Rethinking the Role of Biodosimetry to Assess Risks for Acute Radiation Syndrome in Very Large Radiation Events: Reconsidering Legacy Concepts.

The development of effective uses of biodosimetry in large-scale events has been hampered by residual, i.e., "legacy" thinking based on strategies that scale up from biodosimetry in small accidents.

Re-examining What the Results of "a Measurement of Oxygen Level in Tissues" Really Mean.

Within this special issue, many eminent investigators report on measurements of oxygen (O) levels in tissues. Given the complexities of spatial and temporal heterogeneities of O in tissues and its many sources, this commentary draws attention to what such measurements do and do not actually assess regarding O levels in tissues. Given this limitation, it also discusses how these results can be used most effectively.

A Critical Analysis of Possible Mechanisms for the Oxygen Effect in Radiation Therapy with FLASH.

The aim of this review is to stimulate readers to undertake appropriate investigations of the mechanism for a possible oxygen effect in FLASH. FLASH is a method of delivery of radiation that empirically, in animal models, appears to decrease the impact of radiation on normal tissues while retaining full effect on tumors. This has the potential for achieving a significantly increased effectiveness of radiation therapy.

EPR biodosimetry: challenges and opportunities.

This paper briefly examines electron paramagnetic resonance (EPR) techniques to measure dose from exposure to external radiation, assessing their current status, potential future uses and the challenges impacting their progress. We conclude the uses and potential value of different EPR techniques depend on the number of victims and whether they characterize short- or long-term risks from exposure. For large populations, EPR biodosimetry based on in vivo measurements or using co-located inanimate objects offer the greatest promise for assessing acute, life-threatening risk and the magnitude and extent of such risk.

Implications of "flash" radiotherapy for biodosimetry.

Extremely high dose rate radiation delivery (FLASH) for cancer treatment has been shown to produce less damage to normal tissues while having the same radiotoxic effect on tumor tissue (referred to as the FLASH effect). Research on the FLASH effect has two very pertinent implications for the field of biodosimetry: (1) FLASH is a good model to simulate delivery of prompt radiation from the initial moments after detonating a nuclear weapon and (2) the FLASH effect elucidates how dose rate impacts the biological mechanisms that underlie most types of biological biodosimetry. The impact of dose rate will likely differ for different types of biodosimetry, depending on the specific underlying mechanisms.

A Radiation Biological Analysis of the Oxygen Effect as a Possible Mechanism in FLASH.

The delivery of radiation at an ultra-high dose rate (FLASH) is an important new approach to radiotherapy (RT) that appears to be able to improve the therapeutic ratio by diminishing damage to normal tissues. While the mechanisms by which FLASH improves outcomes have not been established, a role involving molecular oxygen (O) is frequently mentioned. In order to effectively determine if the protective effect of FLASH RT occurs via a differential direct depletion of O (compared to conventional radiation), it is essential to consider the known role of O in modifying the response of cells and tissues to ionising radiation (known as 'the oxygen effect').

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.

Measurement of Tissue Oxygen as a Novel Approach to Optimizing Red Blood Cell Quality Assessment.

The effectiveness of blood transfusions can be impacted by storage and extensive processing techniques that involve treatment of red blood cells (RBCs) with pathogen reduction technologies (e.g., UV-light and chemical treatment), ex vivo stem cell derivation/maturation methods, and bioengineering of RBCs using nanotechnology.

What Is the Meaning of an Oxygen Measurement? : Analysis of Methods Purporting to Measure Oxygen in Targeted Tissues.

Clinical measurements of O in tissues will inevitably provide data that are at best aggregated and will not reflect the inherent heterogeneity of O in tissues over space and time. Additionally, the nature of all existing techniques to measure O results in complex sampling of the volume that is sensed by the technique. By recognizing these potential limitations of the measures, one can focus on the very important and useful information that can be obtained from these techniques, especially data about factors that can change levels of O and then exploit these changes diagnostically and therapeutically.

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.

OxyChip Implantation and Subsequent Electron Paramagnetic Resonance Oximetry in Human Tumors Is Safe and Feasible: First Experience in 24 Patients.

Tumor hypoxia confers both a poor prognosis and increased resistance to oncologic therapies, and therefore, hypoxia modification with reliable oxygen profiling during anticancer treatment is desirable. The OxyChip is an implantable oxygen sensor that can detect tumor oxygen levels using electron paramagnetic resonance (EPR) oximetry. We report initial safety and feasibility outcomes after OxyChip implantation in a first-in-humans clinical trial (NCT02706197, www.

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.

Scientific and Logistical Considerations When Screening for Radiation Risks by Using Biodosimetry Based on Biological Effects of Radiation Rather than Dose: The Need for Prior Measurements of Homogeneity and Distribution of Dose.

An effective medical response to a large-scale radiation event requires prompt and effective initial triage so that appropriate care can be provided to individuals with significant risk for severe acute radiation injury. Arguably, it would be advantageous to use injury rather than radiation dose for the initial assessment; i.e.

Moving organizational theory in health care forward: A discussion with suggestions for critical advancements.

In May 2019, scholars in management and organization of health care organizations and systems met. The opening plenary was a moderated discussion with five distinguished scholars who have exemplified pushing the frontier of organizational theory and practice throughout their careers: Ann Barry Flood of Dartmouth College, John Kimberly of the University of Pennsylvania, Anthony (Tony) Kovner of New York University, Stephen (Steve) Shortell of University of California at Berkeley, and Jacqueline (Jackie) Zinn of Temple University. The discussion was moderated by Ingrid Nembhard of the University of Pennsylvania.

Guidance to Transfer 'Bench-Ready' Medical Technology into Usual Clinical Practice: Case Study - Sensors and Spectrometer Used in EPR Oximetry.

This paper considers the critical role that academics can have in the development of clinical innovations and especially how their impact can be optimized. The focus should be on establishing the safety and efficacy of new approaches while also incorporating human factors and human use considerations into the inventions. It is very advantageous to work in concert with the end-users (operators and clinicians) to help ensure that the innovation will be useful and feasible to be incorporated into actual clinical practice as intended.

Development of a novel mouth model as an alternative tool to test the effectiveness of an in vivo EPR dosimetry system.

In a large-scale radiation event, thousands may be exposed to unknown amounts of radiation, some of which may be life-threatening without immediate attention. In such situations, a method to quickly and reliably estimate dose would help medical responders triage victims to receive life-saving care. We developed such a method using electron paramagnetic resonance (EPR) to make in vivo measurements of the maxillary incisors.

Development of the Implantable Resonator System for Clinical EPR Oximetry.

Hypoxic tumors are more resistant to radiotherapy and chemotherapy, which decreases the efficacy of these common forms of treatment. We have been developing implantable paramagnetic particulates to measure oxygen in vivo using electron paramagnetic resonance. Once implanted, oxygen can be measured repeatedly and non-invasively in superficial tissues (<3 cm deep), using an electron paramagnetic resonance spectrometer and an external surface-loop resonator.

Using India Ink as a Sensor for Oximetry: Evidence of its Safety as a Medical Device.

Unlabelled: Clinical EPR spectroscopy is emerging as an important modality, with the potential to be used in standard clinical practice to determine the extent of hypoxia in tissues and whether hypoxic tissues respond to breathing enriched oxygen during therapy. Oximetry can provide important information useful for prognosis and to improve patient outcomes. EPR oximetry has many potential advantages over other ways to measure oxygen in tissues, including directly measuring oxygen in tissues and being particularly sensitive to low oxygen, repeatable, and non-invasive after an initial injection of the EPR-sensing material is placed in the tumor.

Evolution and Optimization of Tooth Models for Testing In Vivo EPR Tooth Dosimetry.

Testing and verification are an integral part of any cycle to design, manufacture and improve a novel device intended for use in humans. In the case of testing Dartmouth's electron paramagnetic resonance (EPR) in vivo tooth dosimetry device, in vitro studies are needed throughout its development to test its performance, i.e.