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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 -
BioMed Research International 2024Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using...
Identifying G6PC3 as a Potential Key Molecule in Hypoxic Glucose Metabolism of Glioblastoma Derived from the Depiction of F-Fluoromisonidazole and F-Fluorodeoxyglucose Positron Emission Tomography.
PURPOSE
Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (F-FMISO) and fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism.
METHODS
Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma ( = 33) who underwent preoperative F-FMISO and F-FDG PET to identify affected molecules according to hypoxic condition. Tumor metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort ( = 17) and validated by The Cancer Genome Atlas (TCGA) database ( = 167).
RESULTS
Among the genes involving glucose metabolic pathway, mRNA expression of () correlated with F-FDG LNR ( = 0.03). In addition, mRNA expression in F-FMISO high-accumulated glioblastomas was significantly higher than that in F-FMISO low-accumulated glioblastomas ( < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of was associated with poor overall survival in glioblastoma, as validated by TCGA database.
CONCLUSION
G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high F-FDG and F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma.
Topics: Humans; Glioblastoma; Fluorodeoxyglucose F18; Tomography, X-Ray Computed; Positron-Emission Tomography; Glucose; Hypoxia; RNA, Messenger; Glucose-6-Phosphatase; Fluorine Radioisotopes; Misonidazole
PubMed: 38449509
DOI: 10.1155/2024/2973407 -
BMC Veterinary Research May 2024Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric...
BACKGROUND
Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [F]Fluoromisonidazole ([F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors.
RESULTS
Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMR) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMR and HV in [F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [F]FMISO uptake and variable changes in TMR and HV.
CONCLUSIONS
[F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMR and HV in [F]FMISO PET imaging.
Topics: Animals; Dogs; Misonidazole; Positron Emission Tomography Computed Tomography; Dog Diseases; Female; Tumor Hypoxia; Male; Neoplasms; Thiosemicarbazones; Coordination Complexes
PubMed: 38741109
DOI: 10.1186/s12917-024-04061-4 -
Physica Medica : PM : An International... Jun 2024To assess the impact of rigid and deformable image registration methods (RIR, DIR) on the outcome of a hypoxia-based dose painting strategy.
PURPOSE
To assess the impact of rigid and deformable image registration methods (RIR, DIR) on the outcome of a hypoxia-based dose painting strategy.
MATERIALS AND METHODS
Thirty head and neck cancer patients were imaged with [F]FMISO-PET/CT before radiotherapy. [F]FMISO-PET/CT images were registered to the planning-CT by RIR or DIR. The [F]FMISO uptake was converted into oxygen partial pressure (pO) maps. Hypoxic Target Volumes were contoured on pO maps for the deformed (HTV) and non-deformed (HTV) cases. A dose escalation strategy by contours, aiming at 95 % tumour control probability (TCP), was applied. HTVs were characterised based on geometry-related metrics, the underlying pO distribution, and the dose boost level. A dosimetric and radiobiological evaluation of selected treatment plans made considering RIR and DIR was performed. Moreover, the TCP of the RIR dose distribution was evaluated when considering the deformed [F]FMISO-PET image as an indicator of the actual target radiosensitivity to determine the potential impact of an unalignment.
RESULTS
Statistically significant differences were found between HTV and HTV for volume-based metrics and underlying pO distribution. Eight out of nine treatment plans for HTV and HTV showed differences on the level 10 %/3 mm on a gamma analysis. The TCP difference, however, between RIR and the case when the RIR dose distribution was used with the deformed radiosensitivity map was below 2 pp.
CONCLUSIONS
Although the choice of the CT-to-PET registration method pre-treatment impacts the HTV localisation and morphology and the corresponding dose distribution, it negligibly affects the TCP in the proposed dose escalation strategy by contours.
Topics: Humans; Head and Neck Neoplasms; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Positron Emission Tomography Computed Tomography; Image Processing, Computer-Assisted; Misonidazole; Radiation Dosage
PubMed: 38772061
DOI: 10.1016/j.ejmp.2024.103376