~（11）C-胆碱PET/CT显像在前列腺癌及肺癌中的应用价值
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摘要
第一部分11C-胆碱PET/CT显像在前列腺癌中的应用价值及其与AR受体和PTEN、Ki67相关研究
研究目的：探讨新型PET/CT显像剂11C-胆碱在前列腺癌诊断、分期及疗效评价中的临床应用价值以及11C-胆碱PET/CT显像与前列腺组织中AR受体、PTEN和Ki67表达的关系。
研究方法：回顾性分析2004年4月～2007年12月接受11C-胆碱PET/CT显像的前列腺病变患者59例。分为两组：①未经治疗组49例,男性,年龄47～92岁,血清PSA 1.1 ng／ml-100 ng／ml。患者均在经直肠针刺活检前行11C-CH PET/CT显像。②前列腺癌治疗后复查组10例：4例为前列腺癌根治切除术后复查,均为低分化腺癌。6例为前列腺癌去势治疗后复查者,均为中分化腺癌。此10例结果均经手术或长期随访(>1年)或其它影像学检查证实。所有患者均于静脉注射7.4MBq／kg11C-胆碱5min后行仰卧位盆腔PET/CT显像,可疑转移患者行全身显像。测量前列腺病灶(靶组织)及肌肉组织(非靶组织)的最高SUV(SUVmax),并计算其比值(P／M)。前列腺组织石蜡切片经二甲苯脱蜡后,梯度乙醇依次水化至水,3%H202去离子水孵育10分钟。以柠檬酸缓冲液高温高压法进行抗原修复,滴加一抗4℃过夜(稀释度为1：100)。滴加Polymer Helper,37℃孵育20分钟。滴加polyperoxidase-anti -mouse/rabbit IgG,37℃孵育20-30分钟。DAB显色,苏木精复染,逐级脱水、透明、中性树胶封片。以PBS替代一抗作为阴性对照。结果根据免疫组化染色的深度及阳性细胞的数量分别记0～3分,其中染色深度以多数细胞呈色反应为准。不着色为0分,浅棕黄色为1分,棕黄色为2分,深褐色为3分。阳性细胞数<10%为0分,10%～45%为1分,46%～65%为2分,>65%为3分。染色的深度及阳性细胞数两者得分相乘,0分为阴性(-),1～3分为弱阳性(+),4～6分为阳性(++),7～9分为强阳性(+++)。数据均通过SPSS13.0软件进行统计分析,建立ROC曲线,同时对数据进行t检验,P<0.05认为差异有统计学意义。SUVmax与PSA值、Gleason分值、AR、PTEN和ki67表达的相关性行spearman等级相关性分析。
结果：第一组49例患者中35例前列腺病灶经手术病理证实,14例经直肠针刺活检病理证实。49例中21例为前列腺癌,其中高分化腺癌5例,中分化腺癌7例,低分化腺癌9例。Gleason分级≥4的患者占33.3%(7例),临床病理分期(Jewett改良法)≥C期(肿瘤组织已穿透前列腺被膜)的占28.6%(6例)；28例为前列腺增生(BPH),其中BPH伴慢性炎症8例(表1)。21例前列腺癌患者中6例发生淋巴结转移和(或)骨转移。第二组中4例经手术病理证实,6例由穿刺活检证实。①11C-胆碱PET／CT显像结果：所有的前列腺癌病灶均呈放射性浓聚,21例前列腺癌患者中15例为前列腺区域弥漫性放射性浓聚,6例放射性浓聚区位于前列腺外周带呈孤立结节状。28例良性病变中5例前列腺区域未见明显放射性聚集,其余23例前列腺病灶摄取11C-胆碱不同程度增高,其中22例放射性增高区域位于前列腺中央带且较对称呈“桔瓣”状。②半定量分析：以SUV为半定量参数,前列腺癌患者的平均SUVmean为7.25±4.98(1.58～25.28),BPH的平均SUVmean为4.51±4.74(0.67～26.19)。以双样本异方差t检验,两者无显著性差异(t=2.02,p>0.05)。前列腺癌的平均SUVmax为7.87±5.74(2.75～27.85),BPH的平均SUVmax为4.95±5.14(0.89～27.93),两者的差异亦不具有显著性(t=2.02，p>0.05)。以P／M为参数,前列腺癌患者的平均P／M为4.21±1.61(1.85～7.82),前列腺增生患者的平均P／M为1.87±0.98(0.69～5.04)，两者的差异具有显著性(t=2.04,p<0.01)。③建立ROC曲线,以P／M>2.3为鉴别病灶良恶性的标准11C-胆碱PET/CT显像诊断前列腺癌的灵敏度、特异性、阳性预测值、阴性预测值和准确性分别为90.48%(19／21例)、85.71%(24／28例)、82.61%(19／23例)、92.31%(24／26例)、87.76%(43／49例)。④11C-胆碱PET／CT显像共发现6例盆腔、腹股沟区、纵隔、肺门、腹膜后淋巴结转移灶31处,4例患者的29处骨转移灶,有助于前列腺癌的准确临床分期。⑤4例前列腺癌根治切除术后患者中发现1例病灶边缘软组织密度区呈明显放射性浓聚,诊断为术后残留。6例前列腺癌去势治疗复查患者中,发现2例肿瘤复发。⑥采用spearman等级相关分析11C-胆碱PET/CT显像结果与免疫组织化学指标组织评分显示,在所有接受检查的病例以及前列腺癌组中：Ki-67表达与11C-胆碱PET/CT P/M值呈明显正相关性(rs=0.764,P<0.01；rs=0.660,P<0.01)。以P／M>2.3为诊断肿瘤的标准,所筛选出病例中的三例非肿瘤患者中两例前列腺组织免疫组织化学染色Ki67呈阳性反应,提示Ki67与P／M值的相关性。AR及PTEN的表达与P／M值无明显相关关系。
结论：11C-胆碱PET/CT显像是一种诊断前列腺癌的较好的无创性检查方法,良恶性组之间的P／M差异具有统计学意义。PET/CT显像中CT的精确定位意义重大,放射性浓聚区位于前列腺中央带且对称多提示前列腺增生,而放射性浓聚点位于外周带且呈孤立结节则高度警惕前列腺癌。全身显像可以发现局部转移淋巴结及远处转移灶,有助于准确临床分期。对于评价治疗疗效、监测肿瘤残留与复发,11C-胆碱PET/CT显像亦具有重要意义,可以发现部分PSA没有显著升高的肿瘤复发患者,在PSA显著升高的患者中肿瘤残留与复发探测率高。Ki-67表达与11C-胆碱PET/CT SUV(P/M)值呈明显正相关。
第二部分11C-胆碱PET/CT显像在肺癌中的应用价值及胆碱代谢机理的实验研究
研究目的：通过对临床可疑肺癌患者的11C-胆碱PET/CT显像,探讨其在肺癌中的应用价值,以期寻找早期诊断肺癌并进行准确术前分期的更为特异、更为灵敏、性价比更高的PET/CT显像剂。同时探讨了胆碱的两种不同的代谢过程——乙酰胆碱代谢途径(最终生成乙酰胆碱)及磷酸化途径(最终生成磷脂酰胆碱)在不同组织类型肺癌患者中所占的比例,以期阐明胆碱显像的真正机理。
研究方法：具有完整资料的2007年1月～2008年12月接受11C-胆碱PET/CT显像的可疑肺癌患者38例,经手术病理证实者为32例,6例发生远处转移者经长期随访(>1年)或其它影像学检查证实。部分接受肺癌手术患者(18例)留取肿瘤组织及周围正常肺组织进行胆碱代谢的分子生物学检查。患者未禁食,安静休息10min后肘前静脉注射11C-胆碱7.4MBq／kg,5min后行仰卧位PET／CT显像。先行4排螺旋CT扫描,140kV,80mA,层厚5mm,进床速度11.25mm／s。PET采用2D扫描,每个床位采集3分钟,共采集2-3个床位(颈胸部),可疑转移患者采集6个床位(全身)。PET数据经OSEM重建,通过Xeleris工作站进行图像融合分别得到冠状、矢状、横断的CT、PET及PET/CT融合图像。勾画感兴趣区(region of interest, ROI),测量肺部病灶(靶组织)与正常肺组织(非靶组织)的平均SUV(SUVmean)及最高SUV(SUVmax),并计算其比值(T／NT)。同时计算肺部病灶(靶组织)与同层面肌肉组织的最高SUV(SUVmax)的比值(T／M)。采用RT-PCR和Western blot方法将术后取得的肺癌组织及正常肺组织检测胆碱乙酰基转移酶(ChAT)和胆碱激酶(Chok)mRNA及蛋白质的表达；分析肺癌的胆碱显像与肺癌组织细胞中胆碱代谢的变化。
结果：经手术病理证实的32例患者中肺癌为29例,良性病灶为3例。其中10例为腺癌,其中高分化腺癌1例,中分化腺癌6例,低分化腺癌3例。14例为鳞癌,12为鳞状细胞癌Ⅱ级,2例为鳞癌Ⅰ级。3例为不典型类癌。1例为小细胞肺癌。1例为粘液表皮样癌。1例为炎性假瘤,2例为结核。17例肺癌患者发生肺门淋巴结转移。13例发生了纵隔淋巴结转移。①11C-胆碱PET／CT显像结果：所有29例肺癌病灶均呈现胆碱放射性摄取明显增高。部分病灶呈周边放射性浓聚,中心放射性稀疏缺损区为坏死区域。3例良性病灶(1例炎性假瘤,2例结核)同样摄取11C-胆碱增高,无法与恶性肿瘤区分。②半定量分析：以SUV为半定量参数,肺癌患者的平均SUVmax为4.82±1.79(1.45～7.67),良性病变的平均SUVmax为6.95±1.1(6.15～8.2)。以双样本异方差t检验,两者无显著性差异(t=3.18,p>0.05)。以T／NT及T／M为参数,肺癌患者的平均T／NT及T／M分别为5.59±2.19(2.17～7.16),4.05±1.51(2.17～7.16),良性病变患者的平均T／NT及T／M为8.07±1.75(6.07～9.32),3.11±0.66(2.52～3.82),两者的差异亦不具有显著性(t=3.18,p>0.05,t=2.57,p>0.05)。③本研究鳞癌14例,病灶的SUVmax为4.98±1.96(1.45～7.67),T／NT为6.06±2.01(3.29～9.54)。腺癌10例,病灶的SUVmax为4.09±1.62(2.05～7.07),T／NT为4.68±2.05(2.17～7.77)。两者之间不具有显著性差异(t=2.08,P>0.1；t=2.09,P>0.1)。不典型类癌3例,病灶的SUVmax为6.05±1.54(4.41～7.46),T／NT为7.39±2.49(5.75～10.26)。与鳞癌、腺癌相比也不具有显著性差异。④6例发生远处转移的患者PET/CT显像表现为转移灶局限性放射性异常浓聚。17例肺癌患者发生了肺门淋巴结转移,PET/CT检查发现了其中的13例。13例患者发生了37组纵隔淋巴结转移,PET／CT检查发现了10例,31组(其中6组为假阳性)。以淋巴结组数计算,11C-胆碱PET/CT显像检测纵隔淋巴结转移灵敏度、特异性、阳性预测值、阴性预测值及准确度分别为67.6%,84.2%,80.6%,72.7%,72.7%。⑤18例肺癌组织细胞中14例Chok mRNA及蛋白质的表达比正常肺组织升高,9例肺癌组织细胞ChAT mRNA及蛋白质表达升高,其中8例Chok及ChAT表达均升高。
结论：11C-胆碱PET/CT显像所有肺癌病灶均表现为胆碱高摄取。良性病灶如结核早期及炎性假瘤也会出现摄取胆碱增高。通过半定量分析,肺癌及良性病灶两组的SUVmean、SUVmax、T/NT及T／M均无显著性差异。11C-胆碱PET/CT显像不能很好地鉴别肺部病灶的良恶性。不同病理类型的肺癌如鳞癌、腺癌及不典型类癌对胆碱摄取的SUVmax、T/NT均无显著性差异。11C-胆碱PET/CT显像能够发现肺癌患者的纵隔及肺门淋巴结转移及远处转移灶,有助于准确临床分期。11C-胆碱在各种病理类型的肺癌组织细胞中不仅有磷酸化途径的增强,而且均存在乙酰化途径
Part one The value of 11C-choline PET/CT imaging on prostate cancer and correlation with tissue markers of AR, PTEN, Ki 67
Objective To investigate the potential of 11C-choline PET/CT imaging for diagnosis and staging of prostate cancer and detection of recurrent ones. To study the correlation between 11C-choline PET/CT imaging and the tissue markers, including AR, PTEN and ki67. The application of 11C-choline PET/CT imaging on lung caner and the real metabolic mechanism of 11C-choline in vivo were also investigated.
Methods A total of 59 patients with prostate lesions were divided into two groups①49 cases without any therapy, male, age 47-92, PSA 1.1 ng/ml-100 ng/ml.②10 patients who have accepted either radical prostatectomy or maximum androgen blockade therapy. They all underwent 11C-choline PET/CT imaging before transrectal needle biopsy. PET/CT imaging were performed 5min after injection of 7.4 MBq/kg 11C-choline in supine position over 2 bed positions (3 min per position), covering the pelvis, and the whole body (6 bed) when necessary. After correction for measured attenuation, decay and scatter and iterative reconstruction, PET data were analyzed semi quantitatively by measuring maximum standardized uptake values (SUVmax) of the prostate lesions (target) and the muscles (non-target) and calculating their ratios (P/M). Visual analysis was performed using transverse, sagittal and coronal slices as well as three-dimension images. The results of 11C-choline PET/CT were compared to pathologic results which were acquired by radical prostatectomy or biopsies specimens. Sensitivity, specificity, positive and negative predictive value of PET/CT in diagnosis on prostate cancer were calculated and all statistical analysis were made by SPSS 13.0.
Results①21 prostate caner and 28 benign prostate hyperplasia (and/or chronic prostatitis) were proven histologically. All PCa could be visualized as avid accumulation in the gland. Among 28 benign diseases, high uptake of the radioactivity was noticed in 23 BPH while 5 BPH showed little accumulation of C-11 choline. With PET/CT precise localization, a diffuse accumulation of radioactivity in the entire prostate gland was observed in 15 and a solitary hot spot within the peripheral zone of prostate gland was visualized in 6 patients among 21 PCa cases.27 of 28 BPH patients could be seen symmetrical uptake of C-11 choline within the central zone of prostate.②The mean values of SUVmax of PCa and BPH were 7.87±5.74 and 4.95±5.14, respectively. There was no significant difference between these two groups. (t=2.02, p>0.05). The mean P/M of PCa and BPH were 4.21±1.61 and 1.87±0.98, respectively. The statistical differences of P/M between them were significant (t=2.04, p<0.01).③Using 2.3 (P/M) as criterion, C-11 choline PET/CT imaging showed sensitivity of 90.48%, specificity of 85.71% and negative predictive value of 92.31%. The precise localization of the radioactivity hot spot in different part of the prostate could help the diagnosis a lot which is the advantage of PET/CT.④6 patients with focal uptake in lymph node and/or bone metestases were detected by 11C-choline PET/CT which demonstate it is useful in staging of prostate cancer.⑤Among 4 patients who underwent radical prostatectomy 1 patient was found that his postate cancer was still existed. And 2 patients were detected with recurrent tumor in 6 cases which accepted maximum androgen blockade therapy.⑥A significant positive association was found between 11C-choline accumulation and Ki67 (rs=0.764, P<0.01; rs=0.660, P<0.01) respectively in all the 49 patients and prostate cancer patients.
Conclusion 11C-choline PET/CT is a valuable non-invasive imaging technology in the diagnosis, staging and detection of recurrent of prostate cancer. The parameter P/M could differentiate prostate cancer from benign lesions better than SUV. A significant positive association was found between 11C-choline accumulation and Ki67 in prostate cancer patients.
Part two The research of 11C-choline PET/CT imaging and choline metabolism on lung cancer
Objective To investigate the potential of 11C-choline PET/CT imaging for diagnosis and staging of lung cancer in order to find a more accurate tracer than 18F-FDG in early diagnosise of cancer. To study the proportion of phosphorylation pathway and acetylation pathway of choline in different types of lung cancer in order to investigate the real metabolic mechanism of 11C-choline in vivo.
Methods 38 patients with suspicious lung cancer who were examined with 11C-choline PET/CT imaging had finally had lung surgery in 32 while the other 6 patients were found to have distance metastasis. Lung cancer sample and normal lung tissues were saved in 18 patients for further choline metabolism research. Without fasting, patients were injected of 7.4MBq/kg of 11C-choline intravenously five minutes before imaging. PET images were acquired in supine position over 2 bed positions (3 min per positron) from the upper neck to the lower edge of liver and whole body(6 bed positions) when necessary. The parameters of the multidetector helical CT scan were 140 kV,80 mA,0.8 s per tube rotation, slice thickness of 5 mm, pitch of 6, and table speed of 11.25 mm/s. PET images were reconstructed with the iterative reconstruction ordered-subset expectation maximization likelihood algorithm of the manufacturer after attenuation correction based on the CT dataset. Consecutive transverse PET/CT slices of 4.25 mm thickness were generated. Lung cancers were analysed visually and semiquantitatively using the ratio of tumour-to-normal radioactivity (T/N ratio) and standardized uptake value (SUV). Mediastinal lymph node metastases were analysed visually. RT-PCR and Western blot were used to investigate the expression of choline acetyltransferase (ChAT) and choline kinase (ChoK) genes in lung cancer specimens and the normal lung tissues.
Results①All lung cancer could be visualized as avid accumulation in the lesions. But the three benign diseases, including two tuberculosis and one inflammatory pseudotumor also showed high uptake of the radioactivity. It is hard to differentiate malignant from benign lesions in 11C-choline PET/CT imaging.②The mean values of SUVmax of lung cancer and benign lesions were 4.82±1.79 and 6.95±1.1, respectively. There was no significant difference between these two groups. (t=3.18, p>0.05). The mean T/NT of malignant and benign lesions were 5.59±2.19 and 8.07±1.75, respectively.. The statistical differences of T/NT between them were still not significant (t=3.18, p>0.05).③The SUVmax and T/NT of the all 14 squamous cell carcinoma patients were 4.98±1.96 and 6.0612.01 respectively, while the SUVmax and the T/NT of the 10 adenocarcinoma patients were 4.09±1.62 and 4.68±2.05. The difference was not statistically significant between the squamous cell carcinoma and adenocarcinoma.④6 patients with distant metestases were detected by 11C-cholinePET/CT which demonstate it is useful in staging of lung cancer. In the assessment of mediastinal lymph node involvement, 11C-choline PET/CT detected 10 patients in all 13 patients proven by pathology. The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 11C-Choline PET/CT in the detection of lymph node metastasis is 67.6%,84.2%,80.6%,72.7%,72.7%.⑤The expression of ChAT mRNA and protein were enhanced in 9 of 18 lung tumor specimens; and the expression of ChoK mRNA and protein were increased in 14 of 18 lung tumor specimens comparing with the normal lung tissues.8 of 18 lung cancer specimens were obvious increased both in the expression of ChoK and ChAT.
Conclusion In this study, all lung cancer could be visualized as avid accumulation in the lesions while the benign diseases, including tuberculosis and inflammatory pseudotumor could also show high uptake of the radioactivity. No matter SUVmax or T/NT, there was no significant difference between the malignant and bening groups. It is difficult to differentiate malignant from benign lesions in 11C-choline PET/CT imaging. The difference was not statistically significant between the squamous cell carcinoma and adenocarcinoma in SUV and T/NT. Both phosphorylation pathway and acetylation pathway of choline were existed in different types of lung cancer.
研究目的：探讨新型PET/CT显像剂11C-胆碱在前列腺癌诊断、分期及疗效评价中的临床应用价值以及11C-胆碱PET/CT显像与前列腺组织中AR受体、PTEN和Ki67表达的关系。
研究方法：回顾性分析2004年4月～2007年12月接受11C-胆碱PET/CT显像的前列腺病变患者59例。分为两组：①未经治疗组49例,男性,年龄47～92岁,血清PSA 1.1 ng／ml-100 ng／ml。患者均在经直肠针刺活检前行11C-CH PET/CT显像。②前列腺癌治疗后复查组10例：4例为前列腺癌根治切除术后复查,均为低分化腺癌。6例为前列腺癌去势治疗后复查者,均为中分化腺癌。此10例结果均经手术或长期随访(>1年)或其它影像学检查证实。所有患者均于静脉注射7.4MBq／kg11C-胆碱5min后行仰卧位盆腔PET/CT显像,可疑转移患者行全身显像。测量前列腺病灶(靶组织)及肌肉组织(非靶组织)的最高SUV(SUVmax),并计算其比值(P／M)。前列腺组织石蜡切片经二甲苯脱蜡后,梯度乙醇依次水化至水,3%H202去离子水孵育10分钟。以柠檬酸缓冲液高温高压法进行抗原修复,滴加一抗4℃过夜(稀释度为1：100)。滴加Polymer Helper,37℃孵育20分钟。滴加polyperoxidase-anti -mouse/rabbit IgG,37℃孵育20-30分钟。DAB显色,苏木精复染,逐级脱水、透明、中性树胶封片。以PBS替代一抗作为阴性对照。结果根据免疫组化染色的深度及阳性细胞的数量分别记0～3分,其中染色深度以多数细胞呈色反应为准。不着色为0分,浅棕黄色为1分,棕黄色为2分,深褐色为3分。阳性细胞数<10%为0分,10%～45%为1分,46%～65%为2分,>65%为3分。染色的深度及阳性细胞数两者得分相乘,0分为阴性(-),1～3分为弱阳性(+),4～6分为阳性(++),7～9分为强阳性(+++)。数据均通过SPSS13.0软件进行统计分析,建立ROC曲线,同时对数据进行t检验,P<0.05认为差异有统计学意义。SUVmax与PSA值、Gleason分值、AR、PTEN和ki67表达的相关性行spearman等级相关性分析。
结果：第一组49例患者中35例前列腺病灶经手术病理证实,14例经直肠针刺活检病理证实。49例中21例为前列腺癌,其中高分化腺癌5例,中分化腺癌7例,低分化腺癌9例。Gleason分级≥4的患者占33.3%(7例),临床病理分期(Jewett改良法)≥C期(肿瘤组织已穿透前列腺被膜)的占28.6%(6例)；28例为前列腺增生(BPH),其中BPH伴慢性炎症8例(表1)。21例前列腺癌患者中6例发生淋巴结转移和(或)骨转移。第二组中4例经手术病理证实,6例由穿刺活检证实。①11C-胆碱PET／CT显像结果：所有的前列腺癌病灶均呈放射性浓聚,21例前列腺癌患者中15例为前列腺区域弥漫性放射性浓聚,6例放射性浓聚区位于前列腺外周带呈孤立结节状。28例良性病变中5例前列腺区域未见明显放射性聚集,其余23例前列腺病灶摄取11C-胆碱不同程度增高,其中22例放射性增高区域位于前列腺中央带且较对称呈“桔瓣”状。②半定量分析：以SUV为半定量参数,前列腺癌患者的平均SUVmean为7.25±4.98(1.58～25.28),BPH的平均SUVmean为4.51±4.74(0.67～26.19)。以双样本异方差t检验,两者无显著性差异(t=2.02,p>0.05)。前列腺癌的平均SUVmax为7.87±5.74(2.75～27.85),BPH的平均SUVmax为4.95±5.14(0.89～27.93),两者的差异亦不具有显著性(t=2.02，p>0.05)。以P／M为参数,前列腺癌患者的平均P／M为4.21±1.61(1.85～7.82),前列腺增生患者的平均P／M为1.87±0.98(0.69～5.04)，两者的差异具有显著性(t=2.04,p<0.01)。③建立ROC曲线,以P／M>2.3为鉴别病灶良恶性的标准11C-胆碱PET/CT显像诊断前列腺癌的灵敏度、特异性、阳性预测值、阴性预测值和准确性分别为90.48%(19／21例)、85.71%(24／28例)、82.61%(19／23例)、92.31%(24／26例)、87.76%(43／49例)。④11C-胆碱PET／CT显像共发现6例盆腔、腹股沟区、纵隔、肺门、腹膜后淋巴结转移灶31处,4例患者的29处骨转移灶,有助于前列腺癌的准确临床分期。⑤4例前列腺癌根治切除术后患者中发现1例病灶边缘软组织密度区呈明显放射性浓聚,诊断为术后残留。6例前列腺癌去势治疗复查患者中,发现2例肿瘤复发。⑥采用spearman等级相关分析11C-胆碱PET/CT显像结果与免疫组织化学指标组织评分显示,在所有接受检查的病例以及前列腺癌组中：Ki-67表达与11C-胆碱PET/CT P/M值呈明显正相关性(rs=0.764,P<0.01；rs=0.660,P<0.01)。以P／M>2.3为诊断肿瘤的标准,所筛选出病例中的三例非肿瘤患者中两例前列腺组织免疫组织化学染色Ki67呈阳性反应,提示Ki67与P／M值的相关性。AR及PTEN的表达与P／M值无明显相关关系。
结论：11C-胆碱PET/CT显像是一种诊断前列腺癌的较好的无创性检查方法,良恶性组之间的P／M差异具有统计学意义。PET/CT显像中CT的精确定位意义重大,放射性浓聚区位于前列腺中央带且对称多提示前列腺增生,而放射性浓聚点位于外周带且呈孤立结节则高度警惕前列腺癌。全身显像可以发现局部转移淋巴结及远处转移灶,有助于准确临床分期。对于评价治疗疗效、监测肿瘤残留与复发,11C-胆碱PET/CT显像亦具有重要意义,可以发现部分PSA没有显著升高的肿瘤复发患者,在PSA显著升高的患者中肿瘤残留与复发探测率高。Ki-67表达与11C-胆碱PET/CT SUV(P/M)值呈明显正相关。
第二部分11C-胆碱PET/CT显像在肺癌中的应用价值及胆碱代谢机理的实验研究
研究目的：通过对临床可疑肺癌患者的11C-胆碱PET/CT显像,探讨其在肺癌中的应用价值,以期寻找早期诊断肺癌并进行准确术前分期的更为特异、更为灵敏、性价比更高的PET/CT显像剂。同时探讨了胆碱的两种不同的代谢过程——乙酰胆碱代谢途径(最终生成乙酰胆碱)及磷酸化途径(最终生成磷脂酰胆碱)在不同组织类型肺癌患者中所占的比例,以期阐明胆碱显像的真正机理。
研究方法：具有完整资料的2007年1月～2008年12月接受11C-胆碱PET/CT显像的可疑肺癌患者38例,经手术病理证实者为32例,6例发生远处转移者经长期随访(>1年)或其它影像学检查证实。部分接受肺癌手术患者(18例)留取肿瘤组织及周围正常肺组织进行胆碱代谢的分子生物学检查。患者未禁食,安静休息10min后肘前静脉注射11C-胆碱7.4MBq／kg,5min后行仰卧位PET／CT显像。先行4排螺旋CT扫描,140kV,80mA,层厚5mm,进床速度11.25mm／s。PET采用2D扫描,每个床位采集3分钟,共采集2-3个床位(颈胸部),可疑转移患者采集6个床位(全身)。PET数据经OSEM重建,通过Xeleris工作站进行图像融合分别得到冠状、矢状、横断的CT、PET及PET/CT融合图像。勾画感兴趣区(region of interest, ROI),测量肺部病灶(靶组织)与正常肺组织(非靶组织)的平均SUV(SUVmean)及最高SUV(SUVmax),并计算其比值(T／NT)。同时计算肺部病灶(靶组织)与同层面肌肉组织的最高SUV(SUVmax)的比值(T／M)。采用RT-PCR和Western blot方法将术后取得的肺癌组织及正常肺组织检测胆碱乙酰基转移酶(ChAT)和胆碱激酶(Chok)mRNA及蛋白质的表达；分析肺癌的胆碱显像与肺癌组织细胞中胆碱代谢的变化。
结果：经手术病理证实的32例患者中肺癌为29例,良性病灶为3例。其中10例为腺癌,其中高分化腺癌1例,中分化腺癌6例,低分化腺癌3例。14例为鳞癌,12为鳞状细胞癌Ⅱ级,2例为鳞癌Ⅰ级。3例为不典型类癌。1例为小细胞肺癌。1例为粘液表皮样癌。1例为炎性假瘤,2例为结核。17例肺癌患者发生肺门淋巴结转移。13例发生了纵隔淋巴结转移。①11C-胆碱PET／CT显像结果：所有29例肺癌病灶均呈现胆碱放射性摄取明显增高。部分病灶呈周边放射性浓聚,中心放射性稀疏缺损区为坏死区域。3例良性病灶(1例炎性假瘤,2例结核)同样摄取11C-胆碱增高,无法与恶性肿瘤区分。②半定量分析：以SUV为半定量参数,肺癌患者的平均SUVmax为4.82±1.79(1.45～7.67),良性病变的平均SUVmax为6.95±1.1(6.15～8.2)。以双样本异方差t检验,两者无显著性差异(t=3.18,p>0.05)。以T／NT及T／M为参数,肺癌患者的平均T／NT及T／M分别为5.59±2.19(2.17～7.16),4.05±1.51(2.17～7.16),良性病变患者的平均T／NT及T／M为8.07±1.75(6.07～9.32),3.11±0.66(2.52～3.82),两者的差异亦不具有显著性(t=3.18,p>0.05,t=2.57,p>0.05)。③本研究鳞癌14例,病灶的SUVmax为4.98±1.96(1.45～7.67),T／NT为6.06±2.01(3.29～9.54)。腺癌10例,病灶的SUVmax为4.09±1.62(2.05～7.07),T／NT为4.68±2.05(2.17～7.77)。两者之间不具有显著性差异(t=2.08,P>0.1；t=2.09,P>0.1)。不典型类癌3例,病灶的SUVmax为6.05±1.54(4.41～7.46),T／NT为7.39±2.49(5.75～10.26)。与鳞癌、腺癌相比也不具有显著性差异。④6例发生远处转移的患者PET/CT显像表现为转移灶局限性放射性异常浓聚。17例肺癌患者发生了肺门淋巴结转移,PET/CT检查发现了其中的13例。13例患者发生了37组纵隔淋巴结转移,PET／CT检查发现了10例,31组(其中6组为假阳性)。以淋巴结组数计算,11C-胆碱PET/CT显像检测纵隔淋巴结转移灵敏度、特异性、阳性预测值、阴性预测值及准确度分别为67.6%,84.2%,80.6%,72.7%,72.7%。⑤18例肺癌组织细胞中14例Chok mRNA及蛋白质的表达比正常肺组织升高,9例肺癌组织细胞ChAT mRNA及蛋白质表达升高,其中8例Chok及ChAT表达均升高。
结论：11C-胆碱PET/CT显像所有肺癌病灶均表现为胆碱高摄取。良性病灶如结核早期及炎性假瘤也会出现摄取胆碱增高。通过半定量分析,肺癌及良性病灶两组的SUVmean、SUVmax、T/NT及T／M均无显著性差异。11C-胆碱PET/CT显像不能很好地鉴别肺部病灶的良恶性。不同病理类型的肺癌如鳞癌、腺癌及不典型类癌对胆碱摄取的SUVmax、T/NT均无显著性差异。11C-胆碱PET/CT显像能够发现肺癌患者的纵隔及肺门淋巴结转移及远处转移灶,有助于准确临床分期。11C-胆碱在各种病理类型的肺癌组织细胞中不仅有磷酸化途径的增强,而且均存在乙酰化途径
Part one The value of 11C-choline PET/CT imaging on prostate cancer and correlation with tissue markers of AR, PTEN, Ki 67
Objective To investigate the potential of 11C-choline PET/CT imaging for diagnosis and staging of prostate cancer and detection of recurrent ones. To study the correlation between 11C-choline PET/CT imaging and the tissue markers, including AR, PTEN and ki67. The application of 11C-choline PET/CT imaging on lung caner and the real metabolic mechanism of 11C-choline in vivo were also investigated.
Methods A total of 59 patients with prostate lesions were divided into two groups①49 cases without any therapy, male, age 47-92, PSA 1.1 ng/ml-100 ng/ml.②10 patients who have accepted either radical prostatectomy or maximum androgen blockade therapy. They all underwent 11C-choline PET/CT imaging before transrectal needle biopsy. PET/CT imaging were performed 5min after injection of 7.4 MBq/kg 11C-choline in supine position over 2 bed positions (3 min per position), covering the pelvis, and the whole body (6 bed) when necessary. After correction for measured attenuation, decay and scatter and iterative reconstruction, PET data were analyzed semi quantitatively by measuring maximum standardized uptake values (SUVmax) of the prostate lesions (target) and the muscles (non-target) and calculating their ratios (P/M). Visual analysis was performed using transverse, sagittal and coronal slices as well as three-dimension images. The results of 11C-choline PET/CT were compared to pathologic results which were acquired by radical prostatectomy or biopsies specimens. Sensitivity, specificity, positive and negative predictive value of PET/CT in diagnosis on prostate cancer were calculated and all statistical analysis were made by SPSS 13.0.
Results①21 prostate caner and 28 benign prostate hyperplasia (and/or chronic prostatitis) were proven histologically. All PCa could be visualized as avid accumulation in the gland. Among 28 benign diseases, high uptake of the radioactivity was noticed in 23 BPH while 5 BPH showed little accumulation of C-11 choline. With PET/CT precise localization, a diffuse accumulation of radioactivity in the entire prostate gland was observed in 15 and a solitary hot spot within the peripheral zone of prostate gland was visualized in 6 patients among 21 PCa cases.27 of 28 BPH patients could be seen symmetrical uptake of C-11 choline within the central zone of prostate.②The mean values of SUVmax of PCa and BPH were 7.87±5.74 and 4.95±5.14, respectively. There was no significant difference between these two groups. (t=2.02, p>0.05). The mean P/M of PCa and BPH were 4.21±1.61 and 1.87±0.98, respectively. The statistical differences of P/M between them were significant (t=2.04, p<0.01).③Using 2.3 (P/M) as criterion, C-11 choline PET/CT imaging showed sensitivity of 90.48%, specificity of 85.71% and negative predictive value of 92.31%. The precise localization of the radioactivity hot spot in different part of the prostate could help the diagnosis a lot which is the advantage of PET/CT.④6 patients with focal uptake in lymph node and/or bone metestases were detected by 11C-choline PET/CT which demonstate it is useful in staging of prostate cancer.⑤Among 4 patients who underwent radical prostatectomy 1 patient was found that his postate cancer was still existed. And 2 patients were detected with recurrent tumor in 6 cases which accepted maximum androgen blockade therapy.⑥A significant positive association was found between 11C-choline accumulation and Ki67 (rs=0.764, P<0.01; rs=0.660, P<0.01) respectively in all the 49 patients and prostate cancer patients.
Conclusion 11C-choline PET/CT is a valuable non-invasive imaging technology in the diagnosis, staging and detection of recurrent of prostate cancer. The parameter P/M could differentiate prostate cancer from benign lesions better than SUV. A significant positive association was found between 11C-choline accumulation and Ki67 in prostate cancer patients.
Part two The research of 11C-choline PET/CT imaging and choline metabolism on lung cancer
Objective To investigate the potential of 11C-choline PET/CT imaging for diagnosis and staging of lung cancer in order to find a more accurate tracer than 18F-FDG in early diagnosise of cancer. To study the proportion of phosphorylation pathway and acetylation pathway of choline in different types of lung cancer in order to investigate the real metabolic mechanism of 11C-choline in vivo.
Methods 38 patients with suspicious lung cancer who were examined with 11C-choline PET/CT imaging had finally had lung surgery in 32 while the other 6 patients were found to have distance metastasis. Lung cancer sample and normal lung tissues were saved in 18 patients for further choline metabolism research. Without fasting, patients were injected of 7.4MBq/kg of 11C-choline intravenously five minutes before imaging. PET images were acquired in supine position over 2 bed positions (3 min per positron) from the upper neck to the lower edge of liver and whole body(6 bed positions) when necessary. The parameters of the multidetector helical CT scan were 140 kV,80 mA,0.8 s per tube rotation, slice thickness of 5 mm, pitch of 6, and table speed of 11.25 mm/s. PET images were reconstructed with the iterative reconstruction ordered-subset expectation maximization likelihood algorithm of the manufacturer after attenuation correction based on the CT dataset. Consecutive transverse PET/CT slices of 4.25 mm thickness were generated. Lung cancers were analysed visually and semiquantitatively using the ratio of tumour-to-normal radioactivity (T/N ratio) and standardized uptake value (SUV). Mediastinal lymph node metastases were analysed visually. RT-PCR and Western blot were used to investigate the expression of choline acetyltransferase (ChAT) and choline kinase (ChoK) genes in lung cancer specimens and the normal lung tissues.
Results①All lung cancer could be visualized as avid accumulation in the lesions. But the three benign diseases, including two tuberculosis and one inflammatory pseudotumor also showed high uptake of the radioactivity. It is hard to differentiate malignant from benign lesions in 11C-choline PET/CT imaging.②The mean values of SUVmax of lung cancer and benign lesions were 4.82±1.79 and 6.95±1.1, respectively. There was no significant difference between these two groups. (t=3.18, p>0.05). The mean T/NT of malignant and benign lesions were 5.59±2.19 and 8.07±1.75, respectively.. The statistical differences of T/NT between them were still not significant (t=3.18, p>0.05).③The SUVmax and T/NT of the all 14 squamous cell carcinoma patients were 4.98±1.96 and 6.0612.01 respectively, while the SUVmax and the T/NT of the 10 adenocarcinoma patients were 4.09±1.62 and 4.68±2.05. The difference was not statistically significant between the squamous cell carcinoma and adenocarcinoma.④6 patients with distant metestases were detected by 11C-cholinePET/CT which demonstate it is useful in staging of lung cancer. In the assessment of mediastinal lymph node involvement, 11C-choline PET/CT detected 10 patients in all 13 patients proven by pathology. The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 11C-Choline PET/CT in the detection of lymph node metastasis is 67.6%,84.2%,80.6%,72.7%,72.7%.⑤The expression of ChAT mRNA and protein were enhanced in 9 of 18 lung tumor specimens; and the expression of ChoK mRNA and protein were increased in 14 of 18 lung tumor specimens comparing with the normal lung tissues.8 of 18 lung cancer specimens were obvious increased both in the expression of ChoK and ChAT.
Conclusion In this study, all lung cancer could be visualized as avid accumulation in the lesions while the benign diseases, including tuberculosis and inflammatory pseudotumor could also show high uptake of the radioactivity. No matter SUVmax or T/NT, there was no significant difference between the malignant and bening groups. It is difficult to differentiate malignant from benign lesions in 11C-choline PET/CT imaging. The difference was not statistically significant between the squamous cell carcinoma and adenocarcinoma in SUV and T/NT. Both phosphorylation pathway and acetylation pathway of choline were existed in different types of lung cancer.
引文
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10 Yamaguchi T, Lee J, Uemura H, et al. Prostate cancer:a comparative study of 11C-choline PET and MR imaging combined with proton MR spectroscopy. Eur J Nucl Med Mol Imaging 2005; 32:742-748.
11 Meare's EM Jr. Prostatitis and related disorder, in Walsh PC, Gittes RF, Perlmutter AD, et al (eds):Campbell's Urology (ed 6) Philadelphia,PA, Saunders,1992, pp 807-822
12 Sadik M, Suurkula M, Hoglund P, et al. Improved classifications of planar whole-body bone scans using a computer-assisted diagnosis system:a multicenter, multiple-reader, multiple-case study.J Nucl Med. 2009:50:368-75.
13 Sadik M, Suurkula M, Hoglund P, et al. Quality of planar whole-body bone scan interpretations—a nationwide survey.Eur J Nucl Med Mol Imaging.2008:35:1464-72.
14 Xu, J., R. Wang, et al. Prostate cancer metastasis:role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis. [J]. Prostate,2006,66(15):1664-73
15 Beyer T, Townsend DW, Blodgett TM. Dual-modality PET/CT tomography for clinical oncology.Q J Nucl Med. 2002:46:24-34.
16 Siegel, B. A. and F. Dehdashti. Oncologic PET/CT:current status and controversies [J]. Eur Radiol,2005,15 Suppl 4:D127-32.
17 Jana S, Blaufox MD. Nuclear medicine studies of the prostate, testes, and bladder[J]. Semin Nucl Med.2006, 36(1):51-72.
18 Roivainen A, Forsback S, Gronroos T, et al. Blood metabolism of [methyl-11C]choline;implications for in vivo imaging with positron emission tomography. Eur J Nucl Med 2000; 27:25-32.
19 Takahashi, N., T. Inoue, et al. The roles of PET and PET/CT in the diagnosis and management of prostate cancer [J] Oncology,2007,72(3-4):226-33.
20 Delbeke D:Oncological applications of FDG PET imaging: Brain tumors, colorectal cancer, lymphoma and melanoma. J Nucl Med 40:591-603,1999
21 Avril N, Menzel M, Dose J, et al:Glucose metabolism of breast cancer assessed by 18F-FDG PET:Histologic and immunohistochemical tissue analysis. J Nucl Med 42:9-16, 2001)
22 Bos R, van Der Hoeven JJ, van Der Wall E, et al:Biologic correlates of (18) Fluorodeoxyglucose uptake in human breast cancer measured by positron Emission Tomography. J Clin Oncol 20:379-387,2002
23 Liu IJ, Zafar MB, Lai YH, et al:Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology 57:108-111,2001
24 Pascali C, Bogni A, Iwata R, et al. "C-Methylation on C18 SepPak cartridge:a convenient way to produce [N-methyl-11C] choline. J Labelled Compds Radiopharm. 2000:49:195-203
25 张锦明,田嘉禾,杨志等。自动化制备11C-胆碱及临床应用。中华核医学杂志,2004,24：46-48。
26 Oyama N, Akino H, Kanamaru H, et al.11C-acetate PET imaging of prostate cancer. J Nucl Med 2002;43:181-6
27 Toth G, Lengyel Z, Balkay L, et al. Detection of prostate cancer with 11C-methionine positron emission tomography. J Urol 2005; 173:66-9
28 Roivainen A, Forsback S, Gronroos T, et al. Blood metabolism of [methyl-11C]choline;implications for in vivo imaging with positron emission tomography. Eur J Nucl Med 2000; 27:25-32.
29 Ackerstaff E, Pflug BR, Nelson JB, et al. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res 2001;61:3599-603
30 Lawrentschuk N, Davis ID, Bolton DM, et al:Positron emission tomography and molecular imaging of the prostate: an update. BJU Int.2006; 97:923-31.
31 Heinisch M, Dirisamer A, Loidl W, et al:Positron emission tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients:meaningful at PSA< 5 ng/ml? Mol Imaging Biol.2006; 8:43-8.
32 Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer. Eur J Nucl Med Mol Imaging 2005:32:668-73.
33 Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11 choline. J Nucl Med 1998:39:990-5
34 De Jong IJ, Pruim J, Elsinga PH, et al. Visualization of prostate cancer with 11C-choline positron emission tomography. Eur Urol.2002; 42:18-23.
35 De Jong IJ, Pruim J, Elsinga PH, et al. Preoperative staging of pelvic lymph nodes in prostate cancer by 11C-choline PET. J Nucl Med.2003; 44:331-335.
36 De Jong IJ, Pruim J, Elsinga PH, et al. 11C-choline positron emission tomography for the evaluation after treatment of localized prostate cancer. Eur Urol.2003; 44:32-38.
37 Zheng QH, Gardner TA, Raikwar S, et al:[11C]Choline as a PET biomarker for assessment of prostate cancer tumor models. Bioorg Med Chem.2004;12:2887-2893
38 Reske SN, Blumstein NM, Neumaier B, et al:Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med.2006; 47:1249-54.
39 Scher B, Seitz M, Albinger W, et al. Value of 11C-choline PET and PET/CT in patients with suspected prostate cancer. Eur J Nucl Med Mol Imaging,2007; 34:45-53.
40 Sutinen E, Nurmi M, Roivainen A, et al. Kinetics of [(11)C]choline uptake in prostate cancer:a PET study. Eur J Nucl Med Mol Imaging.2004 Mar; 31:317-324.
41 Yoshida S, Nakagomi K, Goto S, et al. 11C-choline positron emission tomography in prostate cancer:primary staging and recurrent site staging. Urol Int.2005; 74:214-220.
42 Fazio F, Picchio M, Messa C. Is 11C-choline the most appropriate tracer for prostate cancer? For. Eur J Nucl Med Mol Imaging.2004 May; 31:753-756.
43 Zophel K, Kotzerke J. Is 11C-choline the most appropriate tracer for prostate cancer? Against. Eur J Nucl Med Mol Imaging.2004 May; 31:756-759.
44 Wachter S, Tomek S, Kurtaran A, et al:11C-acetate positron emission tomography imaging and image fusion with computed tomography and magnetic resonance imaging in patients with recurrent prostate cancer. J Clin Oncol. 2006:24:2513-2519.
45 潘中允。泌尿外科专集(一)。前列腺增生及前列腺癌(郭应禄主编)。北京：人民卫生出版社,1998：188
46 范义湘,罗荣城,李贵平,等。骨显像联合碱性磷酸酶诊断1 59例前列腺癌骨转移。肿瘤学杂志,2004,100-342.
47 田嘉禾。PET、PET/CT诊断学。北京：化学工业出版社,2007：339.
48 Garcia JR, Soler M, Blanch MA, et al. PET/CT with (11)C-choline and (18)F-FDG in patients with elevated PSA after radical treatment of a prostate cancer. Rev Esp Med Nucl.2009;28(3):95-100.
49 Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer.Eur J Nucl Med Mol Imaging. 2008:35(1):18-23.
50 Pucar D, Sella T, Schoder H. The role of imaging in the detection of prostate cancer local recurrence after radiation therapy and surgery.Curr Opin Urol. 2008:18(1):87-97.
51 李云祥,苟欣,王安果,等。MCM2在前列腺癌中的表达及临床意义。现代泌尿外科杂志,2009,14：15-17
52 Yeh SD, Imbriaco M, Larson SM, et al:Detection of bony metastases of androgen-independent prostate cancer by PET-FDG. Nucl Med Biol 23:693-697,1996
53 Kao CH, Hsieh JF, Tsai SC, et al:Comparison and discrepancy of 18F-2-deoxyglucose positron emission tomography and Tc-99m MDP bone scans to detect bone metastases. Anticancer Res 20:2189-2192,2000
54 Morris MJ, Akhurst T, Osman I, et al:Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology 59:913-918,2002
55 Kotzerke J, Volkmer BG, Glatting G, et al: Intraindividual comparison Of [11C] acetate and [11C]choline PET for detection of metastases of prostate cancer. Nuklearmedizin 42:25-30,2003
1.支修益。我国肺癌流行病学现状分析。中国处方药,2009,83：56-57。
2. Ikeda N, Hayashi A, Miura Y, et al. Present strategy of lung cancer screening and surgical management. Ann Thorac Cardiovasc Surg.2005;11(6):363-6.
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4.汤钊猷。现代肿瘤学。上海：复旦大学出版社,2005：868
5. Godden D, Waugh N. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer:systematic reviews. Health Technol Assess. 2006;10(3):1-106.
6.熊华,袁响林,邹燕梅,等。术前CT检查在可手术非小细胞肺癌TNM分期中的应用评价。肿瘤防治研究,2009,36：682-685.
7. Cardinale L, Cortese G, Borasio P, et al. Low dose CT in early lung cancer diagnosis:prevalence data. Radiol Med (Torino).2005;110 (5-6):532-543.
8. Gould MK,Kuschner WG,Rydzak CE,et al. Test performanceof positron emission tomography and computed tomography formediastinal staging in patients with non small-cell lung cancer:a meta-analysis[J]. Ann Intern Med,2003, 139(11):879-892.
9. Bedard N, Pierce M, El-Nagger A, et al. Emerging roles for multimodal optical imaging in early cancer detection:a global challenge. Technol Cancer Res Treat.2010;9:211-8.
10.田嘉禾。北京：化学工业出版社。2007：268-269.
11. Acker MR, Burrell SC. Utility of 18F-FDG PET in evaluating cancer of lung.J Nucl Med Technol,2005/33 (2):69-74.
12. Shim SS, Lee KS, Kim BT, et al.Focal parenchymal lung lesions showing a potential of false-positive and false-negative interpretations on integrated PET/CT.AJR Am J Roentgenol,2006,186 (3):639-648.
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2 孙颍浩。我国前列腺癌的研究现状[J]。中华泌尿外科杂志,2004,25(2)：77-80.
3 朱刚,刘明,万奔。早期前列腺癌的诊断与治疗。中华男科学杂志,2005,11：693-696.
4 熊礼生。关注前列腺癌。现代诊断与治疗,2008,19：321-323.
5 Mackinnon AC, Yan BC, Joseph LJ, et al. Molecular biology underlying the clinical heterogeneity of prostate cancer: an update. Arch Pathol Lab Med.2009;133:1033-40.
6 Peng C, Kainz K, Lawton C, et al. A comparison of daily megavoltage CT and ultrasound image guided radiation therapy for prostate cancer. Med Phys.2008 Dec;35(12):5619-28.
7 Moradi M, Abolmaesumi P, Isotalo PA, et al. Detection of prostate cancer from RF ultrasound echo signals using fractal analysis. Conf Proc IEEE Eng Med Biol Soc. 2006;1:2400-3.
8 Stephan C, Rittenhouse H, Cammann H, et al. New markers and multivariate models for prostate cancer detection. Anticancer Res.2009:29:2589-600.
9 Brassell SA, Rosner IL, McLeod DG. Update on magnetic resonance imaging, ProstaScint, and novel imaging in prostate cancer. Curr Opin Urol.2005; 15:163-166.
10 Yamaguchi T, Lee J, Uemura H, et al. Prostate cancer:a comparative study of 11C-choline PET and MR imaging combined with proton MR spectroscopy. Eur J Nucl Med Mol Imaging 2005; 32:742-748.
11 Meare's EM Jr. Prostatitis and related disorder, in Walsh PC, Gittes RF, Perlmutter AD, et al (eds):Campbell's Urology (ed 6) Philadelphia,PA, Saunders,1992, pp 807-822
12 Sadik M, Suurkula M, Hoglund P, et al. Improved classifications of planar whole-body bone scans using a computer-assisted diagnosis system:a multicenter, multiple-reader, multiple-case study.J Nucl Med. 2009:50:368-75.
13 Sadik M, Suurkula M, Hoglund P, et al. Quality of planar whole-body bone scan interpretations—a nationwide survey.Eur J Nucl Med Mol Imaging.2008:35:1464-72.
14 Xu, J., R. Wang, et al. Prostate cancer metastasis:role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis. [J]. Prostate,2006,66(15):1664-73
15 Beyer T, Townsend DW, Blodgett TM. Dual-modality PET/CT tomography for clinical oncology.Q J Nucl Med. 2002:46:24-34.
16 Siegel, B. A. and F. Dehdashti. Oncologic PET/CT:current status and controversies [J]. Eur Radiol,2005,15 Suppl 4:D127-32.
17 Jana S, Blaufox MD. Nuclear medicine studies of the prostate, testes, and bladder[J]. Semin Nucl Med.2006, 36(1):51-72.
18 Roivainen A, Forsback S, Gronroos T, et al. Blood metabolism of [methyl-11C]choline;implications for in vivo imaging with positron emission tomography. Eur J Nucl Med 2000; 27:25-32.
19 Takahashi, N., T. Inoue, et al. The roles of PET and PET/CT in the diagnosis and management of prostate cancer [J] Oncology,2007,72(3-4):226-33.
20 Delbeke D:Oncological applications of FDG PET imaging: Brain tumors, colorectal cancer, lymphoma and melanoma. J Nucl Med 40:591-603,1999
21 Avril N, Menzel M, Dose J, et al:Glucose metabolism of breast cancer assessed by 18F-FDG PET:Histologic and immunohistochemical tissue analysis. J Nucl Med 42:9-16, 2001)
22 Bos R, van Der Hoeven JJ, van Der Wall E, et al:Biologic correlates of (18) Fluorodeoxyglucose uptake in human breast cancer measured by positron Emission Tomography. J Clin Oncol 20:379-387,2002
23 Liu IJ, Zafar MB, Lai YH, et al:Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology 57:108-111,2001
24 Pascali C, Bogni A, Iwata R, et al. "C-Methylation on C18 SepPak cartridge:a convenient way to produce [N-methyl-11C] choline. J Labelled Compds Radiopharm. 2000:49:195-203
25 张锦明,田嘉禾,杨志等。自动化制备11C-胆碱及临床应用。中华核医学杂志,2004,24：46-48。
26 Oyama N, Akino H, Kanamaru H, et al.11C-acetate PET imaging of prostate cancer. J Nucl Med 2002;43:181-6
27 Toth G, Lengyel Z, Balkay L, et al. Detection of prostate cancer with 11C-methionine positron emission tomography. J Urol 2005; 173:66-9
28 Roivainen A, Forsback S, Gronroos T, et al. Blood metabolism of [methyl-11C]choline;implications for in vivo imaging with positron emission tomography. Eur J Nucl Med 2000; 27:25-32.
29 Ackerstaff E, Pflug BR, Nelson JB, et al. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res 2001;61:3599-603
30 Lawrentschuk N, Davis ID, Bolton DM, et al:Positron emission tomography and molecular imaging of the prostate: an update. BJU Int.2006; 97:923-31.
31 Heinisch M, Dirisamer A, Loidl W, et al:Positron emission tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients:meaningful at PSA< 5 ng/ml? Mol Imaging Biol.2006; 8:43-8.
32 Breeuwsma AJ, Pruim J, Jongen MM, et al. In vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer. Eur J Nucl Med Mol Imaging 2005:32:668-73.
33 Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11 choline. J Nucl Med 1998:39:990-5
34 De Jong IJ, Pruim J, Elsinga PH, et al. Visualization of prostate cancer with 11C-choline positron emission tomography. Eur Urol.2002; 42:18-23.
35 De Jong IJ, Pruim J, Elsinga PH, et al. Preoperative staging of pelvic lymph nodes in prostate cancer by 11C-choline PET. J Nucl Med.2003; 44:331-335.
36 De Jong IJ, Pruim J, Elsinga PH, et al. 11C-choline positron emission tomography for the evaluation after treatment of localized prostate cancer. Eur Urol.2003; 44:32-38.
37 Zheng QH, Gardner TA, Raikwar S, et al:[11C]Choline as a PET biomarker for assessment of prostate cancer tumor models. Bioorg Med Chem.2004;12:2887-2893
38 Reske SN, Blumstein NM, Neumaier B, et al:Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med.2006; 47:1249-54.
39 Scher B, Seitz M, Albinger W, et al. Value of 11C-choline PET and PET/CT in patients with suspected prostate cancer. Eur J Nucl Med Mol Imaging,2007; 34:45-53.
40 Sutinen E, Nurmi M, Roivainen A, et al. Kinetics of [(11)C]choline uptake in prostate cancer:a PET study. Eur J Nucl Med Mol Imaging.2004 Mar; 31:317-324.
41 Yoshida S, Nakagomi K, Goto S, et al. 11C-choline positron emission tomography in prostate cancer:primary staging and recurrent site staging. Urol Int.2005; 74:214-220.
42 Fazio F, Picchio M, Messa C. Is 11C-choline the most appropriate tracer for prostate cancer? For. Eur J Nucl Med Mol Imaging.2004 May; 31:753-756.
43 Zophel K, Kotzerke J. Is 11C-choline the most appropriate tracer for prostate cancer? Against. Eur J Nucl Med Mol Imaging.2004 May; 31:756-759.
44 Wachter S, Tomek S, Kurtaran A, et al:11C-acetate positron emission tomography imaging and image fusion with computed tomography and magnetic resonance imaging in patients with recurrent prostate cancer. J Clin Oncol. 2006:24:2513-2519.
45 潘中允。泌尿外科专集(一)。前列腺增生及前列腺癌(郭应禄主编)。北京：人民卫生出版社,1998：188
46 范义湘,罗荣城,李贵平,等。骨显像联合碱性磷酸酶诊断1 59例前列腺癌骨转移。肿瘤学杂志,2004,100-342.
47 田嘉禾。PET、PET/CT诊断学。北京：化学工业出版社,2007：339.
48 Garcia JR, Soler M, Blanch MA, et al. PET/CT with (11)C-choline and (18)F-FDG in patients with elevated PSA after radical treatment of a prostate cancer. Rev Esp Med Nucl.2009;28(3):95-100.
49 Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer.Eur J Nucl Med Mol Imaging. 2008:35(1):18-23.
50 Pucar D, Sella T, Schoder H. The role of imaging in the detection of prostate cancer local recurrence after radiation therapy and surgery.Curr Opin Urol. 2008:18(1):87-97.
51 李云祥,苟欣,王安果,等。MCM2在前列腺癌中的表达及临床意义。现代泌尿外科杂志,2009,14：15-17
52 Yeh SD, Imbriaco M, Larson SM, et al:Detection of bony metastases of androgen-independent prostate cancer by PET-FDG. Nucl Med Biol 23:693-697,1996
53 Kao CH, Hsieh JF, Tsai SC, et al:Comparison and discrepancy of 18F-2-deoxyglucose positron emission tomography and Tc-99m MDP bone scans to detect bone metastases. Anticancer Res 20:2189-2192,2000
54 Morris MJ, Akhurst T, Osman I, et al:Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology 59:913-918,2002
55 Kotzerke J, Volkmer BG, Glatting G, et al: Intraindividual comparison Of [11C] acetate and [11C]choline PET for detection of metastases of prostate cancer. Nuklearmedizin 42:25-30,2003
1.支修益。我国肺癌流行病学现状分析。中国处方药,2009,83：56-57。
2. Ikeda N, Hayashi A, Miura Y, et al. Present strategy of lung cancer screening and surgical management. Ann Thorac Cardiovasc Surg.2005;11(6):363-6.
3.刘庆伟、刘奇。PET/CT肿瘤学。北京：科学出版社,2006：108.
4.汤钊猷。现代肿瘤学。上海：复旦大学出版社,2005：868
5. Godden D, Waugh N. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer:systematic reviews. Health Technol Assess. 2006;10(3):1-106.
6.熊华,袁响林,邹燕梅,等。术前CT检查在可手术非小细胞肺癌TNM分期中的应用评价。肿瘤防治研究,2009,36：682-685.
7. Cardinale L, Cortese G, Borasio P, et al. Low dose CT in early lung cancer diagnosis:prevalence data. Radiol Med (Torino).2005;110 (5-6):532-543.
8. Gould MK,Kuschner WG,Rydzak CE,et al. Test performanceof positron emission tomography and computed tomography formediastinal staging in patients with non small-cell lung cancer:a meta-analysis[J]. Ann Intern Med,2003, 139(11):879-892.
9. Bedard N, Pierce M, El-Nagger A, et al. Emerging roles for multimodal optical imaging in early cancer detection:a global challenge. Technol Cancer Res Treat.2010;9:211-8.
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