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Journal of Nuclear Medicine : Official... Jul 2016Existing respiratory motion-correction methods are applied only to static PET imaging. We have previously developed an event-by-event respiratory motion-correction...
UNLABELLED
Existing respiratory motion-correction methods are applied only to static PET imaging. We have previously developed an event-by-event respiratory motion-correction method with correlations between internal organ motion and external respiratory signals (INTEX). This method is uniquely appropriate for dynamic imaging because it corrects motion for each time point. In this study, we applied INTEX to human dynamic PET studies with various tracers and investigated the impact on kinetic parameter estimation.
METHODS
The use of 3 tracers-a myocardial perfusion tracer, (82)Rb (n = 7); a pancreatic β-cell tracer, (18)F-FP(+)DTBZ (n = 4); and a tumor hypoxia tracer, (18)F-fluoromisonidazole ((18)F-FMISO) (n = 1)-was investigated in a study of 12 human subjects. Both rest and stress studies were performed for (82)Rb. The Anzai belt system was used to record respiratory motion. Three-dimensional internal organ motion in high temporal resolution was calculated by INTEX to guide event-by-event respiratory motion correction of target organs in each dynamic frame. Time-activity curves of regions of interest drawn based on end-expiration PET images were obtained. For (82)Rb studies, K1 was obtained with a 1-tissue model using a left-ventricle input function. Rest-stress myocardial blood flow (MBF) and coronary flow reserve (CFR) were determined. For (18)F-FP(+)DTBZ studies, the total volume of distribution was estimated with arterial input functions using the multilinear analysis 1 method. For the (18)F-FMISO study, the net uptake rate Ki was obtained with a 2-tissue irreversible model using a left-ventricle input function. All parameters were compared with the values derived without motion correction.
RESULTS
With INTEX, K1 and MBF increased by 10% ± 12% and 15% ± 19%, respectively, for (82)Rb stress studies. CFR increased by 19% ± 21%. For studies with motion amplitudes greater than 8 mm (n = 3), K1, MBF, and CFR increased by 20% ± 12%, 30% ± 20%, and 34% ± 23%, respectively. For (82)Rb rest studies, INTEX had minimal effect on parameter estimation. The total volume of distribution of (18)F-FP(+)DTBZ and Ki of (18)F-FMISO increased by 17% ± 6% and 20%, respectively.
CONCLUSION
Respiratory motion can have a substantial impact on dynamic PET in the thorax and abdomen. The INTEX method using continuous external motion data substantially changed parameters in kinetic modeling. More accurate estimation is expected with INTEX.
Topics: Adult; Aged; Coronary Circulation; Exercise Test; Female; Heart Diseases; Humans; Image Processing, Computer-Assisted; Insulin-Secreting Cells; Male; Misonidazole; Models, Statistical; Motion; Positron-Emission Tomography; Radiopharmaceuticals; Respiratory Mechanics; Rest; Rubidium Radioisotopes; Young Adult
PubMed: 26912437
DOI: 10.2967/jnumed.115.167676 -
European Journal of Nuclear Medicine... Sep 2021Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed...
[F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [F]FDG PET/CT approach.
PURPOSE
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [F]FDG.
METHODS
Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [F]FDG and [F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23.
RESULTS
We demonstrate that mean lung density on CT as well as [F]FDG and [F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [F]FDG and [F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy.
CONCLUSION
[F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
Topics: Animals; Biomarkers; Disease Progression; Fluorodeoxyglucose F18; Humans; Hypoxia; Idiopathic Pulmonary Fibrosis; Mice; Misonidazole; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 33580818
DOI: 10.1007/s00259-021-05209-2 -
Journal of Nuclear Medicine : Official... Jan 2009Glioblastoma multiforme is a primary brain tumor known for its rapid proliferation, diffuse invasion, and prominent neovasculature and necrosis. This study explores the...
UNLABELLED
Glioblastoma multiforme is a primary brain tumor known for its rapid proliferation, diffuse invasion, and prominent neovasculature and necrosis. This study explores the in vivo link between these characteristics and hypoxia by comparing the relative spatial geometry of developing vasculature inferred from gadolinium-enhanced T1-weighted MRI (T1Gd), edematous tumor extent revealed on T2-weighted MRI (T2), and hypoxia assessed by 18F-fluoromisonidazole PET (18F-FMISO). Given the role of hypoxia in upregulating angiogenic factors, we hypothesized that the distribution of hypoxia seen on 18F-FMISO is correlated spatially and quantitatively with the amount of leaky neovasculature seen on T1Gd.
METHODS
A total of 24 patients with glioblastoma underwent T1Gd, T2, and 18F-FMISO-11 studies preceded surgical resection or biopsy, 7 followed surgery and preceded radiation therapy, and 11 followed radiation therapy. Abnormal regions seen on the MRI scan were segmented, including the necrotic center (T0), the region of abnormal blood-brain barrier associated with disrupted vasculature (T1Gd), and infiltrating tumor cells and edema (T2). The 18F-FMISO images were scaled to the blood 18F-FMISO activity to create tumor-to-blood ratio (T/B) images. The hypoxic volume (HV) was defined as the region with T/Bs greater than 1.2, and the maximum T/B (T/Bmax) was determined by the voxel with the greatest T/B value.
RESULTS
The HV generally occupied a region straddling the outer edge of the T1Gd abnormality and into the T2. A significant correlation between HV and the volume of the T1Gd abnormality that relied on the existence of a large outlier was observed. However, there was consistent correlation between surface areas of all MRI-defined regions and the surface area of the HV. The T/Bmax, typically located within the T1Gd region, was independent of the MRI-defined tumor size. Univariate survival analysis found the most significant predictors of survival to be HV, surface area of HV, surface area of T1Gd, and T/Bmax.
CONCLUSION
Hypoxia may drive the peripheral growth of glioblastomas. This conclusion supports the spatial link between the volumes and surface areas of the hypoxic and MRI regions; the magnitude of hypoxia, T/Bmax, remains independent of size.
Topics: Adult; Aged; Female; Gadolinium; Glioblastoma; Humans; Hypoxia; Magnetic Resonance Imaging; Male; Middle Aged; Misonidazole; Neovascularization, Pathologic; Positron-Emission Tomography; Prognosis; Survival Analysis; Tumor Burden
PubMed: 19091885
DOI: 10.2967/jnumed.108.055467 -
Radiology. Imaging Cancer May 2022Purpose To determine the variance and correlation with tumor viability of fluorine 18 (F) fluoromisonidazole (FMISO) uptake in hepatocellular carcinoma (HCC) prior to...
Limitations of Fluorine 18 Fluoromisonidazole in Assessing Treatment-induced Tissue Hypoxia after Transcatheter Arterial Embolization of Hepatocellular Carcinoma: A Prospective Pilot Study.
Purpose To determine the variance and correlation with tumor viability of fluorine 18 (F) fluoromisonidazole (FMISO) uptake in hepatocellular carcinoma (HCC) prior to and after embolization treatment. Materials and Methods In this single-arm, single-center, prospective pilot study between September 2016 and March 2017, participants with at least one tumor measuring 1.5 cm or larger with imaging or histologic findings diagnostic for HCC were enrolled (five men; mean age, 68 years; age range, 61-76 years). Participants underwent F-FMISO PET/CT before and after bland embolization of HCC. A tumor-to-liver ratio (TLR) was calculated by using standardized uptake values of tumor and liver. The difference in mean TLR before and after treatment was compared by using a Wilcoxon rank sum test, and correlation between TLR and tumor viability was assessed by using the Spearman rank correlation coefficient. Results Four participants with five tumors were included in the final analysis. The median tumor diameter was 3.2 cm (IQR, 3.0-3.9 cm). The median TLR before treatment was 0.97 (IQR, 0.88-0.98), with a variance of 0.02, and the median TLR after treatment was 0.85 (IQR, 0.79-1), with a variance of 0.01; both findings indicate a narrow range of F-FMISO uptake in HCC. The Spearman rank correlation coefficient was 0.87, indicating a high correlation between change in TLR and nonviable tumor. Conclusion Although there was a correlation between change in TLR and response to treatment, the low signal-to-noise ratio of F-FMISO in the liver limited its use in HCC. Molecular Imaging-Clinical Translation, Embolization, Abdomen/Gastrointestinal, Liver Clinical trial registration no. NCT02695628 © RSNA, 2022.
Topics: Aged; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fluorine; Humans; Hypoxia; Liver Neoplasms; Male; Middle Aged; Misonidazole; Pilot Projects; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals
PubMed: 35485937
DOI: 10.1148/rycan.210094 -
British Journal of Cancer May 1984Detailed studies of the effects of misonidazole (MISO) on the pharmacokinetics of CCNU in the KHT tumour, bone marrow and the gut have been carried out in order to...
Detailed studies of the effects of misonidazole (MISO) on the pharmacokinetics of CCNU in the KHT tumour, bone marrow and the gut have been carried out in order to elucidate the mechanism of chemosensitisation by MISO, and the therapeutic gain often obtained due to the preferential enhancement of tumour toxicity. In experiments where CCNU concentration and growth delay were both measured in the same transplant group of tumours, we found that tumour response is well correlated with tumour peak CCNU concentration. Further, with MISO treatment the tumour peak CCNU concentration was increased such that the enhancement of tumour response can be entirely accounted for by this increase. The effects of MISO on the CCNU pharmacokinetics in bone marrow and in the gut were different from the tumour in that peak CCNU concentration was not increased. We suggest that this is the explanation for the therapeutic gain.
Topics: Animals; Bone Marrow; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Intestine, Small; Kinetics; Lomustine; Male; Mice; Mice, Inbred C3H; Misonidazole; Nitroimidazoles; Sarcoma, Experimental
PubMed: 6722006
DOI: 10.1038/bjc.1984.92 -
The British Journal of Cancer.... Jun 1978The yields of free radicals and of single strand breaks were studied quantitatively after gamma-irradiation at 77 K of solid calf thymus DNA without and with...
The yields of free radicals and of single strand breaks were studied quantitatively after gamma-irradiation at 77 K of solid calf thymus DNA without and with incorporated misonidazole. At 77 K the rate of formation of the free radicals (the nature of which had been previously elucidated in oriented DNA samples) was found to be 1.7 x 10 (-12) and 2.4 x 10 (-12) per rad per dalton for DNA without and with misonidazole, respectively. The corresponding yield of single strand breaks in samples thawed and dissolved before alkaline sucrose gradient ultracentrifugation was found to be 1.2 x 10(-13) per rad per dalton, not significantly (within 30%) different for DNA without and with misonidazole. The significant quantitative difference between induction of free radicals and single strand breaks shows that there is no simple relation between the appearance of the two types of lesions.
Topics: DNA; DNA, Single-Stranded; Free Radicals; Molecular Weight; Nitroimidazoles; Radiation-Sensitizing Agents
PubMed: 277257
DOI: No ID Found -
The Cochrane Database of Systematic... Apr 2006Treatment of cancer is increasingly more effective but is associated with short and long-term side effects. Oral side effects remain a major source of illness despite... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment of cancer is increasingly more effective but is associated with short and long-term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers).
OBJECTIVES
To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with other potentially active interventions, placebo or no treatment.
SEARCH STRATEGY
The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches: April 2004.
SELECTION CRITERIA
Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life.
DATA COLLECTION AND ANALYSIS
Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and risk ratios (RR) calculated using random-effects models.
MAIN RESULTS
Two hundred and two studies were eligible. One hundred and thirty two were excluded for various reasons, usually as there was no useable information on mucositis. Of the 71 useable studies all had data for mucositis comprising 5217 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, amifostine, antibiotic pastille or paste, benzydamine, beta carotene, calcium phosphate, camomile, chlorhexidine, clarithromycin, folinic acid, glutamine, GM-CSF, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole, oral care, pentoxifylline, povidone, prednisone, propantheline, prostaglandin, sucralfate, traumeel and zinc sulphate. Of the 29 interventions included in trials, 10 showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysis finding a significant difference when compared with a placebo or no treatment were: amifostine which provided minimal benefit in preventing moderate and severe mucositis RR = 0.84 (95% confidence interval (CI) 0.75 to 0.95) and 0.60 (95% CI 0.37 to 0.97), antibiotic paste or pastille demonstrated a moderate benefit in preventing mucositis RR = 0.87 (95% CI 0.79 to 0.97), hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52), and ice chips prevented mucositis at all levels RR = 0.63 (95% CI 0.44 to 0.91), 0.43 (95% CI 0.23 to 0.81), 0.27 (95% CI 0.11 to 0.68). Other interventions showing some benefit with only one study were: benzydamine, calcium phosphate, honey, oral care protocols, povidone and zinc sulphate. The number needed to treat (NNT) to prevent one patient experiencing moderate or severe mucositis over a baseline incidence of 60% for amifostine is 10 (95% CI 7 to 33), antibiotic paste or pastille 13 (95% CI 8 to 56), hydrolytic enzyme 4 (95% CI 3 to 6) and ice chips 5 (95% CI 3 to 19). When the baseline incidence is 40%/90% the NNTs for amifostine are 16/7, for antibiotic paste or pastille 19/7, for hydrolytic enzyme 5/3 and for ice chips 7/3. The general reporting of RCTs was poor. However, the assessments of the quality of the randomisation improved when the authors provided additional information.
AUTHORS' CONCLUSIONS
Several of the interventions were found to have some benefit at preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.
Topics: Antifungal Agents; Antineoplastic Agents; Candidiasis, Oral; Cryotherapy; Humans; Ice; Mouth Mucosa; Neoplasms; Randomized Controlled Trials as Topic; Stomatitis
PubMed: 16625538
DOI: 10.1002/14651858.CD000978.pub2 -
Biochemical Pharmacology Sep 1993Metabolism of misonidazole under hypoxic conditions depletes the parent drug and causes about 4% of the reduced-drug-products to form adducts with cellular... (Comparative Study)
Comparative Study
Metabolism of misonidazole under hypoxic conditions depletes the parent drug and causes about 4% of the reduced-drug-products to form adducts with cellular macromolecules (binding), and this process has been used to detect hypoxia in cells and tissues. The nitrofuran, AF-2 [2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide] has been shown to increase both the metabolic depletion of misonidazole and its binding. In the present study, factors which might affect this process have been examined, in an in vitro system, to test the hypothesis that metabolic depletion of misonidazole could limit its ability to diffuse freely to the hypoxic cell population. Drastic reductions in glucose concentrations from their normal value of 5-10 mM to less than 0.5 mM had no significant effect on the metabolism of either misonidazole or AF-2. Similarly, glucose concentration did not influence the binding of misonidazole, even when concentrations of both oxygen (extreme hypoxia) and glucose were near zero--a very toxic biochemical environment. Similarly, the metabolism of the nitroheterocyclics had no effect on glucose consumption. The bioreductive depletion of misonidazole in extreme hypoxia appeared to be independent of drug concentration between 25 and 100 microM: this nearly zero-order rate of drug metabolism prevented the possibility of working at constant drug concentration. AF-2 exacerbated this effect by greatly enhancing the metabolic depletion of misonidazole. AF-2 was found to increase both the metabolic depletion and binding of misonidazole by the same factor. An unexpected finding was that metabolism of etanidazole, a 2-nitroimidazole closely related to misonidazole, was not enhanced by AF-2. Micromolar amounts of oxygen inhibited the reductive activation of AF-2, and also the interaction between AF-2 and misonidazole. Our results suggest that metabolic depletion of nitroheterocyclics could influence their ability to diffuse adequately to hypoxic tissues, particularly at the low drug concentrations that have been used to measure tissue hypoxia in vivo.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line; Drug Interactions; Etanidazole; Furylfuramide; Glucose; Guinea Pigs; Misonidazole; Nitroimidazoles; Oxidation-Reduction; Oxygen Consumption; Rats; Tumor Cells, Cultured
PubMed: 8216345
DOI: 10.1016/0006-2952(93)90667-l -
Communications Biology Aug 2020Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also...
Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.
Topics: Animals; Brain; Brain Neoplasms; Cell Hypoxia; Cell Proliferation; Female; Ferroptosis; Glioma; Imidazoles; Metabolome; Mice, Inbred C57BL; Mitochondria; Neoplastic Stem Cells; Nitroimidazoles; Radiation-Sensitizing Agents; Stress, Physiological
PubMed: 32807853
DOI: 10.1038/s42003-020-01165-z -
Anticancer Research 2005Four different nitroimidazole derivatives, with up to two iodine atoms on the imidazole ring, were investigated for their radiosensitizing potency under hypoxic...
Four different nitroimidazole derivatives, with up to two iodine atoms on the imidazole ring, were investigated for their radiosensitizing potency under hypoxic conditions, in order to test whether the introduction of iodine atoms increases the radiosensitizing potency of nitroimidazoles. Misonidazole and metronidazole were used as controls. Human colonic adenocarcinoma cells were incubated with the drugs at different concentrations and for different time-periods. Photon energies of 50 kV, 60 kV and 20 MV and total radiation doses of up to 20 Gy were used. The introduction of additional iodine atoms into the nitroimidazole derivatives resulted in a strong increase in cytotoxicity of the compounds. In parallel, there were indications that the radiosensitizing potency was also increased.
Topics: Adenocarcinoma; Cell Line, Tumor; Colonic Neoplasms; Combined Modality Therapy; Humans; Hydrocarbons, Iodinated; Nitroimidazoles; Radiation-Sensitizing Agents
PubMed: 16158957
DOI: No ID Found