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Journal of Molecular and Cellular... Nov 2011Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac... (Review)
Review
Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at sub-pharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically.
Topics: Acidosis; Animals; Copper; Copper Radioisotopes; Coronary Artery Disease; Coronary Circulation; Humans; Hypoxia; Misonidazole; Myocardial Ischemia; Myocardium; Oxygen; Positron-Emission Tomography; Radiation-Sensitizing Agents; Rats; Reducing Agents; Sensitivity and Specificity; Thiosemicarbazones; Tissue Distribution
PubMed: 21781973
DOI: 10.1016/j.yjmcc.2011.07.005 -
SAGE Open Medicine 2020In this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed... (Review)
Review
INTRODUCTION
In this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed tomography.
METHODS
We conducted review of the current literature at PubMed/MEDLINE until February 2020. The search language was English.
RESULTS
The most widely used radiopharmaceuticals are the following:Experimental/pre-clinical approaches: (18)F-Misonidazole (18F-MISO) under clinical development, D(18)F-Fluoro-Methyl-Tyrosine (18F-FMT), 18F-FAMT (L-[3-18F] (18)F-Fluorothymidine (18F-FLT)), (18)F-Fluoro-Azomycin-Arabinoside (18F-FAZA), (68)Ga-Neomannosylated-Human-Serum-Albumin (68Ga-MSA) (23), (68)Ga-Tetraazacyclododecane (68Ga-DOTA) (as theranostic agent), (11)C-Methionine (11C-MET), 18F-FPDOPA, αβ integrin, Ga-RGD, Cu-DOTA-RGD, F-Alfatide, Folate Radio tracers, and immuno-positron emission tomography radiopharmaceutical agents.Clinically approved procedures/radiopharmaceuticals agents: (18)F-Fluoro-Deoxy-Glucose (18F-FDG), (18)F-sodium fluoride (18F-NaF) (bone metastases), and (68)Ga-Tetraazacyclododecane (68Ga-DOTA). The quantitative determination and the change in radiopharmaceutical uptake parameters such as standard uptake value, metabolic tumor volume, total lesion glycolysis, FAZA tumor to muscle ratio, standard uptake value tumor to liver ratio, standard uptake value tumor to spleen ratio, standard uptake value maximum ratio, and the degree of hypoxia have prognostic and predictive (concerning the therapeutic outcome) value. They have been associated with the assessment of overall survival and disease free survival. With the positron emission tomography/computed tomography radiopharmaceuticals, the sensitivity and the specificity of the method have increased.
CONCLUSION
In terms of lung cancer, positron emission tomography/computed tomography may have clinical application and utility (a) in personalizing treatment, (b) as a biomarker for the estimation of overall survival, disease free survival, and (c) apply a cost-effective patient approach because it reveals focuses of the disease, which are not found with the other imaging methods.
PubMed: 33062275
DOI: 10.1177/2050312120961594 -
Computational and Mathematical Methods... 2015The innovation of computational techniques serves as an important step toward optimized, patient-specific management of cancer. In particular, in silico simulation of... (Review)
Review
The innovation of computational techniques serves as an important step toward optimized, patient-specific management of cancer. In particular, in silico simulation of tumour growth and treatment response may eventually yield accurate information on disease progression, enhance the quality of cancer treatment, and explain why certain therapies are effective where others are not. In silico modelling is demonstrated to considerably benefit from information obtainable with PET and PET/CT. In particular, models have successfully integrated tumour glucose metabolism, cell proliferation, and cell oxygenation from multiple tracers in order to simulate tumour behaviour. With the development of novel radiotracers to image additional tumour phenomena, such as pH and gene expression, the value of PET and PET/CT data for use in tumour models will continue to grow. In this work, the use of PET and PET/CT information in in silico tumour models is reviewed. The various parameters that can be obtained using PET and PET/CT are detailed, as well as the radiotracers that may be used for this purpose, their utility, and limitations. The biophysical measures used to quantify PET and PET/CT data are also described. Finally, a list of in silico models that incorporate PET and/or PET/CT data is provided and reviewed.
Topics: Cell Proliferation; Coordination Complexes; Dideoxynucleosides; Diffusion; Fluorodeoxyglucose F18; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glucose; Humans; Hydrogen-Ion Concentration; Hypoxia; Misonidazole; Models, Theoretical; Multimodal Imaging; Neoplasms; Neovascularization, Pathologic; Organometallic Compounds; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Thiosemicarbazones; Tomography, X-Ray Computed
PubMed: 25788973
DOI: 10.1155/2015/415923 -
The British Journal of Radiology Feb 2020The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the...
OBJECTIVE
The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the predictive value of image-based factors for outcome in locally advanced head and neck cancers treated with chemoradiation.
METHODS
In the week prior to the treatment [F]-2-flu-2-deoxy-D-glucose (FDG), [F]-3'-flu-3'deoxythymidine (FLT) and [F]-flumisonidazole (FMISO) imaging was performed. FLT scans were repeated at 14 and 28 Gy and FMISO at 36 Gy. Overall survival, disease-free survival and local control were correlated with subvolume parameters, and with tumour-to-muscle ratio for FMISO. For every tracer, total metabolic tumour volume was calculated.
RESULTS
33 patients were included. No correlation was found between pre-treatment maximum standardised uptake value for FDG, FLT, FMISO and outcomes. Tumour volume measured on initial CT scans and initial FLT volume correlated with disease-free survivall ( = 0.007 and 0.04 respectively). FDG and FLT metabolic tumour volumes correlated significantly with local control ( = 0.005 and 0.02 respectively). In multivariate Cox analysis only individual initial TMRmax correlated with overall survival.
CONCLUSION
PET/CT imaging is a promising tool. However, various aspects of image analysis need further clinical validation in larger multicentre study employing uniform imaging protocol and standardisation, especially for hypoxia tracer.
ADVANCES IN KNOWLEDGE
Monitoring of biological features of the tumour using multitracer PET modality seems to be a feasible option in daily clinical practice.Evaluation of hypoxic subvolumes is more patient dependent; thus, exploration of individual parameters of hypoxia is needed. tumour-to-muscle ratio seems to be the most promising so far.
Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Chemoradiotherapy; Cisplatin; Dideoxynucleosides; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Misonidazole; Positron Emission Tomography Computed Tomography; Prospective Studies; Radiation-Sensitizing Agents; Treatment Outcome; Tumor Hypoxia
PubMed: 31860336
DOI: 10.1259/bjr.20180781 -
Theoretical Biology & Medical Modelling Oct 2007A new two-parameter probability distribution called hypertabastic is introduced to model the survival or time-to-event data. A simulation study was carried out to... (Comparative Study)
Comparative Study
A new two-parameter probability distribution called hypertabastic is introduced to model the survival or time-to-event data. A simulation study was carried out to evaluate the performance of the hypertabastic distribution in comparison with popular distributions. We then demonstrate the application of the hypertabastic survival model by applying it to data from two motivating studies. The first one demonstrates the proportional hazards version of the model by applying it to a data set from multiple myeloma study. The second one demonstrates an accelerated failure time version of the model by applying it to data from a randomized study of glioma patients who underwent radiotherapy treatment with and without radiosensitizer misonidazole. Based on the results from the simulation study and two applications, the proposed model shows to be a flexible and promising alternative to practitioners in this field.
Topics: Brain Neoplasms; Computer Simulation; Glioma; Humans; Multiple Myeloma; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 17963492
DOI: 10.1186/1742-4682-4-40 -
Radiation Research Feb 2007Hypoxic cells are common in tumors and contribute to malignant progression, distant metastasis and resistance to radiotherapy. It is well known that tumors are... (Review)
Review
Hypoxic cells are common in tumors and contribute to malignant progression, distant metastasis and resistance to radiotherapy. It is well known that tumors are heterogeneous with respect to the levels and duration of hypoxia. Several strategies, including high-oxygen-content gas breathing, radiosensitizers and hypoxic cytotoxins, have been developed to overcome hypoxia-mediated radioresistance. However, with these strategies, an increased tumor control rate is often accompanied by more severe side effects. Consequently, development of assays for prediction of tumor response and early monitoring of treatment responses could reduce both over- and undertreatment, thereby avoiding unnecessary side effects. The purpose of this review is to discuss different assays for measurement of hypoxia that can be used to detect changes in oxygen tension. The main focus is on exogenous bioreductive hypoxia markers (2-nitroimidazoles) such as pimonidazole, CCI-103F, EF5 and F-misonidazole. These are specifically reduced and bind to macromolecules in viable hypoxic cells. A number of these bioreductive drugs are approved for clinical use and can be detected with methods ranging from noninvasive PET imaging (low resolution) to microscopic imaging of tumor sections (high resolution). If the latter are stained for multiple markers, hypoxia can be analyzed in relation to different microenvironmental parameters such as vasculature, proliferation and endogenous hypoxia-related markers, for instance HIF1alpha and CA-IX. In addition, temporal and spatial changes in hypoxia can be analyzed by consecutive injection of two different hypoxia markers. Therefore, bioreductive exogenous hypoxia markers are promising as tools for development of predictive assays or as tools for early treatment monitoring and validation of potential endogenous hypoxia markers.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Mucoepidermoid; Carcinoma, Squamous Cell; Cell Line, Tumor; Head and Neck Neoplasms; Humans; Hypoxia; Mice; Neoplasm Metastasis; Neoplasms; Oxygen; Time Factors
PubMed: 17390721
DOI: 10.1667/rr0719.1 -
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 -
Neurologia Medico-chirurgica 2013Glioma is one of the most common brain tumors in adults. Its diagnosis and management have been determined by histological classifications. It is difficult to establish... (Review)
Review
Glioma is one of the most common brain tumors in adults. Its diagnosis and management have been determined by histological classifications. It is difficult to establish new paradigms because the pathology has matured and a great deal of knowledge has accumulated. On the other hand, we understand that there are limitations to this gold-standard because of the heterogeneity of glioma. Thus, it is necessary to find new criteria independent of conventional morphological diagnosis. Molecular imaging such as positron emission tomography (PET) is one of the most promising approaches to this challenge. PET provides live information of metabolism through the behavior of single molecules. The advantage of PET is that its noninvasive analysis does not require tissue sample, therefore examination can be performed repeatedly. This is very useful for capturing changes in the biological nature of tumor without biopsy. In the present clinical practice for glioma, (18)F-fluorodeoxyglucose (FDG) PET is the most common tracer for predicting prognosis and differentiating other malignant brain tumors. Amino acid tracers such as (11)C-methionine (MET) are the most useful for detecting distribution of glioma, including low-grade. Tracers to image hypoxia are under investigation for potential clinical use, and recently, (18)F-fluoromisonidazole (FMISO) has been suggested as an effective tracer to distinguish glioblastoma multiforme from others.
Topics: Adult; Animals; Brain Neoplasms; Diagnosis, Differential; Fluorine Radioisotopes; Glioblastoma; Glioma; Humans; Misonidazole; Oxygen; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Reproducibility of Results
PubMed: 24172591
DOI: 10.2176/nmc.ra2013-0256 -
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