F-fluorothymidine Research Articles

The prognostic value of F18 Fluorothymidine positron emission tomography for assessing the response of malignant pleural mesothelioma to chemotherapy - A prospective cohort study.

Malignant pleural mesothelioma is difficult to prognosticate. F18-Fluorodeoxyglucose positron emission tomography (FDG PET) shows promise for response assessment but is confounded by talc pleurodesis. F18-Fluorothymidine (FLT) PET is an alternative tracer specific for proliferation. We compared the prognostic value of FDG and FLT PET and determined the influence of talc pleurodesis on these parameters. Overall, 29 prospectively recruited patients had FLT PET, FDG PET and CT-scans performed prior to and post one chemotherapy cycle; 10 had prior talc pleurodesis. Patients were followed for overall survival. CT response was assessed using mRECIST. Radiomic features were extracted using the MiM software platform. Changes in maximum SUV (SUVmax), mean SUV (SUVmean), FDG total lesion glycolysis (TLG), FLT total lesion proliferation (TLP) and metabolic tumour volume (MTV) after one chemotherapy cycle. Cox univariate analysis demonstrated FDG PET radiomics were confounded by talc pleurodesis, and that percentage change in FLT MTV was predictive of overall survival. Cox multivariate analysis showed a 10% increase in FLT tumour volume corresponded with 9.5% worsened odds for overall survival (P = 0.028, HR = 1.095, 95% CI [1.010, 1.187]). No other variables were significant on multivariate analysis. This is the first prospective study showing the statistical significance of FLT PET tumour volumes for measuring mesothelioma treatment response. FLT may be better than FDG for monitoring mesothelioma treatment response, which could help optimise mesothelioma treatment regimes.

Abstract WP350: Detecting Endogenous Neurogenesis After Ischemic Stroke: A F-18-fluorothymidine PET Study

Background and Purpose: Adult neural stem cells (NSCs) can be activated after stroke, but currently noninvasive imaging technique to visualize cerebral neurogenesis is lacking. F-18-fluorothymidine (FLT) has been used as a PET tracer to image cell proliferation and could detect endogenous NSCs in vivo . In this study, we assessed the change in cerebral FLT uptake in a rat model of ischemic stroke. Methods: Cerebral FLT PET was performed in rats subjected to transient middle cerebral artery occlusion (MCAO). PET data were semiquantitatively analyzed and expressed as average mean standardized uptake value ratios (SUVRs) of regions of interest using cerebellar cortex as the reference region. Neurological function was assessed via modified Neurological Severity Score (mNSS) 1 day after MCAO, and infarct volume was analyzed by 2,3,5-Triphenyltetrazolium chloride staining method 7 days after MCAO. Results: Seven days after MCAO, rats exhibited a higher number of Ki67 immunoreactive cells at the subventricular zone, striatum, frontal and temporal cortices in the infarcted brain, indicating promotion of neurogenesis (Figure 1A). The FLT PET showed higher SUVR in the infarcted brain compared to the unaffected side (Figure 1B; Striatum: 1.03±0.36 vs 0.74±0.16, p=0.001; Frontal: 1.14±0.27 vs 0.96±0.13, p=0.004; Temporal: 1.16±0.26 vs 1.00±0.15, p=0.01). The cerebral FLT binding activity gradually declined from post MCAO day 7 to day 28 in the infarcted brain (Figure 1C and D). The FLT binding ratio (global SUVR in the infarcted brain divided by that in the contralateral side) was positively correlated to the severity of stroke, including mNSS (r=0.70, p<0.001) and infarct volume (r=0.90, p<0.001). Conclusion: In vivo FLT PET can detect NSCs in a rat model of ischemic stroke. The promising results of FLT PET suggest that it can be potentially applied in clinical studies as noninvasive longitudinal monitoring and quantification of endogenous NSC activation in the human brain.

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

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. 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 (200mg) or high-dose X-82 (400mg) 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. 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). 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.

Targeted Therapy and Immunotherapy Response Assessment with F-18 Fluorothymidine Positron-Emission Tomography/Magnetic Resonance Imaging in Melanoma Brain Metastasis: A Pilot Study.

This pilot study aimed at exploring the utility of the proliferation tracer F-18 fluorothymidine (FLT) and positron-emission tomography (PET)/magnetic resonance imaging (MRI) (FLT-PET/MRI) for early treatment monitoring in patients with melanoma brain metastasis (MBM) who undergo targeted therapy or immunotherapy. Patients with newly diagnosed MBM underwent baseline and follow-up FLT-PET/MRI scans at 3-4 weeks of targeted therapy or immunotherapy. Up to six measurable brain lesions ≥1.0 cm per subject, as identified on T1-weighted post-gadolinium images, were included for quantitative analyses. The maximum SUV of each lesion was divided by the mean SUV of the pons to obtain the SUV ratio (SUVR). Five enrolled subjects underwent the baseline FLT-PET/MRI study in which the MBM showed a median size of 1.7 cm (range 1.0-2.9) and increased metabolic activity with SUVR of 9.9 (range 3.2-18.4). However, only two subjects (cases #1 and #2) returned for a follow-up scan. At baseline, a total of 22 lesions were analyzed in all five subjects, which showed a median size of 1.7 cm (range 1.0-2.9) and median SUVR of 9.9 (range 3.2-18.4). At follow-up, case #1 was a 55-year-old man who received targeted BRAF inhibitor and MEK inhibitor therapy with dabrafenib and trametinib. Fused PET/MRI data of six measured lesions demonstrated a significant reduction in MBM proliferative activity (median -68%; range -38 to -77%) and size (median -23%; range -4 to -55%) at three weeks of therapy. Nevertheless, the subject eventually progressed and died 13 months after therapy initiation. Case #2 was a 36-year-old man who received immunotherapy with nivolumab and ipilimumab. The five measured MBM lesions showed a mixed response at both proliferative and morphologic imaging at 1-month follow-up. Some lesions demonstrated interval decrease while others interval increase in proliferative activity with a median -44% (range -77 to +68%). On MRI, the size change was +7% (range -64 to +50%). The therapy was switched to dabrafenib and trametinib, which led to a partial response. The patient is still alive 16 months following therapy initiation. The five cases presented show the potential benefit of hybrid FLT-PET/MRI for the diagnosis of MBM and treatment monitoring of targeted therapy and immunotherapy. However, further studies are required to assess their complementary role in distinguishing true progression from pseudoprogression.

Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas.

The nucleoside analog 3'-deoxy-3'-18F-fluorothymidine (FLT) has been investigated for evaluating tumor proliferating activity in brain tumors. We evaluated FLT uptake heterogeneity using textural features from the histogram analysis in patients with newly diagnosed gliomas and examined correlation of the results with proliferative activity and patient prognosis, in comparison with the conventional PET parameters. FLT PET was investigated in 37 patients with newly diagnosed gliomas. The conventional parameters [tumor-to-contralateral normal brain tissue (T/N) ratio and metabolic tumor volume (MTV)] and textural parameters (standard deviation, skewness, kurtosis, entropy, and uniformity) were derived from FLT PET images. Linear regression analysis was used to compare PET parameters and the proliferative activity as indicated by the Ki-67 index. The associations between parameters and overall survival (OS) were tested by Cox regression analysis. Median OS was 662days. For the conventional parameters, linear regression analysis indicated a significant correlation between T/N ratio and Ki-67 index (p=0.02) and MTV and Ki-67 index (p=0.02). Among textural parameters, linear regression analysis indicated a significant correlation for kurtosis (p=0.003), entropy (p<0.001), and uniformity (p<0.001) as compared to Ki-67 index, exceeding those of the conventional parameters. The results of univariate analysis suggested that skewness and kurtosis were associated with OS (p=0.03 and 0.02, respectively). Mean survival for patients with skewness values less than 0.65 was 1462days, compared with 917days for those with values greater than 0.65 (p=0.02). Mean survival for patients with kurtosis values less than 6.16 was 1616days, compared with 882days for those with values greater than 6.16 (p=0.006). Based on the results of this preliminary study in a small patient population, textural features reflecting heterogeneity on FLT PET images seem to be useful for the assessment of proliferation and for the potential prediction of survival in newly diagnosed gliomas.

FLT-PET/CT diagnosis of primary and metastatic nodal lesions of gastric cancer: comparison with FDG-PET/CT.

To examine the diagnostic performance of (18)F-fluorothymidine (FLT)-PET/CT of primary and metastatic nodal lesions of gastric cancer by comparing with (18)F-fluorodeoxyglucose (FDG)-PET/CT. The enrolled study population comprised 17 patients with 17 newly diagnosed gastric cancers who underwent surgery of the primary lesion and regional nodes after both FDG- and FLT-PET/CT scans. Visual detectability of the primary gastric lesions was correlated with pathological factors using the Fisher exact or Mann-Whitney U test. The sensitivity, specificity, and accuracy in detecting nodal lesions were compared between both PET/CT scans using the McNemar exact or χ (2) test. Fourteen of 17 (82.4%) primary cancers were visualized by both FDG- and FLT-PET/CT scans. Although FDG or FLT visibility was not significantly associated with tumor size (p=0.16) or histological type (p=1.00), the 3 nonvisible lesions were pathologically early (T1) cancers. The sensitivity, specificity, and accuracy for detecting nodal metastasis were 44.8% (13/29), 98.7% (164/166), and 90.8% (177/195) for FDG-PET/CT, and 31.0% (9/29), 100% (166/166), and 89.7% (175/195) for FLT-PET/CT, respectively. No significant difference was found between the two scans in sensitivity (p=0.13), specificity (p=0.48), or accuracy (p=1.00). FLT-PET/CT may have the same diagnostic value as FDG-PET/CT for detection of primary and nodal lesions of gastric cancer.

Use of serial 18F-Fluorothymidine (FLT) PET and Ki-67 to predict response to aromatase inhibitors (AI) in women with ER+ breast cancer.

e12039Background: 18F-Fluorothymidine (FLT) PET non-invasively estimates cellular proliferation. In estrogen receptor positive (ER+) tumors, a low proliferative index (Ki-67) as little as two weeks...

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

FDG-PET/CT and FLT-PET/CT for differentiating between lipid-poor benign and malignant adrenal tumours.

To compare F-18-fluorodeoxyglucose (FDG) and F-18-fluorothymidine (FLT) PET/CT examinations for differentiating between benign and malignant adrenal tumours. Thirty lipid-poor benign and 11 malignant tumours of 40 patients were included. FDG- and FLT-based indices including visual score, maximum standardized uptake value (SUVmax) and FDG adrenal lesion/liver SUVmax (A/L SUVmax) or FLT adrenal lesion/back muscle SUVmax (A/B SUVmax) ratio were compared between benign and malignant tumours using the Mann-Whitney's U or Wilcoxon signed-rank test, and their diagnostic performances were evaluated by means of the area under the curve (AUC) values derived from the receiver operating characteristic analysis. All indices were significantly higher in malignant than benign tumours on both images (p < 0.05 each). On FDG-PET/CT, the sensitivity, specificity, and accuracy were 91 %, 63 % and 71 % for visual score, 91 %, 67 % and 73 % for SUVmax, and 100 %, 70 % and 78 % for A/L SUVmax ratio, respectively. On FLT-PET/CT, they were 100 %, 97 % and 98 % for visual score, SUVmax and A/B SUVmax ratio, respectively. All FLT indices were significantly higher than those of FDG in AUC (p < 0.05 each). FLT-PET/CT may be superior to FDG-PET/CT in differentiating lipid-poor benign from malignant adrenal tumours because of higher specificity and accuracy. • All FDG indices were significantly higher in malignant than in benign tumours. • All FLT indices were significantly higher in malignant than in benign tumours. • All FLT indices were significantly higher than those of FDG in AUC.

Monitoring the early biologic response of esophageal carcinoma after irradiation with 18F-FLT: an in-vitro and in-vivo study.

The aim of our study was to explore the value of 3'-deoxy-3'-[F]fluorothymidine (F-FLT) and F-FLT PET in monitoring the early biologic response of esophageal carcinoma after irradiation in vitro and in vivo. After 2, 4, and 8 h of irradiation at different doses (0, 5, 10, and 15 Gy) of esophageal carcinoma cells in vitro, the uptake ratio of F-FLT, the relative cell survival rate, and ATP levels were measured. The tumor uptake ratio of F-FLT [tumor-to-nontumor (T/NT)] was measured through PET scans before and on the first, seventh, and 15th day after irradiation. The expression of proliferating cell nuclear antigen and Ki-67 was determined in both untreated and treated tumors. Compared with the control group, the uptake ratio changes of F-FLT after 2 h of irradiation with 5 Gy showed no statistical significance (3.65±0.17 vs. 4.00±0.17%, P>0.05), whereas the uptake ratios of the other groups decreased notably (F=33.93, P<0.01). The differences in the relative survival rates were not statistically significant (F=4.02, P>0.05). Linear regression analysis indicated a significant correlation between F-FLT and ATP levels (r=0.89, P<0.01). On F-FLT PET scan images of the xenografts, the baseline uptake ratio (T/NT) was 2.24±0.06. It decreased to 1.99±0.09, 1.85±0.04, and 1.15±0.10 at 1, 7, and 15 days after irradiation with 10 Gy. Tumor uptake of F-FLT was closely correlated with proliferating cell nuclear antigen and Ki-67 expressions (r=0.83, P<0.001, and r=0.88, P<0.001). The uptake changes of F-FLT in esophageal carcinoma cells and tumor xenografts may reflect the early biological response of esophageal carcinoma after irradiation. Thus, F-FLT PET may be potentially used to monitor the early response of esophageal carcinoma after radiotherapy.

Correlations of (18)F-fluorothymidine uptake with pathological tumour size, Ki-67 and thymidine kinase 1 expressions in primary and metastatic lymph node colorectal cancer foci.

To examine correlations of (18)F-fluorothymidine (FLT) uptake with pathological tumour size and immunohistochemical Ki-67, and thymidine kinase 1 (TK-1) expressions in primary and metastatic node colorectal cancer foci. Thirty primary cancers (PCs) and 37 metastatic nodes (MNs) were included. FLT uptake was assessed by visual scores (non-visible: 0-1 and visible: 2-4), standardized uptake value (SUV), and correlated with size, Ki-67, and TK-1. SUV was measured in visible lesions. FLT heterogeneity was assessed by visual scores (no heterogeneous uptake: 0 and heterogeneous uptake: 1-4). Forty-two lesions were visible. The visible group showed significantly higher values than the non-visible group in size, Ki-67, and TK-1 (each p < 0.05). Size correlated significantly with visual score (PC; ρ = 0.74 and MN; ρ = 0.63), SUVmax (PC; ρ = 0.49, and MN; ρ = 0.76), and SUVmean (PC; ρ = 0.40 and MN; ρ = 0.76) (each p < 0.05). Visual score correlated significantly with size (ρ = 0.86), Ki-67max (ρ = 0.35), Ki-67mean (ρ = 0.38), TK-1max (ρ = 0.35) and TK-1mean (ρ = 0.25) (each p < 0.05). No significant correlations were found between FLT uptake and Ki-67 or TK-1 in 42 visible lesions (each p > 0.05). Heterogeneous FLT uptake was noted in 73 % (22/30) of PCs. FLT uptake correlated with size. Heterogeneous FLT distribution in colorectal cancers may be one of the causes of weak or lack of FLT uptake/Ki-67 or TK-1 correlation. FLT uptake correlated well with tumour size in colorectal cancer. Weak or lack of FLT uptake/Ki-67 and TK-1 correlations were observed. Immunohistochemical Ki-67 and TK-1 expressions are not always correlated with FLT uptake.

Spatiotemporal Stability of Cu-ATSM and FLT Positron Emission Tomography Distributions During Radiation Therapy

In dose painting, in which functional imaging is used to define biological targets for radiation therapy dose escalation, changes in spatial distributions of biological properties during treatment can compromise the quality of therapy. The goal of this study was to assess the spatiotemporal stability of 2 potential dose painting targets--hypoxia and proliferation--in canine tumors during radiation therapy. Twenty-two canine patients with sinonasal tumors (14 carcinoma and 8 sarcoma) were imaged before hypofractionated radiation therapy with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) for hypoxia and 3'-deoxy-3'-(18)F-fluorothymidine (FLT) PET/CT for proliferation. The FLT scans were repeated after 2 fractions and the Cu-ATSM scans after 3 fractions. Midtreatment PET/CT images were deformably registered to pretreatment PET/CT images. Voxel-based Spearman correlation coefficients quantified the spatial stability of Cu-ATSM and FLT uptake distributions between pretreatment and midtreatment scans. Paired t tests determined significant differences between the patients' respective Cu-ATSM and FLT correlations coefficients. Standardized uptake value measures were also compared between pretreatment and midtreatment scans by use of paired t tests. Spatial distributions of Cu-ATSM and FLT uptake were stable through midtreatment for both sarcomas and carcinomas: the population mean ± standard deviation in Spearman correlation coefficient was 0.88 ± 0.07 for Cu-ATSM and 0.79 ± 0.13 for FLT. The patients' Cu-ATSM correlation coefficients were significantly higher than their respective FLT correlation coefficients (P=.001). Changes in Cu-ATSM SUV measures from pretreatment to midtreatment were histology dependent: carcinomas experienced significant decreases in Cu-ATSM uptake (P<.05), whereas sarcomas did not (P>.20). Both histologies experienced significant decreases in FLT uptake (P<.05). Spatial distributions of Cu-ATSM were very stable after a few fractions of radiation therapy. FLT spatial distributions were generally stable early in therapy, although they were significantly less stable than Cu-ATSM distributions. Canine tumors had significantly lower proliferative activity at midtreatment than at pretreatment, and they experienced histology-dependent changes in Cu-ATSM uptake.

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.

Semiautomatic methods for segmentation of the proliferative tumour volume on sequential FLT PET/CT images in head and neck carcinomas and their relation to clinical outcome

Radiotherapy of head and neck cancer induces changes in tumour cell proliferation during treatment, which can be depicted by the PET tracer (18)F-fluorothymidine (FLT). In this study, three advanced semiautomatic PET segmentation methods for delineation of the proliferative tumour volume (PV) before and during (chemo)radiotherapy were compared and related to clinical outcome. The study group comprised 46 patients with 48 squamous cell carcinomas of the head and neck, treated with accelerated (chemo)radiotherapy, who underwent FLT PET/CT prior to treatment and in the 2nd and 4th week of therapy. Primary gross tumour volumes were visually delineated on CT images (GTV CT). PVs were visually determined on all PET scans (PV VIS). The following semiautomatic segmentation methods were applied to sequential PET scans: background-subtracted relative-threshold level (PV RTL), a gradient-based method using the watershed transform algorithm and hierarchical clustering analysis (PV W&C), and a fuzzy locally adaptive Bayesian algorithm (PV FLAB). Pretreatment PV VIS correlated best with PV FLAB and GTV CT. Correlations with PV RTL and PV W&C were weaker although statistically significant. During treatment, the PV VIS, PV W&C and PV FLAB significant decreased over time with the steepest decline over time for PV FLAB. Among these advanced segmentation methods, PV FLAB was the most robust in segmenting volumes in the third scan (67 % of tumours as compared to 40 % for PV W&C and 27 % for PV RTL). A decrease in PV FLAB above the median between the pretreatment scan and the scan obtained in the 4th week was associated with better disease-free survival (4 years 90 % versus 53 %). In patients with head and neck cancer, FLAB proved to be the best performing method for segmentation of the PV on repeat FLT PET/CT scans during (chemo)radiotherapy. This may potentially facilitate radiation dose adaptation to changing PV.

Diagnostic performance of 18F-fluorothymidine PET/CT for primary colorectal cancer and its lymph node metastasis: comparison with 18F-fluorodeoxyglucose PET/CT

To examine the diagnostic performance of (18)F-fluorothymidine (FLT) PET/CT in primary and metastatic lymph node colorectal cancer foci in comparison with (18)F-fluorodeoxyglucose (FDG) PET/CT. The study population comprised 28 patients with 30 newly diagnosed colorectal cancers who underwent surgical resection of the primary lesion and regional lymph nodes after both FLT and FDG PET/CT. The associations between SUVmax levels and pathological factors were evaluated using the Mann-Whitney U or Kruskal-Wallis test. Differences in diagnostic indexes for detecting nodal metastasis between the two tracers were estimated using the McNemar exact or χ(2) test. All 30 primary cancers (43.0 ± 20.0 mm, range 14 - 85 mm) were visualized by both tracers, but none of the FLT SUVmax values exceeded the FDG SUVmax values in any of the primary cancers (6.6 ± 2.4 vs. 13.6 ± 5.8, p < 0.001). The sensitivity, specificity and accuracy for detecting nodal metastasis were 41% (15/37), 98.8% (493/499) and 94.8% (508/536) for FDG PET/CT, and 32% (12/37), 98.8% (493/499) and 94.2% (505/536) for FLT PET/CT, respectively. The sensitivity (p = 0.45), specificity (p = 0.68) and accuracy (p = 0.58) were not different between the tracers. Nodal uptake of FLT and FDG was discordant in 7 (19%) of 37 metastatic nodes. There were ten concordant true-positive nodes of which six showed higher FDG SUVmax and four showed higher FLT SUVmax, but the difference between FDG and FLT SUVmax was not significant (5.56 ± 3.55 and 3.62 ± 1.45, respectively; p = 0.22). FLT has the same potential as FDG in PET/CT for the diagnosis of primary and nodal foci of colorectal cancer despite significantly lower FLT uptake in primary foci.

Monitoring tumor proliferative response to radiotherapy using 18F-fluorothymidine in human head and neck cancer xenograft in comparison with Ki-67

Although radiotherapy is an important treatment strategy for head and neck cancers, it induces tumor repopulation which adversely affects therapeutic outcome. In this regard, fractionated radiotherapy is widely applied to prevent tumor repopulation. Evaluation of tumor proliferative activity using (18)F-fluorothymidine (FLT), a noninvasive marker of tumor proliferation, may be useful for determining the optimal timing of and dose in the repetitive irradiation. Thus, to assess the potentials of FLT, we evaluated the sequential changes in intratumoral proliferative activity in head and neck cancer xenografts (FaDu) using FLT. FaDu tumor xenografts were established in nude mice and assigned to control and two radiation-treated groups (10 and 20 Gy). Tumor volume was measured daily. (3)H-FLT was injected intravenously 2 h before killing. Mice were killed 6, 24, 48 h, and 7 days after the radiation treatment. Intratumoral (3)H-FLT level was visually and quantitatively assessed by autoradiography. Ki-67 immunohistochemistry (IHC) was performed. In radiation-treated mice, the tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. In the visual assessment, intratumoral (3)H-FLT level diffusely decreased 6 h after the radiation treatment and then gradually increased with time, whereas no apparent changes were observed in Ki-67 IHC. Six hours after the radiation treatment at 10 and 20 Gy, the intratumoral (3)H-FLT level markedly decreased to 45 and 40 % of the control, respectively (P < 0.0001 vs control), and then gradually increased with time. In each radiation-treated group, the (3)H-FLT levels at 48 h and on day 7 were significantly higher than that at 6 h. The intratumoral (3)H-FLT levels in both treated groups were 68 and 60 % at 24 h (P < 0.001), 71 and 77 % at 48 h (P < 0.001), and 83 and 81 % on day 7 (P = NS) compared with the control group. Intratumoral FLT uptake level markedly decreased at 6 h and then gradually increased with time. Sequential evaluation of intratumoral proliferative activity using FLT can be beneficial for determining the optimal timing of and dose in repetitive irradiation of head and neck cancer.

Tumor Lesion Glycolysis and Tumor Lesion Proliferation for Response Prediction and Prognostic Differentiation in Patients With Advanced Non–Small Cell Lung Cancer Treated With Erlotinib

The aim was to assess the value of tumor lesion glycolysis (TLG) and tumor lesion proliferation (TLP) determined by FDG and 3'-deoxy-3'-F-fluorothymidine (FLT) PET for response prediction and prognostic differentiation in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib. FDG-PET and FLT-PET were performed in 30 patients with untreated Stage IV NSCLC before start of therapy, 1 (early) and 6 (late) weeks after erlotinib treatment. Functional tumor volume parameters including TLG in FDG-PET and TLP in FLT-PET were measured in the sum of up to 5 lesions per scan. Metabolic response was assessed using different cutoff values for percentage changes of TLG and TLP. Absolute baseline and residual levels of TLG and TLP were used for dichotomizing the patients into 2 groups. Kaplan-Meier analysis and the log-rank test were performed to analyze the association with progression-free survival (PFS). Patients with a metabolic response measured by early changes of TLP and late changes of TLG and TLP showed a significantly better PFS than metabolically nonresponding patients. A lower cutoff value of 20% or 30% for definition of metabolic response showed better differentiation between metabolically responding and nonresponding patients in cases where the 45% cutoff value revealed no significant results. Furthermore, patients with lower absolute early and late residual TLG and TLP levels had a significantly prolonged PFS. In contrast, absolute baseline TLG and TLP levels showed no significant association with PFS. In patients with advanced NSCLC, percentage changes of TLG and TLP and absolute residual TLG and TLP levels under erlotinib treatment emerged as strong predictive factors for PFS. Our findings indicate that a cutoff value of 20% or 30% for definition of metabolic response measured by percentage changes of TLG and TLP provides suitable results for response prediction, which should be further validated.

Comparison of 18F-FLT PET and 18F-FDG PET for detection of cervical lymph node metastases in head and neck cancers

Conclusion: Despite low uptake of tracer, 3′-deoxy-3′-18F-fluorothymidine (FLT) PET could detect cervical lymph node metastases as well as 2-deoxy-2-18F-fluoro-d-glucose (FDG) PET. Objective: The diagnostic efficacy of FLT PET was compared with that of FDG PET regarding nodal staging of head and neck squamous cell cancers. Methods: Twenty-three patients were examined with FLT PET and FDG PET. PET images were evaluated qualitatively for regions of focally increased metabolism and maximum standardized uptake values (SUV) were calculated for semiquantitative analysis. Results: The mean (± SD) FLT SUV in visualized metastatic lymph nodes was 4.8 ± 2.9 as compared with 6.9 ± 4.9 for FDG SUV (p < 0.001). Significant correlations were found between the area of metastatic lymph nodes and both FLT SUV (r = 0.8; p < 0.0001) and FDG SUV (r = 0.84; p < 0.0001). The false-positive (over-staged) and false-negative (under-staged) rates for lymph node staging by FLT PET were 4% (1/23) and 17% (4/23), respectively. Those for FDG PET were 9% (2/23) and 13% (3/23). All metastatic lymph nodes measuring more than 9 mm in short-axis diameter were correctly detected by FLT PET. However, both FLT and FDG PET had low sensitivity for detecting the lymph node metastases ≤ 9 mm in short-axis diameter and tumor deposits < 5 mm.