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Arterial pO2, pCO2 and sO2 levels at 90 min post anaesthesia induction for different anaesthesia regimes (n = 5/group).
Source publication
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Background
Preclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [64Cu]-CuATSM, [99mTc]-HL91 and [18F]-FMISO in a preclinical model of tumo...
Citations
... A PET scan study following hypoxia radiotracers indicated that the tumor is not more oxygenated when mice breathe 100% oxygen in a subcutaneous tumor model. However, the tumor in this model could have a different oxygen availability than the orthotopic brain tumor used in the present study 47 . ...
Background
Radiation-induced neurocognitive dysfunction is a major adverse effect of brain radiation therapy and has specific relevance in pediatric oncology, where serious cognitive deficits have been reported in survivors of pediatric brain tumors. Moreover, many pediatric patients receive proton therapy under general anesthesia or sedation to guarantee precise ballistics with a high oxygen content for safety. The present study addresses the relevant question of the potential effect of supplemental oxygen administered during anesthesia on normal tissue toxicity and investigates the anti-tumor immune response generated following conventional and FLASH proton therapy.
Methods
Rats (Fischer 344) were cranially irradiated with a single high dose of proton therapy (15 Gy or 25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s), and the toxicities in the normal tissue were examined by histological, cytometric and behavioral analysis. Glioblastoma-bearing rats were irradiated in the same manner and tumor-infiltrating leukocytes were quantified by flow cytometry.
Results
Our findings indicate that supplemental oxygen has an adverse impact on both functional and anatomical evaluations of normal brain following conventional and FLASH proton therapy. In addition, oxygen supplementation in anesthesia is particularly detrimental for anti-tumor immune response by preventing a strong immune cell infiltration into tumoral tissues following conventional proton therapy.
Conclusions
These results demonstrate the need to further optimize anesthesia protocols used in radiotherapy with the goal of preserving normal tissues and achieving tumor control, specifically in combination with immunotherapy agents.
... In present study, dog patients were maintained under anesthesia using 1-2% isoflurane in 100% oxygen. In CaNT-bearing CBA mice, [18F]FMISO TMR was reduced when either 100% oxygen or anesthetics were introduced [23]. Another study has reported that CT26 colorectal carcinoma bearing mice showed higher [18F]FAZA TMR when the mice breathed air compared to the 100% oxygen breathing protocols [24]. ...
Purpose
We evaluated the kinetics of the hypoxia PET radiotracers, [18F]fluoromisonidazole ([18F]FMISO) and [18F]fluoroazomycin-arabinoside ([18F]FAZA), for tumor hypoxia detection and to assess the correlation of hypoxic kinetic parameters with static imaging measures in canine spontaneous tumors.
Methods
Sixteen dogs with spontaneous tumors underwent a 150-min dynamic PET scan using either [18F]FMISO or [18F]FAZA. The maximum tumor-to-muscle ratio (TMR max ) > 1.4 on the last image frame was used as the standard threshold to determine tumor hypoxia. The tumor time-activity curves were analyzed using irreversible and reversible two-tissue compartment models and graphical methods. TMR max was compared with radiotracer trapping rate ( k 3 ), influx rate ( K i ), and distribution volume ( V T ).
Results
Tumor hypoxia was detected in 7/8 tumors in the [18F]FMISO group and 4/8 tumors in the [18F]FAZA group. All hypoxic tumors were detected at > 120 min with [18F]FMISO and at > 60 min with [18F]FAZA. [18F]FAZA showed better fit with the reversible model. TMR max was strongly correlated with the irreversible parameters ( k 3 and K i ) for [18F]FMISO at > 90 min and with the reversible parameter ( V T ) for [18F]FAZA at > 120 min.
Conclusions
Our results showed that [18F]FAZA provided a promising alternative radiotracer to [18F]FMISO with detecting the presence of tumor hypoxia at an earlier time (60 min), consistent with its favorable faster kinetics. The strong correlation between TMR max over the 90–150 min and 120–150 min timeframes with [18F]FMISO and [18F]FAZA, respectively, with kinetic parameters associated with tumor hypoxia for each radiotracer, suggests that a static scan measurement (TMR max ) is a good alternative to quantify tumor hypoxia.
... The concomitant use of biomarkers such as [18F]-FMISO-PET or [18F]F-FAZA may galvanize the clinical implementation of combination regimens involving anti-AR treatments as well as anti-angiogenics/anti-hypoxia therapeutics because they enable a more optimal choice and dynamic monitoring of personalized treatments, as well as response assessment during therapy; indeed, such a strategic combination of diagnostics with therapeutics-termed theragnostics-embraces a level of precision oncology that pursues nimble shifts in therapy tailored based on changes in the molecular characteristics of tumors. Thus, the precise identification and quantitation of hypoxic levels via hypoxia-specific in vivo imaging techniques, such as PET and Single Photon Emission Computed Tomography (SPECT), will be critical to successfully designing optimal therapeutic strategies to co-target hypoxia along with AR in each individual TNBC patient [39,146,149]. ...
Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.
... The limitations of this study are given by several experiment-inherent factors. The used anesthesia protocol has been shown to reduce hypoxia tracer uptake in small animal PET-studies (46). This indicates reoxygenation and subsequently masked correlations between histological hypoxia (HF) and MRI features in this study. ...
Background and purpose
Radiomics analyses have been shown to predict clinical outcomes of radiotherapy based on medical imaging-derived biomarkers. However, the biological meaning attached to such image features often remains unclear, thus hindering the clinical translation of radiomics analysis. In this manuscript, we describe a preclinical radiomics trial, which attempts to establish correlations between the expression of histological tumor microenvironment (TME)- and magnetic resonance imaging (MRI)-derived image features.
Materials & Methods
A total of 114 mice were transplanted with the radioresistant and radiosensitive head and neck squamous cell carcinoma cell lines SAS and UT-SCC-14, respectively. The models were irradiated with five fractions of protons or photons using different doses. Post-treatment T1-weighted MRI and histopathological evaluation of the TME was conducted to extract quantitative features pertaining to tissue hypoxia and vascularization. We performed radiomics analysis with leave-one-out cross validation to identify the features most strongly associated with the tumor’s phenotype. Performance was assessed using the area under the curve (AUCValid) and F1-score. Furthermore, we analyzed correlations between TME- and MRI features using the Spearman correlation coefficient ρ.
Results
TME and MRI-derived features showed good performance (AUCValid, TME = 0.72, AUCValid, MRI = 0.85, AUCValid, Combined = 0.85) individual tumor phenotype prediction. We found correlation coefficients of ρ = - 0.46 between hypoxia-related TME features and texture-related MRI features. Tumor volume was a strong confounder for MRI feature expression.
Conclusion
We demonstrated a preclinical radiomics implementation and notable correlations between MRI- and TME hypoxia-related features. Developing additional TME features may help to further unravel the underlying biology.
... The limitations of this study are given by several experimentinherent factors. The used anesthesia protocol has been shown to reduce hypoxia tracer uptake in small animal PET-studies [46]. This indicates reoxygenation and subsequently masked correlations between histological hypoxia (HF) and MRI features in this study. ...
Linked article: This Correspondence comments on Moro et al. Click here to view the article.
... Invasive polarographic electrode probes measure hypoxia in vivo as they are inserted directly into the tissue of interest (Sorger et al. 2003;Barthel et al. 2004;Dubois et al. 2004 Chitneni et al. 2011;Dubois LJ et al. 2011;Hall and Giaccia 2011;Kersemans et al. 2011;Pacheco-Torres et al. 2011;Sun et al. 2011;Winter et al. 2011;Tran et al. 2012;Kelada and Carlson 2014;Fleming et al. 2015;Peeters SG et al. 2015;Xu et al. 2017). However, they are highly invasive, change and damage the tumor morphology, and are not well suited for repeat measurements (Haustermans et al. 2000;Gallez et al. 2004;Krohn et al. 2008;Mason et al. 2010;Sun et al. 2011;Matsuo et al. 2014;Fleming et al. 2015;Wenger et al. 2015;De Bruycker et al. 2018;Mirabello et al. 2018). ...
... Single-photon emission computed tomography (SPECT) is used less than PET for preclinical imaging despite lower costs and better spatial resolution (Franc et al. 2008;Minn et al. 2008;Nuyts et al. 2009;Kersemans et al. 2011). However, SPECT sensitivity is less than that of PET due to its spatial higher resolution (Franc et al. 2008;Minn et al. 2008). ...
... SPECT has the unique property of allowing for multiple probes labeled with different isotopes to be imaged simultaneously through energy discrimination/spectroscopy (Franc et al. 2008;Mason et al. 2010). SPECT hypoxia imaging also has limited clinical use, making it less effective for translation (Krohn et al. 2008;Kersemans et al. 2011;Horsman et al. 2012). ...
Purpose
Tumors exhibit areas of decreased oxygenation due to malformed blood vessels. This low oxygen concentration decreases the effectiveness of radiation therapy, and the resulting poor perfusion can prevent drugs from reaching areas of the tumor. Tumor hypoxia is associated with poorer prognosis and disease progression and is therefore of interest to preclinical researchers. Although there are multiple different ways to measure tumor hypoxia and related factors, there is no standard for quantifying spatial and temporal tumor hypoxia distributions in preclinical research or in the clinic. This review compares imaging methods utilized for the purpose of assessing spatio-temporal patterns of hypoxia in the preclinical setting. Conclusions: Imaging methods provide varying levels of spatial and temporal resolution regarding different aspects of hypoxia, and with varying advantages and disadvantages. The choice of modality requires consideration of the specific experimental model, the nature of the required characterisation and the availability of complementary modalities as well as immunohistochemistry.
... The functional imaging performance depends on the scanner model, acquisition parameters, image reconstruction, and patient status 29 . Kersemans et al. 30 studied the effects of both anesthetic and carrier gas upon the uptake of 64 Cu-CuATSM, 99m Tc-HL91, and 18 F-FMISO in a preclinical model of tumor hypoxia on PET and SPECT. Their results showed that the use of anesthesia can have profound effects on the experimental outcome. ...
Abstract This study aimed to develop and validate a novel rabbit fixator made from a thermoplastic mask for awake imaging experiments. When heated in a hot-water bath at 65–70 °C for 2–5 min, the thermoplastic mask became soft and could be molded to fit over the entire body of an anesthetized rabbit (4 ml of 3% pentobarbital sodium solution by intramuscular injection). Twenty rabbits were randomly divided into fixator (n = 10) and anesthesia (n = 10) groups. The animals’ vital signs, stress hormones (cortisol and adrenaline), and subjective image quality scores for the computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) scanning were measured and compared. Phantom CT, MRI and PET studies were performed to assess the performance with and without the thermoplastic mask by using image agents at different concentrations or with different radioactivity. The respiration rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), peripheral capillary oxygen saturation (SpO2) and body temperature (T) decreased after anesthesia (all P 0.05). The heart rate (HR), cortisol and adrenaline did not significantly decrease after either anesthesia or fixation (all P > 0.05). The subjective image quality scores for the CT and MRI images of the head, thorax, liver, kidney, intestines and pelvis and the subjective image quality scores for the PET images did not significantly differ between the two groups (all P > 0.05). For all examined organs except the muscle, 18F-FDG metabolism was lower after fixation than after anesthesia, and was almost identical of liver between two groups. The phantom study showed that the CT values, standard uptake values and MR T2 signal values did not differ significantly with or without the mask (all P > 0.05). A novel rabbit fixator created using a thermoplastic mask could be used to obtain high-quality images for different imaging modalities in an awake and near-physiological state.
... Fifty µL of a crude cell suspension, prepared by mechanical dissociation of an excized tumor from a donor animal, was injected. Tumors were selected for imaging when the geometric mean diameter reached 6-8 mm (volumes calculated as above), approximately 3 weeks after implantation (11). ...
... Coronal In contrast to PSN-1 tumors, Capan-1 xenografts expressed lower levels of PARP-1, as determined by Western blot and immunohistochemistry (Fig. 5D, Supplemental Figs. [11][12][13]. Consistent with lower tumor PARP-1 levels, and consistent with lower in vitro uptake of 18 F-olaparib, intravenous administration resulted in lower average uptake of 18 F-olaparib in these tumors (2.59 ± 0.32%ID/g), although this was not statistically significant. ...
... Fifty µL of a crude cell suspension, prepared by mechanical dissociation of an excized tumor from a donor animal, was injected. Tumors were selected for imaging when the geometric mean diameter reached 6-8 mm (volumes calculated as above), approximately 3 weeks after implantation (11). ...
... Mice were anesthetized by 4% isoflurane gas (0.5 L/min O 2 ) and placed on a custom-built imaging cradle in a prone position. Animals were intravenously injected with 18 F-olaparib or (3)(4)(5)(8)(9)(10)(11) GBq/µmol, through a only. ...
PARP inhibitors are increasingly being studied as cancer drugs, as single agents or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time, the 18F-radiolabeled isotopologue of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, non-radiolabeled drug. [18F]Olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and [18F]olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of [18F]olaparib in tumors expressing PARP-1 (3.2±0.36%ID/g in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of [18F]olaparib increased by 70% (P = 0.025). Taken together, we show that [18F]olaparib has great potential for non-invasive tumor imaging and monitoring of radiation damage.
... Yet these changes were less pronounced in muscle, resulting in higher [ 18 F]FAZA TBR in ketamine/xylazine-anesthetized animals [101]. In a murine adenocarcinoma model on the other hand, no difference in [ 18 F]FMISO TBR between the two anesthesia regimens was found, despite the observation of higher tumoral uptake in ketamine/xylazine-anesthetized animals compared to their isoflurane counterparts [102]. Surprisingly however, in both imaging studies, it was shown that [ 18 F]FAZA and [ 18 F] FMISO TBR, respectively, did not differ between animals breathing room air or animals breathing O 2 during isoflurane anesthesia [101,102]. ...
... In a murine adenocarcinoma model on the other hand, no difference in [ 18 F]FMISO TBR between the two anesthesia regimens was found, despite the observation of higher tumoral uptake in ketamine/xylazine-anesthetized animals compared to their isoflurane counterparts [102]. Surprisingly however, in both imaging studies, it was shown that [ 18 F]FAZA and [ 18 F] FMISO TBR, respectively, did not differ between animals breathing room air or animals breathing O 2 during isoflurane anesthesia [101,102]. ...
Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies.
