Development of a Monte Carlo model for treatment planning dose verification of the Leksell Gamma Knife Perfexion radiosurgery system.

Detailed Monte Carlo (MC) modeling of the Leksell Gamma Knife (GK) Perfexion (PFX) collimator system is the only accurate ab initio approach appearing in the literature. As a different approach, in this work, we present a MC model based on film measurement. By adjusting the model parameters and fine-tuning the derived fluence map for each individual source to match the manufacturer's ring output factors, we created a reasonable virtual source model for MC simulations to verify treatment planning dose for the GK PFX radiosurgery system. The MC simulation model was commissioned by simple single shots. Dose profiles and both ring and collimator output factors were compared with the treatment planning system (TPS). Good agreement was achieved for dose profiles especially for the region of plateau (< 2%), while larger difference (< 5%) came from the penumbra region. The maximum difference of the calculated output factor was within 0.7%. The model was further validated by a clinical test case. Good agreement was obtained. The DVHs for brainstem and the skull were almost identical and, for the target, the volume covered by the prescription (12.5 Gy to 50% isodose line) was 95.6% from MC calculation versus 100% from the TPS.

Emerging applications of stereotactic body radiotherapy.

Stereotactic body radiotherapy (SBRT) has been used extensively in patients with lung, liver and spinal tumors, and the treatment outcomes are very favorable. For certain conditions such as medically inoperable stage I non-small-cell lung cancer, liver and lung oligometastases, primary liver cancer and spinal metastases, SBRT is regarded as one of the standard therapies. In the recent years, the use of SBRT has been extended to other disease conditions and sites such as recurrent head and neck cancer, renal cell carcinoma, prostate cancer, adrenal metastasis, pancreatic cancer, gynecological malignancies, spinal cord compression, breast cancer, and stage II-III non-small-cell lung cancer. Preliminary data in the literature show promising results but the follow-up intervals are short for most studies. This paper will provide an overview of these emerging applications.

A target definition based on electroanatomic maps for stereotactic arrhythmia radioablation.

PURPOSE: Identifying the target region is critical for successfully treating ventricular tachycardia (VT) with single fraction stereotactic arrhythmia radioablation (STAR). We report the feasibility of target definition based on direct co-registration of electroanatomic maps (EAM) and radioablation planning images. MATERIALS AND METHODS: The EAM consists of 3D cardiac anatomy representation with electrical activity at endocardium and is acquired by a cardiac electrophysiologist (CEP) during electrophysiology study. The CEP generates an EAM using a 3D cardiac mapping system anticipating radioablation planning. Our in-house software read these non-DICOM EAMs, registered them to a planning image set, and converted them to DICOM structure files. The EAM based target volume was finalized based on a consensus of CEPs, radiation oncologists and medical physicists, then expanded to ITV and PTV. The simulation, planning, and treatment is performed with a standard STAR technique: a single fraction of 25 Gy using volumetric-modulated arc therapy or dynamic conformal arc therapy depending on the target shape. RESULTS: Seven patients with refractory VT were treated by defining the target based on registering EAMs on the planning images. Dice similarity indices between reference map and reference contours after registration were 0.814 ± 0.053 and 0.575 ± 0.199 for LV and LA/RV, respectively. CONCLUSIONS: The quality of the transferred EAMs on the MR/CT images was sufficient to localize the treatment region. Five of 7 patients demonstrated a dramatic reduction in VT events after 6 weeks. Longer follow-up is required to determine the true safety and efficacy of this therapy using EAM-based direct registration method.

Bidirectional local distance measure for comparing segmentations.

PURPOSE: To accurately quantify the local difference between two contour surfaces in two- or three-dimensional space, a new, robust point-to-surface distance measure is developed. METHODS: To evaluate and visualize the local surface differences, point-to-surface distance measures have been utilized. However, previously well-known point-to-surface distance measures have critical shortfalls. Previous distance measures termed "normal distance (ND)," "radial distance," or "minimum distance (MD)" can report erroneous results at certain points where the surfaces under comparison meet certain conditions. These skewed results are due to the monodirectional characteristics of these methods. ComGrad distance was also proposed to overcome asymmetric characteristics of previous point-to-surface distance measures, but their critical incapability of dealing with a fold or concave contours. In this regard, a new distance measure termed the bidirectional local distance (BLD) is proposed which minimizes errors of the previous methods by taking into account the bidirectional characteristics with the forward and backward directions. BLD measure works through three steps which calculate the maximum value between the forward minimum distance (FMinD) and the backward maximum distance (BMaxD) at each point. The first step calculates the FMinD as the minimum distance to the test surface from a point, p(ref) on the reference surface. The second step involves calculating the minimum distances at every point on the test surface to the reference surface. During the last step, the BMaxD is calculated as the maximum distance among the minimum distances found at p(ref) on the reference surface. Tests are performed on two- and three-dimensional artificial contour sets in comparison to MD and ND measure techniques. Three-dimensional tests performed on actual liver and head-and-neck cancer patients. RESULTS: The proposed BLD measure provides local distances between segmentations, even in situations where ND, MD, or ComGrad measures fail. In particular, the standard deviation measure is not distorted at certain geometries where ND, MD, and ComGrad measures report skewed results. CONCLUSIONS: The proposed measure provides more reliable statistics on contour comparisons. From the statistics, specific local and global distances can be extracted. Bidirectional local distance is a reliable distance measure in comparing two- or three-dimensional organ segmentations.

Composite Radiation Dose Representation Using Fuzzy Set Theory.

Composite plans created from different image sets are generated through Deformable Image Registration (DIR) and present a challenge in accurately presenting uncertainties, which vary with anatomy. Our effort focuses on the application of Fuzzy Set theory to provide an accurate dose representation of such a composite treatment plan. The accuracy of the DIR is generally verified through geometrical visual checks, including the confirmation of the corresponding anatomies with edge features, such as bone or organ boundaries. However, the remaining volume of the image (mostly soft tissues) has few significant image features and therefore greater uncertainty. We fuzzified the deformation vector and derived a Fuzzy composite dose. The fuzzification was implemented using Gaussian functions based on the varying uncertainties in the DIR. After establishing the theoretical basis for this new approach, we present two-and three-dimensional examples as proof-of-concept. Using Fuzzy Set theory, composite dose plans displaying locality-based uncertainties were successfully created, providing information previously unavailable to clinicians. Previous to Fuzzy Set dose presentations, clinicians had no measure of confidence in the accuracy of a composite dose plan. Using fuzzified composite dose presentations, clinicians can determine a safe additional dose to previously treated anatomy. This will possibly increase the treatment success rate and reduce the rate of complications.

Quantifying Liver Heterogeneity via R2*-MRI with Super-Paramagnetic Iron Oxide Nanoparticles (SPION) to Characterize Liver Function and Tumor.

The use of super-paramagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent (SPION-CA) can safely label hepatic macrophages and be localized within hepatic parenchyma for T2*- and R2*-MRI of the liver. To date, no study has utilized the R2*-MRI with SPIONs for quantifying liver heterogeneity to characterize functional liver parenchyma (FLP) and hepatic tumors. This study investigates whether SPIONs enhance liver heterogeneity for an auto-contouring tool to identify the voxel-wise functional liver parenchyma volume (FLPV). This was the first study to directly evaluate the impact of SPIONs on the FLPV in R2*-MRI for 12 liver cancer patients. By using SPIONs, liver heterogeneity was improved across pre- and post-SPION MRI sessions. On average, 60% of the liver [range 40-78%] was identified as the FLPV in our auto-contouring tool with a pre-determined threshold of the mean R2* of the tumor and liver. This method performed well in 10 out of 12 liver cancer patients; the remaining 2 needed a longer echo time. These results demonstrate that our contouring tool with SPIONs can facilitate the heterogeneous R2* of the liver to automatically characterize FLP. This is a desirable technique for achieving more accurate FLPV contouring during liver radiation treatment planning.

Dosimetric benefits of dynamic conformal arc therapy-combined with active breath-hold in lung stereotactic body radiotherapy.

To test the hypothesis that dynamic conformal arc therapy (DCAT) in Monaco, compared with volumetric modulated arc therapy (VMAT), maintains plan quality with higher delivery efficiency for lung stereotactic body radiotherapy (SBRT) and to investigate dosimetric benefits of DCAT with active breath-hold (DCAT+ABH), compared with free-breathing (DCAT+FB) for varying tumor sizes and motions. Fifty DCAT plans were used for lung SBRT. Randomly selected 17 DCAT plans were evaluated with respect to the retrospectively generated volumetric modulated arc therapy (VMAT) plans. The maximum dose at 2 cm from planning target volume (PTV) in any direction (D2cm/Rx), the ratio of 50% prescription isodose volume to the PTV (R50%), conformity index (CI), the lung volume receiving ≥20 Gy (V20), and monitor unit (MU) were evaluated. A t-test was used to evaluate the difference of plan quality between DCAT and VMAT. Internal target volume (ITV)/integrated-gross target volume (GTV) attributed by intra-fraction motion and lung V20 were stratified for DCAT+ABH and DCAT+FB across varying GTVs. DCAT maintained plan quality (p = 0.154 for D2cm/Rx, p = 0.089 for R50%, p = 0.064 for CI, and p = 0.780 for lung V20) while reducing MUs up to 30% (p <0.001) from 2748 MU (VMAT) to 1868 MU (DCAT). DCAT+ABH, compared to DCAT+FB, reduced tumor motion, resulting in 19% volume reduction of PTV and 60% reduction in lung V20, on average. The difference in lung V20 between DCAT+ABH and DCAT+FB increased as the target size increased. The DCAT is a favorable approach compared with VMAT. These results support the utility of DCAT as a routine planning platform for lung SBRT, especially when utilized with respiratory motion management using the ABH.

A volume-independent conformity index for stereotactic radiosurgery.

PURPOSE: To develop a volume-independent conformity metric called the Gaussian Weighted Conformity Index (GWCI) to evaluate stereotactic radiosurgery/radiotherapy (SRS/SRT) plans for small brain tumors. METHODS: A signed bi-directional local distance (BLD) between the prescription isodose line and the target contour is determined for each point along the tumor contour (positive distance represents under-coverage). A similarity score function (SF) is derived from Gaussian function, penalizing under- and over-coverage at each point by assigning standard deviations of the Gaussian function. Each point along the dose line contour is scored with this SF. The average of the similarity scores determines the GWCI. A total of 40 targets from 18 patients who received Gamma-Knife SRS/SRT treatments were analyzed to determine appropriate penalty criteria. The resulting GWCIs for test cases already deemed clinically acceptable are presented and compared to the same cases scored with the New Conformity Index to determine the influence of tumor volumes on the two conformity indices (CIs). RESULTS: A total of four penalty combinations were tested based on the signed BLDs from the 40 targets. A GWCI of 0.9 is proposed as a cutoff for plan acceptability. The GWCI exhibits no target volume dependency as designed. CONCLUSION: A limitation of current CIs, volume dependency, becomes apparent when applied to SRS/SRT plans. The GWCI appears to be a more robust index, which penalizes over- and under-coverage of tumors and is not skewed by the tumor volume.

Rigid and Deformable Image Registration for Radiation Therapy: A Self-Study Evaluation Guide for NRG Oncology Clinical Trial Participation.

PURPOSE: The registration of multiple imaging studies to radiation therapy computed tomography simulation, including magnetic resonance imaging, positron emission tomography-computed tomography, etc. is a widely used strategy in radiation oncology treatment planning, and these registrations have valuable roles in image guidance, dose composition/accumulation, and treatment delivery adaptation. The NRG Oncology Medical Physics subcommittee formed a working group to investigate feasible workflows for a self-study credentialing process of image registration commissioning. METHODS AND MATERIALS: The American Association of Physicists in Medicine (AAPM) Task Group 132 (TG132) report on the use of image registration and fusion algorithms in radiation therapy provides basic guidelines for quality assurance and quality control of the image registration algorithms and the overall clinical process. The report recommends a series of tests and the corresponding metrics that should be evaluated and reported during commissioning and routine quality assurance, as well as a set of recommendations for vendors. The NRG Oncology medical physics subcommittee working group found incompatibility of some digital phantoms with commercial systems. Thus, there is still a need to provide further recommendations in terms of compatible digital phantoms, clinical feasible workflow, and achievable thresholds, especially for future clinical trials involving deformable image registration algorithms. Nine institutions participated and evaluated 4 commonly used commercial imaging registration software and various versions in the field of radiation oncology. RESULTS AND CONCLUSIONS: The NRG Oncology Working Group on image registration commissioning herein provides recommendations on the use of digital phantom/data sets and analytical software access for institutions and clinics to perform their own self-study evaluation of commercial imaging systems that might be employed for coregistration in radiation therapy treatment planning and image guidance procedures. Evaluation metrics and their corresponding values were given as guidelines to establish practical tolerances. Vendor compliance for image registration commissioning was evaluated, and recommendations were given for future development.

Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A State of the ART Review From NRG Oncology.

The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.

Spatially weighted mutual information image registration for image guided radiation therapy.

PURPOSE: To develop a new metric for image registration that incorporates the (sub)pixelwise differential importance along spatial location and to demonstrate its application for image guided radiation therapy (IGRT). METHODS: It is well known that rigid-body image registration with mutual information is dependent on the size and location of the image subset on which the alignment analysis is based [the designated region of interest (ROI)]. Therefore, careful review and manual adjustments of the resulting registration are frequently necessary. Although there were some investigations of weighted mutual information (WMI), these efforts could not apply the differential importance to a particular spatial location since WMI only applies the weight to the joint histogram space. The authors developed the spatially weighted mutual information (SWMI) metric by incorporating an adaptable weight function with spatial localization into mutual information. SWMI enables the user to apply the selected transform to medically "important" areas such as tumors and critical structures, so SWMI is neither dominated by, nor neglects the neighboring structures. Since SWMI can be utilized with any weight function form, the authors presented two examples of weight functions for IGRT application: A Gaussian-shaped weight function (GW) applied to a user-defined location and a structures-of-interest (SOI) based weight function. An image registration example using a synthesized 2D image is presented to illustrate the efficacy of SWMI. The convergence and feasibility of the registration method as applied to clinical imaging is illustrated by fusing a prostate treatment planning CT with a clinical cone beam CT (CBCT) image set acquired for patient alignment. Forty-one trials are run to test the speed of convergence. The authors also applied SWMI registration using two types of weight functions to two head and neck cases and a prostate case with clinically acquired CBCT/ MVCT image sets. The SWMI registration with a Gaussian weight function (SWMI-GW) was tested between two different imaging modalities: CT and MRI image sets. RESULTS: SWMI-GW converges 10% faster than registration using mutual information with an ROI. SWMI-GW as well as SWMI with SOI-based weight function (SWMI-SOI) shows better compensation of the target organ's deformation and neighboring critical organs' deformation. SWMI-GW was also used to successfully fuse MRI and CT images. CONCLUSIONS: Rigid-body image registration using our SWMI-GW and SWMI-SOI as cost functions can achieve better registration results in (a) designated image region(s) as well as faster convergence. With the theoretical foundation established, we believe SWMI could be extended to larger clinical testing.

Predictors of Treatment Interruption During Frameless Gamma Knife Icon Stereotactic Radiosurgery.

PURPOSE: The Gamma Knife (GK) Icon allows for the delivery of stereotactic radiosurgery using a thermoplastic mask in combination with intrafraction motion monitoring using high definition motion management. The system pauses treatment if the magnitude of motion in all directions exceeds 1 to 1.5 mm, causing a break in treatment and prolongation of the session. We reviewed the records of patients treated in a frameless manner on our GK Icon system to determine predictors for treatment interruption. METHODS AND MATERIALS: We reviewed the records of patients treated between May 2019 and May 2020 on the GK Icon using a frameless technique for brain metastases, gliomas, schwannomas, and meningiomas. We recorded treatment time as noted in the plan document, actual treatment delivery time, and any pauses in treatment. We tabulated baseline characteristics including age, gender, diagnosis, performance status, and shifts at time of treatment. We used a receiver operating curve analysis to determine a timepoint corresponding with treatment interruption. We then conducted a logistic regression analysis to generate odds ratios for likelihood of treatment. RESULTS: We identified 150 patients meeting inclusion criteria. The majority (82%) were patients with brain metastases. The median age was 63 and the median dose was 27 Gy (16-30 Gy) in 3 fractions (1-5 fractions). The median treatment time was 23 minutes (4-108 minutes). Sixty-nine patients (46%) had at least 1 pause in treatment (range, 1-7). Receiver operating curve analysis revealed treatment time >19 minutes and rotation >0.47 degrees to be associated with interruption. Multivariable logistic regression revealed rotation >0.47 degrees and treatment time >19 minutes as predictive of interruption. CONCLUSIONS: For patients with rotations exceeding 0.47 degrees or an extended treatment time, physicians should expect treatment interruptions, consider fractionation to lessen table time, or use a frame-based approach.

Adaptation of a Gamma Knife Icon stereotactic radiosurgery program in the face of the COVID-19 pandemic.

Objective: The COVID-19 pandemic necessitated drastic and rapid changes throughout the field of radiation oncology, some of which were unique to the discipline of radiosurgery. Guidelines called for reduced frame use and reducing the number of fractions. Our institution implemented these guidelines, and herein we show the resultant effect on patient treatments on our Gamma Knife Icon program. Methods: In early March 2020 we rapidly implemented suggested changes according to ASTRO and other consensus guidelines as they relate to stereotactic radiosurgery in the COVID-19 era. We reviewed the GK Icon schedule at our institution between January 01 and April 30, 2020. We documented age, condition treated, technique (frame vs. mask), and number of fractions. We then tabulated and graphed the number of patients, framed cases, and fractions delivered. Results: Seventy-seven patients were treated on the GK Icon over that period, for a total of 231 fractions. The number of unique patients varied from 18 (April) to 22 (January). Of the 77 patients only 5 were treated using a frame. The number of fractions per month decreased significantly over time, from 70 in January to 36 in April. Likewise, the percentage of single fraction cases increased from 4.5% per month in January to 67% in April. Conclusions: The results presented here show that it is possible to quickly and efficiently change work flows to allow for reduced fractionation and frame use in the time of a global pandemic. Multidisciplinary cooperation and ongoing communication are integral to the success of such programs.

Clinical Study of Using Biometrics to Identify Patient and Procedure.

PURPOSE: To reduce patient and procedure identification errors by human interactions in radiotherapy delivery and surgery, a Biometric Automated Patient and Procedure Identification System (BAPPIS) was developed. BAPPIS is a patient identification and treatment procedure verification system using fingerprints. METHODS: The system was developed using C++, the Microsoft Foundation Class Library, the Oracle database system, and a fingerprint scanner. To register a patient, the BAPPIS system requires three steps: capturing a photograph using a web camera for photo identification, taking at least two fingerprints, and recording other specific patient information including name, date of birth, allergies, etc. To identify a patient, the BAPPIS reads a fingerprint, identifies the patient, verifies with a second fingerprint to confirm when multiple patients have same fingerprint features, and connects to the patient's record in electronic medical record (EMR) systems. To validate the system, 143 and 21 patients ranging from 36 to 98 years of ages were recruited from radiotherapy and breast surgery, respectively. The registration process for surgery patients includes an additional module, which has a 3D patient model. A surgeon could mark 'O' on the model and save a snap shot of patient in the preparation room. In the surgery room, a webcam displayed the patient's real-time image next to the 3D model. This may prevent a possible surgical mistake. RESULTS: 1,271 (96.9%) of 1,311 fingerprints were verified by BAPPIS using patients' 2nd fingerprints from 143 patients as the system designed. A false positive recognition was not reported. The 96.9% completion ratio is because the operator did not verify with another fingerprint after identifying the first fingerprint. The reason may be due to lack of training at the beginning of the study. CONCLUSION: We successfully demonstrated the use of BAPPIS to correctly identify and recall patient's record in EMR. BAPPIS may significantly reduce errors by limiting the number of non-automated steps.

MCT4 regulates de novo pyrimidine biosynthesis in GBM in a lactate-independent manner.

BACKGROUND: Necrotic foci with surrounding hypoxic cellular pseudopalisades and microvascular hyperplasia are histological features found in glioblastoma (GBM). We have previously shown that monocarboxylate transporter 4 (MCT4) is highly expressed in necrotic/hypoxic regions in GBM and that increased levels of MCT4 are associated with worse clinical outcomes. METHODS: A combined transcriptomics and metabolomics analysis was performed to study the effects of MCT4 depletion in hypoxic GBM neurospheres. Stable and inducible MCT4-depletion systems were used to evaluate the effects of and underlining mechanisms associated with MCT4 depletion in vitro and in vivo, alone and in combination with radiation. RESULTS: This study establishes that conditional depletion of MCT4 profoundly impairs self-renewal and reduces the frequency and tumorigenicity of aggressive, therapy-resistant, glioblastoma stem cells. Mechanistically, we observed that MCT4 depletion induces anaplerotic glutaminolysis and abrogates de novo pyrimidine biosynthesis. The latter results in a dramatic increase in DNA damage and apoptotic cell death, phenotypes that were readily rescued by pyrimidine nucleosides supplementation. Consequently, we found that MCT4 depletion promoted a significant prolongation of survival of animals bearing established orthotopic xenografts, an effect that was extended by adjuvant treatment with focused radiation. CONCLUSIONS: Our findings establish a novel role for MCT4 as a critical regulator of cellular deoxyribonucleotide levels and provide a new therapeutic direction related to MCT4 depletion in GBM.

NRG Oncology Survey on Practice and Technology Use in SRT and SBRT Delivery.

PURPOSE: To assess stereotactic radiotherapy (SRT)/stereotactic body radiotherapy (SBRT) practices by polling clinics participating in multi-institutional clinical trials. METHODS: The NRG Oncology Medical Physics Subcommittee distributed a survey consisting of 23 questions, which covered general technologies, policies, and procedures used in the Radiation Oncology field for the delivery of SRT/SBRT (9 questions), and site-specific questions for brain SRT, lung SBRT, and prostate SBRT (14 questions). Surveys were distributed to 1,996 radiotherapy institutions included on the membership rosters of the five National Clinical Trials Network (NCTN) groups. Patient setup, motion management, target localization, prescriptions, and treatment delivery technique data were reported back by 568 institutions (28%). RESULTS: 97.5% of respondents treat lung SBRT patients, 77.0% perform brain SRT, and 29.1% deliver prostate SBRT. 48.8% of clinics require a physicist present for every fraction of SBRT, 18.5% require a physicist present for the initial SBRT fraction only, and 14.9% require a physicist present for the entire first fraction, including set-up approval for all subsequent fractions. 55.3% require physician approval for all fractions, and 86.7% do not reposition without x-ray imaging. For brain SRT, most institutions (83.9%) use a planning target volume (PTV) margin of 2 mm or less. Lung SBRT PTV margins of 3 mm or more are used in 80.6% of clinics. Volumetric modulated arc therapy (VMAT) is the dominant delivery method in 62.8% of SRT treatments, 70.9% of lung SBRT, and 68.3% of prostate SBRT. CONCLUSION: This report characterizes SRT/SBRT practices in radiotherapy clinics participating in clinical trials. Data made available here allows the radiotherapy community to compare their practice with that of other clinics, determine what is achievable, and assess areas for improvement.

Unforeseen Computed Tomography Resimulation for Initial Radiation Planning: Associated Factors and Clinical Impact.

PURPOSE: Repeat computed tomography (CT) simulation is problematic because of additional expense of clinic resources, patient inconvenience, additional radiation exposure, and treatment delay. We investigated the factors and clinical impact of unplanned CT resimulations in our network. METHODS AND MATERIALS: We used the billing records of 18,170 patients treated at 5 clinics. A total of 213 patients were resimulated before their first treatment. The disease site, location, use of 4-dimensional CT (4DCT), contrast, image fusion, and cause for resimulation were recorded. Odds ratios determined statistical significance. RESULTS: Our total rate of resimulation was 1.2%. Anal/colorectal (P < .001) and head and neck (P < .001) disease sites had higher rates of resimulation. Brain (P = .001) and lung/thorax (P = .008) had lower rates of resimulation. The most common causes for resimulation were setup change (11.7%), change in patient anatomy (9.8%), and rectal filling (8.5%). The resimulation rate for 4DCTs was 3.03% compared with 1.0% for non-4DCTs (P < .001). Median time between simulations was 7 days. CONCLUSIONS: The most common sites for resimulation were anal/colorectal and head and neck, largely because of change in setup or changes in anatomy. The 4DCT technique correlated with higher resimulation rates. The resimulation rate was 1.2%, and median treatment delay was 7 days. Further studies are warranted to limit the rate of resimulation.

The Ig superfamily protein PTGFRN coordinates survival signaling in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a median survival of approximately 14 months. Despite aggressive treatment of surgical resection, chemotherapy and radiation therapy, only 3-5% of GBM patients survive more than 3 years. Contributing to this poor therapeutic response, it is believed that GBM contains both intrinsic and acquired mechanisms of resistance, including resistance to radiation therapy. In order to define novel mediators of radiation resistance, we conducted a functional knockdown screen, and identified the immunoglobulin superfamily protein, PTGFRN. In GBM, PTGFRN is found to be overexpressed and to correlate with poor survival. Reducing PTGFRN expression radiosensitizes GBM cells and potently decreases the rate of cell proliferation and tumor growth. Further, PTGFRN inhibition results in significant reduction of PI3K p110ß and phosphorylated AKT, due to instability of p110ß. Additionally, PTGFRN inhibition decreases nuclear p110ß leading to decreased DNA damage sensing and DNA damage repair. Therefore overexpression of PTGFRN in glioblastoma promotes AKT-driven survival signaling and tumor growth, as well as increased DNA repair signaling. These findings suggest PTGFRN is a potential signaling hub for aggressiveness in GBM.

Tumor localization accuracy for high-precision radiotherapy during active breath-hold.

BACKGROUND: Conventionally fractionated and stereotactic body radiation therapy (SBRT) for thoracoabdominal tumors may utilize breath-hold techniques. However, there are concerns that differential amounts of inspired airflow may result in unplanned tumor dislocation and underdosing. Thus, we investigated tumor localization accuracy associated with lung volume variations during breath-hold treatment via an automated-gating interface. METHODS: Twelve patients received breath-hold treatment with the active breathing coordinator (ABC) through an automated-gating interface. All breath-hold volumes were recorded at CT simulation, setup imaging, and during treatment, and analyzed as a function of airflow rate into the ABC. The variation of breath-hold volumes was calculated for each fraction over entire course. Intrafraction target motion related to the breathing variation was investigated based on daily imaging acquired before the breath-hold treatment. Correlation between target location and breath-hold variation was statistically analyzed. RESULTS: The air volume held by the ABC increased as the airflow rate increased on inhalation and decreased on exhalation. The mean range of airflow rate was 0.77 L/s and 0.29 L/s in the conventionally fractionated and SBRT patients, respectively. The maximum air volume difference with respect to the reference volume at the CT simulation was 1.0 L for conventional fractionation and 0.16 L for SBRT. The target dislocation caused by 0.25 L of air volume difference was 6 mm for SBRT. Three patients showed significant correlation between the target location and breath-hold variations. CONCLUSIONS: This investigation shows that because variations in the breath-hold volume may cause target dislocation, patient-specific breath-hold setting is required to improve tumor localization accuracy.

Robustness Analysis for External Beam Radiation Therapy Treatment Plans: Describing Uncertainty Scenarios and Reporting Their Dosimetric Consequences.

PURPOSE: With external beam radiation therapy, uncertainties in treatment planning and delivery can result in an undesirable dose distribution delivered to the patient that can compromise the benefit of treatment. Techniques including geometric margins and probabilistic optimization have been used effectively to mitigate the effects of uncertainties. However, their broad application is inconsistent and can compromise the conclusions derived from cross-technique and cross-modality comparisons. METHODS AND MATERIALS: Conventional methods to deal with treatment planning and delivery uncertainties are described, and robustness analysis is presented as a framework that is applicable across treatment techniques and modalities. RESULTS: This report identifies elements that are imperative to include when conducting a robustness analysis and describing uncertainties and their dosimetric effects. CONCLUSION: The robustness analysis approach described here is presented to promote reliable plan evaluation and dose reporting, particularly during clinical trials conducted across institutions and treatment modalities.