Showing papers by "Bo Lu published in 2015"

Targeting brain metastases in ALK-rearranged non-small-cell lung cancer

Abstract: The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

Evaluation of Elekta 4D cone beam CT-based automatic image registration for radiation treatment of lung cancer

Abstract: Objective:The study was aimed to evaluate the precision of Elekta four-dimensional (4D) cone beam CT (CBCT)-based automatic dual-image registrations using different landmarks for clipbox for radiation treatment of lung cancer.Methods:30 4D CBCT scans from 15 patients were studied. 4D CBCT images were registered with reference CT images using dual-image registration: a clipbox registration and a mask registration. The image registrations performed in clinic using a physician-defined clipbox, were reviewed by physicians, and were taken as the standard. Studies were conducted to evaluate the automatic dual registrations using three kinds of landmarks for clipbox: spine, spine plus internal target volume (ITV) and lung (including as much of the lung as possible). Translational table shifts calculated from the automatic registrations were compared with those of the standard.Results:The mean of the table shift differences in the lateral direction were 0.03, 0.03 and 0.03 cm, for clipboxes based on spine, spine ...

Impact of scanning parameters and breathing patterns on image quality and accuracy of tumor motion reconstruction in 4D CBCT: a phantom study

Abstract: Four-dimensional, cone-beam CT (4D CBCT) substantially reduces respiration-induced motion blurring artifacts in three-dimension (3D) CBCT. However, the image quality of 4D CBCT is significantly degraded which may affect its accuracy in localizing a mobile tumor for high-precision, image-guided radiation therapy (IGRT). The purpose of this study was to investigate the impact of scanning parameters hereinafter collectively referred to as scanning sequence) and breathing patterns on the image quality and the accuracy of computed tumor trajectory for a commercial 4D CBCT system, in preparation for its clinical implementation. We simulated a series of periodic and aperiodic sinusoidal breathing patterns with a respiratory motion phantom. The aperiodic pattern was created by varying the period or amplitude of individual sinusoidal breathing cycles. 4D CBCT scans of the phantom were acquired with a manufacturer-supplied scanning sequence (4D-S-slow) and two in-house modified scanning sequences (4D-M-slow and 4D-M-fast). While 4D-S-slow used small field of view (FOV), partial rotation (200°), and no imaging filter, 4D-M-slow and 4D-M-fast used medium FOV, full rotation, and the F1 filter. The scanning speed was doubled in 4D-M-fast (100°/min gantry rotation). The image quality of the 4D CBCT scans was evaluated using contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and motion blurring ratio (MBR). The trajectory of the moving target was reconstructed by registering each phase of the 4D CBCT with a reference CT. The root-mean-squared-error (RMSE) analysis was used to quantify its accuracy. Significant decrease in CNR and SNR from 3D CBCT to 4D CBCT was observed. The 4D-S-slow and 4D-M-fast scans had comparable image quality, while the 4D-M-slow scans had better performance due to doubled projections. Both CNR and SNR decreased slightly as the breathing period increased, while no dependence on the amplitude was observed. The difference of both CNR and SNR between periodic and aperiodic breathing patterns was insignificant (p > 0.48). At end-exhale phases, the motion blurring was negligible for both periodic and aperiodic breathing patterns; at mid-inhale phase, the motion blurring increased as the period, the amplitude or the amount of cycle-to-cycle variation on amplitude increased. Overall, the accuracy of localizing the moving target in 4D CBCT was within 2 mm under all studied cases. No difference in the RMSEs was noticed among the three scanning sequences. The 4D-M-fast scans, free of volume truncation artifacts, exhibited comparable image quality and accuracy in tumor motion reconstruction as the 4D-S-slow scans with reduced imaging dose (0.60 cGy vs. 0.99 cGy) due to the use of faster gantry rotation and the F1 filter, suggesting its suitability for clinical use.

nab-Paclitaxel in Combination With Weekly Carboplatin With Concurrent Radiotherapy in Stage III Non-Small Cell Lung Cancer

Abstract: Lessons learned The concomitant use of weekly nab-paclitaxel and carboplatin with concurrent radiotherapy was demonstrated to be a safe therapeutic approach in this phase I trial of 10 evaluable patients with stage III NSCLC.Despite the lack of systemic glucocorticoids, there were no reported infusion reactions or cases of peripheral neuropathy in this trial, both of which are known to occur with the use of paclitaxel. Background Unresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC. Methods Escalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy. Results Eleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m(2)), 2 DLTs were observed: esophagitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m(2)) with no DLTs. Nine of 10 evaluable patients had a partial response. Conclusion Concurrent chemoradiotherapy with nab-paclitaxel 40 mg/m(2) and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way.

TNF Receptors Predict Hip Fracture Risk in the WHI Study and Fatty Acid Intake Does Not Modify This Association

Abstract: Context: Chronic inflammation may increase the risk of fracture, and omega-3 polyunsaturated fatty acids (PUFAs) may reduce fracture risk via down-regulation of inflammatory cytokine gene expression and other mechanisms. Objective: We investigated associations between baseline samples of inflammatory markers, TNFα soluble receptors 1 and 2 (TNFα-sR1 and -sR2), and incident hip fracture. These associations were then tested for effect modification by dietary PUFA intake estimated by a baseline food frequency questionnaire. Design and Setting: A nested case-control study was conducted among participants of the Women's Health Initiative Observational Study (ages, 50–79 y). Multivariable conditional logistic regression models were constructed to account for the paired design. Participants: This study sampled 400 pairs of hip fracture cases and controls without incident hip fracture, matched on age, year of enrollment, and menopausal hormone use. Main Outcome Measures: Odds ratio of hip fracture by quartile of ...

Comparative study of ED mortality risk of US trauma patients treated at level I and level II vs nontrauma centers

Abstract: Background Prior studies of undertriage have not made comparisons across multiple trauma levels. Methods Emergency department data was extracted from the Nationwide Emergency Department Sample for major trauma patients. We considered patients with moderate injuries (Injury Severity Score, ISS=16-24) and severe injuries (ISS=25-75) separately. Conditional logistic regression modeling was used to compare the odds of ED mortality for level I trauma centers (TC I) vs. nontrauma centers (NTC) and level II trauma centers (TC II) vs. NTC. An innovative 1:1:1 optimal matching (an extension of the traditional pair matching) was used to balance patient characteristics in three groups. To facilitate matching of all NTC patients, 3 subgroups were developed for ISS=16-24 and 2 subgroups for ISS=25-75. Sensitivity analyses were performed to assess the strength of the association between trauma center designation and ED mortality. Results For ISS=16-24, 2 of 3 subgroups had marginally significant reduced odds of ED mortality when properly triaged (TC I vs. NTC [T1:OR=0.63; 95%CI: 0.45 - 0.89, T2:OR=0.71;95%CI:0.51-0.99]). For ISS=25-75, both subgroups had significantly reduced odds of emergency department mortality when properly triaged (H1: TC I vs. NTC [OR=0.61; 95%CI: 0.50-0.74]; TC II vs. NTC [OR=0.49; 95%CI: 0.38 - 0.63]; H2: TC I vs. NTC [OR=0.50; 95%CI: 0.41 - 0.60]; TC II vs. NTC [OR=0.42; 95%CI: 0.33 - 0.53]). Conclusions for ISS 25-75 were robust to a hypothesized unobserved confounding variable as shown in sensitivity analysis. Conclusions Trauma patients with ISS≥25 received most benefit from proper triage. Efforts to reduce undertriage should focus on this population.

Effects of Climate and Rodent Factors on Hemorrhagic Fever with Renal Syndrome in Chongqing, China, 1997–2008

Abstract: China has the highest global incidence of hemorrhagic fever with renal syndrome (HFRS), constituting 90% of the cases in the world. Chongqing, located in the Three Gorges Reservoir Region, has been experiencing differences in the occurrence of HFRS from 1997 to 2008. The current study was designed to explore the effects of climate and rodent factors on the transmission of HFRS in Chongqing. Data on monthly HFRS cases, rodent strains, and climatic factors were collected from 1997 to 2008. Spatio-temporal analysis indicated that most HFRS cases were clustered in central Chongqing and that the incidence of HFRS decreased from 1997 to 2008. Poisson regression models showed that temperature (with lagged months of 0 and 5) and rainfall (with 2 lagged months) were key climatic factors contributing to the transmission of HFRS. A zero-inflated negative binomial model revealed that rodent density was also significantly associated with the occurrence of HFRS in the Changshou district. The monthly trend in HFRS incidence was positively associated with rodent density and rainfall and negatively associated with temperature. Possible mechanisms are proposed through which construction of the dam influenced the incidence of HFRS in Chongqing. The findings of this study may contribute to the development of early warning systems for the control and prevention of HFRS in the Three Gorges Reservoir Region.

Image-domain shading correction for cone-beam CT without prior patient information

Abstract: In the era of high-precision radiotherapy, cone-beam CT (CBCT) is frequently utilized for on-board treatment guidance. However, CBCT images usually contain severe shading artifacts due to strong photon scatter from illumination of a large volume and non-optimized patient-specific data measurements, limiting the full clinical applications of CBCT. Many algorithms have been proposed to alleviate this problem by data correction on projections. Sophisticated methods have also been designed when prior patient information is available. Nevertheless, a standard, efficient, and effective approach with large applicability remains elusive for current clinical practice. In this work, we develop a novel algorithm for shading correction directly on CBCT images. Distinct from other image-domain correction methods, our approach does not rely on prior patient information or prior assumption of patient data. In CBCT, projection errors (mostly from scatter and non-ideal usage of bowtie filter) result in dominant low-frequency shading artifacts in image domain. In circular scan geometry, these artifacts often show global or local radial patterns. Hence, the raw CBCT images are first preprocessed into the polar coordinate system. Median filtering and polynomial fitting are applied on the transformed image to estimate the low-frequency shading artifacts (referred to as the bias field) angle-by-angle and slice-by-slice. The low-pass filtering process is done firstly along the angular direction and then the radial direction to preserve image contrast. The estimated bias field is then converted back to the Cartesian coordinate system, followed by 3D low-pass filtering to eliminate possible high-frequency components. The shading-corrected image is finally obtained as the uncorrected volume divided by the bias field. The proposed algorithm was evaluated on CBCT images of a pelvis patient and a head patient. Mean CT number values and spatial non-uniformity on the reconstructed images were used as image quality metrics. Within selected regions of interest, the average CT number error was reduced from around 300 HU to 42 and 38 HU, and the spatial nonuniformity error was reduced from above 17.5% to 2.1% and 1.7% for the pelvis and the head patients, respectively. As our method suppresses only low-frequency shading artifacts, patient anatomy and contrast were retained in the corrected images for both cases. Our shading correction algorithm on CBCT images offers several advantages. It has a high efficiency, since it is deterministic and directly operates on the reconstructed images. It requires no prior information or assumptions, which not only achieves the merits of CBCT-based treatment monitoring by retaining the patient anatomy, but also facilitates its clinical use as an efficient image-correction solution.

Reproducibility of thoracic and abdominal aortic wall measurements with three-dimensional, variable flip angle (SPACE) MRI.

Abstract: Purpose To evaluate the reproducibility and repeatability of high-resolution, isotropic thoracic and abdominal aortic wall measurements, and determine the implications they have on the number of subjects necessary for future clinical trials. Materials and Methods Using a T1-weighted three-dimensional MRI SPACE sequence, we evaluated the interobserver, intraobserver, and scan–rescan variability of isotropic thoracic and abdominal aortic wall measurements in 15 cardiovascular diseased patients and 6 normal volunteers. Main outcome analyses were intracorrelation coefficient (ICC), mean relative error (mRE), and sample size calculation at 80% power to be used to compare placebo group and treatment group means in future two-arm randomized clinical trials. Results Excellent reliability, ICC > 0.8 (P < 0.001) and small mRE < 10% were demonstrated for the interobserver, intraobserver, and scan–rescan variability for all investigated measures: lumen area (LA), outer wall area (OWA), wall area (VWA), total wall volume (TWV), and percentage wall volume (%WV). Sample size calculation revealed slightly different sample size per treatment arm for thoracic and abdominal aorta segments (maximum number of subjects: 352 subjects for thoracic segment versus 421 subjects for abdominal segment for LA at 5% difference, and minimum of 3 thoracic versus 4 abdominal subjects needed for %WV evaluation at 25% difference). Conclusion Our study demonstrates the reproducibility and repeatability of SPACE aortic plaque measurements, and gives insight into the number of subjects needed for the design of therapeutic studies in aortic atherosclerosis. J. Magn. Reson. Imaging 2015;41:202–212. © 2013 Wiley Periodicals, Inc.

Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests

Abstract: Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long-term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non-small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n = 773) and testing (n = 388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low-, medium- and high-risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p < 0.0001). Compared with low-risk group, patients in the medium- and high-risk groups had a significantly higher risk of death at 1 year, with hazard ratio (HR) of 1.95 (95% CI 1.62-2.36) and 5.22 (4.30-6.34), respectively. These results were validated in the testing cohort. Overall, we developed a prognostic model relying entirely on readily available variables, with similar predictive power to those which depend on more specialized and expensive molecular assays. Further study is necessary to validate and further refine this model, and compare its performance to models based on more specialized and expensive testing.

Common-mask guided image reconstruction (c-MGIR) for enhanced 4D cone-beam computed tomography.

Abstract: Compared to 3D cone beam computed tomography (3D CBCT), the image quality of commercially available four-dimensional (4D) CBCT is severely impaired due to the insufficient amount of projection data available for each phase. Since the traditional Feldkamp-Davis-Kress (FDK)-based algorithm is infeasible for reconstructing high quality 4D CBCT images with limited projections, investigators had developed several compress-sensing (CS) based algorithms to improve image quality. The aim of this study is to develop a novel algorithm which can provide better image quality than the FDK and other CS based algorithms with limited projections. We named this algorithm 'the common mask guided image reconstruction' (c-MGIR).In c-MGIR, the unknown CBCT volume is mathematically modeled as a combination of phase-specific motion vectors and phase-independent static vectors. The common-mask matrix, which is the key concept behind the c-MGIR algorithm, separates the common static part across all phase images from the possible moving part in each phase image. The moving part and the static part of the volumes were then alternatively updated by solving two sub-minimization problems iteratively. As the novel mathematical transformation allows the static volume and moving volumes to be updated (during each iteration) with global projections and 'well' solved static volume respectively, the algorithm was able to reduce the noise and under-sampling artifact (an issue faced by other algorithms) to the maximum extent. To evaluate the performance of our proposed c-MGIR, we utilized imaging data from both numerical phantoms and a lung cancer patient. The qualities of the images reconstructed with c-MGIR were compared with (1) standard FDK algorithm, (2) conventional total variation (CTV) based algorithm, (3) prior image constrained compressed sensing (PICCS) algorithm, and (4) motion-map constrained image reconstruction (MCIR) algorithm, respectively. To improve the efficiency of the algorithm, the code was implemented with a graphic processing unit for parallel processing purposes.Root mean square error (RMSE) between the ground truth and reconstructed volumes of the numerical phantom were in the descending order of FDK, CTV, PICCS, MCIR, and c-MGIR for all phases. Specifically, the means and the standard deviations of the RMSE of FDK, CTV, PICCS, MCIR and c-MGIR for all phases were 42.64 ± 6.5%, 3.63 ± 0.83%, 1.31% ± 0.09%, 0.86% ± 0.11% and 0.52 % ± 0.02%, respectively. The image quality of the patient case also indicated the superiority of c-MGIR compared to other algorithms.The results indicated that clinically viable 4D CBCT images can be reconstructed while requiring no more projection data than a typical clinical 3D CBCT scan. This makes c-MGIR a potential online reconstruction algorithm for 4D CBCT, which can provide much better image quality than other available algorithms, while requiring less dose and potentially less scanning time.

Priori mask guided image reconstruction (p-MGIR) for ultra-low dose cone-beam computed tomography.

Abstract: Recently, the compressed sensing (CS) based iterative reconstruction method has received attention because of its ability to reconstruct cone beam computed tomography (CBCT) images with good quality using sparsely sampled or noisy projections, thus enabling dose reduction. However, some challenges remain. In particular, there is always a tradeoff between image resolution and noise/streak artifact reduction based on the amount of regularization weighting that is applied uniformly across the CBCT volume. The purpose of this study is to develop a novel low-dose CBCT reconstruction algorithm framework called priori mask guided image reconstruction (p-MGIR) that allows reconstruction of high-quality low-dose CBCT images while preserving the image resolution. In p-MGIR, the unknown CBCT volume was mathematically modeled as a combination of two regions: (1) where anatomical structures are complex, and (2) where intensities are relatively uniform. The priori mask, which is the key concept of the p-MGIR algorithm, was defined as the matrix that distinguishes between the two separate CBCT regions where the resolution needs to be preserved and where streak or noise needs to be suppressed. We then alternately updated each part of image by solving two sub-minimization problems iteratively, where one minimization was focused on preserving the edge information of the first part while the other concentrated on the removal of noise/artifacts from the latter part. To evaluate the performance of the p-MGIR algorithm, a numerical head-and-neck phantom, a Catphan 600 physical phantom, and a clinical head-and-neck cancer case were used for analysis. The results were compared with the standard Feldkamp-Davis-Kress as well as conventional CS-based algorithms. Examination of the p-MGIR algorithm showed that high-quality low-dose CBCT images can be reconstructed without compromising the image resolution. For both phantom and the patient cases, the p-MGIR is able to achieve a clinically-reasonable image with 60 projections. Therefore, a clinically-viable, high-resolution head-and-neck CBCT image can be obtained while cutting the dose by 83%. Moreover, the image quality obtained using p-MGIR is better than the quality obtained using other algorithms. In this work, we propose a novel low-dose CBCT reconstruction algorithm called p-MGIR. It can be potentially used as a CBCT reconstruction algorithm with low dose scan requests.

Characteristics of nonfatal occupational injuries among U.S. workers with and without disabilities.

Abstract: BACKGROUND: Workers with disabilities have a higher risk of nonfatal occupational injuries than workers without disabilities. The characteristics of these injuries are not well described. METHODS: Using 1997-2011 National Health Interview Survey (NHIS) data, we compared the nonfatal occupational injuries sustained by U.S. workers with and without disabilities. RESULTS: Overexertion or strenuous movements and falls accounted for 56.7% of all occupational injuries in workers with disabilities, compared with 45.6% in workers without a disability. Workers with disabilities were more frequently injured in the lower extremity (32.3% vs. 26.6%) or torso (22.9% vs. 16.9%). Workers with disabilities sustained more unspecified injuries (13.5% vs. 7.9%) and fewer open wound injuries (15.7% vs. 24.2%) than their counterparts without a disability. CONCLUSIONS: U.S. workers with disabilities had a higher rate of occupational injuries and these injuries tended to be more severe and were more likely to be caused by overexertion/ strenuous movement or falls. Am. J. Ind. Med. 58:168-177, 2015. © 2015 Wiley Periodicals, Inc. Language: en

Adaptive beamlet-based finite-size pencil beam dose calculation for independent verification of IMRT and VMAT

Abstract: Purpose: The use of sophisticated dose calculation procedure in modern radiation therapy treatment planning is inevitable in order to account for complex treatment fields created by multileaf collimators (MLCs). As a consequence, independent volumetric dose verification is time consuming, which affects the efficiency of clinical workflow. In this study, the authors present an efficient adaptive beamlet-based finite-size pencil beam (AB-FSPB) dose calculation algorithm that minimizes the computational procedure while preserving the accuracy. Methods: The computational time of finite-size pencil beam (FSPB) algorithm is proportional to the number of infinitesimal and identical beamlets that constitute an arbitrary field shape. In AB-FSPB, dose distribution from each beamlet is mathematically modeled such that the sizes of beamlets to represent an arbitrary field shape no longer need to be infinitesimal nor identical. As a result, it is possible to represent an arbitrary field shape with combinations of different sized and minimal number of beamlets. In addition, the authors included the model parameters to consider MLC for its rounded edge and transmission. Results: Root mean square error (RMSE) between treatment planning system and conventional FSPB on a 10 × 10 cm2 square field using 10 × 10, 2.5 × 2.5, and 0.5 × 0.5 cm2 beamlet sizes were 4.90%, 3.19%, and 2.87%, respectively, compared with RMSE of 1.10%, 1.11%, and 1.14% for AB-FSPB. This finding holds true for a larger square field size of 25 × 25 cm2, where RMSE for 25 × 25, 2.5 × 2.5, and 0.5 × 0.5 cm2 beamlet sizes were 5.41%, 4.76%, and 3.54% in FSPB, respectively, compared with RMSE of 0.86%, 0.83%, and 0.88% for AB-FSPB. It was found that AB-FSPB could successfully account for the MLC transmissions without major discrepancy. The algorithm was also graphical processing unit (GPU) compatible to maximize its computational speed. For an intensity modulated radiation therapy (∼12 segments) and a volumetric modulated arc therapy fields (∼90 control points) with a 3D grid size of 2.0 × 2.0 × 2.0 mm3, dose was computed within 3–5 and 10–15 s timeframe, respectively. Conclusions: The authors have developed an efficient adaptive beamlet-based pencil beam dose calculation algorithm. The fast computation nature along with GPU compatibility has shown better performance than conventional FSPB. This enables the implementation of AB-FSPB in the clinical environment for independent volumetric dose verification.

[Prognostic value of combined expression of Aurora A, p53 and p21 WAF1 in patients after curative resection of non-small cell lung cancer].

Abstract: Objective The aim of this study was to investigate the prognostic value of combined expression of Aurora A, Ki-67, p53 and p21 WAF1 in patients after curative resection of non-small cell lung cancer(NSCLC). Methods Expressions of Aurora A, Ki-67, p53 and p21 WAF1 in 58 tumor samples from resected primary NSCLCs were detected by immunohistochemistry. The correlation of proteins, survival and clinicopathological characteristics was analyzed. Results The positive rates of Aurora A, Ki-67, p53 and p21 WAF1 expression were 89.7% (52/58), 53.4% (31/58), 46.6% (27/58) and 34.5% (20/58), respectively. Aurora A expression was positively correlated with nodal metastasis(69.2% vs. 37.8% , P=0.045). The univariable analysis showed that the overall survival (OS) was 75.0%in patients with low Aurora A expression and 46.0% in patients with high Aurora A expression (P=0.039). The 3-year survival rate was 40.0% in patients with positive expression of Aurora A and p53, 65.0% in the patients with positive expression of Aurora A or p53, and 82.1% in the patients with negative expression of Aurora A and p53 (P=0.039). The Cox regression model showed that combined expression of Aurora and p53 is an independent factor affecting the prognosis of NSCLC patients (P=0.015). Conclusions Our findings suggest that the positive expression of Aurora A, Ki-67 and p53 proteins is an unfavorable factor affecting the prognosis for NSCLC patients, and the overexpression of Aurora A is an independent unfavorable factor association with shorter OS in NSCLC patients. Detection of positive Aurora A and p53 expression may be a useful predictive prognostic indicator for NSCLC patients. Key words: Carcinoma, non-small-cell lung; Prognosis; Immunohistochemistry; Aurora kinase A; Ki-67 antigen; p53; Cyclin-dependent kinase inhibitor p21 WAF1

Pre-exposure to fine particulate matters may induce endotoxin tolerance in a mouse model.

Abstract: Exposure to low or moderate doses of lipopolysaccharides (LPS) renders the host tolerance to a subsequent lethal dose of LPS, which is termed as endotoxin tolerance. It is characterized as the decrease in production of pro-inflammatory cytokines and the increase in production of anti-inflammatory mediators in response to a second LPS challenge. The alteration of cytokine profile protects LPS-primed hosts against a normally lethal dose of subsequent LPS challenge. Nevertheless, whether other environmental factors also trigger endotoxin tolerance remains unclear. Both epidemiologic and experimental studies have provided a link between particulate matter and human health. Here, we speculated on the effect of fine particles priming on endotoxin tolerance in a mouse model.

Abstract A93: The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity

Abstract: Introduction: Radiotherapy (RT) kills cancer cells, increases tumor antigenicity, and stimulates the immune response which can be further augmented by systemic immune-modulating agents. Debio 1143 is an oral antagonist of the inhibitors of apoptosis proteins (IAPs) currently in clinical development, which sensitizes tumor cells to RT- or chemotherapy-induced apoptosis, and modulates NFκ-B signalling. We hypothesized that, in addition to its activity on apoptosis, Debio 1143 could improve antitumor immunity by increasing the effects of RT and anti-PD1 treatment. Experimental procedures: Using immunocompetent mouse models of lung cancer (Lewis lung cancer) and melanoma (B16F10), the anti-tumor activity of RT and anti-PD-1 was tested either alone or in combination with Debio 1143. The effects of the treatment on the immunological components were determined by FACS. Results: Combining radiotherapy and Debio 1143 in vivo potently prevented tumor growth and increased the local accumulation of cytotoxic T cells. Activation of cytotoxic T cells proved to be mediated through the release of tumor necrosis factor alpha in the tumor microenvironment. In addition, Debio 1143 was able to potently stimulate the ability of an anti-PD1 antibody to kill tumor cells in vivo. Conclusions: These data offer a new paradigm to improve the tumor immune response elicited by RT and immune checkpoint inhibitors and serve as the foundation for future clinical translation of combination therapy between Debio 1143, radiotherapy and immune-oncology agents. Citation Format: Darryll BARKHOUSE, Zhen TAO, Carey MYERS, Norbert WIEDEMANN, Bruno GAVILLET, Larry HARSHYNE, Adam DICKER, D.Craig HOOPER, Gregoire VUAGNIAUX, Bo Lu. The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A93.

Immune biomarkers of treatment failure for a patient with renal cell carcinoma on a Phase I trial of pembrolizumab plus radiotherapy

Abstract: Meeting abstracts Pembrolizumab is an antibody designed against programmed cell-death protein-1 (PD-1), which is expressed on the surface of activated T cells. Tumor cells can upregulate PD-L1, which binds to PD-1 and mediates T cell anergy. By antagonizing the PD-1/PD-L1 binding, pembrolizumab can

SU-E-T-597: Parameterization of the Photon Beam Dosimetry for a Commercial Linear Accelerator

Abstract: Purpose: In radiation therapy, accurate data acquisition of photon beam dosimetric quantities is important for (1) beam modeling data input into a treatment planning system (TPS), (2) comparing measured and TPS modelled data, (3) a linear accelerator’s (linac) beam characteristics quality assurance process, and (4) establishing a standard data set for data comparison, etcetera. Parameterization of the photon beam dosimetry creates a portable data set that is easy to implement for different applications such as those previously mentioned. The aim of this study is to develop methods to parameterize photon percentage depth doses(PDD), profiles, and total scatter output factors(Scp). Methods: Scp, PDDs and profiles for different field sizes (from 2×2 to 40×40cm{sup 2}), depths and energies were measured in a linac using a three-dimensional water tank. All data were smoothed and profile data were also centered, symmetrized and geometrically scaled. The Scp and PDD data were analyzed using exponential functions. For modelling of open and wedge field profiles, each side was divided into three regions described by exponential, sigmoid and Gaussian equations. The model’s equations were chosen based on the physical principles described by these dosimetric quantities. The equations’ parameters were determined using a least square optimization method with themore » minimal amount of measured data necessary. The model’s accuracy was then evaluated via the calculation of absolute differences and distance–to–agreement analysis in low gradient and high gradient regions, respectively. Results: All differences in the PDDs’ buildup and the profiles’ penumbra regions were less than 2 mm and 0.5 mm, respectively. Differences in the low gradient regions were 0.20 ± 0.20% and 0.50 ± 0.35% for PDDs and profiles, respectively. For Scp data, all differences were less than 0.5%. Conclusion: This novel analytical model with minimum measurement requirements proved to accurately calculate PDDs, profiles, and Scp for different field sizes, depths and energies.« less

SU-E-T-584: Optical Tracking Guided Patient-Specific VMAT QA with ArcCHECK

Abstract: Purpose: To investigate the novel use of an in-house optical tracking system (OTS) to improve the efficacy of VMAT QA with a cylindrical dosimeter (ArcCHECK™). Methods: The translational and rotational setup errors of ArcCHECK are convoluted which makes it challenging to position the device efficiently and accurately. We first aligned the ArcCHECK to the machine cross-hair at three cardinal angles (0°, 90°, and 270°) to establish a reference position. Four infrared reflective markers were attached to the back of the device. An OTS with 0.2mm/0.2° accuracy was used to control its setup uncertainty. Translational uncertainties of 1 mm and 2 mm in three directions (in, right, and up) were applied on the device. Four open beams of various field sizes and six clinical VMAT arcs were delivered and measured for all simulated setup errors. The measurements were compared with Pinnacle™ calculations using Gamma analysis to evaluate the impact of setup uncertainty. This study also evaluated the improvement in setup reproducibility and efficiency with the aid of the OTS. Results: For open beams, with 3%/3mm, the mean passing rates dropped by less than 5% for all shifts; with 2%/2mm, two significant drops(>5%) were observed: 15.38±6.75% for 2 mm lateral shift and 9.35±4.88% for 2 mm longitudinal shift. For VMAT arcs, the mean passing rates using 2%/2mm dropped by 10.47±7.46% and 22.02±11.39% for 1 and 2 mm shift, respectively. With 3%/3mm, significant drop only occurred with 2 mm longitudinal shift (13.73±8.30%). Setup time could be reduced by >15 min with the aid of the OTS. Conclusion: OTS is an effective tool for separating translational and rotational uncertainties. The current VMAT QA solution was not strongly sensitive to translation errors of 2mm with widely accepted criterion (3%/3mm). This finding raises concerns regarding the efficacy of such QA system in detecting errors in the dynamic VMAT delivery.

WE‐G‐207‐03: Mask Guided Image Reconstruction (MGIR): A Novel Method for Ultra‐Low‐Dose 3D and Enhanced 4D Cone‐Beam Computer‐Tomography

Abstract: Purpose: Recently, compressed sensing (CS) based iterative reconstruction (IR) method is receiving attentions to reconstruct high quality cone beam computed tomography (CBCT) images using sparsely sampled or noisy projections. The aim of this study is to develop a novel baseline algorithm called Mask Guided Image Reconstruction (MGIR), which can provide superior image quality for both low-dose 3DCBCT and 4DCBCT under single mathematical framework. Methods: In MGIR, the unknown CBCT volume was mathematically modeled as a combination of two regions where anatomical structures are 1) within the priori-defined mask and 2) outside the mask. Then we update each part of images alternatively thorough solving minimization problems based on CS type IR. For low-dose 3DCBCT, the former region is defined as the anatomically complex region where it is focused to preserve edge information while latter region is defined as contrast uniform, and hence aggressively updated to remove noise/artifact. In 4DCBCT, the regions are separated as the common static part and moving part. Then, static volume and moving volumes were updated with global and phase sorted projection respectively, to optimize the image quality of both moving and static part simultaneously. Results: Examination of MGIR algorithm showed that high quality of both low-dose 3DCBCT and 4DCBCT images can be reconstructed without compromising the image resolution and imaging dose or scanning time respectively. For low-dose 3DCBCT, a clinical viable and high resolution head-and-neck image can be obtained while cutting the dose by 83%. In 4DCBCT, excellent quality 4DCBCT images could be reconstructed while requiring no more projection data and imaging dose than a typical clinical 3DCBCT scan. Conclusion: The results shown that the image quality of MGIR was superior compared to other published CS based IR algorithms for both 4DCBCT and low-dose 3DCBCT. This makes our MGIR algorithm potentially useful in various on-line clinical applications. Provisional Patent: UF#15476; WGS Ref. No. U1198.70067US00

A novel method for 4D Cone-Beam Computer-Tomography Reconstruction

Abstract: Image quality of Four Dimensional Cone-Beam Computer-Tomography (4DCBCT) is severely impaired by highly insufficient amount of projection data available for each phase. Therefore, making good use of limited projection data is crucial to solve this problem. Noticing that usually only a portion of the images is affected by motion, we separate the moving part (different between phases) of the images from the static part (identical among all phases) with the help of prior image reconstructed using all projection data. Then we update the moving part and the static part of images alternatively through solving minimization problems based on a global (use full projection data) and several local (use projection data for respective phase) linear systems. In the other word, we rebuild a large over-determined linear system for static part from the original under-determined systems and we reduce the number of unknowns in the original system for each phase as well. As a result, image quality for both static part and moving part are greatly improved and reliable 4D CBCT images are then reconstructed.