David J. Gladstone

Superficial dosimetry imaging of Čerenkov emission in electron beam radiotherapy of phantoms

Čerenkov emission is generated from ionizing radiation in tissue above 264 keV energy. This study presents the first examination of this optical emission as a surrogate for the absorbed superficial dose. Čerenkov emission was imaged from the surface of flat tissue phantoms irradiated with electrons, using a range of field sizes from 6 cm × 6 cm to 20 cm × 20 cm, incident angles from 0° to 50°, and energies from 6 to 18 MeV. The Čerenkov images were compared with the estimated superficial dose in phantoms from direct diode measurements, as well as calculations by Monte Carlo and the treatment planning system. Intensity images showed outstanding linear agreement (R(2) = 0.97) with reference data of the known dose for energies from 6 to 18 MeV. When orthogonal delivery was carried out, the in-plane and cross-plane dose distribution comparisons indicated very little difference (± 2-4% differences) between the different methods of estimation as compared to Čerenkov light imaging. For an incident angle 50°, the Čerenkov images and Monte Carlo simulation show excellent agreement with the diode data, but the treatment planning system had a larger error (OPT = ± 1~2%, diode = ± 2~3%, TPS = ± 6-8% differences) as would be expected. The sampling depth of superficial dosimetry based on Čerenkov radiation has been simulated in a layered skin model, showing the potential of sampling depth tuning by spectral filtering. Taken together, these measurements and simulations indicate that Čerenkov emission imaging might provide a valuable method of superficial dosimetry imaging from incident radiotherapy beams of electrons.

DEVELOPMENT OF IN VIVO TOOTH EPR FOR INDIVIDUAL RADIATION DOSE ESTIMATION AND SCREENING

The development of in vivo EPR has made it feasible to perform tooth dosimetry measurements in situ, greatly expanding the potential for using this approach for immediate screening after radiation exposures. The ability of in vivo tooth dosimetry to provide estimates of absorbed dose has been established through a series of experiments using unirradiated volunteers with specifically irradiated molar teeth placed in situ within gaps in their dentition and in natural canine teeth of patients who have completed courses of radiation therapy for head and neck cancers. Multiple measurements in patients who have received radiation therapy demonstrate the expected heterogeneous dose distributions. Dose-response curves have been generated using both populations and, using the current methodology and instrument, the standard error of prediction based on single 4.5-min measurements is approximately 1.5 Gy for inserted molar teeth and between 2.0 and 2.5 Gy in the more irregularly shaped canine teeth. Averaging of independent measurements can reduce this error significantly to values near 1 Gy. Developments to reduce these errors are underway, focusing on geometric optimization of the resonators, detector positioning techniques, and optimal data averaging approaches. In summary, it seems plausible that the EPR dosimetry techniques will have an important role in retrospective dosimetry for exposures involving large numbers of individuals.

ELECTRON PARAMAGNETIC RESONANCE DOSIMETRY FOR A LARGE-SCALE RADIATION INCIDENT

Abstract With possibilities for radiation terrorism and intensified concerns about nuclear accidents since the recent Fukushima Daiichi event, the potential exposure of large numbers of individuals to radiation that could lead to acute clinical effects has become a major concern. For the medical community to cope with such an event and avoid overwhelming the medical care system, it is essential to identify not only individuals who have received clinically significant exposures and need medical intervention but also those who do not need treatment. The ability of electron paramagnetic resonance to measure radiation-induced paramagnetic species, which persist in certain tissues (e.g., teeth, fingernails, toenails, bone, and hair), has led to this technique becoming a prominent method for screening significantly exposed individuals. Although the technical requirements needed to develop this method for effective application in a radiation event are daunting, remarkable progress has been made. In collaboration with General Electric and through funding committed by the Biomedical Advanced Research and Development Authority, electron paramagnetic resonance tooth dosimetry of the upper incisors is being developed to become a Food and Drug Administration-approved and manufacturable device designed to carry out triage for a threshold dose of 2 Gy. Significant progress has also been made in the development of electron paramagnetic resonance nail dosimetry based on measurements of nails in situ under point-of-care conditions, and in the near future this may become a second field-ready technique. Based on recent progress in measurements of nail clippings, it is anticipated that this technique may be implementable at remotely located laboratories to provide additional information when the measurements of dose on-site need to be supplemented. The authors conclude that electron paramagnetic resonance dosimetry is likely to be a useful part of triage for a large-scale radiation incident.

Real-time, in vivo measurement of radiation dose during radioimmunotherapy in mice using a miniature MOSFET dosimeter probe

This report presents the first real-time measurement of absorbed radiation dose during radioimmunotherapy in mice. Dose rate and total dose at the center of the tumor were measured after administration of 90Y-labeled antibodies using a miniature metal oxide semiconductor field-effect transistor radiation dosimeter probe which was inserted into the center of the tumor volume. Continuous real-time measurements were made for as long as 23 h after injection of the radiolabeled antibodies. Comparison of the real-time dose-rate measurements with estimates based on the MIRD formalism indicates good agreement. The real-time measurements are further compared to measurements made in a second experiment in which groups of mice were sacrificed at individual times after injection of the same radiolabeled antibodies. The real-time measurements agree well with the measurements in excised tumors. The real-time measurements have greater time resolution and are much more efficient than traditional uptake measurements.

Oxygen tomography by Cerenkov-excited phosphorescence during external beam irradiation.

Abstract. The efficacy of radiation therapy depends strongly on tumor oxygenation during irradiation. However, current techniques to measure this parameter in vivo do not facilitate routine monitoring in patients. Herein, we demonstrate a noninvasive method for tomographic imaging of oxygen partial pressure (pO2) in deep tissue using the phosphorescence decay of an oxygen-sensitive probe excited by Čerenkov radiation induced by external beam radiotherapy. Tissue-simulating scattering phantoms (60 mm diameter with a 20 mm anomaly) containing platinum(II)-G4 (PtG4), a dendritic porphyrin-based phosphor, whose phosphorescence is quenched in the presence of oxygen, were irradiated with a clinical linear accelerator. The emitted phosphorescence was measured at various positions on the phantom boundary using a spectrograph coupled to an intensified charge-coupled device (ICCD). At each position, PtG4 phosphorescence decay curves were measured by synchronizing the ICCD to the linear accelerator pulses. Tomographic images of phosphorescence yield and lifetime were recovered for phantoms with homogenous PtG4 concentrations and heterogeneous pO2. Since PtG4 lifetime is strongly and predictably dependent on pO2 through the Stern-Volmer relationship, tomographic images of pO2 were also reported, and showed excellent agreement with independent oxygenation measurements. Translating this approach to the clinic could facilitate direct sensing of pO2 during radiotherapy.

Cherenkov radiation fluence estimates in tissue for molecular imaging and therapy applications.

Cherenkov radiation has recently emerged as an interesting phenomenon for a number of applications in the biomedical sciences. Its unique properties, including broadband emission spectrum, spectral weight in the ultraviolet and blue wavebands, and local generation of light within a given tissue, have made it an attractive new source of light within tissue for molecular imaging and phototherapy applications. While several studies have investigated the total Cherenkov light yield from radionuclides in units of [photons/decay], further consideration of the light propagation in tissue is necessary to fully consider the utility of this signal in vivo. Therefore, to help further guide the development of this novel field, quantitative estimates of the light fluence rate of Cherenkov radiation from both radionuclides and radiotherapy beams in a biological tissue are presented for the first time. Using Monte Carlo simulations, these values were found to be on the order of 0.01-1 nW cm(-2) per MBq g(-1) for radionuclides, and 1-100 μW cm(-2) per Gy s(-1) for external radiotherapy beams, dependent on the given waveband, optical properties, and radiation source. For phototherapy applications, the total light fluence was found to be on the order of nJ cm(-2) for radionuclides, and mJ cm(-2) for radiotherapy beams. The results indicate that diagnostic potential is reasonable for Cherenkov excitation of molecular probes, but phototherapy may remain elusive at such exceedingly low fluence values. The results of this study are publicly available for distribution online at www.dartmouth.edu/optmed/.

Comparison of Cherenkov excited fluorescence and phosphorescence molecular sensing from tissue with external beam irradiation.

Ionizing radiation delivered by a medical linear accelerator (LINAC) generates Cherenkov emission within the treated tissue. A fraction of this light, in the 600-900 nm wavelength region, propagates through centimeters of tissue and can be used to excite optical probes in vivo, enabling molecular sensing of tissue analytes. The success of isolating the emission signal from this Cherenkov excitation background is dependent on key factors such as: (i) the Stokes shift of the probe spectra; (ii) the excited state lifetime; (iii) the probe concentration; (iv) the depth below the tissue surface; and (v) the radiation dose used. Previous studies have exclusively focused on imaging phosphorescent dyes, rather than fluorescent dyes. However there are only a few biologically important phosphorescent dyes and yet in comparison there are thousands of biologically relevant fluorescent dyes. So in this study the focus was a study of efficacy of Cherenkov-excited luminescence using fluorescent commercial near-infrared probes, IRDye 680RD, IRDye 700DX, and IRDye 800CW, and comparing them to the well characterized phosphorescent probe Oxyphor PtG4, an oxygen sensitive dye. Each probe was excited by Cherenkov light from a 6 MV external radiation beam, and measured in continuous wave or time-gated modes. The detection was performed by spectrally resolving the luminescence signals, and measuring them with spectrometer-based separation on an ICCD detector. The results demonstrate that IRDye 700DX and PtG4 allowed for the maximal signal to noise ratio. In the case of the phosphorescent probe, PtG4, with emission decays on the microsecond (μs) time scale, time-gated acquisition was possible, and it allowed for higher efficacy in terms of the probe concentration and detection depth. Phantoms containing the probe at 5 mm depth could be detected at concentrations down to the nanoMolar range, and at depths into the tissue simulating phantom near 3 cm. In vivo studies showed that 5 nmol of dye was readily detected with radiation doses less than 5 cGy. Since concentration, radiation dose and depth each contribute to the level of the detected signal, it may be possible to improve any of these parameters at expense of the others. This paradigm of nanoMolar sensitivity for optical reporters in vivo introduces the concept of molecular sensing of tumors during therapy or diagnostically with biologically relevant concentrations of fluorescent reporters.

Light sheet luminescence imaging with Cherenkov excitation in thick scattering media

Light scattering leads to a severe loss of axial and transverse resolution with depth into tissue, limiting accuracy and value of biomedical luminescence imaging techniques. High-resolution imaging beyond a few-millimeter depth is prohibited because diffusive transport dominates beyond a few scattering distances. In this study, light sheet imaging through scattering media is demonstrated using a radiotherapy linear accelerator to deliver well-defined thin scanned sheets of x-rays. These sheets produce Cherenkov light within the medium, which in turn excites luminescence of an optical probe across the sheet plane. This luminescence can then be imaged by an intensified camera positioned perpendicular to the sheet plane. The precise knowledge of the light sheet position within the medium allowed for efficient attenuation correction of the signal with depth as well as spatial deconvolution of the excitation light. Together these methods allowed for the first time, to the best of our knowledge, high-resolution imaging of tissue-equivalent phantoms up to 3 cm thick, yielding the precise position and shape of luminescent lesions located deep in tissue without the need for nonlinear image reconstruction.

Effect of radiation energy and intracellular iron dose on iron oxide nanoparticle enhancement of radiation cytotoxicity

Iron oxide nanoparticles (IONPs) are one of several high-Z materials currently being investigated for their ability to enhance the cytotoxic effects of therapeutic ionizing radiation. Studies with iron oxide, silver, gold, and hafnium oxide suggest radiation dose, radiation energy, cell type, and the type and level of metallic nanoparticle are all critical factors in achieving radiation enhancement in tumor cells. Using a single 4 Gy radiation dose, we compared the level of tumor cell cytotoxicity at two different intracellular iron concentrations and two different radiation energies in vitro. IONPs were added to cell culture media at concentrations of 0.25 mg Fe/mL and 1.0 mg Fe/mL and incubated with murine breast adenocarcinoma (MTG-B) cells for 72 hours. Extracellular iron was then removed and cells were irradiated at either 662 keV or 10 MV. At the 0.25 mg Fe/mL dose (4 pg Fe/cell), radiation energy did not affect the level of cytotoxicity. However with 1.0 mg Fe/mL (9 pg Fe/cell), the higher 10 MV radiation energy resulted in 50% greater cytotoxicity as compared to cells without IONPs irradiated at this energy. These results suggest IONPs may be able to significantly enhance the cytotoxic effects of radiation and improve therapeutic ratio if they can be selectively associated with cancer cells and/or tumors. Ongoing in vivo studies of IONP radiation enhancement in a murine tumor model are too immature to draw conclusions from at this time, however preliminary data suggests similar effectiveness of IONP radiation enhancement at 6 MV and 18 MV energy levels. In addition to the IONP-based radiation enhancement demonstrated here, the use of tumor-localized IONP with an externally delivered, non-toxic alternating magnetic field affords the opportunity to selectively heat and kill tumor cells. Combining IONP-based radiation sensitization and heat-based cytotoxicity provides a unique and potentially highly effective opportunity for therapeutic ratio enhancement.

Cherenkov imaging in the potential roles of radiotherapy QA and delivery

Cherenkov emission has a direct proportionality to the deposited dose at the local level, and capture of these emitted light signals allows visualization of real time maps of dose in vivo. Mapping the Cherenkov signals through water tanks illustrates how 3D Cherenkov can be achieved, either as 2D plus time, or 3D in static imaging. Imaging Cherenkov from patients shows how signals can be acquired which map out radiation dose in real time. The signals are affected by several factors, each of which will take some calibration to resolve, yet intrinsically the signal is shown to be a linear reporter of dose delivered. Development of calibration methodologies is ongoing in both research and development work.