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A National Institutes of Health (NIH) and U.S. Department of Energy (DOE) Office of Science virtual workshop on shared general topics was held in July of 2021 and reported on in this publication in January of 2023. Following the inaugural 2021 joint meeting representatives from the DOE Office of Science and NIH met to discuss organizing a second joint workshop that would concentrate on radiation detection to bring together teams from both agencies and their grantee populations to stimulate collaboration and efficiency. To meet this scientific mission within the NIH and DOE radiation detection space, the organizers assembled workshop sessions covering the state‐of‐the‐art in cameras, detectors, and sensors for radiation external and internal (diagnostic and therapeutic) to human, data acquisition and electronics, image reconstruction and processing, and the application of artificial intelligence. NIH and DOE are committed to continuing the process of convening a joint workshop every 12–24 months. This Special Report recaps the findings of this second workshop. Beyond showing only the innovations and areas of success, important gaps in our knowledge were defined and presented. We summarize by defining four areas of greatest opportunity and need that emerged from the unique, dynamic dialogue the in‐person workshop provided the attendees. [ABSTRACT FROM AUTHOR]

Background: Normal tissue sparing from radiation damage upon ultra-high dose rate irradiation, known as the FLASH effect with an equivalent tumor response, has been widely reported in murine skin models, and translation of this type of radiotherapy to humans has already begun, with skin sparing being a primary outcome expected. Methods: This study reviews the status of the field, focusing on the proposed mechanisms and skin response assays, outlining what has become known in terms of input parameters that might control the magnitude of the FLASH effect. Results: Murine studies have largely focused on acute damage responses, developing over 3–8 weeks, to single doses of FLASH versus conventional dose rate (CDR), suggesting that at dose rates above tens of Gray per second, with a total dose of more than 20 Gy, the FLASH effect is induced. Fractionated delivery appears to be possible, although fraction sizes >17 Gy appear to be needed for sparing efficacy. The interplay between the dose rate and total dose per fraction remains to be fully elucidated. Oxygen is a modulator of efficacy, with both hypoxia and hyperoxia diminishing the effect of FLASH. Measurement of transient changes in oxygen levels is possible and may be a marker of treatment efficacy. Conclusion: Taken together, murine skin data provide important information for translational studies, despite the associated limitations. Studies of later-term sparing effects, as well as studies on pig skin, are needed to take the next step in assessing translational FLASH efficacy. The control of biological factors, such as tissue oxygenation, may be required to understand and control the response. [ABSTRACT FROM AUTHOR]

Significance: Hyperspectral dark-field microscopy (HSDFM) and data cube analysis algorithms demonstrate successful detection and classification of various tissue types, including carcinoma regions in human post-lumpectomy breast tissues excised during breast-conserving surgeries. Aim: We expand the application of HSDFM to the classification of tissue types and tumor subtypes in pre-histopathology human breast lumpectomy samples. Approach: Breast tissues excised during breast-conserving surgeries were imaged by the HSDFM and analyzed. The performance of the HSDFM is evaluated by comparing the backscattering intensity spectra of polystyrene microbead solutions with the Monte Carlo simulation of the experimental data. For classification algorithms, two analysis approaches, a supervised technique based on the spectral angle mapper (SAM) algorithm and an unsupervised technique based on the K-means algorithm are applied to classify various tissue types including carcinoma subtypes. In the supervised technique, the SAM algorithm with manually extracted endmembers guided by H&E annotations is used as reference spectra, allowing for segmentation maps with classified tissue types including carcinoma subtypes. Results: The manually extracted endmembers of known tissue types and their corresponding threshold spectral correlation angles for classification make a good reference library that validates endmembers computed by the unsupervised K-means algorithm. The unsupervised K-means algorithm, with no a priori information, produces abundance maps with dominant endmembers of various tissue types, including carcinoma subtypes of invasive ductal carcinoma and invasive mucinous carcinoma. The two carcinomas' unique endmembers produced by the two methods agree with each other within <2% residual error margin. Conclusions: Our report demonstrates a robust procedure for the validation of an unsupervised algorithm with the essential set of parameters based on the ground truth, histopathological information. We have demonstrated that a trained library of the histopathology-guided endmembers and associated threshold spectral correlation angles computed against well-defined reference data cubes serve such parameters. Two classification algorithms, supervised and unsupervised algorithms, are employed to identify regions with carcinoma subtypes of invasive ductal carcinoma and invasive mucinous carcinoma present in the tissues. The two carcinomas' unique endmembers used by the two methods agree to <2% residual error margin. This library of high quality and collected under an environment with no ambient background may be instrumental to develop or validate more advanced unsupervised data cube analysis algorithms, such as effective neural networks for efficient subtype classification. [ABSTRACT FROM AUTHOR]

Fluorescence guidance is routinely used in surgery to enhance perfusion contrast in multiple types of diseases. Pressure-enhanced sensing of tissue oxygenation (PRESTO) via fluorescence is a technique extensively analyzed here, that uses an FDA-approved human precursor molecule, 5-aminolevulinic acid (ALA), to stimulate a unique delayed fluorescence signal that is representative of tissue hypoxia. The ALA precontrast agent is metabolized in most tissues into a red fluorescent molecule, protoporphyrin IX (PpIX), which has both prompt fluorescence, indicative of the concentration, and a delayed fluorescence, that is amplified in low tissue oxygen situations. Applied pressure from palpation induces transient capillary stasis and a resulting transient PRESTO contrast, dominant when there is near hypoxia. This study examined the kinetics and behavior of this effect in both normal and tumor tissues, with a prolonged high PRESTO contrast (contrast to background of 7.3) across 5 tumor models, due to sluggish capillaries and inhibited vasodynamics. This tissue function imaging approach is a fundamentally unique tool for real-time palpation-induced tissue response in vivo, relevant for chronic hypoxia, such as vascular diseases or oncologic surgery. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high‐dose‐rate (UHDR) electron beams have been commonly utilized in FLASH studies and the translation of FLASH Radiotherapy (RT) to the clinic. The EDGE diode detector has potential use for UHDR dosimetry albeit with a beam energy dependency observed. Purpose: The purpose is to present the electron beam response for an EDGE detector in dependence on beam energy, to characterize the EDGE detector's response under UHDR conditions, and to validate correction factors derived from the first detailed Monte Carlo model of the EDGE diode against measurements, particularly under UHDR conditions. Methods: Percentage depth doses (PDDs) for the UHDR Mobetron were measured with both EDGE detectors and films. A detailed Monte Carlo (MC) model of the EDGE detector has been configured according to the blueprint provided by the manufacturer under an NDA agreement. Water/silicon dose ratios of EDGE detector for a series of mono‐energetic electron beams have been calculated. The dependence of the water/silicon dose ratio on depth for a FLASH relevant electron beam was also studied. An analytical approach for the correction of PDD measured with EDGE detectors was established. Results: Water/silicon dose ratio decreased with decreasing electron beam energy. For the Mobetron 9 MeV UHDR electron beam, the ratio decreased from 1.09 to 1.03 in the build‐up region, maintained in range of 0.98–1.02 at the fall‐off region and raised to a plateau in value of 1.08 at the tail. By applying the corrections, good agreement between the PDDs measured by the EDGE detector and those measured with film was achieved. Conclusions: Electron beam response of an UHDR capable EDGE detector was derived from first principles utilizing a sophisticated MC model. An analytical approach was validated for the PDDs of UHDR electron beams. The results demonstrated the capability of EDGE detector in measuring PDDs of UHDR electron beams. [ABSTRACT FROM AUTHOR]

Background: While careful planning and pre‐treatment checks are performed to ensure patient safety during external beam radiation therapy (EBRT), inevitable daily variations mean that in vivo dosimetry (IVD) is the only way to attain the true delivered dose. Several countries outside the US require daily IVD for quality assurance. However, elsewhere, the manual labor and time considerations of traditional in vivo dosimeters may be preventing frequent use of IVD in the clinic. Purpose: This study expands upon previous research using plastic scintillator discs for optical dosimetry for electron therapy treatments. We present the characterization of scintillator discs for in vivo x‐ray dosimetry and describe additional considerations due to geometric complexities. Methods: Plastic scintillator discs were coated with reflective white paint on all sides but the front surface. An anti‐reflective, matte coating was applied to the transparent face to minimize specular reflection. A time‐gated iCMOS camera imaged the discs under various irradiation conditions. In post‐processing, background‐subtracted images of the scintillators were fit with Gaussian‐convolved ellipses to extract several parameters, including integral output, and observation angle. Results: Dose linearity and x‐ray energy independence were observed, consistent with ideal characteristics for a dosimeter. Dose measurements exhibited less than 5% variation for incident beam angles between 0° and 75° at the anterior surface and 0–60∘$^\circ $ at the posterior surface for exit beam dosimetry. Varying the angle between the disc surface and the camera lens did not impact the integral output for the same dose up to 55°. Past this point, up to 75°, there is a sharp falloff in response; however, a correction can be used based on the detected width of the disc. The reproducibility of the integral output for a single disc is 2%, and combined with variations from the gantry angle, we report the accuracy of the proposed scintillator disc dosimeters as ±5.4%. Conclusions: Plastic scintillator discs have characteristics that are well‐suited for in vivo optical dosimetry for x‐ray radiotherapy treatments. Unlike typical point dosimeters, there is no inherent readout time delay, and an optical recording of the measurement is saved after treatment for future reference. While several factors influence the integral output for the same dose, they have been quantified here and may be corrected in post‐processing. [ABSTRACT FROM AUTHOR]

Background: FLASH radiotherapy based on ultra‐high dose rate (UHDR) is actively being studied by the radiotherapy community. Dedicated UHDR electron devices are currently a mainstay for FLASH studies. Purpose: To present the first Monte Carlo (MC) electron beam model for the UHDR capable Mobetron (FLASH‐IQ) as a dose calculation and treatment planning platform for preclinical research and FLASH‐radiotherapy (RT) clinical trials. Methods: The initial beamline geometry of the Mobetron was provided by the manufacturer, with the first‐principal implementation realized in the Geant4‐based GAMOS MC toolkit. The geometry and electron source characteristics, such as energy spectrum and beamline parameters, were tuned to match the central‐axis percentage depth dose (PDD) and lateral profiles for the pristine beam measured during machine commissioning. The thickness of the small foil in secondary scatter affected the beam model dominantly and was fine tuned to achieve the best agreement with commissioning data. Validation of the MC beam modeling was performed by comparing the calculated PDDs and profiles with EBT‐XD radiochromic film measurements for various combinations of applicators and inserts. Results: The nominal 9 MeV electron FLASH beams were best represented by a Gaussian energy spectrum with mean energy of 9.9 MeV and variance (σ) of 0.2 MeV. Good agreement between the MC beam model and commissioning data were demonstrated with maximal discrepancy < 3% for PDDs and profiles. Hundred percent gamma pass rate was achieved for all PDDs and profiles with the criteria of 2 mm/3%. With the criteria of 2 mm/2%, maximum, minimum and mean gamma pass rates were (100.0%, 93.8%, 98.7%) for PDDs and (100.0%, 96.7%, 99.4%) for profiles, respectively. Conclusions: A validated MC beam model for the UHDR capable Mobetron is presented for the first time. The MC model can be utilized for direct dose calculation or to generate beam modeling input required for treatment planning systems for FLASH‐RT planning. The beam model presented in this work should facilitate translational and clinical FLASH‐RT for trials conducted on the Mobetron FLASH‐IQ platform. [ABSTRACT FROM AUTHOR]

Purpose: ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for fluorescence-guided surgery of sarcomas. To date, studies using ABY-029 have occurred in tumors naïve to chemotherapy (CTx) and radiation therapy (RTx), although these neoadjuvant therapies are frequently used for sarcoma treatment in humans. The goal of this study was to evaluate the impact of CTx and RTx on tumor EGFR expression and ABY-029 fluorescence of human soft-tissue sarcoma xenografts in a murine model. Procedures: Immunodeficient mice (n = 98) were divided into five sarcoma xenograft groups and three treatment groups – CTx only, RTx only, and CTx followed by RTx, plus controls. Four hours post-injection of ABY-029, animals were sacrificed followed by immediate fluorescence imaging of ex vivo adipose, muscle, nerve, and tumor tissues. Histological hematoxylin and eosin staining confirmed tumor type, and immunohistochemistry staining determined EGFR, cluster of differentiation 31 (CD31), and smooth muscle actin (SMA) expression levels. Correlation analysis (Pearson's correlation coefficients, r) and linear regression (unstandardized coefficient estimates, B) were used to determine statistical relationships in molecular expression and tissue fluorescence between xenografts and treatment groups. Results: Neoadjuvant therapies had no broad impact on EGFR expression (|B|≤ 7.0, p ≥ 0.4) or on mean tissue fluorescence (any tissue type, (|B|≤ 2329.0, p ≥ 0.1). Mean tumor fluorescence was significantly related to EGFR expression (r = 0.26, p = 0.01), as expected. Conclusion: Results suggest that ABY-029 as an EGFR-targeted, fluorescent probe is not negatively impacted by neoadjuvant soft-tissue sarcoma therapies, although validation in humans is required. [ABSTRACT FROM AUTHOR]

The last decade has seen a large growth in fluorescence‐guided surgery (FGS) imaging and interventions. With the increasing number of clinical specialties implementing FGS, the range of systems with radically different physical designs, image processing approaches, and performance requirements is expanding. This variety of systems makes it nearly impossible to specify uniform performance goals, yet at the same time, utilization of different devices in new clinical procedures and trials indicates some need for common knowledge bases and a quality assessment paradigm to ensure that effective translation and use occurs. It is feasible to identify key fundamental image quality characteristics and corresponding objective test methods that should be determined such that there are consistent conventions across a variety of FGS devices. This report outlines test methods, tissue simulating phantoms and suggested guidelines, as well as personnel needs and professional knowledge bases that can be established. This report frames the issues with guidance and feedback from related societies and agencies having vested interest in the outcome, coming from an independent scientific group formed from academics and international federal agencies for the establishment of these professional guidelines. [ABSTRACT FROM AUTHOR]

Significance: Fluorescence guidance is used clinically by surgeons to visualize anatomical and/or physiological phenomena in the surgical field that are difficult or impossible to detect by the naked eye. Such phenomena include tissue perfusion or molecular phenotypic information about the disease being resected. Conventional fluorescence-guided surgery relies on long, microsecond scale laser pulses to excite fluorescent probes. However, this technique only provides two-dimensional information; crucial depth information, such as the location of malignancy below the tissue surface, is not provided. Aim: We developed a depth sensing imaging technique using light detection and ranging (LiDAR) time-of-flight (TOF) technology to sense the depth of target tissue while overcoming the influence of tissue optical properties and fluorescent probe concentration. Approach: The technology is based on a large-format (512 × 512 pixel), binary, gated, single-photon avalanche diode (SPAD) sensor with an 18 ps time-gate step, synchronized with a picosecond pulsed laser. The fast response of the sensor was developed and tested for its ability to quantify fluorescent inclusions at depth and optical properties in tissue-like phantoms through analytical model fitting of the fast temporal remission data. Results: After calibration and algorithmic extraction of the data, the SPAD LiDAR technique allowed for sub-mm resolution depth sensing of fluorescent inclusions embedded in tissue-like phantoms, up to a maximum of 5 mm in depth. The approach provides robust depth sensing even in the presence of variable tissue optical properties and separates the effects of fluorescence depth from absorption and scattering variations. Conclusions: LiDAR TOF fluorescence imaging using an SPAD camera provides both fluorescence intensity images and the temporal profile of fluorescence, which can be used to determine the depth at which the signal is emitted over a wide field of view. The proposed tool enables fluorescence imaging at a higher depth in tissue and with higher spatial precision than standard, steady-state fluorescence imaging tools, such as intensity-based near-infrared fluorescence imaging, optical coherence tomography, Raman spectroscopy, or confocal microscopy. Integration of this technique into a standard surgical tool could enable rapid, more accurate estimation of resection boundaries, thereby improving the surgeon's efficacy and efficiency, and ultimately improving patient outcomes. [ABSTRACT FROM AUTHOR]

This paper presents a technique for high sensitivity measurement of singlet oxygen luminescence generated during photodynamic therapy (PDT) and ultraviolet (UV) irradiation on skin. The high measurement sensitivity is achieved by using a computational spectroscopy (CS) approach that provides improved photon detection efficiency compared to spectral filtering methodology. A solid-state InGaAs photodiode is used as the CS detector, which significantly reduces system cost and improves robustness compared to photomultiplier tubes. The spectral resolution enables high-accuracy determination and subtraction of photosensitizer fluorescence baseline without the need for time-gating. This allows for high sensitivity detection of singlet oxygen luminescence emission generated by continuous wave light sources, such as solar simulator sources and those commonly used in PDT clinics. The value of the technology is demonstrated during in vivo and ex vivo experiments that show the correlation of measured singlet oxygen with PDT treatment efficacy and the illumination intensity on the skin. These results demonstrate the potential use of the technology as a dosimeter to guide PDT treatment and as an analytical tool supporting the development of improved sunscreen products for skin cancer prevention. [ABSTRACT FROM AUTHOR]

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose. [ABSTRACT FROM AUTHOR]

Background: Ultra‐high dose rate (UHDR) FLASH beams typically deliver dose at rates of >40 Gy/sec. Characterization of these beams with respect to dose, mean dose rate, and dose per pulse requires dosimeters which exhibit high temporal resolution and fast readout capabilities. Purpose: A diode EDGE Detector with a newly designed electrometer has been characterized for use in an UHDR electron beam and demonstrated appropriateness for UHDR FLASH radiotherapy dosimetry. Methods: Dose linearity, mean dose rate, and dose per pulse dependencies of the EDGE Detector were quantified and compared with dosimeters including a W1 scintillator detector, radiochromic film, and ionization chamber that were irradiated with a 10 MeV UHDR beam. The dose, dose rate, and dose per pulse were controlled via an in‐house developed scintillation‐based feedback mechanism, repetition rate of the linear accelerator, and source‐to‐surface distance, respectively. Depth‐dose profiles and temporal profiles at individual pulse resolution were compared to the film and scintillation measurements, respectively. The radiation‐induced change in response sensitivity was quantified via irradiation of ∼5kGy. Results: The EDGE Detector agreed with film measurements in the measured range with varying dose (up to 70 Gy), dose rate (nearly 200 Gy/s), and dose per pulse (up to 0.63 Gy/pulse) on average to within 2%, 5%, and 1%, respectively. The detector also agreed with W1 scintillation detector on average to within 2% for dose per pulse (up to 0.78 Gy/pulse). The EDGE Detector signal was proportional to ion chamber (IC) measured dose, and mean dose rate in the bremsstrahlung tail to within 0.4% and 0.2% respectively. The EDGE Detector measured percent depth dose (PDD) agreed with film to within 3% and per pulse output agreed with W1 scintillator to within −6% to +5%. The radiation‐induced response decrease was 0.4% per kGy. Conclusions: The EDGE Detector demonstrated dose linearity, mean dose rate independence, and dose per pulse independence for UHDR electron beams. It can quantify the beam spatially, and temporally at sub millisecond resolution. It's robustness and individual pulse detectability of treatment deliveries can potentially lead to its implementation for in vivo FLASH dosimetry, and dose monitoring. [ABSTRACT FROM AUTHOR]

We assessed the effects of conventional and ultra-high dose rate (UHDR) electron irradiation on behavioral and cognitive performance one month following exposure and assessed whether these effects were associated with alterations in the number of immune cells in the hippocampus using flow cytometry. Two-month-old female and male C57BL/6J mice received whole-brain conventional or UHDR irradiation. UHDR mice were irradiated with 9 MeV electrons, delivered by the Linac-based/modified beam control. The mice were irradiated or sham-irradiated at Dartmouth, the following week shipped to OHSU, and behaviorally and cognitively tested between 27 and 41 days after exposure. Conventional- and UHDR-irradiated mice showed impaired novel object recognition. During fear learning, conventional- and UHDR-irradiated mice moved less during the inter-stimulus interval (ISI) and UHDR-irradiated mice also moved less during the baseline period (prior to the first tone). In irradiated mice, reduced activity levels were also seen in the home cage: conventional- and UHDR-irradiated mice moved less during the light period and UHDR-irradiated mice moved less during the dark period. Following behavioral and cognitive testing, infiltrating immune cells in the hippocampus were analyzed by flow cytometry. The percentage of Ly6G+ CD45+ cells in the hippocampus was lower in conventional- and UHDR-irradiated than sham-irradiated mice, suggesting that neutrophils might be particularly sensitive to radiation. The percentage of Ly6G+ CD45+ cells in the hippocampus was positively correlated with the time spent exploring the novel object in the object recognition test. Under the experimental conditions used, cognitive injury was comparable in conventional and UHDR mice. However, the percentage of CD45+ CD11b+ Ly6+ and CD45+ CD11b+ Ly6G- cells in the hippocampus cells in the hippocampus was altered in conventional- but not UHDR-irradiated mice and the reduced percentage of Ly6G+ CD45+ cells in the hippocampus might mediate some of the detrimental radiation-induced cognitive effects. [ABSTRACT FROM AUTHOR]

Background: Breast-conserving surgery (BCS) is an integral component of early-stage breast cancer treatment, but costly reexcision procedures are common due to the high prevalence of cancer-positive margins on primary resections. A need exists to develop and evaluate improved methods of margin assessment to detect positive margins intraoperatively. Methods: A prospective trial was conducted through which micro-computed tomography (micro-CT) with radiological interpretation by three independent readers was evaluated for BCS margin assessment. Results were compared to standard-of-care intraoperative margin assessment (i.e., specimen palpation and radiography [abbreviated SIA]) for detecting cancer-positive margins. Results: Six hundred margins from 100 patients were analyzed. Twenty-one margins in 14 patients were pathologically positive. On analysis at the specimen-level, SIA yielded a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 42.9%, 76.7%, 23.1%, and 89.2%, respectively. SIA correctly identified six of 14 margin-positive cases with a 23.5% false positive rate (FPR). Micro-CT readers achieved sensitivity, specificity, PPV, and NPV ranges of 35.7–50.0%, 55.8–68.6%, 15.6–15.8%, and 86.8–87.3%, respectively. Micro-CT readers correctly identified five to seven of 14 margin-positive cases with an FPR range of 31.4–44.2%. If micro-CT scanning had been combined with SIA, up to three additional margin-positive specimens would have been identified. Discussion: Micro-CT identified a similar proportion of margin-positive cases as standard specimen palpation and radiography, but due to difficulty distinguishing between radiodense fibroglandular tissue and cancer, resulted in a higher proportion of false positive margin assessments. [ABSTRACT FROM AUTHOR]

There are a wide range of applications with ionizing radiation and a common theme throughout these is that accurate dosimetry is usually required, although many newer demands are provided by improved features in higher range, multi-spectral and particle type detected. Today, the array of dosimeters includes both offline and online tools, such as gel dosimeters, thermoluminescence (TL), scintillators, optically stimulated luminescence (OSL), radiochromic polymeric films, gels, ionization chambers, colorimetry, and electron spin resonance (ESR) measurement systems. Several future nanocomposite features and interpretation of their substantial behaviors are discussed that can lead to improvements in specific features, such as (1) lower sensitivity range, (2) less saturation at high range, (3) overall increased dynamic range, (4) superior linearity, (5) linear energy transfer and energy independence, (6) lower cost, (7) higher ease of use, and (8) improved tissue equivalence. Nanophase versions of TL and ESR dosimeters and scintillators each have potential for higher range of linearity, sometimes due to superior charge transfer to the trapping center. Both OSL and ESR detection of nanomaterials can have increased dose sensitivity because of their higher readout sensitivity with nanoscale sensing. New nanocrystalline scintillators, such as perovskite, have fundamentally important advantages in sensitivity and purposeful design for key new applications. Nanoparticle plasmon coupled sensors doped within a lower Zeff material have been an effective way to achieve enhanced sensitivity of many dosimetry systems while still achieving tissue equivalency. These nanomaterial processing techniques and unique combinations of them are key steps that lead to the advanced features. Each must be realized through industrial production and quality control with packaging into dosimetry systems that maximize stability and reproducibility. Ultimately, recommendations for future work in this field of radiation dosimetry were summarized throughout the review. [ABSTRACT FROM AUTHOR]

Medical physics doctoral programs have large variations in organization, administration and financing. Blending a medical physics stream into an engineering graduate program has advantages of pre‐existing financial and educational infrastructures. A case study of the accredited program at Dartmouth was carried out, analyzing operational, financial, educational and outcome features. The support structures provided by each institutional partner were outlined, including engineering school, graduate school, and radiation oncology. The initiatives undertaken by founding faculty were reviewed, along with allocated resources, financial model, and peripheral entrepreneurship activities, each with quantitative outcome metrics. Currently 14 PhD students are enrolled, supported by 22 faculty across both engineering and clinical departments. The total peer‐reviewed publications are ≈75/year, while the conventional medical physics fraction of this is about 14/year. Following program formation, a significant rise was seen in jointly published papers between engineering and medical physics faculty, up from 5.6 to 13.3 papers/year, with students publishing an average of 11.3/person with 5.7/person as first author. Student support was predominantly via federal grants, with a stable $5.5million/year, using about $610K/year supporting student stipends and tuition. First year funding, recruiting and staff support were via engineering school. Faculty teaching effort was supported by agreement with each home department, and student services were provided by engineering and graduate schools. Student outcomes were exceptional, with high numbers of presentations, awards, and residency placements at research universities. The lack of financial and student support in medical physics can be mitigated by this hybrid design of blending medical physics doctoral students into an engineering graduate program, providing complementary strengths. Future growth in medical physics programs might consider following this pathway, strengthening research collaborations for clinical physics and engineering faculty, as long as there is vested commitment to teach by the faculty and department leadership. [ABSTRACT FROM AUTHOR]

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: Imaging Cherenkov light during radiotherapy allows the visualization and recording of frame‐by‐frame relative maps of the dose being delivered to the tissue at each control point used throughout treatment, providing one of the most complete real‐time means of treatment quality assurance. In non‐turbid media, the intensity of Cherenkov light is linear with surface dose deposited, however the emission from patient tissue is well‐known to be reduced by absorbing tissue components such as hemoglobin, fat, water, and melanin, and diffused by the scattering components of tissue. Earlier studies have shown that bulk correction could be achieved by using the patient planning computed tomography (CT) scan for attenuation correction. Methods: In this study, CT maps were used for correction of spatial variations in emissivity. Testing was completed on Cherenkov images from radiotherapy treatments of post‐lumpectomy breast cancer patients (n = 13), combined with spatial renderings of the patient radiodensity (CT number) from their planning CT scan. Results: The correction technique was shown to provide a pixel‐by‐pixel correction that suppressed many of the inter‐ and intra‐patient differences in the Cherenkov light emitted per unit dose. This correction was established from a calibration curve that correlated Cherenkov light intensity to surface‐rendered CT number (R6MV2=0.70$R_{6{\rm{MV}}}^2 = 0.70$ and R10MV2=0.72$R_{10{\rm{MV}}}^2 = 0.72$). The corrected Cherenkov intensity per unit dose standard error was reduced by nearly half (from ∼30% to ∼17%). Conclusions: This approach provides evidence that the planning CT scan can mitigate some of the tissue‐specific attenuation in Cherenkov images, allowing them to be translated into near surface dose images. [ABSTRACT FROM AUTHOR]

High positive margin rates in oncologic breast-conserving surgery are a pressing clinical problem. Volumetric X-ray scanning is emerging as a powerful ex vivo specimen imaging technique for analyzing resection margins, but X-rays lack contrast between non-malignant and malignant fibrous tissues. In this study, combined micro-CT and wide-field optical image radiomics were developed to classify malignancy of breast cancer tissues, demonstrating that X-ray/optical radiomics improve malignancy classification. Ninety-two standardized features were extracted from co-registered micro-CT and optical spatial frequency domain imaging samples extracted from 54 breast tumors exhibiting seven tissue subtypes confirmed by microscopic histological analysis. Multimodal feature sets improved classification performance versus micro-CT alone when adipose samples were included (AUC = 0.88 vs. 0.90; p-value = 3.65e−11) and excluded, focusing the classification task on exclusively non-malignant fibrous versus malignant tissues (AUC = 0.78 vs. 0.85; p-value = 9.33e−14). Extending the radiomics approach to high-dimensional optical data—termed "optomics" in this study—offers a promising optical image analysis technique for cancer detection. Radiomic feature data and classification source code are publicly available. [ABSTRACT FROM AUTHOR]

We report a high light‐throughput spectroscopic dosimeter system that is able to noninvasively measure luminescence signals of singlet oxygen (1O2) produced during photodynamic therapy (PDT) using a CW (continuous wave) light source. The system is based on a compact, fiber‐coupled, high collection efficiency spectrometer (>50% transmittance) designed to maximize optical throughput but with sufficient spectral resolution (~7 nm). This is adequate to detect 1O2 phosphorescence in the presence of strong luminescence background in vivo. This system provides simultaneous acquisition of multiple spectral data points, allowing for more accurate determination of luminescence baseline via spectral fitting and thus the extraction of 1O2 phosphorescence signal based solely on spectroscopic decomposition, without the need for time‐gating. Simultaneous collection of photons at different wavelengths improves the quantum efficiency of the system when compared to sequential spectral measurements such as filter‐wheel or tunable‐filter based systems. A prototype system was tested during in vivo PDT tumor regression experiments using benzoporphyrin derivative (BPD) photosensitizer. It was found that the treatment efficacy (tumor growth inhibition rate) correlated more strongly with 1O2 phosphorescence than with PS fluorescence. These results indicate that this high photon‐collection efficiency spectrometer instrument may offer a viable option for real‐time 1O2 dosimetry during PDT treatment using CW light. [ABSTRACT FROM AUTHOR]

Oxygen sensing with light has been developing for many decades using injectable molecules called Oxyphors, which are pegylated, dendrimer-encapsulated metalloporphyrins that have a phosphorescence emission lifetime that is a direct reporter of the local oxygen partial pressure (pO2). In recent years, the ability to image this emission from tissue with Cherenkov light excitation during high-energy X-ray-based radiation therapy has been shown and developed for research studies. The main value of this type of lifetime-based pO2 sensing, termed Cherenkov-Excited Luminescence Imaging (CELI) is in its ability to image values of pO2 from within the tissue during radiation therapy using tracers that are systemic and biologically compatible. Spatial mapping of pO2 can realized either as surface imaging or deep tissue tomography through a few centimeters. The spatial resolution is radiation dose-dependent but can be near 0.1 mm, based upon radiation doses expected in a fractionated treatment plan. When imaging tumors with a broad beam irradiation, histograms of pO2 values across the surface have been demonstrated illustrating microscopic sensitivity to the ranges of oxygen levels present, and the ability to track these microscopic histograms during daily fractionated radiation therapy is possible. The pO2 distributions provide for sensitivity to the hypoxic fraction of the tumor—a unique capability of oxygen imaging that has microscopic spatial sampling. Comparisons of the CELI pO2 method to other oxygen-sensing methods, as well as the ability to use the CELI technique as a tool to examine the optimization of radiation therapy treatment technique is ongoing. [ABSTRACT FROM AUTHOR]

Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP's TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity in human PDAC cells (MIA PaCa-2), co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner. TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) offers localized focal ablation in unresectable pancreatic tumors while tissues surrounding the treatment volume experience a lower light dose, termed photodynamic priming (PDP). While PDP does not cause tissue damage, it has been demonstrated to promote vascular permeability, improve drug delivery, alleviate tumor cell density, and reduce desmoplasia and the resultant internal pressure in pre-clinical evaluation. Preclinical data supports PDP as a neoadjuvant therapy beneficial to subsequent chemotherapy or immunotherapy, yet it is challenging to quantify PDP effects in clinical treatment without additional imaging and testing. This study investigated the potential of radiomic analysis using CT scans acquired before and after PDT to identify areas experiencing PDT-induced necrosis as well as quantify PDP effects in the surrounding tissues. A total of 235 CT tumor slices from seven patients undergoing PDT for pancreatic tumors were examined. Radiomic features assessed included intensity metrics (CT number in Hounsfield Units) and texture analysis using several gray-level co-occurrence matrix (GLCM) parameters. Pre-treatment scans of tumor areas that resulted in PDT-induced necrosis showed statistically significant differences in intensity and texture-based features that could be used to predict the regions that did respond (paired t-test, response versus no response, p < 0.001). Evaluation of PDP effects on the surrounding tissues also demonstrated statistically significant differences, in tumor mean value, standard deviation, and GLCM parameters of contrast, dissimilarity and homogeneity (t-test, pre versus post, p < 0.001). Using leave-one-out cross validation, six intensity and texture-based features were combined into a support-vector machine model which demonstrated reliable prediction of treatment effects for six out of seven patients (ROC curve, AUC = 0.93). This study provides pilot evidence that texture features extracted from CT scans could be utilized as an effective clinical diagnostic prediction and assessment of PDT and PDP effects in pancreatic tumors. (clinical trial NCT03033225) [ABSTRACT FROM AUTHOR]

X-ray induced molecular luminescence (XML) is a phenomenon that can be utilized for clinical, deep-tissue functional imaging of tailored molecular probes. In this study, a survey of common or clinically approved fluorophores was carried out for their megavoltage X-ray induced excitation and emission characteristics. We find that direct scintillation effects and Cherenkov generation are two possible ways to cause these molecules' excitation. To distinguish the contributions of each excitation mechanism, we exploited the dependency of Cherenkov radiation yield on X-ray energy. The probes were irradiated by constant dose of 6 MV and 18 MV X-ray radiation, and their relative emission intensities and spectra were quantified for each X-ray energy pair. From the ratios of XML, yield for 6 MV and 18 MV irradiation we found that the Cherenkov radiation dominated as an excitation mechanism, except for aluminum phthalocyanine, which exhibited substantial scintillation. The highest emission yields were detected from fluorescein, proflavin and aluminum phthalocyanine, in that order. XML yield was found to be affected by the emission quantum yield, overlap of the fluorescence excitation and Cherenkov emission spectra, scintillation yield. Considering all these factors and XML emission spectrum respective to tissue optical window, aluminum phthalocyanine offers the best XML yield for deep tissue use, while fluorescein and proflavine are most useful for subcutaneous or superficial use. [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]

The 3D printing of fluorescent materials could help develop, validate, and translate imaging technologies, including systems for fluorescence-guided surgery. Despite advances in 3D printing techniques for optical targets, no comprehensive method has been demonstrated for the simultaneous incorporation of fluorophores and fine-tuning of absorption and scattering properties. Here, we introduce a photopolymer-based 3D printing method for manufacturing fluorescent material with tunable optical properties. The results demonstrate the ability to 3D print various individual fluorophores at reasonably high fluorescence yields, including IR-125, quantum dots, methylene blue, and rhodamine 590. Furthermore, tuning of the absorption and reduced scattering coefficients is demonstrated within the relevant mamalian soft tissue coefficient ranges of 0.005–0.05 mm−1 and 0.2–1.5 mm−1, respectively. Fabrication of fluorophore-doped biomimicking and complex geometric structures validated the ability to print feature sizes less than 200 μm. The presented methods and optical characterization techniques provide the foundation for the manufacturing of solid 3D printed fluorescent structures, with direct relevance to biomedical optics and the broad adoption of fast manufacturing methods in fluorescence imaging. [ABSTRACT FROM AUTHOR]

Purpose. In this study, spatio-temporal beam profiling for electron ultra-high dose rate (UHDR; >40 Gy s−1) radiation via Cherenkov emission and radioluminescence imaging was investigated using intensified complementary metal–oxide–semiconductor cameras. Methods. The cameras, gated to FLASH optimized linear accelerator pulses, imaged radioluminescence and Cherenkov emission incited by single pulses of a UHDR (>40 Gy s−1) 10 MeV electron beam delivered to the isocenter. Surface dosimetry was investigated via imaging Cherenkov emission or scintillation from a solid water phantom or Gd2O2S:Tb screen positioned on top of the phantom, respectively. Projected depth–dose profiles were imaged from a tank filled with water (Cherenkov emission) and a 1 g l−1 quinine sulfate solution (scintillation). These optical results were compared with projected lateral dose profiles measured by Gafchromic film at different depths, including the surface. Results. The per-pulse beam output from Cherenkov imaging agreed with the photomultiplier tube Cherenkov output to within 3% after about the first five to seven ramp-up pulses. Cherenkov emission and scintillation were linear with dose (R2 = 0.987 and 0.995, respectively) and independent of dose rate from ∼50 to 300 Gy s−1 (0.18–0.91 Gy/pulse). The surface dose distribution from film agreed better with scintillation than with Cherenkov emission imaging (3%/3 mm gamma pass rates of 98.9% and 88.8%, respectively). Using a 450 nm bandpass filter, the quinine sulfate-based water imaging of the projected depth optical profiles agreed with the projected film dose to within 5%. Conclusion. The agreement of surface dosimetry using scintillation screen imaging and Gafchromic film suggests it can verify the consistency of daily beam quality assurance parameters with an accuracy of around 2% or 2 mm. Cherenkov-based surface dosimetry was affected by the target's optical properties, prompting additional calibration. In projected depth–dose profiling, scintillation imaging via spectral suppression of Cherenkov emission provided the best match to film. Both camera-based imaging modalities resolved dose from single UHDR beam pulses of up to 60 Hz repetition rate and 1 mm spatial resolution. [ABSTRACT FROM AUTHOR]

In patients undergoing breast-conserving surgery (BCS), the rate of re-excision procedures to remove residual tumor left behind after initial resection can be high. Projection radiography, and recently, volumetric x-ray imaging are used to assess margin adequacy, but x-ray imaging lacks contrast between healthy, abnormal benign, and malignant fibrous tissues important for surgical decision making. The purpose of this study was to compare micro-CT and optical scatter imagery of surgical breast specimens and to demonstrate enhanced contrast-to intra-tumoral morphologies and tumor boundary features revealed by optical scatter imaging. A total of 57 breast tumor slices from 57 patients were imaged ex vivo by spatially co-registered micro-CT and optical scatter scanning. Optical scatter exhibited greater similarity with micro-CT in 89% (51/57) of specimens versus diffuse white light (DWL) luminance using mutual information (mean ± standard deviation of 0.48 ± 0.21 versus 0.24 ± 0.12; p < 0.001) and in 81% (46/57) of specimens using the Sřrensen–Dice coefficient (0.48 ± 0.21 versus 0.33 ± 0.18; p < 0.001). The coefficient of variation (CV) quantified the feature content in each image. Optical scatter exhibited the highest CV in every specimen (optical scatter: 0.70 ± 0.17; diffuse luminance: 0.24 ± 01; micro-CT: 0.15 ± 0.03 for micro-CT; p < 0.001). Optical scatter also exhibited the highest contrast ratios across representative tumor boundaries with adjacent healthy/benign fibrous tissues (1.5–3.7 for optical scatter; 1.0–1.1 for diffuse luminance; 1.0–1.1 for micro-CT). The two main findings from this study were: first, optical scatter contrast was in general similar to the radiological view of the tissue relative to DWL imaging; and second, optical scatter revealed additional features associated with fibrous tissue structures of similar radiodensity that may be relevant to diagnosis. The value of micro-CT lies in its rapid three-dimensional scanning of specimen morphology, and combined with optical scatter imaging with sensitivity to fibrous surface tissues, may be an attractive solution for margin assessment during BCS. [ABSTRACT FROM AUTHOR]

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 (R2 > 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. [ABSTRACT FROM AUTHOR]

The field of medical physics has struggled with the role of research in recent years, as professional interests have dominated its growth toward clinical service. This article focuses on the subset of medical physics programs within academic medical centers and how a refocused academic mission within these centers should drive and support Discovery and Invention with Ventures and Engineering for Research Translation (DIVERT). A roadmap to a DIVERT‐based scholarly research program is discussed here around the core building blocks of: (a) creativity in research and team building, (b) improved quality metrics to assess activity, (c) strategic partnerships and spinoff directions that extend capabilities, and (d) future directions driven by faculty‐led initiatives. Within academia, it is the unique discoveries and inventions of faculty that lead to their recognition as scholars, and leads to financial support for their research programs and reconition of their intellectual contributions. Innovation must also be coupled to translation to demonstrate outcome successes. These ingredients are critical for research funding, and the two‐decade growth in biomedical engineering research funding is an illustration of this, where technology invention has been the goal. This record can be contrasted with flat funding within radiation oncology and radiology, where a growing fraction of research is more procedure‐based. However, some centers are leading the change of the definition of medical physics, by the inclusion or assimilation of researchers in fields such as biomedical engineering, machine learning, or data science, thereby widening the scope for new discoveries and inventions. New approaches to the assessment of research quality can help realize this model, revisiting the measures of success and impact. While research partnerships with large industry are productive, newer efforts that foster enterprise startups are changing how institutions see the benefits of the connection between academic innovation and affiliated startup company formation. This innovation‐to‐enterprise focus can help to cultivate a broader bandwidth of donor‐to‐investor networks. There are many predictions on future directions in medical physics, yet the actual inventive and discovery steps come from individual research faculty creativity. All success through a DIVERT model requires that faculty‐led initiatives span the gap from invention to translation, with support from institutional leadership at all steps in the process. Institutional investment in faculty through endowments or clinical revenues will likely need to increase in the coming years due to the relative decreasing size of grants. Yet, radiology and radiation oncology are both high‐revenue, translational fields, with the capacity to synergistically support clinical and research operations through large infrastructures that are mutually beneficial. These roadmap principles can provide a pathway for committed academic medical physics programs in scholarly leadership that will preserve medical physics as an active part of university academics. [ABSTRACT FROM AUTHOR]

Is it possible to find deterministic relationships between optical measurements and pathophysiology in an unsupervised manner and based on data alone? Optical property quantification is a rapidly growing biomedical imaging technique for characterizing biological tissues that shows promise in a range of clinical applications, such as intraoperative breast-conserving surgery margin assessment. However, translating tissue optical properties to clinical pathology information is still a cumbersome problem due to, amongst other things, inter- and intrapatient variability, calibration, and ultimately the nonlinear behavior of light in turbid media. These challenges limit the ability of standard statistical methods to generate a simple model of pathology, requiring more advanced algorithms. We present a data-driven, nonlinear model of breast cancer pathology for real-time margin assessment of resected samples using optical properties derived from spatial frequency domain imaging data. A series of deep neural network models are employed to obtain sets of latent embeddings that relate optical data signatures to the underlying tissue pathology in a tractable manner. These self-explanatory models can translate absorption and scattering properties measured from pathology, while also being able to synthesize new data. The method was tested on a total of 70 resected breast tissue samples containing 137 regions of interest, achieving rapid optical property modeling with errors only limited by current semi-empirical models, allowing for mass sample synthesis and providing a systematic understanding of dataset properties, paving the way for deep automated margin assessment algorithms using structured light imaging or, in principle, any other optical imaging technique seeking modeling. Code is available. [ABSTRACT FROM AUTHOR]

Purpose: High dose rate conditions, coupled with problems related to small field dosimetry, make dose characterization for FLASH‐RT challenging. Most conventional dosimeters show significant dependence on dose rate at ultra‐high dose rate conditions or fail to provide sufficiently fast temporal data for pulse to pulse dosimetry. Here fast 2D imaging of radioluminescence from a water and quinine phantom was tested for dosimetry of individual 4 μs linac pulses. Methods: A modified clinical linac delivered an electron FLASH beam of >50 Gy/s to clinical isocenter. This modification removed the x‐ray target and flattening filter, leading to a beam that was symmetric and gaussian, as verified with GafChromic EBT‐XD film. Lateral projected 2D dose distributions for each linac pulse were imaged in a quinine‐doped water tank using a gated intensified camera, and an inverse Abel transform reconstruction provided 3D images for on‐axis depth dose values. A total of 20 pulses were delivered with a 10 MeV, 1.5 cm circular beam, and beam with jaws wide open (40 × 40 cm2), and a 3D dose distribution was recovered for each pulse. Beam output was analyzed on a pulse by pulse basis. Results: The Rp, Dmax, and the R50 measured with film and optical methods agreed to within 1 mm for the 1.5 cm circular beam and the beam with jaws wide open. Cross beam profiles for both beams agreed with film data with >95% passing rate (2%/2 mm gamma criteria). The optical central axis depth dose agreed with film data, except for near the surface. A temporal pulse analysis revealed a ramp‐up period where the dose per pulse increased for the first few pulses and then stabilized. Conclusions: Optical imaging of radioluminescence was presented as a valuable tool for establishing a baseline for the recently initiated electron FLASH beam at our institution. [ABSTRACT FROM AUTHOR]

The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ near-infrared (NIR) molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with epidermal growth factor receptor (EGFR) expression in U251, U87, and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson's r = 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Purpose: A Geant4‐based TOPAS Monte Carlo toolkit was utilized to model a Varian ProBeam proton therapy system, with the aim of providing an independent computational platform for validating advanced dosimetric methods. Materials and Methods: The model was tested for accuracy of dose and linear energy transfer (LET) prediction relative to the commissioning data, which included integral depth dose (IDD) in water and spot profiles in air measured at varying depths (for energies of 70 to 240 MeV in increments of 10 MeV, and 242 MeV), and absolute dose calibration. Emittance was defined based on depth‐dependent spot profiles and Courant–Snyder's particle transport theory, which provided spot size and angular divergence along the inline and crossline plane. Energy spectra were defined as Gaussian distributions that best matched the range and maximum dose of the IDD. The validity of the model was assessed based on measurements of range, dose to peak difference, mean point to point difference, spot sizes at different depths, and spread‐out Bragg peak (SOBP) IDD and was compared to the current treatment planning software (TPS). Results: Simulated and commissioned spot sizes agreed within 2.5%. The single spot IDD range, maximum dose, and mean point to point difference of each commissioned energy agreed with the simulated profiles generally within 0.07 mm, 0.4%, and 0.6%, respectively. A simulated SOBP plan agreed with the measured dose within 2% for the plateau region. The protons/MU and absolute dose agreed with the current TPS to within 1.6% and exhibited the greatest discrepancy at higher energies. Conclusions: The TOPAS model agreed well with the commissioning data and included inline and crossline asymmetry of the beam profiles. The discrepancy between the measured and TOPAS‐simulated SOBP plan may be due to beam modeling simplifications of the current TPS and the nuclear halo effect. The model can compute LET, and motivates future studies in understanding equivalent dose prediction in treatment planning, and investigating scintillation quenching. [ABSTRACT FROM AUTHOR]

In this study the metric of detective quantum efficiency (DQE) was applied to Cherenkov imaging systems for the first time, and results were compared for different detector hardware, gain levels and with imaging processing for noise suppression. Intensified complementary metal oxide semiconductor cameras using different image intensifier designs (Gen3 and Gen2+) were used to image Cherenkov emission from a tissue phantom in order to measure the modulation transfer function (MTF) and noise power spectrum (NPS) of the systems. These parameters were used to calculate the DQE for varying acquisition settings and image processing steps. MTF curves indicated that the Gen3 system had superior contrast transfer and spatial resolution than the Gen2+ system, with values of 0.52 mm−1 and 0.31 mm−1, respectively. With median filtering for noise suppression, these values decreased to 0.50 mm−1 and 0.26 mm−1. The maximum NPS values for the Gen3 and Gen2+ systems at high gain were 1.3 × 106 mm2 and 9.1 × 104 mm2 respectively, representing a 14x decrease in noise power for the Gen2+ system. Both systems exhibited increased NPS intensity with increasing gain, while median filtering lowered the NPS. The DQE of each system increased with increasing gain, and at the maximum gain levels the Gen3 system had a low-frequency DQE of 0.31%, while the Gen2+ system had a value of 1.44%. However, at a higher frequency of 0.4 mm−1, these values became 0.54% and 0.03%. Filtering improved DQE for the Gen3 system and reduced DQE for the Gen2+ system and had a mix of detrimental and beneficial qualitative effects by decreasing the spatial resolution and sharpness but also substantially lowering noise. This methodology for DQE measurement allowed for quantitative comparison between Cherenkov imaging cameras and improvements to their sensitivity, and yielded the first formal assessment of Cherenkov image formation efficiency. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the potential benefits of remote camera‐based scintillation imaging for routine quality assurance (QA) measurements for magnetic resonance guided radiotherapy (MRgRT) linear accelerators. Methods: A wall‐mounted CMOS camera with a time‐synchronized intensifier was used to image photons produced from a scintillation screen in response to dose deposition from a 6 MV FFF x‐ray beam produced by a 0.35 T MR‐linac. The oblique angle of the field of view was corrected using a projective transform from a checkerboard calibration target. Output sensitivity and constancy was measured using the scintillator and benchmarked against an A28 ion chamber. Field cross‐plane and in‐plane profiles were measured for field sizes ranging from 1.68 × 1.66 cm2 to 20.02 × 19.92 cm2 with both scintillation imaging and using an IC profiler. Multileaf collimator (MLC) shifts were introduced to test sensitivity of the scintillation imaging system to small spatial deviations. A picket fence test and star‐shot were delivered to both the scintillator and EBT3 film to compare accuracy in measuring MLC positions and isocenter size. Results: The scintillation imaging system showed comparable sensitivity and linearity to the ion chamber in response to changes in machine output down to 0.5 MU (R2 = 0.99). Cross‐plane profiles show strong agreement with defined field sizes using full width half maximum (FWHM) measurement of <2 mm for field sizes below 15 cm, but the oblique viewing angle was the limiting factor in accuracy of in‐plane profile widths. However, the system provided high‐resolution profiles in both directions for constancy measurements. Small shifts in the field position down to 0.5 mm were detectable with <0.1 mm accuracy. Multileaf collimator positions as measured with both scintillation imaging and EBT3 film were measured within ± 1 mm tolerance and both detection systems produced similar isocenter sizes from the star‐shot analysis (0.81 and 0.83 mm radii). Conclusions: Remote scintillation imaging of a two‐dimensional screen provided a rapid, versatile, MR‐compatible solution to many routine quality assurance procedures including output constancy, profile flatness and symmetry constancy, MLC position verification and isocenter size. This method is high‐resolution, does not require post‐irradiation readout, and provides simple, instantaneous data acquisition. Full automation of the readout and processing could make this a very simple but effective QA tool, and is adaptable to all medical accelerators. [ABSTRACT FROM AUTHOR]

Objective: Tumor stiffening in pancreatic adenocarcinoma (PDAC) has been linked to cancer progression and lack of therapy response, yet current elastography tools cannot map stiffness in a whole tumor field-of-view with biologically relevant spatial resolution. Therefore, this study was developed to assess stiffness heterogeneity and geometrical patterns across whole PDAC xenograft ex vivo tumors. Methods: The ex vivo elastography (EVE) mapping system was capable of creating stiffness map at 300-micron spatial resolution under a 5–20 mm field of view relevant to whole tumor assessment. The stiffness value at each location was determined by compression testing and an absolute tumor Young's modulus map was calculated based on the calibration between the system and ultrasound elastography (R2 = 0.95). Results: Two PDAC tumor lines AsPC-1 and BxPC-3 implanted in xenograft models were assessed to show tumor stiffness and its linear relationship to collagen content (R2 = 0.59). EVE was able to capture stiffness heterogeneity ranging between 5 and 100 kPa in pancreatic tumors with collagen content up to 25%. More importantly, data shows the inverse relationship of local stiffness to local drug distribution (R2 = 0.66) and vessel patency (R2 = 0.61) in both PDAC tumor lines. Conclusion: The results suggested that elastography could be utilized to predict drug penetration in PDAC tumors or assess response to biological modifying adjunct therapies. Significance: This study presents the first attempt to map out stiffness on a biologically relevant spatial scale across whole PDAC tumor slices with spatial resolution in the hundreds of microns. [ABSTRACT FROM AUTHOR]