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American Journal of Nuclear Medicine... 2013The objective of this study was to determine whether (18)F-misonidazole could detect hypoxia in macroscopic and microscopic tumors in mice. In nude mice, subcutaneous...
(18)F-misonidazole PET imaging of hypoxia in micrometastases and macroscopic xenografts of human non-small cell lung cancer: a correlation with autoradiography and histological findings.
The objective of this study was to determine whether (18)F-misonidazole could detect hypoxia in macroscopic and microscopic tumors in mice. In nude mice, subcutaneous xenografts and peritoneal metastases were generated utilizing human non-small cell lung cancer A549 and HTB177 cells. Animals were co-injected with (18)F-misonidazole, pimonidazole and bromodeoxyuridine, and tumor perfusion was assessed by Hoechst 33342 injection. The intratumoral distribution of (18)F-misonidazole was determined by micro-PET scan and autoradiography. Pimonidazole, bromodeoxyuridine and Hoechst 33342 were detected by immunohistochemistry on the autoradiography sections. Submillimeter micrometastases found to be severely hypoxic. In both peritoneal metastases and subcutaneous xenografts models, PET images displayed significant (18)F-misonidazole uptake, and its distribution was non-uniform in these macroscopic subcutaneous tumors. In frozen sections, digital autoradiography and immunohistochemistry revealed similar distributions of (18)F-misonidazole, pimonidazole and glucose transporter-1, in both microscopic and macroscopic tumors. Bromodeoxyuridine stained-positive proliferative regions were well perfused, as judged by Hoechst 33342, and displayed low (18)F-misonidazole accumulation. (18)F-misonidazole uptake was low in tumor stroma and necrotic zones as well. Microscopic non-small cell lung cancer metastases are severely hypoxic. (18)F-misonidazole PET is capable to image hypoxia noninvasively not only in macroscopic tumors but also in micrometastases growing in mice. Accordingly, (18)F-misonidazole may be a promising agent to detect the burden of micrometastatic diseases.
PubMed: 23526377
DOI: No ID Found -
European Journal of Nuclear Medicine... Aug 2023Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic...
PURPOSE
Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic resonance imaging (MRI) are established prognostic imaging modalities to identify radiation resistance in head-and-neck cancer (HNC). The aim of this preclinical study was to develop a multi-parametric imaging parameter specifically for focal radiotherapy (RT) dose escalation using HNC xenografts of different radiation sensitivities.
METHODS
A total of eight human HNC xenograft models were implanted into 68 immunodeficient mice. Combined PET/MRI using dynamic [18F]-fluoromisonidazole (FMISO) hypoxia PET, diffusion-weighted (DW), and dynamic contrast-enhanced MRI was carried out before and after fractionated RT (10 × 2 Gy). Imaging data were analyzed on voxel-basis using principal component (PC) analysis for dynamic data and apparent diffusion coefficients (ADCs) for DW-MRI. A data- and hypothesis-driven machine learning model was trained to identify clusters of high-risk subvolumes (HRSs) from multi-dimensional (1-5D) pre-clinical imaging data before and after RT. The stratification potential of each 1D to 5D model with respect to radiation sensitivity was evaluated using Cohen's d-score and compared to classical features such as mean/peak/maximum standardized uptake values (SUV) and tumor-to-muscle-ratios (TMR) as well as minimum/valley/maximum/mean ADC.
RESULTS
Complete 5D imaging data were available for 42 animals. The final preclinical model for HRS identification at baseline yielding the highest stratification potential was defined in 3D imaging space based on ADC and two FMISO PCs ([Formula: see text]). In 1D imaging space, only clusters of ADC revealed significant stratification potential ([Formula: see text]). Among all classical features, only ADC showed significant correlation to radiation resistance ([Formula: see text]). After 2 weeks of RT, FMISO_c1 showed significant correlation to radiation resistance ([Formula: see text]).
CONCLUSION
A quantitative imaging metric was described in a preclinical study indicating that radiation-resistant subvolumes in HNC may be detected by clusters of ADC and FMISO using combined PET/MRI which are potential targets for future functional image-guided RT dose-painting approaches and require clinical validation.
Topics: Humans; Animals; Mice; Diffusion Magnetic Resonance Imaging; Positron-Emission Tomography; Misonidazole; Magnetic Resonance Imaging; Head and Neck Neoplasms; Hypoxia; Radiopharmaceuticals
PubMed: 37148296
DOI: 10.1007/s00259-023-06254-9 -
Frontiers in Chemistry 2019Photoionization mass spectrometry, photoelectron-photoion coincidence spectroscopic technique, and computational methods have been combined to investigate the...
Photoionization mass spectrometry, photoelectron-photoion coincidence spectroscopic technique, and computational methods have been combined to investigate the fragmentation of two nitroimidazole derived compounds: the metronidazole and misonidazole. These molecules are used in radiotherapy thanks to their capability to sensitize hypoxic tumor cells to radiation by "mimicking" the effects of the presence of oxygen as a damaging agent. Previous investigations of the fragmentation patterns of the nitroimidazole isomers (Bolognesi et al., 2016; Cartoni et al., 2018) have shown their capacity to produce reactive molecular species such as nitric oxide, carbon monoxide or hydrogen cyanide, and their potential impact on the biological system. The results of the present work suggest that different mechanisms are active for the more complex metronidazole and misonidazole molecules. The release of nitric oxide is hampered by the efficient formation of nitrous acid or nitrogen dioxide. Although both metronidazole and misonidazole contain imidazole ring in the backbone, the side branches of these molecules lead to very different bonding mechanisms and properties.
PubMed: 31157205
DOI: 10.3389/fchem.2019.00329 -
European Journal of Nuclear Medicine... Apr 2017Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose...
PURPOSE
Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients.
EXPERIMENTAL DESIGN
Glioblastoma patients (n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV × FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis.
RESULTS
All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS (p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS (p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV, patients' age, or Karnofsky performance scale (KPS) was significantly correlated with PSF or OS. The hMTV and hTLG were found to be independent factors affecting PFS and OS on multivariate analysis.
CONCLUSIONS
We introduced hMTV and hTLG using FDG and FMISO PET to define metabolically active hypoxic volume. Univariate and multivariate analyses demonstrated that both hMTV and hTLG are significant predictors for PFS and OS in glioblastoma patients.
Topics: Adult; Aged; Blood Glucose; Brain Neoplasms; Cell Hypoxia; Female; Fluorodeoxyglucose F18; Glioblastoma; Glycolysis; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Misonidazole; Oxygen; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals
PubMed: 27752745
DOI: 10.1007/s00259-016-3541-z -
Seminars in Nuclear Medicine Mar 2015Hypoxia in solid tumors is one of the seminal mechanisms for developing aggressive trait and treatment resistance in solid tumors. This evolutionarily conserved... (Review)
Review
Hypoxia in solid tumors is one of the seminal mechanisms for developing aggressive trait and treatment resistance in solid tumors. This evolutionarily conserved biological mechanism along with derepression of cellular functions in cancer, although resulting in many challenges, provide us with opportunities to use these adversities to our advantage. Our ability to use molecular imaging to characterize therapeutic targets such as hypoxia and apply this information for therapeutic interventions is growing rapidly. Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. Fluoromisonidazole (FMISO) continues to be the lead radiopharmaceutical in PET imaging for the evaluation, prognostication, and quantification of tumor hypoxia, one of the key elements of the tumor microenvironment. FMISO is less confounded by blood flow, and although the images have less contrast than FDG-PET, its uptake after 2 hours is an accurate reflection of inadequate regional oxygen partial pressure at the time of radiopharmaceutical administration. By virtue of extensive clinical utilization, FMISO remains the lead candidate for imaging and quantifying hypoxia. The past decade has seen significant technological advances in investigating hypoxia imaging in radiation treatment planning and in providing us with the ability to individualize radiation delivery and target volume coverage. The presence of widespread hypoxia in the tumor can be effectively targeted with a systemic hypoxic cell cytotoxin or other agents that are more effective with diminished oxygen partial pressure, either alone or in combination. Molecular imaging in general and hypoxia imaging in particular will likely become an important in vivo imaging biomarker of the future, complementing the traditional direct tissue sampling methods by providing a snap shot of a primary tumor and metastatic disease and in following treatment response and will serve as adjuncts to personalized therapy.
Topics: Animals; Cell Hypoxia; Humans; Misonidazole; Molecular Imaging; Neoplasms; Precision Medicine; Tumor Microenvironment
PubMed: 25704387
DOI: 10.1053/j.semnuclmed.2014.10.006 -
Yakugaku Zasshi : Journal of the... 2018Hypoxia in tumor tissues plays a pivotal role in tumor progression and angiogenesis, and is associated with cancer therapeutic resistance. For the diagnosis of hypoxia,... (Review)
Review
Hypoxia in tumor tissues plays a pivotal role in tumor progression and angiogenesis, and is associated with cancer therapeutic resistance. For the diagnosis of hypoxia, non-invasive imaging techniques, especially positron emission tomography (PET) with 2-nitroimidazole-based probes, are used, since 2-nitroimidazole-based probes are considered to undergo reductive metabolism on their 2-nitroimidazole moiety and become trapped in hypoxic cells. However, the detailed mechanism of their accumulation remains unclear because of the difficulty in estimating the metabolites by radioisotopic analysis. Imaging mass spectrometry (IMS) can distinguish the distribution patterns of the drug and its metabolites. To clarify the accumulation mechanism of 2-nitroimidazole-based probes in hypoxic cells, we evaluated [F]fluoromisonidazole (FMISO), a 2-nitroimidazole-based PET probe, in combination with radioisotopic analysis and IMS. We found that the glutathione conjugate of reduced FMISO (amino-FMISO-GS) was the main FMISO metabolite, and was specifically distributed in the hypoxic regions of tumors. The same phenomenon was observed when we examined another 2-nitroimidazole-based probe, pimonidazole. The in vitro cellular uptake study revealed that FMISO accumulation in hypoxic cells depends on the cell type. In those cells exhibiting higher FMISO uptake, the reactive glutathione level and enzyme (glutathione S-transferase; GST) activity catalyzing the glutathione conjugation reaction was significantly higher, whereas the expression level of the efflux transporter (multidrug resistance-associated protein 1; MRP1) was significantly lower. Our study suggests that 2-nitroimidazole-based probes accumulate in hypoxic cells via glutathione conjugation following reductive metabolism, which depends not only on the glutathione conjugation capacity of the cells but also on hypoxic conditions.
Topics: Animals; Glutathione; Glutathione Transferase; Humans; Hypoxia; Mass Spectrometry; Mice; Misonidazole; Molecular Imaging; Molecular Probes; Multidrug Resistance-Associated Proteins; Neoplasms; Nitroimidazoles; Positron-Emission Tomography
PubMed: 30381642
DOI: 10.1248/yakushi.18-00146 -
Scientific Reports Dec 2022Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is...
Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PET/CT images acquired at baseline and pre-surgery visits (n = 58) were compared. Cohort 1 (n = 14) received atovaquone treatment, while cohort 2 (n = 15) did not. Spearman's rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n = 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV ρ = 0.87, SUV ρ = 0.91, TBR ρ = 0.83 and TBR ρ = 0.81 between 2- and 4-h scans. Tumour HV was moderately correlated (P < 0.001) with ρ = 0.69 between 2- and 4-h scans. Yet, in tumour subregions, the correlation of HV decreased from the centre ρ = 0.71 to the edge ρ = 0.45 (P < 0.001). SUV, TBR, and HV values were consistently higher on 4-h scans than on 2-h scans, indicating better tracer-to-background contrast. For instance, for TBR, the mean, median, and interquartile range were 1.9, 1.7, and 1.6-2.0 2-h p.i., and 2.6, 2.4, and 2.0-3.0 4-h p.i., respectively. Our results support that FMISO-PET scans should be performed at 4 h p.i. to evaluate tumour hypoxia in NSCLC.Trial registration: ClinicalTrials.gov, NCT02628080. Registered 11/12/2015, https://clinicaltrials.gov/ct2/show/NCT02628080 .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Positron Emission Tomography Computed Tomography; Atovaquone; Radiopharmaceuticals; Lung Neoplasms; Misonidazole; Positron-Emission Tomography; Hypoxia; Cell Hypoxia
PubMed: 36526815
DOI: 10.1038/s41598-022-26199-7 -
Scientific Reports Apr 2021Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide...
Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (r = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (r = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
Topics: Adult; Aged; Bevacizumab; Biomarkers, Pharmacological; Brain Neoplasms; Cerebral Blood Volume; Drug Resistance, Neoplasm; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Misonidazole; Neoplasm Recurrence, Local; Positron-Emission Tomography; Progression-Free Survival; Tumor Hypoxia; Young Adult
PubMed: 33828310
DOI: 10.1038/s41598-021-84331-5 -
European Journal of Nuclear Medicine... Oct 2022To identify the optimal threshold in F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO...
The optimal F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO electron paramagnetic resonance imaging as reference truth.
PURPOSE
To identify the optimal threshold in F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO EPRI) as ground truth for hypoxia, defined by pO [Formula: see text] 10 mmHg.
METHODS
Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of K and v were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO EPRI.
RESULTS
FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUV and SUV [Formula: see text] 0.6 [Formula: see text] SUV. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (K) or fractional extracellular-extravascular space (v) from DCE-MRI.
CONCLUSION
This is the first in vivo comparison of FMISO uptake with pO EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.
Topics: Animals; Carcinoma, Squamous Cell; Cell Hypoxia; Electron Spin Resonance Spectroscopy; Hypoxia; Mice; Misonidazole; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed; Tumor Hypoxia
PubMed: 35792927
DOI: 10.1007/s00259-022-05889-4 -
British Journal of Cancer Jan 1980Both misonidazole (MISO) and hyperthermia are known to enhance the radiation response of hypoxic cells, and to be selectively cytotoxic against cells in a hypoxic and...
Both misonidazole (MISO) and hyperthermia are known to enhance the radiation response of hypoxic cells, and to be selectively cytotoxic against cells in a hypoxic and acidic environment. The ability of these conditions to modify the effect of irradiation and their individual relationship was studied in a C3H mammary carcinoma and its surrounding skin. Simultaneous treatment with MISO, hyperthermia and radiation increased the radiation effect, with enhancement ratios (ER) of up to about 15 (1 mg/g MISO and 43.5 degrees C for 60 min.). However, such treatment also caused a smaller hyperthermic radiosensitization of the normal tissue, so that the therapeutic ratio was only increased by a factor of about 3 compared to radiation alone. Simultaneous MISO and radiation followed by hyperthermia 4 h later gave a moderate enhancement, with ER up to 3 in the tumour, but with no enhancement of the normal tissue, so that there is a similar 3-fold increase in therapeutic gain. The mechanism by which MISO and hyperthermia enhanced the radiation response may be explained as an independent action of the hypoxic radiosensitization of MISO and the selective hyperthermic cytotoxicity against acidic and chronic hypoxic cells; simultaneous hyperthermia added a further heat-induced general radiosensitization. Surprisingly, no MISO cytotoxicity could be detected in this tumour system, with or without simultaneous hyperthermia. The results indicate that in the proper treatment schedule, MISO may be a valuable addition to a combined hyperthermia and radiation treatment.
Topics: Animals; Dose-Response Relationship, Drug; Female; Hot Temperature; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Misonidazole; Nitroimidazoles; Radiation Tolerance; Skin; Time Factors
PubMed: 7362770
DOI: 10.1038/bjc.1980.2