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.

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.

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.

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.

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.

A Supervised Learning Tool for Prostate Cancer Foci Detection and Aggressiveness Identification using Multiparametric magnetic resonance imaging/magnetic resonance spectroscopy imaging.

Prostate cancer is the most frequently diagnosed cancer in men in the United States. The current main methods for diagnosing prostate cancer include prostate-specific antigen test and transrectal biopsy. Prostate-specific antigen screening has been criticized for overdiagnosis and unnecessary treatment, and transrectal biopsy is an invasive procedure with low sensitivity for diagnosis. We provided a quantitative tool using supervised learning with multiparametric imaging to be able to accurately detect cancer foci and its aggressiveness. A total of 223 specimens from patients who received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging prior to the surgery were studied. Multiparametric imaging included extracting T2-map, apparent diffusion coefficient (ADC) using diffusion-weighted MRI, Ktrans using dynamic contrast-enhanced MRI, and 3-dimensional-MR spectroscopy. A pathologist reviewed all 223 specimens and marked cancerous regions on each and graded them with Gleason scores, which served as the ground truth to validate our prediction model. In cancer aggressiveness prediction, the average area under the receiver operating characteristic curve (AUC) value was 0.73 with 95% confidence interval (0.72-0.74) and the average sensitivity and specificity were 0.72 (0.71-0.73) and 0.73 (0.71-0.75), respectively. For the cancer detection model, the average AUC value was 0.68 (0.66-0.70) and the average sensitivity and specificity were 0.73 (0.70-0.77) and 0.62 (0.60-0.68), respectively. Our method included capability to handle class imbalance using adaptive boosting with random undersampling. In addition, our method was noninvasive and allowed for nonsubjective disease characterization, which provided physician information to make personalized treatment decision.

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.

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.

GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3.

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and ß-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43-/- mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and ß-defensins in intestinal epithelial enteroids generated from WT but not GPR43-/- mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and ß-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

Novel protein therapeutic joint retention strategy based on collagen-binding Avimers.

Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross-linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra-articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein-protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen-binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen-binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra-articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL-1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL-1 receptor. In vitro, IL-1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra-articular IL-1-induced IL-6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL-1Ra_M26 and native IL-1Ra inhibited IL-6 output when co-administered with the IL-1 challenge, only IL-1Ra_M26 inhibited when administered 1 week prior to IL-1 challenge. Collagen-binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238-1247, 2018.

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.

Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses.

Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production. Unexpectedly, and in contrast to the current belief, specific GPR43 agonists failed to exhibit similar barrier enhancing and anti-inflammatory properties. These findings demonstrate that SCFA possess broad protective functions in IBD and agonizing GPR43 alone is unlikely to be beneficial in patients.

Adaptive region-growing with maximum curvature strategy for tumor segmentation in 18F-FDG PET.

Accurate tumor segmentation in PET is crucial in many oncology applications. We developed an adaptive region-growing (ARG) algorithm with a maximum curvature strategy (ARG_MC) for tumor segmentation in PET. The ARG_MC repeatedly applied a confidence connected region-growing algorithm with increasing relaxing factor f. The optimal relaxing factor (ORF) was then determined at the transition point on the f-volume curve, where the volume just grew from the tumor into the surrounding normal tissues. The ARG_MC along with five widely used algorithms were tested on a phantom with 6 spheres at different signal to background ratios and on two clinic datasets including 20 patients with esophageal cancer and 11 patients with non-Hodgkin lymphoma (NHL). The ARG_MC did not require any phantom calibration or any a priori knowledge of the tumor or PET scanner. The identified ORF varied with tumor types (mean ORF = 9.61, 3.78 and 2.55 respectively for the phantom, esophageal cancer, and NHL datasets), and varied from one tumor to another. For the phantom, the ARG_MC ranked the second in segmentation accuracy with an average Dice similarity index (DSI) of 0.86, only slightly worse than Daisne's adaptive thresholding method (DSI = 0.87), which required phantom calibration. For both the esophageal cancer dataset and the NHL dataset, the ARG_MC had the highest accuracy with an average DSI of 0.87 and 0.84, respectively. The ARG_MC was robust to parameter settings and region of interest selection, and it did not depend on scanners, imaging protocols, or tumor types. Furthermore, the ARG_MC made no assumption about the tumor size or tumor uptake distribution, making it suitable for segmenting tumors with heterogeneous FDG uptake. In conclusion, the ARG_MC was accurate, robust and easy to use, it provides a highly potential tool for PET tumor segmentation in clinic.

Randomized Phase II Study of Preoperative Chemoradiotherapy ± Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non-Small Cell Lung Cancer: NRG Oncology RTOG 0839.

INTRODUCTION: Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. METHODS: Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed. RESULTS: The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1-86.1) and 50.0% (95% confidence interval: 33.4-66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). CONCLUSION: The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.

Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinoma.

PURPOSE: To develop an individually optimized contrast-enhanced (CE) 4D-computed tomography (CT) for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). METHODS: Ten PDA patients were enrolled. Each underwent three CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. Image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) were compared in the three CTs. Interobserver variations were also evaluated in contouring the tumor using simultaneous truth and performance level estimation. RESULTS: Average image quality scores for CE 3D-CT and CE 4D-CT were comparable (4.0 and 3.8, respectively; P = 0.082), and both were significantly better than that for 4D-CT (2.6, P < 0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 Hounsfield units (HU), respectively; P = 0.21), and the latter was significantly higher than in 4D-CT (9.2 HU, P = 0.001). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P = 0.013) and 4D-CT (19.4 HU, P = 0.009). CNRs were comparable in CE 3D-CT and CE 4D-CT (1.4 and 0.8, respectively; P = 0.42), and both were significantly better in 4D-CT (0.6, P = 0.008 and 0.014). Mean tumor volumes were significantly smaller in CE 3D-CT (29.8 cm3, P = 0.03) and CE 4D-CT (22.8 cm3, P = 0.01) than in 4D-CT (42.0 cm3). Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P = 0.17). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. CONCLUSIONS: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan.

Should regional ventilation function be considered during radiation treatment planning to prevent radiation-induced complications?

PURPOSE: To investigate the incorporation of pretherapy regional ventilation function in predicting radiation fibrosis (RF) in stage III nonsmall cell lung cancer (NSCLC) patients treated with concurrent thoracic chemoradiotherapy. METHODS: Thirty-seven patients with stage III NSCLC were retrospectively studied. Patients received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrently with involved-field thoracic radiotherapy (46-66 Gy; 2 Gy/fraction). Pretherapy regional ventilation images of the lung were derived from 4D computed tomography via a density change-based algorithm with mass correction. In addition to the conventional dose-volume metrics (V20, V30, V40, and mean lung dose), dose-function metrics (fV20, fV30, fV40, and functional mean lung dose) were generated by combining regional ventilation and radiation dose. A new class of metrics was derived and referred to as dose-subvolume metrics (sV20, sV30, sV40, and subvolume mean lung dose); these were defined as the conventional dose-volume metrics computed on the functional lung. Area under the receiver operating characteristic curve (AUC) values and logistic regression analyses were used to evaluate these metrics in predicting hallmark characteristics of RF (lung consolidation, volume loss, and airway dilation). RESULTS: AUC values for the dose-volume metrics in predicting lung consolidation, volume loss, and airway dilation were 0.65-0.69, 0.57-0.70, and 0.69-0.76, respectively. The respective ranges for dose-function metrics were 0.63-0.66, 0.61-0.71, and 0.72-0.80 and for dose-subvolume metrics were 0.50-0.65, 0.65-0.75, and 0.73-0.85. Using an AUC value = 0.70 as cutoff value suggested that at least one of each type of metrics (dose-volume, dose-function, dose-subvolume) was predictive for volume loss and airway dilation, whereas lung consolidation cannot be accurately predicted by any of the metrics. Logistic regression analyses showed that dose-function and dose-subvolume metrics were significant (P values ≤ 0.02) in predicting volume airway dilation. Likelihood ratio test showed that when combining dose-function and/or dose-subvolume metrics with dose-volume metrics, the achieved improvements of prediction accuracy on volume loss and airway dilation were significant (P values ≤ 0.04). CONCLUSIONS: The authors' results demonstrated that the inclusion of regional ventilation function improved accuracy in predicting RF. In particular, dose-subvolume metrics provided a promising method for preventing radiation-induced pulmonary complications.

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.

Automated compromised right lung segmentation method using a robust atlas-based active volume model with sparse shape composition prior in CT.

To resolve challenges in image segmentation in oncologic patients with severely compromised lung, we propose an automated right lung segmentation framework that uses a robust, atlas-based active volume model with a sparse shape composition prior. The robust atlas is achieved by combining the atlas with the output of sparse shape composition. Thoracic computed tomography images (n=38) from patients with lung tumors were collected. The right lung in each scan was manually segmented to build a reference training dataset against which the performance of the automated segmentation method was assessed. The quantitative results of this proposed segmentation method with sparse shape composition achieved mean Dice similarity coefficient (DSC) of (0.72, 0.81) with 95% CI, mean accuracy (ACC) of (0.97, 0.98) with 95% CI, and mean relative error (RE) of (0.46, 0.74) with 95% CI. Both qualitative and quantitative comparisons suggest that this proposed method can achieve better segmentation accuracy with less variance than other atlas-based segmentation methods in the compromised lung segmentation.

Response assessment in locally advanced head and neck cancer based on RECIST and volume measurements using cone beam CT images.

The purpose of this work was to find potential trends in RECIST measurements and volume regressions obtained from weekly cone-beam computed tomography images and to evaluate their relationship to clinical outcomes in locally advanced head and neck cancer. We examined thirty head and neck cancer patients who underwent a pre-treatment planning CT and weekly cone-beam computed tomography (CBCT) during the 5-7 week treatment period. The gross tumor volume (GTV) and lymph nodes were manually contoured on the treatment planning CT. The regions of interest enclosed by delineated contours were converted to binary masks and warped to weekly CBCT images using the 3D deformation field obtained by deformable image registration. The RECIST diameters and volumes were measured from these warped masks. Different predictor variables based on these measurements were calculated and correlated with clinical outcomes, based on a clinical exam and a PET imaging study. We found that there was substantial regression of the gross tumor volume over the treatment course (average gross tumor volume regression of 25%). Among the gross tumor volume predicators, it was found that the early regression of gross tumor volume showed a marginal statistical significance (p = 0.045) with complete response and non-complete response treatment outcomes. RECIST diameter measurements during treatment varied very little and did not correlate with clinical outcomes. We concluded that regression of the gross tumor volume obtained from weekly CBCT images is a promising predictor of clinical outcomes for head and neck patients. A larger sample is needed to confirm its statistical significance.