Search

We present a new upper limit on the cosmic molecular gas density at $z=2.4-3.4$ obtained using the first year of observations from the CO Mapping Array Project (COMAP). COMAP data cubes are stacked on the 3D positions of 282 quasars selected from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) catalog, yielding a 95% upper limit for flux from CO(1-0) line emission of 0.210 Jy km/s. Depending on the assumptions made, this value can be interpreted as either an average CO line luminosity $L'_\mathrm{CO}$ of eBOSS quasars of $\leq 7.30\times10^{10}$ K km pc$^2$ s$^{-1}$, or an average molecular gas density $\rho_\mathrm{H_2}$ in regions of the universe containing a quasar of $\leq 2.02\times10^8$ M$_\odot$ cMpc$^{-3}$. The $L'_\mathrm{CO}$ upper limit falls among CO line luminosities obtained from individually-targeted quasars in the COMAP redshift range, and the $\rho_\mathrm{H_2}$ value is comparable to upper limits obtained from other Line Intensity Mapping (LIM) surveys and their joint analyses. Further, we forecast the values obtainable with the COMAP/eBOSS stack after the full 5-year COMAP Pathfinder survey. We predict that a detection is probable with this method, depending on the CO properties of the quasar sample. Based on these achieved sensitivities, we believe that this technique of stacking LIM data on the positions of traditional galaxy or quasar catalogs is extremely promising, both as a technique for investigating large galaxy catalogs efficiently at high redshift and as a technique for bolstering the sensitivity of LIM experiments, even with a fraction of their total expected survey data., Comment: 15 pages, 8 figures. To be submitted to ApJ

Background and purposeStereotactic body radiation therapy (SBRT) has become a standard-of-care option for localized prostate cancer. While prostate SBRT has traditionally been delivered using computed-tomography-guided radiation therapy (CTgRT), MR-imaging-guided radiation therapy (MRgRT) is now available. MRgRT offers real-time soft-tissue visualization and ease of adaptive planning, obviating the need for fiducial markers, and potentially allowing for smaller planning target volume (PTV) margins. Although prior studies have focused on evaluating the cost-effectiveness of MRgRT vs CTgRT from a payor perspective, the difference in provider costs to deliver such treatments remains unknown. This study thus used time-driven activity-based costing (TDABC) to determine the difference in provider resources consumed by delivering prostate SBRT via MRgRT vs CTgRT.MethodsData was collected from a single academic institution where prostate SBRT is routinely performed using both CTgRT and MRgRT. Five-fraction SBRT (40 Gy total dose) was assumed to be delivered through volumetric-modulated arc therapy for CTgRT patients, and through step-and-shoot, fixed-gantry intensity-modulated radiation therapy for MRgRT patients. Process maps were constructed for each portion of the radiation delivery process via interviews/surveys with departmental personnel and by measuring CTgRT and MRgRT treatment times. Prior to simulation, only CTgRT patients underwent placement of three gold fiducial markers. Personnel capacity cost rates were calculated by dividing total personnel costs by the annual minutes worked by a given personnel. Equipment costs included both an annualized purchase price and annual maintenance costs. Ultimately, the total costs of care encompassing personnel, space/equipment, and materials were aggregated across the entire chain of care for both CTgRT and MRgRT patients in a base case.ResultsDirect costs associated with delivering a 5-fraction course of prostate SBRT were $1,497 higher with MRgRT than with CTgRT - comprised of personnel costs ($210 higher with MRgRT), space/equipment ($1,542 higher with MRgRT), and materials ($255 higher with CTgRT). Only CTgRT patients underwent fiducial placement, which accounted for $591. MRgRT patients were assumed to undergo both CT simulation (for electron density calculation) and MRI simulation, with the former accounting for $168. Mean time spent by patients in the treatment vault per fraction was 20 minutes (range 15-26 minutes) for CTgRT, and 31 minutes (range 30-34 minutes) for MRgRT. Patient time spent during fiducial placement (CTgRT only) was 60 minutes. Modifying the number of fractions treated would result in the cost difference of $1,497 (5 fractions) changing to $441 (1 fraction) or to $2,025 (7 fractions).ConclusionThis study provides an approximate comparison of the direct resources required for a radiation oncology provider to deliver prostate SBRT with CTgRT vs MRgRT. We await findings from the currently accruing phase III MIRAGE trial, which is comparing these modalities, and will subsequently measure acute and late genitourinary/gastrointestinal (GU/GI) toxicities, temporal change in quality-of-life outcomes, and 5-year biochemical, recurrence-free survival. Results from studies comparing the efficacy and safety of MRgRT vs CTgRT will ultimately allow us to put this cost difference into context.

Additional file 1: Table S1. Organ-At-Risk Dose Constraints.

PurposeOn-board magnetic resonance imaging (MRI) greatly enhances real-time target tracking capability during radiotherapy treatments. However, multislice and volumetric MRI techniques are frame rate limited and introduce unacceptable latency between the target moving out of position and the beam being turned off. We present a technique to estimate continuous volumetric tissue motion using motion models built from a repeated acquisition of a stack of MR slices. Applications including multislice target visualization and out-of-slice motion estimation during MRI-guided radiotherapy are demonstrated.MethodsEight healthy volunteer studies were performed using a 0.35T MRI-guided radiotherapy system. Images were acquired at three frames per second in an interleaved fashion across ten adjacent sagittal slice positions covering 4.5cm using a balanced steady-state-free precession sequence. A previously published five-dimensional (5D) linear motion model used for MRI-guided radiotherapy gating was extended to include multiple slices. This model utilizes an external respiratory bellows signal recorded during imaging to simultaneously estimate motion across all imaged slices. For comparison to an image-based approach, the manifold learning technique local linear embedding (LLE) was used to derive a respiratory surrogate for motion modeling. Manifolds for every slice were aligned during LLE in a group-wise fashion, enabling motion estimation outside the current imaged slice using a motion model, a process which we denote as mSGA. Additionally, a method is developed to evaluate out-of-slice motion estimates. The multislice motion model was evaluated in a single slice with each newly acquired image using a leave-one-out approach. Model-generated gating decision accuracy and beam-on positive predictive value (PPV) are reported along with the median and 95th percentile distance between model and ground truth target centroids.ResultsThe average model gating decision accuracy and PPV across all volunteer studies was 93.7% and 92.8% using the 5D model, and 96.8% and 96.1% using the mSGA model, respectively. The median and 95th percentile distance between model and ground truth target centroids was 0.91 and 2.90mm, respectively, using the 5D model and 0.58 and 1.49mm using the mSGA model, averaged over all eight subjects. The mSGA motion model provided a statistically significant improvement across all evaluation metrics compared to the external surrogate-based 5D model.ConclusionThe proposed techniques for out-of-slice target motion estimation demonstrated accuracy likely sufficient for clinical use. Results indicate the mSGA model may provide higher accuracy, however, the external surrogate-based model allows for unbiased invivo accuracy evaluation.

PurposeTo develop and validate a technique for radiation therapy gating using slow (≤1 frame per second) magnetic resonance imaging (MRI) and a motion model. Proposed uses of the technique include radiation therapy gating using T2-weighted images and conducting additional imaging studies during gated treatments.Methods and materialsThe technique uses a physiologically guided breathing motion model to interpolate deformed target position between 2-dimensional (2D) MRI images acquired every 1 to 3 seconds. The model is parameterized by a 1-dimensional respiratory bellows surrogate and is continuously updated with the most recently acquired 2D images. A phantom and 8 volunteers were imaged with a 0.35T MRI-guided radiation therapy system. A balanced steady-state free precession sequence with a 2D frame rate of 3 frames per second was used to evaluate the technique. The accuracy and beam-on positive predictive value (PPV) of the model-based gating decisions were evaluated using the gating decisions derived from imaging as a ground truth. A T2-weighted gating offline proof-of-concept study using a half-Fourier, single-shot, turbo-spin echo sequence is reported.ResultsModel-interpolated gating accuracy, beam-on PPV, and median absolute distances between model and image-tracked target centroids were, on average, 98.3%, 98.4%, and 0.33 mm, respectively, in the balanced steady-state free precession phantom studies and 93.7%, 92.1%, and 0.86 mm, respectively, in the volunteer studies. T2 model-interpolated gating in 6 volunteers yielded an average accuracy and PPV of 94.3% and 92.5%, respectively, and the mean absolute median distance between modeled and imaged target centroids was 0.86 mm.ConclusionsThis work demonstrates the concept of model-interpolated gating for MRI-guided radiation therapy. The technique was found to be potentially sufficiently accurate for clinical use. Further development is needed to accommodate out-of-plane motion and the use of an internal MR-based respiratory surrogate.

PurposeTo demonstrate the preliminary feasibility of a longitudinal diffusion magnetic resonance imaging (MRI) strategy for assessing patient response to radiotherapy at 0.35 T using an MRI-guided radiotherapy system (ViewRay).MethodsSix patients (three head and neck cancer, three sarcoma) who underwent fractionated radiotherapy were enrolled in this study. A 2D multislice spin echo single-shot echo planar imaging diffusion pulse sequence was implemented on the ViewRay system and tested in phantom studies. The same pulse sequence was used to acquire longitudinal diffusion data (every 2-5 fractions) on the six patients throughout the entire course of radiotherapy. The reproducibility of the apparent diffusion coefficient (ADC) measurements was assessed using reference regions and the temporal variations of the tumor ADC values were evaluated.ResultsIn diffusion phantom studies, the ADC values measured on the ViewRay system matched well with reference ADC values with

PurposeTo develop a technique that assesses the accuracy of the breathing phase-specific volume image generation process by patient-specific breathing motion model using the original free-breathing computed tomographic (CT) scans as ground truths.MethodsSixteen lung cancer patients underwent a previously published protocol in which 25 free-breathing fast helical CT scans were acquired with a simultaneous breathing surrogate. A patient-specific motion model was constructed based on the tissue displacements determined by a state-of-the-art deformable image registration. The first image was arbitrarily selected as the reference image. The motion model was used, along with the free-breathing phase information of the original 25 image datasets, to generate a set of deformation vector fields that mapped the reference image to the 24 nonreference images. The high-pitch helically acquired original scans served as ground truths because they captured the instantaneous tissue positions during free breathing. Image similarity between the simulated and the original scans was assessed using deformable registration that evaluated the pointwise discordance throughout the lungs.ResultsQualitative comparisons using image overlays showed excellent agreement between the simulated images and the original images. Even large 2-cm diaphragm displacements were very well modeled, as was sliding motion across the lung-chest wall boundary. The mean error across the patient cohort was 1.15 ± 0.37 mm, and the mean 95th percentile error was 2.47 ± 0.78 mm.ConclusionThe proposed ground truth-based technique provided voxel-by-voxel accuracy analysis that could identify organ-specific or tumor-specific motion modeling errors for treatment planning. Despite a large variety of breathing patterns and lung deformations during the free-breathing scanning session, the 5-dimensionl CT technique was able to accurately reproduce the original helical CT scans, suggesting its applicability to a wide range of patients.

PurposeTo determine if and by how much the commercial 4DCT protocols under- and overestimate tumor breathing motion.Methods1D simulations were conducted that modeled a 16-slice CT scanner and tumors moving proportionally to breathing amplitude. External breathing surrogate traces of at least 5-min duration for 50 patients were used. Breathing trace amplitudes were converted to motion by relating the nominal tumor motion to the 90th percentile breathing amplitude, reflecting motion defined by the more recent 5DCT approach. Based on clinical low-pitch helical CT acquisition, the CT detector moved according to its velocity while the tumor moved according to the breathing trace. When the CT scanner overlapped the tumor, the overlapping slices were identified as having imaged the tumor. This process was repeated starting at successive 0.1 s time bin in the breathing trace until there was insufficient breathing trace to complete the simulation. The tumor size was subtracted from the distance between the most superior and inferior tumor positions to determine the measured tumor motion for that specific simulation. The effect of the scanning parameter variation was evaluated using two commercial 4DCT protocols with different pitch values. Because clinical 4DCT scan sessions would yield a single tumor motion displacement measurement for each patient, errors in the tumor motion measurement were considered systematic. The mean of largest 5% and smallest 5% of the measured motions was selected to identify over- and underdetermined motion amplitudes, respectively. The process was repeated for tumor motions of 1-4 cm in 1 cm increments and for tumor sizes of 1-4 cm in 1 cm increments.ResultsIn the examined patient cohort, simulation using pitch of 0.06 showed that 30% of the patients exhibited a 5% chance of mean breathing amplitude overestimations of 47%, while 30% showed a 5% chance of mean breathing amplitude underestimations of 36%; with a separate simulation using pitch of 0.1 showing, respectively, 37% overestimation and 61% underestimation.ConclusionsThe simulation indicates that commercial low-pitch helical 4DCT processes potentially yield large tumor motion measurement errors, both over- and underestimating the tumor motion.

PurposeTo characterize radiation therapy patient breathing patterns based on measured external surrogate information.MethodsBreathing surrogate data were collected during 4DCT from a cohort of 50 patients including 28 patients with lung cancer and 22 patients without lung cancer. A spirometer and an abdominal pneumatic bellows were used as the surrogates. The relationship between these measurements was assumed to be linear within a small phase difference. The signals were correlated and drift corrected using a previously published method to convert the signal into tidal volume. The airflow was calculated with a first order time derivative of the tidal volume using a window centered on the point of interest and with a window length equal to the CT gantry rotation period. The airflow was compared against the tidal volume to create ellipsoidal patterns that were binned into 25 ml × 25 ml∕s bins to determine the relative amount of time spent in each bin. To calculate the variability of the maximum inhalation tidal volume within a free-breathing scan timeframe, a metric based on percentile volume ratios was defined. The free breathing variability metric (κ) was defined as the ratio between extreme inhalation tidal volumes (defined as >93 tidal volume percentile of the measured tidal volume) and normal inhalation tidal volume (defined as >80 tidal volume percentile of the measured tidal volume).ResultsThere were three observed types of volume-flow curves, labeled Types 1, 2, and 3. Type 1 patients spent a greater duration of time during exhalation with κ = 1.37 ± 0.11. Type 2 patients had equal time duration spent during inhalation and exhalation with κ = 1.28 ± 0.09. The differences between the mean peak exhalation to peak inhalation tidal volume, breathing period, and the 85th tidal volume percentile for Type 1 and Type 2 patients were statistically significant at the 2% significance level. The difference between κ and the 98th tidal volume percentile for Type 1 and Type 2 patients was found to be statistically significant at the 1% significance level. Three patients did not display a breathing stability curve that could be classified as Type 1 or Type 2 due to chaotic breathing patterns. These patients were classified as Type 3 patients.ConclusionsBased on an observed volume-flow curve pattern, the cohort of 50 patients was divided into three categories called Type 1, Type 2, and Type 3. There were statistically significant differences in breathing characteristics between Type 1 and Type 2 patients. The use of volume-flow curves to classify patients has been demonstrated as a physiological characterization metric that has the potential to optimize gating windows in radiation therapy.

Organ motion induced by respiration may cause clinically significant targeting errors and greatly degrade the effectiveness of conformal radiotherapy. It is therefore crucial to be able to model respiratory motion accurately. A recently proposed lung motion model based on principal component analysis (PCA) has been shown to be promising on a few patients. However, there is still a need to understand the underlying reason why it works. In this paper, we present a much deeper and detailed analysis of the PCA-based lung motion model. We provide the theoretical justification of the effectiveness of PCA in modeling lung motion. We also prove that under certain conditions, the PCA motion model is equivalent to 5D motion model, which is based on physiology and anatomy of the lung. The modeling power of PCA model was tested on clinical data and the average 3D error was found to be below 1 mm., Comment: 4 pages, 1 figure. submitted to International Conference on the use of Computers in Radiation Therapy 2010

A continuous breeding reproduction study design was utilized to examine the reproductive toxicity of ethylene glycol monobutyl ether (EGBE) and ethylene glycol monophenyl ether (EGPE). Swiss CD-1 mice were administered EGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3, and 2.1 g/kg body wt/day) and EGPE was administered via the feed (0, 0.25, 1.25, and 2.5%, i.e., 0, 0.4, 2.0, and 4 g/kg body wt/day). Both male and female mice were dosed for 7 days prior to and during a 98-day cohabitation period. EGBE was toxic at the high (2%) and mid dose (1%) to adult F0 female mice: 13 out of 22 females at the high dose and 6 out of 20 at the mid dose died during the cohabitation period. Both the high- and mid-dose animals produced fewer litters/pair, fewer pups/litter, with decreased pup weight. These effects occurred in the presence of decreased body weight, decreased water consumption, and increased kidney weight. A crossover mating trial indicated that the reproductive effects could be attributed primarily to an effect on the female. This was substantiated at necropsy where testes and epididymis weights were normal as were sperm number and motility. Fertility of the offspring of the 0.5% group was normal in the presence of increased liver weights. With respect to EGPE, there was no change in the ability to produce five litters during the continuous breeding period. There was, however, a significant but small (10-15%) decrease in the number of pups/litter and in pup weight in the high-dose group. A crossover mating trial suggested a female component of the reproductive toxicity of EGPE. While fertility was only minimally compromised, severe neonatal toxicity was observed. By Day 21 there were only 8 out of 40 litters in the mid- and high-dose groups which had at least one male and female/litter. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight. In summary the reproductive toxicity of EGBE and EGPE was only evident in the female and occurred at doses which elicited general toxicity. EGBE was particularly toxic to adult female mice while EGPE was particularly toxic to immature mice of both sexes.

The U.S. Environmental Protection Agency (EPA) has broad authority to require testing various types of testing under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). EPA uses that authority to ensure that sufficient data are developed on the toxicity of a pesticide. Although the statute specifies the broad principles or standards that EPA applies in deciding what data are needed, the specific test types and procedures are not spelled out in the statute (FIFRA). The general testing requirements are outlined in regulations found at 40 CFR 158. While these rules specify the general minimum toxicity testing requirements for various types of pesticide products, they also provide for liberal discretion to adjust, replace, or even waive the requirements on a case-by-case basis. The rules require testing guidelines, which are specific descriptions of the typical test, but they are not so prescriptive that they cannot be amended, replaced, or eliminated as the science progresses. The Agency...