Evaluation of multiple-vendor AI autocontouring solutions.

BACKGROUND: Multiple artificial intelligence (AI)-based autocontouring solutions have become available, each promising high accuracy and time savings compared with manual contouring. Before implementing AI-driven autocontouring into clinical practice, three commercially available CT-based solutions were evaluated. MATERIALS AND METHODS: The following solutions were evaluated in this work: MIM-ProtégéAI+ (MIM), Radformation-AutoContour (RAD), and Siemens-DirectORGANS (SIE). Sixteen organs were identified that could be contoured by all solutions. For each organ, ten patients that had manually generated contours approved by the treating physician (AP) were identified, totaling forty-seven different patients. CT scans in the supine position were acquired using a Siemens-SOMATOMgo 64-slice helical scanner and used to generate autocontours. Physician scoring of contour accuracy was performed by at least three physicians using a five-point Likert scale. Dice similarity coefficient (DSC), Hausdorff distance (HD) and mean distance to agreement (MDA) were calculated comparing AI contours to "ground truth" AP contours. RESULTS: The average physician score ranged from 1.00, indicating that all physicians reviewed the contour as clinically acceptable with no modifications necessary, to 3.70, indicating changes are required and that the time taken to modify the structures would likely take as long or longer than manually generating the contour. When averaged across all sixteen structures, the AP contours had a physician score of 2.02, MIM 2.07, RAD 1.96 and SIE 1.99. DSC ranged from 0.37 to 0.98, with 41/48 (85.4%) contours having an average DSC ≥ 0.7. Average HD ranged from 2.9 to 43.3 mm. Average MDA ranged from 0.6 to 26.1 mm. CONCLUSIONS: The results of our comparison demonstrate that each vendor's AI contouring solution exhibited capabilities similar to those of manual contouring. There were a small number of cases where unusual anatomy led to poor scores with one or more of the solutions. The consistency and comparable performance of all three vendors' solutions suggest that radiation oncology centers can confidently choose any of the evaluated solutions based on individual preferences, resource availability, and compatibility with their existing clinical workflows. Although AI-based contouring may result in high-quality contours for the majority of patients, a minority of patients require manual contouring and more in-depth physician review.

Radiosensitization beyond DNA damage: Monte Carlo simulations of realistic nanomaterial biodistributions.

We investigated cellular distribution of a tumor-specific gadolinium chelate in 4T1 and U87 cancer cells with the goal to generate more realistic geometries for Monte Carlo simulations of radiation interaction with nanoparticles in cells. Cells were exposed to the agent in-vitro for 30 minutes to 72 hours before being fixed and imaged using transmission electron microscopy. Initially, electron-dense areas consistent with gadolinium were observable throughout the cytoplasm. At six hours those areas were restricted to endosomes and at 24 hours or longer electron dense areas were only found in lysosomes. Lysosomes were on average larger in 4T1 cells, which were exposed to 1 mM concentration compared to U87 cells, exposed to 1 uM. Based on this information we built an extended cell model for Monte Carlo simulations that includes lysosomes with discrete nanoparticle enclaves in addition to mitochondria and the nucleus.

Reproducibility study of Monte Carlo simulations for nanoparticle dose enhancement and biological modeling of cell survival curves.

Nanoparticle-derived radiosensitization has been investigated by several groups using Monte Carlo simulations and biological modeling. In this work we replicated the physical simulation and biological modeling of previously published research for 50 nm gold nanoparticles irradiated with monoenergetic photons, various 250 kVp photon spectra, and spread-out Bragg peak (SOBP) protons. Monte Carlo simulations were performed using TOPAS and used condensed history Penelope low energy physics models for macroscopic dose deposition and interaction with the nanoparticle; simulation of the microscopic dose deposition from nanoparticle secondaries was performed using Geant4-DNA track structure physics. Biological modeling of survival fractions was performed using a local effect model-type approach for MDA-MB-231 breast cancer cells. Physical simulation results agreed extraordinarily well at all distances (1 nm to 10µm from nanoparticle) for monoenergetic photons and SOBP protons in terms of dose per interaction, dose kernel ratio (often labeled dose enhancement factor), and secondary electron spectra. For 250 kVp photons the influence of the gold K-edge was investigated and found to appreciably affect the results. Calculated survival fractions similarly agreed well within one order of magnitude at macroscopic doses (i.e. without nanoparticle contribution) from 1 Gy to 10 Gy. Several 250 kVp spectra were tested to find one yielding closest agreement with previous results. This highlights the importance of a detailed description of the low energy (< 150 keV) component of photon spectra used forin-silico, as well asin-vitro, andin-vivostudies to ensure reproducibility of the experiments by the scientific community. Both, Monte Carlo simulations of physical interactions of the nanoparticle with photons and protons, as well as the biological modelling of cell survival curves agreed extraordinarily well with previously published data. Further investigation of the stochastic nature of nanoparticle radiosenstiziation is ongoing.

Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation.

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. SIGNIFICANCE: Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.

Improving Adjuvant Liver-Directed Treatment Recommendations for Unresectable Hepatocellular Carcinoma: An Artificial Intelligence-Based Decision-Making Tool.

PURPOSE: Liver-directed therapy after transarterial chemoembolization (TACE) can lead to improvement in survival for selected patients with unresectable hepatocellular carcinoma (HCC). However, there is uncertainty in the appropriate application and modality of therapy in current clinical practice guidelines. The aim of this study was to develop a proof-of-concept, machine learning (ML) model for treatment recommendation in patients previously treated with TACE and select patients who might benefit from additional treatment with combination stereotactic body radiotherapy (SBRT) or radiofrequency ablation (RFA). METHODS: This retrospective observational study was based on data from an urban, academic hospital system selecting for patients diagnosed with stage I-III HCC from January 1, 2008, to December 31, 2018, treated with TACE, followed by adjuvant RFA, SBRT, or no additional liver-directed modality. A feedforward, ML ensemble model provided a treatment recommendation on the basis of pairwise assessments evaluating each potential treatment option and estimated benefit in survival. RESULTS: Two hundred thirty-seven patients met inclusion criteria, of whom 54 (23%) and 49 (21%) received combination of TACE and SBRT or TACE and RFA, respectively. The ML model suggested a different consolidative modality in 32.7% of cases among patients who had previously received combination treatment. Patients treated in concordance with model recommendations had significant improvement in progression-free survival (hazard ratio 0.5; P = .007). The most important features for model prediction were cause of cirrhosis, stage of disease, and albumin-bilirubin grade (a measure of liver function). CONCLUSION: In this proof-of-concept study, an ensemble ML model was able to provide treatment recommendations for HCC who had undergone prior TACE. Additional treatment in line with model recommendations was associated with significant improvement in progression-free survival, suggesting a potential benefit for ML-guided medical decision making.

Organ-at-risk dose prediction using a machine learning algorithm: Clinical validation and treatment planning benefit for lung SBRT.

OBJECTIVE: To quantify the clinical performance of a machine learning (ML) algorithm for organ-at-risk (OAR) dose prediction for lung stereotactic body radiation therapy (SBRT) and estimate the treatment planning benefit from having upfront access to these dose predictions. METHODS: ML models were trained using multi-center data consisting of 209 patients previously treated with lung SBRT. Two prescription levels were investigated, 50 Gy in five fractions and 54 Gy in three fractions. Models were generated using a gradient-boosted regression tree algorithm using grid searching with fivefold cross-validation. Twenty patients not included in the training set were used to test OAR dose prediction performance, ten for each prescription. We also performed blinded re-planning based on OAR dose predictions but without access to clinically delivered plans. Differences between predicted and delivered doses were assessed by root-mean square deviation (RMSD), and statistical differences between predicted, delivered, and re-planned doses were evaluated with one-way analysis of variance (ANOVA) tests. RESULTS: ANOVA tests showed no significant differences between predicted, delivered, and replanned OAR doses (all p ≥ 0.36). The RMSD was 2.9, 3.9, 4.3, and 1.7Gy for max dose to the spinal cord, great vessels, heart, and trachea, respectively, for 50 Gy in five fractions. Average improvements of 1.0, 1.4, and 2.0 Gy were seen for spinal cord, esophagus, and trachea max doses in blinded replans compared to clinically delivered plans with 54 Gy in three fractions, and 1.8, 0.7, and 1.5 Gy, respectively, for the esophagus, heart and bronchus max doses with 50 Gy in five fractions. Target coverage was similar with an average PTV V100% of 94.7% for delivered plans compared to 97.3% for blinded re-plans for 50 Gy in five fractions, and respectively 98.4% versus 99.2% for 54 Gy in three fractions. CONCLUSION: This study validated ML-based OAR dose prediction for lung SBRT, showing potential for improved OAR dose sparing and more consistent plan quality using dose predictions for patient-specific planning guidance.

A positron emission tomography radiomic signature for distant metastases risk in oropharyngeal cancer patients treated with definitive chemoradiotherapy.

BACKGROUND AND PURPOSE: Disease recurrence and distant metastases (DM) are major concerns for oropharyngeal cancer (OPC) patients receiving definitive chemo-radiotherapy. Here, we investigated whether pre-treatment primary tumor positron emission tomography (PET) features could predict progression-free survival (PFS) or DM. METHODS AND MATERIALS: Primary tumors were delineated on pre-treatment PET scans for patients treated between 2005 and 2018 using gradient-based segmentation. Radiomic image features were extracted, along with SUV metrics. Features with zero variance and strong correlation to tumor volume, stage, p16 status, age or smoking were excluded. A random forest model was used to identify features associated with PFS. Kaplan-Meier methods, Cox regression and logistic regression with receiver operating characteristics (ROC) and 5-fold cross-validated areas-under-the-curve (CV-AUCs) were used. RESULTS: A total of 114 patients were included. With median follow-up 40 months (range: 3-138 months), 14 patients had local recurrence, 21 had DM and 38 died. Two-year actuarial local control, distant control, PFS and overall survival was 89%, 84%, 70% and 84%, respectively. The wavelet_LHL_GLDZM_LILDE feature slightly improved PFS prediction compared to clinical features alone (CV-AUC 0.73 vs. 0.71). Age > 65 years (HR = 2.64 (95%CI: 1.36-5.2), p = 0.004) and p16-negative disease (HR = 3.38 (95%CI: 1.72-6.66), p < 0.001) were associated with poor PFS. A binary radiomic classifier strongly predicted DM with multivariable HR = 3.27 (95%CI: 1.15-9.31), p = 0.027, specifically for patients with p16-negative disease with 2-year DM-free survival 83% for low-risk vs. 38% for high-risk patients (p = 0.004). CONCLUSIONS: A radiomics signature strongly associated with DM risk could provide a tool for improved risk stratification, potentially adding adjuvant immunotherapy for high-risk patients.

Clinical Assessment of a Novel Ring Gantry Linear Accelerator-Mounted Helical Fan-Beam kVCT System.

PURPOSE: To assess clinically relevant image quality metrics (IQMs) of helical fan beam kilovoltage (kV) fan beam computed tomography (CT). METHODS AND MATERIALS: kVCT IQMs were evaluated on an Accuray Radixact unit equipped with helical fan beam kVCT to assess the capabilities of this newly available modality. kVCT IQMs were evaluated and compared to a kVCT simulator and linear accelerator-based cone beam CTs (CBCT) using a commercial CBCT image quality phantom. kVCTs were acquired on the Accuray Radixact for all combinations of kVp and mAs in fine mode using a 440-mm field of view (FOV). Evaluated IQMs were spatial resolution, overall uniformity, subject contrast, contrast-to-noise ratio (CNR), and effective slice thickness. Imaging dose was assessed for planar kV imaging. RESULTS: On this kVCT system spatial resolution and contrast were consistent across all settings with 0.28 ± 0.03 lp/mm and 9.8% ± 0.7% (both 95% confidence interval). CNR strongly depended on selected mode (views per rotation) and body size (mA per view) and ranged between 7.9 and 34.9. Overall uniformity was greater than 97% for all settings. Large FOV was not found to substantially affect the IQMs whereas small FOV affected IQMs due to its effect on pitch. Technique-matched CT simulator scans were comparable for uniformity and contrast, while spatial resolution was higher (0.43 ± 0.06 lp/mm), and CNR was between 4% (140 kVp) and 51% (100 kVp) lower. For kV-CBCT, spatial resolutions ranging from 0.37 to 0.44 lp/mm were achieved with comparable contrast, CNR, and uniformity to kVCT. All kVCT scans exhibit imaging artifacts due to helical acquisition. Clinical acquisitions of megavoltage (MV) CT, kV-CBCT, and kVCT on the same patient showed improved and comparable image quality of kVCT compared to MVCT and kV-CBCT, respectively. CONCLUSIONS: Helical fan beam kVCT allows for daily image guidance for localization and setup verification with comparable performance to existing kV-CBCT systems. Scan parameters must be selected carefully to maximize image quality for the desired tasks. Due to the large effective slice thicknesses for all parameter combinations, kVCT scans should not be used for simulation or planning of stereotactic procedures. Finally, improved image quality over MVCT has the potential to greatly improve manual and automated adaptive monitoring and planning.

The effect of low-dose radiation spillage during stereotactic radiosurgery for brain metastases on the development of de novo metastases.

PURPOSE/OBJECTIVES: Stereotactic radiosurgery (SRS) for metastatic disease to the brain is associated with higher in-brain failures compared to whole brain radiation therapy (WBRT). Here we investigated the relationship between low-dose fall off during SRS and location of new brain lesions. MATERIALS AND METHODS: One hundred sixty-seven patients treated with single fraction or fractionated SRS for intact or resected brain metastases at our institution from January 2016 to June 2018 were reviewed. Patients with imaging findings of new brain metastases after the initial SRS were included. Patients with WBRT before SRS were excluded. MRI scans for repeat treatments were fused with initial SRS plan. New lesions were outlined on the initial SRS planning CT. The mean dose that the site of new lesions received from initial SRS was tabulated. RESULTS: Thirty-eight patients met inclusion criteria. 165 new lesions were evaluated. There was a lower propensity to develop new brain lesions with increasing dose received by the regions from prior SRS, with 66%, 34%, 19%, 13%, 6%, 5%, 2% and 1% of new lesions appearing in regions that received less than 1 Gy, greater than or equal to 1, 2, 3, 4, 5, 6, and 7 Gy, respectively. Higher doses are received by smaller brain volumes during SRS. After accounting for volume, 14, 14, 11, 7, 2, 2, 1 and 1 new lesions appeared per 100 cm3 of brain in regions that received doses of less than 1 Gy, greater than or equal to 1, 2, 3, 4, 5, 6, and 7 Gy, respectively, from prior SRS. CONCLUSIONS: We identified low dose spillage during SRS to be associated with lower incidence of new brain metastases. Validation in larger dataset or prospective study of the combination of SRS with low dose WBRT would be crucial in order to establish causality of these findings.

Hybrid tandem and ovoids brachytherapy in locally advanced cervical cancer: impact of dose and tumor volume metrics on outcomes.

PURPOSE: To report the impact of dose and tumor volume metrics at brachytherapy on outcomes for locally advanced cervical cancer treated with tandem and ovoids intracavitary/interstitial brachytherapy. MATERIAL AND METHODS: FIGO stage IB1-IIIB locally advanced cervical cancer treated with intracavitary/interstitial brachytherapy via a tandem and ovoids hybrid applicator were analyzed. Median high-risk clinical target volume (HR-CTV), rate of tumor volume reduction, EQD2 D90, organ at risk doses, and outcomes were recorded. Univariable and multivariable Cox regression was applied for survival analysis, and logistic regression was used for toxicity analysis. RESULTS: Seventy-one patients were identified. Median follow-up was 24.9 months, with a 2-year local control of 83.6%, loco-regional control of 72.0%, and overall survival of 88.6%. Median HR-CTV D90 was 87.4 Gy (IQR = 85.7-90.2). Median HR-CTV D90 > 90 Gy10 showed a trend toward improved local control (LC) (p = 0.19). Median HR-CTV was 37.9 cm3, and median V100 was 86.5%. A median HR-CTV of ≥ 40 cm3 demonstrated worse loco-regional control (LRC) (p = 0.018) and progression-free survival (p = 0.021). Two-year LC and LRC for stage IIB patients with a median HR-CTV < 40 cm3 were significantly improved as compared to ≥ 40 cm3 at 100% and 71.8%, respectively (p = 0.019) and 100% and 56.5%, respectively (p = 0.001). However, this trend was not statistically significant for stage IIIB patients. Higher percent per day reduction in HR-CTV during brachytherapy showed improved LRC (p = 0.045). Four percent of patients experienced acute grade 3 genitourinary toxicity, 1% late grade 3 genitourinary and 1% late grade 3 gastrointestinal toxicity. CONCLUSIONS: Tandem and ovoids intracavitary/interstitial brachytherapy provides satisfactory outcomes with modest toxicity. Higher HR-CTV D90 coverage demonstrated a trend toward improved tumor control. Tumor volume based on median HR-CTV ≥ 40 cm3 at brachytherapy was prognostic for poor outcomes, even within initial FIGO stage groups warranting caution.

Single isocenter treatment planning techniques for stereotactic radiosurgery of multiple cranial metastases.

BACKGROUND AND PURPOSE: Whole brain radiation therapy use has decreased in favor of stereotactic radiosurgery (SRS) for the treatment of multiple brain metastases due to reduced neurotoxicity. Here we compare two single isocenter radiosurgery planning techniques, volumetric modulated arc therapy (VMAT) and dynamic conformal arcs (DCA) in terms of their dosimetric and delivery performance. MATERIALS AND METHODS: Sixteen patients with 2- 18 brain metastases (total 103; median 4) previously treated with single fraction SRS were replanned for multiple lesion single isocenter treatments using VMAT and DCA using different treatment planning systems for each and three different plan geometries for DCA. Plans were evaluated using the Paddick conformity index, normal tissue V12Gy, the probability for symptomatic brain necrosis (S-NEC), maximum organ-at-risk (OAR) point doses, and total number of monitor units (MU). RESULTS: Conformity was not significantly different between VMAT and DCA plans. VMAT plans showed a trend towards higher MU with a median difference between 18% and 24% (p ≤ 0.09). Median V12Gy differences were 7.0 cm3-8.6 cm3 favoring DCA plans (p < 0.01). VMAT plans had median excess absolute and relative S-NEC risks compared to DCA plans of 8%-10% and 25%-31%, respectively (p < 0.01). Moreover for VMAT compared to DCA, maximum OAR doses were significantly higher for the brainstem (1.9 Gy; p < 0.01), chiasm (0.5 Gy; p ≤ 0.02), and optic nerves (0.5 Gy; p ≤ 0.04). CONCLUSIONS: In most cases DCA plans were found to be dosimetrically superior to VMAT plans with reduced V12Gy and associated risk for S-NEC. Maximum doses to important OARs showed significant improvement, increasing the ability for subsequent salvage treatments involving radiation.

Recommendations of megavoltage computed tomography settings for the implementation of adaptive radiotherapy on helical tomotherapy units.

Megavoltage computed tomography (MVCT) image quality metrics were evaluated on an Accuray Radixact unit to recommend scan settings for the implementation of a consistent adaptive radiotherapy program. Megavoltage computed tomography image quality was evaluated and compared to a kilovoltage CT (kVCT) simulator using a commercial cone beam computed tomography image quality phantom. Megavoltage computed tomographies were acquired on the Accuray Radixact using fine, normal, and coarse pitches, with all available reconstruction slice thicknesses, each of which were reconstructed using standard and iterative reconstruction (IR). Image quality metrics (IQM) were evaluated using DoseLab: automatically and manually calculated spatial resolution, subject contrast, and contrast-to-noise ratio (CNR). Scanning time was 15.6 s/cm for fine, 8.1 s/cm for normal, and 5.6 s/cm for coarse pitch. Automatically evaluated spatial resolutions ranged from 0.39, 0.41, to 0.42 lp/mm for standard reconstruction and from 0.24, 0.21, to 0.18 lp/mm for soft-tissue IR, respectively, with general IR yielding values in between these. Spatial resolution for kVCT was measured to be at least 0.42 lp/mm. Contrast was consistent across MVCT settings with 8.1 ± 0.2%, while kVCT contrast was 10.27 ± 0.05%. CNR was calculated to be 3.3 ± 0.4 for standard reconstruction, 7.4 ± 0.4 for general IR, and 12.0 ± 1.9 for soft-tissue IR. It was found that increasing reconstruction slice thickness for a given pitch does not improve IQMs. Based on the consistency of contrast metrics across pitch values and the only slightly reduced spatial resolution using normal compared to fine pitch, we recommend the use of normal pitch with 2 mm slice thickness to maximize image quality for ART while limiting scanning time. Only for sites for which improved CNR is required and reduced spatial resolution is acceptable, soft-tissue IR is recommended.

3D isocentricity analysis for clinical linear accelerators.

PURPOSE: To perform a three-dimensional (3D) concurrent isocentricity measurement of a clinical linear accelerator's (linac) using a single 3D dosimeter, PRESAGE. METHODS: A 3D dosimeter, PRESAGE, set up on the treatment couch of a Varian TrueBeam LINAC using the setup lasers, was irradiated under gantry angles of 0 ∘ , 50 ∘ , 160 ∘ , and 270 ∘ with the couch fixed at 0 ∘ and subsequently, under couch angles of 10 ∘ , 330 ∘ , 300 ∘ , and 265 ∘ with the gantry fixed at 270 ∘ . The 1 cm 2 (at 100 cm SAD) square fields were delivered at 6 MV with 800 MU/field. After irradiation, the dosimeter was scanned using a single-beam optical scanner and images were reconstructed with submillimeter resolution using filtered back-projection. Postprocessing was used to extract views parallel to the star-shot planes from which beam trajectories and the smallest circles enclosing these were drawn and extracted. These circles and information from the view orthogonal to both star-shots were used to represent the rotational centers as spheroids. The linac isocenter was defined by the distribution of midpoints between any, randomly selected, points lying inside the center spheroids defined by the table and gantry rotations; isocenter location and size were defined by the average midpoint and the distribution's semi-axes. Collimator rotations were not included in this study. RESULTS: Relative to the setup center defined by lasers, the table and gantry rotation center coordinates (lat., long., vert.) were measured in units of millimeters, to be (-0.24, 0.18, -0.52) and (0.10, 0.53, -0.52), respectively. Displacements from the setup center were 0.60 and 0.75 mm for the table and gantry centers, while the distance between them measured 0.49 mm. The linac's radiation isocenter was calculated to be at (-0.07, -0.17, 0.51) relative to the setup lasers and its size was found to be most easily described by a spheroid prolate in vertical direction with semi-axis lengths of 0.13 and 0.23 mm for the lateral-longitudinal and vertical directions, respectively. CONCLUSIONS: This study demonstrates how to measure the location and sizes of rotational centers in 3D with one setup. The proposed method provides a more comprehensive view on the isocentricity of LINAC than the conventional two-dimensional film measurements. Additionally, a new definition of isocenter and its size was proposed.

Simulation of spread-out bragg peaks in proton beams using Geant4/TOPAS.

The simulation of proton Spread-Out Bragg Peaks (SOBPs) was implemented using the Geant4-based TOPAS Monte Carlo software. Dynamic proton energy switching was implemented using TOPAS time features, while beam weights were calculated using an empirical power law formalism with Bragg peaks spaced by 0.5 mm. To find power parameters yielding flat SOBPs we sampled power parameters for maximum kinetic energies of 50 MeV to 250 MeV and SOBP widths of 15% to 40% of the depth of the distal SOBP end. Simulations were run in a 50 cm cubic water phantom using a uniform squared proton beam. Depth dose was scored along the central axis in a binned cylinder with 1 cm diameter in 2.5 mm increments. Power parameters yielding a flat SOBPs were found to vary with, both energy and SOBP width and differed significantly from previously reported values based on simulations with MCNPX.

Disease characteristics, prognosis and miglustat treatment effects on disease progression in patients with Niemann-Pick disease Type C: an international, multicenter, retrospective chart review.

BACKGROUND: Niemann-Pick disease Type C (NP-C) is a lysosomal lipid storage disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales. METHODS: This retrospective, observational chart review included patients with NP-C from five expert NP-C centers. Patient disability scores were recorded using three published NP-C disability scales, and a unified disability scale was developed to allow comparison of data from each scale. Disease progression was represented by scores on the unified NP-C disability scale. Patients were stratified as infantile (< 4 years), juvenile (≥ 4 - < 16 years), and adult (≥ 16 years) based on age at diagnosis, and treated ≥1 year and non-treated/treated < 1 year based on the duration of miglustat treatment. RESULTS: The analysis included 63 patients; the majority (61.9%) were on miglustat therapy for ≥1 year. Ataxia and clumsiness/frequent fall were the most common neurologic symptoms across age groups, whereas, hypotonia and delayed developmental milestones were specific to infantile patients. In both infantile and juvenile patients, visceral signs preceded diagnosis and neurologic signs were noted at or shortly after diagnosis. Adult patients presented with a range of visceral, neurologic, and psychiatric signs in years preceding diagnosis. Patients on miglustat therapy for ≥1 year had a lower mean annual disease progression compared with those untreated/treated < 1 year (1.32 vs 3.54 points/year). A significant reduction in annual disease progression in infantile patients, and a trend towards reduced disease progression in juvenile patients after ≥1 year of miglustat treatment, translated into higher age at last contact or death in these groups. CONCLUSIONS: The type and onset of symptoms varied across age groups and were consistent with descriptions of NP-C within the literature. Miglustat treatment was associated with a reduced rate of disability score worsening in infantile and juvenile patients, both in agreement with increased age at last contact.

Systematic review of psychiatric signs in Niemann-Pick disease type C.

Objectives: We conducted the first systematic literature review and analysis of psychiatric manifestations in Niemann-Pick disease type C (NPC) to describe: (1) time of occurrence of psychiatric manifestations relative to other disease manifestations; and (2) frequent combinations of psychiatric, neurological and visceral disease manifestations. Methods: A systematic EMBase literature search was conducted to identify, collate and analyze published data from patients with NPC associated with psychiatric symptoms, published between January 1967 and November 2015. Results: Of 152 identified publications 40 were included after screening that contained useable data from 58 NPC patients (mean [SD] age at diagnosis of NPC 27.8 [15.1] years). Among patients with available data, cognitive, memory and instrumental impairments were most frequent (90% of patients), followed by psychosis (62%), altered behavior (52%) and mood disorders (38%). Psychiatric manifestations were reported before or at neurological disease onset in 41 (76%) patients; organic signs (e.g., hepatosplenomegaly, hearing problems) were reported before psychiatric manifestations in 12 (22%). Substantial delays to diagnosis were observed (5-6 years between psychiatric presentation and NPC diagnosis). Conclusions: NPC should be considered as a possible cause of psychiatric manifestations in patients with an atypical disease course, acute-onset psychosis, treatment failure, and/or certain combinations of psychiatric/neurological/visceral symptoms.

An investigation of clinical treatment field delivery verification using cherenkov imaging: IMRT positioning shifts and field matching.

PURPOSE: Cherenkov light emission has been shown to correlate with ionizing radiation dose delivery in solid tissue. An important clinical application of Cherenkov light is the real-time verification of radiation treatment delivery in vivo. To test the feasibility of treatment field verification, Cherenkov light images were acquired concurrent with radiation beam delivery to standard and anthropomorphic phantoms. Specifically, we tested two clinical treatment scenarios: (a) Observation of field overlaps or gaps in matched 3D fields and (b) Patient positioning shifts during intensity modulated radiation therapy (IMRT) field delivery. Further development of this technique would allow real-time detection of treatment delivery errors on the order of millimeters so that patient safety and treatment quality can be improved. METHODS: Cherenkov light emission was captured using a PI-MAX4 intensified charge coupled device (ICCD) system (Princeton Instruments). All radiation delivery was performed using a Varian Trilogy linear accelerator (linac) operated at 6 MV or 18 MV for photon and 6 MeV or 16 MeV for electron studies. Field matching studies were conducted with photon and electron beams at gantry angles of 0°, 15°, and 45°. For each modality and gantry angle, a total of three data sets were acquired. Overlap and gap distances of 0, 2, 5, and 10 mm were tested and delivered to solid phantom material of 30 × 30 × 5 cm3 . Phantom materials used were white plastic water and brown solid water. Tests were additionally performed on an anthropomorphic phantom with an irregular surface. Positioning shift studies were performed using IMRT fields delivered to a thoracic anthropomorphic phantom. For thoracic phantom measurements, the camera was placed laterally to observe the entire right side of the phantom. Fields were delivered with known translational patient positioning shifts in four directions. Changes in the Cherenkov fluence were evaluated through the generation of difference maps from unshifted Cherenkov images. All images were evaluated using ImageJ, Python, and MATLAB software packages. RESULTS: For matched fields, Cherenkov images were able to quantitate matched field separations with discrepancies between 2 and 4 mm, depending on gantry angle and beam energy or modality. For all photon and electron beams delivered at a gantry angle of 0°, image analysis indicated average discrepancies of less than 2 mm for all field gaps and overlaps, with 83% of matched fields exhibiting discrepancies less than 1 mm. Beams delivered obliquely to the phantom surface exhibited average discrepancies as high as 4 mm for electron beams delivered at large oblique angles. Finally, for IMRT field delivery, vertical and lateral patient positioning shifts of 2 mm were detected in some cases, indicating the potential detectability threshold of using this technique alone. CONCLUSIONS: Our study indicates that Cherenkov imaging can be used to support and bolster current treatment delivery verification techniques, improving our ability to recognize and rectify millimeter-scale delivery and positioning errors.

Dosimetric and geometric characteristics of a small animal image-guided irradiator using 3D dosimetry/optical CT scanner.

PURPOSE: The precise dosimetric and geometric characteristics of small animal irradiators are essential to achieving reproducible dose delivery, especially in cases where image-guidance is utilized. Currently, radiochromic film is the established measurement tool used to evaluate beam characteristics for these systems. However, only 2D information can be acquired with film. This study characterized both the dosimetric and geometric properties of the small animal research radiation platform (SARRP, Xstrahl) for commissioning purposes using a 3D radiochromic dosimetry system with a submillimeter resolution optical computed tomography (OCT) scanner. METHODS: Like a modern clinical linear accelerator, the SARRP features both a beam delivery system and a cone beam computed tomography (CBCT) imaging system. Dosimetric and geometric characteristics of the SARRP were studied using EBT3 radiochromic film and 3D PRESAGE dosimeters. Dosimetric measurements included percent depth dose (PDD) curves and beam profiles. For geometric evaluation, the isocenter sizes of the treatment stage and gantry rotations as well as their coincidence were measured using star shot patterns. A commercial Epson Expression 11000XL flatbed scanner was used for readout of irradiated EBT3 films at 300 dpi resolution. Each irradiated PRESAGE dosimeter was scanned using a submillimeter resolution single laser beam OCT scanner. Acquired data were reconstructed with a resolution of 0.3 mm/pixel. RESULTS: PDD data measured from films and 3D dosimeters agree to within ±3% for depths up to 5 cm, for both 3 × 3 and 10 × 10 mm2 fixed collimation. Profiles were analyzed at 10, 20, and 30 mm depth for 3 × 3 mm2 and 10 × 10 mm2 fields. The FWHM measurements for both dosimeters agreed to within 0.01 mm, and the penumbras agreed to within 0.1 mm for 3 × 3 mm2 and 0.5 mm for 10 × 10 mm2 . Gantry and treatment stage isocenter sizes were determined to be 0.21 and 0.43 mm using EBT3 film, and 1.72 and 0.75 mm using PRESAGE dosimeters. Absolute isocenter shifts, evaluated with 3D phantoms, were 0.80 mm for the gantry rotation isocenter (treatment isocenter) with respect to the laser-defined setup isocenter, and 0.71 mm for the gantry rotation isocenter relative to treatment stage rotation isocenter (CBCT isocenter). The difference between CBCT isocenter and laser-defined setup isocenter was 0.68 mm. CONCLUSIONS: This study demonstrated that 3D PRESAGE dosimeters can be used for verification of precise targeting for the SARRP. This 3D dosimetry system can be utilized to obtain information on both geometric and dosimetric properties, as well as acquire beam data parameters for the purpose of commissioning image-guided small animal irradiator systems.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. METHODS: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. FINDINGS: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. CONCLUSIONS: Several clinical niches have been identified that harbor patients at increased risk of NP-C.