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Purpose: This study demonstrates a robust Cherenkov imaging-based solution to MR-Linac daily QA, including mechanical-imaging-radiation isocenter coincidence verification., Methods: A fully enclosed acrylic cylindrical phantom was designed to be mountable to the existing jig, indexable to the treatment couch. An ABS plastic conical structure was fixed inside the phantom, held in place with 3D-printed spacers, and filled with water allowing for high edge contrast on MR imaging scans. Both a star shot plan and a four-angle sheet beam plan were delivered to the phantom; the former allowed for radiation isocenter localization in the x-z plane (A/P and L/R directions) relative to physical landmarks on the phantom, and the latter allowed for the longitudinal position of the sheet beam to be encoded as a ring of Cherenkov radiation emitted from the phantom, allowing for isocenter localization on the y-axis (S/I directions). A custom software application was developed to perform near-real-time analysis of the data by any clinical user., Results: Calibration procedures show that linearity between longitudinal position and optical ring diameter is high (R 2  > 0.99), and that RMSE is low (0.184 mm). The star shot analysis showed a minimum circle radius of 0.34 mm. The final isocenter coincidence measurements in the lateral, longitudinal, and vertical directions were -0.61 mm, 0.55 mm, and -0.14 mm, respectively, and the total 3D distance coincidence was 0.83 mm, with each of these being below 2 mm tolerance., Conclusion: This novel system provided an efficient, MR safe, all-in-one method for acquisition and near-real-time analysis of isocenter coincidence data. This represents a direct measurement of the 3D isocentricity. The combination of this phantom and the custom analysis application makes this solution readily clinically deployable after the longitudinal analysis of performance consistency., (© 2021 American Association of Physicists in Medicine.)

Purpose: Treatment planning systems (TPSs) for MR-linacs must employ Monte Carlo-based simulations of dose deposition to model the effects of the primary magnetic field on dose. However, the accuracy of these simulations, especially for areas of tissue-air interfaces where the electron return effect (ERE) is expected, is difficult to validate due to physical constraints and magnetic field compatibility of available detectors. This study employs a novel dosimetric method based on remotely captured, real-time optical Cherenkov and scintillation imaging to visualize and quantify the ERE., Methods: An intensified CMOS camera was used to image two phantoms with designed ERE cavities. Phantom A was a 40 cm × 10 cm × 10 cm clear acrylic block drilled with five holes of increasing diameters (0.5, 1, 2, 3, 4 cm). Phantom B was a clear acrylic block (25 cm × 20 cm × 5 cm) with three cavities of increasing diameter (3, 2, 1 cm) split into two halves in the transverse plane to accommodate radiochromic film. Both phantoms were imaged while being irradiated by 6 MV flattening filter free (FFF) beams within a MRIdian Viewray (Viewray, Cleveland, OH) MR-linac (0.34 T primary field). Phantom A was imaged while being irradiated by 6 MV FFF beams on a conventional linac (TrueBeam, Varian Medical Systems, San Jose, CA) to serve as a control. Images were post processed in Matlab (Mathworks Inc., Natick, MA) and compared to TPS dose volumes., Results: Control imaging of Phantom A without the presence of a magnetic field supports the validity of the optical image data to a depth of 6 cm. In the presence of the magnetic field, the optical data shows deviations from the commissioned TPS dose in both intensity and localization. The largest air cavity examined (3 cm) indicated the largest dose differences, which were above 20% at some locations. Experiments with Phantom B illustrated similar agreement between optical and film dosimetry comparisons with TPS data in areas not affected by ERE., Conclusion: There are some appreciable differences in dose intensity and spatial dose distribution observed between the novel experimental data set and the dose models produced by the current clinically implemented MR-IGRT TPS., (© 2019 American Association of Physicists in Medicine.)

An approach using direct regularization from co-registered dynamic contrast enhanced magnetic reson- ance images was used to reconstruct near-infrared spectral tomography patient images, which does not need image segmentation. 20 patients with mammography/ultrasound confirmed breast abnormalities were involved in this paper, and the resulting images indicated that tumor total hemoglobin concentration contrast differentiated malignant from benign cases (p-value = 0.021). The approach prod- uced reconstructed images, which significantly reduced surface artifacts near the source-detector locations (p-value = 4.16e-6).

Background: While dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is recognized as the most sensitive examination for breast cancer detection, it has a substantial false positive rate and gadolinium (Gd) contrast agents are not universally well tolerated. As a result, alternatives to diagnosing breast cancer based on endogenous contrast are of growing interest. In this study, endogenous near-infrared spectral tomography (NIRST) guided by T2 MRI was evaluated to explore whether the combined imaging modality, which does not require contrast injection or involve ionizing radiation, can achieve acceptable diagnostic performance., Methods: Twenty-four subjects-16 with pathologically confirmed malignancy and 8 with benign abnormalities-were simultaneously imaged with MRI and NIRST prior to definitive pathological diagnosis. MRIs were evaluated independently by three breast radiologists blinded to the pathological results. Optical image reconstructions were constrained by grayscale values in the T2 MRI. MRI and NIRST images were used, alone and in combination, to estimate the diagnostic performance of the data. Outcomes were compared to DCE results., Results: Sensitivity, specificity, accuracy, and area under the curve (AUC) of noncontrast MRI when combined with T2-guided NIRST were 94%, 100%, 96%, and 0.95, respectively, whereas these values were 94%, 63%, 88%, and 0.81 for DCE MRI alone, and 88%, 88%, 88%, and 0.94 when DCE-guided NIRST was added., Conclusion: In this study, the overall accuracy of imaging diagnosis improved to 96% when T2-guided NIRST was added to noncontrast MRI alone, relative to 88% for DCE MRI, suggesting that similar or better diagnostic accuracy can be achieved without requiring a contrast agent.

Purpose: The purpose of this study was to determine the diagnostically most important molecular biomarkers quantified by magnetic resonance-guided (MR) near-infrared spectral tomography (NIRST) that distinguish malignant breast lesions from benign abnormalities when combined with outcomes from clinical breast MRI., Experimental Design: The study was HIPAA compliant and approved by the Dartmouth Institutional Review Board, the NIH, the United States State Department, and Xijing Hospital. MR-guided NIRST evaluated hemoglobin, water, and lipid content in regions of interest defined by concurrent dynamic contrast-enhanced MRI (DCE-MRI) in the breast. MRI plus NIRST was performed in 44 subjects (median age, 46, age range, 20-81 years), 28 of whom had subsequent malignant pathologic diagnoses, and 16 had benign conditions. A subset of 30 subject examinations yielded optical data that met minimum sensitivity requirements to the suspicious lesion and were included in the analyses of diagnostic performance., Results: In the subset of 30 subject examinations meeting minimum optical data sensitivity criterion, the MR-guided NIRST separated malignant from benign lesions using total hemoglobin (HbT; P < 0.01) and tissue optical index (TOI; P < 0.001). Combined MRI plus TOI data caused one false positive and 1 false negative, and produced the best diagnostic performance, yielding an AUC of 0.95, sensitivity of 95%, specificity of 89%, positive predictive value of 95%, and negative predictive value of 89%, respectively., Conclusions: MRI plus NIRST results correlated well with histopathologic diagnoses and could provide additional information to reduce the number of MRI-directed biopsies., (©2015 American Association for Cancer Research.)

An optimized approach to nonlinear iterative reconstruction of magnetic resonance imaging (MRI)-guided near-infrared spectral tomography (NIRST) images was developed using an L-curve-based algorithm for the choice of regularization parameter. This approach was applied to clinical exam data to maximize the reconstructed values differentiating malignant and benign lesions. MRI/NIRST data from 25 patients with abnormal breast readings (BI-RADS category 4-5) were analyzed using this optimal regularization methodology, and the results showed enhanced p values and area under the curve (AUC) for the task of differentiating malignant from benign lesions. Of the four absorption parameters and two scatter parameters, the most significant differences for benign versus malignant were total hemoglobin (HbT) and tissue optical index (TOI) with p values = 0.01 and 0.001, and AUC values = 0.79 and 0.94, respectively, in terms of HbT and TOI. This dramatically improved the values relative to fixed regularization (p value = 0.02 and 0.003; AUC = 0.75 and 0.83) showing that more differentiation was possible with the optimal method. Through a combination of both biomarkers, HbT and TOI, the AUC increased from 82.9% (fixed regulation = 0.1) to 94.3% (optimal method).

The ability to image targeted tracer binding to epidermal growth factor receptor (EGFR) was studied in vivo in orthotopically grown glioma tumors of different sizes. The binding potential was quantified using a dual-tracer approach, which employs a fluorescently labeled peptide targeted to EGFR and a reference tracer with similar pharmacokinetic properties but no specific binding, to estimate the relative bound fraction from kinetic compartment modeling. The recovered values of binding potential did not vary significantly as a function of tumor size (1 to 33 mm3), suggesting that binding potential may be consistent in the U251 tumors regardless of size or stage after implantation. However, the fluorescence yield of the targeted fluorescent tracers in the tumor was affected significantly by tumor size, suggesting that dual-tracer imaging helps account for variations in absolute uptake, which plague single-tracer imaging techniques. Ex vivo analysis showed relatively high spatial heterogeneity in each tumor that cannot be resolved by tomographic techniques. Nonetheless, the dual-tracer tomographic technique is a powerful tool for longitudinal bulk estimation of receptor binding., (© The Authors.)

Rationale and Objectives: Near-infrared spectroscopy (NIRS) of breast can provide functional information on the vascular and structural compartments of tissues in regions identified during simultaneous magnetic resonance imaging (MRI). NIRS can be acquired during dynamic contrast-enhanced MRI (DCE-MRI) to accomplish image-guided spectroscopy of the enhancing regions, potentially increasing the diagnostic specificity of the examination and reducing the number of biopsies performed as a result of inconclusive MRI breast imaging studies., Materials and Methods: We combine synergistic attributes of concurrent DCE-MRI and NIRS with a new design of the clinical NIRS breast interface that couples to a standard MR breast coil and allows imaging of variable breast sizes. Spectral information from healthy volunteers and cancer patients is recovered, providing molecular information in regions defined by the segmented MR image volume., Results: The new coupling system significantly improves examination utility by allowing improved coupling of the NIR fibers to breasts of all cup sizes and lesion locations. This improvement is demonstrated over a range of breast sizes (cup size A through D) and normal tissue heterogeneity using a group of eight healthy volunteers and two cancer patients. Lesions located in the axillary region and medial-posterior breast are now accessible to NIRS optodes. Reconstructed images were found to have biologically plausible hemoglobin content, oxygen saturation, and water and lipid fractions., Conclusions: In summary, a new NIRS/MRI breast interface was developed to accommodate the variation in breast sizes and lesion locations that can be expected in clinical practice. DCE-MRI-guided NIRS quantifies total hemoglobin, oxygenation, and scattering in MR-enhancing regions, increasing the diagnostic information acquired from MR examinations., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

A new optical parallel detection system of hybrid frequency and continuous-wave domains was developed to improve the data quality and accuracy in recovery of all breast optical properties. This new system was deployed in a previously existing system for magnetic resonance imaging (MRI)-guided spectroscopy, and allows incorporation of additional near-infrared wavelengths beyond 850 nm, with interlaced channels of photomultiplier tubes (PMTs) and silicon photodiodes (PDs). The acquisition time for obtaining frequency-domain data at six wavelengths (660, 735, 785, 808, 826, and 849 nm) and continuous-wave data at three wavelengths (903, 912, and 948 nm) is 12 min. The dynamic ranges of the detected signal are 105 and 106 for PMT and PD detectors, respectively. Compared to the previous detection system, the SNR ratio of frequency-domain detection was improved by nearly 103 through the addition of an RF amplifier and the utilization of programmable gain. The current system is being utilized in a clinical trial imaging suspected breast cancer tumors as detected by contrast MRI scans.

Tissue spectroscopy inside the magnetic resonance imaging (MRI) system adds a significant value by measuring fast vascular hemoglobin responses or completing spectroscopic identification of diagnostically relevant molecules. Advances in this type of spectroscopy instrumentation have largely focused on fiber coupling into and out of the MRI; however, nonmagnetic detectors can now be placed inside the scanner with signal amplification performed remotely to the high field environment for optimized light detection. In this study, the two possible detector options, such as silicon photodiodes (PD) and silicon photomultipliers (SiPM), were systematically examined for dynamic range and wavelength performance. Results show that PDs offer 10⁸(160 dB) dynamic range with sensitivity down to 1 pW, whereas SiPMs have 10⁷(140 dB) dynamic range and sensitivity down to 10 pW. A second major difference is the spectral sensitivity of the two detectors. Here, wavelengths in the 940 nm range are efficiently captured by PDs (but not SiPMs), likely making them the superior choice for broadband spectroscopy guided by MRI.

The up-regulation of cell surface receptors has become a central focus in personalized cancer treatment; however, because of the complex nature of contrast agent pharmacokinetics in tumor tissue, methods to quantify receptor binding in vivo remain elusive. Here, we present a dual-tracer optical technique for noninvasive estimation of specific receptor binding in cancer. A multispectral MRI-coupled fluorescence molecular tomography system was used to image the uptake kinetics of two fluorescent tracers injected simultaneously, one tracer targeted to the receptor of interest and the other tracer a nontargeted reference. These dynamic tracer data were then fit to a dual-tracer compartmental model to estimate the density of receptors available for binding in the tissue. Applying this approach to mice with deep-seated gliomas that overexpress the EGF receptor produced an estimate of available receptor density of 2.3 ± 0.5 nM (n = 5), consistent with values estimated in comparative invasive imaging and ex vivo studies.

The sensitivity and specificity of in vivo magnetic resonance (MR) imaging is compared with production of protoporphyrin IX (PpIX), determined ex vivo, in a diffusely infiltrating glioma. A human glioma transfected with green fluorescent protein, displaying diffuse, infiltrative growth, was implanted intracranially in athymic nude mice. Image contrast from corresponding regions of interest (ROIs) in in vivo MR and ex vivo fluorescence images was quantified. It was found that all tumor groups had statistically significant PpIX fluorescence contrast and that PpIX contrast demonstrated the best predictive power for tumor presence. Contrast from gadolinium enhanced T1-weighted (T1W+Gd) and absolute T2 images positively predicted the presence of a tumor, confirmed by the GFP positive (GFP+) and hematoxylin and eosin positive (H&E+) ROIs. However, only the absolute T2 images had predictive power from controls in ROIs that were GFP+ but H&E negative. Additionally, PpIX fluorescence and T1W+Gd image contrast were linearly correlated in both the GFP+ (r = 0.79, p<1×10(-8)) and H&E+ (r = 0.74, p<0.003) ROIs. The trace diffusion images did not have predictive power or significance from controls. This study indicates that gadolinium contrast enhanced MR images can predict the presence of diffuse tumors, but PpIX fluorescence is a better predictor regardless of tumor vascularity.

The design and testing of a pneumatic optical positioning interface produced with the goal of improving fiber positioning in magnetic resonance (MR)-guided diffuse spectral imaging of breast cancer is presented. The system was created for vertical positioning of optical fibers inside the MR bore during a patient exam to target suspicious lesions with MR scans for reference and collect multiple planes of optical data. The interface includes new fiber plates for mechanical and optical coupling to the breast, and was tested in phantoms and human imaging. Reconstructions with data taken in the new interface show acceptable linearity over different absorber concentrations (residual norm = 0.067), and exhibit good contrast recovery at different imaging planes, which is consistent with previous work. An example of human breast imaging through the new interface is shown and a discussion of how it compares to other patient interfaces for breast imaging is presented. Design goals of increasing the available degrees of freedom for fiber positioning while maintaining good patient-fiber contact and comfort were accomplished. This interface allows improved volumetric imaging with interactive and accurate slice selection to quantify targeted suspicious lesions.

Magnetic resonance (MR) guided optical breast imaging is a promising modality to improve the specificity of breast imaging, because it provides high-resolution quantitative maps of total hemoglobin, oxygen saturation, water content, and optical scattering. These properties have been shown to distinguish malignant from benign lesions. However, the optical detection hardware required for deep tissue imaging has poor spectral sensitivity which limits accurate water quantification; this reduces the accuracy of hemoglobin quantification. We present a methodology to improve optical quantification by utilizing the ability of Dixon MR imaging to quantitatively estimate water and fat; this technique effectively reduces optical crosstalk between water and oxyhemoglobin. The techniques described in this paper reduce hemoglobin quantification error by as much as 38%, as shown in a numerical phantom, and an experimental phantom. Error is reduced by as much 20% when imperfect MR water quantification is given. These techniques may also increase contrast between diseased and normal tissue, as shown in breast tissue in vivo. It is also shown that using these techniques may permit fewer wavelengths to be used with similar quantitative accuracy, enabling higher temporal resolution. In addition, it is shown that these techniques can improve the ability of MRI to quantify water in the presence of bias in the Dixon water/fat separation.

A near-IR (NIR) tomography system with spectral-encoded sources was built to quantify the temporal contrast in human breast tissue using guidance from magnetic resonance imaging. The systems were integrated with a custom breast coil interface to provide simultaneous acquisition. The NIR signal was synchronized to simultaneous finger pulse oximeter plethysmogram, which offered a frequency reference. A 0.1 s temporal delay of the absorption pulse within adipose tissue relative to fibroglandular tissue was found, in an initial human study, showing the potential for novel contrast imaging of fast flow signals in deep tissue.

We demonstrate quantitative functional imaging using image-guided near-infrared spectroscopy (IG-NIRS) implemented with the boundary element method (BEM) for reconstructing 3-D optical property estimates in breast tissue in vivo. A multimodality MRI-NIR system was used to collect measurements of light reflectance from breast tissue. The BEM was used to model light propagation in 3-D based only on surface discretization in order to reconstruct quantitative values of total hemoglobin (HbT), oxygen saturation, water, and scatter. The technique was validated in experimental measurements from heterogeneous breast-shaped phantoms with known values and applied to a total of seven subjects comprising six healthy individuals and one participant with cancer imaged at two time points during neoadjuvant chemotherapy. Using experimental measurements from a heterogeneous breast phantom, BEM for IG-NIRS produced accurate values for HbT in the inclusion with a <3% error. Healthy breast tissues showed higher HbT and water in fibroglandular tissue than in adipose tissue. In a subject with cancer, the tumor showed higher HbT compared to the background. HbT in the tumor was reduced by 9 μM during treatment. We conclude that 3-D MRI-NIRS with BEM provides quantitative and functional characterization of breast tissue in vivo through measurement of hemoglobin content. The method provides potentially complementary information to DCE-MRI for tumor characterization.

This study investigates differences in the response of breast tumor tissue versus healthy fibroglandular tissue to inspired gases. Cycles of carbogen and oxygen gas are administered while measuring the changes with magnetic-resonance-guided near-infrared imaging in a pilot study of breast cancers. For two patients, analyses are performed with cross-correlation techniques, which measure the strength of hemodynamic modulation. The results show that the overall vasoresponse, indicated by total hemoglobin, of healthy tissue has approximately a 72% and 41% greater correlation to the gas stimulus than the tumor region, in two patients respectively, when background physiological changes are controlled. These data support the hypothesis that tumor vasculature has a poorly functioning vasodilatory mechanism, most likely caused by dysfunctional smooth muscle cells lining the vasculature. This study presents a methodology to quantitatively analyze inspired gas changes in human breast tumors, and demonstrates this technique in a pilot patient population.

Rationale and Objectives: This report demonstrates the diagnostic potential of magnetic resonance imaging (MRI)-coupled fluorescence molecular tomography (FMT) to determine epidermal growth factor receptor (EGFR) status in brain cancer., Materials and Methods: Two orthotopic glioma xenograft models were used in this study: one represented high EGFR expression and the other low expression. Nude mice were inoculated with cells from either one of the tumor lines or were used in a sham surgery control group. Animals were imaged using a unique MRI-FMT scanner 48 hours after intravenous injection of a near-infrared fluorophore bound to epidermal growth factor (EGF) ligand. Coronal images of fluorescence activity of the injected dye in the mouse brain were recovered using the MRI images as anatomical templates., Results: In vivo images of fluorescence activity showed significant differences between animal populations, an observation confirmed by receiver operating characteristic analysis that revealed 100% sensitivity and specificity between animal groups implanted with EGFR((+)) and EGFR((-)) tumor lines. Similar performance was observed between EGFR((+)) and sham surgery control animals., Conclusions: This preclinical study suggests that MRI-FMT with fluorescent EGF provides excellent discrimination between tumors based on EGFR status. Reliable quantification of receptor status using minimally invasive techniques would be an important innovation for investigating new and existing cancer treatments that target these cellular mechanisms in research animals, and may be applied to identify receptor amplification in human brain cancer patients. This study represents the first systematic multianimal validation of receptor-specific imaging using MRI-guided fluorescence tomography.

Purpose: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed., Methods and Materials: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively., Results: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line., Conclusions: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

A high frame-rate near-infrared (NIR) tomography system was created to allow transmission imaging of thick tissues with spectral encoding for parallel source implementation. The design was created to maximize tissue penetration through up to 10 cm of tissue, allowing eventual use in human imaging. Eight temperature-controlled laser diodes (LD) are used in parallel with 1.5 nm shifts in their lasing wavelengths. Simultaneous detection is achieved with eight high-resolution, CCD-based spectrometers that were synchronized to detect the intensities and decode their source locations from the spectrum. Static and dynamic imaging is demonstrated through a 64 mm tissue-equivalent phantom, with acquisition rates up to 20 frames per second. Imaging of pulsatile absorption changes through a 72 mm phantom was demonstrated with a 0.5 Hz varying object having only 1% effect upon the transmitted signal. This subtle signal change was used to show that while reconstructing the signal changes in a tissue may not be possible, image-guided recovery of the pulsatile change in broad regions of tissue was possible. The ability to image thick tissue and the capacity to image periodic changes in absorption makes this design well suited for tracking thick tissue hemodynamics in vivo during MR or CT imaging.

A multichannel spectrally resolved optical tomography system to image molecular targets in small animals from within a clinical MRI is described. Long source/detector fibers operate in contact mode and couple light from the tissue surface in the magnet bore to 16 spectrometers, each containing two optical gratings optimized for the near infrared wavelength range. High sensitivity, cooled charge coupled devices connected to each spectrograph provide detection of the spectrally resolved signal, with exposure times that are automated for acquisition at each fiber. The design allows spectral fitting of the remission light, thereby separating the fluorescence signal from the nonspecific background, which improves the accuracy and sensitivity when imaging low fluorophore concentrations. Images of fluorescence yield are recovered using a nonlinear reconstruction approach based on the diffusion approximation of photon propagation in tissue. The tissue morphology derived from the MR images serves as an imaging template to guide the optical reconstruction algorithm. Sensitivity studies show that recovered values of indocyanine green fluorescence yield are linear to concentrations of 1 nM in a 70 mm diameter homogeneous phantom, and detection is feasible to near 10 pM. Phantom data also demonstrate imaging capabilities of imperfect fluorophore uptake in tissue volumes of clinically relevant sizes. A unique rodent MR coil provides optical fiber access for simultaneous optical and MR data acquisition of small animals. A pilot murine study using an orthotopic glioma tumor model demonstrates optical-MRI imaging of an epidermal growth factor receptor targeted fluorescent probe in vivo.

Magnetic resonance (MR)-guided near-infrared spectral tomography was developed and used to image adipose and fibroglandular breast tissue of 11 normal female subjects, recruited under an institutional review board-approved protocol. Images of hemoglobin, oxygen saturation, water fraction, and subcellular scattering were reconstructed and show that fibroglandular fractions of both blood and water are higher than in adipose tissue. Variation in adipose and fibroglandular tissue composition between individuals was not significantly different across the scattered and dense breast categories. Combined MR and near-infrared tomography provides fundamental molecular information about these tissue types with resolution governed by MR T1 images.

An imaging system that simultaneously performs near infrared (NIR) tomography and magnetic resonance imaging (MRI) is used to study breast tissue phantoms and a healthy woman in vivo. An NIR image reconstruction that exploits the combined data set is presented that implements the MR structure as a soft-constraint in the NIR property estimation. The algorithm incorporates the MR spatially segmented regions into a regularization matrix that links locations with similar MR properties, and applies a Laplacian-type filter to minimize variation within each region. When prior knowledge of the structure of phantoms is used to guide NIR property estimation, root mean square (rms) image error decreases from 26 to 58%. For a representative in vivo case, images of hemoglobin concentration, oxygen saturation, water fraction, scattering power, and scattering amplitude are derived and the properties of adipose and fibroglandular breast tissue types, identified from MRI, are quantified. Fibroglandular tissue is observed to have more than four times as much water content as adipose tissue, almost twice as much blood volume, and slightly reduced oxygen saturation. This approach is expected to improve recovery of abnormalities within the breast, as the inclusion of structural information increases the accuracy of recovery of embedded heterogeneities, at least in phantom studies.

A novel magnetic-resonance-coupled broadband near-infrared (NIR) tomography system for small animal brain studies is described. Several features of the image formation approach are new in NIR tomography and represent major advances in the path to recovering high-resolution hemoglobin and oxygen saturation images of tissue. The NIR data were broadband and continuous wave and were used along with a second-derivative-based estimation of the path length from water absorption. The path length estimation from water was then used along with the attenuation spectrum to recover absorption and reduced scattering coefficient images at multiple wavelengths and then to recover images of total hemoglobin and oxygen saturation. Going beyond these basics of NIR tomography, software has been developed to allow inclusion of structures derived from MR imaging (MRI) for the external and internal tissue boundaries, thereby improving the accuracy and spatial resolution of the properties in each tissue type. The system has been validated in both tissue-simulating phantoms, with 10% accuracy observed, and in a rat cranium imaging experiment. The latter experiment used variation in inspired oxygen (FiO2) to vary the observed hemoglobin and oxygen saturation images. Quantitative agreement was observed between the changes in deoxyhemoglobin values derived from NIR and the changes predicted with blood-oxygen-level-dependent (BOLD) MRI. This system represents the initial stage in what will likely be a larger role for NIR tomography, coupled to MRI, and illustrates that the technological challenges of using continuous-wave broadband data and inclusion of a priori structural information can be met with careful phantom studies.

Diffuse optical imaging (DOI) is a noninvasive optical technique that employs near-infrared (NIR) light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast transillumination (also called diaphanography) nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging (i.e., since the mid-1990s). In this review, the state of the art in DOI for breast cancer is outlined and a multi-institutional Network for Translational Research in Optical Imaging (NTROI) is described, which has been formed by the National Cancer Institute to advance diffuse optical spectroscopy and imaging (DOSI) for the purpose of improving breast cancer detection and clinical management. DOSI employs broadband technology both in near-infrared spectral and temporal signal domains in order to separate absorption from scattering and quantify uptake of multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality in the data is provided by integrating and co-registering the functional information of DOSI with x-ray mammography and magnetic resonance imaging (MRI), which provide structural information or vascular flow information, respectively. Factors affecting DOSI performance, such as intrinsic and extrinsic contrast mechanisms, quantitation of biochemical components, image formation/visualization, and multimodality co-registration are under investigation in the ongoing research NTROI sites. One of the goals is to develop standardized DOSI platforms that can be used as stand-alone devices or in conjunction with MRI, mammography, or ultrasound. This broad-based, multidisciplinary effort is expected to provide new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer, including: Detecting disease in mammographically dense tissue, distinguishing between malignant and benign lesions, and understanding the impact of neoadjuvant chemotherapies.

FLASH radiotherapy (FLASH‐RT) is an emerging ultra‐high dose (>40 Gy/s) delivery that promises to improve the therapeutic potential by limiting toxicities compared to conventional RT while maintaining similar tumor eradication efficacy. Image guidance is an essential component of modern RT that should be harnessed to meet the special emerging needs of FLASH‐RT and its associated high risks in planning and delivering of such ultra‐high doses in short period of times. Hence, this contribution will elaborate on the imaging requirements and possible solutions in the entire chain of FLASH‐RT treatment, from the planning, through the setup and delivery with online in vivo imaging and dosimetry, up to the assessment of biological mechanisms and treatment response. In patient setup and delivery, higher temporal sampling than in conventional RT should ensure that the short treatment is delivered precisely to the targeted region. Additionally, conventional imaging tools such as cone‐beam computed tomography will continue to play an important role in improving patient setup prior to delivery, while techniques based on magnetic resonance imaging or positron emission tomography may be extremely valuable for either linear accelerator (Linac) or particle FLASH therapy, to monitor and track anatomical changes during delivery. In either planning or assessing outcomes, quantitative functional imaging could supplement conventional imaging for more accurate utilization of the biological window of the FLASH effect, selecting for or verifying things such as tissue oxygen and existing or transient hypoxia on the relevant timescales of FLASH‐RT delivery. Perhaps most importantly at this time, these tools might help improve the understanding of the biological mechanisms of FLASH‐RT response in tumor and normal tissues. The high dose deposition of FLASH provides an opportunity to utilize pulse‐to‐pulse imaging tools such as Cherenkov or radiation acoustic emission imaging. These could provide individual pulse mapping or assessing the 3D dose delivery superficially or at tissue depth, respectively. In summary, the most promising components of modern RT should be used for safer application of FLASH‐RT, and new promising developments could be advanced to cope with its novel demands but also exploit new opportunities in connection with the unique nature of pulsed delivery at unprecedented dose rates, opening a new era of biological image guidance and ultrafast, pulse‐based in vivo dosimetry. [ABSTRACT FROM AUTHOR]

Purpose: Demonstrate a novel phantom design using a remote camera imaging method capable of concurrently measuring the position of the x‐ray isocenter and the magnetic resonance imaging (MRI) isocenter on an MR‐linac. Methods: A conical frustum with distinct geometric features was machined out of plastic. The phantom was submerged in a small water tank, and aligned using room lasers on a MRIdian MR‐linac (ViewRay Inc., Cleveland, OH). The phantom physical isocenter was visualized in the MR images and related to the DICOM coordinate isocenter. To view the x‐ray isocenter, an intensified CMOS camera system (DoseOptics LLC., Hanover, NH) was placed at the foot of the treatment couch, and centered such that the optical axis of the camera was coincident with the central axis of the treatment bore. Two or four 8.3mm x 24.1cm beams irradiated the phantom from cardinal directions, producing an optical ring on the conical surface of the phantom. The diameter of the ring, measured at the peak intensity, was compared to the known diameter at the position of irradiation to determine the Z‐direction offset of the beam. A star‐shot method was employed on the front face of the frustum to determine X‐Y alignment of the MV beam. Known shifts were applied to the phantom to establish the sensitivity of the method. Results: Couch translations, demonstrative of possible isocenter misalignments, on the order of 1mm were detectable for both the radiotherapy and MRI isocenters. Data acquired on the MR‐linac demonstrated an average error of 0.28mm(N=10, R2=0.997, σ=0.37mm) in established Z displacement, and 0.10mm(N=5, σ=0.34mm) in XY directions of the radiotherapy isocenter. Conclusions: The phantom was capable of measuring both the MRI and radiotherapy treatment isocenters. This method has the potential to be of use in MR‐linac commissioning, and could be streamlined to be valuable in daily constancy checks of isocenter coincidence. [ABSTRACT FROM AUTHOR]

Breast conserving surgery (BCS) is an effective treatment for early-stage cancers as long as the margins of the resected tissue are free of disease according to consensus guidelines for patient management. However, 15% to 35% of patients undergo a second surgery since malignant cells are found close to or at the margins of the original resection specimen. This review highlights imaging approaches being investigated to reduce the rate of positive margins, and they are reviewed with the assumption that a new system would need high sensitivity near 95% and specificity near 85%. The problem appears to be twofold. The first is for complete, fast surface scanning for cellular, structural, and/or molecular features of cancer, in a lumpectomy volume, which is variable in size, but can be large, irregular, and amorphous. A second is for full, volumetric imaging of the specimen at high spatial resolution, to better guide internal radiologic decision-making about the spiculations and duct tracks, which may inform that surfaces are involved. These two demands are not easily solved by a single tool. Optical methods that scan large surfaces quickly are needed with cellular/molecular sensitivity to solve the first problem, but volumetric imaging with high spatial resolution for soft tissues is largely outside of the optical realm and requires x-ray, micro-CT, or magnetic resonance imaging if they can be achieved efficiently. In summary, it appears that a combination of systems into hybrid platforms may be the optimal solution for these two very different problems. This concept must be cost-effective, image specimens within minutes and be coupled to decision-making tools that help a surgeon without adding to the procedure. The potential for optical systems to be involved in this problem is emerging and clinical trials are underway in several of these technologies to see if they could reduce positive margin rates in BCS. [ABSTRACT FROM AUTHOR]

Purpose: Tools to perform regular quality assurance of magnetic resonance image‐guided radiotherapy (MRIgRT) systems should ideally be independent of interference from the magnetic fields. Remotely acquired optical Cherenkov imaging‐based dosimetry measurements in water were investigated for this purpose, comparing measures of dose accuracy, temporal dynamics, and overall integrated IMRT delivery. Methods: A 40 × 30.5 × 37.5 cm3 water tank doped with 1 g/L of quinine sulfate was imaged using an intensified charge‐coupled device (ICCD) to capture the Cherenkov emission while being irradiated by a commercial MRIgRT system (ViewRay™). The ICCD was placed down‐bore at the end of the couch, 4 m from treatment isocenter and behind the 5‐Gauss line of the 0.35‐T MRI. After establishing optimal camera acquisition settings, square beams of increasing size (4.2 × 4.2 cm2, 10.5 × 10.5 cm2, and 14.7 × 14.7 cm2) were imaged at 0.93 frames per second, from an individual cobalt‐60 treatment head, to develop projection measures related to percent depth dose (PDD) curves and cross beam profiles (CPB). These Cherenkov‐derived measurements were compared to ionization chamber (IC) and radiographic film dosimetry data, as well as simulation data from the treatment planning system (TPS). An intensity‐modulated radiotherapy (IMRT) commissioning plan from AAPM TG‐119 (C4:C‐Shape) was also imaged at 2.1 frames per second, and the single linear sum image from 509 s of plan delivery was compared to the dose volume prediction generated by the TPS using gamma index analysis. Results: Analysis of standardized test target images (1024 × 1024 pixels) yielded a pixel resolution of 0.37 mm/pixel. The beam width measured from the Cherenkov image‐generated projection CBPs was within 1 mm accuracy when compared to film measurements for all beams. The 502 point measurements (i.e., pixels) of the Cherenkov image‐based projection percent depth dose curves (pPDDs) were compared to pPDDs simulated by the treatment planning system (TPS), with an overall average error of 0.60%, 0.56%, and 0.65% for the 4.2, 10.5, and 14.7 cm square beams, respectively. The relationships between pPDDs and central axis PDDs derived from the TPS were used to apply a weighting factor to the Cherenkov pPDD, so that the Cherenkov data could be directly compared to IC PDDs (average error of −0.07%, 0.10%, and −0.01% for the same sized beams, respectively). Finally, the composite image of the TG‐119 C4 treatment plan achieved a 95.1% passing rate using 4%/4 mm gamma index agreement criteria between Cherenkov intensity and TPS dose volume data. Conclusions: This is the first examination of Cherenkov‐generated pPDDs and pCBPs in an MR‐IGRT system. Cherenkov imaging measurements were fast to acquire, and minimal error was observed overall. Cherenkov imaging also provided novel real‐time data for IMRT QA. The strengths of this imaging are the rapid data capture ability providing real‐time, high spatial resolution data, combined with the remote, noncontact nature of imaging. The biggest limitation of this method is the two‐dimensional (2D) projection‐based imaging of three‐dimensional (3D) dose distributions through the transparent water tank. [ABSTRACT FROM AUTHOR]

Background: While dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is recognized as the most sensitive examination for breast cancer detection, it has a substantial false positive rate and gadolinium (Gd) contrast agents are not universally well tolerated. As a result, alternatives to diagnosing breast cancer based on endogenous contrast are of growing interest. In this study, endogenous near-infrared spectral tomography (NIRST) guided by T2 MRI was evaluated to explore whether the combined imaging modality, which does not require contrast injection or involve ionizing radiation, can achieve acceptable diagnostic performance.Methods: Twenty-four subjects-16 with pathologically confirmed malignancy and 8 with benign abnormalities-were simultaneously imaged with MRI and NIRST prior to definitive pathological diagnosis. MRIs were evaluated independently by three breast radiologists blinded to the pathological results. Optical image reconstructions were constrained by grayscale values in the T2 MRI. MRI and NIRST images were used, alone and in combination, to estimate the diagnostic performance of the data. Outcomes were compared to DCE results.Results: Sensitivity, specificity, accuracy, and area under the curve (AUC) of noncontrast MRI when combined with T2-guided NIRST were 94%, 100%, 96%, and 0.95, respectively, whereas these values were 94%, 63%, 88%, and 0.81 for DCE MRI alone, and 88%, 88%, 88%, and 0.94 when DCE-guided NIRST was added.Conclusion: In this study, the overall accuracy of imaging diagnosis improved to 96% when T2-guided NIRST was added to noncontrast MRI alone, relative to 88% for DCE MRI, suggesting that similar or better diagnostic accuracy can be achieved without requiring a contrast agent. [ABSTRACT FROM AUTHOR]

Tissue phantoms that mimic the optical and radiologic properties of human or animal tissue play an important role in the development, characterization, and evaluation of imaging systems. Phantoms that are easily produced and stable for longitudinal studies are highly desirable. A new type of long-lasting phantom was developed with commercially available materials and was assessed for fabrication ease, stability, and optical property control. Magnetic resonance imaging (MRI) and x-ray computed tomography (CT) contrast properties were also evaluated. A systematic investigation of relationships between concentrations of skin-like pigments and composite optical properties was conducted to realize optical property phantoms in the red and near-infrared (NIR) wavelength range that also offered contrast for CT and MRI. Phantom fabrication time was <1 h and did not involve any heating or cooling processes. Changes in optical properties were <2 % over a 12-month period. Phantom optical and spectral features were similar to human soft tissue over the red to NIR wavelength ranges. Pigments used in the study also had CT and MRI contrasts for multimodality imaging studies. The phantoms described here mimic optical properties of soft tissue and are suitable for multimodality imaging studies involving CT or MRI without adding secondary contrast agents. [ABSTRACT FROM AUTHOR]

An optimized approach to nonlinear iterative reconstruction of magnetic resonance imaging (MRI)-guided near-infrared spectral tomography (NIRST) images was developed using an L-curve-based algorithm for the choice of regularization parameter. This approach was applied to clinical exam data to maximize the reconstructed values differentiating malignant and benign lesions. MRI/NIRST data from 25 patients with abnormal breast readings (BI-RADS category 4-5) were analyzed using this optimal regularization methodology, and the results showed enhanced p values and area under the curve (AUC) for the task of differentiating malignant from benign lesions. Of the four absorption parameters and two scatter parameters, the most significant differences for benign versus malignant were total hemoglobin (HbT) and tissue optical index (TOI) with p values = 0.01 and 0.001, and AUC values = 0.79 and 0.94, respectively, in terms of HbT and TOI. This dramatically improved the values relative to fixed regularization (p value = 0.02 and 0.003; AUC = 0.75 and 0.83) showing that more differentiation was possible with the optimal method. Through a combination of both biomarkers, HbT and TOI, the AUC increased from 82.9% (fixed regulation = 0.1) to 94.3% (optimal method). [ABSTRACT FROM AUTHOR]

Purpose: We developed a deep learning (DL) model for fast deformable image registration using 2-dimensional sagittal cine magnetic resonance imaging (MRI) acquired during radiation therapy and evaluated its potential for real-time target tracking compared with conventional image registration methods.Methods and Materials: Our DL model uses a pair of cine MRI images as input and provides a motion vector field (MVF) as output. The MVF is then applied to align the input images. A retrospective study was conducted to train and evaluate our model using cine MRI data from patients undergoing treatment for abdominal and thoracic tumors. For each treatment fraction, MR-linear accelerator delivery log files, tracking videos, and cine image files were analyzed. Individual MRI frames were temporally sampled to construct a large set of image registration pairs used to evaluate multiple methods. The DL model was optimized using 5-fold cross validation, and model outputs (transformed images and MVFs) using test set images were saved for comparison with 3 conventional registration methods (affine, b-spline, and demons). Evaluation metrics were 3-fold: (1) registration error, (2) MVF stability (both spatial and temporal), and (3) average computation time.Results: We analyzed >21 hours of cine MRI (>629,000 frames) acquired during 86 treatment fractions from 21 patients. In a test set of 10,320 image registration pairs, DL registration outperformed conventional methods in both registration error (affine, b-spline, demons, DL; root mean square error: 0.067, 0.040, 0.036, 0.032; paired t test demons vs DL: t[20] = 4.2, P < .001) and computation time per frame (51, 1150, 4583, 8 ms). Among deformable methods, spatial stability of resulting MVFs was comparable; however, the DL model had significantly improved temporal consistency.Conclusions: DL-based image registration can leverage large-scale MR cine data sets to outperform conventional registration methods and is a promising solution for real-time deformable motion estimation in radiation therapy. [ABSTRACT FROM AUTHOR]

Abstract: Fluorescence sampling of cellular function is widely used in all aspects of biology, allowing the visualization of cellular and sub-cellular biological processes with spatial resolutions in the range from nanometers up to centimeters. Imaging of fluorescence in vivo has become the most commonly used radiological tool in all pre-clinical work. In the last decade, full-body pre-clinical imaging systems have emerged with a wide range of utilities and niche application areas. The range of fluorescent probes that can be excited in the visible to near-infrared part of the electromagnetic spectrum continues to expand, with the most value for in vivo use being beyond the 630nm wavelength, because the absorption of light sharply decreases. Whole-body in vivo fluorescence imaging has not yet reached a state of maturity that allows its routine use in the scope of large-scale pre-clinical studies. This is in part due to an incomplete understanding of what the actual fundamental capabilities and limitations of this imaging modality are. However, progress is continuously being made in research laboratories pushing the limits of the approach to consistently improve its performance in terms of spatial resolution, sensitivity and quantification. This paper reviews this imaging technology with a particular emphasis on its potential uses and limitations, the required instrumentation, and the possible imaging geometries and applications. A detailed account of the main commercially available systems is provided as well as some perspective relating to the future of the technology development. Although the vast majority of applications of in vivo small animal imaging are based on epi-illumination planar imaging, the future success of the method relies heavily on the design of novel imaging systems based on state-of-the-art optical technology used in conjunction with high spatial resolution structural modalities such as MRI, CT or ultrasound. [Copyright &y& Elsevier]