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

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. Conclusions: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes

A characterization of pyrin: Investigating the molecular pathophysiology of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder commonly found in populations indigenous to the Mediterranean basin. Clinically, it is characterized by episodic attacks of fever accompanied by inflammation of the abdomen, joints, or skin. The gene mutated in FMF codes for pyrin, a member of both the pyrin d omain (PyD) and ret-finger- protein (rfp) family of proteins. This thesis is an investigation of both the evolution and molecular biology of pyrin, as a stepping-stone to understanding the molecular pathophysiology underlying FMF. Our first study encompassed an evolutionary analysis of the pyrin's rfp domain, as it contains the majority of FMF mutations. The data revealed that, in several cases, human mutations are present as wild-type in the rfp domain of non-human primates. Thus, human mutations represent a reversal to an ancestral state. Furthermore, this domain has been under positive selection throughout primate evolution. Together, these data suggest that pyrin's function has been changing over evolutionary time. In our second series of experiments, a yeast two-hybrid screen revealed that pyrin interacts with the apoptosic speck protein containing a CARD (ASC). ASC is a proapoptotic protein that forms a cytosolic aggregate termed a speck. Using immunofluorescence, we determined that pyrin's PyD is necessary and sufficient for recruitment to ASC specks. Furthermore, pyrin modulates ASC-induced cell death. These transfection studies were complemented by investigations of endogenous pyrin and ASC. In neutrophils, pyrin is primarily nuclear, but exits the nucleus upon progression to apoptosis. In monocytes, pyrin is both nuclear and cytoplasmic; importantly, pyrin is recruited to ASC specks, and these specks are also associated with cell death. Interestingly, investigations of endogenous pyrin (and ASC) revealed that both are recruited to actin structures in the cytoplasm of human monocytes. It thus appears that pyrin is shuttled between different subcellular compartments (i.e. the speck, f-actin, and the nucleus). In summary, we have found that pyrin is linked to pathways implicated in both cellular death and inflammation, and that subcellular compartmentalization may be important in the regulation of its function. These studies represent an initial foray into pyrin's function, and lay the groundwork for future investigations.Ph.D.Biological SciencesCellular biologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124926/2/3163922.pd

How best to interpret measures of levels of oxygen in tissues to make them effective clinical tools for care of patients with cancer and other oxygen-dependent pathologies.

It is well understood that the level of molecular oxygen (O ) in tissue is a very important factor impacting both physiology and pathological processes as well as responsiveness to some treatments. Data on O in tissue could be effectively utilized to enhance precision medicine. However, the nature of the data that can be obtained using existing clinically applicable techniques is often misunderstood, and this can confound the effective use of the information. Attempts to make clinical measurements of O in tissues will inevitably provide data that are aggregated over time and space and therefore will not fully represent the inherent heterogeneity of O in tissues. Additionally, the nature of existing techniques to measure O may result in uneven sampling of the volume of interest and therefore may not provide accurate information on the "average" O in the measured volume. By recognizing the potential limitations of the O measurements, one can focus on the important and useful information that can be obtained from these techniques. The most valuable clinical characterizations of oxygen are likely to be derived from a series of measurements that provide data about factors that can change levels of O , which then can be exploited both diagnostically and therapeutically. The clinical utility of such data ultimately needs to be verified by careful studies of outcomes related to the measured changes in levels of O

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

Direct and Repeated Clinical Measurements of pO2 for Enhancing Cancer Therapy and Other Applications

The first systematic multi-center study of the clinical use of EPR oximetry has begun, with funding as a PPG from the NCI. Using particulate oxygen sensitive EPR, materials in three complementary forms (India Ink, "OxyChips", and implantable resonators) the clinical value of the technique will be evaluated. The aims include using repeated measurement of tumor pO2 to monitor the effects of treatments on tumor pO2, to use the measurements to select suitable subjects for the type of treatment including the use of hyperoxic techniques, and to provide data that will enable existing clinical techniques which provide data relevant to tumor pO2 but which cannot directly measure it to be enhanced by determining circumstances where they can give dependable information about tumor pO2

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial

Importance: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, Setting, and Participants: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions: Chemoradiation and consolidation chemotherapy with or without metformin. Main Outcomes and Measures: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and Relevance: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT02186847