F-fluorothymidine Positron Emission Tomography Research Articles

Dynamic 18F-FLT PET imaging of spatiotemporal changes in tumor cell proliferation and vasculature reveals the mechanistic actions of anti-angiogenic therapy

Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3′-deoxy-3′-18F-fluorothymidine positron emission tomography (18F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic 18F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR-TKI treatment, and following a one week treatment break. 18F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters Vb and K1 were extracted to quantify changes in tumor vasculature and the 18F-FLT flux constant Ki was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in Vb (median −21%, P = 0.07), K1 (median −39%, P < 0.01), and Ki (median −37%, P < 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in Vb (median +42%, P < 0.01), K1 (median +46%, P < 0.01), and Ki (median +39%, P < 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ⩽ −0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic 18F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation.

Can Imaging Parameters Provide Information Regarding Histopathology in Head and Neck Squamous Cell Carcinoma? A Meta-Analysis

OBJECT: Our purpose was to provide data regarding relationships between different imaging and histopathological parameters in HNSCC. METHODS: MEDLINE library was screened for associations between different imaging parameters and histopathological features in HNSCC up to December 2017. Only papers containing correlation coefficients between different imaging parameters and histopathological findings were acquired for the analysis. RESULTS: Associations between 18F-FDG positron emission tomography (PET) and KI 67 were reported in 8 studies (236 patients). The pooled correlation coefficient was 0.20 (95% CI = [−0.04; 0.44]). Furthermore, in 4 studies (64 patients), associations between 18F-fluorothymidine PET and KI 67 were analyzed. The pooled correlation coefficient between SUVmax and KI 67 was 0.28 (95% CI = [−0.06; 0.94]). In 2 studies (23 patients), relationships between KI 67 and dynamic contrast-enhanced magnetic resonance imaging were reported. The pooled correlation coefficient between Ktrans and KI 67 was −0.68 (95% CI = [−0.91; −0.44]). Two studies (31 patients) investigated correlation between apparent diffusion coefficient (ADC) and KI 67. The pooled correlation coefficient was −0.61 (95% CI = [−0.84; −0.38]). In 2 studies (117 patients), relationships between 18F-FDG PET and p53 were analyzed. The pooled correlation coefficient was 0.0 (95% CI = [−0.87; 0.88]). There were 3 studies (48 patients) that investigated associations between ADC and tumor cell count in HNSCC. The pooled correlation coefficient was −0.53 (95% CI = [−0.74; −0.32]). Associations between 18F-FDG PET and HIF-1α were investigated in 3 studies (72 patients). The pooled correlation coefficient was 0.44 (95% CI = [−0.20; 1.08]). CONCLUSIONS: ADC may predict cell count and proliferation activity, and SUVmax may predict expression of HIF-1α in HNSCC. SUVmax cannot be used as surrogate marker for expression of KI 67 and p53.

PETを用いた癌分子イメージング：頭頸部がん領域への応用

The imaging of specific molecular targets associated with cancer can be expected to allow earlier diagnosis and better management of oncology cancer patients. Positron emission tomography (PET) is a highly sensitive non-invasive technology that is ideally suited to clinical imaging of cancer biology. 2’-Deoxy-2’-18F-fluorodeoxy glucose (FDG) PET is now widely used for the diagnosis of malignant tumors and assessment of the therapeutic response. However, FDG is also metabolized at sites of inflammation and in other physiologically reactive organs, so that development of newer imaging probes with specificity for cancer are needed. The amount of DNA synthesis is a measure of cellular proliferation, and increased cellular proliferation is a feature of cancer. Thymidine analogs, 3’-deoxy-3’-18F-fluorothymidine (FLT) and 4’-[methyl-11C]-thiothymidine (4DST), have been introduced as stable cell proliferation imaging agents. Our recent researches have shown that FLT and 4DST PET show high sensitivity for the detection of head and neck cancer, despite the low uptake level of the tracers. In regard to assessment of the therapeutic response, FLT PET during treatment and early follow-up has the potential to predict therapeutic responses, with the ability to discriminate residual tumors from inflammatory changes. Volume-based parameters of pretreatment 4DST-PET can provide important prognostic information in patients with head and neck cancer.A depth-of interaction (DOI) detector is a key device to obtain any significant improvement of the sensitivity while maintaining high spatial resolution. DOI measurement also has the potential to expand the field of application of PET, because it allows for more flexible detector arrangement.New molecular imaging probes have also been developed for visualization of the brain and nervous system functions. Future applications are expected to allow analysis of the functions of sensory areas and diagnosis of sensory nerve disorders.

Comparison of 18F-FET and 18F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

BackgroundThe radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (FET) and thymidine analogue 3′-deoxy-3′-18F-fluorothymidine (FLT) are widely used for positron emission tomography (PET) brain tumor imaging; however, comparative studies are scarce. The aim of this study therefore was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. MethodsXenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow treatment response. Tracer uptake of FLT and FET was quantified using maximum standardized uptake (SUVmax) values and tumor-to-background ratios (TBRs). Survival, the Ki67 proliferation index and micro-vessel density (MVD) were evaluated. ResultsIn contrast to FLT TBRs, FET TBRs were significantly lower as early as one week after treatment initiation in the anti-VEGF group as compared to the control group. Following two weeks of treatment, both FLT and FET TBRs were significantly lower in the anti-VEGF group. In contrast, no significant difference between the treatment groups was detected using BLI. Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. ConclusionFET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET.Advances in knowledge and implications for patient care FET PET appears to be an early predictor of anti-VEGF efficacy. Confirmation of these results in clinical studies is needed.

FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma.

BackgroundMetastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5 mg sunitinib therapy.MethodsTwenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using 18 F-fluorodeoxyglucose (FDG) and 18 F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4 weeks) with 37.5 mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment.ResultsProliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (p = 0.0036). Conversely, baseline 18 F-fluorothymidine PET imaging did not have prognostic value (p = 0.56) but showed a greater early response rate at 1–2 weeks after initiating therapy.ConclusionsWhile preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed metabolic response beginning after two weeks in metastatic renal cell carcinoma treated with a continuous daily dose of 37.5 mg sunitinib. The results provide evidence of tumor response to lower-dose sunitinib while also supporting the inclusion of PET imaging as a tool for early assessment in oncological clinical trials.Trial registrationID: NCT00694096

FLT PET-CT in evaluation of treatment response.

Purpose:Review published studies to investigate the value of clinical 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (PET) in predicting response to treatment.Materials and Methods:Interrogate databases to identify suitable publications between 2007 and 2013 with a minimum of five patients. Articles within the inclusion criteria were reviewed with major findings reported leading to a descriptive analysis of FLT PET in therapy response.Results:Lesions investigated included glioma, head and neck, esophageal, lung, breast, gastric, renal, rectal, sarcomas, germ cell, lymphomas, leukemia, and melanoma resulting in a total of 34 studies analyzed. A variety of therapies were applied and dissimilar PET protocols were widespread making direct comparison between studies challenging. Though baseline, early and late therapy scans were popular particularly in chemotherapy regimes. Most studies investigated showed significantly reduced FLT uptake during or after therapy compared with pretreatment scans.Conclusion:Current evidence suggests FLT PET has a positive role to play in predicting therapy response especially in brain, lung, and breast cancers where good correlation with Ki-67 is observed. However, careful attention must be placed in undertaking larger clinical trials where harmonization of scanning and analysis protocols are strictly adhered to fully assess the true potential of FLT PET in predicting response to treatment.

The Feasibility of (18)F-Fluorothymidine PET for Prediction of Tumor Response after Induction Chemotherapy Followed by Chemoradiotherapy with S-1/Oxaliplatin in Patients with Resectable Esophageal Cancer.

The aim of this study was to determine whether (18)F-fluorothymidine (FLT) PET is feasible for the early prediction of tumor response to induction chemotherapy followed by concurrent chemoradiotherapy in patients with esophageal cancer. This study was prospectively performed as a collateral study of "randomized phase II study of preoperative concurrent chemoradiotherapy with or without induction chemotherapy with S-1/oxaliplatin in patients with resectable esophageal cancer". (18)F-FLT positron emission tomography (PET) images were obtained before and after two cycles of induction chemotherapy, and the percent change of maximum standardized uptake value (SUVmax) was calculated. All patients underwent esophagography, gastrofiberoscopy, endoscopic ultrasonography (EUS), computed tomography (CT) and (18)F-fluorodeoxyglucose (FDG) PET at baseline and 3-4weeks after completion of concurrent chemoradiotherapy. Final tumor response was determined by both clinical and pathologic tumor responses after surgery. The 13 patients for induction chemotherapy group were enrolled until interim analysis. In a primary tumor visual analysis, the tumor detection rates of baseline (18)F-FLT and (18)F-FDG PET were 85% and 100%, respectively. The tumor uptakes on (18)F-FLT PET were lower than those of (18)F-FDG PET. Among nine patients who completed second (18)F-FLT PET, eight patients were responders and one patient was a non-responder in the assessment of final tumor response. The percent change of SUVmax in responders ranged from 41.2% to 79.2% (median 57.1%), whereas it was 10.2% in one non-responder. The percent change of tumor uptake in (18)F-FLT PET after induction chemotherapy might be feasible for early prediction of tumor response after induction chemotherapy and concurrent chemoradiotherapy in patients with esophageal cancer.

Correlation of 18F-FLT uptake with equilibrative nucleoside transporter-1 and thymidine kinase-1 expressions in gastrointestinal cancer

We examined equilibrative nucleoside transporter-1 (ENT1) and thymidine kinase-1 (TK1) messenger ribonucleic acid (mRNA) expressions in cancer tissue samples to elucidate the mechanism of 3'-deoxy-3'-F-fluorothymidine (FLT) uptake by positron emission tomography (PET) scan in gastrointestinal cancer. A total of 21 patients with newly diagnosed gastrointestinal cancer were examined with FLT PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. The expressions of ENT1 and TK1 in cancer tissue samples were compared with that of FLT SUV. Of all gastrointestinal cancer lesions only one gastric cancer showed focally increased uptake of FLT PET. The mean (±standard deviation) FLT SUV in gastrointestinal cancer was 5.48±1.87. There was no significant correlation between FLT SUV and ENT1 (P=0.90) mRNA expression. There was a significant correlation between FLT SUV and TK1 mRNA expression (P<0.05). Results of this preliminary study indicate that TK1 activity is an important determinant of FLT uptake in gastrointestinal cancer. In this study, it was found that ENT1 activity and FLT uptake were not related.

Detection of colorectal cancer using 18F-FLT PET: comparison with 18F-FDG PET

We investigated the feasibility of 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of colorectal cancer, in comparison with 2-deoxy-2-¹⁸F-fluoro-D-glucose (FDG) PET, and investigated correlation of the two radiotracers used with proliferative activity as indicated by Ki-67 index. A total of 26 patients with newly diagnosed colorectal cancer were examined with FLT PET and FDG PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. In all 26 patients, colorectal cancers were detected by both FLT PET and FDG PET. The mean (± SD) values of FLT SUV in colon cancer (5.4 ± 2.4) and in rectal cancer (5.6 ± 1.3) were significantly lower than the corresponding values of FDG SUV (12.4 ± 6.3 and 12.5 ± 4.7, respectively) (P < 0.003). There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. Although uptake of FLT was found to be significantly lower than that of FDG, both FLT PET and FDG PET were able to detect colorectal cancers in all 26 patients. Neither of the two radiotracers used was correlated with proliferative activity.

Detection of gastric cancer using 18F-FLT PET: comparison with 18F-FDG PET

We prospectively investigated the feasibility of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-(18)F-fluoro-D-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index. A total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. For detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (+/-SD) SUV for FLT (7.0 +/- 3.3) was significantly lower than that for FDG (9.4 +/- 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (+/-SD) FLT SUV in poorly differentiated tumours (8.5 +/- 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 +/- 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. FLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.

3???-Deoxy-3???-18F-Fluorothymidine as a Proliferation Imaging Tracer for Diagnosis of Lung Tumors

The purpose of this study was to evaluate the accuracy of 3'-deoxy-3'-F-fluorothymidine (FLT) positron emission tomography (PET) for detection of lung tumor in comparison with 2-deoxy-2-F-fluoro-D-glucose (FDG) PET. Fifty-four patients with newly diagnosed pulmonary nodules on chest computed tomographic (CT) scan suggestive of a malignant tumor were examined with both FLT and FDG PET. The intensity of uptake in lung tumors was scored. For visualized lesions, the maximum standardized uptake value (SUV) was calculated. Thirty-six patients were found to have lung cancer; and 18, benign lesions. Using visual analysis, the sensitivity of FLT PET for detection of lung cancer was 83%; the specificity, 83%; and the accuracy, 83%. The corresponding values for FDG PET were 97%, 50%, and 81%, respectively. The specificity of FLT PET was significantly higher than that of FDG PET. The uptake of FLT in lung cancer was significantly lower than that of FDG. Using semiquantitative analysis, the sensitivity of FLT was 86%; the specificity, 72%; and the accuracy, 81%. The corresponding values for FDG were 89%, 67%, and 81%, respectively. These preliminary results indicate that FLT PET may be specific for malignant tumors although uptake of FLT in lung cancer was significantly lower than that of FDG.

Taming Glioblastoma: Targeting Angiogenesis

More than 30 years ago, Judah Folkman hypothesized that tumor angiogenesis could be a target of anticancer therapy. Some of the initial studies were actually performed in patients with glioblastomas, which had the greatest extent of tumor angiogenesis among a variety of human malignancies. The identification of vascular endothelial growth factor (VEGF) also provided a firm foundation for the development of antiangiogenic drugs. Fast forward to 2007: We now have multiple agents that specifically block tumor angiogenesis in various malignancies. In this issue of the Journal of Clinical Oncology, two groups independently describe phase II clinical trials of bevacizumab plus irinotecan for recurrent glioblastomas. Vredenburgh et al noted an objective response rate of 57% and a 6-month progression-free survival of 46% with this regimen. These results are remarkable indeed when compared with a benchmark response rate of 6% and 6-month progression-free survival of 15% from salvage cytotoxic chemotherapies. Although the radiographic responses were impressive, resolution of gadolinium enhancement could also be caused by bevacizumab-induced changes in vascular permeability, impairing our ability to visualize these tumors on magnetic resonance imaging (MRI). To demonstrate that bevacizumab plus irinotecan had an impact on the underlying tumor, Chen et al went one step further by using F-fluorothymidine positron emission tomography (FLT-PET) as an adjunctive measure of tumor response. They reported a 47% response rate by FLT-PET and a 65% 6-month survival, whereas metabolic responders lived three times longer than did nonresponders. These results are consistent with earlier findings that response to cytotoxic chemotherapies was associated with a significantly lower treatment failure rate and a hazard ratio of 0.5. Taken together, both studies establish a role for combining antiangiogenic drug and cytotoxic chemotherapy to treat recurrent glioblastomas. However, these results should be interpreted within the context of glioblastoma behaviors and our ability to measure treatment efficacy. The rationale for combining an antiangiogenic agent with cytotoxic chemotherapy is based on the phenomenon of vascular normalization, which leads to increased tissue oxygenation, decreased interstitial hypertension, and improved drug delivery to tumors. This was demonstrated experimentally with DTC101, a monoclonal antibody specific for VEGF receptor 2. As hyperpermeable vasculatures were pruned away by DTC101, increased tissue oxygenation acted synergistically with external-beam radiation in controlling U87 glioblastomas implanted in mouse brains. Interestingly, this normalization window peaked at day 5 of DTC101 treatment. For combination bevacizumab and cytotoxic chemotherapy, precise scheduling does not appear to be important, possibly because of immediate permeability changes and the prolonged half-life of bevacizumab. In patients treated with AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, Batchelor et al observed improvement in glioblastoma perfusion and permeability as measured by dynamic susceptibility contrast MRI within the first 24 hours. This is in contradiction to vascular damaging agents, which shut down well-developed tumor blood vessels and are highly schedule dependent when combined with cytotoxic chemotherapies. For example, ZD6126 induced hypoxia in U87 glioblastomas and interfered with radiation efficacy when administered 1hour before radiation, but it was synergistic with radiation when administered 24 hours after radiation. Similarly, 5,6-dimethyl-xanthenone-4 acetic acid and combretastatin A-4 disodium phosphate had the greatest tumor-cell kill when administered 1 to 3 hours after cisplatin. The current response criteria, or Macdonald’s criteria, may not be adequate for assessing glioblastoma response to antiangiogenic drugs. This is because tumor size is “estimated” on the basis of gadolinium leakage from hyperpermeable vasculatures. When antiangiogenic drugs change vascular permeability, they may alter the apparent size of glioblastomas on contrast-enhanced MRI or computed tomography, without affecting the underlying tumor mass. Therefore, it is critically important to incorporate adjunctive measures of tumor response, such as dynamic susceptibility contrast MRI for vascular perfusion and permeability and FLT or C-methylmethionine PET for tumor metabolism. Chen et al used FLT-PET and noted that metabolic response correlated with MRI response and patient survival. Unlike [F]fluorodeoxyglucose PET, FLT-PET has higher signal-to-noise ratio and is not confounded by a high rate of glucose utilization in the brain. But in order for FLT and C-methylmethionine PET to become accepted methods of assessing response in glioblastomas, more data are needed to evaluate their positive and negative predictive values. It is equally notable that not all patients responded to bevacizumab plus irinotecan. Heterogeneity in vascular response to bevacizumab may explain some of these failures. In the AZD2171 trial, some patients had worsening or unchanged perfusion and permeability, whereas others responded favorably. There may be secondary pathways for tumor angiogenesis to occur in nonresponders when either VEGF or the VEGF receptor is blocked. In Chen et al’s cohort, metabolic heterogeneity was also noted, as seen JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 30 OCTOBER 2

Comparison of 18F-FLT PET and 18F-FDG PET for preoperative staging in non-small cell lung cancer

The nucleoside analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) has been introduced for imaging cell proliferation with positron emission tomography (PET). We prospectively compared the diagnostic efficacy of FLT PET with that of 2-deoxy-2-(18)F-fluoro-D-glucose (FDG) PET for the preoperative nodal and distant metastatic staging of non-small cell lung cancer (NSCLC). A total of 34 patients with NSCLC underwent FLT PET and FDG PET. PET imaging was performed at 60 min after each radiotracer injection. The PET images were evaluated qualitatively for regions of focally increased metabolism. For visualized primary tumors, the maximum standardized uptake value (SUV) was calculated. Nodal stages were determined by using the American Joint Committee on Cancer staging system and surgical and histologic findings reference standards. For the depiction of primary tumor, sensitivity of FLT PET was 67%, compared with 94% for FDG PET (P = 0.005). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for lymph node staging on a per-patient basis were 57, 93, 67, 89, and 85%, respectively, with FLT PET and 57, 78, 36, 91, and 74%, respectively, with FDG PET (P > 0.1 for all comparisons). Two of the three distant metastases were detected with FLT and FDG PET. In NSCLC, FLT PET showed better (although not statistically significant) specificity, positive predictive value and accuracy for N staging on a per-patient basis than FDG PET. However, FDG PET was found to have higher sensitivity for depiction of primary tumor than FLT PET.

A preliminary clinical study on the chest tumors with 18 F-fluorothymidine positron emission tomography-CT imaging

Objective To evaluate ~(18)F-fluorothymidine positron emission tomography(~(18)F-FLT PET)/CT diagnosis value in chest oncology for ~(18)F-fluorodeoxygen-D-glucose(~(18)F-FDG)PET-CT positive imaging of uncertain diseases.Methods 17 patients underwent ~(18)F-FDG PET-CT.After 2 or 3 days ~(18)F-FLT PET-CT scan was done,and the lesion differences were compared for two different tracers, measured maximum standard uptake value(maxSUV)in both of them.GE Minitrace and TracerLab FX-fn were used to automatically produce ~(18)F-FDG and ~(18)F-FLT.Results In 8 malignant tumor patients(five lung cancers,one mediastinal lymphoma,one malignant tumor of thoracic vertebra,one metastatic cancer of thoracic vertebra),7 of 8 showed positive PET-CT ~(18)F-FLT results,average maxSUV was 4.2 in 5 lung cancer.Nine cases benign diseases found no or low-grade ~(18)F-FLT uptake,average maxSUV was 1.6 in 6 pulmonary benign foci.In 9 benign lesion patients,8 of 9 had ~(18)F-FDG uptake,average maxSUV was 3.Nine in 6 pulmonary benign foci.Three tuberculosis in mediastinum lymph can see obviously ~(18)F-FDG uptake,average maxSUV was 11.0.The sensitivity,specificity and accuracy of ~(18)F-FDG and ~(18)F-FLT imaging for pulmonary foci were 100.0%(5/5),16.7%(1/6)、54.5%(6/11)和80.0%(4/5),66.7% (4/6)、72.7%(8/11),respectively.Conclusion ~(18)F-FLT has higher specialization in chest tumor,when ~(18)F-FDG results is uncertain,~(18)F-FLT PET-CT scan provides useful supplementary information which assists chest tumor diagnosis.

Correlation of 18F-FLT and 18F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer

The nucleoside analogue 3'-deoxy-3'-(18)F-fluorothymidine (FLT) has recently been introduced for imaging cell proliferation with positron emission tomography (PET). We prospectively evaluated whether FLT uptake reflects proliferative activity as indicated by the Ki-67 index in non-small cell lung cancer (NSCLC), in comparison with 2-deoxy-2-(18)F-fluoro-D-glucose (FDG). A total of 18 patients with newly diagnosed NSCLC were examined with both FLT PET and FDG PET. PET imaging was performed at 60 min after each radiotracer injection. Tumour lesions were identified as areas of focally increased uptake, exceeding background uptake in the lungs. For semi-quantitative analysis, the maximum standardised uptake value (SUV) was calculated. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens. Immunohistochemical findings were correlated with SUVs. The sensitivity of FLT and FDG PET for the detection of lung cancer was 72% and 89%, respectively. Four of the five false-negative FLT PET findings occurred in bronchiolo-alveolar carcinoma. The mean FLT SUV was significantly lower than the mean FDG SUV. A significant correlation was observed between FLT SUV and Ki-67 index (r = 0.77; p < 0.0002) and for FDG SUV (r = 0.81; p < 0.0001). The results of this preliminary study suggest that, compared with FDG, FLT may be less sensitive for primary staging in patients with NSCLC. Although FLT uptake correlated significantly with proliferative activity in NSCLC, the correlation was not better than that for FDG uptake.

Early Detection of Chemoradioresponse in Esophageal Carcinoma by 3′-Deoxy-3′-3H-Fluorothymidine Using Preclinical Tumor Models

Early identification of esophageal cancer patients who are responding or resistant to combined chemoradiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemoradiotherapy in experimental models of esophageal carcinoma. The in vitro and ex vivo tumor uptake of [(3)H]FLT in SEG-1 human esophageal adenocarcinoma cells were studied at various early time points after docetaxel plus irradiation and validated with conventional assessments of cellular proliferation [thymidine (Thd) and Ki-67] and [(18)F]FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [(18)F]FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments. In vitro [(3)H]FLT and [(3)H]Thd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P = 0.005). The [(3)H]FLT tumor-to-muscle uptake ratio in xenografts declined by 75% compared with baseline (P < 0.005) by 2 days after chemoradiotherapy, despite the lack of change in tumor size. In contrast, the decline of [(3)H]FDG uptake was gradual and less pronounced. Tumor uptake of [(3)H]FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [(3)H]FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [(18)F]FLT and [(18)F]FDG tumor uptake. Autoradiographs displayed spatial correlations between [(18)F]FLT uptake and histologic Ki-67 distribution in preliminary studies. FLT-PET is suitable and more specific than FDG-PET for depicting early reductions in tumor proliferation that precede tumor size changes after chemoradiotherapy.