Emerging Role of [18F]FLT PET/CT in Lymphoid Malignancies: A Review of Clinical Results.

Fluorine-18 fluorodeoxyglucose ([18F]FDG) is nowadays the leading positron emission tomography (PET) tracer for routine clinical work-ups in hematological malignancies; however, it is limited by false positive findings. Notably, false positives can occur in inflammatory and infective cases or in necrotic tumors that are infiltrated by macrophages and other inflammatory cells. In this context, 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been shown to be a promising imaging biomarker of hematological malignant cell proliferation. In this review, a total of 15 papers were reviewed to collect literature data regarding the clinical application of [18F]FLT PET/CT in hematological malignancies. This imaging modality seems to be a suitable tool for noninvasive assessment of tumor grading, also showing a correlation with Ki-67 immunostaining. Moreover, [18F]FLT PET/CT demonstrated high sensitivity in detecting aggressive lymphoma lesions, especially when applying a standardized uptake value (SUV) cutoff of 3. At baseline, the potential of [18F]FLT imaging as a predictive tool is demonstrated by the low tracer uptake in patients with a complete response. However, its use is limited in evaluating bone diseases due to its high physiological uptake in bone marrow. Interim [18F]FLT PET/CT (iFLT) has the potential to identify high-risk patients with greater precision than [18F]FDG PET/CT, optimizing risk-adapted therapy strategies. Moreover, [18F]FLT uptake showed a greater ability to differentiate tumor from inflammation compared to [18F]FDG, allowing the reduction of false-positive findings and making the first one a more selective tracer. Finally, FLT emerges as a superior independent predictor of PFS and OS compared to FDG and ensures a reliable early response assessment with greater accuracy and predictive value.

The Role of 18F-FLT PET/CT in Assessing Early Response to Transarterial Radioembolization and Chemoembolization in Patients with Primary and Metastatic Liver Tumors.

Objectives: Metastases and primary malignancies are common in the liver. Local ablative applications such as transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) provide minimally invasive and safe treatment in unresectable liver tumors. Early detection of response to treatment prevents unnecessary toxicity and cost in non-responder patients and provides an earlier use of other options that may be effective. This study aimed to identify the role of 18F-fluorothymidine (FLT) positron emission tomography/computed tomography (PET/CT) in the assessment of early response to TACE and TARE treatments in patients with unresectable primary and metastatic liver tumors. Methods: This single-center study included 63 patients who underwent 18F-FLT PET/CT for response evaluation after TACE and TARE. After excluding 20 patients whose data were missing 43 TARE-receiving patients were analyzed. The compatibility of change in semi-quantitative values obtained from the 18F-FLT PET/CT images with the treatment responses detected in 18F-fluorodeoxyglucose PET/CT, CT, and MR images and survival was evaluated. Results: There was no correlation between early metabolic, morphological response, and 18F-FLT uptake pattern, and change in standardized uptake values (SUV) which were ΔSUVmax, ΔSUVmean, ΔSUVpeak., ΔSUVmean, Δ SUVpeak values. There was no significant correlation between 18F-FLT uptake pattern, ΔSUVmax, ΔSUVmean, ΔSUVpeak, and overall survival, progression-free survival (PFS) for the target lobe PFS for the whole-body. The survival distributions for the patients with >30% change in Δ SUVmax and ΔSUVpeak values were statistically significantly longer than the patients with <30% change (p<0.009 and p<0.024, respectively). Conclusion: There was significant longer PFS for target liver lobe in patients with more than 30% decrease in 18F-FLT SUVmax and SUVpeak of the liver lesion in primary and metastatic unresectable liver tumors undergoing TARE.

Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase.

Introduction: Pegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT. Methods: A total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer-based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen's kappa. Results: ADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT. Conclusions: Early FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

Evaluating the Accuracy of FUCCI Cell Cycle In Vivo Fluorescent Imaging to Assess Tumor Proliferation in Preclinical Oncology Models.

PURPOSE: The primary goal of this study is to evaluate the accuracy of the fluorescence ubiquitination cell cycle indicator (FUCCI) system with fluorescence in vivo imaging compared to 3'-deoxy-3'-[18F]fluorothymidine ([18F]-FLT) positron emission tomography (PET)/computed tomography (CT) and biological validation through histology. Imaging with [18F]-FLT PET/CT can be used to noninvasively assess cancer cell proliferation and has been utilized in both preclinical and clinical studies. However, a cost-effective and straightforward method for in vivo, cell cycle targeted cancer drug screening is needed prior to moving towards translational imaging methods such as PET/CT. PROCEDURES: In this study, fluorescent MDA-MB-231-FUCCI tumor growth was monitored weekly with caliper measurements and fluorescent imaging. Seven weeks post-injection, [18F]-FLT PET/CT was performed with a preclinical PET/CT, and tumors samples were harvested for histological analysis. RESULTS: RFP fluorescent signal significantly correlated with tumor volume (r = 0.8153, p < 0.0001). Cell proliferation measured by GFP fluorescent imaging was correlated with tumor growth rate (r = 0.6497, p < 0.001). Also, GFP+ cells and [18F]-FLT regions of high uptake were both spatially located in the tumor borders, indicating that the FUCCI-IVIS method may provide an accurate assessment of tumor heterogeneity of cell proliferation. The quantification of total GFP signal was correlated with the sum of tumor [18F]-FLT standard uptake value (SUV) (r = 0.5361, p = 0.0724). Finally, histological analysis confirmed viable cells in the tumor and the correlation of GFP + and Ki67 + cells (r = 0.6368, p = 0.0477). CONCLUSION: Fluorescent imaging of the cell cycle provides a noninvasive accurate depiction of tumor progression and response to therapy, which may benefit in vivo testing of novel cancer therapeutics that target the cell cycle.

Quantification of uptake in pelvis F-18 FLT PET-CT images using a 3D localization and segmentation CNN.

PURPOSE: The purpose of this work was to develop and validate a deep convolutional neural network (CNN) approach for the automated pelvis segmentation in computed tomography (CT) scans to enable the quantification of active pelvic bone marrow by means of Fluorothymidine F-18 (FLT) tracer uptake measurement in positron emission tomography (PET) scans. This quantification is a critical step in calculating bone marrow dose for radiopharmaceutical therapy clinical applications as well as external beam radiation doses. METHODS: An approach for the combined localization and segmentation of the pelvis in CT volumes of varying sizes, ranging from full-body to pelvis CT scans, was developed that utilizes a novel CNN architecture in combination with a random sampling strategy. The method was validated on 34 planning CT scans and 106 full-body FLT PET-CT scans using a cross-validation strategy. Specifically, two different training and CNN application options were studied, quantitatively assessed, and statistically compared. RESULTS: The proposed method was able to successfully locate and segment the pelvis in all test cases. On all data sets, an average Dice coefficient of 0.9396 ± $\pm$ 0.0182 or better was achieved. The relative tracer uptake measurement error ranged between 0.065% and 0.204%. The proposed approach is time-efficient and shows a reduction in runtime of up to 95% compared to a standard U-Net-based approach without a localization component. CONCLUSIONS: The proposed method enables the efficient calculation of FLT uptake in the pelvis. Thus, it represents a valuable tool to facilitate bone marrow preserving adaptive radiation therapy and radiopharmaceutical dose calculation. Furthermore, the method can be adapted to process other bone structures as well as organs.

Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer.

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01-1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

18F-FLT PET/CT Adds Value to 18F-FDG PET/CT for Diagnosing Relapse After Definitive Radiotherapy in Patients with Lung Cancer: Results of a Prospective Clinical Trial.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has previously demonstrated higher specificity for malignancy than 18F-FDG PET. We investigated the value of 18F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18F-FLT PET/CT was higher than that of 18F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [P = 0.0020]). The difference in specificity between 18F-FLT PET/CT and 18F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18F-FLT PET/CT was lower than that of 18F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [P = 0.0078]). Adding 18F-FLT PET/CT when 18F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion:18F-FLT PET/CT adds diagnostic value to 18F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18F-FLT PET/CT was highest after cRT. We suggest adding 18F-FLT PET/CT when 18F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained.

Molecular Imaging with 3'-deoxy-3'[(18)F]-Fluorothymidine (18F-FLT) PET/CT for Early Response to Targeted Therapies in Sarcomas: A Pilot Study.

Although 3'-deoxy-3'[(18)F]-fluorothymidine (FLT)- positron emission tomography (PET) has been utilized for tumor response assessment to neoadjuvant chemotherapy in soft tissue sarcomas, it has not been exploited for the assessment of early response to systematically targeted therapies. Herein, we investigated the 18F-FLT PET/CT kinetics in patients with sarcoma who received targeted therapies. Among 15 patients with sarcoma who underwent 18F-FLT PET/CT, 5 patients (33%) patients were imaged at three time points: At baseline and at 1-15 weeks (MDM2-inhibitor treatment), and 10 patients (67%) were imaged twice: At baseline and at 1-4 weeks (MDM2 inhibitor, n = 5 ;c-met inhibitor n = 5). The patients with sarcoma had a total of 18 identifiable tumors. Twelve of 15 patients (80%) demonstrated 18F-FLT concentrations changes early, i.e., at 1-4 weeks. Eight patients responded (53.3%), four patients progressed (26.7%) based on FLT change of more than 10% increase, and three patients (20%) demonstrated no change. 18F-FLT PET/CT may be used for early response imaging to molecularly targeted therapies in patients with sarcoma. Further larger studies in specific sarcoma sub-types are warranted.

Comparison of different images in gross target volume delineating on VX2 nasopharyngeal transplantation tumor models.

Background: To determine the optimum conditions for diagnosis of nasopharyngeal carcinoma, we established VX2 rabbit model to delineate gross target volume (GTV) in different imaging methods. Methods: The orthotopic nasopharyngeal carcinoma (NPC) was established in sixteen New Zealand rabbits. After 7-days inoculation, the rabbits were examined by CT scanning and then sacrificed for pathological examination. To achieve the best delineation, different GTVs of CT, MRI, 18F-FDG PET/CT, and 18F-FLT PET/CT images were correlated with pathological GTV (GTVp). Results: We found 45% and 60% of the maximum standardized uptake value (SUVmax) as the optimal SUV threshold for the target volume of NPC in 18F-FDG PET/CT and 18F-FLT PET/CT images, respectively (GTVFDG45% and GTVFLT60%). Moreover, the GTVMRI and GTVCT were significantly higher than the GTVp (P ≤ 0.05), while the GTVFDG45% and especially GTVFLT60% were similar to the GTVp (R = 0.892 and R = 0.902, respectively; P ≤ 0.001). Conclusions: Notably, the results suggested that 18F-FLT PET/CT could reflect the tumor boundaries more accurately than 18F-FDG PET/CT, MRI and CT, which makes 18F-FLT PET-CT more advantageous for the clinical delineation of the target volume in NPC.

Early Response Assessment to Targeted Therapy Using 3'-deoxy-3'[(18)F]-Fluorothymidine (18F-FLT) PET/CT in Lung Cancer.

Although 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a sensitive nuclear medicine modality, specificity for characterizing lung cancer is limited. Tumor proliferation and early response to molecularly targeted therapy could be visualized using 3'-deoxy-3'[(18)F]-fluorothymidine (18F-FLT) PET/CT. The superiority of 18F-FLT PET/CT over 18F-FDG PET/CT in early therapeutic monitoring has been well described in patients after chemotherapy, radiotherapy, and/or chemo/radiotherapy. In thispilot study, we explorethe use of 18F-FLT PET/CT as an early response evaluation modality in patients with lung cancerand provide specific case studies of patients with small cell lung cancer and non-small cell lung cancer who received novel targeted therapies. Early response for c-MET inhibitor was observed in four weeks and for MDM2 inhibitor in nine days.

Spatial Concordance of Tumor Proliferation and Accelerated Repopulation from Pathologic Images to 3'-[18F]Fluoro-3'-Deoxythymidine PET Images: a Basic Study Guided for PET-Based Radiotherapy Dose Painting.

PURPOSE: To assess tumor cell proliferation and repopulation during fractionated radiotherapy and investigate the spatial concordance of cell proliferation and repopulation according to the uptake of 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT). PROCEDURES: Mice bearing A549 xenograft tumors were assigned to five irradiated groups, including 3 fraction (f)/6 days (d), 6f/12d, 9f/18d, 12f/24d, and 18f/36d with 2 Gy/f irradiations performed every other day and one non-irradiated group. Serial [18F]FLT positron emission tomography (PET) scans were performed at different time points as the groups finished the radiotherapy. The maximum of standard uptake values (SUVmax) were measured to confirm the likely time of tumor repopulation. A layer-by-layer comparison between SUVmax of PET images and Ki-67 LI of pathology images, including the thresholds at which maximum overlap occurred between FLT-segmented areas and cell proliferation areas were conducted to evaluate the spatial correlation. RESULTS: The SUVmax decreased in the 3f/6d group (P = 0.000) compared to the non-irradiated group, increased in the 6f/12d group and then gradually reduced with prolonged treatment. Proliferation changes in 6f/12d group on pathology images were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI in each in vitro tumor of cell proliferation group and accelerated repopulation group (both of the P < 0.001). Furthermore, the mean overlap region rates (ORRs) were 56.21 % and 57.82 % in the proliferation group and repopulation group, respectively. The data represented the preferable registration. CONCLUSIONS: [18F]FLT PET is a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and may help make an adaptive radiation oncology treatment plan to realize radiotherapy dose painting.

Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.

BACKGROUND: A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82. METHODS: Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models. RESULTS: 14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased - 44% (p = 0.03). CONCLUSIONS: The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.

A pilot study for texture analysis of 18F-FDG and 18F-FLT-PET/CT to predict tumor recurrence of patients with colorectal cancer who received surgery.

PURPOSE: This retrospective study was done to examine whether the heterogeneity in primary tumor F-18-fluorodeoxyglucose (18F-FDG) and 18F-3'-fluoro-3'-deoxythymidine (18F-FLT) distribution can predict prognosis of patients with colorectal cancer who received surgery. METHODS: The enrolled 32 patients with colorectal cancer underwent both 18F-FDG- and 18F-FLT-PET/CT studies before surgery. Clinicopathological factors, stage, SUVmax, SUVmean, metabolic tumor volume (SUV ≥ 2.5), total lesion glycolysis, total lesion proliferation and seven texture heterogeneity parameters (coefficient of variation, local parameters: entropy, homogeneity, and dissimilarity; and regional parameters: intensity variability [IV], size-zone variability [SZV], and zone percentage [ZP]) were obtained. Progression free survival (PFS) was calculated by the Kaplan-Meier method. Prognostic significance was assessed by Cox proportional hazards analysis. RESULTS: Eight patients had eventually come to progression, and 24 patients were alive without progression during clinical follow-up [mean follow-up PFS; 55.9 months (range, 1-72)]. High stage (p = 0.004), high 18F-FDG-IV (p = 0.015), high 18F-FDG-SZV (p = 0.013) and high 18F-FLT-entropy (p = 0.015) were significant in predicting poor 5-year PFS. Other parameters did not predict the disease outcome. At bivariate analysis, disease event hazards ratios for 18F-FDG-IV and 18F-FDG-SZV remained significant when adjusted for stage and 18F-FLT-entropy (18F-FDG-IV; p = 0.004 [adjusted for stage], 0.007 [adjusted for 18F-FLT-entropy]; 18F-FDG-SZV; p = 0.028 [adjusted for stage], 0.040 [adjusted for 18F-FLT-entropy]). CONCLUSION: 18F-FDG PET heterogeneity parameters, IV and SZV, have a potential to be strong prognostic factors to predict PFS of patients with surgically resected colorectal cancer and are more useful than 18F-FLT-PET/CT heterogeneity parameters.

A comparison of FLT to FDG PET/CT in the early assessment of chemotherapy response in stages IB-IIIA resectable NSCLC.

BACKGROUND: The aim of this study was to compare the percentage change in 18F-fluorothymidine (FLT) standard uptake value (SUV) between baseline and after one cycle of chemotherapy in patients categorized by RECIST 1.1 computed tomography (CT) as responders or non-responders after two cycles of therapy. Change in 18F-fluorodeoxyglucose (FDG) uptake was also compared between these time points. Nine patients with newly diagnosed, operable, non-small cell lung cancer (NSCLC) were imaged with FDG positron emission tomography/CT (PET), FLT PET/CT, and CT at baseline, following one cycle of neoadjuvant therapy (75 mg/m2 docetaxel + 75 mg/m2 cisplatin), and again after the second cycle of therapy. All patients had a biopsy prior to enrollment and underwent surgical resection within 4 weeks of post-cycle 2 imaging. RESULTS: Between baseline and post-cycle 1, non-responders had mean SULmax (maximum standard uptake value adjusted for lean body mass) increases of 7.0 and 3.4% for FDG and FLT, respectively. Responders had mean decreases of 44.8 and 32.0% in FDG and FLT SULmax, respectively, between baseline and post-cycle 1 imaging. On post-cycle 1 imaging, primary tumor FDG SUL values were significantly lower in responders than in non-responders (P = 0.016). Primary tumor FLT SUL values did not differ significantly between these groups. Using the change from baseline to post-cycle 1, receiver-operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.94 for FDG and 0.78 for FLT in predicting anatomic tumor response after the second cycle of therapy. CONCLUSIONS: Fractional decrease in FDG SULmax from baseline to post-cycle 1 imaging was significantly different between anatomic responders and non-responders, while percentage changes in FLT SULmax were not significantly different between these groups over the same period of time.

The role of new PET tracers for lung cancer.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is established for characterising indeterminate pulmonary nodules and staging lung cancer where there is curative intent. Whilst a sensitive technique, specificity for characterising lung cancer is limited. There is recognition that evaluation of other aspects of abnormal cancer biology in addition to glucose metabolism may be more helpful in characterising tumours and predicting response to novel targeted cancer therapeutics. Therefore, efforts have been made to develop and evaluate new radiopharmaceuticals in order to improve the sensitivity and specificity of PET imaging in lung cancer with regards to characterisation, treatment stratification and therapeutic monitoring. 18F-fluorothymidine (18F-FLT) is a marker of cellular proliferation. It shows a lower accumulation in tumours than 18F-FDG as it only accumulates in the cells that are in the S phase of growth and demonstrates a low sensitivity for nodal staging. Its main role is in evaluating treatment response. Methionine is an essential amino acid. 11C-methionine is more specific and sensitive than 18F-FDG in differentiating benign and malignant thoracic nodules. 18Ffluoromisonidazole (18F-FMISO) is used for imaging tumour hypoxia. Tumour response to treatment is significantly related to the level of tumour oxygenation. Angiogenesis is the process by which new blood vessels are formed in tumours and is involved in tumour growth and metastatic tumour spread and is a therapeutic target. Most clinical studies have focused on targeted integrin PET imaging of which αvß3 integrin is the most extensively investigated. It is upregulated on activated endothelial cells in association with tumour angiogenesis. Neuroendocrine tumour tracers, particularly 68Ga-DOTA-peptides, have an established role in imaging of carcinoid tumours. Whilst most of these tracers have predominantly been used in the research environment, they offer exciting opportunities for improving staging, characterisation, stratification and response assessment in an era of increased personalised therapy in lung cancer.

Comparison of FLT-PET/CT and CECT in gastric cancer diagnosis.

AIM: To date, no data are available on the use of 18-fluorothymidine positron emission tomography/computed tomography (FLT-PET/CT) for preoperative gastric cancer staging. Herein, we attempt to assess the value of FLT-PET/CT for preoperative gastric cancer staging in comparison with contrast-enhanced computed tomography (CECT). MATERIALS AND METHODS: In a group of 96 gastric cancer patients, 96 FLT-PET/CT, 56 abdominal cavity CECT, and 51 resective operations were done. All three (FLT-PET/CT, CECT, and resective operation) were done in 29 patients. The results of FLT-PET/CT, CECT, and histopathological examinations were used to assess the ability of FLT-PET/CT and CECT to identify primary tumors, regional nodal metastases, and distant abdominal metastases. Assessment of regional lymph nodes was based on SUVmax in FLT-PET/CT and SAD (short-axis diameter) in CECT. RESULTS: In the group of 56 patients examined with FLT-PET/CT and CECT, identification of the primary tumor was possible in 56 cases (100%) and in 53 cases (94.6%), respectively, (p = 0.013). Using ROC curve, the sensitivity and specificity of FLT-PET/CT in metastatic regional lymph node assessment were higher than those of CECT (p = 0.0033). FLT-PE/CT enabled identification of a greater number of extraregional abdominal metastases than CECT (n = 56; 19 vs. 15, respectively), but the difference was not statistically significant (p > 0.41). CONCLUSIONS: The ability of FLT-PET/CT to identify primary tumors is greater than that of CECT, and thus FLT-PET/CT was better in evaluating regional nodal metastases. FLT-PET/CT enabled identification of a greater number of abdominal metastases than CECT, but the difference was not statistically significant.

(18)F-FDG and (18)F-FLT PET/CT imaging in the characterization of mediastinal lymph nodes.

PURPOSE: There is currently no single modality for accurate characterization of enlarged mediastinal lymph nodes into benign or malignant. Recently (18)F-fluorothymidine (FLT) has been used as a proliferation marker. In this prospective study, we examined the role of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and (18)F-FLT PET/CT in categorizing mediastinal lymph nodes as benign or malignant. MATERIALS AND METHODS: A total of 70 consecutive patients with mediastinal lymphadenopathy detected on computed tomography (CT) or chest radiograph underwent whole body (18)F-FLT PET/CT and (18)F-FDG PET/CT (within 1 week of each other). Lymph nodal tracer uptake was determined by calculation of standardized uptake value (SUV) with both the tracers. Results of PET/CT were compared with histopathology of the lymph nodes. RESULTS: Histopathology results showed thirty-seven patients with sarcoidosis, seven patients with tuberculosis, nine patients with non-small cell lung cancer, five patients with Hodgkin's lymphoma and twelve patients with non-Hodgkin's lymphoma. The mean FDG SUVmax of sarcoidosis, tuberculosis, Hodgkin's and non-Hodgkin's lymphoma was 12.7, 13.4, 8.2, and 8.8, respectively, and the mean FLT SUVmax was 6.0, 5.4, 4.4, and 3.8, respectively. It was not possible to characterize mediastinal lymphadenopathy as benign or malignant solely based on FDG SUVmax values (p > 0.05) or FLT SUVmax values (p > 0.05). There was no significant difference in FDG uptake (p > 0.9) or FLT uptake (p > 0.9) between sarcoidosis and tuberculosis. In lung cancer patients, the FDG SUVmax and FLT SUVmax of those lymph nodes with tumor infiltration on biopsy was 6.7 and 3.9, respectively, and those without nodal infiltration was 6.4 and 3.7, respectively, and both the tracers were not able to characterize the nodal status as malignant or benign (p > 0.05). CONCLUSION: Though (18)F-FLT PET/CT and (18)F-FDG PET/CT reflect different aspects of biology, i.e., proliferation and metabolism, respectively, neither tracer could provide satisfactory categorization of benign and malignant lymph nodes. The results of this study clearly suggest that differentiation of mediastinal nodes into benign and malignant solely based on SUVmax values cannot be relied upon, especially in settings where tuberculosis and sarcoidosis are common.

Mapping Radiation Injury and Recovery in Bone Marrow Using 18F-FLT PET/CT and USPIO MRI in a Rat Model.

UNLABELLED: We present and test the use of multimodality imaging as a topological tool to map the amount of the body exposed to ionizing radiation and the location of exposure, which are important indicators of survival and recovery. To achieve our goal, PET/CT imaging with 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was used to measure cellular proliferation in bone marrow (BM), whereas MRI using ultra-small superparamagnetic iron oxide (USPIO) particles provided noninvasive information on radiation-induced vascular damage. METHODS: Animals were x-ray-irradiated at a dose of 7.5 Gy with 1 of 3 radiation schemes-whole-body irradiation, half-body shielding (HBS), or 1-leg shielding (1LS)-and imaged repeatedly. The spatial information from the CT scan was used to segment the region corresponding to BM from the PET scan using algorithms developed in-house, allowing for quantification of proliferating cells, and BM blood volume was estimated by measuring the changes in the T2 relaxation rates (ΔR2) collected from MR scans. RESULTS: (18)F-FLT PET/CT imaging differentiated irradiated from unirradiated BM regions. Two days after irradiation, proliferation of 1LS animals was significantly lower than sham (P = 0.0001, femurs; P < 0.0001, tibias) and returned to sham levels by day 10 (P = 0.6344, femurs; P = 0.3962, tibias). The degree of shielding affected proliferation recovery, showing an increase in the irradiated BM of the femurs, but not the tibias, of HBS animals when compared with 1LS (P = 0.0310, femurs; P = 0.5832, tibias). MRI of irradiated spines detected radiation-induced BM vascular damage, measured by the significant increase in ΔR2 2 d after whole-body irradiation (P = 0.0022) and HBS (P = 0.0003) with a decreasing trend of values, returning to levels close to baseline over 10 d. Our data were corroborated using γ-counting and histopathology. CONCLUSION: We demonstrated that (18)F-FLT PET/CT and USPIO MRI are valuable tools in mapping regional radiation exposure and the effects of radiation on BM. Analysis of the (18)F-FLT signal allowed for a clear demarcation of exposed BM regions and elucidated the kinetics of BM recovery, whereas USPIO MRI was used to assess vascular damage and recovery.

Pre-clinical validation of orthotopically-implanted pulmonary tumor by imaging with 18F-fluorothymidine-positron emission tomography/computed tomography.

The development of positron-emission tomography (PET) and X-ray computed tomography (CT) imaging has improved the detection of tumor burden and, in turn, pre-clinical drug development and clinical treatment. In pre-clinical drug development, clinically-relevant murine cancer models, such as orthotopic models of lung cancer, have provided an accurate representation of tumor burden in humans. However, evidence demonstrating the capability of imaging-guided evaluation of these clinically-relevant models is limited. Here, we combined (18)F-fluorothymidine (FLT)-PET/CT imaging and a murine model of human non-small cell lung cancer (NSCLC) to improve the accuracy of anticancer drug evaluation in pre-clinical studies. We found that FLT-PET/CT imaging enabled the progression of pulmonary tumors to be longitudinally monitored rather than FDG-PET/CT. Furthermore, in an efficacy study of a standard treatment of docetaxel in a murine lung cancer model, FLT-PET imaging detected the anticancer response earlier than volumetric analysis by CT imaging. We, thus, observed a relationship between the alteration of FLT signals and Ki-67 index in the pulmonary tumor during the period of chemotherapy. These results indicate that the combination of FLT-PET/CT imaging and an orthotopic NSCLC model is an effective strategy for evaluating clinical efficacy and potential of an anticancer agent during pre-clinical development.

Evaluation of FLT-PET/CT usefulness in diagnosis and qualification for surgical treatment of gastric cancer.

AIM OF THE STUDY: Evaluation of FLT/PET/ CT usefulness in diagnosis and qualification for surgical treatment of gastric cancer. MATERIAL AND METHODS: The FLT/PET/CT test was carried out in a group of 50 gastric cancer patients. Based on the test result, a decision followed about the therapeutic procedure to be applied. A comparison was made with regards to the consistency of the cancer growth advancement degree evaluation in the initial preoperative FLT/PET/CT test against the evaluation of postoperative degree of cancer advancement in histopathology. RESULTS: In the group of 50 diagnosed patients a surgical treatment was used for 37 patients. 21 resections were performed out of which 19 operations were radical In the group of 16 non-resective operations 2 post-laparotomic patients were selected for inductive treatment. In the group of 13 patients who did not undergo any surgery, 10 were directed to palliative care and 3 for inductive treatment. In the group of 50 patients, the applied FLT-PET/CT test confirmed presence of primary tumor in 49 patients. The presence of increased uptake of FLT in the local lymph nodes during the preoperative FLT-PET/CT test was confirmed in 22 cases. In 14 patients with FLT-PET/Ct N(+) with the M(-) feature resection surgery was performed. The increased uptake of FLT in localizing metastases (nodal and non-nodal) FLT-PET/CT (M+) was detected in 22 patients. The presence of nodal metastases in the postoperative histopathology examination (hpN+) was detected in 14 cases. In these cases preoperative FLT-PET/CT test proved the N(+) feature in 11 patients. The result FLT-PET/CT N(-) was truly negative in 2 patients, and false negative in 1 patient. In the group of 7 operated hpN(-) patients, in 3 patients a preoperative result FLT-PET/ CT N(+) (false positive result) was obtained. The consistency (positive) of nodal metastases identification in FLT-PET/CT as compared to post-surgical histopathology examination scored 11/15, which equals 73.3%. In the group of patients in whom resection surgery was performed, 4 false negative results were obtained [hp(N+), FLT-PET/CT (N-)] and 3 false positive results [hp(N-), FLT-PET/CT N(+)]. CONCLUSIONS: The initial test results indicate that FLT-PET/CT is an effective method in evaluating the primary tumor and the regional lymph nodes and is useful and beneficial in the diagnosis and further treatment evaluation of gastric cancer. FLT-PET/CT examination facilitates making proper therapeutic decisions - it allows the number of unnecessary laparotomies to be lowered.