The impact of particulate electron paramagnetic resonance oxygen sensors on fluorodeoxyglucose imaging characteristics detected via positron emission tomography

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Bridging the gap between tumor hypoxia and tumor response : assessing the value of imaging biomarkers to guide hypoxia-driven interventions in radiotherapy

Tumor hypoxia is known as a major cause of radioresistance. However, clinical practice actually does not integrate on a routine basis this factor in the definition of radiation protocols. This is in sharp contrast with the recent developments including the imaging techniques that monitor non-invasively tumor hypoxia, the emerging hypoxia-targeted therapies and the predictive tools to anticipate treatment outcome. Combining these advances offers the opportunity to translate knowledge on tumor hypoxia into an optimized, integrated and individualized anti-cancer treatment. In an attempt to bridge together tumor hypoxia and tumor response, the research presented here has consisted of three important tasks: validating the hypoxia imaging by 18F-FAZA PET; assessing the prognostic value of 18F-FAZA PET and its predictive potential to guide hypoxia-driven interventions in radiotherapy; assessing the utility of DW-MRI and 18F-FLT PET to early monitor the tumor response to irradiation.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Characterization of a clinically used charcoal suspension for in vivo EPR oximetry.

Electron paramagnetic resonance (EPR) oximetry using particulate materials allows repeatable measurements of oxygen in tissues. However, the materials identified so far are not medical devices, thus precluding their immediate use in clinical studies. The aim of this study was to assess the magnetic properties of Carbo-Rep, a charcoal suspension used as a liquid marker for preoperative tumor localization. Calibration curves (EPR linewidth as a function of pO) were built using 9-GHz EPR spectrometry. The feasibility of performing oxygen measurements was examined in vivo by using a low-frequency (1 GHz) EPR spectrometer and by inducing ischemia in the gastrocnemius muscle of mice or by submitting rats bearing tumors to different oxygen-breathing challenges. Paramagnetic centers presenting a high oxygen sensitivity were identified in Carbo-Rep. At 1 GHz, the EPR linewidth varied from 98 to 426 µT in L-band in nitrogen and air, respectively. The sensor allowed repeated measurements of oxygen over 6 months in muscles of mice. Subtle variations of tumor oxygenation were monitored in rats when switching gas breathing from air to carbogen. The magnetic properties of Carbo-Rep are promising for its future use as oxygen sensor in clinical EPR oximetry

Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: A comparison with Oxylite, EPR Oximetry and 19F-MRI Relaxometry

Background and purpose: Tumor hypoxia has been considered as an important prognosis factor in oncology [1]. Quantitative information and distribution of oxygen concentration would be valuable for the improvement of therapeutic strategies. Given the importance of this aspect, there has been many techniques reported to be useful for hypoxia detection in tumors [2,3]; but a limited number of methods have been implemented into clinical practice. One of techniques currently available for detection of hypoxia in human application is Positron Emission Tomography (PET). The accumulation of hypoxia-specific PET tracers can reflect hypoxic areas inside tumors that are relevant in terms of radiation resistance; however, this is an indirect method that cannot provide absolute values of pO2. Therefore, to evaluate the potential of PET hypoxia images with tracer 18F-fluoroazomycin-arabinoside (18F-FAZA), we compared PET hypoxia imaging to other oximetry techniques: Oxylite, Electron Paramagnetic Resonance (EPR) spectroscopy and Nuclear Magnetic Resonance Imaging by fluorine relaxometry (19F-MRI), respectively. Methods: Male adult WAG/Rij rats grafted with rhabdomyosarcoma in thighs were used for this study. In all comparisons, animals were randomly divided into two groups, breathing either room air or carbogen. PET imaging was performed on a dedicated small-animal PET scanner 3h after intravenous injection of 18.5-29.6 MBq 18F-FAZA. The median pO2 value of each tumor measured by Oxylite was calculated from the measurement at ten independent sites within the tumor. EPR acquisition was carried out 24h after charcoal implantation by using an L-band EPR spectrometer. For MRI oximetry, perfluoro-15-crown-5ether (15C5) was used as oxygen sensitive sensor, the spin-lattice relaxation time (T1) of 19F nuclei was acquired by an 11.7 T system with a tunable 1H/19F surface coil. Linewidth of EPR spectra and T1-value obtained by MRI were then converted to pO2 using the calibration curves. Results: The results from both Oxylite and EPR showed an increase of pO2 in the breathing carbogen group. In accordance with this tendency, the tumor-to-background (T/B) ratio measured by PET under high oxygen condition exhibited about 1.3-fold decrease than that under normoxic condition. The scatter-plots of T/B ratio versus measured pO2 were traced by using data from all individual tumors. There was a good correlation between the results obtained by PET and EPR (R = 0.9306). In the case of Oxylite, although the poorer correlation coefficient was observed (R = 0.5469), the trend for two values to agree was still related to the inverse function theoretically predicted. For the comparison of 18F-FAZA and 15C5 marker, we could not found the significant difference in values T1. This could be explained by the lower sensitivity of 19F-relaxometry compared to EPR and OxyLite. Conclusions: Our present study demonstrated a clear correlation between 18F-FAZA-PET signal intensities and tumor oxygenation. These results suggest that 18F-FAZA is an effective surrogate of hypoxia fractions and support the use of 18F-FAZA PET as an imaging technique to guide cancer therapy

Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: A comparision with OxyLite, EPR oxymetry and 19F-MRI relaxometry

Background and purpose: Tumor hypoxia has been considered as an important prognosis factor in oncology. Quantitative information and distribution of oxygen concentration would be valuable for the improvement of therapeutic strategies. Given the importance of this aspect, there has been many techniques reported to be useful for hypoxia detection in tumors; but a limited number of methods have been implemented into clinical practice. One of techniques currently available for detection of hypoxia in human application is Positron Emission Tomography (PET). The accumulation of hypoxia-specific PET tracers can reflect hypoxic areas inside tumors that are relevant in terms of radiation resistance; however, this is an indirect method that cannot provide absolute values of pO2. Therefore, to evaluate the potential of PET hypoxia images with tracer 18F-fluoroazomycin-arabinoside (18F-FAZA), we compared PET hypoxia imaging to other oximetry techniques: Oxylite, Electron Paramagnetic Resonance (EPR) spectroscopy and Nuclear Magnetic Resonance Imaging by fluorine relaxometry (19F-MRI), respectively. Methods: Male adult WAG/Rij rats grafted with rhabdomyosarcoma in thighs were used for this study. In all comparisons, animals were randomly divided into two groups, breathing either room air or carbogen. PET imaging was performed on a dedicated small-animal PET scanner 3h after intravenous injection of 18.5-29.6 MBq 18F-FAZA. The median pO2 value of each tumor measured by Oxylite was calculated from the measurement at ten independent sites within the tumor. EPR acquisition was carried out 24h after charcoal implantation by using an L-band EPR spectrometer. For MRI oximetry, perfluoro-15-crown-5ether (15C5) was used as oxygen sensitive sensor, the spin-lattice relaxation time (T1) of 19F nuclei was acquired by an 11.7 T system with a tunable 1H/19F surface coil. Linewidth of EPR spectra and T1-value obtained by MRI were then converted to pO2 using the calibration curves. Results: The results from both Oxylite and EPR showed an increase of pO2 in the breathing carbogen group. In accordance with this tendency, the tumor-to-background (T/B) ratio measured by PET under high oxygen condition exhibited about 1.3-fold decrease than that under normoxic condition. The scatter-plots of T/B ratio versus measured pO2 were traced by using data from all individual tumors. There was a good correlation between the results obtained by PET and EPR (R = 0.93). In the case of Oxylite, although the poorer correlation coefficient was observed (R = 0.55), the trend for two values to agree was still related to the inverse function theoretically predicted. For the comparison of 18F-FAZA and 15C5 marker, we could not found the significant difference in values T1. This could be explained by the lower sensitivity of 19F-relaxometry compared to EPR and OxyLite. Conclusions: Our present study demonstrated a clear correlation between 18F-FAZA-PET signal intensities and tumor oxygenation. These results suggest that 18F-FAZA is an effective surrogate of hypoxia fractions and support the use of 18F-FAZA PET as an imaging technique to guide cancer therapy

Impact of myo-inositol trispyrophosphate (ITPP) on tumour oxygenation and response to irradiation in rodent tumour models.

Tumour hypoxia is a well-established factor of resistance in radiation therapy (RT). Myo-inositol trispyrophosphate (ITPP) is an allosteric effector that reduces the oxygen-binding affinity of haemoglobin and facilitates the release of oxygen by red blood cells. We investigated herein the oxygenation effect of ITPP in six tumour models and its radiosensitizing effect in two of these models. The evolution of tumour pO upon ITPP administration was monitored on six models using 1.2 GHz Electron Paramagnetic Resonance (EPR) oximetry. The effect of ITPP on tumour perfusion was assessed by Hoechst staining and the oxygen consumption rate (OCR) in vitro was measured using 9.5 GHz EPR. The therapeutic effect of ITPP with and without RT was evaluated on rhabdomyosarcoma and 9L-glioma rat models. ITPP enhanced tumour oxygenation in six models. The administration of 2 g/kg ITPP once daily for 2 days led to a tumour reoxygenation for at least 4 days. ITPP reduced the OCR in six cell lines but had no effect on tumour perfusion when tested on 9L-gliomas. ITPP plus RT did not improve the outcome in rhabdomyosarcomas. In 9L-gliomas, some of tumours receiving the combined treatment were cured while other tumours did not benefit from the treatment. ITPP increased oxygenation in six tumour models. A decrease in OCR could contribute to the decrease in tumour hypoxia. The association of RT with ITPP was beneficial for a few 9L-gliomas but was absent in the rhabdomyosarcomas

Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: A comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry

Background and purpose: 18F-FAZA is a nitroimidazole PET tracer that can provide images of tumor hypoxia. However, it cannot provide absolute pO 2 values. To qualify 18F-FAZA PET, we compared PET images to pO 2 measured by OxyLite, EPR oximetry and 19F-MRI. Materials and methods: Male WAG/Rij rats grafted with rhabdomyosarcoma were used. Tumor oxygenation was modified by gas breathing (air or carbogen). The same day of PET acquisition, the pO 2 was measured in the same tumor either by OxyLite probes (measurement at 10 different sites), EPR oximetry using low frequency EPR or 19F-relaxometry using 15C5 on an 11.7 T MR system. Results: There was a good correlation between the results obtained by PET and EPR (R = 0.93). In the case of OxyLite, although a weaker correlation was observed (R = 0.55), the trend for two values to agree was still related to the inverse function theoretically predicted. For the comparison of 18F-FAZA PET and 19F-MRI, no change in T 1 was observed. Conclusions: A clear correlation between 18F-FAZA PET image intensities and tumor oxygenation was demonstrated, suggesting that 18F-FAZA PET is a promising imaging technique to guide cancer therapy. © 2011 Elsevier Ireland Ltd. All rights reserved

Predictive value of (18)F-FAZA PET imaging for guiding the association of radiotherapy with nimorazole: a preclinical study

PURPOSE: To assess the predictive value of hypoxia imaging by (18)F-FAZA PET in identifying tumors that may benefit from radiotherapy combined with nimorazole, a hypoxic radiosensitizer. MATERIAL AND METHODS: Rats of two tumor models (Rhabdomyosarcoma and 9L-glioma) were divided into two treated groups: radiotherapy (RT) alone or RT plus nimorazole. (18)F-FAZA PET images were obtained to evaluate tumor hypoxia before the treatment. Treatment outcome was assessed through the tumor growth time assay, defined as the time required for tumor to grow to 1.5 times its size before irradiation. RESULTS: For rhabdomyosarcomas, the benefit of adding nimorazole to RT was not significant when considering all tumors. When stratifying into more and less hypoxic tumors according to the median (18)F-FAZA T/B ratio, we found that the combined treatment significantly improved the response of the "more hypoxic" subgroup, while there was no significant difference in the tumor growth time between the two treatment modalities for the "less hypoxic" subgroup. For 9L-gliomas, a clear benefit was demonstrated for the group receiving RT+nimorazole. However, the individual responses within the RT+nimorazole group were highly variable and independent of the (18)F-FAZA uptake. CONCLUSIONS: (18)F-FAZA PET may be useful to guide hypoxia-directed RT using nimorazole as radiosensitizer. It identified a subgroup of more hypoxic tumors (displaying T/B ratio>2.72) that would benefit from this combined treatment. Nevertheless, the predictive power was limited to rhabdomyosarcomas and ineffective for 9L-gliomas

Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy.

BACKGROUND AND PURPOSE: Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions. MATERIAL AND METHODS: Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas. RESULTS: For 9L-gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen. CONCLUSIONS: (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F-FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non-responsive to carbogen