Positron Emission Tomography with [18F]-3′-Deoxy-3′fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: a Pilot Study

Purpose

This pilot study was performed to evaluate whether tumor uptake of ¹⁸F-labeled 3′-deoxy-3′fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally advanced rectal cancer.

Procedures

Fourteen patients underwent positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) and FLT before therapy and PET with FLT approximately 2 weeks after initiating neoadjuvant chemoradiotherapy. FLT and FDG uptake were evaluated qualitatively and by maximum standardized uptake value (SUV_max). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS).

Results

Thirteen patients underwent surgery after therapy, one died before surgery with progressive disease. FDG-PET/computed tomography detected regional lymph node metastases in five and FLT-PET was positive in one. High pretherapy FDG uptake (SUV_max?≥?14.3), low during-therapy FLT uptake (SUV_max?<?2.2), and high percentage change in FLT uptake (≥60 %) were predictive of improved DFS (p?<?0.05 for all three values).

Conclusion

Pretherapy FDG uptake, during-therapy FLT uptake, and percentage change in FLT uptake were equally predictive of DFS.     

Evaluation of 2-Deoxy-2-[18F]Fluoro-D-glucose- and 3′-Deoxy-3′-[18F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer

Purpose

We evaluated whether 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer.

Procedures

Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET.

Results

The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p????0.006, n?=?6 per group). [¹⁸F]FDG-PET and [¹⁸F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p????0.006, n?=?6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [¹⁸F]FLT response.

Conclusions

Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [¹⁸F]FDG-PET and [¹⁸F]FLT-PET warranting further assessment.     

Examining Changes in [18 F]FDG and [18 F]FLT Uptake in U87-MG Glioma Xenografts as Early Response Biomarkers to Treatment with the Dual mTOR1/2 Inhibitor AZD8055

Purpose

The mTOR kinase inhibitor AZD8055 inhibits both mTORC1 and mTORC2 leading to disruption of glucose metabolism and proliferation pathways. This study assessed the impact of single and multiple doses of AZD8055 on the uptake of the glucose metabolism marker 2-deoxy-2-[¹⁸?F]fluoro-d-glucose ([¹⁸?F]FDG) and the proliferation marker 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT) in U87-MG glioma xenografts.

Procedures

Mice bearing U87-MG tumours received either vehicle or AZD8055 (20 mg/kg) once daily p.o. Mice were imaged with either [¹⁸?F]FDG or [¹⁸?F]FLT PET to assess treatment response. Comparisons were made between in vivo imaging and ex vivo histopathology data.

Results

Tumour uptake of [¹⁸?F]FDG was reduced by 33 % 1 h after a single dose of AZD8055 and by 49 % following 4 days of dosing. These changes coincided with suppression of the mTOR pathway biomarkers pS6 and pAKT. In contrast, the effect of AZD8055 on [¹⁸?F]FLT uptake was inconsistent.

Conclusions

The very rapid change in [¹⁸?F]FDG uptake following acute AZD8055 treatment suggests that this could be used as an early mechanistic biomarker of metabolic changes resulting from mTOR inhibition. The utility of [¹⁸?F]FLT for measuring the anti-proliferative effect of AZD8055 remains unclear.     

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

Purpose

3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2??-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [¹⁸F]FLT in tumor xenografts.

Methods

The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[¹²⁵I]iodo-2??-deoxyuridine biodistribution measurements. In [¹⁸F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [¹⁸F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [¹⁸F]FDG tumor uptake. Using microPET, the dynamic distribution of [¹⁸F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation.

Results

FdUrd induced an immediate increase in tumor uptake of 5-[¹²⁵I]iodo-2??-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [¹⁸F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [¹⁸F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [¹⁸F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [¹⁸F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis.

Conclusion

We showed a reliable and significant uptake increase of [¹⁸F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [¹⁸F]FLT PET.     

Validity of Simplified 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Measures for Monitoring Response to Chemotherapy in Locally Advanced Breast Cancer

Purpose

Positron emission tomography using 3??-deoxy-3??-[¹⁸F]fluorothymidine ([¹⁸F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [¹⁸F]FLT in locally advanced breast cancer (LABC).

Procedures

Fifteen LABC patients underwent dynamic [¹⁸F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [¹⁸F]FLT, K _i , determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [¹⁸F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.

Results

No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.

Conclusions

In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [¹⁸F]FLT.     

Preclinical Evaluation of a Novel c-Met Inhibitor in a Gastric Cancer Xenograft Model Using Small Animal PET

Purpose

Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) versus 3′-deoxy-3′-18F-fluorothymidine ([¹⁸F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.

Procedures

The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96 h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels.

Results

BAY 853474 significantly reduces tumor growth. [¹⁸F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [¹⁸F]FLT uptake in the tumor tissue was completely absent 96 h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals.

Conclusion

These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.     

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

Purpose

To examine the diagnostic performance of ¹⁸F-fluorothymidine (FLT)-PET/CT of primary and metastatic nodal lesions of gastric cancer by comparing with ¹⁸F-fluorodeoxyglucose (FDG)-PET/CT.

Methods

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.

Results

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).

Conclusion

FLT-PET/CT may have the same diagnostic value as FDG-PET/CT for detection of primary and nodal lesions of gastric cancer.

     

Evaluation of [<Superscript>18</Superscript>F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer

Purpose

In oncology, positron emission tomography imaging using dedicated tracers as biomarkers may assist in early evaluation of therapy efficacy. Using 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT), we investigated the early effects of chemotherapeutic treatment on cancer cell proliferation in a BRAF-mutated colorectal cancer xenograft model.

Procedures

Colo205 subcutaneously inoculated animals underwent 90-min dynamic imaging before and 24 h after treatment with vehicle (control), cetuximab (resistant) or irinotecan (sensitive). Total distribution volume was quantified from dynamic data, and standardized uptake values as well as tumor-to-blood ratios were calculated from static images averaged over the last 20 min. In vivo imaging data was correlated with ex vivo proliferation and thymidine metabolism proteins.

Results

All imaging parameters showed a significant post-treatment decrease from [¹⁸F]FLT baseline uptake for the irinotecan group (p?≤?0.001) as compared with the cetuximab and vehicle group and correlated strongly with each other (p?≤?0.0001). In vivo data were in agreement with Ki67 staining, showing a significantly lower percentage of Ki67-positive cells in the irinotecan group as compared with other groups (p?≤?0.0001). Tumor expression of thymidine kinase 1 phosphorylated on serine 13, thymidylate synthase, and thymidine phosphorylase remained unaffected, while thymidine kinase 1 expression was, surprisingly, significantly higher in irinotecan-treated animals (p?≤?0.01). In contrast, tumor ATP levels were lowest in this group.

Conclusions

[¹⁸F]FLT positron emission tomography was found to be a suitable biomarker of early tumor response to anti-proliferative treatment, with static imaging not being inferior to full compartmental analysis in our xenograft model. The dynamics of thymidine kinase 1 protein expression and protein activity in low ATP environments merits further investigation.

     

Dynamic Changes of FDG Uptake and Clearance in Normal Tissues

Purpose

This study aims to evaluate dynamic 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in normal tissues.

Procedures

Thirty male patients underwent FDG positron emission tomography (PET)/computed tomography imaging at 1, 2, and 3 h after tracer injection. Standardized uptake values (SUV) were obtained in regions of interest of normal tissues.

Results

The aorta (blood pool), liver, and spleen FDG activity demonstrated significantly and continuously decreased activity from 1 to 2 and 2 to 3 h, while FDG uptake in the lungs, pancreas, lymph nodes, and skeletal muscle decreased from 1 to 2 h only. In contrast, the left ventricular myocardium demonstrated two patterns of dynamic changes: myocardium with higher FDG uptake (SUV_max?≥?3.25) on the initial images had more remarkable increased activity on the delayed images, while myocardium with lower FDG uptake (SUV_max?<?3.25) on the initial imaging had no increased uptake on delayed imaging. Increased FDG uptake was also observed in the bones on the delayed images. No significant changes of FDG uptake were noted in the parotid gland, thyroid gland, and prostate gland.

Conclusions

These findings may help nuclear medicine physicians when comparing images performed at different time points, when using FDG uptake in internal reference regions as a relative indicator of FDG uptake in a specific lesion, and when reading a delayed FDG PET imaging.     

Longitudinal PET Imaging of Doxorubicin-Induced Cell Death with 18F-Annexin V

Purpose

This study aims to apply longitudinal positron emission tomography (PET) imaging with ¹⁸?F-Annexin V to visualize and evaluate cell death induced by doxorubicin in a human head and neck squamous cell cancer UM-SCC-22B tumor xenograft model.

Procedures

In vitro toxicity of doxorubicin to UM-SCC-22B cells was determined by a colorimetric assay. Recombinant human Annexin V protein was expressed and purified. The protein was labeled with fluorescein isothiocyanate for fluorescence staining and ¹⁸?F for PET imaging. Established UM-SCC-22B tumors in nude mice were treated with two doses of doxorubicin (10?mg/kg each dose) with 1?day interval. Longitudinal ¹⁸?F-Annexin V PET was performed at 6?h, 24?h, 3?days, and 7?days after the treatment started. Following PET imaging, direct tissue biodistribution study was performed to confirm the accuracy of PET quantification.

Results

Two doses of doxorubicin effectively inhibited the growth of UM-SCC-22B tumors by inducing cell death including apoptosis. The cell death was clearly visualized by ¹⁸?F-Annexin V PET. The peak tumor uptake, which was observed at day 3 after treatment started, was significantly higher than that in the untreated tumors (1.56?±?0.23 vs. 0.89?±?0.31%ID/g, p?<?0.05). Moreover, the tumor uptake could be blocked by co-injection of excess amount of unlabeled Annexin V protein. At day 7 after treatment, the tumor uptake of ¹⁸?F-Annexin had returned to baseline level.

Conclusions

¹⁸?F-Annexin V PET imaging is sensitive enough to allow visualization of doxorubicin-induced cell death in UM-SCC-22B xenograft model. The longitudinal imaging with ¹⁸?F-Annexin will be helpful to monitor early response to chemotherapeutic anti-cancer drugs.     

99mTc-labeled Rituximab for Imaging B Lymphocyte Infiltration in Inflammatory Autoimmune Disease Patients

Purpose

The rationale of the present study was to radiolabel rituximab with 99m-technetium and to image B lymphocytes infiltration in the affected tissues of patients with chronic inflammatory autoimmune diseases, in particular, the candidates to be treated with unlabelled rituximab, in order to provide a rationale for ??evidence-based?? therapy.

Procedures

Rituximab was labelled with ^99mTc via 2-ME reduction method. In vitro quality controls of ^99mTc-rituximab included stability assay, cysteine challenge, SDS-PAGE, immunoreactive fraction assay and competitive binding assay on CD20+ve Burkitt lymphoma-derived cells. For the human pilot study, 350?C370?MBq (100???g) of ^99mTc-rituximab were injected in 20 patients with different chronic inflammatory autoimmune diseases. Whole body anteroposterior planar scintigraphic images were acquired 6 and 20?h p.i.

Results

Rituximab was labelled to a high labelling efficiency (>98%) and specific activity (3515?C3700?MBq/mg) with retained biochemical integrity, stability and biological activity. Scintigraphy with ^99mTc-rituximab in patients showed a rapid and persistent spleen uptake, and the kidney appeared to be a prominent source for the excretion of radioactivity. Inflamed joints showed a variable degree of uptake at 6?h p.i. in patients with rheumatoid arthritis indicating patient variability; similarly, the salivary and lacrimal glands showed variable uptake in patients with Sj?gren??s syndrome, Beh?et??s disease and sarcoidosis. Inflammatory disease with particular characteristics showed specific uptake in inflammatory lesions, such as, dermatopolymyositis patients showed moderate to high skin uptake, a sarcoidosis patient showed moderate lung uptake, a Beh?et??s disease patient showed high oral mucosa uptake and a polychondritis patient showed moderate uptake in neck cartilages. In one patient with systemic lupus erythematosus, we did not find any non-physiological uptake.

Conclusion

Rituximab can be efficiently labelled with ^99mTc with high labelling efficiency. The results suggest that this technique might be used to assess B lymphocyte infiltration in affected organs in patients with autoimmune diseases; this may provide a rationale for anti-CD20 therapies.     

Micro-Autoradiographic Assessment of Cell Types Contributing to 2-Deoxy-2-[18F]Fluoro-d-Glucose Uptake During Ventilator-Induced and Endotoxemic Lung Injury

Purpose

The aim of the study was to use micro-autoradiography to investigate the lung cell types responsible for 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in murine models of acute lung injury (ALI).

Procedures

C57/BL6 mice were studied in three groups: controls, ventilator-induced lung injury (VILI), and endotoxin. VILI was produced by high tidal volumes and zero end-expiratory pressure and endotoxin ALI, by intranasal administration. Following FDG injection, the lungs were processed and exposed to autoradiographic emulsion. Grain density over cells was used to quantify FDG uptake.

Results

Neutrophils, macrophages, and type 2 epithelial cells presented higher grain densities during VILI and endotoxin ALI than controls. Remarkably, cell grain density in specific cell types was dependent on the injury mechanism. Whereas macrophages showed high grain densities during endotoxin ALI, similar to those exhibited by neutrophils, type 2 epithelial cells demonstrated the second highest grain density (with neutrophils as the highest) during VILI.

Conclusions

In murine models of VILI and endotoxin ALI, FDG uptake occurs not only in neutrophils but also in macrophages and type 2 epithelial cells. FDG uptake by individual cell types depends on the mechanism underlying ALI.     

Chronic Cannabinoid Administration to Periadolescent Rats Modulates the Metabolic Response to Acute Cocaine in the Adult Brain

Purpose

To analyze brain metabolic response to acute cocaine in male and female Wistar rats with or without a history of cannabinoid exposure during periadolescence.

Procedures

The synthetic cannabinoid agonist CP 55,940 (CP) or its vehicle (VH), were administered to male and female rats during periadolescence. When these animals reached adulthood, saline and cocaine-induced changes in 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) uptake were studied by positron emission tomography.

Results

The baseline (post-saline) metabolism in the septal nuclei was higher in CP-females than in VH-females, although septal metabolism was lower in CP-females after cocaine, reaching similar values to those of VH-females at baseline. Cocaine did not affect metabolism in VH-females. Periadolescent cannabinoid treatment did not influence baseline metabolism in males although cocaine reduced the FDG uptake in the dorsal striatum of males that received the VH but not CP.

Conclusions

These results suggest that cannabinoids during periadolescence modify baseline and cocaine-evoked brain metabolism in a sex-dependent manner. In the case of CP-females, the involvement of septal metabolic alterations in their susceptibility to the rewarding effects of cocaine should be further investigated.     

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [<Superscript>18</Superscript>F]FDG PET and acidoCEST MRI

Purpose

We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment.

Procedures

A standard 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1 day before treatment, 1 day after initiating daily treatment with metformin, and 7 days after initiating treatment. Longitudinal changes in SUV_max and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUV_max and pHe between metformin-treated and control groups were also evaluated.

Results

MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [¹⁸F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUV_max of the tumor model had a significant decrease after 7 days of treatment with metformin, as expected. The average tumor pHe decreased after 7 days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUV_max of the tumor model was not significantly different between the metformin-treated and control groups after 7 days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUV_max and pHe measurements significantly differed between the treatment group and control group on Day 7.

Conclusions

[¹⁸F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.

     

Response Monitoring with [<Superscript>18</Superscript>F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases

Purpose

The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases.

Procedures

Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [¹⁸F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression.

Results

5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [¹⁸F]FLT SUV_mean and SUV_max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV_max at days ?1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [¹⁸F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADC_mean) did not change in 5-FU-treated rats compared to untreated rats.

Conclusion

This study suggests that 5-FU treatment induces a flare in [¹⁸F]FLT uptake of responsive CC531 tumors in the liver, while the ADC_mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [¹⁸F]FLT PET can discriminate between disease progression and treatment response.

     

Dose-Dependent Uptake of 3′-deoxy-3′-[18 F]Fluorothymidine by the Bowel after Total-Body Irradiation

Purpose

The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT).

Procedures

Twenty-nine male C57BL/6 mice were investigated by [¹⁸?F]FLT positron emission tomography for 7 days after total body irradiation (1, 4, and 8 Gy) versus ‘sham’ irradiation (0 Gy). Target/background ratios were determined. The imaging results were validated by histology and immunohistochemistry (Thymidine kinase 1, Ki-67).

Results

[¹⁸?F]FLT demonstrated a dose-dependent intestinal accumulation post irradiation. Mean target/background ratio (±standard error) 0 Gy: 1.4 (0.2), 1 Gy: 1.7 (0.1), 4 Gy: 3.1 (0.3), 8 Gy: 4.2 (0.6). Receiver operating characteristic analysis (area under the curve, p value): 0 vs. 1 Gy: 0.81, 0.049; 0 vs. 4 Gy: 1.0, 0.0016; and 0 vs. 8 Gy: 1.0, 0.0020. Immunohistochemistry confirmed the results.

Conclusions

[¹⁸?F]FLT seems to provide dose-dependent information on radiation-induced proliferation in the bowel. This opens the perspective for monitoring therapy-related side-effects as well as assessing, e.g., radiation accident victims.     

The Relationship Between Serial [18 F]PBR06 PET Imaging of Microglial Activation and Motor Function Following Stroke in Mice

Purpose

Using [¹⁸?F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [¹⁸?F]PBR06 PET as a therapeutic assessment tool.

Procedures

Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).

Results

The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.

Conclusion

[18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.     

Baseline [<Superscript>18</Superscript>F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

Purpose

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

Procedures

Therapy response to 5-FU?±?PX-12 was assessed with baseline [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) and longitudinal 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n?=?36) during breathing of a hypoxic (10 % O₂) or normoxic (21 % O₂) atmosphere. Ex vivo, immunohistochemistry was performed.

Results

Baseline [¹⁸F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU?+?PX-12 administration correlated significantly (p?≤?0.01). Under hypoxic breathing conditions, [¹⁸F]FDG uptake (?53.1?±?8.4 %) and Ki67 expression (?16 %) decreased and RTV stagnated in the 5-FU?+?PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [¹⁸F]FDG uptake (?23.5?±?15.2 % and ?72.8?±?7.1 %) and Ki67 expression (?5 % and ?19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively.

Conclusion

Baseline [¹⁸F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

     

The Synergistic Effect of Selumetinib/Docetaxel Combination Therapy Monitored by [<Superscript>18</Superscript> F]FDG/[<Superscript>18</Superscript> F]FLT PET and Diffusion-Weighted Magnetic Resonance Imaging in a Colorectal Tumor Xenograft Model

Purpose

Positron emission tomography (PET) and diffusion-weighted MRI (DW-MRI) were used to characterize the treatment effects of the MEK1/2 inhibitor selumetinib (AZD6244), docetaxel, and their combination in HCT116 tumor-bearing mice on the molecular level.

Procedures

Mice were treated with vehicle, selumetinib (25 mg/kg), docetaxel (15 mg/kg), or a combination of both drugs for 7 days and imaged at four time points with 2-deoxy-2-[¹⁸?F]fluoro-D-glucose ([¹⁸?F]FDG) or 3′-deoxy-3′-[¹⁸?F]fluorothymidine ([¹⁸?F]FLT) followed by DW-MRI to calculate the apparent diffusion coefficient (ADC). Data was cross-validated using the Pearson correlation coefficient (PCC) and compared to histology (IHC).

Results

Each drug led to tumor growth inhibition but their combination resulted in regression. Separate analysis of PET or ADC could not provide significant differences between groups. Only PCC combined with IHC analysis revealed the highest therapeutic impact for combination therapy.

Conclusion

Combination treatment of selumetinib/docetaxel was superior to the respective mono-therapies shown by PCC of PET and ADC in conjunction with histology.

     

Deep Brain Stimulation of the Prelimbic Medial Prefrontal Cortex: Quantification of the Effect on Glucose Metabolism in the Rat Brain Using [18 F]FDG MicroPET

Purpose

Prefrontal cortex (PFC) deep brain stimulation (DBS) has been proposed as a therapy for addiction and depression. This study investigates changes in rat cerebral glucose metabolism induced by different DBS frequencies using μPET.

Procedures

One hour DBS of the prelimbic area (PL) of the medial PFC (mPFC) (60 Hz, 130 Hz or sham) in rats (n?=?9) was followed by 2-deoxy-2-[¹⁸?F] fluoro-d-glucose ([¹⁸?F]FDG) μPET.

Results

Sixty Hz DBS elicited significant hypermetabolism in the ipsilateral PL ([¹⁸?F]FDG uptake +5.2?±?2.3 %, p?Conclusions This study suggests the potential of 60 Hz PL mPFC DBS for the treatment of disorders associated with prefrontal hypofunction.