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Nuclear Medicine and Biology 2024Hypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen...
CONTEXT
Hypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen supply, characteristic of hypoxia, has been recognized as a central determinant in the progression of various cancers. The reemergence of evofosfamide, a hypoxia-activated prodrug, as a potential treatment strategy has sparked interest in addressing the role of hypoxia in immunotherapy response. This investigation sought to understand the kinetics and heterogeneity of tumor hypoxia and their implications in affecting responses to immunotherapeutic interventions with and without evofosfamide.
PURPOSE
This study aimed to investigate the influence of hypoxia on immune checkpoint inhibition, evofosfamide monotherapy, and their combination on colorectal cancer (CRC). Employing positron emission tomography (PET) imaging, we developed novel analytical methods to quantify and characterize tumor hypoxia severity and distribution.
PROCEDURES
Murine CRC models were longitudinally imaged with [F]-fluoromisonidazole (FMISO)-PET to quantify tumor hypoxia during checkpoint blockade (anti-CTLA-4 + and anti-PD1 +/- evofosfamide). Metrics including maximum tumor [F]FMISO uptake (FMISOmax) and mean tumor [F]FMISO uptake (FMISOmean) were quantified and compared with normal muscle tissue (average muscle FMISO uptake (mAvg) and muscle standard deviation (mSD)). Histogram distributions were used to evaluate heterogeneity of tumor hypoxia.
FINDINGS
Severe hypoxia significantly impeded immunotherapy effectiveness consistent with an immunosuppressive microenvironment. Hypoxia-specific PET imaging revealed a striking degree of spatial heterogeneity in tumor hypoxia, with some regions exhibiting significantly more severe hypoxia than others. The study identified FMISOmax as a robust predictor of immunotherapy response, emphasizing the impact of localized severe hypoxia on tumor volume control during therapy. Interestingly, evofosfamide did not directly reduce hypoxia but markedly improved the response to immunotherapy, uncovering an alternative mechanism for its efficacy.
CONCLUSIONS
These results enhance our comprehension of the interplay between hypoxia and immune checkpoint inhibition within the tumor microenvironment, offering crucial insights for the development of personalized cancer treatment strategies. Non-invasive hypoxia quantification through molecular imaging evaluating hypoxia severity may be an effective tool in guiding treatment planning, predicting therapy response, and ultimately improving patient outcomes across diverse cancer types and tumor microenvironments. It sets the stage for the translation of these findings into clinical practice, facilitating the optimization of immunotherapy regimens by addressing tumor hypoxia and thereby enhancing the efficacy of cancer treatments.
Topics: Animals; Positron-Emission Tomography; Mice; Misonidazole; Tumor Hypoxia; Immune Checkpoint Inhibitors; Cell Line, Tumor; Colorectal Neoplasms; Female; Tumor Microenvironment
PubMed: 38772123
DOI: 10.1016/j.nucmedbio.2024.108918 -
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 -
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 -
Physics in Medicine and Biology Apr 2024Equivalent uniform aerobic dose (EUAD) is proposed for comparison of integrated cell survival in tumors with different distributions of hypoxia and radiation dose.The...
Equivalent uniform aerobic dose (EUAD) is proposed for comparison of integrated cell survival in tumors with different distributions of hypoxia and radiation dose.The EUAD assumes that for any non-uniform distributions of radiation dose and oxygen enhancement ratio (OER) within a tumor, there is a uniform distribution of radiation dose under hypothetical aerobic conditions with OER = 1 that produces equal integrated survival of clonogenic cells. This definition of EUAD has several advantages. First, the EUAD allows one to compare survival of clonogenic cells in tumors with intra-tumor and inter-tumor variation of radio sensitivity due to hypoxia because the cell survival is recomputed under the same benchmark oxygen level (OER = 1). Second, the EUAD for homogeneously oxygenated tumors is equal to the concept of equivalent uniform dose.. We computed the EUAD using radiotherapy dose and the OER derived from theF-Fluoromisonidazole PET (F-FMISO PET) images of hypoxia in patients with glioblastoma, the most common and aggressive type of primary malignant brain tumor. TheF-FMISO PET images include a distribution of SUV (Standardized Uptake Value); therefore, the SUV is converted to partial oxygen pressure (pO) and then to the OER. The prognostic value of EUAD in radiotherapy for hypoxic tumors is demonstrated using correlation between EUAD and overall survival (OS) in radiotherapy for glioblastoma. The correction to the EUAD for the absolute hypoxic volume that traceable to the tumor control probability improves the correlation with OS.. While the analysis proposed in this research is based on theF-FMISO PET images for glioblastoma, the EUAD is a universal radiobiological concept and is not associated with any specific cancer or any specific PET or MRI biomarker of hypoxia. Therefore, this research can be generalized to other cancers, for example stage III lung cancer, and to other hypoxia biomarkers.
Topics: Humans; Glioblastoma; Hypoxia; Lung Neoplasms; Misonidazole; Oxygen; Cell Hypoxia; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 38457839
DOI: 10.1088/1361-6560/ad31c8 -
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 -
Methods in Molecular Biology (Clifton,... 2024Tumor hypoxia is an essential factor related to malignancy, prognosis, and resistance to treatment. Positron emission tomography (PET) is a modality that visualizes the...
Tumor hypoxia is an essential factor related to malignancy, prognosis, and resistance to treatment. Positron emission tomography (PET) is a modality that visualizes the distribution of radiopharmaceuticals administered into the body. PET imaging with [F]fluoromisonidazole ([F]FMISO) identifies hypoxic tissues. Unlike [F]fluorodeoxyglucose ([F]FDG)-PET, fasting is not necessary for [F]FMISO-PET, but the waiting time from injection to image acquisition needs to be relatively long (e.g., 2-4 h). [F]FMISO-PET images can be displayed on an ordinary commercial viewer on a personal computer (PC). While visual assessment is fundamental, various quantitative indices such as tumor-to-muscle ratio have also been proposed. Several novel hypoxia tracers have been invented to compensate for the limitations of [F]FMISO.
Topics: Humans; Fasting; Fluorodeoxyglucose F18; Hypoxia; Misonidazole; Positron-Emission Tomography
PubMed: 38319574
DOI: 10.1007/978-1-0716-3633-6_9 -
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 -
Clinical Nuclear Medicine Apr 2023Solitary intracranial tuberculomas are rare and frequently misdiagnosed as brain tumors. We report a case of intracranial tuberculous granuloma mimicking a high-grade...
Solitary intracranial tuberculomas are rare and frequently misdiagnosed as brain tumors. We report a case of intracranial tuberculous granuloma mimicking a high-grade glioma with avid uptake on 18 F-fluoromisonidazole PET/CT. It has been believed that hypoxia exists within the tuberculosis granuloma, and that this hypoxic environment causes Mycobacterium tuberculosis to lie dormant and asymptomatic infection to occur. This hypoxic and necrotic condition inside tuberculous granuloma may lead to high accumulation of 18 F-fluoromisonidazole in this case.
Topics: Humans; Positron Emission Tomography Computed Tomography; Tuberculoma, Intracranial; Misonidazole; Brain Neoplasms; Tuberculosis
PubMed: 36730900
DOI: 10.1097/RLU.0000000000004471 -
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 -
NMR in Biomedicine Mar 2023Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the...
Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (S O -MRI) to the fluorine-18 fluoromisonidazole ([ F]FMISO) positron emission tomography (PET) volume for hypoxia imaging validation, and to analyze the ability of S O -MRI to depict the different hypoxic tissue types in the acute phase of stroke. In a pertinent model of stroke in the rat, the volume of tissue with decreased S O -MRI signal and that with increased uptake of [ F]FMISO were equivalent and correlated (r = 0.706; p = 0.015). The values of S O in the tissue at risk were significantly greater than those quantified in the core of the lesion, and were less than those for healthy tissue (52.3% ± 2.0%; 43.3% ± 1.9%, and 67.9 ± 1.4%, respectively). A threshold value for S O of ≈60% as the cut-off for the identification of the tissue at risk was calculated. Tissue volumes with reduced S O -MRI correlated with the final lesion (r = 0.964, p < 0.0001). The findings show that the S O -MRI approach is sensitive for the detection of hypoxia and for the prediction of the final lesion after stroke. Once validated in acute clinical settings, this approach might be used to enhance the stratification of patients for potential therapeutic interventions.
Topics: Rats; Animals; Ischemic Stroke; Positron-Emission Tomography; Stroke; Misonidazole; Hypoxia; Magnetic Resonance Imaging; Radiopharmaceuticals
PubMed: 36285719
DOI: 10.1002/nbm.4858