| Part Ⅰ:18F-FLT PET Detects Accelerated Repopulation in Non-Small Cell Lung CancerPurpose:A series of studies have verified the phenomenon of tumor accelerated repopulation during irradiation.In this study,we try to detect the tumor response during irradiation and the exact accelerated repopulation time point through repetitive 18F-FLT PET imaging in non-small cell lung cancer(NSCLC).Mehods:A549 xenografts were established in nude mice and assigned to irradiated daily or every second day groups,with total dose of 36Gy/18 fractions.18F-FLT micro-PET scans were performed for in vivo tumors after irradiation being completed,FLT parameters(SUVmax,SUVmean,and T/NT)were measured to detect the feasible time of tumor accelerated repopulation during irradiation.Results:The SUVmax,SUVmean and T/NT increased significantly after 6 times of irradiation at irradiated daily group(2.527,P<0.001;1.614,P<0.001;4.250,P=0.001,respectively)and after 3 times at irradiated every second day group(2.494,P=0.001;1.300,P=0.027;4.750,P=0.002,respectively),suggesting accelerated repopulation,while with treatment time prolonged,the FLT uptake decreased again at later time.Conclusions:Re-proliferation of tumor cell during fractionated radiotherapy could be detected through repeated 18F-FLT scanning in NSCLC.Accelerated repopulation appeared after irradiation of 12Gy/6f at irradiated daily group and after irradiation of 6Gy/3f at irradiated every second day groupPart II:Spatial Consistency of 18F-FLT PET/CT Imaging and Ki67 Expression In Non-small Cell Lung cancerOBJECTIVE:In the first part of the study,it has been demonstrated that there is an accelerated repopulation during the delivery of radiotherapy in non-small cell lung cancer.Continuous monitoring of 18F-FLT PET imaging during radiotherapy in non-small cell lung cancer could find the accurate time point of tumoral accelerated repopulation.But whether PET imaging could accurately display the precise location of accelerated repopulation within the tumor and guide radiotherapy is not clear until now.METHODS:A549 lung adenocarcinoma tumor-bearing mice models were established and randomly divided into daily radiotherapy group and every-second-day radiotherapy group.The total radiation dose was 36Gy/18f.At the end of radiotherapy,tumor bearing mice were subjected to experience 18F-FLT PET/CT scan.After the scanning being completed,the tumors were immediately removed and fastened by a tumor fixer.18F-FLT PET/CT scans were performed for the in vitro tumors.Then,the tumors were sliced and stained for the analysis of Ki67 expression.18F-FLT PET imaging and Ki67 immunohistochemical staining images were integrated with CT images.The FLT uptake parameters(SUVmax,SUVmean,tumor tissue/normal tissue ratio(T/NT))of every PET scan layers were analyzed to determine its spatial correlation with Ki67 expression index.Results:Similar to the results the first part,in the daily radiotherapy group,SUVmax,SUVmean and T/NT values were significantly increased(SUVmax=2.527,P<0.001;SUVmean=1.614,P<0.001;T/NT=4.250(P=0.001)when the irradiation dose reached 12 Gy;for the every-second-day radiotherapy group,the SUVmax and T/NT values were significantly increase when the irradiation dose reached 6 Gy(SUVmax＝2.494,P=0.001;SUVmean=1.300,P=0.027;T/NT=4.750,P=0.002).With radiotherapy dose increasing,FLT uptake of tumor gradually decreased,indicating the tumor accelerated re-proliferation.Comparison between 18F-FLT uptake parameters of ex vivo and in vivo tumors in the 12Gy/6f subgroup(P suvmax=0.245,P suvmean＝0.082)in the daily radiotherapy group as well as the 6Gy/3f subgroup in the every second day radiotherapy group(Psuvmax=0.494,Psuvmean=0.317),showed no significant difference,indicating the consistency of 18F-FLT uptake parameters in vivo and ex vivo tumor.In both two subgroups,there was a significant correlation between 18F-FLT uptake parameters and Ki67 expression index:SUVmax was significantly correlated with Ki67 expression index(12Gy/6f/6d,Rsuvmax=0.954,Psuvmax=0.046;6Gy/3f/6d,Rsuvmax = 0.998,Psuvmax = 0.039),SUVmean was also significantly associated with Ki67 expression index(Rsuvmean = 0.972,Psuvmean ＝0.028;Rsuvmean = 0.998,Psuvmean = 0.043).To further compare the PET scan imaging with the pathological data layer by layer,4 non-overlapped regions of interest at each selected layer was randomly selected,labeled as 1-4.And the 18F FLT uptake parameters and Ki67 expression index was calculated.Both SUVmax and SUVmean were significantly correlated with Ki67 expression index(P<0.05).The overlapped region between high 18F-FLT uptake(80%SUVmax)in 18F FLT PET images and the high expression region of Ki67(Ki67 LI>80%)in pathological sections in all tumors of these two subgroups reached up to 50%.Conclusions:Continuous monitoring of 18F-FLT PET imaging could help detect the accelerated repopulation phenomenon during fractional radiotherapy for non-small cell lung cancer.Spatial consistency of 18F-FLT uptake parameters and Ki67 expression index appears at the time point of accelerate tumor repopulation.All the results indicated that 18F-FLT PET/CT images could reflect the tumor’s proliferative response to fractional radiotherapy,and may help modify the treatment plan during the radiotherapy for non-small cell lung cancer.Part III:In-vivo Evaluation of Accelerated Repopulation during Radiotherapy for Non-Small Cell Lung Cancer with 18F-FLT PET,CT Number,Tumor VolumeObjective:Accelerated repopulation has been observed in various tumors.This study was aimed to evaluate the potential of 3’-deoxy-3’-18F-fluorothymidine(18F-FLT)uptake and Computed Tomography Number(CTN)in monitoring tumor responses to radiotherapy compared with tumor volume(TV)changes in non-small cell lung cancer(NSCLC).Methods:Tumor bearing nude mice were assigned to either irradiated daily or every second day group and then randomized to 6 sub-groups to receive OGy,6Gy,12Gy,18Gy,24Gy,36Gy irradiation,respectively.TV was measured every 3 days.18F-FLT micro-PET/CT scans were performed after irradiation being completed.Tumor sections were stained to calculate the immunohistochemical(Ki67)labeling index(LI).Comparison analysis between FLT uptake parameters,CTNs,VTs and Ki-67 LI results were conducted to determine the correlation.Result:Ki67 LI increased signifcantly after 6 times of irradiation at irradiated daily group and after 3 times at irradiated every second day group,suggesting accelerated repopulation.No shrinkage of TV was noticed at two groups during irradiation delivery.Both 18F-FLT uptake and CTN increased signifcantly after irradiation of 12Gy/6f/6d and 6Gy/3f/6d.Comparison analysis found a signifcant relationship between Ki67 LI and 18F-FLT uptake parameters as well as CTN.Conclusion:Both 18F-FLT PET and CT have the potential to reflect the tumor proliferative response during radiation delivery in NSCLC.Part IV:Comparison of Tumor Volumes as Determined by Pathologic Examination and 18F-fluorothymidine(,8F-FLT)Images for Non-Small-Cell Lung Cancer:A Pilot StudyPurpose:To determine the cut-off value of standardized uptake value(SUV)on 3-deoxy-3-18F-fluorothymidine(FLT)positron emission tomography/computed tomography(FLT-PET/CT)images that generates the best volumetric match to pathologic gross tumor volume(GTVpath)for non-small-cell lung cancer(NSCLC).Methods and Materials:Twelve patients with NSCLC who received no antineoplastic therapy before and underwent FLT-PET/CT scans one or two days before lobectomy were enrolled.The surgical specimen was dissected into 5-7 μm sections at approximately 4-mm intervals and stained with hematoxylin and eosin.The tumor-containing area was outlined slice by slice and the GTVpath was determined by summing over all the slices with taking into account the inter slice thickness and fixation-induced volume reduction of tumor tissue.The GTV in PET images(GTVPEt)was determined with the function of cut-off SUV.Then,the GTVPET(suv)value was determined at different cut-off values of the absolute SUV,from 1.2 to 2.1 at 0.1 intervals.Similarly,GTVPET(%suv)was determined at various percentage thresholds of the maximal SUV,from 30%to 70%at an interval of 5%.The optimal threshold of%SUVmax or optimal absolute SUV was defined as the value with which the GTVPET was outlined as the same as the GTVpath.Results:There were 5 male and 7 female patients were included in this study,with the median age of 62 years(range 43-71).According the pathologic classifications,there were 8 adenocarcinomas and 4 squamous cell carcinomas.Three tumors were located at superior lobe of left lung,2 inferior lobe of left lung,5 superior lobe of right lung and 2 inferior lobe of right lung,respectively.The fixation process induced a volumetric reduction of tumors:70.84%± 5.71%(range,60.4-79.7%)of the original tumor volume.The maximal SUV(SUVmax)was 3.50 ± 0.97(range,1.96-5.05).The GTVpath was 11.07± 10.30 cm3(range,2.39-33.10cm3).The mean optimal threshold were%SUVmax of 56%± 11%SUVmax and absolute SUV of 1.84士 0.33,which would produce the best agreement between GTVpath,and GTVPET.The optimal absolute SUV had a positive correlation with SUVmax(P = 0.037),whereas the optimal%SUVmax showed no significant correlation(P = 0.52).On the other hand,the optimal threshold of%SUVmax was correlated with volume retraction(P<0.05),while the optimal absolute SUV had no significant correlation with volume retraction(P>0.05).Conclusion:This study evaluated the utilization of GTVpath as a criterion for determining optimal cut-off SUV for NSCLC in FLT-PET/CT images.Absolute SUV of 1.8 and%SUVmax of 56%might be used as the optimal cut-off SUV for NSCLC tarsget volume delineation. |
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