^(18)F-FDOPA PET显像在脑胶质瘤中的临床应用价值

脑胶质瘤是发病率最高的神经系统来源肿瘤。目前临床上诊断胶质瘤的方法主要为MRI平扫及增强,但存在一定的局限性。近年来,随着PET与核素显像剂的不断发展和改进,其在胶质瘤领域的研究越来越深入,尤其是18F-FDOPA PET显像在原发性及复发性胶质瘤的诊断、鉴别、分级、定位、治疗和预后评估中具有较高的临床应用价值。本文就此进行综述。     

18F-FLT实验研究与临床应用进展

放射性核素标记的胸腺嘧啶类似物能够在一定程度上反映细胞增殖的状况,3′-脱氧-3′-18F-氟代胸苷(3′-deoxy-3′18F-fluorothymidine,18F-FLT)是此类药物中发展较为完善的一种示踪剂.18F-FLT PET通过反映胸苷激酶-1的活性而间接反映肿瘤细胞的增殖状况,有助于对肿瘤进行良恶性鉴别、疗效评估和预后判断,是一种具有良好应用前景的PET显像剂.     

^18F-FLT实验研究与临床应用进展

放射性核素标记的胸腺嘧啶类似物能够在一定程度上反映细胞增殖的状况，3’-脱氧-3’-^18F-氟代胸苷(3’-deoxy-3’-’^18F-fluorothymidine，^18F-FLT)是此类药物中发展较为完善的一种示踪剂。^18F-FLT PET通过反映胸苷激酶-l的活性而间接反映肿瘤细胞的增殖状况，有助于对肿瘤进行良恶性鉴别、疗效评估和预后判断，是一种具有良好应用前景的PET显像剂。     

18F-FDG和18F-FLT PET对肿瘤放化疗疗效评价的实验研究

PET可从分子水平观察细胞生物学行为。目前,临床上最常用的葡萄糖代谢显像剂是18F-FDG,而最常用的细胞增殖显像剂是3’-脱氧-3’-18F-氟胸腺嘧啶(18F-FLT)。这两种显像剂在肿瘤的诊断和分期方面已有深入广泛的研究,而在治疗后疗效评价方面的研究近年也很受重视,特别是肿瘤在放化疗前后对18F-FDG和18F-...     

18F-FLT联合18F-FDG诊断高分化肝癌一例

笔者报道了一例18F-FDG联合18F-胸腺嘧啶脱氧核苷（18F-FLT）诊断原发性高分化肝癌的显像病例，从临床症状、实验室检查、影像学等方面分析该病特点，阐述了PET/CT在肝脏疾病诊断中的优势，同时指出18F-FDG在肝癌诊断中的不足，并通过文献回顾了18F-FLT、11C-乙酸盐在肝癌中的应用。不同显像剂的联合使用对肝脏占位的诊断具有重要价值。     

肿瘤增殖显像剂3′-脱氧-3′-18F-氟代胸苷

18F-氟代脱氧葡萄糖（18F-FDG）是广泛用于肿瘤诊断的PET显像剂,由于所有细胞都利用葡萄糖,因此,18F-FDG不是特异的肿瘤显像剂.3′-脱氧-3′-18F-氟代胸苷（18F-FLT）克服了18F-FDG的局限性,并可以进行细胞增殖显像.对于肿瘤的PET研究,18F-FLT是理想的反映增殖特性的示踪剂,18F-FLT利用胸苷激酶催化的磷酸化作用来评价DNA复制过程,可以准确地评估肿瘤细胞DNA的合成和细胞增殖活性,可用于肿瘤的早期诊断及鉴别诊断、化疗和放疗的疗效监测,是很有希望和发展前途的PET显像剂.     

肿瘤增殖显像剂3'-脱氧-3'-18F-氟代胸苷

18F-氟代脱氧葡萄糖(18F-FDG)是广泛用于肿瘤诊断的PET显像剂,由于所有细胞都利用葡萄糖,因此,18F-FDG不是特异的肿瘤显像剂.3'-脱氧-3'-18F-氟代胸苷(18F-FLT)克服了18F-FDG的局限性,并可以进行细胞增殖显像.对于肿瘤的PET研究,18F-FLT是理想的反映增殖特性的示踪剂,18F-FLT利用胸苷激酶催化的磷酸化作用来评价DNA复制过程,可以准确地评估肿瘤细胞DNA的合成和细胞增殖活性,可用于肿瘤的早期诊断及鉴别诊断、化疗和放疗的疗效监测,是很有希望和发展前途的PET显像剂.     

脑胶质瘤治疗后复发或残存的影像学研究进展

胶质瘤是颅内最常见的恶性肿瘤,其治疗后复发与残留的准确诊断一直是困扰预后的重要因素.影像新技术为研究颅内胶质瘤治疗后的影像学诊断提供了有力的依据,对评价治疗效果、评估预后及指导临床有着极其重要的意义.综述了脑胶质瘤治疗后的灌注成像、MR功能成像、核医学成像及融合成像的诊断价值及研究进展.     

18F-氟脱氧胸苷PET的肿瘤分子显像研究进展

近年来,细胞增殖显像剂^18F-氟脱氧胸苷（^18F-FLT）受到重视。^18F-FLTPET细胞增殖显像为肿瘤的诊断、分期、预后和疗效观察提供了非创伤性的手段,与^18F-氟脱氧葡萄糖（^18F-FDG）比较表明,^18F-FLT与肿瘤细胞增殖的相关性明显高于^18F-FDG,但敏感性低,而且不能反映所有类型的肿瘤细胞增殖情况。     

脑胶质瘤的11C-甲硫氨酸和11C-胆碱PET和PET-CT

18F-氟脱氧葡萄糖(18F-FDG)在脑肿瘤检查中较常用的诊断用显像剂,但由于其正常的生理分布和自身的缺点影响了其在胶质瘤术前尤其是治疗后的诊断和评估.研究表明,11C标记的甲硫氨酸(11C-MET)和胆碱(11C-胆碱)在脑胶质瘤PET和PET-CT检查中的术前诊断价值、疗效监测以及治疗后肿瘤复发或残存与放射性坏死或治疗后反应的鉴别和评估方面克服了18F-FDG的局限性,是18F-FDG PET和PET-CT的一个重要替代或补充.     

18F-氟脱氧葡萄糖和11C-胆碱在孤立性肺结节诊断中的应用

^18F-．氟脱氧葡萄糖（^18F-FDG）和^11C-胆碱（^11C-choline）在孤立性肺结节（SPN）的定性诊断方面各有优势，两者联用可以互相弥补不足，效果较好。^18F-FDG对恶性SPN以及淋巴结转移判断的敏感性和特异性较高，^11C-胆碱可以降低炎性病变的假阳性率，有利于恶性SPN脑转移的诊断。但^11C-胆碱PET和^18F-FDGPET一样无法显示细支气管肺泡癌、小细胞肺癌等代谢较低的SPN。有报道，^18F-氟脱氧胸苷（^18F-FLT）可用于对肿瘤进行良恶性鉴别、疗效评估和预后判断，被认为是一种具有良好应用前景的PET显像剂。     

Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized (18)F-FLT PET of brain gliomas and compared (18)F-FLT with (18)F-FDG PET in side-by-side studies of the same patients. METHODS: Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with (18)F-FLT and (18)F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of (18)F-FLT and (18)F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of (18)F-FLT and (18)F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12-20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan-Meier statistics. RESULTS: (18)F-FLT uptake in tumors was rapid, peaking at 5-10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. (18)F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable (18)F-FLT uptake and neither did the stable lesions. The absolute uptake of (18)F-FLT was low (maximum-pixel SUV [SUV(max)], 1.33) but image contrast was better than with (18)F-FDG (T/N ratio, 3.85 vs. 1.49). (18)F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1-3 mo. (18)F-FLT SUV(max) correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than (18)F-FDG SUV(max) (r = 0.51; P = 0.07). (18)F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively). CONCLUSION: Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.     

18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors.

Because of the high glucose metabolism in normal brain tissue 18F-FDG is not the ideal tracer for the detection of gliomas. Methyl-11C-l-methionine (11C-MET) is better suited for imaging the extent of gliomas, because it is transported specifically into tumors but only insignificantly into normal brain. 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been introduced as a proliferation marker in a variety of neoplasias and has promising potential for the detection of brain tumors, because its uptake in normal brain is low. Additionally, the longer half-life might permit differentiation between transport and intracellular phosphorylation. METHODS: PET of 18F-FLT and 11C-MET was performed on 23 patients (age range, 20-70 y) with histologically verified gliomas of different grades. On all patients, conventional MRI was performed, and 16 patients additionally underwent contrast-enhanced imaging. Images were coregistered, and the volumes of abnormality were defined for PET and MRI. Uptake ratios and standardized uptake values (SUVs) of various tumors and regions were assessed by region-of-interest analysis. Kinetic modeling was performed on 14 patients for regional time-activity curves of 18F-FLT from tumorous and normal brain tissue. RESULTS: Sensitivity for the detection of tumors was lower for 18F-FLT than for 11C-MET (78.3% vs. 91.3%), especially for low-grade astrocytomas. Tumor volumes detected by 18F-FLT and 11C-MET were larger than tumor regions displaying gadolinium enhancement (P<0.01). Uptake ratios of 18F-FLT were higher than uptake ratios of 11C-MET (P<0.01). Uptake ratios of 18F-FLT were higher in glioblastomas than in astrocytomas (P<0.01). Absolute radiotracer uptake of 18F-FLT was low and significantly lower than that of 11C-MET (SUV, 1.3+/-0.7 vs. 3.1+/-1.0; P<0.01). Some tumor regions were detected only by either 18F-FLT (7 patients) or 11C-MET (13 patients). Kinetic modeling revealed that 18F-FLT uptake in tumor tissue seems to be predominantly due to elevated transport and net influx. However, a moderate correlation was found between uptake ratio and phosphorylation rate k3 (r=0.65 and P=0.01 for grade II-IV gliomas; r=0.76 and P<0.01 for grade III-IV tumors). CONCLUSION: 18F-FLT is a promising tracer for the detection and characterization of primary central nervous system tumors and might help to differentiate between low- and high-grade gliomas. 18F-FLT uptake is mainly due to increased transport, but irreversible incorporation by phosphorylation might also contribute. In some tumors and tumor areas, 18F-FLT uptake is not related to 11C-MET uptake. In view of the high sensitivity and specificity of 11C-MET PET for imaging of gliomas, it cannot be excluded that 18F-FLT PET was false positive in these areas. However, the discrepancies observed for the various imaging modalities (18F-FLT and 11C-MET PET as well as gadolinium-enhanced MRI) yield complementary information on the activity and the extent of gliomas and might improve early evaluation of treatment effects, especially in patients with high-grade gliomas. Further studies are needed, including coregistered histology and kinetic analysis in patients undergoing chemotherapy.     

多种不同PET或PET／CT分子探针在胶质瘤中的应用进展

胶质瘤是一种发病率最高的中枢神经系统原发性肿瘤,约占颅内肿瘤的40％～50％,其恶性程度及病死率极高,加之病理学类型多样、生物学行为各异,胶质瘤对各种治疗手段的反应也是不尽相同的。胶质瘤预后凶险,尤其是高级别胶质瘤。CT是一种以组织密度差异来反映局部解剖结构的影像学检查方法,它能清晰地显示组织结构,但不能反映肿瘤的代谢状况。MRI虽然具有良好的组织分辨率,也能从一定程度上反映肿瘤的代谢状况,但依然具有一定的局限性。PET及PET／CT是一种相对而言比较新兴的检查方法,主要反映肿瘤的代谢状况,随着mF．FDGPET或PET／CT的广泛应用,以及各种非FDG显像剂的发展,PET或PET／CT在胶质瘤诊断中的应用将越来越受到重视。     

Dynamic small-animal PET imaging of tumor proliferation with 3'-deoxy-3'-18F-fluorothymidine in a genetically engineered mouse model of high-grade gliomas.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), a partially metabolized thymidine analog, has been used in preclinical and clinical settings for the diagnostic evaluation and therapeutic monitoring of tumor proliferation status. We investigated the use of (18)F-FLT for detecting and characterizing genetically engineered mouse (GEM) high-grade gliomas and evaluating the pharmacokinetics in GEM gliomas and normal brain tissue. Our goal was to develop a robust and reproducible method of kinetic analysis for the quantitative evaluation of tumor proliferation. METHODS: Dynamic (18)F-FLT PET imaging was performed for 60 min in glioma-bearing mice (n = 10) and in non-tumor-bearing control mice (n = 4) by use of a dedicated small-animal PET scanner. A 3-compartment, 4-parameter model was used to characterize (18)F-FLT kinetics in vivo. For compartmental analysis, the arterial input was measured by placing a region of interest over the left ventricular blood pool and was corrected for partial-volume averaging. The (18)F-FLT "trapping" and tissue flux model parameters were correlated with measured uptake (percentage injected dose per gram [%ID/g]) values at 60 min. RESULTS: (18)F-FLT uptake values (%ID/g) at 1 h in brain tumors were significantly greater than those in control brains (mean +/- SD: 4.33 +/- 0.58 and 0.86 +/- 0.22, respectively; P < 0.0004). Kinetic analyses of the measured time-activity curves yielded independent, robust estimates of tracer transport and metabolism, with compartmental model-derived time-activity data closely fitting the measured data. Except for tracer transport, statistically significant differences were found between the applicable model parameters for tumors and normal brains. The tracer retention rate constant strongly correlated with measured (18)F-FLT uptake values (r = 0.85, P < 0.0025), whereas a more moderate correlation was found between net (18)F-FLT flux and (18)F-FLT uptake values (r = 0.61, P < 0.02). CONCLUSION: A clinically relevant mouse glioma model was characterized by both static and dynamic small-animal PET imaging of (18)F-FLT uptake. Time-activity curves were kinetically modeled to distinguish early transport from a subsequent tracer retention phase. Estimated (18)F-FLT rate constants correlated positively with %ID/g measurements. Dynamic evaluation of (18)F-FLT uptake offers a promising approach for noninvasively assessing cellular proliferation in vivo and for quantitatively monitoring new antiproliferation therapies.     

Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model.

Increased glucose metabolism of inflammatory tissues is the main source of false-positive (18)F-FDG PET findings in oncology. It has been suggested that radiolabeled nucleosides might be more tumor specific. METHODS: To test this hypothesis, we compared the biodistribution of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) and (18)F-FDG in Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus (30 MBq) of either (18)F-FLT (n = 5) or (18)F-FDG (n = 5). Pretreatment of the animals with thymidine phosphorylase (>1,000 U/kg, intravenously) before injection of (18)F-FLT proved to be necessary to reduce the serum levels of endogenous thymidine and achieve satisfactory tumor uptake of radioactivity. RESULTS: Tumor-to-muscle ratios of (18)F-FDG at 2 h after injection (13.2 +/- 3.0) were higher than those of (18)F-FLT (3.8 +/- 1.3). (18)F-FDG showed high physiologic uptake in brain and heart, whereas (18)F-FLT was avidly taken up by bone marrow. (18)F-FDG accumulated in the inflamed muscle, with 4.8 +/- 1.2 times higher uptake in the affected thigh than in the contralateral healthy thigh, in contrast to (18)F-FLT, for which this ratio was not significantly different from unity (1.3 +/- 0.4). CONCLUSION: In (18)F-FDG PET images, both tumor and inflammation were visible, but (18)F-FLT PET showed only the tumor. Thus, the hypothesis that (18)F-FLT has a higher tumor specificity was confirmed in our animal model.     

谷氨酸与谷氨酰胺类似物PET显像剂研究进展

谷氨酰胺是血浆中浓度最高的氨基酸，肿瘤细胞的生长与增殖依赖于谷氨酰胺及其中间代谢产物（如谷氨酸、乳酸、脯氨酸、氨等），肿瘤细胞的生长速度与细胞内谷氨酰胺和谷氨酸的浓度密切相关，谷氨酰胺与谷氨酸在肿瘤代谢中起着重要作用。肿瘤细胞摄取谷氨酸与谷氨酰胺类似物PET显像剂的机制主要涉及氨基酸转运与蛋白质合成。谷氨酸与谷氨酰胺类似物PET显像剂在肝细胞癌、脑肿瘤、胶质瘤以及其他多种肿瘤的鉴别诊断中具有优势，可以弥补18F-氟脱氧葡萄糖 PET显像的一些不足。笔者主要对谷氨酸与谷氨酰胺类似物PET显像剂的研究进展进行综述。     

Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) has been recently described as a radiopharmaceutical for measuring cellular proliferation using PET imaging. Evaluation of tumor proliferative activity by PET using (18)F-FLT could be a procedure to assess the viability of tumor, such as histologic grade, clinical stage, and prognosis as well as the early effects of cancer therapy. This study was undertaken to determine whether (18)F-FLT is useful in the detection of prostate cancer as well as monitoring therapeutic effects in a human tumor model. METHODS: The androgen-dependent human prostate tumor, CWR22, was implanted into athymic mice. This well-established model of prostate cancer was used in all studies. To determine the optimal imaging times for (18)F-FLT, a biodistribution was performed in CWR22 mice. (18)F-FLT (740 kBq [20 micro Ci]) was administered via the tail vein and uptake was determined in selected tissues at 5 min, 20 min, and 1, 2, and 4 h after injection (n = 5, each time point). Androgen ablation studies were conducted in the CWR22 model with either diethylstilbestrol (DES) or surgical castration. Animals received DES every 2 d for 3 wk. The effectiveness of therapy was monitored using (18)F-FLT microPET as baseline, during treatment, and after treatment. Tracer accumulation in the tumor was then analyzed by comparing tumor-to-muscle ratios derived from reconstructed microPET data. RESULTS: At 2 h after injection, the (18)F-FLT uptake in tumor was 0.69 +/- 0.14 percentage injected dose per gram of tissue, showing the highest activity of all organs measured. The microPET study with dynamic imaging showed that (18)F-FLT uptake in blood reached its plateau within 1 min and was rapidly cleared, whereas (18)F-FLT uptake in tumor reached its plateau in 30 min and remained up to 60 min. microPET using (18)F-FLT successfully imaged the implanted CWR22 tumor in the mice at both 1 and 2 h after injection. There was a marked reduction of (18)F-FLT uptake in tumor after castration or DES treatment; however, there were no differences in (18)F-FLT uptake in the tumor in the control group. These changes of (18)F-FLT uptake in tumor parallel the changes of actual tumor measurement. CONCLUSION: These results indicate that (18)F-FLT is a useful tracer for detection of prostate cancer in an animal model. (18)F-FLT has the potential for monitoring the therapeutic effect of androgen ablation therapy in prostate cancer.