A practical cyberattack contingency plan for radiation oncology.

PURPOSE: This article presents a solution for continuing radiation therapy without interruption in the event of a cyberattack to the radiation oncology information systems (ROIS). This process could be easily deployed to any radiation oncology practice, with little clinical overhead or burden. METHODS AND MATERIALS: The solution automatically retrieves all essential information from the clinical ROIS for each under-treatment patient and periodically (e.g., daily) saves these data to a dedicated secure server for recovery. In the event that the clinical ROIS is not functioning as a result of a cyberattack, this essential information is used to build a new secondary ROIS server to continue radiotherapy treatments until the main ROIS is recovered. Once the cyberattack threat is cleared, the clinical ROIS server is rebuilt from the institution's enterprise backup. The newly accumulated treatment information for each patient is then exported from the secondary ROIS to bring the clinical ROIS up to date. RESULTS: The Department of Radiation Oncology at the University of Maryland Medical System implemented this solution for clinical use with the Varian ARIA ROIS in the management of ~250 daily radiotherapy treatments, inclusive of a proton center. This solution was determined to be a feasible and affordable business continuity plan for the radiation oncology practice by minimizing radiation treatment downtime to a couple of hours in a simulated cyberattack drill. CONCLUSIONS: The proposed solution can achieve continuation of radiation therapy treatment without treatment breaks in the event of a cyberattack. It also provides cushion time for radiation oncology departments to rebuild their clinical ROIS systems from the enterprise data backup.

Knockout of MCT1 results in total absence of spermatozoa, sex hormones dysregulation, and morphological alterations in the testicular tissue.

Lactate is a key metabolite for the normal occurrence of spermatogenesis. In the testis, lactate is produced by the Sertoli cells and transported to germline cells. Monocarboxylate transporters (MCTs) are key players in that process. Among the family of MCTs, MCT1 is at least partly responsible for lactate uptake by the germ cells. We aimed to perform a first assessment of the role of MCT1 in male reproductive potential. Mct1 conditional knockout (cKO) mice were used for morphometric evaluation, testicular morphology, and sperm parameter assessment. Serum steroid hormones levels were also measured. cKO animals showed a decrease in gonadosomatic index, testis weight, and seminiferous tubular diameters. Deletion of MCT1 also causes morphological changes in the organization of the seminiferous tubules and on Sertoli cell morphology. These changes resulted in failure of spermatogenesis with depletion of germ cells and total absence of spermatozoa. MCT1 cKO animals presented also hormonal dysregulation, with a decrease in serum 17ß-estradiol levels. In conclusion, MCT1 is pivotal for male reproductive potential. Absence of MCT1 results in maintenance of undifferentiated spermatogonia pool and compromised sperm production.

Liposomes: Clinical Applications and Potential for Image-Guided Drug Delivery.

Liposomes have been extensively studied and are used in the treatment of several diseases. Liposomes improve the therapeutic efficacy by enhancing drug absorption while avoiding or minimizing rapid degradation and side effects, prolonging the biological half-life and reducing toxicity. The unique feature of liposomes is that they are biocompatible and biodegradable lipids, and are inert and non-immunogenic. Liposomes can compartmentalize and solubilize both hydrophilic and hydrophobic materials. All these properties of liposomes and their flexibility for surface modification to add targeting moieties make liposomes more attractive candidates for use as drug delivery vehicles. There are many novel liposomal formulations that are in various stages of development, to enhance therapeutic effectiveness of new and established drugs that are in preclinical and clinical trials. Recent developments in multimodality imaging to better diagnose disease and monitor treatments embarked on using liposomes as diagnostic tool. Conjugating liposomes with different labeling probes enables precise localization of these liposomal formulations using various modalities such as PET, SPECT, and MRI. In this review, we will briefly review the clinical applications of liposomal formulation and their potential imaging properties.

Feasibility of CBCT-based dose with a patient-specific stepwise HU-to-density curve to determine time of replanning.

PURPOSE: (a) To investigate the accuracy of cone-beam computed tomography (CBCT)-derived dose distributions relative to fanbeam-based simulation CT-derived dose distributions; and (b) to study the feasibility of CBCT dosimetry for guiding the appropriateness of replanning. METHODS AND MATERIALS: Image data corresponding to 40 patients (10 head and neck [HN], 10 lung, 10 pancreas, 10 pelvis) who underwent radiation therapy were randomly selected. Each patient had both intensity-modulated radiation therapy and volumetric-modulated arc therapy plans; these 80 plans were subsequently recomputed on the CBCT images using a patient-specific stepwise curve (Hounsfield units-to-density). Planning target volumes (PTVs; D98%, D95%, D2%), mean dose, and V95% were compared between simulation-CT-derived treatment plans and CBCT-based plans. Gamma analyses were performed using criterion of 3%/3 mm for three dose zones (>90%, 70%~90%, and 30%~70% of maximum dose). CBCT-derived doses were then used to evaluate the appropriateness of replanning decisions in 12 additional HN patients whose plans were previously revised during radiation therapy because of anatomic changes; replanning in these cases was guided by the conventional observed source-to-skin-distance change-derived approach. RESULTS: For all disease sites, the difference in PTV mean dose was 0.1% ± 1.1%, D2% was 0.7% ± 0.1%, D95% was 0.2% ± 1.1%, D98% was 0.2% ± 1.0%, and V95% was 0.3% ± 0.8%; For 3D dose comparison, 99.0% ± 1.9%, 97.6% ± 4.4%, and 95.3% ± 6.0% of points passed the 3%/3 mm criterion of gamma analysis in high-, medium-, and low-dose zones, respectively. The CBCT images achieved comparable dose distributions. In the 12 previously replanned 12 HN patients, CBCT-based dose predicted well changes in PTV D2% (Pearson linear correlation coefficient = 0.93; P < 0.001). If 3% of change is used as the replanning criteria, 7/12 patients could avoid replanning. CONCLUSIONS: CBCT-based dose calculations produced accuracy comparable to that of simulation CT. CBCT-based dosimetry can guide the decision to replan during the course of treatment.

Colloidal Properties of Nanoerythrosomes Derived from Bovine Red Blood Cells.

Liposomes are nanoscale containers that are typically synthesized from lipids using a high-shear process such as extrusion or sonication. While liposomes are extensively used in drug delivery, they do suffer from certain problems including limited colloidal stability and short circulation times in the body. As an alternative to liposomes, we explore a class of container structures derived from erythrocytes (red blood cells). The procedure involves emptying the inner contents of these cells (specifically hemoglobin) and resuspending the empty structures in buffer, followed by sonication. The resulting structures are termed nanoerythrosomes (NERs), i.e., they are membrane-covered nanoscale containers, much like liposomes. Cryo-transmission electron microscopy (cryo-TEM) and small-angle neutron scattering (SANS) are employed for the first time to study these NERs. The results reveal that the NERs are discrete spheres (∼110 nm diameter) with a unilamellar membrane of thickness ∼4.5 nm. Remarkably, the biconcave disc-like shape of erythrocytes is also exhibited by the NERs under hypertonic conditions. Moreover, unlike typical liposomes, NERs show excellent colloidal stability in both buffer as well as in serum at room temperature, and are also able to withstand freeze-thaw cycling. We have explored the potential for using NERs as colloidal vehicles for targeted delivery. Much like conventional liposomes, NER membranes can be decorated with fluorescent or other markers, solutes can be encapsulated in the cores of the NERs, and NERs can be targeted to specifically bind to mammalian cells. Our study shows that NERs are a promising and versatile class of nanostructures. NERs that are harvested from a patient's own blood and reconfigured for nanomedicine can potentially offer several benefits including biocompatibility, minimization of immune response, and extended circulation time in the body.

Optimizing the MLC model parameters for IMRT in the RayStation treatment planning system.

Unlike other commercial treatment planning systems (TPS) which model the rounded leaf end differently (such as the MLC dosimetric leaf gap (DLG) or rounded leaf-tip radius), the RayStation TPS (RaySearch Laboratories, Stockholm, Sweden) models transmission through the rounded leaf end of the MLC with a step function, in which the radiation transmission through the leaf end is the square root of the average MLC transmission factor. We report on the optimization of MLC model parameters for the RayStation planning system. This (TPS) models the rounded leaf end of the MLC with the following parameters: eaf-tip offset, leaf-tip width, average transmission factor, and tongue and groove. We optimized the MLC model parameters for IMRT in the RayStation v. 4.0 planning system and for a Varian C-series linac with a 120-leaf Millennium MLC, and validated the model using measured data. The leaf-tip offset is the geometric offset due to the rounded leaf-end design and resulting divergence of the light/radiation field. The offset value is a function of the leaf-tip position, and tabulated data are available from the vendor. The leaf-tip width was iteratively evaluated by comparing computed and measured transverse dose profiles of MLC defined fields at dmax in water. In-water profile comparisons were also used to verify the MLC leaf position (leaf-tip offset). The average transmission factor and leaf tongue-and-groove width were derived iteratively by maximizing the agreement between measurements and RayStation TPS calculations for five clinical IMRT QA plans. Plan verifications were performed by comparing MapCHECK2 measurements and Monte Carlo calculations. The MLC model was validated using five test IMRT cases from the AAPM Task Group 119 report. Absolute gamma analyses (3 mm/3% and 2 mm/2%) were applied. In addition, computed output factors for MLC-defined small fields (2 × 2, 3 × 3, 4 × 4, 6× 6cm2) of both 6 MV and 18 MV photons were compared to those independently measured by the Imaging and Radiation Oncology Core (IROC), Houston, TX. 6MV and 18 MV models were both determined to have the same MLC parameters: leaf-tip offset = 0.3 cm, 2.5% transmission, and leaf tongue-and-groove width = 0.05 cm. IMRT QA analysis for five test cases in TG-119 resulted in a 100% passing rate with 3 mm/3% gamma analysis for 6 MV, and > 97.5% for 18 MV. The passing rate was > 94.6% for 6 MV and > 90.9% for 18 MV when the 2 mm/2% gamma analysis criteria was applied. These results compared favorably with those published in AAPM Task Group 119. The reported MLC model parameters serve as a reference for other users.

Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD(2) receptors CRTH2 and DP.

Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.

Polar opposites: Erk direction of CD4 T cell subsets.

Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on TCR, coreceptor, and cytokine signals. In this reverse genetic study, we show that the MAPK Erk2 is not essential for T cell proliferation in the presence of optimum costimulation. Instead, it has opposite effects on T-bet and Gata3 expression and, hence, on Th1 and Th2 differentiation. Alternatively, in the presence of TGF-ß, the Erk pathway suppresses a large program of gene expression, effectively limiting the differentiation of Foxp3(+) regulatory T cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3, induction of Tbx21, phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3(+)-induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling.

Online monitoring and error detection of real-time tumor displacement prediction accuracy using control limits on respiratory surrogate statistics.

PURPOSE: To evaluate Hotelling's T(2) statistic and the input variable squared prediction error (Q((X))) for detecting large respiratory surrogate-based tumor displacement prediction errors without directly measuring the tumor's position. METHODS: Tumor and external marker positions from a database of 188 Cyberknife Synchrony™ lung, liver, and pancreas treatment fractions were analyzed. The first ten measurements of tumor position in each fraction were used to create fraction-specific models of tumor displacement using external surrogates as input; the models were used to predict tumor position from subsequent external marker measurements. A partial least squares (PLS) model with four scores was developed for each fraction to determine T(2) and Q((X)) confidence limits based on the first ten measurements in a fraction. The T(2) and Q((X)) statistics were then calculated for every set of external marker measurements. Correlations between model error and both T(2) and Q((X)) were determined. Receiver operating characteristic analysis was applied to evaluate sensitivities and specificities of T(2), Q((X)), and T(2)∪Q((X)) for predicting real-time tumor localization errors >3 mm over a range of T(2) and Q((X)) confidence limits. RESULTS: Sensitivity and specificity of detecting errors >3 mm varied with confidence limit selection. At 95% sensitivity, T(2)∪Q((X)) specificity was 15%, 2% higher than either T(2) or Q((X)) alone. The mean time to alarm for T(2)∪Q((X)) at 95% sensitivity was 5.3 min but varied with a standard deviation of 8.2 min. Results did not differ significantly by tumor site. CONCLUSIONS: The results of this study establish the feasibility of respiratory surrogate-based online monitoring of real-time respiration-induced tumor motion model accuracy for lung, liver, and pancreas tumors. The T(2) and Q((X)) statistics were able to indicate whether inferential model errors exceeded 3 mm with high sensitivity. Modest improvements in specificity were achieved by combining T(2) and Q((X)) results.

Deformable planning CT to cone-beam CT image registration in head-and-neck cancer.

PURPOSE: The purpose of this work was to implement and validate a deformable CT to cone-beam computed tomography (CBCT) image registration method in head-and-neck cancer to eventually facilitate automatic target delineation on CBCT. METHODS: Twelve head-and-neck cancer patients underwent a planning CT and weekly CBCT during the 5-7 week treatment period. The 12 planning CT images (moving images) of these patients were registered to their weekly CBCT images (fixed images) via the symmetric force Demons algorithm and using a multiresolution scheme. Histogram matching was used to compensate for the intensity difference between the two types of images. Using nine known anatomic points as registration targets, the accuracy of the registration was evaluated using the target registration error (TRE). In addition, region-of-interest (ROI) contours drawn on the planning CT were morphed to the CBCT images and the volume overlap index (VOI) between registered contours and manually delineated contours was evaluated. RESULTS: The mean TRE value of the nine target points was less than 3.0 mm, the slice thickness of the planning CT. Of the 369 target points evaluated for registration accuracy, the average TRE value was 2.6 +/- 0.6 mm. The mean TRE for bony tissue targets was 2.4 +/- 0.2 mm, while the mean TRE for soft tissue targets was 2.8 +/- 0.2 mm. The average VOI between the registered and manually delineated ROI contours was 76.2 +/- 4.6%, which is consistent with that reported in previous studies. CONCLUSIONS: The authors have implemented and validated a deformable image registration method to register planning CT images to weekly CBCT images in head-and-neck cancer cases. The accuracy of the TRE values suggests that they can be used as a promising tool for automatic target delineation on CBCT.

Optimal beam arrangement for stereotactic body radiation therapy delivery in lung tumors.

PURPOSE: To compare the different beam arrangement and delivery techniques for stereotactic body radiation therapy (SBRT) of lung lesions using the criteria of Radiation Therapy Oncology Group (RTOG) 0236 protocol. MATERIAL AND METHODS: Thirty-seven medically inoperable lung cancers were evaluated with various planning techniques including multiple coplanar multiple static beams, multiple non-coplanar static beams and arc delivery. Twelve plans were evaluated for each case, including five plans using coplanar fixed beams, six plans using non-coplanar fixed beams and one plan using arc therapy. These plans were compared using the target prescription isodose coverage, high and low dose volumes, and critical organ dose-volume limits. RESULTS: The prescription isodose coverage, high dose evaluation criteria and dose to critical organs were similar among treatment delivery techniques. However, there were differences in low dose criteria, especially in the ratio of the volume of 50% isodose of the prescription dose to the volume of planning treatment volume (R(50%)). The R(50%) in plans using non-coplanar static beams was lower than other plans in 30 of 37 cases (81%). CONCLUSION: Based on the dosimetric criteria outlined in RTOG 0236, the treatment technique using non-coplanar static beams showed the most preferable results for SBRT of lung lesions.

The Erk2 MAPK regulates CD8 T cell proliferation and survival.

The magnitude of T cell responses is determined by proliferation and survival decisions made by the responding cells. We now demonstrate that the Erk MAPK pathway plays a critical role in these cell fate decisions within CD8 T cells. While Erk1 is dispensable for all aspects of CD8 T cell activation, Erk2 is required for the proliferation of CD8 T cells activated in the absence of costimulation. Surprisingly, Erk2 is not required for proliferation following the addition of a costimulatory signal in vitro, or upon viral infection in vivo, but regulates the size of the responding population by enhancing cell survival. An important component of this Erk2-derived signal is the transcriptional regulation of Bcl-2 family members Bcl-x(L) and Bim, and impaired Erk2-deficient CD8 T cell survival can be rescued by genetic ablation of Bim. These studies ascribe multifaceted functions specific to Erk2 in CD8 T cell activation, proliferation, and survival.

A systematic quality assurance framework for the upgrade of radiation oncology information systems.

In spite of its importance, no systematic and comprehensive quality assurance (QA) program for radiation oncology information systems (ROIS) to verify clinical and treatment data integrity and mitigate against data errors/corruption and/or data loss risks is available. Based on data organization, format and purpose, data in ROISs falls into five different categories: (1) the ROIS relational database and associated files; (2) the ROIS DICOM data stream; (3) treatment machine beam data and machine configuration data; (4) electronic medical record (EMR) documents; and (5) user-generated clinical and treatment reports from the ROIS. For each data category, this framework proposes a corresponding data QA strategy to very data integrity. This approach verified every bit of data in the ROIS, including billions of data records in the ROIS SQL database, tens of millions of ROIS database-associated files, tens of thousands of DICOM data files for a group of selected patients, almost half a million EMR documents, and tens of thousands of machine configuration files and beam data files. The framework has been validated through intentional modifications with test patient data. Despite the 'big data' nature of ROIS, the multiprocess and multithread nature of our QA tools enabled the whole ROIS data QA process to be completed within hours without clinical interruptions. The QA framework suggested in this study proved to be robust, efficient and comprehensive without labor-intensive manual checks and has been implemented for our routine ROIS QA and ROIS upgrades.

Investigation of motion sickness and inertial stability on a moving couch for intra-fraction motion compensation.

BACKGROUND. Respiration-induced tumor motion compensation using a treatment couch requires moving the patient at non-trivial speeds. The purpose of this work was to investigate motion sickness and stability of the patient's external surface due to a moving couch with respiration-comparable velocities and accelerations. MATERIAL AND METHODS. A couch was designed to move with a peak-peak displacement of 5 cm and 1 cm in the S-I and A-P directions, respectively, and a period of 3.6 s. Fifty patients completed a 16-question motion sickness assessment questionnaire (MSAQ) prior to, during, and after the study. Seven optical reflectors affixed to the abdomen of each patient were monitored by infrared cameras. The relationship between reflector positions under stationary and moving conditions was evaluated to assess the stability of the patient's external surface. RESULTS AND DISCUSSION. Among the 4800 responses, 95% were 1 (no discomfort) of 9, and there were no scores of 6 or higher. Mild discomfort (scores of 4-5) was similar during couch motion and before couch motion (p = 0.39). Mild discomfort was less common after couch motion (p = 0.039) than before or during couch movement. There was a near 1:1 correspondence between marker-pair regression coefficients and phase offset values during couch-stationary and couch-moving conditions. Our results show that patients do not suffer motion sickness or external surface instability on a moving couch.

Action Levels on Dose and Anatomic Variation for Adaptive Radiation Therapy Using Daily Offline Plan Evaluation: Preliminary Results.

PURPOSE: This study aimed to develop action levels for replanning to accommodate dosimetric variations resulting from anatomic changes during the course of treatments, using daily cone beam computed tomography (CBCT). METHODS AND MATERIALS: Daily or weekly CBCT images of 20 patients (10 head and neck, 5 lung, and 5 prostate cancers) who underwent resimulation per physicians' clinical decisions, mainly from the comparison of CBCT scans, were used to determine action levels. The first CBCT image acquired before the first treatment was used as the reference image to rule out effects of dose inaccuracy from the CBCT. The Pearson correlation of clinical target volume (CTV) was used as a parameter of anatomic variation. Parameters for action levels on dose and anatomic variation were deduced by comparing the parameters and clinical decisions made for replanning. A software tool was developed to automatically perform all procedures, including dose calculations, using the CBCT and plan evaluations. RESULTS: Replans were clinically decided based on either significant dose or anatomic changes in 13 cases. The 7 cases that did not require replanning showed dose differences <5%, and the Pearson correlation of the CTV was >75% for all fractions. A difference in planning target volume dose >5% or a difference in the image correlation coefficient of the CTV <0.75 proved to be indicators for replanning. Once the results of the CBCT plan met the replanning criteria, the software tool automatically alerted the attending physician and physicist by both e-mail and pager so that the case could be examined closely. CONCLUSIONS: Our study shows that a dose difference of 5% and/or anatomy variation at 0.75 Pearson correlations are practical action levels on dose and anatomic variation for replanning for the given data sets.

The Feasibility of Integrating Resting-State fMRI Networks into Radiotherapy Treatment Planning.

BACKGROUND: Functional magnetic resonance imaging (fMRI) presents the ability to selectively protect functionally significant regions of the brain when primary brain tumors are treated with radiation therapy. Previous research has focused on task-based fMRI of language and sensory networks; however, there has been limited investigation on the inclusion of resting-state fMRI into the design of radiation treatment plans. METHODS AND MATERIALS: In this pilot study of 9 patients with primary brain tumors, functional data from the default mode network (DMN), a network supporting cognitive functioning, was obtained from resting-state fMRI and retrospectively incorporated into the design of radiation treatment plans. We compared the dosimetry of these fMRI DMN avoidance treatment plans with standard of care treatment plans to demonstrate feasibility. In addition, we used normal tissue complication probability models to estimate the relative benefit of fMRI DMN avoidance treatment plans over standard of care treatment plans in potentially reducing memory loss, a surrogate for cognitive function. RESULTS: On average, we achieved 20% (P = 0.002) and 12% (P = 0.002) reductions in the mean and maximum doses, respectively, to the DMN without compromising the dose coverage to the planning tumor volume or the dose-volume constraints to organs at risk. Normal tissue complication probability models revealed that when the fMRI DMN was considered during radiation treatment planning, the probability of developing memory loss was lowered by more than 20%. CONCLUSION: In this pilot study, we demonstrated the feasibility of including rs-MRI data into the design of radiation treatment plans to spare cognitively relevant brain regions during radiation therapy. These results lay the groundwork for future clinical trials that incorporate such treatment planning methods to investigate the long-term behavioral impact of this reduction in dose to the cognitive areas and their neural networks that support cognitive performance.

An evaluation of planning techniques for stereotactic body radiation therapy in lung tumors.

PURPOSE: To evaluate four planning techniques for stereotactic body radiation therapy (SBRT) in lung tumors. METHODS AND MATERIALS: Four SBRT plans were performed for 12 patients with stage I/II non-small-cell lung cancer under the following conditions: (1) conventional margins on free-breathing CT (plan 1), (2) generation of an internal target volume (ITV) using 4DCT with beam delivery under free-breathing conditions (plan 2), (3) gating at end-exhale (plan 3), and (4) gating at end-inhale (plan 4). Planning was performed following the RTOG 0236 protocol with a prescription dose of 54 Gy (3 fractions). For each plan 4D dose was calculated using deformable-image registration. RESULTS: There was no significant difference in tumor dose delivered by the 4 plans. However, compared with plan 1, plans 2-4 reduced total lung BED by 1.9+/-1.2, 3.1+/-1.6 and 3.5+/-2.1 Gy, reduced mean lung dose by 0.8+/-0.5, 1.5+/-0.8, and 1.6+/-1.0 Gy, reduced V20 by 1.5+/-1.0%, 2.7+/-1.4%, and 2.8+/-1.8%, respectively, with p<0.01. Compared with plan 2, plans 3-4 reduced lung BED by 1.2+/-1.0 and 1.6+/-1.5 Gy, reduced mean lung dose by 0.6+/-0.5 and 0.8+/-0.7 Gy, reduced V20 by 1.2+/-1.1% and 1.3+/-1.5%, respectively, with p<0.01. The differences in lung BED, mean dose and V20 of plan 4 compared with plan 3 were insignificant. CONCLUSIONS: Tumor dose coverage was statistically insignificant between all plans. However, compared with plan 1, plans 2-4 significantly reduced lung doses. Compared with plan 2, plan 3-4 also reduced lung toxicity. The difference in lung doses between plan 3 and plan 4 was not significant.

Locating and targeting moving tumors with radiation beams.

The current climate of rapid technological evolution is reflected in newer and better methods to modulate and direct radiation beams for cancer therapy. This Vision 20/20 paper focuses on part of this evolution, locating and targeting moving tumors. The two processes are somewhat independent and in principle different implementations of the locating and targeting processes can be interchanged. Advanced localization and targeting methods have an impact on treatment planning and also present new challenges for quality assurance (QA), that of verifying real-time delivery. Some methods to locate and target moving tumors with radiation beams are currently FDA approved for clinical use-and this availability and implementation will increase with time. Extensions of current capabilities will be the integration of higher order dimensionality, such as rotation and deformation in addition to translation, into the estimate of the patient pose and real-time reoptimization and adaption of delivery to the dynamically changing anatomy of cancer patients.

A nested partitions framework for beam angle optimization in intensity-modulated radiation therapy.

Coupling beam angle optimization with dose optimization in intensity-modulated radiation therapy (IMRT) increases the size and complexity of an already large-scale combinatorial optimization problem. We have developed a novel algorithm, nested partitions (NP), that is capable of finding suitable beam angle sets by guiding the dose optimization process. NP is a metaheuristic that is flexible enough to guide the search of a heuristic or deterministic dose optimization algorithm. The NP method adaptively samples from the entire feasible region, or search space, and coordinates the sampling effort with a systematic partitioning of the feasible region at successive iterations, concentrating the search in promising subsets. We used a 'warm-start' approach by initiating NP with beam angle samples derived from an integer programming (IP) model. In this study, we describe our implementation of the NP framework with a commercial optimization algorithm. We compared the NP framework with equi-spaced beam angle selection, the IP method, greedy heuristic and random sampling heuristic methods. The results of the NP approach were evaluated using two clinical cases (head and neck and whole pelvis) involving the primary tumor and nodal volumes. Our results show that NP produces better quality solutions than the alternative considered methods.

A Treatment Planning Method for Better Management of Radiation-Induced Oral Mucositis in Locally Advanced Head and Neck Cancer.

PURPOSE/AIM: To describe a two-phase intensity-modulated radiation therapy (IMRT) treatment planning approach, that is, promising for reduction of oral mucositis risk in locally advanced head-and-neck cancer. MATERIALS AND METHODS: Ten locally advanced head-and-neck cancer patients who underwent RT were retrospectively collected. Conventional IMRT and volumetric-modulated arc therapy (VMAT) plans were generated for these patients following clinical protocol. Following the first phase of generating conventional IMRT plans, our approach utilized data from Monte Carlo-based kernel superposition dose calculations corresponding to beam apertures (generated from the conventional IMRT plans) and used an exact mathematical programming-based optimization approach applying linear programming (LP) to dose optimization in the second phase. RESULTS: Compared with conventional IMRT and VMAT treatment plans, our novel method achieved better preservation of oral cavity (16%-29% lower mean dose, P < 0.01), parotid glands (6%-17% lower mean dose, P < 0.04), and spinal cord (3-11 Gy lower maximum dose, P < 0.03) and lower doses to nonorgan-at-risk/nontarget normal tissues, with the same or better target coverage. CONCLUSIONS: Our LP-based method can be practically implemented in routine clinical use with a goal of limiting radiation-induced oral mucositis for head-and-neck cancer patients.