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PurposeThis study aims to investigate practice changes among Southern and Northern California's radiation oncology centers during the COVID-19 pandemic.MethodsOn the online survey platform SurveyMonkey, we designed 10 survey questions to measure changes in various aspects of medical physics practice. The questions covered patient load and travel rules; scopes to work from home; new protocols to reduce corona virus disease-2019 (COVID-19) infection risk; availability of telemedicine; and changes in fractionation schedules and/or type of treatment plans. We emailed the survey to radiation oncology centers throughout Northern and Southern California, requesting one completed survey per center. All responses were anonymized, and data were analyzed using both qualitative and quantitative research methods.ResultsAt the end of a 4-month collection period (July 2, 2021 to October 11, 2021), we received a total of 61 responses throughout Southern and Northern California. On average, 4111 patients were treated per day across the 61 centers. New COVID-19-related department and hospital policies, along with hybrid workflow changes, infectious control policies, and changes in patient load have been reported. Results also showed changes in treatment methods during the pandemic, such as increased use of telemedicine, hypofractionation for palliative, breast cancer, and prostate cancer cases; and simultaneous boosts, compared to sequential boosts.ConclusionOur California radiation oncology center population study shows changes in various aspects of radiation oncology practices during the COVID-19 pandemic. This study serves as a pilot study to identify possible correlations and new strategies that allow radiation oncology centers to continue providing quality patient care while ensuring the safety of both staff and patients.

Purpose The goal of this work was to develop and test nontoxic electron collimation technologies for clinical use. Methods Two novel technologies were investigated: tungsten‐silicone composite and 3D printed electron cutouts. Transmission, dose uniformity, and profiles were measured for the tungsten‐silicone. Surface dose, relative dose output, and field size were measured for the 3D printed cutouts and compared with the standard cerrobend cutouts in current clinical use. Quality assurance tests including mass measurements, Megavoltage (MV) imaging, and drop testing were developed for the 3D printed cutouts as a guide to safe clinical implementation. Results Dose profiles of the flexible tungsten‐silicone skin shields had an 80–20 penumbra values of 2–3 mm compared to 7–8 mm for cerrobend. In MV transmission image measurements of the tungsten‐silicone, 80% of the pixels had a transmission value within 2% of the mean. An ∼90% reduction in electron intensity was measured for 6 MeV and a 6.4 mm thickness of tungsten‐silicone and 12.7 mm thickness for 16 MeV. The maximum difference in 3D printed cutout versus cerrobend output, surface dose, and full width at half‐maximum (FWHM) was 1.7%, 1.2%, and 1.5%, respectively, for the 10 cm × 10 cm cutouts. Conclusions Both flexible tungsten‐silicone and 3D printed cutouts were found to be feasible for clinical use. The flexible tungsten‐silicone was of adequate density, flexibility, and uniformity to serve as skin shields for electron therapy. The 3D printed cutouts were dosimetrically equivalent to standard cerrobend cutouts and were robust enough for handling in the clinical environment.

We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100-1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups. Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA. Data obtained between replicate experiments for all dosimeters were in excellent agreement (±3%). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose. In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect.

Purpose Electron radiation therapy dose distributions are affected by irregular body surface contours. This study investigates the feasibility of three‐dimensional (3D) cameras to substitute for the treatment planning computerized tomography (CT) scan by capturing the body surfaces to be treated for accurate electron beam dosimetry. Methods Dosimetry was compared for six electron beam treatments to the nose, toe, eye, and scalp using full CT scan, CT scan with Hounsfield Unit (HU) overridden to water (mimic 3D camera cases), and flat‐phantom techniques. Radiation dose was prescribed to a depth on the central axis per physician’s order, and the monitor units (MUs) were calculated. The 3D camera spatial accuracy was evaluated by comparing the 3D surface of a head phantom captured by a 3D camera and that generated with the CT scan in the treatment planning system. A clinical case is presented, and MUs were calculated using the 3D camera body contour with HU overridden to water. Results Across six cases the average change in MUs between the full CT and the 3Dwater (CT scan with HU overridden to water) calculations was 1.3% with a standard deviation of 1.0%. The corresponding hotspots had a mean difference of 0.4% and a standard deviation of 1.9%. The 3D camera captured surface of a head phantom was found to have a 0.59 mm standard deviation from the surface derived from the CT scan. In‐vivo dose measurements (213 ± 8 cGy) agreed with the 3D‐camera planned dose of 209 ± 6 cGy, compared to 192 ± 6 cGy for the flat‐phantom calculation (same MUs). Conclusions Electron beam dosimetry is affected by irregular body surfaces. 3D cameras can capture irregular body contours which allow accurate dosimetry of electron beam treatment as an alternative to costly CT scans with no extra exposure to radiation. Tools and workflow for clinical implementation are provided.

Purpose As C‐arm linac radiation therapy evolves toward faster, more efficient delivery, and more conformal dosimetry, treatments with increasingly complex couch motions are emerging. Monitoring the patient motion independently of the couch motion during non‐coplanar, non‐isocentric, or dynamic couch treatments is a key bottleneck to their clinical implementation. The goal of this study is to develop a prototype real‐time monitoring system for unconventional beam trajectories to ensure a safe and accurate treatment delivery. Methods An in‐house algorithm was developed for tracking using a couch‐mounted three‐dimensional (3D) depth camera. The accuracy of patient motion detection on the couch was tested on a 3D printed phantom created from the body surface contour exported from the treatment planning system. The technique was evaluated against a commercial optical surface monitoring system with known phantom displacements of 3, 5, and 7 mm in lateral, longitudinal, and vertical directions by placing a head phantom on a dynamic platform on the treatment couch. The stability of the monitoring system was evaluated during dynamic couch trajectories, at speeds between 10.6 and 65 cm/min. Results The proposed monitoring system agreed with the ceiling mounted optical surface monitoring system in longitudinal, lateral, and vertical directions within 0.5 mm. The uncertainty caused by couch vibration increased with couch speed but remained sub‐millimeter for speeds up to 32 cm/min. For couch speeds of 10.6, 32.2, and 65 cm/min, the uncertainty ranges were 0.27– 0.73 mm, 0.15–0.87 mm, and 0.28–1.29 mm, respectively. Conclusion By mounting a 3D camera in the same frame‐of‐reference as the patient and eliminating dead spots, this proof of concept demonstrates real‐time patient monitoring during couch motion. For treatments with non‐coplanar beams, multiple isocenters, or dynamic couch motion, this provides additional safety without additional radiation dose and avoids some of the complexity and limitations of room mounted systems.

Background 2-(4'- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques.

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.

Brain stereotactic radiosurgery (SRS) treatments require multiple quality assurance (QA) procedures to ensure accurate and precise treatment delivery. As single-isocenter multitarget SRS treatments become more popular, the quantification of off-axis accuracy of the linear accelerator is crucial. In this study, a novel brain SRS integrated phantom was developed and validated to enable SRS QA with a single phantom to facilitate implementation of a frameless single-isocenter, multitarget SRS program. This phantom combines the independent verification of each positioning system, the Winston-Lutz, off-axis accuracy evaluation (i.e. off-axis Winston-Lutz), and the dosimetric accuracy utilizing both point dose measurements as well as film measurement, without moving the phantom. A novel 3D printed phantom, coined OneIso, was designed with a movable insert which can switch between the Winston-Lutz test target and dose measurement without moving the phantom itself. For dose verification, ten brain SRS clinical treatment plans with 10 MV flattening-filter-free beams were delivered on a Varian TrueBeam with a high-definition multileaf collimator (HD-MLC). Radiochromic film and pinpoint ion chamber comparison measurements were made between the OneIso and solid water (SW) phantom setups. For the off-axis Winston-Lutz measurements, a row of off-axis ball bearings (BBs) was integrated into the OneIso. To quantify the spatial accuracy versus distance from the isocenter, two-dimensional displacements were calculated between the planned and delivered BB locations relative to their respective MLC defined field border. OneIso and the SW phantoms agree within 1%, for both film and point dose measurements. OneIso identified a reduction in spatial accuracy further away from the isocenter. Differences increased as distance from the isocenter increased, exceeding recommended SRS accuracy tolerances at 7 cm away from the isocenter. OneIso provides a streamlined, single-setup workflow for single-isocenter multitarget frameless linac-based SRS QA. Additionally, with the ability to quantify off-axis spatial discrepancies, we can determine limitations on the maximum distance between targets to ensure a single-isocenter multitarget SRS program meets recommended guidelines.

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Despite current surgery, chemotherapy and targeted therapies, the majority of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall survival rates remain poor. It is known that ovarian cancer is a radiosensitive tumor. Historically, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of chemotherapy sensitive and resistant ovarian cancer. However, TAI fell out of favor due to high toxicity, particularly of the gastrointestinal tract. We have developed a preclinical irradiation platform that allows for total abdominal ultrahigh dose rate FLASH irradiation. We demonstrate that TAI-FLASH reduces radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. Single high dose TAI-FLASH reduced mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Importantly, FLASH and CONV irradiation had similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of metastatic ovarian cancer in women.

BackgroundCurrent diagnostic techniques are inadequate for rapid microbial diagnosis and optimal management of patients with suspected sepsis. We assessed the clinical impact of three powerful molecular diagnostic methods.MethodsWith blood samples from 200 consecutive patients with suspected sepsis, we evaluated 1) metagenomic shotgun sequencing together with a Bayesian inference approach for contaminant sequence removal, for detecting bacterial DNA; 2) viral capture sequencing; and 3) transcript-based host response profiling for classifying patients as infected or not, and if infected, with bacteria or viruses. We then evaluated changes in diagnostic decision-making among three expert physicians by unblinding the results of these methods in a staged fashion.ResultsMetagenomic shotgun sequencing confirmed positive blood culture results in 14 of 26 patients. In 17 of 200 patients, metagenomic sequencing and viral capture sequencing revealed organisms that were 1) not detected by conventional hospital tests within 5 days after presentation, and 2) classified as of probable clinical relevance by physician consensus. Host response profiling led at least two of three physicians to change their diagnostic decisions in 46 of 100 patients. The data suggested possible bacterial DNA translocation in 8 patients who were originally classified by physicians as noninfected and illustrate how host response profiling can guide interpretation of metagenomic shotgun sequencing results.ConclusionsThe integration of host response profiling, metagenomic shotgun sequencing, and viral capture sequencing enhances the utility of each, and may improve the diagnosis and management of patients with suspected sepsis.

Purpose Stereotactic ablative radiation therapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using noncoplanar volumetric modulated arc radiation therapy (VMAT) to reduce chest wall dose from lung SABR. Methods and materials Twenty lung SABR VMAT plans in which the chest wall volume receiving 30 Gy or higher (V30) exceeded 30 mL were replanned by noncoplanar VMAT with opposite 15° couch kicks. Dosimetric parameters including chest wall V30 and V40; lung V5, V10, V20, and mean dose; Paddick high-dose conformity index; intermediate-dose conformity index; and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t test was used to evaluate the difference of the dosimetric parameters between coplanar 1 arc (cVMAT1), coplanar 2 arcs (cVMAT2), and noncoplanar two arcs (nVMAT2) plans; differences with P Results V30 and V40 for chest wall were reduced on average by 20% ± 9% and 15% ± 11% (mean ± standard deviation) from cVMAT2 plans to nVMAT2 plans (P Conclusions We found that noncoplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.

Purpose: The aim of this study is to evaluate the tracking accuracy of a commercial ultrasound system under relevant treatment conditions and demonstrate its clinical utility for detecting significant treatment deviations arising from inadvertent intrafractional target motion. Methods: A multimodality male pelvic phantom was used to simulate prostate image-guided radiotherapy with the system under evaluation. Target motion was simulated by placing the phantom on a motion platform. The tracking accuracy of the ultrasound system was evaluated using an independent optical tracking system under the conditions of beam-on, beam-off, poor image quality with an acoustic shadow introduced, and different phantom motion cycles. The time delay between the ultrasound-detected and actual phantom motion was investigated. A clinical case example of prostate treatment is presented as a demonstration of the utility of the system in practice. Results: Time delay between the motion phantom and ultrasound tracking system is 223 ± 45.2 milliseconds including video and optical tracking system frame rates. The tracking accuracy and precision were better with a longer period. The precision of ultrasound tracking performance in the axial (superior–inferior) direction was better than that in the lateral (left–right) direction (root mean square errors are 0.18 and 0.25 mm, respectively). The accuracy of ultrasound tracking performance in the lateral direction was better than that in the axial direction (the mean position errors are 0.23 and 0.45 mm, respectively). Interference by radiation and image quality do not affect tracking ability significantly. Further, utilizing the tracking system as part of a clinical study for prostate treatment further verified the accuracy and clinical appropriateness. Conclusions: It is feasible to use transperineal ultrasound daily to monitor prostate motion during treatment. Our results verify the accuracy and precision of an ultrasound system under typical external beam treatment conditions and further demonstrate that the tracking system was able to identify important prostate shifts in a clinical case.

Purpose A correct body contour is essential for reliable treatment planning in radiation therapy. While modern medical imaging technologies provide highly accurate patient modeling, there are times when a patient's anatomy cannot be fully captured or there is a lack of easy access to computed tomography (CT) simulation. Here we provide a practical solution to the surface contour truncation problem by using a handheld stereo depth camera (HSDC) to obtain the missing surface anatomy and a surface-surface image registration to stich the surface data into the CT dataset for treatment planning. Methods For a subject with truncated simulation CT images, a HSDC is used to capture the surface information of the truncated anatomy. A mesh surface model is created using a software tool provided by the camera manufacturer. A surface-to-surface registration technique is used to merge the mesh model with the CT and fill in the missing surface information thereby obtaining a complete surface model of the subject. To evaluate the accuracy of the proposed approach, experiments were performed with the following steps. First, we selected three previously treated patients and fabricated a phantom mimicking each patient using the corresponding CT images and a 3D printer. Second, we removed part of the CT images of each patient to create hypothetical cases with image truncations. Next, a HSDC was used to image the 3D-printed phantoms and the HSDC-derived surface models were registered with the hypothetically truncated CT images. The contours obtained using the approach were then compared with the ground truth contours derived from the original simulation CT without image truncation. The distance between the two contours was calculated in order to evaluate the accuracy of the method. Finally, the dosimetric impact of the approach is assessed by comparing the volume within the 95% isodose line and global maximum dose (Dmax) computed based on the two surface contours for the breast case that exhibited the largest contour variation in the treated breast. Results A systematic strategy of using a 3D HSDC to compensate for missing surface information caused by the truncation of CT images was established. Our study showed that the proposed technique was able to reliably provide the full contours for treatment planning in the case of severe CT image truncation(s). The root-mean-square error for the registration between the aligned HDSC surface model and the ground truth data was found to be 2.1 mm. The average distance between the two models was 0.4 ± 1.7 mm (mean ± SD). Maximum deviations occurred in areas of high concavity or when the skin was close to the couch. The breast tissue covered by 95% isodose line decreased by 3% and Dmax increased by 0.2% with the use of the HSDC model. Conclusions The use of HSDC for obtaining missing surface data during simulation has a number of advantages, such as, ease of use, low cost, and no additional ionizing radiation. It may provide a clinically practical solution to deal with the longstanding problem of CT image truncations in radiation therapy treatment planning. This article is protected by copyright. All rights reserved.

2-Deoxy-2-(18)F-fluoro-d-glucose (2-FDG) with PET is undeniably useful in the clinic, being able, among other uses, to monitor change over time using the 2-FDG SUV metric. This report suggests some potentially serious caveats for this and related roles for 2-FDG PET. Most critical is the assumption that there is an exact proportionality between glucose metabolism and 2-FDG metabolism, called the lumped constant, or LC. This report describes that LC is not constant for a specific tissue and may be variable before and after disease treatment. The purpose of this work is not to deny the clinical value of 2-FDG PET; it is a reminder that when one extends the use of an appropriately qualified imaging method, new observations may arise and further validation would be necessary. The current understanding of glucose-based energetics in vivo is based on the quantification of glucose metabolic rates with 2-FDG PET, a method that permits the noninvasive assessment of various human disorders. However, 2-FDG is a good substrate only for facilitated-glucose transporters (GLUTs), not for sodium-dependent glucose cotransporters (SGLTs), which have recently been shown to be distributed in multiple human tissues. Thus, the GLUT-mediated in vivo glucose utilization measured by 2-FDG PET would be masked to the potentially substantial role of functional SGLTs in glucose transport and use. Therefore, under these circumstances, the 2-FDG LC used to quantify in vivo glucose utilization should not be expected to remain constant. 2-FDG LC variations have been especially significant in tumors, particularly at different stages of cancer development, affecting the accuracy of quantitative glucose measures and potentially limiting the prognostic value of 2-FDG, as well as its accuracy in monitoring treatments. SGLT-mediated glucose transport can be estimated using α-methyl-4-deoxy-4-(18)F-fluoro-d-glucopyranoside (Me-4FDG). Using both 2-FDG and Me-4FDG should provide a more complete picture of glucose utilization via both GLUT and SGLT transporters in health and disease states. Given the widespread use of 2-FDG PET to infer glucose metabolism, it is relevant to appreciate the potential limitations of 2-FDG as a surrogate for glucose metabolic rate and the potential reasons for variability in LC. Even when the readout for the 2-FDG PET study is only an SUV parameter, variability in LC is important, particularly if it changes over the course of disease progression (e.g., an evolving tumor).

The death rate due to stroke is decreasing, resulting in more individuals living with stroke related disabilities. Following stroke, dying cells contribute to the large influx of highly reactive astrocytes and pro-inflammatory microglia that release cytokines and lead to a cytotoxic environment that causes further brain damage and prevents endogenous repair. Paradoxically, these same cells also activate pro-repair mechanisms that contribute to endogenous repair and brain plasticity. Here, we show that the direct injection of a hyaluronic acid based microporous annealed particle (HA-MAP) hydrogel into the stroke core reduces the percent of highly reactive astrocytes and increases the percent of alternatively activated microglia in and around the lesion. Further, we show that HA-MAP hydrogel promotes reparative astrocyte infiltration into the lesion, which directly coincides with axonal penetration into the lesion. Additionally, HA-MAP injection decreases cerebral atrophy and preserves nigrostriatal bundles after stroke. This work shows that the injection of a porous scaffold into the stroke core can lead to clinically relevant decrease in cerebral atrophy and modulates the phenotype of astrocytes and microglia towards a pro-repair phenotype.

Purpose. Radiation dose delivered to targets located near the upper-abdomen or in the thorax are significantly affected by respiratory-motion. Relatively large-margins are commonly added to compensate for this motion, limiting radiation-dose-escalation. Internal-surrogates of target motion, such as a radiofrequency (RF) tracking system, i.e. Calypso® System, are used to overcome this challenge and improve normal-tissue sparing. RF tracking systems consist of implanting transponders in the vicinity of the tumor to be tracked using radiofrequency-waves. Unfortunately, although the manufacture provides a universal quality-assurance (QA) phantom, QA-phantoms specifically for lung-applications are limited, warranting the development of alternative solutions to fulfil the tests mandated by AAPM’s TG142. Accordingly, our objective was to design and develop a motion-phantom to evaluate Calypso for lung-applications that allows the Calypso® Beacons to move in different directions to better simulate true lung-motion. Methods and Materials. A Calypso lung QA-phantom was designed, and 3D-printed. The design consists of three independent arms where the transponders were attached. A pinpoint-chamber with a buildup-cap was also incorporated. A 4-axis robotic arm was programmed to drive the motion-phantom to mimic breathing. After acquiring a four-dimensional-computed-tomography (4DCT) scan of the motion-phantom, treatment-plans were generated and delivered on a Varian TrueBeam® with Calypso capabilities. Stationary and gated-treatment plans were generated and delivered to determine the dosimetric difference between gated and non-gated treatments. Portal cine-images were acquired to determine the temporal-accuracy of delivery by calculating the difference between the observed versus expected transponders locations with the known speed of the transponders’ motion. Results. Dosimetric accuracy is better than the TG142 tolerance of 2%. Temporal accuracy is greater than, TG142 tolerance of 100 ms for beam-on, but less than 100 ms for beam-hold. Conclusions. The robotic QA-phantom designed and developed in this study provides an independent phantom for performing Calypso lung-QA for commissioning and acceptance testing of Calypso for lung treatments.

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

Glucose transporters are central players in glucose homeostasis. There are two major classes of glucose transporters in the body, the passive facilitative glucose transporters (GLUTs) and the secondary active sodium-coupled glucose transporters (SGLTs). In the present study, we report the use of a non-invasive imaging technique, positron emission tomography, in mice aiming to evaluate the role of GLUTs and SGLTs in controlling glucose distribution and utilization. We show that GLUTs are most significant for glucose uptake into the brain and liver, whereas SGLTs are important in glucose recovery in the kidney. This work provides further support for the use of SGLT imaging in the investigation of the role of SGLT transporters in human physiology and diseases such as diabetes and cancer. The importance of sodium-coupled glucose transporters (SGLTs) and facilitative glucose transporters (GLUTs) in glucose homeostasis was studied in mice using fluorine-18 labelled glucose molecular imaging probes and non-invasive positron emission tomography (PET) imaging. The probes were: α-methyl-4-[F-18]-fluoro-4-deoxy-d-glucopyranoside (Me-4FDG), a substrate for SGLTs; 4-deoxy-4-[F-18]-fluoro-d-glucose (4-FDG), a substrate for SGLTs and GLUTs; and 2-deoxy-2-[F-18]-fluoro-d-glucose (2-FDG), a substrate for GLUTs. These radiolabelled imaging probes were injected i.v. into wild-type, Sglt1(-/-) , Sglt2(-/-) and Glut2(-/-) mice and their dynamic whole-body distribution was determined using microPET. The distribution of 2-FDG was similar to that reported earlier (i.e. it accumulated in the brain, heart, liver and kidney, and was excreted into the urinary bladder). There was little change in the distribution of 2-FDG in Glut2(-/-) mice, apart from a reduction in the rate of uptake into liver. The major differences between Me-4FDG and 2-FDG were that Me-4FDG did not enter the brain and was not excreted into the urinary bladder. There was urinary excretion of Me-4FDG in Sglt1(-/-) and Sglt2(-/-) mice. However, Me-4FDG was not reabsorbed in the kidney in Glut2(-/-) mice. There were no differences in Me-4FDG uptake into the heart of wild-type, Sglt1(-/-) and Sglt2(-/-) mice. We conclude that GLUT2 is important in glucose liver transport and reabsorption of glucose in the kidney along with SGLT2 and SGLT1. Complete reabsorption of Me-4FDG from the glomerular filtrate in wild-type mice and the absence of reabsorption in the kidney in Glut2(-/-) mice confirm the importance of GLUT2 in glucose absorption across the proximal tubule.

Objective: Ovarian cancer often presents with advanced stage disease. Despite surgery and chemotherapy, recurrence remains inevitable and prognosis poor. Advances in immunotherapy including programmed cell death-1 (PD-1) inhibition show promise, however clinical trials show modest response rates as a single agent therapy in ovarian cancer patients. Radiation therapy is an attractive strategy to enhance the efficacy of immune checkpoint blockade in ovarian cancer due to its ability to increase tumor-infiltrating lymphocytes and enhance immune activation. While ovarian cancer is known to be radiosensitive, total abdominal radiation is not routinely utilized due to high abdominopelvic toxicity. We have recently shown that ultra-high dose rate FLASH irradiation reduces intestinal radiation-induced toxicity. Importantly, we demonstrated efficient tumor control in preclinical models of ovarian cancer peritoneal metastasis. Here we sought to determine the efficacy and safety of FLASH irradiation combined with PD-1 inhibition in preclinical models of ovarian cancer. Methods: Female C57BL/6 mice were intraperitoneally inoculated with ID8-Asc or UPK10 ovarian cancer cells. Total abdominal FLASH irradiation at 14 Gy was administered 10 days post-inoculation. Anti-PD-1 and isotype control antibodies were injected on days 7, 10, and 13 post-inoculation. Mice were sacrificed 22-27 days post-inoculation for tumor burden and immune cell analysis. Stool count, stool weight, complete blood count, and survival were evaluated to compare acute and chronic toxicity as well as efficacy in the treatment arms. Results: Four cohorts of mice were analyzed: Isotype control antibody (IgG), anti-PD-1 (aPD-1), FLASH + IgG, and FLASH + aPD-1. In the ID8-Asc model, irradiated mice showed a 44% decrease in solid stool production with subsequent recovery to baseline by 14 days post-treatment. There was no evidence of hematopoietic toxicity in any of the treatment arms. Survival analysis is ongoing. Exploratory necropsy demonstrated significant tumor burden control in the FLASH cohorts, and in particular, a 25-fold decrease in tumor number in the FLASH + aPD-1 cohort compared to control (mean tumor weight 1.82 mg vs. 357.2 mg, respectively). FLASH + aPD-1 increased intratumoral CD4+ and CD8+ T cells and correlated with enhanced tumor control compared to FLASH or aPD-1 single agent treatments. Similar results were observed in the UPK10 model. Conclusion: Combination FLASH and PD-1 inhibition enhanced tumor control and recruitment of tumor infiltrating lymphocytes compared to IgG, aPD-1, and FLASH treatments alone, while demonstrating safety and tolerability. Our data identify a new opportunity for FLASH and checkpoint inhibition in the treatment of ovarian cancer. Citation Format: Stephanie Chow, Joshua T. Eggold, Karen Levy, Jinghui Wang, Rakesh Manjappa, Dylan Y. Breitkreutz, Amy S. Yu, Karl Bush, Oliver Dorigo, Billy W. Loo, Erinn B. Rankin. Total abdominal ultra-rapid FLASH irradiation enhances the efficacy of PD-1 inhibition in preclinical models of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5357.

Radiation therapy is the most effective cytotoxic cancer therapy available for the treatment of localized tumors. However, radiation-induced toxicity to normal tissues limits the radiation dose and therefore the curative potential of radiotherapy. In particular, the highly radiosensitive intestine greatly limits the use of radiation for patients with intra-abdominal tumor diseases including women with ovarian cancer. Here we sought to investigate the safety and efficacy of FLASH radiation therapy in the treatment of widespread ovarian cancer peritoneal metastases. We performed abdominal irradiation on healthy and ovarian tumor-bearing mice at conventional (CONV, (0.07 Gy/sec)) or FLASH (200 Gy/sec) dose rates and examined gut function by stool counts, DNA damage in crypt cells by γ-H2AX staining, cell death and proliferation by TUNEL/ caspase-3 staining and BrdU immunohistochemistry respectively. We report that ultrahigh dose rate FLASH irradiation causes significantly less radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to CONV dose rate irradiation. Abdominal FLASH reduced the mortality from gastrointestinal syndrome, preserved gut function and epithelial integrity as reflected by their stool counts and FITC-Dextran analysis. In addition, we found decreased cell death and enhanced proliferation of crypt base columnar cells (CBCs) following FLASH irradiation in comparison to CONV irradiation. We also detected reduced number of γ-H2AX foci in crypt cells indicating less DNA damage and/or increased DNA repair after FLASH compared to CONV irradiation. Importantly, FLASH and CONV irradiation have similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation has biological advantages compared to conventional dose rate irradiation in reducing radiation-induced intestinal injury within the irradiation field and therefore may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of abdominal and pelvic tumor disease. Citation Format: Suchitra Natarajan, Karen Levy, Jinghui Wang, Stephanie Chow, Joshua Eggold, Phoebe Loo, Rakesh Manjappa, Frederick M. Lartey, Emil Schüler, Lawrie Skinner, Marjan Rafat, Ryan Ko, Anna Kim, Duaa Al Rawi, Rie von Eyben, Oliver Dorigo, Kerriann M. Casey, Edward E. Graves, Karl Bush, Amy S. Yu, Albert C. Koong, Peter G. Maxim, Billy W. Loo, Erinn B. Rankin. FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5351.

Purpose Various localization and positioning systems utilizing radiographic or nonradiographic methods have been developed to improve the accuracy of radiation treatment. Each quality assurance (QA) procedure requires its own phantom and is independent from each other, so the deviation between each system is unavailable. The purpose of this work is to develop and evaluate a single-integrated QA phantom for different localization and positioning systems. Methods The integrated phantom was designed in three-dimensional (3D) CAD software and 3D printed. The phantom was designed with laser alignment marks, a raised letter "S" on the anterior surface for optical surface monitoring system registration, a core for radiofrequency (RF) tracking system alignment, eight internal fiducials for image alignment, and an isocentric bearing for Winston-Lutz test. Tilt legs and rotational stage were designed for rotational verification of optical surface mapping system and RF tracking system, respectively. The phantom was scanned using a CT scanner and a QA plan was created. This prototype phantom was evaluated against established QA techniques. Results The QA result between the proposed procedure and established QA technique are 1.12 ± 0.31 and 1.14 ± 0.31 mm, respectively, for RF tracking system and 0.18 ± 0.06 and 0.18 ± 0.05 mm for Winston-Lutz test. There is no significant difference for the QA results between the established QA and proposed procedure (P > 0.05, t test). The accuracy of rotational verification for surface mapping system and RF tracking system are less than 0.5 and 1° compared the predefined value. The isocenter deviation of each location system is around l mm. Conclusion We have designed and evaluated a novel-integrated phantom for radiographic and nonradiographic localization and positioning systems for radiotherapy. With this phantom, we will reduce the variation in measurements and simplify the QA procedures.

Background and purpose To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring. Methods and materials We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring. Results For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung. Conclusion We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.

Purpose Radiotherapy treatment planning of extended volume typically necessitates the utilization of multiple field isocenters and abutting dosimetrically matched fields in order to enable coverage beyond the field size limits. A common example includes total lymphoid irradiation (TLI) treatments, which are conventionally planned using dosimetric matching of the mantle, para-aortic/spleen, and pelvic fields. Due to the large irradiated volume and system limitations, such as field size and couch extension, a combination of couch shifts and sliding of patients are necessary to be correctly executed for accurate delivery of the plan. However, shifting of patients presents a substantial safety issue and has been shown to be prone to errors ranging from minor deviations to geometrical misses warranting a medical event. To address this complex setup and mitigate the safety issues relating to delivery, a practical technique for couch indexing of TLI treatments has been developed and evaluated through a retrospective analysis of couch position. Methods The indexing technique is based on the modification of the commonly available slide board to enable indexing of the patient position. Modifications include notching to enable coupling with indexing bars, and the addition of a headrest used to fixate the head of the patient relative to the slide board. For the clinical setup, a Varian Exact CouchTM (Varian Medical Systems, Inc, Palo Alto, CA) was utilized. Two groups of patients were treated: 20 patients with table indexing and 10 patients without. The standard deviations (SDs) of the couch positions in longitudinal, lateral, and vertical directions through the entire treatment cycle for each patient were calculated and differences in both groups were analyzed with Student's t-test. Results The longitudinal direction showed the largest improvement. In the non-indexed group, the positioning SD ranged from 2.0 to 7.9 cm. With the indexing device, the positioning SD was reduced to a range of 0.4 to 1.3 cm (p < 0.05 with 95% confidence level). The lateral positioning was slightly improved (p < 0.05 with 95% confidence level), while no improvement was observed in the vertical direction. Conclusions The conventional matched field TLI treatment is error-prone to geometrical setup error. The feasibility of full indexing TLI treatments was validated and shown to result in a significant reduction of positioning and shifting errors.

Purpose: While critical for safe and accurate radiotherapy, monthly quality assurance of medical linear accelerators is time-consuming and takes physics resources away from other valuable tasks. The previous methods at our institution required 5 hours to perform the mechanical and dosimetric monthly linear accelerator quality assurance tests. An improved workflow was developed to perform these tests with higher accuracy, with fewer error pathways, in significantly less time. Methods: A commercial ion chamber array (IC profiler, Sun Nuclear, Melbourne, Florida) is combined with automation scripts to consolidate monthly linear accelerator QA. The array was used to measure output, flatness, symmetry, jaw positions, gated dose constancy, energy constancy, collimator walkout, crosshair centering, and dosimetric leaf gap constancy. Treatment plans were combined with automation scripts that interface with Sun Nuclear’s graphical user interface. This workflow was implemented on a standard Varian clinac, with no special adaptations, and can be easily applied to other C-arm linear accelerators. Results: These methods enable, in 30 minutes, measurement and analysis of 20 of the 26 dosimetric and mechanical monthly tests recommended by TG-142. This method also reduces uncertainties in the measured beam profile constancy, beam energy constancy, field size, and jaw position tests, compared to our previous methods. One drawback is the increased uncertainty associated with output constancy. Output differences between IC profiler and farmer chamber in plastic water measurements over a 6-month period, across 4 machines, were found to have a 0.3% standard deviation for photons and a 0.5% standard deviation for electrons, which is sufficient for verifying output accuracy according to TG-142 guidelines. To minimize error pathways, automation scripts which apply the required settings, as well as check the exported data file integrity were employed. Conclusions: The equipment, procedure, and scripts used here reduce the time burden of routine quality assurance tests and in most instances improve precision over our previous methods.

Pet with 18F-FDG provides a noninvasive quantitative approach to measuring the glucose utilization rates in various brain regions in vivo (1–3). Quantitative studies in rodents have been improved with the aid of better image resolutions of small-animal PET in recent years (∼1.3-mm full width at half maximum [FWHM] at the center of the field of view) (4). The quantification of cMRglc requires either dynamic imaging with an input function (i.e., using the kinetic model fitting or the Patlak analysis) or static imaging with the input function (i.e., using the operational equations) (5–8). The latter also needs the typical values of 18F-FDG rate constants (K1*,k2*,k3*, and k4*). In mouse studies, the 18F-FDG rate constants of mouse cerebral cortex have not been reported; therefore, the constants estimated from the rat brain have been usually used in the operational equation (9). An input function is required by both of the dynamic and static imaging methods. The blood samples are usually collected manually from the femoral artery of a rodent (10). The total blood volume of a mouse is approximately 2 mL (e.g., ∼7.5% of the body weight of a mouse) (11). Up to 10% (e.g., ∼0.2 mL for an adult mouse) of the total blood volume can be taken from a mouse without altering significantly the physiologic conditions (12). To minimize blood loss and to overcome the procedural difficulty in sampling blood from a mouse during a dynamic small-animal PET scan, a microfluidic blood sampler was developed previously. The amount of blood loss in a quantitative study with this device was less than 5% of the total blood volume in the animal (13). Because of the technical difficulty involved in arterial catheterization for taking blood samples from a mouse, the liver time–activity curve derived from small-animal PET dynamic images is sometimes used as a surrogate input function based on the assumption that the liver is a large blood pool and has relatively low 18F-FDG retention (14,15). Without the need of arterial catheterization, the derivation of the input function from a liver time–activity curve is highly desirable for longitudinal studies. In this study, we performed dynamic 18F-FDG PET studies in 13 mice and, for each study, took blood samples using the microfluidic blood sampler to estimate the mouse cerebral 18F-FDG rate constants K1*−k4*. A noninvasive-image-derived input function from the liver for estimating cMRglc by various quantification methods was also evaluated. The merits and the limitations of various quantification approaches for calculating cMRglc were discussed.

Purpose The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans. Methods and materials Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent. Results Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent. Conclusions For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed.

Aggregation of the Alzheimer amyloid beta peptide (Abeta) Abeta1-42 forms neurotoxic fibrils. In contact with human neurons the fibrils cause rapid influx of external calcium through AMPA/kainate-channels. If this molecular mechanism reflects in vivo events, it could explain the pathogenesis of Alzheimer's disease; activation of AMPA/kainate channels is therefore a likely target for therapeutic intervention. Here we show that short antagonistic "decoy peptides", made of D-amino acids, eliminate this "calcium effect" of Ab1-42. Since chronically elevated calcium levels in the disease trigger activation of pathways that lead to neuron dysfunction and cell death, our decoy peptides are obvious candidates for drug development.

This work provides evidence of previously unrecognized uptake of glucose via sodium-coupled glucose transporters (SGLTs) in specific regions of the brain. The current understanding of functional glucose utilization in brain is largely based on studies using positron emission tomography (PET) with the glucose tracer 2-deoxy-2-[F-18]fluoro-d-glucose (2-FDG). However, 2-FDG is only a good substrate for facilitated-glucose transporters (GLUTs), not for SGLTs. Thus, glucose accumulation measured by 2-FDG omits the role of SGLTs. We designed and synthesized two high-affinity tracers: one, α-methyl-4-[F-18]fluoro-4-deoxy-d-glucopyranoside (Me-4FDG), is a highly specific SGLT substrate and not transported by GLUTs; the other one, 4-[F-18]fluoro-4-deoxy-d-glucose (4-FDG), is transported by both SGLTs and GLUTs and will pass through the blood brain barrier (BBB). In vitro Me-4FDG autoradiography was used to map the distribution of uptake by functional SGLTs in brain slices with a comparable result from in vitro 4-FDG autoradiography. Immunohistochemical assays showed that uptake was consistent with the distribution of SGLT protein. Ex vivo 4-FDG autoradiography showed that SGLTs in these areas are functionally active in the normal in vivo brain. The results establish that SGLTs are a normal part of the physiology of specific areas of the brain, including hippocampus, amygdala, hypothalamus, and cerebral cortices. 4-FDG PET imaging also established that this BBB-permeable SGLT tracer now offers a functional imaging approach in humans to assess regulation of SGLT activity in health and disease.

The challenge of sampling blood from small animals has hampered the realization of quantitative small-animal PET. Difficulties associated with the conventional blood-sampling procedure need to be overcome to facilitate the full use of this technique in mice.We developed an automated blood-sampling device on an integrated microfluidic platform to withdraw small blood samples from mice. We demonstrate the feasibility of performing quantitative small-animal PET studies using (18)F-FDG and input functions derived from the blood samples taken by the new device. (18)F-FDG kinetics in the mouse brain and myocardial tissues were analyzed.The studies showed that small ( approximately 220 nL) blood samples can be taken accurately in volume and precisely in time from the mouse without direct user intervention. The total blood loss in the animal was0.5% of the body weight, and radiation exposure to the investigators was minimized. Good model fittings to the brain and the myocardial tissue time-activity curves were obtained when the input functions were derived from the 18 serial blood samples. The R(2) values of the curve fittings are0.90 using a (18)F-FDG 3-compartment model and0.99 for Patlak analysis. The (18)F-FDG rate constants K(1)(*), k(2)(*), k(3)(*), and k(4)(*), obtained for the 4 mouse brains, were comparable. The cerebral glucose metabolic rates obtained from 4 normoglycemic mice were 21.5 +/- 4.3 mumol/min/100 g (mean +/- SD) under the influence of 1.5% isoflurane. By generating the whole-body parametric images of K(FDG)(*) (mL/min/g), the uptake constant of (18)F-FDG, we obtained similar pixel values as those obtained from the conventional regional analysis using tissue time-activity curves.With an automated microfluidic blood-sampling device, our studies showed that quantitative small-animal PET can be performed in mice routinely, reliably, and safely in a small-animal PET facility.

To minimize blood loss in a mouse during quantitative PET imaging, we developed an automated blood sampling device using microfluidic technology. The integrated technology was proven reliable in measuring the cerebral glucose metabolism. In this study, we validated the performance of the microfluidic device using in vivo mouse studies. We examined the stability of the mouse in sequential PET scans to access the feasibility of acquiring multiple measurements from the same mouse over time. Cardiac output and body temperature were chosen as physiological indicators of mouse stability. Three control and three tumor-bearing mice were studied. Sixty minutes of PET data were acquired for each mouse following a bolus injection of 3'-deoxy-3'-[F- 18]fluorothymidine (FLT; ~250 muCi). 18 serial blood samples, 0.25 mul each, were taken from the femoral artery using the microfluidic device. Body temperatures were monitored before and after the scan. Immediately following the FLT scan, a 40-minute quantitative FDG (~300 muCi) PET scan was performed on the tumor-bearing mouse. Using a previously described first-pass angiographic method, we calculated two cardiac outputs for each mouse using the first 15-second data of the FLT and FDG scans respectively. The FLT data showed that the image-derived blood curve correlated (R squares > 0.95) well with the blood curve derived from the 18 arterial blood samples. The body temperatures (mean: 32.1degC) of the animal varied < 1% after the FLT studies. The cardiac outputs of the three tumor- bearing mice before the 18 blood samples were taken were 19.2, 15.7, 18.3 and were 18.7, 16.3, 18.9 ml/min afterward (i.e. < 4% change). We validated the performance of the microfluidic device using in vivo FLT-PET imaging. The physiology of the animal remained stable after the imaging and blood sampling procedure. Reliable longitudinal measurements using PET imaging are expected to be feasible with a protected arterial catheter.

Purpose: The accuracy of dose calculation for lung stereotactic ablative radiotherapy (SABR) of small lesions critically depends on the proper modeling of the lateral scatter in heterogeneous media. In recent years, grid-based Boltzman solvers such as Acuros XB (AXB) have been introduced for enhanced modeling of radiation transport in heterogeneous media. The purpose of this study is to evaluate the dosimetric impact of dose calculation between AXB and convolution-superposition algorithms such as analytical anisotropic algorithm (AAA) for small lesion sizes and different beam energies. Methods: Five lung SABR VMAT cases with GTV ranged from 0.8cm to 2.5cm in diameter were studied. For each case, doses were calculated by AAA, AXB (V11031) and Monte Carlo simulation (MC) with the same plan parameters for 10MV and 6MV. The dose calculation accuracy were evaluated by comparing DVHs and dose distributions with MC as the benchmark. The accuracy of calculated dose was also validated by EBT3 film measurement with a field size of 3cmx3cm in a thorax phantom. Results: For 10MV and GTV less than 1cm, dose calculated by AXB agrees well with MC compared to AAA. Dose difference calculated with AXB and AAA could be up to 30%. For GTV greater than 2cm, calculation results of AXB and AAA agree within 5% in GTV. For 6MV, the difference between calculated doses by AXB and AAA is less 10% for GTV less than 1cm. Based on film measurements, lung dose was overestimated 10% and 20% by AAA for 6MV and 10MV. Conclusion: Lateral scatter and transport is modeled more accurately by AXB than AAA in heterogeneous media, especially for small field size and high energy beams. The accuracy depends on the assigned material in calculation. If grid-based Boltzman solvers or MC are not available for calculation, lower energy beams should be used for treatment.