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.     

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.     

How Long of a Dynamic 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET Acquisition Is Needed for Robust Kinetic Analysis in Breast Cancer?

Molecular Imaging and Biology - To quantitatively evaluate the minimally required scanning time of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) dynamic...     

3′-Deoxy-3′-[<Superscript>18</Superscript>F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models

Purpose

We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models.

Procedures

Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [¹⁸F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations.

Results

Expression of TP correlated positively with [¹⁸F]FLT SUV_max (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = ??0.939, P < 0.001).

Conclusions

In a broad range of tumors, [¹⁸F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [¹⁸F]FLT uptake.

     

Monitoring Tumor Response after Liposomal Doxorubicin in Combination with Liposomal Vinorelbine Treatment Using 3′-Deoxy-3′-[<Superscript>18</Superscript>F]Fluorothymidine PET

Purpose

Surgical resection is the standard treatment for localized colorectal cancer, which is the most common type of gastrointestinal cancer. However, over 40 % cases are diagnosed metastasized and apparently inoperable. Systemic chemotherapy provides an alternative to these patients. This study aims to evaluate the therapeutic potential of liposomal doxorubicin (lipoDox) in combination with liposomal vinorelbine (lipoVNB) in a CT-26 colon carcinoma-bearing mouse model.

Procedures

The in vitro cytotoxicity of Dox and VNB on CT-26 cancer cells was determined by MTT and colony formation assays. Mice were subcutaneously inoculated with 2 × 10⁵ of CT-26 cells in the right hind flank. When tumor size reached 200 ± 50 mm³, mice were assigned to receive different treatment protocols. The pharmacokinetics, micro single-photon emission computed tomography/x-ray computed tomography imaging, biodistribution, and immunohistochemical staining studies were performed to survey the therapeutic efficacy of each regimen.

Results

Based on the results of pharmacokinetic study, co-administration of lipoDox and lipoVNB did not affect their individual systemic distribution, while lipoDox retained longer in blood than lipoVNB did. Superior tumor growth retardation was observed in the group received lipoDox plus lipoVNB administration (1 mg/kg each, namely D₁V₁) than those injected with lipoDox plus VNB (1 mg/kg each, namely D₁fV₁). No severe side effects were detected in each group. The tumor-to-muscle ratio (T/M) derived from 3′-dexoy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) micro positron emission tomography (PET) images of D₁V₁- and D₁fV₁-treated mice and the controls on day 7 was 6.88 ± 0.54, 7.50 ± 0.84, and 9.87 ± 0.73, respectively, suggesting that D₁V₁ is a more efficacious regimen against CT-26 xenografts. The results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining were consistent with those findings obtained from [¹⁸F]FLT microPET imaging.

Conclusion

This study demonstrated that lipoDox in combination with lipoVNB was more efficacious than clinically used regimen, lipoDox plus VNB, in the treatment of colon carcinoma and [¹⁸F]FLT-PET is a promising approach in monitoring the treatment outcome at early stage.

     

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.     

An Evaluation of 2-deoxy-2-[18F]Fluoro-D-Glucose and 3′-deoxy-3′-[18F]-Fluorothymidine Uptake in Human Tumor Xenograft Models

Purpose

The aim of this study is to assess the variability of 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]-FDG) and 3??-deoxy-3??-[¹⁸F]-fluorothymidine ([¹⁸F]-FLT) uptake in pre-clinical tumor models and examine the relationship between imaging data and related histological biomarkers.

Procedures

[¹⁸F]-FDG and [¹⁸F]-FLT studies were carried out in nine human tumor xenograft models in mice. A selection of the models underwent histological analysis for endpoints relevant to radiotracer uptake. Comparisons were made between in vitro uptake, in vivo imaging, and ex vivo histopathology data using quantitative and semi-quantitative analysis.

Results

In vitro data revealed that [1-¹⁴C]-2-deoxy-d-glucose ([¹⁴C]-2DG) uptake in the tumor cell lines was variable. In vivo, [¹⁸F]-FDG and [¹⁸F]-FLT uptake was highly variable across tumor types and uptake of one tracer was not predictive for the other. [¹⁴C]-2DG uptake in vitro did not predict for [¹⁸F]-FDG uptake in vivo. [¹⁸F]-FDG SUV was inversely proportional to Ki67 and necrosis levels and positively correlated with HKI. [¹⁸F]-FLT uptake positively correlated with Ki67 and TK1.

Conclusion

When evaluating imaging biomarkers in response to therapy, the choice of tumor model should take into account in vivo baseline radiotracer uptake, which can vary significantly between models.     

Early 2′-Deoxy-2′-[18F]Fluoro-d-Glucose PET Metabolic Response after Corticosteroid Therapy to Differentiate Cancer from Sarcoidosis and Sarcoid-like Lesions

Purpose  We aimed at investigating whether early metabolic response to corticosteroid therapy may be used as a diagnostic tool to discriminate between cancer and sarcoidosis, a well-known cause of false-positive 2-deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography (FDG-PET) findings in oncology. Procedure  Two cancer patients with biopsy-proven sarcoidosis or sarcoid-like reaction had multiple thoracic FDG foci. After infectious disease had been excluded, patients received oral corticosteroids for 16 and 14 days, respectively, and underwent posttherapeutic FDG-PET examination. Results  Posttreatment PET revealed a complete metabolic response in both patients, and clinical and imaging follow-up showed no sign of cancer progression. Conclusion  Early metabolic response to systemic corticosteroid treatment may be used as a tool in the establishment of final diagnosis when sarcoidosis is suspected in a cancer patient and could be capable of differentiating cancer from sarcoidosis in the case of coexisting diseases.     

Does Measurement of First-Order and Heterogeneity Parameters Improve Response Assessment of Bone Metastases in Breast Cancer Compared to SUVmax in [18F]fluoride and [18F]FDG PET?

Molecular Imaging and Biology - To establish whether first-order statistical features from [18F]fluoride and 2-deoxy-2-[18F] fluoro-d-glucose ([18F]FDG) positron emission tomography/x-ray computed...     

NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of 3′-Deoxy-3′-[18F]fluorothymidine (FLT) as a Marker of Proliferation in Patients with Recurrent Gliomas: Preliminary Efficacy Studies

Purpose  3′-Deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-d-glucose (FDG). Procedures  Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [¹⁸F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K _FLT), blood to tissue transport (K ₁), and phosphorylation (k ₃). FDG-PET scans were obtained 75–90 min postinjection. Results   K _FLT and k ₃, but not K ₁ or k ₃/k ₂ + k ₃, reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance. Conclusions   K _FLT (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer.     

Monitoring the Progression of Chronic Liver Damage in Rats Using [18F]PBR06

Molecular Imaging and Biology - Accurate and rapid assessment of liver condition is the key to therapy for hepatitis patients. This study aim is to evaluate the peripheral benzodiazepine receptor...     

Hybrid MicroPET Imaging for Dosimetric Applications in Mice: Improvement of Activity Quantification in Dynamic MicroPET Imaging for Accelerated Dosimetry Applied to 6-[18 F]Fluoro-l-DOPA and 2-[18 F]Fluoro-l-Tyrosine

Purpose

Dynamic microPET imaging has advantages over traditional organ harvesting, but is prone to quantification errors in small volumes. Hybrid imaging, where microPET activities are cross-calibrated using post scan harvested organs, can improve quantification. Organ harvesting, dynamic imaging and hybrid imaging were applied to determine the human and mouse radiation dosimetry of 6-[18 F]fluoro-l-DOPA and 2-[18 F]fluoro-l-tyrosine and compared.

Procedures

Two-hour dynamic microPET imaging was performed with both tracers in four separate mice for 18 F-FDOPA and three mice for 18 F-FTYR. Organ harvesting was performed at 2, 5, 10, 30, 60 and 120 min post tracer injection with n?=?5 at each time point for 18 F-FDOPA and n?=?3 at each time point for 18 F-FTYR. Human radiation dosimetry projected from animal data was calculated for the three different approaches for each tracer using OLINDA/EXM. S-factors for the MOBY phantom were used to calculate the animal dosimetry.

Results

Correlations between dose estimates based on organ harvesting and imaging was improved from r?=?0.997 to r?=?0.999 for 18 F-FDOPA and from r?=?0.985 to r?=?0.996 (p?<?0.0001 for all) for 18 F-FTYR by using hybrid imaging.

Conclusion

Hybrid imaging yields comparable results to traditional organ harvesting while partially overcoming the limitations of pure imaging. It is an advantageous technique in terms of number of animals needed and labour involved.     

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.     

PET Imaging of l-Type Amino Acid Transporter (LAT1) and Cystine-Glutamate Antiporter (xc−) with [18F]FDOPA and [18F]FSPG in Breast Cancer Models

Molecular Imaging and Biology - The present study describes the analysis of amino acid transporters ASCT1, ASCT2, LAT1, and xc? in breast cancer under normoxic and hypoxic conditions....     

Relationship Between Tumor Immune Markers and Fluorine-18-α-Methyltyrosine ([18F]FAMT) Uptake in Patients with Lung Cancer

Molecular Imaging and Biology - 3-[18F]Fluoro-α-methyl-L-tyrosine ([18F]FAMT) is an amino acid positron emission tomography (PET) tracer specific for cancer detection by assessment of tumor...     

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

Molecular Imaging and Biology - To assess tumor cell proliferation and repopulation during fractionated radiotherapy and investigate the spatial concordance of cell proliferation and repopulation...