1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma.

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.

Identifying novel mechanisms of biallelic TP53 loss refines poor outcome for patients with multiple myeloma.

Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53.

Measurement of neutron yield for a medical linear accelerator below 10 MV.

BACKGROUND: The recent trend toward 10 MV for volumetric radiotherapy treatment such as volumetric modulated arc therapy (VMAT), stereotactic radiosurgery (SRS), and stereotactic ablative body radiotherapy (SABR) introduces photoneutron production, with implications for non-therapeutic patient dose and additional shielding requirements for treatment room design. The sharply nonlinear drop-off in photoneutron production below 10 MV to negligible at 6 MV has scarcely been characterized quantitatively, yet can elucidate important practical insights. PURPOSE: To measure photoneutron yields in a medical linac at 8 MV, which may strike a reasonable balance between usefully increased beam penetration and dose rate as compared to 6 MV while reducing photoneutron production which is present at 10 MV. METHODS: A Varian iX linear accelerator undergoing decommissioning at our clinic was made to operate over a range of photon energies between 6 and 15 MV by calibrating the bending magnet and adjusting other beam generation parameters. Neutron dose within the treatment room was measured using an Anderson-Braun type detector over a continuum of intermediate energies. RESULTS: The photoneutron production for energies below 10 MV was measured, adding to data that is otherwise scarce in the literature. Our results are consistent with previously published results for neutron yield. We found that the photoneutron production at 8 MV was about 1/10 of the value at 10 MV, and about 10 times higher than detector background at 6 MV. CONCLUSIONS: Photoneutron production drops off below 10 MV, but is still present at 8 MV. An 8 MV beam is more penetrating than a 6 MV beam, and may offer a suitable tradeoff for modern radiotherapy techniques such as VMAT, SRS, and SABR. Further studies are needed to better understand the impact on treatment plan quality between 8 and 10 MV beams considering the benefits to facility requirements and non-therapeutic patient dose.

Alternative splicing in multiple myeloma is associated with the non-homologous end joining pathway.

Alternative splicing plays a pivotal role in tumorigenesis and proliferation. However, its pattern and pathogenic role has not been systematically analyzed in multiple myeloma or its subtypes. Alternative splicing profiles for 598 newly diagnosed myeloma patients with comprehensive genomic annotation identified primary translocations, 1q amplification, and DIS3 events to have more differentially spliced events than those without. Splicing levels were correlated with expression of splicing factors. Moreover, the non-homologous end joining pathway was an independent factor that was highly associated with splicing frequency as well as an increased number of structural variants. We therefore identify an axis of high-risk disease encompassing expression of the non-homologous end joining pathway, increase structural variants, and increased alternative splicing that are linked together. This indicates a joint pathogenic role for DNA damage response and alternative RNA processing in myeloma.

Automated conversion of Millennium-120 VMAT plans to HDMLC geometry: Software development and treatment of first patients.

PURPOSE: To provide plan backup resiliency for patients treated on a solitary high definition multileaf collimator (HDMLC) linac by developing a fully integrated Eclipse script, which converts patient plans initially optimized on Millennium-120 (M120) MLC to dosimetrically equivalent leaf motions for delivery on HDMLC. In the event of HDMLC machine downtime, affected patients can be transferred to Millennium-120 units, and their backup plan delivered without delay. METHODS: Write-enabled Eclipse scripting is leveraged to generate HDMLC treatment fields with control points parameterized to mimic apertures of an existing Millennium-120 VMAT plan. Non-parity between intermediate control point gantry angles of script generated arcs relative to VMAT is reconciled through an interpolation subroutine to correct for the apertures and monitor units that would have existed at intermediate angles. Differences in dosimetric leaf gap are corrected by displacing the subset of leaves undergoing dynamic motion. A nominal change to plan normalization corrects for remaining discrepancies between beam models. RESULTS: Over 220 non-SABR VMAT patients were treated on a solitary HDMLC linac with plans converted using the developed script. All have undergone streamlined RO review and physics quality assurance (QA), where the converted plan replicates the original leaf patterns, representing a minor dosimetric perturbation. Analyzing a subset of converted plans delivered at four anatomical sites, on average 99.3% of points pass the 1%/1 mm gamma criterion. Dose-volume histograms between the original and converted plans are in excellent agreement. ArcCheck measurements comparing delivery of the converted HDMLC plan to the calculated M120 dose distribution averaged a gamma pass rate of 99.4% (95.2%) at a 3%/3 mm (2%/2 mm) criterion. The conversion process takes 30 s to run, avoids errors in exporting/re-importing, and generates leaf motions deliverable within machine limits. CONCLUSION: The methodology developed for automated plan conversion helped maximize the utilization of a solitary HDMLC linac, while preserving backup interoperability with minimal overhead.

Competency-Based Medical Education in Radiation Therapy Treatment Planning.

PURPOSE: To develop a technology-enhanced education methodology with competency-based evaluation for radiation therapy treatment planning. The education program is designed for integration in the existing framework of Commission on Accreditation of Medical Physics Education Programs (CAMPEP) accredited medical physics residency programs. METHODS AND MATERIALS: This education program pairs an accessible, multi-institutional infrastructure with established medical education evaluation tools to modernize treatment planning education. This program includes 3 evaluation components: (1) competency-based evaluation, (2) inter- and intramodality comparison, and (3) learner feedback. For this study, synchronous bilateral breast cancer was selected to demonstrate a complex treatment site and nonstandardized technique. Additionally, an online study was made available to a public cohort of worldwide participants of certified Medical Dosimetrists and Medical Physicists to benchmark performance. Before evaluation, learners were given a disease site-specific education session on potential clinical treatment strategies. During the assessment, learners generated treatment plans in their institutional planning system under the direct observation of an expert evaluator. Qualitative proficiency was evaluated for all learners on a 5-point scale of graduated task independence. Quantitative dosimetry was compared between the learner cohort and public cohort. A feedback session provided learners context of multi-institutional experience through multimodality and technique comparison. After study completion, learners were provided a survey that was used to gauge their perception of the education program. RESULTS: In the public study, 34 participants submitted treatment plans. Across 3 CAMPEP-accredited residency programs, 6 learners participated in the education and evaluation program. All learners successfully completed treatment plans that met the dosimetric constraints described in the case study. All learners favorably reviewed the study either comprehensively or in specified domains. CONCLUSIONS: The competency-based education and evaluation program developed in this work has been incorporated in CAMPEP-accredited residency programs and is adaptable to other residency programs with minimal resource commitment.

Declines in skeletal muscle quality vs. size following two weeks of knee joint immobilization.

BACKGROUND: Disuse of a muscle group, which occurs during bedrest, spaceflight, and limb immobilization, results in atrophy. It is unclear, however, if the magnitude of decline in skeletal muscle quality is similar to that for muscle size. The purpose of this study was to examine the effects of two weeks of knee joint immobilization on vastus lateralis and rectus femoris echo intensity and cross-sectional area. METHODS: Thirteen females (mean ± SD age = 21 ± 2 years) underwent two weeks of left knee joint immobilization via ambulating on crutches and use of a brace. B-mode ultrasonography was utilized to obtain transverse plane images of the immobilized and control vastus lateralis and rectus femoris at pretest and following immobilization. Effect size statistics and two-way repeated measures analyses of variance were used to interpret the data. RESULTS: No meaningful changes were demonstrated for the control limb and the rectus femoris of the immobilized limb. Analyses showed a large increase in vastus lateralis echo intensity (i.e., decreased muscle quality) for the immobilized limb (p = .006, Cohen's d = .918). For vastus lateralis cross-sectional area, no time × limb interaction was observed (p = .103), but the effect size was moderate (d = .570). There was a significant association between the increase in vastus lateralis echo intensity and the decrease in cross-sectional area (r =  - .649, p = .016). CONCLUSION: In female participants, two weeks of knee joint immobilization resulted in greater deterioration of muscle quality than muscle size. Echo intensity appears to be an attractive clinical tool for monitoring muscle quality during disuse.

Minimizing General Anesthetic Use in Pediatric Radiation Therapy.

PURPOSE: At our institution, a multifaceted approach is used to reduce general anesthetic (GA) use for children receiving photon radiation therapy (RT) as standard-of-care treatment. The purpose of this study was to evaluate the effectiveness of our methods. METHODS AND MATERIALS: Patients treated as part of the pediatric radiation therapy program from 2010 to 2018 were retrospectively reviewed. GA use was defined as need for intravenous propofol or inhaled gaseous anesthetic for at least 1 simulation or RT session. Methods to reduce GA use included presence of a dedicated pediatric nurse for procedural preparation, audiovisual distraction (television during RT), and 2-way audio communication with caregivers. RESULTS: There were 779 unique patients who received RT over 14 163 fractions of radiation. GA utilization was 90% in those under age 3, 28% in those age 3 to 6, 1% in those age 7 to 11, and <1% in those ≥12 years of age. Four years of age is a cutoff age at which the majority of patients switch from needing GA (56.6% for those aged 3) to not needing GA (29.8% for those aged 4). Younger age, use of total body irradiation, and craniospinal irradiation were independently associated with requiring GA. CONCLUSIONS: Using methods designed to reduce GA use, most children aged 4 years or older were able receive RT awake. Our GA rates compare favorably to other literature reports; thus, pediatric RT centers should consider adopting specific interventions to reduce GA use.

Performance characterization of an integrated cone-beam CT system for dedicated gamma radiosurgery.

PURPOSE: This work describes the performance characterization of a cone-beam CT-guided radiosurgery device, the Gamma Knife® Icon™. METHODS: The performance tests have been categorized into: (a) image quality and mechanical integrity; (b) image coregistration fidelity; (c) adaptive treatment delivery quality; (d) high definition motion management performance characterization; (e) software communication performance testing of the integrated cone-beam CT (CBCT) system. RESULTS: All image quality performance characterization satisfied or exceeded manufacturer specifications. The image quality and mechanical stability of the CBCT system over a 3-month period was within tolerance with negligible (<0.1°) detector tilt angle. The CBCT definition of the stereotactic space had a measured average discrepancy of 0.15-0.16 mm in x, y, and z directions. On average, the high definition motion management system performance was within 0.05 mm with a residual offset of 0.15 mm when large displacements in a given direction were taken. The adaptive treatment delivery component as measured with CBCT coregistration of daily setups against reference setup images was accurate to within 0.2°. Comprehensive end-to-end testing showed a total uncertainty of better than 0.2 mm in positioning and 0.4% in dosimetry for treatment of centrally located lesions. CONCLUSIONS: A set of system performance characterization tests spanning all aspects of the Gamma Knife Icon are presented. Overall, the system performance was in line with manufacturer specifications.

Quality control methods for linear accelerator radiation and mechanical axes alignment.

PURPOSE: The delivery accuracy of highly conformal dose distributions generated using intensity modulation and collimator, gantry, and couch degrees of freedom is directly affected by the quality of the alignment between the radiation beam and the mechanical axes of a linear accelerator. For this purpose, quality control (QC) guidelines recommend a tolerance of ±1 mm for the coincidence of the radiation and mechanical isocenters. Traditional QC methods for assessment of radiation and mechanical axes alignment (based on pointer alignment) are time consuming and complex tasks that provide limited accuracy. In this work, an automated test suite based on an analytical model of the linear accelerator motions was developed to streamline the QC of radiation and mechanical axes alignment. METHODS: The proposed method used the automated analysis of megavoltage images of two simple task-specific phantoms acquired at different linear accelerator settings to determine the coincidence of the radiation and mechanical isocenters. The sensitivity and accuracy of the test suite were validated by introducing actual misalignments on a linear accelerator between the radiation axis and the mechanical axes using both beam steering and mechanical adjustments of the gantry and couch. RESULTS: The validation demonstrated that the new QC method can detect sub-millimeter misalignment between the radiation axis and the three mechanical axes of rotation. A displacement of the radiation source of 0.2 mm using beam steering parameters was easily detectable with the proposed collimator rotation axis test. Mechanical misalignments of the gantry and couch rotation axes of the same magnitude (0.2 mm) were also detectable using the new gantry and couch rotation axis tests. For the couch rotation axis, the phantom and test design allow detection of both translational and tilt misalignments with the radiation beam axis. For the collimator rotation axis, the test can isolate the misalignment between the beam radiation axis and the mechanical collimator rotation axis from the impact of field size asymmetry. The test suite can be performed in a reasonable time (30-35 min) due to simple phantom setup, prescription-based beam delivery, and automated image analysis. As well, it provides a clear description of the relationship between axes. After testing the sensitivity of the test suite to beam steering and mechanical errors, the results of the test suite were used to reduce the misalignment errors of the linac to less than 0.7-mm radius for all axes. CONCLUSIONS: The proposed test suite offers sub-millimeter assessment of the coincidence of the radiation and mechanical isocenters and the test automation reduces complexity with improved efficiency. The test suite results can be used to optimize the linear accelerator's radiation to mechanical isocenter alignment by beam steering and mechanical adjustment of gantry and couch.

Evidence-based region of interest matching guidelines for sarcoma volumetric image-guided radiation therapy.

PURPOSE: Region-of-interest (ROI) guidelines for online cone-beam computed tomography (CBCT) radiotherapy may improve matching reproducibility and reduce inter-user variability of soft tissue sarcoma (STS) image guidance. The purpose of this work is to standardize ROI STS CBCT image registration guidelines using the plan-do-study-act (PDSA) cycle for the lower extremity, retroperitoneal, pelvis, and thorax. METHODS: Based on anatomic bony surrogates, initial ROI matching guidelines for STS were developed by a team of radiation therapists, physicists and oncologists (Plan). Retrospective, qualitative evaluation of the guidelines was completed by the designated sarcoma lead therapist to determine clinical feasibility (Do). Validation of the ROI guidelines was performed through independent evaluation by radiation therapy CBCT imaging experts on a cohort of 10 patients per anatomic region (Study). RESULTS: Draft ROI guidelines were evaluated by 2 independent observers who registered weekly CBCT images to test their validity. Each observer assessed 5 patients per anatomic site, testing ROI options for accuracy of image registration and feasibility, while some ROI borders were adjusted based on algorithm matching performance. Validated ROI guidelines were presented to the sarcoma multidisciplinary site group, and an inter-professional committee of imaging experts for approval prior to clinical implementation (Act). CONCLUSION: ROI matching guidelines for STS IGRT were standardized for 4 anatomic sites using the PDSA cycle for change testing and implementation. IGRT guidelines are intended to improve STS image registration reproducibility, and in turn, are expected to improve the confidence of IGRT decision making and workflow efficiencies for a rare disease with diverse presentation.

Serial 4DCT/4DPET imaging to predict and monitor response for locally-advanced non-small cell lung cancer chemo-radiotherapy.

BACKGROUND AND PURPOSE: A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power. MATERIALS AND METHODS: Consecutive consenting patients with LA-NSCLC receiving curative intent CRT were enrolled. 4DPET/4DCT scans were acquired 0, 2, 4, and 7 weeks during IMRT treatment. Eleven image features and their rates of change were recorded for each time point and tested for each of the possible outcome 2 years post CRT using the Kaplan-Meier method. RESULTS: 32 consecutive patients were recruited, 27 completing all scans. Restricting analysis to 4DPET/4DCT features and rates of change with p < 0.005, several volume-based features and their rates of change reached significance. Image features involving nodal disease were the only ones associated with overall survival. CONCLUSIONS: Several 4DPET/CT features and rates of change can reach significant association (p < 0.005) with outcomes, including overall survival, at many time points. The optimal time for adaptive CRT is therefore not constrained uniquely on imaging.

The value of adaptive preoperative radiotherapy in management of soft tissue sarcoma.

PURPOSE: To determine the value of preoperative adaptive radiotherapy (ART) for soft tissue sarcoma patients (STS) by modeling the dosimetric consequences of tumour volume changes (TVC) using different external beam radiotherapy techniques. METHODS AND MATERIALS: A subset of 22 STS patients from a recent trial (NCT00188175) underwent a repeat CT scan (CT2) prompted by TVC>1cm during IMRT; 14 tumours grew, 8 shrank. Conformal and conventional plans were modelled in addition to IMRT replicating original criteria from the initial planning dataset (CT1):95% PTV encompassed by 97% prescribed dose. CT1 RT parameters for all plans were applied to CT2 for dosimetric assessment of TVC. Co-registration of CT1 and CT2 permitted comparison of original and new contours. RESULTS: Mean TVC was 45% for growing and 33% for the shrinking cohort with TVC prompting CT2 at a mean of 13 fractions. For growers, the lack of target coverage on CT2 was statistically significant but was adequate for shrinkers. CONCLUSION: GTV expansion of >1cm during RT may result in target underdosage independent of RT technique. ART applied offline for TV increases >1cm is a practical adaptive strategy to ensure tumour coverage during RT. TV shrinkage may allow for normal tissue sparing, which should be investigated prospectively.

Predicting Radiation Esophagitis Using 18F-FDG PET During Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Treatment of locally advanced non-small cell lung cancer with chemoradiotherapy (CRT) is limited by development of toxicity in normal tissue, including radiation esophagitis (RE). Increasingly, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is being used for adaptive planning. Our aim was to assess changes in esophageal FDG uptake during CRT and relate the changes to the onset and severity of RE. METHODS: This prospective study in patients with stage II-III non-small cell lung cancer involved serial four-dimensional computed tomography and PET scans during CRT (60-74Gy). RE was recorded weekly using the Common Terminology Criteria for Adverse Events (v4.0), and imaging was performed at weeks 0, 2, 4, and 7. Changes in the esophagus's peak standard uptake value (SUVpeak) were analyzed for each time point and correlated with grade of RE using the Wilcoxon rank-sum test. The volume of esophagus receiving 50 Gy (V50) and volume of esophagus receiving 60 Gy (V60) were correlated with the development of RE, and the C-statistic (area under the curve [AUC]) was calculated to measure predictivity of grade 3 RE. RESULTS: RE developed in 20 of 27 patients (74%), with grade 3 reached in 6 (22%). A significant percentage increase in SUVpeak in the patients with RE was noted at week 4 (p = 0.01) and week 7 (p = 0.03). For grade 3 RE, a significant percentage increase in SUVpeak was noted at week 2 (p = 0.01) and week 7 (p = 0.03) compared with that for less than grade 3 RE. Median V50 (46.3%) and V60 (33.4%) were significantly higher in patients with RE (p = 0.04). The AUC measurements suggested that the percentage change in SUVpeak at week 2 (AUC = 0.69) and V50 (AUC = 0.67) and V60 (AUC = 0.66) were similarly predictive of grade 3 RE. CONCLUSIONS: Serial FDG-PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and early intervention.

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy.

PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

The value of nodal information in predicting lung cancer relapse using 4DPET/4DCT.

PURPOSE: There is evidence that computed tomography (CT) and positron emission tomography (PET) imaging metrics are prognostic and predictive in nonsmall cell lung cancer (NSCLC) treatment outcomes. However, few studies have explored the use of standardized uptake value (SUV)-based image features of nodal regions as predictive features. The authors investigated and compared the use of tumor and node image features extracted from the radiotherapy target volumes to predict relapse in a cohort of NSCLC patients undergoing chemoradiation treatment. METHODS: A prospective cohort of 25 patients with locally advanced NSCLC underwent 4DPET/4DCT imaging for radiation planning. Thirty-seven image features were derived from the CT-defined volumes and SUVs of the PET image from both the tumor and nodal target regions. The machine learning methods of logistic regression and repeated stratified five-fold cross-validation (CV) were used to predict local and overall relapses in 2 yr. The authors used well-known feature selection methods (Spearman's rank correlation, recursive feature elimination) within each fold of CV. Classifiers were ranked on their Matthew's correlation coefficient (MCC) after CV. Area under the curve, sensitivity, and specificity values are also presented. RESULTS: For predicting local relapse, the best classifier found had a mean MCC of 0.07 and was composed of eight tumor features. For predicting overall relapse, the best classifier found had a mean MCC of 0.29 and was composed of a single feature: the volume greater than 0.5 times the maximum SUV (N). CONCLUSIONS: The best classifier for predicting local relapse had only tumor features. In contrast, the best classifier for predicting overall relapse included a node feature. Overall, the methods showed that nodes add value in predicting overall relapse but not local relapse.

External respiratory motion analysis and statistics for patients and volunteers.

We analyzed a large patient and volunteer study of external respiratory motion in order to develop a population database of respiratory information. We analyzed 120 lung, liver, and abdominal patients and 25 volunteers without lung disease to determine the extent of motion using the Varian Real-Time Position Management system. The volunteer respiratory motion was measured for both abdominal and thoracic placement of the RPM box. Evaluation of a subset of 55 patients demonstrates inter- and intrafraction variation over treatment. We also calculated baseline drift and duty cycle for patients and volunteers. The mean peak-to-peak amplitude (SD) for the patients was 1.0 (0.5) cm, and for the volunteers it was abdomen 0.8 (0.3) cm and thoracic 0.2 (0.2) cm. The mean period (SD) was 3.6 (1.0) s, 4.2 (1.1)s, and 4.1 (0.8) s, and the mean end exhale position (SD) was 60% (6), 58% (7), and 56% (7) for patient, volunteer abdomen, and volunteer thoracic, respectively. Baseline drift was greater than 0.5 cm for 40% of patients. We found statistically significant differences between the patient and volunteer groups. Peak-to-peak amplitude was significantly larger for patients than the volunteer abdominal measurement and the volunteer abdominal measurement is significantly larger than the volunteer thoracic measurement. The patient group also exhibited significantly larger baseline drift than the volunteer group. We also found that peak-to-peak amplitude was the most variable parameter for both intra- and interfraction motion. This database compilation can be used as a resource for expected motion when using external surrogates in radiotherapy applications.

A comparison of phase, amplitude, and velocity binning for cone-beam computed tomographic projection-based motion reconstruction.

PURPOSE: We previously developed a motion estimation technique based on direct cone-beam projection analysis. It is able to reconstruct the complete motion trajectory of a radio-opaque marker, including cycle-to-cycle variability, using respiratory binning of the projection images. This paper investigates the use of phase, amplitude, and amplitude-velocity binning in the context of projection-based cone-beam motion estimation (CBME). METHODS AND MATERIALS: We simulated cone-beam computed tomographic scans of 160 tumor trajectories estimated by a CyberKnife Synchrony System (Accuray, Sunnyvale, CA), and reconstructed the complete trajectory with CBME using phase, amplitude, and amplitude-velocity binning of the projection data. Various numbers of respiratory bins, from 1 (no binning) to 100, were used for phase and amplitude binning, while 1 to 100 amplitude bins with 4 velocity bins were used for amplitude-velocity binning. From this large pool of data, we correlated the reconstruction accuracy with bin type, total number of bins, number of breathing cycles per bin, and the position of the bin within the breathing cycle. RESULTS: CBME predicted the true motion of the marker with a 3-dimensional (3D) mean root mean square (RMS) error of 0.24 mm for amplitude-velocity binning, 0.31 mm for amplitude binning, and 0.52 mm for phase binning. Reconstruction 3D RMS error increased to over 1 mm when less than 3 breathing cycles contributed to a bin. We found that reconstruction accuracy was optimized when about 20 bins were used. Accuracy also decreased in bins located around the inhale portion of the breath cycle, compared with the mid- and end-exhale positions. CONCLUSIONS: This study provides a quantitative assessment of phase, amplitude, and amplitude-velocity binning for CBME. A joint binning approach should be used to give both the accuracy of amplitude binning, as well as the robustness of phase binning, in areas of limited motion sampling.

External respiratory motion: shape analysis and custom realistic respiratory trace generation.

PURPOSE: The authors developed a realistic respiratory trace generating (RTG) tool for use with phantom and simulation studies. METHODS: The authors analyzed the extent of abdominal wall motion from a real-time position management system database comprised of 125 lung, liver, and abdominal patients to determine the shape and extent of motion. Using Akaike's information criterion (AIC), the authors compared different model types to find the optimal realistic model of respiratory motion. RESULTS: The authors compared a family of sigmoid curves and determined a four parameter sigmoid fit was optimal for over 98% patient inhale and exhale traces. This fit was also better than sin (2)(x) for 98% of patient exhale and 70% of patient inhale traces and better than sin (x) for 100% of both patient inhale and exhale traces. This analysis also shows that sin (2)(x) is better than sin (x) for over 95% of patient inhale and exhale traces. With results from shape and extent of motion analysis, we developed a realistic respiratory trace generating (RTG) software tool. The software can be run in two modes: population and user defined. In population mode, the RTG draws entirely from the population data including inter- and intra fraction amplitude and period variability and baseline drift. In user-defined mode, the user customizes the respiratory parameters by inputting the peak-to-peak amplitude, period, end exhale position, as well as controls variability in these parameters and baseline drift. CONCLUSIONS: This work provides a method of generating custom respiratory data that can be used for initial implementation and testing of new technologies.