致,均具有较高敏感性、特异性和准确性,二者之间无明显差异。
3. PET-CT双时相显像对乳腺癌术后复发和/或转移的诊断价值
14例乳腺癌术后患者行PET-CT双时相显像,9例患者被确诊为复发和/或转移,其中早期显像5例SUV值为阳性,延迟显像明显增高(ΔSUV>10%);4例早期显像病灶SUV值为可疑阳性,延迟显像均有不同程度增高(ΔSUV>10%)。5例未见复发和转移的患者中,1例早期显像SUV值为阳性,延迟显像增高(ΔSUV>10%),经手术后病检证实为假阳性,组织病理学检查结果为甲状腺腺瘤;余4例延迟显像未见明显增高,经临床随访证实均为良性病变。
4. PET-CT、CT、PET在乳腺癌术后远处转移诊断的比较
37例乳腺癌术后患者中,综合诊断最终确诊27例患者有复发和/或转移病灶,其中经PET-CT显像检查确诊的患者有26例,经螺旋CT检查确诊的患者有17例,经PET显像检查确诊的患者有22例。
26例经PET-CT显像检查诊断为术后淋巴结和/或脏器转移的患者中,17例有腋窝及锁骨上淋巴结转移,3例胸膜转移,8例远处淋巴结和/或远处脏器转移,5例骨转移。8例远处淋巴结和/或远处脏器转移包括4例肺转移伴纵隔淋巴结转移,3例肝转移伴腹腔或腹膜后淋巴结转移,及1例腹股沟淋巴结转移。
17例经螺旋CT检查诊断为术后淋巴结和/或脏器转移的患者中,13例有腋窝及锁骨上淋巴结转移,1例肝转移,4例肺转移,2例胸膜转移,1例肝门区、胃窦后部及腹主动脉旁转移。
22例经PET检查诊断为术后淋巴结和/或脏器转移的患者中,15例有腋窝及锁骨上淋巴结转移,2例肝脏转移,4例肺转移伴纵隔淋巴结转移,3例腹部及盆腔转移,5例全身骨转移。
18F-FDG PET-CT显像、CT显像和PET显像检出复发和/或转移灶的灵敏度分别为96.30%(26/27例)、62.96%(17/27例)、81.48%(22/27例),PET-CT显像和CT显像监测复发及转移灶的灵敏度两者差异有显著性(x~2=9.247),P<0.05,即PET-CT监测乳腺癌术后复发及转移灶的灵敏度明显于CT。
结论:螺旋CT对乳腺癌术后复发和/或转移定性诊断有较高的特异性及阳性预测值,能为临床诊断提供较准确的信息,是监测乳腺癌术后复发和/或转移的一种有效方法。但CT对乳腺癌术后复发和/或转移定性诊断的灵敏度、准确性和阴性预测值明显低于PET-CT。PET在灵敏度、特异性、阳性预测值和阴性预测值方面较准确,但其准确性明显低于PET-CT。
PET-CT诊断乳腺癌术后淋巴结转移时明显较CT准确,假阴性率较CT小。对乳腺癌术后淋巴结转移定性诊断,CT与PET-CT时的特异性相当。在对短径小于5mm的淋巴结作为转移定性诊断时,其准确率优于螺旋CT;而对于短径大于5mm的淋巴结作转移定性时,PET-CT和螺旋CT的准确率相当,没有明显的优劣之分。
PET-CT双时相显像有助于鉴别乳腺癌术后患者早期显像中难以鉴别的良恶性高~(18)F-FDG浓聚病灶,可以排除正常生理结构摄取~(18)F-FDG、放化疗后炎症或瘢痕增生所带来的干扰,提高诊断准确率。
对于远处转移,PET-CT在肝脏转移及全身骨转移的诊断方面比螺旋CT灵敏,在肺及腹部转移的诊断显像方面PET-CT和CT诊断的准确率相当。PET对于肺及腹部转移的诊断准确率较CT和PET-CT要低。
综上所述,PET-CT在恶性肿瘤的治疗疗效评价方面具有传统影像检查难以比及的优势。PET-CT将具有解剖功能的CT和功能分子代谢的PET有机结合了在一起,具有同机图像融合的功能。对于那些临床检查或常规影像学检查难以进行或诊断不明确的患者,特别是不愿意接受创伤性诊断的病人,PET-CT可作为其诊断乳腺癌有无复发及转移的最佳选择。与CT和PET比较,PET-CT能更准确诊断乳腺癌复发及转移,能为指导临床制定正确的治疗方案提供重要信息。
目的:研究99Tcm标记肿瘤新生血管多肽的标记制备方法,其在正常小鼠体内的生物学分布特征以及对荷乳腺癌裸鼠模型进行显像,探讨核素标记抗血管内皮生长因子的七肽ATWLPPR用于肿瘤分子影像诊断的价值。
方法:~(99m)Tc-HYNIC-ATWLPPR标记条件及其特性的研究:合成ATWLPPR,采用间接标记法,以联结剂肼基尼古酰胺(HYNIC)为双功能螯合剂,三(羟甲基)甲基甘氨酸(tricine)与乙二胺二乙酸(EDDA)作为协同配体。紫外(280nm)分光和γ计数仪分别检测标记物蛋白质含量和标记率。设立三个实验组,ATWLPPR与HYNIC偶联后分别采用tricine、EDDA、和tricine/EDDA作为协同配体,研究协同配体的改变对标记率的影响。用不同放射性活度锝(185MBq,74MBq和37MBq)标记HYNIC-ATWLPPR,研究其对标记率的影响。对标记物的标记率、放化纯、稳定性进行研究。
生物分布和显像研究:(1)正常小鼠体内生物学分布研究:正常昆明小鼠25只,随机分为5组,分别于尾静脉注射~(99m)Tc-HYNIC-ATWLPPR,每只动物注入标记物7.4MBq,注射后15min、30min、60min、180min、300min处死,取不同组织器官称重并测量放射性计数,经时间衰减校正后计算每克组织的百分注射量(%ID/g)。(2)荷乳腺癌裸鼠显像研究:荷乳腺癌裸鼠于注射示踪剂后30min、60min、120min、180min、360min进行全身平面显像,图像处理采用感兴趣区(ROI)技术,计算不同时间肿瘤与胸部及对侧相应部位的放射性比值。(3)荷乳腺癌裸鼠体内分布研究:5只荷瘤裸鼠于注射示踪剂180min后处死,取不同组织器官及肿瘤组织称重并测量放射性计数,计算各脏器及肿瘤的摄取比值。(4)肿瘤组织切片免疫组织化学研究:采用免疫组织化学染色SP法(链霉卵白素-过氧化物酶法技术),检测VEGF165的表达水平,并设立阴性对照组。
结果:~(99m)Tc-HYNIC-ATWLPPR标记条件及其特性的研究:分别采用tricine、EDDA和tricine/EDDA作为协同配体,~(99m)Tc-HYNIC-ATWLPPR标记率依次为77.75%,68.09%和91.531%。使用不同放射性活度185MBq、74MBq和37MBq的99Tcm标记时,标记率分别为88.06%±1.05%、94.00%±1.25%和91.61%±2.70%(n=5)。用tricine/EDDA作为协同配体标记,99Tcm-HYNIC-ATWLPPR放化纯为94.14%±1.75%。标记物与新鲜人血清孵育30min和120min后,放射化学纯度分别为91.5%和90.8%;经Sep-Pak C18反相层析柱分析,其间放射性峰均未见漂移。于室温下放置5h,其放射化学纯度仍为91.35%。
生物分布和显像的研究:(1)正常小鼠体内生物学分布研究:~(99m)Tc-HYNIC-ATWLPPR在血中清除较快,主要以肾脏和肝脏排泄(。2)荷乳腺癌裸鼠显像研究:注射后180min肿瘤部位的放射性浓聚最高,显像效果最佳,肿瘤与对侧相应部位的放射性比值为3.758。(3)荷乳腺癌裸鼠体内生物学分布研究:肝脏和肾脏的摄取最高,脑部的摄取最低;T/NT摄取比显示肿瘤与脑,肿瘤与心脏的摄取比值较高,分别为22.18和4.63,其次为肿瘤与肌肉,肿瘤与骨骼,肿瘤与肌肉分别为2.85、1.89和1.59。(4)VEGF165的表达主要见于血管内皮细胞胞浆中,呈棕色颗粒状或弥漫性分布。阴性对照的血管内皮细胞胞浆中未见染色。
结论:以HYNIC作为双功能螯合剂标记肿瘤新生血管多肽ATWLPPR方法可行,步骤简便,标记率高,体外稳定性好;体内主要以肾脏和肝脏排泄,肿瘤部位~(99m)Tc标记的HYNIC-ATWLPPR有较高浓聚。体内显像和生物分布研究均表明标记后的~(99m)Tc-HYNIC-ATWLPPR仍保持良好的生物学特性,是一种有良好应用前景的肿瘤诊断显像剂。
OBJECTIVE: To evaluate the applicable value of ~(18)F-fluorodeoxyglucose(FDG) PET-CT in the prediction of recurrences and metastases of breast cancer by comparing helical CT, PET with PET-CT.
MATERIALS AND METHODS: The analysis was based on 37 cases with breast cancer (37 females, age range 37~68y, mean age 51±6.3y) which were collected from December, 2003 to March, 2006. All patients underwent ~(18)F-FDG PET-CT imaging with GE Discovery PET-CT and helical CT. PET-CT imaging was reconstructed and transferred to the working station (GE Entegra) for images fusion. The scan 2 of the dual-time point ~(18)F-FDG-PET-CT imaging was at 150– 180 min after the intravenous injection, and the acquisition parameters of the scan 2 were the same as the scan 1 in the PET-CT dual-time point imaging. PET-CT images were evaluated by two experienced nuclear medicine physicians and one radiologist in consensus. The positive diagnosis standards for metastases of the axillary lymph nodes were as the following: the long diameter (L) was greater than 10mm or the short diameter (S) was greater than 5mm, or L/S less than 2, and the fat around the node with high density. Distant lymph node metastasis assessment was based on its size, with a short axis diameter exceeding. But if the lymph nodes were bunchiness or ringlike enhanced, their size can not be emphasized. When the lymph node was accorded to the standarde, the diagnosis was positive, otherwise negative. Two kinds of methods were used to analyze the PET-CT images: (1) Eyeballing analysis: the lesions were divided into two types according to the degrees of radioactivity accumulation. Positive account: ~(18)F-FDG uptake in lesion was higher than that in surrounding normal tissue; negative account: ~(18)F-FDG uptakes in lession were similar to or lower than that in surrounding normal tissue. (2) Semiquantitative analysis: The regions of interest (ROI) were placed in lesions, and the average standard uptake value (SUVmean) and the maximum standard uptake value (SUVmax) of the lesions were automatically calculated with the computer software. SUVmean≥2.5 were diagnosed as positive lesions, and SUVmean<2.5 were diagnosed as negative lesions. The SUV changes >10% (ΔSUV%=(SUV_2-(SUV_1)/(SUV_1)×100%) between the first and second scans was as a criterion for abnormal increase or decrease. All lesions were analysed with both eyeballing and semiquantitative analysis.
The results of PET-CT, PET and CT were compared with those of the histopathology, biopsy, cytological examination, and clinical follow-up results.
The results were statistically analyzed with exact probabilities in 2×2 tables or t-test (SPSS software). P<0.05 was defined as a criterion for significant difference.
RESULTS: Recurrences and metastases were confirmed in 27 patients with breast cancer by positively pathological results and clinical follow-up. No recurrences and metastases in the remaining 10 patients.
1. The comparison of PET-CT, CT with PET in diagnosis of recurrences and metastases of breast cancer
PET-CT showed positive results in 28 patients with breast cancer. 27 patients were diagnosed correctly, and 8 negative PET-CT studies had no recurrences and metastases diseases. The sensitivity, specificity, accuracy, positive and negative predictive value in ~(18)F-FDG PET-CT prediction in recurrences and metastases of breast cancer was 96.30%, 80.00%, .91.89%, 92.86% and 88.89%.
In 27 patients of recurrences and metastases with breast cancer, 17 of them were diagnosed as positive and 10 as negative by helical CT; and in 10 patients of no recurrences and metastases, 7 of them were negative and 3 were positive by helical CT. The sensitivity, specificity, accuracy, positive and negative predictive value in CT prediction in recurrences and metastases of breast cancer was 62.96%, 70.00%, 64.86%, 85.00% and 41.18%.
Also,in 27 patients of recurrences and metastases with breast cancer, 21 of them were diagnosed as positive and 6 as negative by PET, and in 10 patients of no recurrences and metastases, 6 of them were negative and 4 were positive by PET. The sensitivity, specificity, accuracy, positive and negative predictive value in PET prediction in recurrences and metastases of breast cancer was 77.76%, 60.00%, 72.97%, 84.00% and 50.00%.
There was significant difference in sensitivity, accuracy and negative prediction between PET-CT and CT in prediction of recurrences and metastases of breast cancer (P<0.05). PET-CT and CT did not have significant differences in specificities and positive predictive value (P>0.05). There was a significant difference in accuracy between PET-CT and PET in prediction of recurrences and metastases of breast cancer (P<0.05). PET-CT and PET did not have significant differences in sensitivity, specificities, positive and negative prediction (P>0.05).
2. The comparison of PET-CT with CT in diagnosing lymph node metastases
55 lymph nodes of 37 patients were detected by helical CT, which 33 lymph nodes were proved positive by histopathology, biopsy, cytological examination, and clinical follow-up, and 22 lymph nodes were negative. 37 of all were diagnosed as positive and 18 as negative by helical CT. The sensitivity, specificity, accuracy, positive and negative predictive value in CT prediction in lymph nodes metastases of breast cancer was 81.82%, 54.55%, 70.91%, 72.97% and 66.67%.
64 lymph nodes of 37 patients were detected by PET-CT, which 39 lymph nodes were proved positive by histopathology, biopsy, cytological examination, and clinical follow-up, 25 lymph nodes were negative. 44 of all were diagnosed as positive and 20 as negative by PET-CT. The sensitivity, specificity, accuracy, positive and negative predictive value in ~(18)F-FDG PET-CT prediction in lymph nodes metastases of breast cancer was 97.44%, 76.00%, 89.06%, 86.36% and 95.00%.
There was significant difference in sensitivity, accuracy and negative prediction value between PET-CT and CT in prediction of lymph node metastases of breast cancer (P<0.05). PET-CT and CT did not have significant differences in specificities and positive prediction value (P>0.05). PET-CT is much better than helical CT in predicting whether the it was involved of the lymph nodes that the longest-shortest (SD) less than 5mm, PET-CT and helical CT have equal accuracy in predicting whether the lymph nodes that SD were greater than 5mm were involved cancer.
3. The diagnostic value of PET-CT dual-time point imaging
14 patients with breast cancer underwent PET-CT dual-time point imaging. Recurrences and metastases were diagnosis in 9 patients. Among them, 5 patients had SUV> 2.5 at (the early imaging) scan 1, and all showed increased at the delayed imaging (scan 2); the other 4 patients had SUVs between 1.5 and 2.5 at scan 1 which showed suspected positive, all of their SUVs increased at time point 2. 5 patients with no recurrences and metastases, only 1 patient with benign lesions had SUV> 2.5 at scan 1, and SUVs increased at time point 2; the other 4 patients that confirmed by clinical follow-up showed suspected positive at early and no change of SUV in scan 2.
4. The comparision of PET-CT, CT with PET in diagnosing distant metastases
27 patients with breast cancer that were detected distant metastases by positively pathological results and clinical follow-up, PET-CT showed positive results in 26 patients. There were 17 patients with axillary and supraclavicular lymph nodes metastases, 3 patients with pleura metastases, 8 patients with distant lymph nodes and (or) distant organ metastases (including 4 patients with lung and mediastinal lymph nodes metastases, 3 patients with liver, pleural and abdominal lymph nodes metastases, and 1 patient with inguinal lymph nodes metastases,), and 5 patients with bone metastases.
17 patients were detected distant metastases by helical CT, and there were 13 patients with axillary and supraclavicular lymph nodes metastases, 1 patient with liver metastases, 4 patients with lung metastases, 2 patients with pleural metastases, 1 patient with abdominal metastases.
22 patients were detected distant metastases by PET, and there were 15 patients with axillary and supraclavicular lymph nodes metastases, 2 patients with liver metastases, 4 patients with lung and mediastinal lymph nodes metastases, 3 patients with pleural and abdominal metastases, and 5 patients with bone metastases.
The sensitivity in ~(18)F-FDG PET-CT, CT and PET prediction in recurrences and metastases of breast cancer was 96.30%, 62.96%, .81.48%. There was significant difference in snesitivity between PET-CT and CT in prediction of recurrences and metastases of breast cancer (x2=9.247, P<0.05).
CONCLUSIONS: The specificity and positive predictive value in prediction the recurrences and metastases of breast cancer of helical CT are relatively high. It can provide correct information, and it is one of the effective methods in predicting the recurrences and metastases of breast cancer. But the sensitivity, accuracy and negative prediction in prediction of the recurrences and metastases of breast cancer is much lower than those of PET-CT. The sensitivity, specificity, positive predictive value and negative predictive value in prediction the recurrences and metastases of breast cancer of PET are relatively high. But the accuracy in prediction of the recurrences and metastases of breast cancer is much lower than those of PET-CT.
PET-CT is more accuracy than CT in diagnosing the positive lymph node metastasis and the false negative value is fewer than that of CT. There are no significant differences in specificities between PET-CT and CT for the lymph node metastases of breast cancer. But PET-CT is much better than helical CT in predicting whether it is involved of the lymph nodes that the SD less than 5mm. PET-CT and helical CT have equal accuracy in predicting whether it is involved the lymph node that SD is greater than 5mm.
PET-CT dual-time point imaging appeares to be helpful for differentiating benign lesions from malignant lesions, that the lesions have high uptake of ~(18)F-FDG at scan 1, and eliminate the interference from ~(18)F-FDG uptake in normal physiologic formation, post radio-chemotherapy inflammation or scar. It can improve the accuracy in the diagnosis of recurrence and metastasis of breast cancer.
In distant metastasis, PET-CT is more sensitive than helical CT in detecting liver metastasis and bone metastasis, but in detecting lung and abdominal metastasis PET-CT and CT have equal accuracy. Compared with CT and PET-CT, PET has low accuracy in detecting lung metastasis and abdominal metastasis.
In an overview, Integrated PET-CT scanner realizes the fuse of functional and anatomic imaging in one device, and it is superior to traditional imaging in evaluating curative effect for malignant tumors. For the patients with brast cancer who cannot be confirmed recurrence or metastasis by traditional diagnosis, PET-CT is the best choice.
. Compared with CT and PET, PET-CT can provide more information for choosing the best clinical treatment.
OBJECTIVE: To establish the method of labeling ATWLPPR with ~(99m)Tc, and the biodistribution of the anti-VEGF peptide in normal mice and the imaging study on tumour bearing nude mice were carried out. The purpose is to evaluate the feasibility of tumour receptor imaging with radiolabelled HYNIC-ATWLPPR in early diagnosis of malignancy.
METHODS: ATWLPPR labeling and character analysis of 99Tcm-HYNIC-ATWLPPR: ATWLPPR conjugating the bifunctional chelator-HYNIC was synthesized. The peptide was labeled with 99Tcm through an indirect method using tricine/EDDA as co-ligands. After 30～40 minutes at room temperature, the labeled mixture, named 99Tcm-HYNIC-ATWLPPR was completed. Absorbency at 280 nm and radioactivity were used to identigy peak fractions and count yield. We compared the radiolabeling yield of using different co-ligands for HYNIC conjugation and different activity of radioactivity. The radiolabeling yield, radiochemical purity, and stability of the 99Tcm-HYNIC-ATWLPPPR were assessed.
Mice model preparation, biodistribution study and imaging: (1) Biodistribution in normal mice: A total of 25 normal KM mice were used in biodistribution. Immediately after labeling, 1μg of radiolabeled ATWLPPR in 100μl eluent was injected into each mouse via a tail vein. At different time point post-injection, Whole blood samples were collected and the mice were sacrificed by cervical dislocation. The myocardium, liver, spleen, lung, kidney, brain, stomach, intestines, muscle, and bone were harvested, rinsed, weighed and counted on aγcounter. The percent uptake per gram tissue was calculated. (2) In vivo tumour imaging in tumour bearing nude mice: BALB/c A nude mice bearing human breast cancer cancer MCF-7 xenografts were studied. After injection of the radiotracers, static acquisitions imaging were performed at different time point with a gammar camera fitted with a general-purpose low-energy pinprick using a 256×256 matrix with a 20% energy window set at 140 keV. And radioactivity ratios of tumour to contralateral limbs were calculated using ROI technique. (3) Biodistribution in tumour bearing nude mice: Five tumour model nude mice were sacrificed 180min after radiotracer injection. Tumours, blood samples and organs were harvested, rinsed, weighed and counted on aγcounter. (4) Immunohistochemical analysis of tumour histological paraffin section: the expression of VEGF165 was examined by using SP method. And the negative control was set up.
RESULTS: ATWLPPR labeling and character analysis of 99Tcm-HYNIC-ATWLPPR: Using tricine, EDDA, and tricine/EDDA as co-ligands, the labeling yield of ~(99m)Tc-HYNIC-ATWLPPR was 77.75%,68.09%,91.531%,80% respectively. When the activities of 99TcmO4- were 185MBq, 74MBq and 37MBq, the radiolabeling yield of 99Tcm-HYNIC-ATWLPPR were 88.06%±1.05%、94.00%±1.25% and 91.61%±2.70%, respectively. The radiochemical purity of the 99Tcm-HYNIC-ATWLPPR was 94.14%±1.75%. After incubation with fresh human serum for 30min and 120min, the radiochemical purities were 91.5% and 90.8%, and analyzed by Sep-Pak C18 column, the radioactivity peak showed no shift to early or late fractions. The reaction mixture was incubated at room temperature for 5h, and the radiochemical purity was 91.35%. Mice model preparation, biodistribution study and imaging: (1) Biodistribution in normal mice: It indicated that the disappearance of radioactivity from plasma was rapid. ~(99m)Tc-HYNIC-ATWLPPR was mainly excreted through kidney and liver. (2) In vivo tumour imaging in tumour bearing nude mice: Tumour lesions were clearly visible 180min after injection and the ratios of tumour/contralateral limbs were 3.758 respectively. The ectent of accumulation increases with time with a peak tumour/contralateral limbs ratio (T/L) of 3.758 at three hours and then decreased to 1.754 at six hours in tumour mice. (3) Biodistribution in tumour bearing nude mice: The radioactivity of tumour nude mice accumulated in the kidney and liver was the highest, and in the brain was the lowest. The radioactivity ratios of tumour/brain and tumour/heart were 22.18 and 4.63, which were the highest. And the radioactivity ratios of tumour/muscle, tumour/skeleton and tumour/blood were 2.85, 1.89 and 1.59. (4) Immunohistochemical analysis of tumour histological paraffin section: the expression of VEGF165 was mainly seen in the endochylema of vascular endothelial cells, and there were brown granulocorpuscle or diffuse distribution. But in the negative control, the endochylema of vascular endothelial cells was not seen staining.
CONCLUSION: The labeling method of ATWLPPR conjugated by HYNIC has been proved successful. It is an optimal method with simple steps, high radiolabeling yield and well stability. Radiochemical was mainly excreted through kidney and liver, and high accumulation in the tumour in tumour bearing nude mice. The study of in vivo imaging and biodistribution showed that ~(99m)Tc-HYNIC-ATWLPPR remains fine biological activity, our data suggest ~(99m)Tc-HYNIC-ATWLPPR is a promising tumour radiotracer.
材料与方法:收集2003年11月至2006年3月间,临床疑乳腺癌术后复发或转移患者37例(均为女性,年龄37 ~ 68岁,平均51±6.3岁)。37例均采用GE Discovery LS PET-CT行~(18)F-脱氧葡萄糖(~(18)F-FDG)PET-CT显像,图像经迭代重建后传至工作站(GE Entegra)进行图像融合。局部延迟显像于注射后2.5 ~ 3h进行双时相显像。2次显像条件一致。37例患者在PET-CT之前或之后1月内进行了多层螺旋CT扫描。经二位有经验的核医学医师和1位放射学医师分别对PET、CT及融合图像进行分析评价。螺旋CT诊断腋窝淋巴结转移的标准是:淋巴结长径(L)大于10mm或短径(S)大于5mm;淋巴结长短径比率(L/S)小于或等于2,即L/S≤2;淋巴结周围脂肪密度增高模糊。远处区域淋巴结最小径≥8mm,如果淋巴结成串或呈环状增强,则不必强调大小。当符合以上标准时,该淋巴结记录为阳性(淋巴结有转移),不符合标准时记录为阴性(淋巴结无转移)。PET-CT图像分析采用两种方法对图像进行分析:(1)目测法:根据放射性浓聚程度,将病灶分为两种类型:病灶的~(18)F-FDG摄取量高于正常周围组织为阳性;~(18)F-FDG摄取量与周围组织相近或其摄取量低于周围组织或无摄取为阴性。(2)半定量分析法:在~(18)F-FDG浓聚的病灶部位设感兴趣区(region of interest,ROI),由计算机程序自动计算病灶部位的最大标准摄取值(SUVmax)和平均标准摄取值(SUVmean),以SUVmean≥2.5为阳性,SUVmean<2.5为阴性。双时相显像以延迟显像SUV值增加(ΔSUV%=(SUV_(延迟)-SUV_(早期))/(SUV_(早期))×100%)大于10%判断为增高阳性。最后通过融合图像进行具体诊断、准确定位。
将PET-CT、螺旋CT及PET对乳腺癌复发及转移病灶的检出结果分别与近期组织病理检查、活检或细胞学检查,和临床随访(4 ~ 29个月)结果进行对照。
采用x~2检验和四格表资料的精确概率法,计算P值,统计学检验结果均以P<0.05作为有显著性差异的判断标准。
结果:经组织病理学、活检或细胞学检查,和临床随访,37例患者中,27例乳腺癌患者诊断为术后复发和/或转移,余10例未见乳腺癌复发及转移。
1. PET-CT,CT和PET在乳腺癌术后复发和/或转移诊断的中比较
PET-CT:28例患者PET-CT显像为阳性,其中26例最终确诊为真阳性,2例诊断为假阳性。18F-FDG PET-CT检出乳腺癌术后复发和/或转移的灵敏度为96.30%(26/27例),特异性为80.00%(8/10例),准确性为.91.89%(34/37例),阳性预测值为92.86%(26/28例),阴性预测值为88.89%(8/9例)。
螺旋CT:27例经确诊为术后乳腺癌复发和/或转移的患者中,17例CT诊断为阳性,10例CT诊断为阴性;10例经确诊为术后未见复发和/或转移的患者中,7例为CT诊断为阴性,3例CT诊断为阳性。螺旋CT对乳腺癌术后复发和/或转移诊断的灵敏度为62.96%(17/27例),特异性为70.00%(7/10例),准确性为64.86%(24/37例),阳性预测值为85.00%(17/20例),阴性预测值为41.18%(7/17例)。
PET:27例经确诊为术后乳腺癌复发和/或转移的患者中,21例PET诊断为阳性,6例PET诊断为阴性;10例经确诊为术后未见复发和/或转移的患者中,6例PET诊断为阴性,4例PET诊断为阳性。PET诊断乳腺癌术后复发和/或转移的灵敏度为77.76%(21/27例),特异性为60.00%(6/10例),准确性为72.97%(27/37例),阳性预测值为84.00%(21/25例),阴性预测值为50.00%(6/12例)。
CT与PET-CT对乳腺癌术后复发和/或转移定性诊断的灵敏度之间、准确性之间和阴性预测值差异有显著意义,P<0.05,即PET-CT对乳腺癌术后复发和/或转移诊断的灵敏度、准确性和阴性预测值明显较CT高。CT、PET-CT对乳腺癌术后复发和/或转移定性诊断的特异性之间和阳性预测值之间差异不存在显著意义,P>0.05,即CT与PET-CT对乳腺癌术后复发和/或转移定性诊断的特异性和阳性预测值相当。
PET与PET-CT在诊断乳腺癌复发和/或转移定性方面的灵敏度之间、特异性之间、阳性预测值之间和阴性预测值之间差异无明显意义,P>0.05,即PET与PET-CT对乳腺癌术后复发和/或转移定性诊断的灵敏度、特异性、阳性预测值和阴性预测值相当。在PET和PET-CT对乳腺癌术后复发和/或转移诊断的准确性之间差异有明显意义,P<0.05,即PET-CT的准确性高于PET。
2. PET-CT和CT在乳腺癌术后淋巴转移诊断的比较
37例患者行螺旋CT局部检查共检出淋巴结55枚,其中37枚CT诊断为阳性,18枚为阴性;经组织病理学、活检或细胞学检查,和临床随访诊断,有33枚被确诊为阳性,22枚为阴性。行PET-CT全身检查患者共检出淋巴结64枚,其中44枚PET-CT显像为阳性,20枚为阴性;经组织病理学、活检或细胞学检查,和临床随访诊断,有39枚被确诊为阳性,25枚为阴性。
CT对淋巴结转移定性诊断的灵敏度、特异性、准确性、阳性预测值及阴性预测值分别为81.82%(27/33例)、54.55%(12/22例)、70.91%(39/55例)、72.97%(27/37例)、66.67%(12/18例);PET-CT对淋巴结转移定性诊断的灵敏度、特异性、准确性、阳性预测值及阴性预测值,分别为97.44%(38/39例)、76.00%(19/25例)、89.06%(57/64例)、86.36%(38/44例)及95.00%(19/20例)。
CT与PET-CT对乳腺癌术后淋巴结转移定性诊断的灵敏度之间、准确性之间及阴性预测值之间的差异有显著意义,P<0.05,即PET-CT显像在乳腺癌术后诊断淋巴结转移阳性时明显较CT准确;CT、PET-CT对淋巴结转移定性的特异性之间及阳性预测值之间的差异无明显意义,P>0.05,即CT与PET-CT对乳腺癌术后淋巴结转移的特异性和阳性预测值相当。PET-CT对短径小于5mm的淋巴结检测准确性优于螺旋CT。对于短径大于5mm的淋巴结的检测,CT与PET-CT检测的结果基本一致,均具有较高敏感性、特异性和准确性,二者之间无明显差异。
3. PET-CT双时相显像对乳腺癌术后复发和/或转移的诊断价值
14例乳腺癌术后患者行PET-CT双时相显像,9例患者被确诊为复发和/或转移,其中早期显像5例SUV值为阳性,延迟显像明显增高(ΔSUV>10%);4例早期显像病灶SUV值为可疑阳性,延迟显像均有不同程度增高(ΔSUV>10%)。5例未见复发和转移的患者中,1例早期显像SUV值为阳性,延迟显像增高(ΔSUV>10%),经手术后病检证实为假阳性,组织病理学检查结果为甲状腺腺瘤;余4例延迟显像未见明显增高,经临床随访证实均为良性病变。
4. PET-CT、CT、PET在乳腺癌术后远处转移诊断的比较
37例乳腺癌术后患者中,综合诊断最终确诊27例患者有复发和/或转移病灶,其中经PET-CT显像检查确诊的患者有26例,经螺旋CT检查确诊的患者有17例,经PET显像检查确诊的患者有22例。
26例经PET-CT显像检查诊断为术后淋巴结和/或脏器转移的患者中,17例有腋窝及锁骨上淋巴结转移,3例胸膜转移,8例远处淋巴结和/或远处脏器转移,5例骨转移。8例远处淋巴结和/或远处脏器转移包括4例肺转移伴纵隔淋巴结转移,3例肝转移伴腹腔或腹膜后淋巴结转移,及1例腹股沟淋巴结转移。
17例经螺旋CT检查诊断为术后淋巴结和/或脏器转移的患者中,13例有腋窝及锁骨上淋巴结转移,1例肝转移,4例肺转移,2例胸膜转移,1例肝门区、胃窦后部及腹主动脉旁转移。
22例经PET检查诊断为术后淋巴结和/或脏器转移的患者中,15例有腋窝及锁骨上淋巴结转移,2例肝脏转移,4例肺转移伴纵隔淋巴结转移,3例腹部及盆腔转移,5例全身骨转移。
18F-FDG PET-CT显像、CT显像和PET显像检出复发和/或转移灶的灵敏度分别为96.30%(26/27例)、62.96%(17/27例)、81.48%(22/27例),PET-CT显像和CT显像监测复发及转移灶的灵敏度两者差异有显著性(x~2=9.247),P<0.05,即PET-CT监测乳腺癌术后复发及转移灶的灵敏度明显于CT。
结论:螺旋CT对乳腺癌术后复发和/或转移定性诊断有较高的特异性及阳性预测值,能为临床诊断提供较准确的信息,是监测乳腺癌术后复发和/或转移的一种有效方法。但CT对乳腺癌术后复发和/或转移定性诊断的灵敏度、准确性和阴性预测值明显低于PET-CT。PET在灵敏度、特异性、阳性预测值和阴性预测值方面较准确,但其准确性明显低于PET-CT。
PET-CT诊断乳腺癌术后淋巴结转移时明显较CT准确,假阴性率较CT小。对乳腺癌术后淋巴结转移定性诊断,CT与PET-CT时的特异性相当。在对短径小于5mm的淋巴结作为转移定性诊断时,其准确率优于螺旋CT;而对于短径大于5mm的淋巴结作转移定性时,PET-CT和螺旋CT的准确率相当,没有明显的优劣之分。
PET-CT双时相显像有助于鉴别乳腺癌术后患者早期显像中难以鉴别的良恶性高~(18)F-FDG浓聚病灶,可以排除正常生理结构摄取~(18)F-FDG、放化疗后炎症或瘢痕增生所带来的干扰,提高诊断准确率。
对于远处转移,PET-CT在肝脏转移及全身骨转移的诊断方面比螺旋CT灵敏,在肺及腹部转移的诊断显像方面PET-CT和CT诊断的准确率相当。PET对于肺及腹部转移的诊断准确率较CT和PET-CT要低。
综上所述,PET-CT在恶性肿瘤的治疗疗效评价方面具有传统影像检查难以比及的优势。PET-CT将具有解剖功能的CT和功能分子代谢的PET有机结合了在一起,具有同机图像融合的功能。对于那些临床检查或常规影像学检查难以进行或诊断不明确的患者,特别是不愿意接受创伤性诊断的病人,PET-CT可作为其诊断乳腺癌有无复发及转移的最佳选择。与CT和PET比较,PET-CT能更准确诊断乳腺癌复发及转移,能为指导临床制定正确的治疗方案提供重要信息。
目的:研究99Tcm标记肿瘤新生血管多肽的标记制备方法,其在正常小鼠体内的生物学分布特征以及对荷乳腺癌裸鼠模型进行显像,探讨核素标记抗血管内皮生长因子的七肽ATWLPPR用于肿瘤分子影像诊断的价值。
方法:~(99m)Tc-HYNIC-ATWLPPR标记条件及其特性的研究:合成ATWLPPR,采用间接标记法,以联结剂肼基尼古酰胺(HYNIC)为双功能螯合剂,三(羟甲基)甲基甘氨酸(tricine)与乙二胺二乙酸(EDDA)作为协同配体。紫外(280nm)分光和γ计数仪分别检测标记物蛋白质含量和标记率。设立三个实验组,ATWLPPR与HYNIC偶联后分别采用tricine、EDDA、和tricine/EDDA作为协同配体,研究协同配体的改变对标记率的影响。用不同放射性活度锝(185MBq,74MBq和37MBq)标记HYNIC-ATWLPPR,研究其对标记率的影响。对标记物的标记率、放化纯、稳定性进行研究。
生物分布和显像研究:(1)正常小鼠体内生物学分布研究:正常昆明小鼠25只,随机分为5组,分别于尾静脉注射~(99m)Tc-HYNIC-ATWLPPR,每只动物注入标记物7.4MBq,注射后15min、30min、60min、180min、300min处死,取不同组织器官称重并测量放射性计数,经时间衰减校正后计算每克组织的百分注射量(%ID/g)。(2)荷乳腺癌裸鼠显像研究:荷乳腺癌裸鼠于注射示踪剂后30min、60min、120min、180min、360min进行全身平面显像,图像处理采用感兴趣区(ROI)技术,计算不同时间肿瘤与胸部及对侧相应部位的放射性比值。(3)荷乳腺癌裸鼠体内分布研究:5只荷瘤裸鼠于注射示踪剂180min后处死,取不同组织器官及肿瘤组织称重并测量放射性计数,计算各脏器及肿瘤的摄取比值。(4)肿瘤组织切片免疫组织化学研究:采用免疫组织化学染色SP法(链霉卵白素-过氧化物酶法技术),检测VEGF165的表达水平,并设立阴性对照组。
结果:~(99m)Tc-HYNIC-ATWLPPR标记条件及其特性的研究:分别采用tricine、EDDA和tricine/EDDA作为协同配体,~(99m)Tc-HYNIC-ATWLPPR标记率依次为77.75%,68.09%和91.531%。使用不同放射性活度185MBq、74MBq和37MBq的99Tcm标记时,标记率分别为88.06%±1.05%、94.00%±1.25%和91.61%±2.70%(n=5)。用tricine/EDDA作为协同配体标记,99Tcm-HYNIC-ATWLPPR放化纯为94.14%±1.75%。标记物与新鲜人血清孵育30min和120min后,放射化学纯度分别为91.5%和90.8%;经Sep-Pak C18反相层析柱分析,其间放射性峰均未见漂移。于室温下放置5h,其放射化学纯度仍为91.35%。
生物分布和显像的研究:(1)正常小鼠体内生物学分布研究:~(99m)Tc-HYNIC-ATWLPPR在血中清除较快,主要以肾脏和肝脏排泄(。2)荷乳腺癌裸鼠显像研究:注射后180min肿瘤部位的放射性浓聚最高,显像效果最佳,肿瘤与对侧相应部位的放射性比值为3.758。(3)荷乳腺癌裸鼠体内生物学分布研究:肝脏和肾脏的摄取最高,脑部的摄取最低;T/NT摄取比显示肿瘤与脑,肿瘤与心脏的摄取比值较高,分别为22.18和4.63,其次为肿瘤与肌肉,肿瘤与骨骼,肿瘤与肌肉分别为2.85、1.89和1.59。(4)VEGF165的表达主要见于血管内皮细胞胞浆中,呈棕色颗粒状或弥漫性分布。阴性对照的血管内皮细胞胞浆中未见染色。
结论:以HYNIC作为双功能螯合剂标记肿瘤新生血管多肽ATWLPPR方法可行,步骤简便,标记率高,体外稳定性好;体内主要以肾脏和肝脏排泄,肿瘤部位~(99m)Tc标记的HYNIC-ATWLPPR有较高浓聚。体内显像和生物分布研究均表明标记后的~(99m)Tc-HYNIC-ATWLPPR仍保持良好的生物学特性,是一种有良好应用前景的肿瘤诊断显像剂。
OBJECTIVE: To evaluate the applicable value of ~(18)F-fluorodeoxyglucose(FDG) PET-CT in the prediction of recurrences and metastases of breast cancer by comparing helical CT, PET with PET-CT.
MATERIALS AND METHODS: The analysis was based on 37 cases with breast cancer (37 females, age range 37~68y, mean age 51±6.3y) which were collected from December, 2003 to March, 2006. All patients underwent ~(18)F-FDG PET-CT imaging with GE Discovery PET-CT and helical CT. PET-CT imaging was reconstructed and transferred to the working station (GE Entegra) for images fusion. The scan 2 of the dual-time point ~(18)F-FDG-PET-CT imaging was at 150– 180 min after the intravenous injection, and the acquisition parameters of the scan 2 were the same as the scan 1 in the PET-CT dual-time point imaging. PET-CT images were evaluated by two experienced nuclear medicine physicians and one radiologist in consensus. The positive diagnosis standards for metastases of the axillary lymph nodes were as the following: the long diameter (L) was greater than 10mm or the short diameter (S) was greater than 5mm, or L/S less than 2, and the fat around the node with high density. Distant lymph node metastasis assessment was based on its size, with a short axis diameter exceeding. But if the lymph nodes were bunchiness or ringlike enhanced, their size can not be emphasized. When the lymph node was accorded to the standarde, the diagnosis was positive, otherwise negative. Two kinds of methods were used to analyze the PET-CT images: (1) Eyeballing analysis: the lesions were divided into two types according to the degrees of radioactivity accumulation. Positive account: ~(18)F-FDG uptake in lesion was higher than that in surrounding normal tissue; negative account: ~(18)F-FDG uptakes in lession were similar to or lower than that in surrounding normal tissue. (2) Semiquantitative analysis: The regions of interest (ROI) were placed in lesions, and the average standard uptake value (SUVmean) and the maximum standard uptake value (SUVmax) of the lesions were automatically calculated with the computer software. SUVmean≥2.5 were diagnosed as positive lesions, and SUVmean<2.5 were diagnosed as negative lesions. The SUV changes >10% (ΔSUV%=(SUV_2-(SUV_1)/(SUV_1)×100%) between the first and second scans was as a criterion for abnormal increase or decrease. All lesions were analysed with both eyeballing and semiquantitative analysis.
The results of PET-CT, PET and CT were compared with those of the histopathology, biopsy, cytological examination, and clinical follow-up results.
The results were statistically analyzed with exact probabilities in 2×2 tables or t-test (SPSS software). P<0.05 was defined as a criterion for significant difference.
RESULTS: Recurrences and metastases were confirmed in 27 patients with breast cancer by positively pathological results and clinical follow-up. No recurrences and metastases in the remaining 10 patients.
1. The comparison of PET-CT, CT with PET in diagnosis of recurrences and metastases of breast cancer
PET-CT showed positive results in 28 patients with breast cancer. 27 patients were diagnosed correctly, and 8 negative PET-CT studies had no recurrences and metastases diseases. The sensitivity, specificity, accuracy, positive and negative predictive value in ~(18)F-FDG PET-CT prediction in recurrences and metastases of breast cancer was 96.30%, 80.00%, .91.89%, 92.86% and 88.89%.
In 27 patients of recurrences and metastases with breast cancer, 17 of them were diagnosed as positive and 10 as negative by helical CT; and in 10 patients of no recurrences and metastases, 7 of them were negative and 3 were positive by helical CT. The sensitivity, specificity, accuracy, positive and negative predictive value in CT prediction in recurrences and metastases of breast cancer was 62.96%, 70.00%, 64.86%, 85.00% and 41.18%.
Also,in 27 patients of recurrences and metastases with breast cancer, 21 of them were diagnosed as positive and 6 as negative by PET, and in 10 patients of no recurrences and metastases, 6 of them were negative and 4 were positive by PET. The sensitivity, specificity, accuracy, positive and negative predictive value in PET prediction in recurrences and metastases of breast cancer was 77.76%, 60.00%, 72.97%, 84.00% and 50.00%.
There was significant difference in sensitivity, accuracy and negative prediction between PET-CT and CT in prediction of recurrences and metastases of breast cancer (P<0.05). PET-CT and CT did not have significant differences in specificities and positive predictive value (P>0.05). There was a significant difference in accuracy between PET-CT and PET in prediction of recurrences and metastases of breast cancer (P<0.05). PET-CT and PET did not have significant differences in sensitivity, specificities, positive and negative prediction (P>0.05).
2. The comparison of PET-CT with CT in diagnosing lymph node metastases
55 lymph nodes of 37 patients were detected by helical CT, which 33 lymph nodes were proved positive by histopathology, biopsy, cytological examination, and clinical follow-up, and 22 lymph nodes were negative. 37 of all were diagnosed as positive and 18 as negative by helical CT. The sensitivity, specificity, accuracy, positive and negative predictive value in CT prediction in lymph nodes metastases of breast cancer was 81.82%, 54.55%, 70.91%, 72.97% and 66.67%.
64 lymph nodes of 37 patients were detected by PET-CT, which 39 lymph nodes were proved positive by histopathology, biopsy, cytological examination, and clinical follow-up, 25 lymph nodes were negative. 44 of all were diagnosed as positive and 20 as negative by PET-CT. The sensitivity, specificity, accuracy, positive and negative predictive value in ~(18)F-FDG PET-CT prediction in lymph nodes metastases of breast cancer was 97.44%, 76.00%, 89.06%, 86.36% and 95.00%.
There was significant difference in sensitivity, accuracy and negative prediction value between PET-CT and CT in prediction of lymph node metastases of breast cancer (P<0.05). PET-CT and CT did not have significant differences in specificities and positive prediction value (P>0.05). PET-CT is much better than helical CT in predicting whether the it was involved of the lymph nodes that the longest-shortest (SD) less than 5mm, PET-CT and helical CT have equal accuracy in predicting whether the lymph nodes that SD were greater than 5mm were involved cancer.
3. The diagnostic value of PET-CT dual-time point imaging
14 patients with breast cancer underwent PET-CT dual-time point imaging. Recurrences and metastases were diagnosis in 9 patients. Among them, 5 patients had SUV> 2.5 at (the early imaging) scan 1, and all showed increased at the delayed imaging (scan 2); the other 4 patients had SUVs between 1.5 and 2.5 at scan 1 which showed suspected positive, all of their SUVs increased at time point 2. 5 patients with no recurrences and metastases, only 1 patient with benign lesions had SUV> 2.5 at scan 1, and SUVs increased at time point 2; the other 4 patients that confirmed by clinical follow-up showed suspected positive at early and no change of SUV in scan 2.
4. The comparision of PET-CT, CT with PET in diagnosing distant metastases
27 patients with breast cancer that were detected distant metastases by positively pathological results and clinical follow-up, PET-CT showed positive results in 26 patients. There were 17 patients with axillary and supraclavicular lymph nodes metastases, 3 patients with pleura metastases, 8 patients with distant lymph nodes and (or) distant organ metastases (including 4 patients with lung and mediastinal lymph nodes metastases, 3 patients with liver, pleural and abdominal lymph nodes metastases, and 1 patient with inguinal lymph nodes metastases,), and 5 patients with bone metastases.
17 patients were detected distant metastases by helical CT, and there were 13 patients with axillary and supraclavicular lymph nodes metastases, 1 patient with liver metastases, 4 patients with lung metastases, 2 patients with pleural metastases, 1 patient with abdominal metastases.
22 patients were detected distant metastases by PET, and there were 15 patients with axillary and supraclavicular lymph nodes metastases, 2 patients with liver metastases, 4 patients with lung and mediastinal lymph nodes metastases, 3 patients with pleural and abdominal metastases, and 5 patients with bone metastases.
The sensitivity in ~(18)F-FDG PET-CT, CT and PET prediction in recurrences and metastases of breast cancer was 96.30%, 62.96%, .81.48%. There was significant difference in snesitivity between PET-CT and CT in prediction of recurrences and metastases of breast cancer (x2=9.247, P<0.05).
CONCLUSIONS: The specificity and positive predictive value in prediction the recurrences and metastases of breast cancer of helical CT are relatively high. It can provide correct information, and it is one of the effective methods in predicting the recurrences and metastases of breast cancer. But the sensitivity, accuracy and negative prediction in prediction of the recurrences and metastases of breast cancer is much lower than those of PET-CT. The sensitivity, specificity, positive predictive value and negative predictive value in prediction the recurrences and metastases of breast cancer of PET are relatively high. But the accuracy in prediction of the recurrences and metastases of breast cancer is much lower than those of PET-CT.
PET-CT is more accuracy than CT in diagnosing the positive lymph node metastasis and the false negative value is fewer than that of CT. There are no significant differences in specificities between PET-CT and CT for the lymph node metastases of breast cancer. But PET-CT is much better than helical CT in predicting whether it is involved of the lymph nodes that the SD less than 5mm. PET-CT and helical CT have equal accuracy in predicting whether it is involved the lymph node that SD is greater than 5mm.
PET-CT dual-time point imaging appeares to be helpful for differentiating benign lesions from malignant lesions, that the lesions have high uptake of ~(18)F-FDG at scan 1, and eliminate the interference from ~(18)F-FDG uptake in normal physiologic formation, post radio-chemotherapy inflammation or scar. It can improve the accuracy in the diagnosis of recurrence and metastasis of breast cancer.
In distant metastasis, PET-CT is more sensitive than helical CT in detecting liver metastasis and bone metastasis, but in detecting lung and abdominal metastasis PET-CT and CT have equal accuracy. Compared with CT and PET-CT, PET has low accuracy in detecting lung metastasis and abdominal metastasis.
In an overview, Integrated PET-CT scanner realizes the fuse of functional and anatomic imaging in one device, and it is superior to traditional imaging in evaluating curative effect for malignant tumors. For the patients with brast cancer who cannot be confirmed recurrence or metastasis by traditional diagnosis, PET-CT is the best choice.
. Compared with CT and PET, PET-CT can provide more information for choosing the best clinical treatment.
OBJECTIVE: To establish the method of labeling ATWLPPR with ~(99m)Tc, and the biodistribution of the anti-VEGF peptide in normal mice and the imaging study on tumour bearing nude mice were carried out. The purpose is to evaluate the feasibility of tumour receptor imaging with radiolabelled HYNIC-ATWLPPR in early diagnosis of malignancy.
METHODS: ATWLPPR labeling and character analysis of 99Tcm-HYNIC-ATWLPPR: ATWLPPR conjugating the bifunctional chelator-HYNIC was synthesized. The peptide was labeled with 99Tcm through an indirect method using tricine/EDDA as co-ligands. After 30～40 minutes at room temperature, the labeled mixture, named 99Tcm-HYNIC-ATWLPPR was completed. Absorbency at 280 nm and radioactivity were used to identigy peak fractions and count yield. We compared the radiolabeling yield of using different co-ligands for HYNIC conjugation and different activity of radioactivity. The radiolabeling yield, radiochemical purity, and stability of the 99Tcm-HYNIC-ATWLPPPR were assessed.
Mice model preparation, biodistribution study and imaging: (1) Biodistribution in normal mice: A total of 25 normal KM mice were used in biodistribution. Immediately after labeling, 1μg of radiolabeled ATWLPPR in 100μl eluent was injected into each mouse via a tail vein. At different time point post-injection, Whole blood samples were collected and the mice were sacrificed by cervical dislocation. The myocardium, liver, spleen, lung, kidney, brain, stomach, intestines, muscle, and bone were harvested, rinsed, weighed and counted on aγcounter. The percent uptake per gram tissue was calculated. (2) In vivo tumour imaging in tumour bearing nude mice: BALB/c A nude mice bearing human breast cancer cancer MCF-7 xenografts were studied. After injection of the radiotracers, static acquisitions imaging were performed at different time point with a gammar camera fitted with a general-purpose low-energy pinprick using a 256×256 matrix with a 20% energy window set at 140 keV. And radioactivity ratios of tumour to contralateral limbs were calculated using ROI technique. (3) Biodistribution in tumour bearing nude mice: Five tumour model nude mice were sacrificed 180min after radiotracer injection. Tumours, blood samples and organs were harvested, rinsed, weighed and counted on aγcounter. (4) Immunohistochemical analysis of tumour histological paraffin section: the expression of VEGF165 was examined by using SP method. And the negative control was set up.
RESULTS: ATWLPPR labeling and character analysis of 99Tcm-HYNIC-ATWLPPR: Using tricine, EDDA, and tricine/EDDA as co-ligands, the labeling yield of ~(99m)Tc-HYNIC-ATWLPPR was 77.75%,68.09%,91.531%,80% respectively. When the activities of 99TcmO4- were 185MBq, 74MBq and 37MBq, the radiolabeling yield of 99Tcm-HYNIC-ATWLPPR were 88.06%±1.05%、94.00%±1.25% and 91.61%±2.70%, respectively. The radiochemical purity of the 99Tcm-HYNIC-ATWLPPR was 94.14%±1.75%. After incubation with fresh human serum for 30min and 120min, the radiochemical purities were 91.5% and 90.8%, and analyzed by Sep-Pak C18 column, the radioactivity peak showed no shift to early or late fractions. The reaction mixture was incubated at room temperature for 5h, and the radiochemical purity was 91.35%. Mice model preparation, biodistribution study and imaging: (1) Biodistribution in normal mice: It indicated that the disappearance of radioactivity from plasma was rapid. ~(99m)Tc-HYNIC-ATWLPPR was mainly excreted through kidney and liver. (2) In vivo tumour imaging in tumour bearing nude mice: Tumour lesions were clearly visible 180min after injection and the ratios of tumour/contralateral limbs were 3.758 respectively. The ectent of accumulation increases with time with a peak tumour/contralateral limbs ratio (T/L) of 3.758 at three hours and then decreased to 1.754 at six hours in tumour mice. (3) Biodistribution in tumour bearing nude mice: The radioactivity of tumour nude mice accumulated in the kidney and liver was the highest, and in the brain was the lowest. The radioactivity ratios of tumour/brain and tumour/heart were 22.18 and 4.63, which were the highest. And the radioactivity ratios of tumour/muscle, tumour/skeleton and tumour/blood were 2.85, 1.89 and 1.59. (4) Immunohistochemical analysis of tumour histological paraffin section: the expression of VEGF165 was mainly seen in the endochylema of vascular endothelial cells, and there were brown granulocorpuscle or diffuse distribution. But in the negative control, the endochylema of vascular endothelial cells was not seen staining.
CONCLUSION: The labeling method of ATWLPPR conjugated by HYNIC has been proved successful. It is an optimal method with simple steps, high radiolabeling yield and well stability. Radiochemical was mainly excreted through kidney and liver, and high accumulation in the tumour in tumour bearing nude mice. The study of in vivo imaging and biodistribution showed that ~(99m)Tc-HYNIC-ATWLPPR remains fine biological activity, our data suggest ~(99m)Tc-HYNIC-ATWLPPR is a promising tumour radiotracer.
引文
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35. Siggelkow W, Zimny M, Faridi A, et al. The value of positron emission tomography in the follow-up for breast caner. Anticancer Res, 2003, 23(2C):1859-1867
1. Li WW, Jaffe M, Li VW, et al. Lwssons to be learned from clinical trials of angiogenesis modulators in ischemic diseases. In: Rubanyi GM, ed. Angiogenesis in heslth and disease: basic mechanisms and clinical application. New York, NY: Dekker, 2000, 519-536.
2. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 1992, 359: 843-845.
3. Ikeda E, Achen MG, Breier G, et al. Vascular endothelial growth factor, a potent and selective angiogenic agent [J]. Biol Chem, 1995, 270:19761-19766.
4. Ferrara N, Davis-Smith T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18:4-25.
5. Neufeld G, Cohen T, Shraga N. The Neuropilins: Multifunctional Semaphorin and VEGF receptor that modulate axon guidance and angiogenesis. Trends Cardiovasc Med, 2002,12: 13-19.
6. Binetruy-Tournaire R, Demangel C, Malavaud B, et al. Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. EMBO J 2000; 19(7):1525-1533.
7. Starzec A, Vassy R, Hamma-Kourbali Y, et al. Heptapeptide A7R competes forVEGF165 binding to neuropilin-1 but not to VEGFR2/KDR. First Interdisciplinary Conference on Angiogenesis: Paris 6–9 October 2001.
8. Rodrigues S, Van Aken E, Van Bocxlaer S, et al. Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J, 2003, 17(1): 7-16.
9. Janssen AP, Schiffelers RM, ten Hagen TL, et al. Peptide-targeted PEG-liposomes in anti-angiogenic therapy. Int J Pharm, 2003, 254(1): 55-58.
10. Renno RZ, Terada Y, Haddadin MJ, et al. Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2. Arch Ophthalmol, 2004, 122(7): 1002-1011.
11. Winer RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases [J]. Apple Radiat Isot, 2002, 57(5): 749-763.
12. Decristoforo C, Mather SJ. Technetium-99m somatostatin analogues: effect of labeling methods and peptide sequece. Eur J Nucl Med. 1999; 26:869-876.
13. Holash J, Maisonpierre PC, Compton DR, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284: 1994-1998.
14. Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its veceptors. FASEB J 1999 ; 13 (1) : 9.
15. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by bypoxia may mediate bypoxia - initiated angiogenesis. Nature 1992; 359: 843.
16. Brown FJ, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract [J]. Cancer Res, 1993, 53: 4727-4735.
17. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor induced angiogenesis suppresses tumour growth i n vivo[J]. Nature, 1993, 362: 841-844.
18. Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell, 1998, 92 (6): 735-745.
19. Soker S, Fidder H, Neufeld G, et al. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J Biol Chem, 1996, 271 (10): 5761-5767.
20. Miao HQ, Lee P, Lin H et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J, 2000, 14 (15):2532-2539.
21. Bachelder RE, Crago A, Chung J, et al. Vascular Endot helial growt h factor is an autocrine survival factor for neuropilin-expression breast carcinoma cells [J]. Cancer Research, 2001, 61 (15):5736-5740.
22. Perret GY, Starzec A, Hauet N, et al. In vitro evaluation and biodistribution of a 99mTc-labeled anti-VEGF peptide targeting neuropilin-1. Nucl Med Biol. 2004 Jul; 31(5):575-581.
23. Labrceque L, Royal I, Surprenant DS, et al. Regulation of vascular endothelial growth factor recetor-2 activity by caveolin-1 and plasma membrane cholesterol. Mol Biol Cell. 2003, 14(1):334-347.
24. Maeshima Y, Sudhakar A, Lively JC, et al. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science, 2002, 295(5552):140-143.
25. Liu S, Edwards DS. 99mTc-Labeled Small Peptides as Diagnostic Radiopharmaceuticals. Chem Rev, 1999; 99(9): 2235-68.
26. Liu S, Edwards DS, Looby RJ, et al. Labeling a hydrazino nicotinamide-modified cyclic IIb/IIIa receptor antagonist with 99mTc using aminocarboxylates as coligands. Bioconjug Chem, 1996; 7(1): 63-71
27. Edwards DS, Liu S. 99mTc-labelling of hydrazenonicotinamide(HYNIC) modified highly potent small molecules: problems and solutions[J]. Transition Met Chem, 1997, 22(40: 425-426.
28. Verbeke K, Kieffer D , Vanderheyden J L et al. Optimization of the preparation of 99m Tc labeled Hynic-derivatized AnnexinⅤfor human use1 Nucl Med Biol, 2003, 30: 771.
1. Pederson M W, Holm S, Lund K L, et al. Coregulation of glucose uptake and vascular endothelial factor(VEGF) IN two small-cell lung cancer(SCLC) sublines in vivo and in vitro[J]. Neoplasia, 2001, 3(1): 80-87
2. Wolfgang A, Weber. Use of PET for monitoring cancer therapy and for predicting outcome [J]. J Nucl Med, 2005, 46(6): 983-995.
3. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer[J]. J Clin Oncol, 2003, 21(7): 1285-1292.
4. Holloway CL, Robinson D, Murray B, et al. Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET-CT imaging with induction chemotherapy for patients with non-small cell lung cancer[J].Radiother Oncol, 2004, 73(3): 285-287.
5. Kostakoglu L, Goldsmith SJ. 18F–FDG PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma [J]. J Nucl Med, 2003, 44(2): 224-239.
6. Brock CS, Young H, O’Reilly SM, et al. Early evaluation of tumor metabolic response using18F-fluorodeoxyglucose and positron emission tomography: a pilot study following the phaseⅡchemotherapy schedule for temozolomide in recurrent high grade gliomas. Br J Cancer, 2000, 82(3):608-615.
7. Yen TD, Chang JT, Ng SH, et al. The value of 18F-FDG in the detection of stage M0 carcinoma of the nasopharynx [J]. J Nucl Med, 2005, 46(3): 405-410.
8. Wild D, Eyrich GK, Ciernik IF,et al. In-line (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT) in patients with carcinoma of the sinus/nasal area and orbit. J Craniomaxillofac Surg. 2006; 34(1): 9-16.
9. Nahas Z, Goldenberg, D, Fakhry C, et al. The role of positron emission tomography/computed tomography in the management of recurrent papillary thyroid carcinoma [J]. Laryngoscope, 2005, 115(2): 237-243.
10. Keidar Z, Haim N, Guralnik L, et al. PET-CT using 18F-FDG in suspected lung cancer recurrence: diagnostic value and impact on patient management [J]. J Nucl Med, 2004, 45(10): 1640-1646.
11. Weber WA, Peterson V, Schmidt B, et al. Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol, 2003, 21(14):2651-2657.
12. Pottgen C, Levegrun S, Theegarten D, et al. Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res, 2006, 12(1):97-106.
13. Smith IC, Welch AE, Hutcheon AW, et al. Positron emission tomography using 18F -fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy [J]. J Clin Oncol, 2000, 18: 1676-1688.
14. Biersack HJ, Bender H, Palmedo H, et al. FDG-PET in monitoring therapy of breast cancer [J]. Eur J Nucl Med Imaging, 2004, 31(Suppl 1): S112-S117.
15. Biersack HJ, Palmedo H. Locally advanced breast cancer: is PET useful for monitoring primary chemotherapy? [J]. J Nucl Med, 2003, 44(11): 1815-1817.
16. Lind P, Igerc I, Beywe T, et al. Advantages and limitations of FDG PET in the follow-up of breast cancer [J]. Eur J Nucl Med Mol Imaging, 2004, 31(Suppl 1): S125-S134.
17. Pelosi E, Messa C, Picchio M, et al. Value of integrated PET-CT for lesion localization in cancer patients: a comparative study [J]. Eur J Nucl Med Med Imaging, 2004, 31(7): 932-939.
18. Pannu HK, Cohade C, Bristow RE, et al. PET-CT detection of abdominal recurrence of ovarian cancer: Radiological-surgical, correlation. Abdom Imaging, 2004, 29:398-403.
19. Sironi S, Messa C, Mangili G, et al. Integrated FDG PET-CT in patients with persistent ovarian cancer: correlation with histologic findings. Radiology. 2004, 233(2): 433-440.
20. Bristow RE, Giuntoli RL 2nd, Pannu HK, et al. Combined PET-CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes. Gynecol Oncol. 2005; 99(2): 294-300.
21. Nanni C, Rubello D, Farsad M, et al. (18) F-FDG PET-CT in the evaluation of recurrent ovarian cancer: a prospective study on forty-one patients. Eur J Surg Oncol. 2005; 31(7): 792-797.
22. Goshen E, Davidson T, Zwas ST, et al. PET-CT in the evaluation of response to treatment of liver metastases from colorectal cancer with bevacizumab and irinotecan [J]. Technol Cancer Res Treat, 2006, 5(1): 37-43.
23. Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dual-modality PET-CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med, 2004, 45(3): 357-365.
24. Wieder HA, Beer AJ, Lordick F, et al. Comparison of changes in tumor metabolic activity and tumor size during chemotherapy of adenocarcinomas of theesophagogastric junction. J Nucl Med, 2005, 46(12): 2029-2034.
25. Cerfolio RJ, Bryant AS, Ohja B, et al. The accuracy of endoscopic ultrasonography with fine-needle aspiration, integrated positron emission tomography with computed tomography, and computed tomography in restaging patients with esophageal cancer after neoadjuvant chemoradiotherapy [J]. J Thorac Cardiovasc Surg, 2005, 129(6):1232-1241.
26. Delbeke D, Martin WH. PET and PET-CT for evaluation of colorectal carcinoma [J]. Semin Nucl Med, 2004, 34(3): 209-223.
27. Freudenberg LS, Antoch G, Schutt P, et al. FDG PET-CT in restaging of patients with lymphoma [J]. Eur J Nucl Med Mol Imaging, 2004, 31(3): 325-329.
28. Meignan M, Haioun C, Itti E, et al. Value of [18F] fluorodeoxyglucose-positron emission tomography in managing patients with aggressive non-Hodgkin’s lymphoma. Clin Lymphoma Mveloma, 2006, 6(4): 306-313.
2. Phelps ME, Coleman RE. Nuclear medicine in the new millennium. J Nucl Med [J], 2000, 41(1): 1-4.
3.赵晶,刘雅丽,陈林河,等.乳癌中腋窝淋巴结的CT病理对照[J].临床放射学杂志,1996,15(6): 349-351.
4. Takayoshi U, Muneaki S, Kenchi H, et al. In vitro high-resolution helical CT of small axillary lymph node in patients with breast cancer: correlation of CT and histology [J]. AJR, 2001, 176: 1069-1074.
5. Matthies A,Hickeson M,Cuchiara A,et a1.Dual time point 18F-FDG PET for the evaluation of pulmonary nodules.J Nucl Med,2002,43(7):871-875.
6. Hustinx R , Smith RJ , Benard F , et a1 . Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography : a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck.Eur J Nucl Med,1999,26(10):1345-1348.
7. Hciken JP, Brink JA, Vannier MW. Spiral CT [J]. Radiology. 1993, 189(6): 647-656
8.张永学主编.核医学[M].北京,科学出版社,2003,227-228.
9. Pederson M W, Holm S, Lund K L, et al. Coregulation of glucose uptake and vascular endothelial factor(VEGF) IN two small-cell lung cancer(SCLC) sublines in vivo and in vitro[J]. Neoplasia, 2001, 3(1): 80-87.
10. David W. PET-CT: Today and tomorrow. J Nucl Med [J], 2004, 45(1, suppl): 4-8.
11. Phelps ME, Coleman RE. Nuclear medicine in the new millennium. J Nucl Med [J], 2000, 41(1):1-4.
12. Beyer T, Townsend DW, Brun T, et al. A combined PET-CT scanner for clinical oncology. J Nncl Med [J], 2004, 41(8): 1369-1379.
13. Zangheri B, Messa C, Picchio M, et al. PET-CT and breast cancer. Eur J Nucl Med Mol Imaging. 2004, 31(Suppl): S135-S142.
14. Goerres GW, Michel SC, Fehr MK, et al. Follow-up of women with breast cancer: comparison between MRI and FDG-PET [J]. Eur Radiol, 2003, 13(7): 932-939.
15. Gallowitsch HJ, Kresnik E, Gasser J, et al. F-18 fluorodeoxyglucose positron-emission tomography in the diagnosis of tumor recurrence and metastasis in the follow-up of patients with breast carcinoma: a comparison to conventional imaging. Invest Radiol[J], 2003, 38(5): 250-256.
16. Moon DH, Maddahi J, Siverman DH, et al. Accuracy of whole-body fluorine-18-FDG PET for the detection of recurrent or metastatic breast carcinoma. J Nucl Med. 1998, 16: 3375-3379.
17. Dose J, Bleckmann C, Bachmann S, et al. Comparison of fluorodeoxyglucose positron emission tomography and“conventional diagnostic procedures”for the detection of distant metastasis in breast cancer patients [J]. Nucl Med Commun, 2002, 23: 857-864.
18. Lind P, Igerc I, Beywe T, et al. Advantages and limitations of FDG PET in the follow-up of breast cancer [J]. Eur J Nucl Med Mol Imaging, 2004, 31(Suppl 1): S125-S134.
19. Kamel EM, Wyes MT, Fehr MK, et al. [18F]-Fluorodeoxyglucose positron emission tomography in patients with suspected recurrence of breast cancer. J Cancer Res Clin Oncol, 2003, 129(3):147-153.
20. Hubner KF, Smith GT, Thie JA, et al. The Potential of F-18-FDG PET in breast cancer: detection of primary lesions, axillary lymph node metastases, or distant metastases. Clin Pos Imag, 2000, 3(5):197-205.
21. Kim TS, Moon WK, Lee DS, et al. Fluorodeoxyglucose positron emission tomography for detection of recurrent or metastatic breast cancer. World J Surg, 2001, 25(7):829-834.
22. Goerres GW, von Schulthess GK, Steinert HC. Why most PET of lung and head-and-neck cancer will be PET-CT. J Nucl Med, 2004, 45(Suppl): S66-S71.
23. Minn H, Soini I. F-18 fluorodeoxyglucoes scintigraphy in diagnosis and follow up of treatment in advanced breast cancer. Am J. Clin. Pathol; 1989. 91: 535-541
24. Eubank WB, Mankoff DA, Takasugi J, et al. 18Fluorodeoxyglucose positron emissiontomography to detect mediastinal or internal mammary metastasis in breast cancer. J Clin Oncol, 2001, 19(15): 3516-3523
25. Hathaway PB, Mankoff DA, Maravilla KR, et al. Value of combined FDG PET and MR imaging in the evaluation of suspected recurrent local-regional breast cancer: preliminary experience. Radiology, 1999, 210(3):807-814
26. Kelemen PR, Lowe V, Phillips N. Positron emission tomography and sentinel lymph node dissection in breast cancer. Clin Breast Cancer 2002; 3: 73-77
27. Guller U, Nitzsche EU, Schirp U, et al. Selective axillary surgery in breast cancer patients based on positron emission tomography with 18F-fluoro-2-deoxy-D-glucose: not yet. Breast Cancer Res Treat, 2002; 71: 171-173
28. Khan N, Oriuchi N, Yoshizaki A, et al. Diagnostic accuracy of FDG PET imaging for the detection of recurrent or metastatic gynecologic cancer. Ann Nucl Med, 2005, 19(2): 137-145.
29. Schirrmeister H, Kuhn T, Guhlmann A, et al. Fluorine-18 2-deoxy-2-fluoro-D-glucose PET in the preoperative staging of breast cancer: comparison with the standard staging procedures. Eur J Nucl Med, 2001, 28(3): 351-358
30. Pelosi E, Messa C, Picchio M, et al. Value of integrated PET-CT for lesion localization in cancer patients: a comparative study [J]. Eur J Nucl Med Med Imaging, 2004, 31(7): 932-939
31. Khan S, Tan YM, John A, et al. An audit of fusion CT-PET in the management of colorectal liver metastasis. Eur J Srug Oncol. 2006, 32(5): 564-567
32. Selzner M, Hany TF, Wildbrett P, et al. Does the novel PET-CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg. 2004; 240(6):1027-1034
33. Fu CG, Wang HT, Kong LS, et al. Application of positron emission tomography in diagnosis of liver metastasis from colorectal cancer. Zhonghua Wei Chang Wai Ke Zha Zhi. 2005, 8(1): 17-19
34. Bender H, Kirst J, Palmedo H, et al. Value of 18fluoro-deoxyglucose positron emission tomography in the staging of recurrent breast carcinoma. Anticancer Res. 1997, 17(3B): 1687-1692
35. Siggelkow W, Zimny M, Faridi A, et al. The value of positron emission tomography in the follow-up for breast caner. Anticancer Res, 2003, 23(2C):1859-1867
1. Li WW, Jaffe M, Li VW, et al. Lwssons to be learned from clinical trials of angiogenesis modulators in ischemic diseases. In: Rubanyi GM, ed. Angiogenesis in heslth and disease: basic mechanisms and clinical application. New York, NY: Dekker, 2000, 519-536.
2. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 1992, 359: 843-845.
3. Ikeda E, Achen MG, Breier G, et al. Vascular endothelial growth factor, a potent and selective angiogenic agent [J]. Biol Chem, 1995, 270:19761-19766.
4. Ferrara N, Davis-Smith T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18:4-25.
5. Neufeld G, Cohen T, Shraga N. The Neuropilins: Multifunctional Semaphorin and VEGF receptor that modulate axon guidance and angiogenesis. Trends Cardiovasc Med, 2002,12: 13-19.
6. Binetruy-Tournaire R, Demangel C, Malavaud B, et al. Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. EMBO J 2000; 19(7):1525-1533.
7. Starzec A, Vassy R, Hamma-Kourbali Y, et al. Heptapeptide A7R competes forVEGF165 binding to neuropilin-1 but not to VEGFR2/KDR. First Interdisciplinary Conference on Angiogenesis: Paris 6–9 October 2001.
8. Rodrigues S, Van Aken E, Van Bocxlaer S, et al. Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J, 2003, 17(1): 7-16.
9. Janssen AP, Schiffelers RM, ten Hagen TL, et al. Peptide-targeted PEG-liposomes in anti-angiogenic therapy. Int J Pharm, 2003, 254(1): 55-58.
10. Renno RZ, Terada Y, Haddadin MJ, et al. Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2. Arch Ophthalmol, 2004, 122(7): 1002-1011.
11. Winer RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases [J]. Apple Radiat Isot, 2002, 57(5): 749-763.
12. Decristoforo C, Mather SJ. Technetium-99m somatostatin analogues: effect of labeling methods and peptide sequece. Eur J Nucl Med. 1999; 26:869-876.
13. Holash J, Maisonpierre PC, Compton DR, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284: 1994-1998.
14. Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its veceptors. FASEB J 1999 ; 13 (1) : 9.
15. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by bypoxia may mediate bypoxia - initiated angiogenesis. Nature 1992; 359: 843.
16. Brown FJ, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract [J]. Cancer Res, 1993, 53: 4727-4735.
17. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor induced angiogenesis suppresses tumour growth i n vivo[J]. Nature, 1993, 362: 841-844.
18. Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell, 1998, 92 (6): 735-745.
19. Soker S, Fidder H, Neufeld G, et al. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J Biol Chem, 1996, 271 (10): 5761-5767.
20. Miao HQ, Lee P, Lin H et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J, 2000, 14 (15):2532-2539.
21. Bachelder RE, Crago A, Chung J, et al. Vascular Endot helial growt h factor is an autocrine survival factor for neuropilin-expression breast carcinoma cells [J]. Cancer Research, 2001, 61 (15):5736-5740.
22. Perret GY, Starzec A, Hauet N, et al. In vitro evaluation and biodistribution of a 99mTc-labeled anti-VEGF peptide targeting neuropilin-1. Nucl Med Biol. 2004 Jul; 31(5):575-581.
23. Labrceque L, Royal I, Surprenant DS, et al. Regulation of vascular endothelial growth factor recetor-2 activity by caveolin-1 and plasma membrane cholesterol. Mol Biol Cell. 2003, 14(1):334-347.
24. Maeshima Y, Sudhakar A, Lively JC, et al. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science, 2002, 295(5552):140-143.
25. Liu S, Edwards DS. 99mTc-Labeled Small Peptides as Diagnostic Radiopharmaceuticals. Chem Rev, 1999; 99(9): 2235-68.
26. Liu S, Edwards DS, Looby RJ, et al. Labeling a hydrazino nicotinamide-modified cyclic IIb/IIIa receptor antagonist with 99mTc using aminocarboxylates as coligands. Bioconjug Chem, 1996; 7(1): 63-71
27. Edwards DS, Liu S. 99mTc-labelling of hydrazenonicotinamide(HYNIC) modified highly potent small molecules: problems and solutions[J]. Transition Met Chem, 1997, 22(40: 425-426.
28. Verbeke K, Kieffer D , Vanderheyden J L et al. Optimization of the preparation of 99m Tc labeled Hynic-derivatized AnnexinⅤfor human use1 Nucl Med Biol, 2003, 30: 771.
1. Pederson M W, Holm S, Lund K L, et al. Coregulation of glucose uptake and vascular endothelial factor(VEGF) IN two small-cell lung cancer(SCLC) sublines in vivo and in vitro[J]. Neoplasia, 2001, 3(1): 80-87
2. Wolfgang A, Weber. Use of PET for monitoring cancer therapy and for predicting outcome [J]. J Nucl Med, 2005, 46(6): 983-995.
3. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer[J]. J Clin Oncol, 2003, 21(7): 1285-1292.
4. Holloway CL, Robinson D, Murray B, et al. Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET-CT imaging with induction chemotherapy for patients with non-small cell lung cancer[J].Radiother Oncol, 2004, 73(3): 285-287.
5. Kostakoglu L, Goldsmith SJ. 18F–FDG PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma [J]. J Nucl Med, 2003, 44(2): 224-239.
6. Brock CS, Young H, O’Reilly SM, et al. Early evaluation of tumor metabolic response using18F-fluorodeoxyglucose and positron emission tomography: a pilot study following the phaseⅡchemotherapy schedule for temozolomide in recurrent high grade gliomas. Br J Cancer, 2000, 82(3):608-615.
7. Yen TD, Chang JT, Ng SH, et al. The value of 18F-FDG in the detection of stage M0 carcinoma of the nasopharynx [J]. J Nucl Med, 2005, 46(3): 405-410.
8. Wild D, Eyrich GK, Ciernik IF,et al. In-line (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT) in patients with carcinoma of the sinus/nasal area and orbit. J Craniomaxillofac Surg. 2006; 34(1): 9-16.
9. Nahas Z, Goldenberg, D, Fakhry C, et al. The role of positron emission tomography/computed tomography in the management of recurrent papillary thyroid carcinoma [J]. Laryngoscope, 2005, 115(2): 237-243.
10. Keidar Z, Haim N, Guralnik L, et al. PET-CT using 18F-FDG in suspected lung cancer recurrence: diagnostic value and impact on patient management [J]. J Nucl Med, 2004, 45(10): 1640-1646.
11. Weber WA, Peterson V, Schmidt B, et al. Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol, 2003, 21(14):2651-2657.
12. Pottgen C, Levegrun S, Theegarten D, et al. Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res, 2006, 12(1):97-106.
13. Smith IC, Welch AE, Hutcheon AW, et al. Positron emission tomography using 18F -fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy [J]. J Clin Oncol, 2000, 18: 1676-1688.
14. Biersack HJ, Bender H, Palmedo H, et al. FDG-PET in monitoring therapy of breast cancer [J]. Eur J Nucl Med Imaging, 2004, 31(Suppl 1): S112-S117.
15. Biersack HJ, Palmedo H. Locally advanced breast cancer: is PET useful for monitoring primary chemotherapy? [J]. J Nucl Med, 2003, 44(11): 1815-1817.
16. Lind P, Igerc I, Beywe T, et al. Advantages and limitations of FDG PET in the follow-up of breast cancer [J]. Eur J Nucl Med Mol Imaging, 2004, 31(Suppl 1): S125-S134.
17. Pelosi E, Messa C, Picchio M, et al. Value of integrated PET-CT for lesion localization in cancer patients: a comparative study [J]. Eur J Nucl Med Med Imaging, 2004, 31(7): 932-939.
18. Pannu HK, Cohade C, Bristow RE, et al. PET-CT detection of abdominal recurrence of ovarian cancer: Radiological-surgical, correlation. Abdom Imaging, 2004, 29:398-403.
19. Sironi S, Messa C, Mangili G, et al. Integrated FDG PET-CT in patients with persistent ovarian cancer: correlation with histologic findings. Radiology. 2004, 233(2): 433-440.
20. Bristow RE, Giuntoli RL 2nd, Pannu HK, et al. Combined PET-CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes. Gynecol Oncol. 2005; 99(2): 294-300.
21. Nanni C, Rubello D, Farsad M, et al. (18) F-FDG PET-CT in the evaluation of recurrent ovarian cancer: a prospective study on forty-one patients. Eur J Surg Oncol. 2005; 31(7): 792-797.
22. Goshen E, Davidson T, Zwas ST, et al. PET-CT in the evaluation of response to treatment of liver metastases from colorectal cancer with bevacizumab and irinotecan [J]. Technol Cancer Res Treat, 2006, 5(1): 37-43.
23. Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dual-modality PET-CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med, 2004, 45(3): 357-365.
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