Optical photon emission is observed when a charged particle moves faster than the speed of light in a given dielectric medium [1]. This phenomenon, known as Cherenkov emission, has found applications in the field of optical molecular imaging through Cherenkov luminescence imaging, a novel technique for tracking $\beta$-emitting radionuclides in vivo [2–8]. Additionally, linear accelerator (LINAC)-induced Cherenkov emission spectroscopy (CES) has recently been investigated for both fluorescence and absorption spectroscopy methods [9,10]. As a result of the exponential dependence of the Cherenkov photon yield with particle energy, the optical emission per particle from a 6 to 24 MeV LINAC beam is approximately 2 to 3 orders of magnitude greater than Cherenkov emission from isotopic $\beta$-emitters, which are typically less than 1 MeV. As such, the CES signal strength during external beam radiotherapy (EBRT) is reasonably high (${10}^{-6}$ to ${10}^{-9}\mathrm{W}/{\mathrm{cm}}^2$) and could potentially be used for clinical disease treatment and monitoring. While sufficiently high to measure, it is still well below room light levels, which is a challenge for practical use. In this study, we address the issue of signal acquisition during ambient room lighting by demonstrating gated detection of Cherenkov emission from a LINAC when operating in a standard pulsed delivery mode.

Previous CES studies have relied on the cw signal collection in the absence of ambient lighting. [9,10] While commercial incandescent lights have an irradiance of ${10}^{-1}$ to ${10}^{-3}\mathrm{W}/{\mathrm{cm}}^2$, the Cherenkov emission irradiances from a LINAC or PET agent are roughly ${10}^{-6}$ to ${10}^{-9}\mathrm{W}/{\mathrm{cm}}^2$ and ${10}^{-8}$ to ${10}^{-12}\mathrm{W}/{\mathrm{cm}}^2$, depending directly upon the dose rate of irradiation. Direct measurement of room light varies considerably around a room due to the directionality of light sources, so the ranges here are meant to cover the widest range of variation. These large differences in optical irradiance make CW detection of Cherenkov emission impossible in the presence of ambient light. PET agent CES works through imaging in a closed environment with a near complete absence of light. In comparison, LINAC radiation is produced in pulsed microseconds-long bursts, as generated by the accelerator waveguide. Thus, by taking advantage of a linear accelerator’s inherent pulsed operation, time-gated detection of Cherenkov emission is possible to significantly improve the signal-to-ambient light ratio.

The linear accelerator (Varian LINAC 2100C, Varian Medical Systems, Palo Alto, CA) used in this study delivers a 5 μs radiation pulse every 5 ms, resulting in a potential $\sim 1000\times$ rejection of room light during gated detection. As a result, under dimmed room lighting conditions, the ambient and Cherenkov optical signals are nearly equivalent in intensity. Additionally, by picking up light directionally from the tissue using fiber optics or a lens system, it is feasible to increase the Cherenkov signal over the ambient room light by at least 1 to 2 orders of magnitude.

In this study, optical spectra were detected using an imaging spectrograph (SpectraPro 300, Princeton Instruments, Acton, Mass.) equipped with a $300\text{lines}/\mathrm{mm}$ grating blazed at 750 nm, connected to a front-illuminated CCD camera (PI-MAX3 RB GEN II, Princeton Instruments, Acton, Mass.) cooled to $-25°\mathrm{C}$. The system was placed outside of the treatment room, and light was collected using a 13 m long fiber bundle (Zlight, Latvia) comprised of seven 400 μm diameter silica fibers in a hexagonal tip geometry (see Fig. 1). For every experiment, the fiber tip was placed in the center of the radiation beam at the phantom surface. An analog trigger out voltage was obtained from the linear accelerator control unit and fed into the external trigger port of the CCD camera using a BNC cable. In an iterative manner, the delay between the falling edge of the trigger signal and rising edge of the linear accelerator beam on pulse was found to be 3 μs. The trigger delay, gate width, and frequency were used in conjunction with the LIGHTFIELD software package (Princeton Instruments, Acton, Mass.) for accurate gating and signal acquisition from the spectrometer-CCD coupled system (see Fig. 2).

 

Fig. 1. (a) The experimental setup is shown with the computer-controlled spectrometer CCD system located outside of the treatment room with Cherenkov light collected through a 13 m optical fiber. The trigger signal was obtained from the LINAC external control unit outside the room. (b) Schematic of Cherenkov emission in a phantom is illustrated. The radiation beam travels downward with a rectangular cross-section producing a column of Cherenkov emission below the surface. The optical fiber was placed on the phantom surface with the tip in the center of the beam.

Download Full Size | PDF

 

Fig. 2. The timeline of events for the ambient lights, output trigger, radiation beam output, and CCD shutter is shown. The periods of beam on and subsequent Cherenkov emission are shown in shaded blue.

Download Full Size | PDF

Spectra were first acquired in a scattering phantom composed of phosphate-buffered solution and 1% $\mathrm{v}/\mathrm{v}$ Intralipid (Sigma Aldrich, Saint Louis, MO) (see Fig. 3). For all experiments, a $4\times 4\mathrm{cm}$ 18 MeV ${\beta }^{-}$ radiation beam at a dose rate of $4\mathrm{Gy}/\min$ was used to maximize the Cherenkov emission. Each spectrum was acquired at $100/100\times$ gain by averaging 1000 consecutive frames for a total acquisition time of approximately 6 s, corresponding to an acceptable treatment dose of $\sim 40\mathrm{cGy}$. The gated signal spectrum was triggered externally by the linear accelerator with the beam and ambient lights on. Similarly, the ambient lights spectrum was triggered internally with the beam off and gating parameters identical to that of the gated signal. Isolation of the Cherenkov emission signal was obtained by calculating the difference between the two. All spectra were subject to background subtraction to account for characteristic system noise buildup at the high $100/100\times$ gain. The results, shown in Fig. 3(a), demonstrate that gated acquisition is successful in reducing the ambient lights signal to a low-intensity DC signal similar to noise. The signal-to-noise ratio for the Cherenkov was $S/N=60$ for this acquisition in an individual pixel on the CCD, and signal to background ($S/B$) was 72, whereas similar acquisition in a nongated manner would have $S/B$ much less than unity. This means the signal is readily measured in this subdued lighting, and small lighting offsets can be subtracted off as need be.

 

Fig. 3. (a) The gated detection of Cherenkov emission with room lights on is shown with spectra acquired from a scattering phantom. The Cherenkov emission is obtained by calculating the difference between the gated signal and ambient lighting signal. (b) A photograph of the room with a corresponding image of Cherenkov emission from a human head phantom for radiation therapy are overlaid to illustrate the amount of ambient lighting present for all experiments.

Download Full Size | PDF

For illustrative purposes, an autoexposure white light image of the tissue head phantom with ambient lighting levels was used in all experiments and was overlaid with a 30 s exposure image of the induced Cherenkov emission in the absence of ambient lights [Fig. 3(b)]. Both images were captured using a standard CMOS camera (Rebel T3i, Canon, Tokyo, Japan) with a standard kit lens, and the latter was processed with a $20\times 20$ pixel median filter.

To further explore the implications of this system for CES applications, tissue-mimicking phantoms were mixed with phosphate buffered solution, 1% $\mathrm{v}/\mathrm{v}$ Intralipid and 1% $\mathrm{v}/\mathrm{v}$ porcine blood (see Fig. 4). Phantoms were deoxygenated using a glucose oxidase-catalase reaction (Thermo Fisher Scientific, Waltham, Mass.), and reference oxygenation saturation measurements were performed using an ischemia monitoring system (Spectros T-Stat, Spectros, Portola Valley, Calif.) [11]. The absorption signatures due to hemoglobin are apparent in the acquired spectrum relative to the absence of an absorber and the isobestic points of oxy/deoxy hemoglobin easily visible in the 550 to 600 nm spectral region. Using a diffusion-theory-based fitting algorithm, these changes have been made quantitative in recovery of factors such as hemoglobin concentration and oxygen saturation, which could have clinical significance in monitoring disease progression and treatment efficacy [9].

 

Fig. 4. The gated detection of Cherenkov emission in a tissue-simulating phantom is shown in with spectra of a phantom having no blood (black line), as well as oxygenated and deoxygenated blood (red and blue lines, respectively). Inset highlights the isosbestic region observed in the signal at the 550 to 600 nm spectral range.

Download Full Size | PDF

The benefit of such a system can be realized when considering the importance of tumor oxygenation in the outcome of EBRT, as studies have shown hypoxic tumors to be less responsive to treatment due to inadequate damage to tumor DNA [12,13]. Additional clinical studies have also correlated tissue oxygen pressure (${\mathrm{pO}}_2$) to EBRT effect in head and neck cancers and suggested that ${\mathrm{pO}}_2$ increases during fractionated treatment plans [14,15]. Therefore, there is great potential value in a noninvasive technique, such as CES, for monitoring tumor oxygen saturation during EBRT. One previous issue with this modality was the inability to acquire a signal in the presence of ambient room lighting. Due to the irradiance differences between typical room lighting and Cherenkov emission from LINAC radiation, previous studies in CW-CES acquisition were not feasible due to ambient light contamination. This inability to make measurements in a conventional radiation treatment environment raises concern for patient and physician compliance; however, the gated CCD system presented here offers a partial solution to this problem through a $\sim 1000\times$ reduction in ambient light contribution to the CES signal when the radiation is gated, such as with a LINAC. Future studies can further increase this gain by creation of pick-up fibers, which have shaded regions to further suppress directional room light in even brighter light conditions.