-
Journal of Nuclear Medicine : Official... Aug 2012(18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have...
UNLABELLED
(18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have demonstrated conclusive superiority. The aim of this study was to compare the intratumoral accumulation of (18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole and relate this to specific components of the tumor microenvironment in mouse models of human non-small cell lung cancer (NSCLC).
METHODS
We used NSCLC A549 and HTB177 cells to generate subcutaneous and peritoneal xenografts in nude mice. Animals were coinjected with a PET radiotracer, pimonidazole (hypoxia marker), and bromodeoxyuridine (proliferation marker) intravenously 1 h before animal euthanasia. Tumor perfusion was assessed by Hoechst 33342 injection, given 1 min before sacrifice. The intratumoral distribution of PET radiotracers was visualized by digital autoradiography and related to microscopic visualization of proliferation, hypoxia, perfusion, stroma, and necrosis.
RESULTS
NSCLC xenografts had complex structures with intermingled regions of viable cancer cells, stroma, and necrosis. Cancer cells were either well oxygenated (staining negatively for pimonidazole) and highly proliferative (staining positively for bromodeoxyuridine) or hypoxic (pimonidazole-positive) and noncycling (little bromodeoxyuridine). Hypoxic cancer cells with a low proliferation rate had high(18)F-FDG and (18)F-misonidazole uptake but low (18)F-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of (18)F-fluorothymidine but low (18)F-FDG and(18)F-misonidazole. Tumor stroma and necrotic zones were always associated with low (18)F-FDG, (18)F-misonidazole, and (18)F-fluorothymidine activity.
CONCLUSION
In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, (18)F-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas (18)F-misonidazole and (18)F-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. (18)F-FDG and (18)F-misonidazole display similar intratumoral distribution patterns, and both mutually exclude (18)F-fluorothymidine.
Topics: Animals; Biological Transport; Bromodeoxyuridine; Carcinoma, Non-Small-Cell Lung; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Dideoxynucleosides; Disease Models, Animal; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Mice; Misonidazole; Necrosis; Nitroimidazoles; Pilot Projects; Positron-Emission Tomography; Radioactive Tracers; Tumor Microenvironment
PubMed: 22717978
DOI: 10.2967/jnumed.111.098087 -
Physics in Medicine and Biology Dec 2016Positron emission tomography (PET) using F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy...
Positron emission tomography (PET) using F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ([Formula: see text]) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 μm versus ∼4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (∼20 min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of [Formula: see text] and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local [Formula: see text] of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue [Formula: see text] : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at ∼5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing [Formula: see text] and necrotic fraction, but simulated TACs indicate that additional early-phase information may allow discrimination of hypoxic and necrotic signals. We conclude that a robust approach to FMISO interpretation (and dose-painting prescription) is likely to be based on dynamic PET analysis.
Topics: Computer Simulation; Humans; Hypoxia; Misonidazole; Models, Theoretical; Necrosis; Neoplasms; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Spheroids, Cellular
PubMed: 27880734
DOI: 10.1088/1361-6560/61/24/8596 -
Nuclear Medicine Review. Central &... 2011During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by... (Comparative Study)
Comparative Study Review
During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.
Topics: Cell Hypoxia; Coordination Complexes; Copper Radioisotopes; Humans; Misonidazole; Neoplasms; Organometallic Compounds; Positron-Emission Tomography; Radiation-Sensitizing Agents; Thiosemicarbazones
PubMed: 22219149
DOI: 10.5603/nmr.2011.00022 -
Journal of Nuclear Medicine : Official... Oct 2021Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to...
Simultaneous Mapping of Vasculature, Hypoxia, and Proliferation Using Dynamic Susceptibility Contrast MRI, F-FMISO PET, and F-FLT PET in Relation to Contrast Enhancement in Newly Diagnosed Glioblastoma.
Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of F-3'-deoxy-3'-F-fluorothymidine (F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of F-fluoromisonidazole (F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Dynamic susceptibility contrast-enhanced MRI (31 patients), F-FLT PET (20 patients), or F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%-155.5%, 1.5%-89.5%, and 3.1%-78.0% for F-FLT, rCBV, and F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.
Topics: Adult; Glioblastoma; Humans; Middle Aged; Misonidazole; Positron-Emission Tomography
PubMed: 34016725
DOI: 10.2967/jnumed.120.249524 -
International Journal of Oncology Mar 2013Accurate imaging to identify hypoxic regions in tumors is key for radiotherapy planning. [F-18]‑fluoro-misonidazole ([F-18]-FMISO) is widely used for tumor hypoxia...
Accurate imaging to identify hypoxic regions in tumors is key for radiotherapy planning. [F-18]‑fluoro-misonidazole ([F-18]-FMISO) is widely used for tumor hypoxia imaging and has the potential to optimize radiotherapy planning. However, the biological characteristics of intratumoral [F-18]-FMISO distribution have not yet been fully investigated. In hypoxic cells, the hypoxia-inducible factor-1 (HIF-1) target proteins that induce cellular proliferation and glucose metabolism, glucose transporter-1 (Glut-1) and hexokinase-II (HK-II), are upregulated. In this study, we determined the intratumoral distribution of [F-18]-FMISO by autoradiography (ARG) and compared it with pimonidazole uptake, expression of Glut-1, tumor proliferative activity (Ki-67 index) and glucose metabolism ([C-14]2-fluoro-2-deoxy-D-glucose uptake; [C-14]-FDG) in a glioma rat model. Five C6 glioma‑bearing rats were injected with [F-18]-FMISO and [C-14]-FDG. After 90 min, the rats were injected with pimonidazole and 60 min later, the rats were sacrificed and tumor tissues were sectioned into slices. The adjacent slices were used for ARG and immunohistochemical (IHC) analyses of pimonidazole, Glut-1 and Ki-67. [F-18]-FMISO ARG images were divided into regions of high [F-18]-FMISO uptake (FMISO+) and low [F-18]-FMISO uptake (FMISO-). Pimonidazole and Glut-1 expression levels, Ki-67 index and [C-14]-FDG distribution were evaluated in the regions of interest (ROIs) placed on FMISO+ and FMISO-. [F-18]-FMISO distribution was generally consistent with pimonidazole distribution. The percentage of positively stained areas (% positive) of Glut-1 in FMISO+ was significantly higher compared to FMISO- (24 ± 8% in FMISO+ and 9 ± 4% in FMISO-; P<0.05). There were no significant differences in Ki-67 index and [C-14]-FDG uptake between FMISO+ and FMISO- (for Ki-67, 10 ± 5% in FMISO+ and 12 ± 5% in FMISO-, P=ns; for [C-14]-FDG, 1.4 ± 0.3% ID/g/kg in FMISO+ and 1.3 ± 0.3% ID/g/kg in FMISO-, P = ns). Intratumoral [F-18]-FMISO distribution reflected tumor hypoxia and expression of the hypoxia‑related gene product Glut-1; it did not, however, reflect tumor proliferation or glucose metabolism. Our findings help elucidate the biological characteristics of intratumoral [F-18]-FMISO distribution that are relevant to radiotherapy planning.
Topics: Animals; Autoradiography; Biological Transport; Brain Neoplasms; Cell Hypoxia; Cell Proliferation; Fluorodeoxyglucose F18; Glioma; Glucose; Glucose Transporter Type 1; Hexokinase; Hypoxia-Inducible Factor 1; Ki-67 Antigen; Male; Misonidazole; Nitroimidazoles; Rats; Rats, Wistar; Tissue Distribution
PubMed: 23338175
DOI: 10.3892/ijo.2013.1781 -
Cancer Imaging : the Official... Oct 2006Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour progression. Tumour hypoxia can... (Review)
Review
Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour progression. Tumour hypoxia can be detected by non-invasive and invasive techniques but the inter-relationships between these remains largely undefined. [18F]Fluoromisonidazole-3-fluoro-1-(2'-nitro-1'-imidazolyl)-2-propanol ([18F]MISO) and Cu-diacetyl-bis(N4-methylthiosemicarbazone (Cu-ATSM)-positron emission tomography (PET), and blood oxygen level-dependent (BOLD)-magnetic resonance imaging (MRI) are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability; PET techniques are the primary focus of this review.
Topics: Cell Hypoxia; Coordination Complexes; Humans; Magnetic Resonance Imaging; Misonidazole; Neoplasms; Organometallic Compounds; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Thiosemicarbazones
PubMed: 17114063
DOI: 10.1102/1470-7330.2006.9018 -
Radiology. Imaging Cancer Mar 2021To enhance the spatial accuracy of fluorine 18 (F) misonidazole (MISO) PET imaging of hypoxia by using dynamic contrast-enhanced (DCE) MR images as a basis for modifying...
Improving Tumor Hypoxia Location in F-Misonidazole PET with Dynamic Contrast-enhanced MRI Using Quantitative Electron Paramagnetic Resonance Partial Oxygen Pressure Images.
PURPOSE
To enhance the spatial accuracy of fluorine 18 (F) misonidazole (MISO) PET imaging of hypoxia by using dynamic contrast-enhanced (DCE) MR images as a basis for modifying PET images and by using electron paramagnetic resonance (EPR) partial oxygen pressure (pO) as the reference standard.
MATERIALS AND METHODS
Mice ( = 10) with leg-borne MCa4 mammary carcinomas underwent EPR imaging, T2-weighted and DCE MRI, and F-MISO PET/CT. Images were registered to the same space for analysis. The thresholds of hypoxia for PET and EPR images were tumor-to-muscle ratios greater than or equal to 2.2 mm Hg and less than or equal to 14 mm Hg, respectively. The Dice similarity coefficient (DSC) and Hausdorff distance (d ) were used to quantify the three-dimensional overlap of hypoxia between pO EPR and F-MISO PET images. A training subset ( = 6) was used to calculate optimal DCE MRI weighting coefficients to relate EPR to the PET signal; the group average weights were then applied to all tumors (from six training mice and four test mice). The DSC and d were calculated before and after DCE MRI-corrected PET images were obtained to quantify the improvement in overlap with EPR pO images for measuring tumor hypoxia.
RESULTS
The means and standard deviations of the DSC and d between hypoxic regions in original PET and EPR images were 0.35 mm ± 0.23 and 5.70 mm ± 1.7, respectively, for images of all 10 mice. After implementing a preliminary DCE MRI correction to PET data, the DSC increased to 0.86 mm ± 0.18 and the d decreased to 2.29 mm ± 0.70, showing significant improvement ( < .001) for images of all 10 mice. Specifically, for images of the four independent test mice, the DSC improved with correction from 0.19 ± 0.28 to 0.80 ± 0.29 ( = .02), and the d improved from 6.40 mm ± 2.5 to 1.95 mm ± 0.63 ( = .01).
CONCLUSION
Using EPR information as a reference standard, DCE MRI information can be used to correct F-MISO PET information to more accurately reflect areas of hypoxia. Animal Studies, Molecular Imaging, Molecular Imaging-Cancer, PET/CT, MR-Dynamic Contrast Enhanced, MR-Imaging, PET/MR, Breast, Oncology, Tumor Mircoenvironment, Electron Paramagnetic Resonance© RSNA, 2021.
Topics: Animals; Electron Spin Resonance Spectroscopy; Hypoxia; Magnetic Resonance Imaging; Mice; Misonidazole; Oxygen; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Tumor Hypoxia
PubMed: 33817651
DOI: 10.1148/rycan.2021200104 -
British Journal of Cancer Mar 1981The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in...
The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in gassed spinner flasks has been investigated. Flagyl (5 mM) was only cytotoxic at high initial cell densities. However, when lactate (20 mM) was included in the medium the cytotoxicity of Flagyl at low cell densities was considerable, and similar to that of misonidazole under the same conditions. The relevance of this "lactate effect" to in vivo systems, and the possible mechanisms involved, are discussed.
Topics: Animals; Cell Survival; Cells, Cultured; Cricetinae; Cricetulus; Drug Synergism; Female; Lactates; Metronidazole; Misonidazole; Nitroimidazoles; Ovary
PubMed: 7225286
DOI: 10.1038/bjc.1981.55 -
Journal of Nuclear Medicine : Official... Jul 2017Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric...
Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric imaging of tumor hypoxia and perfusion with F-fluoromisonidazole (F-FMISO) dynamic PET (dPET) in head and neck cancer. One hundred twenty head and neck cancer patients underwent 0- to 30-min F-FMISO dPET in a customized immobilization mask, followed by 10-min static acquisitions starting at 93 ± 6 and 160 ± 13 min after injection. A total of 248 lesions (≥2 cm) were analyzed. Voxelwise pharmacokinetic modeling was conducted using an irreversible 1-plasma 2-tissue-compartment model to calculate surrogate biomarkers of tumor hypoxia (), perfusion (), and F-FMISO distribution volume. The analysis was repeated with truncated dPET datasets. Substantial inter- and intratumor heterogeneity was observed for all investigated metrics. Equilibration between the blood and unbound F-FMISO was rapid in all tumors. F-FMISO distribution volume deviated from the expected value of unity, causing discrepancy between maps and total F-FMISO uptake and reducing the dynamic range of total F-FMISO uptake for quantifying the degree of hypoxia. Both positive and negative trends between hypoxia and perfusion were observed in individual lesions. All investigated metrics were reproducible when calculated from a truncated 20-min dataset. F-FMISO dPET provides the data necessary to generate parametric maps of tumor hypoxia, perfusion, and radiotracer distribution volume. These data clarify the ambiguity in interpreting F-FMISO uptake and improve the characterization of lesions. We show total acquisition times can be reduced to 20 min, facilitating the translation of F-FMISO dPET into the clinic.
Topics: Adult; Aged; Aged, 80 and over; Female; Head and Neck Neoplasms; Humans; Image Interpretation, Computer-Assisted; Male; Middle Aged; Misonidazole; Multimodal Imaging; Neovascularization, Pathologic; Observer Variation; Oxygen; Perfusion Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Tumor Hypoxia
PubMed: 28183993
DOI: 10.2967/jnumed.116.188649 -
Journal of Nuclear Medicine : Official... Mar 2013Although endocrine therapy is an effective method to treat estrogen receptor (ER)-positive breast cancer, approximately 30%-40% of all hormone receptor-positive tumors...
UNLABELLED
Although endocrine therapy is an effective method to treat estrogen receptor (ER)-positive breast cancer, approximately 30%-40% of all hormone receptor-positive tumors display de novo resistance. The aim of our current study was to analyze whether (18)F-labeled fluoromisonidazole (1-(2-nitro-1-imidazolyl)-2-hydroxy-3-fluoropropane [(18)F-FMISO]) PET/CT could predict primary resistance to hormonal therapy in ER-positive breast cancer.
METHODS
Postmenopausal women who had ER-α-positive breast cancer, stages II-IV, and had never received prior endocrine therapy were prospectively enrolled in this study. Patients underwent both (18)F-FDG and (18)F-FMISO PET/CT scans before and after treatment. The hottest (18)F-FDG standardized uptake value (SUV) in the tumor foci, the SUVs at 2 and 4 h, and the TBR2 h and TBR4 h for the target lesions were calculated (TBR2 h = SUV2 hT/SUV2 hB and TBR4 h = SUV4 hT/SUV4 hB [TBR is the tumor-to-background ratio]). Clinical outcomes of primary endocrine therapy with letrozole were evaluated according to the criteria of the World Health Organization after at least 3 mo of treatment. Immunohistochemistry for markers of proliferation (Ki67) and hypoxia-induced factor 1α was performed on a subset of tumors that had undergone biopsy or surgery. Pearson and Spearman analysis was used to determine the correlation between the parameters of (18)F-FDG and (18)F-FMISO uptake and clinical or immunohistochemistry outcomes with a 0.01 threshold for statistical significance.
RESULTS
A total of 45 lesions (13 primary, 32 metastatic) from 20 patients met the inclusion criteria in this study. Baseline (18)F-FDG and (18)F-FMISO PET/CT scans were obtained for 33 lesions from 16 patients. The correlation between baseline (18)F-FDG uptake and clinical outcome was weak and did not reach statistical significance (r = 0.37, P = 0.031). However, there was a significantly positive correlation between baseline (18)F-FMISO uptake (SUV2 hT, TBR2 h, SUV4 hT, and TBR4 h) and clinical outcomes after ≥3 mo of primary endocrine therapy with letrozole (r = 0.77, 0.76, 0.71, and 0.78, respectively; P < 0.0001). The application of a TBR4 h cutoff of ≥1.2 allowed the prediction of 88% of the cases of progressive disease (15/17). Despite poor correlation between (18)F-FMISO uptake and hypoxia-induced factor 1α expression, a marginal positive correlation between TBR4 h and Ki67 expression was measured (r = 0.51, P = 0.011) in a subset of malignant lesions acquired by biopsy or surgery.
CONCLUSION
(18)F-FMISO PET/CT can be used to predict primary endocrine resistance in ER-positive breast cancer.
Topics: Aged; Aged, 80 and over; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Ki-67 Antigen; Letrozole; Middle Aged; Misonidazole; Multimodal Imaging; Neoplasms, Hormone-Dependent; Nitriles; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed; Triazoles
PubMed: 23401605
DOI: 10.2967/jnumed.112.111963