Cancer Prevention Research Institute Of Texas Research Articles

Burden of high-risk phenotype of heavy alcohol consumption among obese U.S. population: results from National Health and Nutrition Examination Survey, 1999–2020

The phenotype of combined heavy alcohol consumption and obesity has the potential to pose as a considerable health burden in the U.S. No studies using nationally representative data in the U.S. have reported their secular joint prevalence trends. We estimated the prevalence and examined the joint trends of heavy alcohol use and obesity over time among adult U.S. men and women in different age groups and according to race/ethnicity. Using data from 10 cycles of the U.S. National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020, we examined secular trends in the combined phenotype of heavy drinking and obesity overall and by age-group, sex, and race/ethnicity. The main outcome measures were prevalence of heavy alcohol consumption (>14 drinks/week in men and >7 drinks/week in women) and obesity (BMI ≥30). In 45,292 adults (22,684 men, mean age 49.26 years; and 22,608 women, mean age 49.86), the overall weighted prevalence of combined heavy alcohol drinking and obesity increased from 1.8% (95% CI: 1.2%, 3.1%) in 1999–2000 to 3.1% (95% CI: 2.7%, 3.7%) in 2017–2020 representing an increase of 72% over time. In the joinpoint regression, the combined phenotype of heavy alcohol consumption and obesity increased by 3.25% (95% CI: 1.67%, 4.85%) per year overall from 1999 to 2017. An increasing trend of 9.94% (95% CI: 2.37%, 18.06%) per year was observed among adults aged between 40 and 59 years from 2007 onwards. Prevalence of heavy alcohol consumption in obesity increased at a faster rate among women (APC, 3.96%; 95% CI: 2.14%, 5.82%) than men (APC, 2.47%; 95% CI: 0.63%, 4.35%), and increased among non-Hispanic Whites (APC, 4.12%; 95% CI: 1.50%, 6.82%) and non-Hispanic Blacks (APC, 2.78%; 95% CI: 0.47%, 5.14%), but not Hispanics. The prevalence of combined heavy alcohol consumption and obesity increased overall in the U.S., but the rate of increase differed by age, sex, and race/ethnic groups. Given their independent and potential synergistic effects on premature mortality, public health policies on alcohol consumption need to reflect the background obesity epidemic. Cancer Prevention & Research Institute of Texas (CPRIT) for the Systems Epidemiology of Cancer Training (SECT) Program (RP210037; PI: A. Thrift).

Vista blockade reprograms tumor myeloid cells and relieves adaptive resistance

Abstract treatment. Significantly, VISTA shows broad expression in many cancer types, with enhanced expression upon development of adaptive immune checkpoint resistance. In the CT26 colon cancer model, growth of small tumors (40mm3), are retarded by anti-VISTA monotherapy, and are readily rejected following anti-CTLA4/anti-PD-L1 (CP)therapy. In contrast, very large tumors (>600mm3), are refractory to CP therapy. However, combinatorial therapy of CP with anti-VISTA leads to rejection of about half the tumors. Both in monotherapy and combination therapy the mechanisms of enhanced anti-tumor immunity were investigated using scRNAseq, multiplex image analysis and flow cytometry of the tumor immune infiltrate. In both treatment models, anti-VISTA upregulated stimulated myeloid antigen-presentation pathways and reduced myeloid mediated suppression. Multi-spectral imaging revealed an anti-VISTA stimulated increase in contacts between CD8+ T cells and myeloid cells, further supporting the notion of increased antigen presentation upon anti-VISTA treatment. Transcriptional analysis of antigen-specific CD8 T cells showed that anti-VISTA therapy induced T cell pathways highly distinct from the anti-exhaustion effects of CP. These data suggest the non-redundancy of CP and anti-VISTA treatment, and support the use of these treatments in combination to overcome the adaptive resistance seen in contemporary treatments involving PD-1 and/or CTLA-4. Research was supported by NIH grants R01AR070760 (R.J.N.), R01CA214062 (R.J.N.), and 1R21CA227996 (C.C.) and the Cancer Prevention Research Institute of Texas (CPRIT) (RR180061 to C.C.). C.C. is a CPRIT Scholar in Cancer Research.

Immune infiltration difference between tumor and adjacent normal regions is prognostic for gastric cancer patients.

Immune infiltration difference between tumor and adjacent normal regions is prognostic for gastric cancer patients.

1009 Sleep Apnea and Colorectal Adenoma in the Veteran Population: A Case-Control Study

Abstract Introduction Colorectal cancer is the third most common cancer in the United States, with over half of colorectal cancers estimated to be the result of modifiable risk factors. Studies relating sleep apnea (SA) and colorectal adenoma (CRA) are limited and the findings are equivocal. The objective of this study was to examine the association between SA and risk of CRA. Methods This was a retrospective cross-sectional case-control study of data collected from 460 veterans, ages 50-79, seen in the colonoscopy clinic at the Michael E. DeBakey VA Medical Center between 2014 and 2018. Information on demographics, sleep history, and co-morbidities were obtained through lifestyle questionnaire. Self-reported SA was diagnosed by a prior sleep study. Cases consisted of 297 participants had pathologically confirmed adenoma (including 117 participants having advanced CRA with villous component or diameter of polyp > 1 cm). Controls consisted of 173 polyp-free participants. The distribution of demographics and lifestyle factors were compared between CRA and non-CRA using the Student’s t or chi-square tests. Odds ratios (OR) and 95% confidence intervals (CI) of CRA in association with CRA were calculated using univariate and multivariate unconditional logistic regression models. The confounding factors included age, sex, ethnicity, obesity, smoking status, alcohol use, hypertension, and sleep duration. Results Compared with non-SA, the multivariable OR (95% CI) for CRA was 0.92 (0.58-1.48); for non-advanced CRA was 1.14 (0.68-1.91), and for advanced CRA was 0.61 (0.32-1.17) in SA participants. Adjustment of sleep duration in the model did not change the risk estimates. Conclusion Sleep-study diagnosed SA was not associated with development of CRA in this veteran population. Further studies are needed to confirm this observation and incorporate the severity and treatment of SA, and undiagnosed SA in risk assessment. Support This research is supported in part by the Gillson Longenbaugh Foundation, and Golfers Against Cancer organization (to LJ), the Cancer Prevention Research Institute of Texas (CPRIT) (RP#140767, to LJ).

Phase II Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemo Naive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905, NCT01064648)

Background: Anti-angiogenic agents combined with chemotherapy have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) inhibitor, demonstrated therapeutic potential in a prior phase I trial. A phase II randomized trial of cisplatin-pemetrexed with and without cediranib was evaluated for efficacy. Methods: S0905 phase II randomized cediranib (20 mg daily) or placebo with platinum-pemetrexed for 6 cycles followed by maintenance cediranib/placebo in unresectable chemo-naive MPM patients of any histologic subtype. The primary endpoint was RECIST 1.1 progression-free survival (PFS). Secondary endpoints included overall survival, PFS by modified RECIST 1.1, response rate (RR), disease control rate, safety/toxicity. The trial was designed to detect a difference in RECIST 1.1 PFS at the 1-sided 0.1 level using a stratified log-rank test. Findings: 92 eligible patients were enrolled with 75% epithelioid and 25% biphasic or sarcomatoid histology. The cediranib arm had more grade 3-4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved median PFS by RECIST 1.1 (7.2 vs 5.6 months, HR 0.71, p=0.062) and increased RR by modified RECIST 1.1 (50% vs 20%, p=0.006) and by RECIST 1.1 (26% vs 15%, p=0.15). By modified RECIST 1.1, cediranib numerically increased median PFS (6.9 vs 5.6 months, HR 0.77, p=0.12). The median OS was numerically improved with cediranib (10 vs 8.5 months, HR 0.88, p=0.28). Interpretation: The addition of cediranib to platinum-pemetrexed improved PFS by RECIST 1.1 and RR by modified RECIST in patients with unresectable MPM. While adding anti-angiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes further development in MPM. Strategies to incorporate immunotherapies to prolong beneficial responses and survival may be needed. Funding National Institutes of Health, National Cancer Institute grant numbers CA180888, CA180819, CA180858, CA180801, CA189830, CA189821, CA189872, CA180830 CA180835, CA189858, CA189971, CA189972 and CA180846. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Declaration of Interest: AT reports personal fees and other from AstraZeneca during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, grants and personal fees from Lilly, grants from Millennium/Takeda, grants from Seattle Genetics, grants and personal fees from Ariad, grants and personal fees from Boehringer-Ingelheim, grants from Polaris, grants from Epizyme, grants from Merck, outside the submitted work. JVH reports grants from NIH/NCI, grants from American Cancer Society (ACS), grants from Cancer Prevention & Research Institute of Texas (CPRIT), other from EMD Serono, other from GlaxoSmithKline, other from AstraZeneca, other from Bristol-Myers Squibb, other from Merck, other from Genentech, other from Boehringer-Ingelheim, other from Spectrum, other from Eli Lilly, other from Novartis, during the conduct of the study. SG reports personal fees from Astra-Zeneca, outside the submitted work; Dr. Wistuba reports grants and personal fees from Genentech/Roche, grants and personal fees from AstraZeneca/Medimmune, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants from Amgen, grants from Adaptimmune, grants from Takeda, grants and personal fees from GlaxoSmithKlein, grants from Merck, grants and personal fees from Asuragen, grants from DepArray, grants from Adaptive, Inc, grants from EMD Serono, personal fees from MSD, outside the submitted work; KK reports personal fees from AstraZeneca, outside the submitted work. Ethical Approval: The protocol and informed consent document were approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and the institutional review boards of participating SWOG member sites. Written informed consent was obtained from all patients before enrollment. This study was monitored by the Data and Safety Monitoring Committee of SWOG. An additional patient consent was required for the banking and future use of specimens.

Abstract 5285: Evaluation of a postpartum human papillomavirus vaccination program

Abstract Evaluation of a postpartum human papillomavirus vaccination program Berenson AB, Hirth JM, Kuo YF, Rupp RE Purpose: To evaluate the effectiveness of a large vaccination program which offers the human papillomavirus (HPV) vaccine to women during their postpartum hospitalization. Methods: Based on the success of a pilot which offered the HPV vaccine to a select group of women, a postpartum HPV vaccination program was expanded in 2016 to include all eligible mothers who gave birth in a large Texas hospital serving low income women. Women from 23 different counties were included. With funding from the Cancer Prevention Research Institute of Texas (CPRIT), patient navigators were hired to identify and personally counsel all eligible women who met catch-up recommendation guidelines prior to their hospital discharge. Women were informed about the need and availability of the HPV vaccine during their hospitalization and offered it free of charge. Follow-up doses are coordinated with postpartum visits as well as well-baby visits in collaboration with the Department of Pediatrics. With Institutional Review Board approval, records of women who were approached during the first 11 months of the expanded program were reviewed to determine the number who chose to participate. Results: Baseline HPV vaccination rates were low. A total of 1,782 postpartum women were counseled about the HPV vaccine of which 168 (9.4%) were already vaccinated and 5 others were ineligible. Of the remaining 1,609 women, 71.2% received a dose of the HPV vaccine during their hospitalization. The refusal rate among eligible women was 24%. Another 4.3% (n-76) agreed to get vaccinated, but were released from the hospital before the injection was given. Of these, 48 (63.2%) received the dose at a later clinic visit. Conclusions: Offering the HPV vaccine as part of postpartum care can increase catch-up vaccination of young women who did not have the opportunity to be vaccinated at a younger age. Citation Format: Abbey B. Berenson, Jacqueline M. Hirth, Yong-Fang Kuo, Richard E. Rupp. Evaluation of a postpartum human papillomavirus vaccination program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5285.

A Genomewide Transcriptomic Approach Identifies a Novel Gene Expression Signature for the Detection of Lymph Node Metastasis in Patients with Early Stage Gastric Cancer

BACKGROUND & AIMS: Although identification of lymph node (LN) metastasis is a well-recognized strategy for improving outcomes in patients with gastric cancer (GC), currently there is lack of availability of adequate molecular biomarkers that can identify such metastasis. Herein we have developed a robust gene-expression signature for detecting LN metastasis in early stage GC by using a transcriptomic-wide biomarker discovery and subsequent validation in multiple clinical cohorts. METHODS: A total of 532 patients with pathological T1 and T2 GC from 4 different cohorts were analyzed. Two independent datasets (n=96, and n=188) were used to establish a gene signature for the identification of LN metastasis in GC patients. The diagnostic performance of our gene-expression signature was subsequently assessed in two independent clinical cohorts using qRT-PCR assays (n = 101, and n = 147), and subsequently compared against conventional tumor markers and image-based diagnostics. RESULTS: We established a 15-gene signature by analyzing multiple high throughput datasets, which robustly distinguished LN status in both testing (AUC = 0.765, 95% CI 0.667 - 0.863) and validation cohorts (AUC = 0.742, 95% CI 0.630 - 0.852). Notably, the 15-gene signature was significantly superior compared to the conventional tumor markers, CEA (P = 0.04) and CA19-9 (P = 0.005), as well as computed tomography-based imaging (P = 0.04). CONCLUSIONS: We have established and validated a 15-gene signature for detecting LN metastasis in GC patients, which offers a robust diagnostic tool for potentially improving treatment outcomes in gastric cancer patients. FUNDING STATEMENT: The present work was supported by the grants CA72851, CA181572, CA184792, CA202797 and CA187956 from the National Cancer Institute; a grant (RP140784) from the Cancer Prevention Research Institute of Texas (CPRIT), pilot grants from the Baylor Sammons Cancer Center, as well as funds from the Baylor Scott & White Research Institute awarded to Ajay Goel, and a VPRT grant (9610337) from the City University of Hong Kong, grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. CityU 21101115, 11102317, 11103718), a grant from The Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20170307091256048) awarded to Xin Wang, and was partially supported by the Shenzhen Research Institute, City University of Hong Kong. DECLARATION OF INTERESTS: None of the authors has any potential conflicts to disclose. ETHICS APPROVAL STATEMENT: Written informed consent was obtained from all patients, and the study was approved by the institutional review boards of all the participating institutions.

SU-F-T-350: Continuous Leaf Optimization (CLO) for IMRT Leaf Sequencing

Purpose: To study a new step-and-shoot IMRT leaf sequencing model that avoids the two main pitfalls of conventional leaf sequencing: (1) target fluence being stratified into a fixed number of discrete levels and/or (2) aperture leaf positions being restricted to a discrete set of locations. These assumptions induce error into the sequence or reduce the feasible region of potential plans, respectively. Methods: We develop a one-dimensional (single leaf pair) methodology that does not make assumptions (1) or (2) that can be easily extended to a multi-row model. The proposed continuous leaf optimization (CLO) methodology takes in an existing set of apertures and associated intensities, or solution “seed,” and improves the plan without the restrictiveness of 1or (2). It then uses a first-order descent algorithm to converge onto a locally optimal solution. A seed solution can come from models that assume (1) and (2), thus allowing the CLO model to improve upon existing leaf sequencing methodologies. Results: The CLO model was applied to 208 generated target fluence maps in one dimension. In all cases for all tested sequencing strategies, the CLO model made improvements on the starting seed objective function. The CLO model also was able to keep MUs low. Conclusion: The CLO model can improve upon existing leaf sequencing methods by avoiding the restrictions of (1) and (2). By allowing for more flexible leaf positioning, error can be reduced when matching some target fluence. This study lays the foundation for future models and solution methodologies that can incorporate continuous leaf positions explicitly into the IMRT treatment planning model. Supported by Cancer Prevention & Research Institute of Texas (CPRIT) - ID RP150485

TU‐D‐207B‐02: Delta‐Radiomics: The Prognostic Value of Therapy‐Induced Changes in Radiomics Features for Stage III Non‐Small Cell Lung Cancer Patients

Purpose:To determine how radiomics features change during radiation therapy and whether those changes (delta‐radiomics features) can improve prognostic models built with clinical factors.Methods:62 radiomics features, including histogram, co‐occurrence, run‐length, gray‐tone difference, and shape features, were calculated from pretreatment and weekly intra‐treatment CTs for 107 stage III NSCLC patients (5–9 images per patient). Image preprocessing for each feature was determined using the set of pretreatment images: bit‐depth resample and/or a smoothing filter were tested for their impact on volume‐correlation and significance of each feature in univariate cox regression models to maximize their information content. Next, the optimized features were calculated from the intratreatment images and tested in linear mixed‐effects models to determine which features changed significantly with dose‐fraction. The slopes in these significant features were defined as delta‐radiomics features. To test their prognostic potential multivariate cox regression models were fitted, first using only clinical features and then clinical+delta‐radiomics features for overall‐survival, local‐recurrence, and distant‐metastases. Leave‐one‐out cross validation was used for model‐fitting and patient predictions. Concordance indices(c‐index) and p‐values for the log‐rank test with patients stratified at the median were calculated.Results:Approximately one‐half of the 62 optimized features required no preprocessing, one‐fourth required smoothing, and one‐fourth required smoothing and resampling. From these, 54 changed significantly during treatment. For overall‐survival, the c‐index improved from 0.52 for clinical factors alone to 0.62 for clinical+delta‐radiomics features. For distant‐metastases, the c‐index improved from 0.53 to 0.58, while for local‐recurrence it did not improve. Patient stratification significantly improved (p‐value<0.05) for overallsurvival and distant‐metastases when delta‐radiomics features were included. The delta‐radiomics versions of autocorrelation, kurtosis, and compactness were selected most frequently in leave‐one‐out iterations.Conclusion:Weekly changes in radiomics features can potentially be used to evaluate treatment response and predict patient outcomes. High‐risk patients could be recommended for dose escalation or consolidation chemotherapy.This project was funded in part by grants from the National Cancer Institute (NCI) and the Cancer Prevention Research Institute of Texas (CPRIT).

WE‐AB‐207B‐10: On Spinal Nerve Toxicity from Single‐Session SAbR in Pigs and the Translation of Small Animal NTCP Models

Purpose:The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose‐tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single‐session irradiation to the pig spinal nerves exhibit a similar dose‐tolerance as that of the spinal cord and that a dose‐length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data.Methods:To date, 16 of 25 Yucatan minipigs have received single‐session SAbR to a 1.5cm length and 4 of 25 have received irradiation to a 0.5cm length of left‐sided C6‐C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose‐response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose‐response data and to preliminary peripheral nerve response data was evaluated through residual analysis.Results:No rodent‐derived dose‐response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long‐length irradiated spinal cord data well, with the more serial‐like models fitting best. Preliminary data on the short‐length irradiation suggests no length effect exists, disproving our hypothesis.Conclusion:Direct application of small‐animal NTCP models to pig data suggests dose‐length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low‐to‐mid dose levels in the penumbral region will improve this match.This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).

A New Oridonin Analogue Suppresses Triple‐Negative Breast Cancer Cells and Tumor Growth via Inducing the Expression of Death Receptor 5

Triple‐negative breast cancer (TNBC) remains the leading cause of death among women with breast cancer worldwide. Oridonin is a natural anti‐cancer compound isolated from the traditional Chinese herb Rabdosia rubescens. However, the antitumor efficacy of oridonin for TNBC and other cancers is far away from ideal. In this study, we investigated a series of newly designed oridonin analogues against HCC1806 and HCC1937 TNBC cell lines and identified CYD‐6‐28 that significantly inhibits cancer cell proliferation, induces G2/M phase cell cycle arrests and apoptosis. CYD‐6‐28 induces the expression of p21 and the cleavage of caspase‐8, −3, −7 and PARP, and inhibits the expression of Cyclin D1, FLIP and XIAP. CYD‐6‐28 also inhibits the activation of STAT3 and AKT while inducing the activation of ERK. We demonstrated that CYD‐6‐28 induces apoptosis at least partially through inducing the expression of Death Receptor 5 (DR5). Finally, CYD‐6‐28 significantly suppresses HCC1806 xenograft tumor growth in nude mice at 5 mg/kg without significant toxicity. Taken together, CYD‐6‐28 has the potential to be developed as a promising therapeutic agent to treat TNBC.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (81120108019, U1132605, and 81325016 to Chen, C), and the grants P30 DA028821 and R01 DA038446 from the National Institutes of Health, and Cancer Prevention Research Institute of Texas (CPRIT) award (to Zhou, J).

A Retrospective: On Clinical Studies with 5-Fluorouracil.

See related article by Curreri et al., [Cancer Res 1958:18:478–484][1] . Visit the Cancer Research 75th Anniversary [timeline][2]. The 1950s saw the rise of rational drug design to target DNA synthesis in cancer cells. The concept was simple; cancer was replicating uncontrolled compared with

The systematic design and biophysical evaluation of cationic sulfonamide aminolipids for siRNA delivery

Event Abstract Back to Event The systematic design and biophysical evaluation of cationic sulfonamide aminolipids for siRNA delivery Jason B. Miller1, 2*, Victor Tieu3* and Daniel J. Siegwart1, 2* 1 UT Southwestern Medical Center, Department of Biochemistry, United States 2 UT Southwestern Medical Center, Simmons Comprehensive Cancer Center, United States 3 University of California, Berkeley, Department of Bioengineering, United States Introduction: The use of RNA interference (RNAi) as a therapeutic is an exciting and rapidly developing field that offers a promising alternative to small molecule drugs for the treatment of dysregulatory diseases, including cancer [1],[2]. Small interfering RNA (siRNA) can be designed against any mRNA target, and upon loading into the RNA-induced silencing complex (RISC) can enable the sequence-specific recognition and degradation of the target oncogene. Because siRNA has a high molecular weight (~13 kDa) and is highly hydrophilic and anionic, it is unable to passively diffuse across cell membranes and into the cell [3]. To date, many successful carriers have been designed using amphiphilic lipid-like compounds containing amine-rich cores [4][5], but the challenge of efficient endosomal release remains a major bottleneck in the field of RNAi therapeutics. Cationic sulfonamide amino lipids (CSALs) are a novel class of modular synthetic lipids that possess chemical and structural properties that make them promising candidates for RNAi-based anticancer therapies. Sulfonamide functionalities, though prevalent in many pharmaceutical drugs, have not been explored in lipid carriers for siRNA delivery. Due to a positively-charged quaternary ammonium, CSALs are excellent candidates for enhanced siRNA binding and endosomal membrane interaction and disruption upon cell uptake, which can enable siRNA release. Materials and Methods: CSALs were readily chemically synthesized from commercially available reagents via a zwitterionic aminolipid intermediate bearing a sulfobetaine headgroup. The sidearm functionality was introduced by reaction at the alcohol positions, while the characteristic sulfonamide was introduced by further sequential reaction with thionyl chloride and a primary amine bearing the amino headgroup. A systematic, modular design enabled the evaluation of the effect of structural modifications on the biophysical properties of CSAL nanoparticles in terms of size, surface charge, siRNA encapsulation, and in vitro siRNA delivery efficacy to human cervical cancer cells. Results and Discussion: Systematic SAR of CSALs was established by modifying the linker length between the sulfonamide and the amine headgroup, sterics at tertiary amine headgroup and quaternary ammonium, the number of hydrophobic tails, and a sidearm alcohol functionality on the periphery of the amine core in terms of both sterics and electronics (Figure 1). CSALs showed the ability to form stable nanoparticles (Dh ~100 nm) in the presence of helper lipids DSPC, cholesterol, and PEG-lipid. Lead materials, showed excellent uptake into cells as evaluated by confocal microscopy, efficient siRNA encapsulation (97%) and in vitro target gene silencing in human cervical cancer cells with up to 90% knockdown and minimal material-derived cytotoxicity (Figure 2). Conclusion: Systematic rational design of a library of CSALs, a novel class of synthetic lipids, has elucidated SAR in properties governing effective siRNA delivery. This led to the discovery of lead CSAL materials that enable efficacious siRNA delivery to cancer cells. Cancer Prevention Research Institute of Texas (CPRIT) Training Grant RP140110; UT Southwestern Summer Undergraduate Research Fellowship Program

SU-E-J-108: Solving the Chinese Postman Problem for Effective Contour Deformation

Purpose: To develop a practical approach for accurate contour deformation when deformable image registration (DIR) is used for atlas-based segmentation or contour propagation in image-guided radiotherapy. Methods: A contour deformation approach was developed on the basis of 3D mesh operations. The 2D contours represented by a series of points in each slice were first converted to a 3D triangular mesh, which was deformed by the deformation vectors resulting from DIR. A set of parallel 2D planes then cut through the deformed 3D mesh, generating unordered points and line segments, which should be reorganized into a set of 2D contour points. It was realized that the reorganization problem was equivalent to solving the Chinese Postman Problem (CPP) by traversing a graph built from the unordered points with the least cost. Alternatively, deformation could be applied to a binary mask converted from the original contours. The deformed binary mask was then converted back into contours at the CT slice locations. We performed a qualitative comparison to validate the mesh-based approach against the image-based approach. Results: The DIR could considerably change the 3D mesh, making complicated 2D contour representations after deformation. CPP was able to effectively reorganize the points in 2D planes no matter how complicated the 2D contours were. The mesh-based approach did not require a post-processing of the contour, thus accurately showing the actual deformation in DIR. The mesh-based approach could keep some fine details and resulted in smoother contours than the image-based approach did, especially for the lung structure. Image-based approach appeared to over-process contours and suffered from image resolution limits. The mesh-based approach was integrated into in-house DIR software for use in routine clinic and research. Conclusion: We developed a practical approach for accurate contour deformation. The efficiency of this approach was demonstrated in both clinic and research applications. This work was partially supported by Cancer Prevention & Research Institute of Texas (CPRIT) RP110562.

SU-D-BRA-07: A Phantom Study to Assess the Variability in Radiomics Features Extracted From Cone-Beam CT Images

Purpose: Several studies have demonstrated the prognostic potential for texture features extracted from CT images of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to determine if these features could be extracted with high reproducibility from cone-beam CT (CBCT) images in order for features to be easily tracked throughout a patient’s treatment. Methods: Two materials in a radiomics phantom, designed to approximate NSCLC tumor texture, were used to assess the reproducibility of 26 features. This phantom was imaged on 9 CBCT scanners, including Elekta and Varian machines. Thoracic and head imaging protocols were acquired on each machine. CBCT images from 27 NSCLC patients imaged using the thoracic protocol on Varian machines were obtained for comparison. The variance for each texture measured from these patients was compared to the variance in phantom values for different manufacturer/protocol subsets. Levene’s test was used to identify features which had a significantly smaller variance in the phantom scans versus the patient data. Results: Approximately half of the features (13/26 for material1 and 15/26 for material2) had a significantly smaller variance (p<0.05) between Varian thoracic scans of the phantom compared to patient scans. Many of these same features remained significant for themore » head scans on Varian (12/26 and 8/26). However, when thoracic scans from Elekta and Varian were combined, only a few features were still significant (4/26 and 5/26). Three features (skewness, coarsely filtered mean and standard deviation) were significant in almost all manufacturer/protocol subsets. Conclusion: Texture features extracted from CBCT images of a radiomics phantom are reproducible and show significantly less variation than the same features measured from patient images when images from the same manufacturer or with similar parameters are used. Reproducibility between CBCT scanners may be high enough to allow the extraction of meaningful texture values for patients. This project was funded in part by the Cancer Prevention Research Institute of Texas (CPRIT). Xenia Fave is a recipient of the American Association of Physicists in Medicine Graduate Fellowship.« less

SU‐F‐BRF‐06: Density Correction for Deformable Image Registration to Improve CT Number Mapping

Purpose:To improve the accuracy of CT number mapping inside the lung using deformable image registration for cases having substantially large lung volume differences.Methods:The deep‐inspiration‐breath‐hold (DIBH) CT image and the end‐of‐exhalation (EE) phase image in 4DCT of three thoracic cancer patients were enrolled in this study. The lung volumes were manually delineated and the lung volume ratio of DIBH‐CT over EECT is 1.7, 1.8, and 2.0 respectively, demonstrating large volume differences. A demons‐based deformable registration was first applied to register the EECT to the DIBH‐CT for each patient, and the resulting deformation field deformed the EE‐CT image to the DIBH‐CT space. Based on the assumption that the mass of lung remains the same during respiration, we created a mass preserving model to correlate the lung density variations with the lung volumetric changes, which were characterized by the Jacobian derived from the deformation field. The Jacobian is used to correct the lung CT number transferred from the EE‐CT image. The deformed images with and without the density correction were compared using absolute intensity difference created by subtracting the deformed image from the DIBH‐CT image.Results:The deformable registration could register the lung shape very well, but the CT numbers inside the lung could not be registered correctly. Without density correction, the mean and standard deviation of the absolute CT number difference inside the lung were 59±48, 69±49, and 71±42 for the three cases. After density correction, these numbers changed to 18±35, 20±35, and 14±29, respectively, demonstrating an improvement in the accuracy of CT number mapping. The accumulative histogram of the intensity difference also showed that density correction improved CT number mapping.Conclusion:Density correction improved the CT number mapping inside the lung using deformable image registration for difficult cases having large lung volume differences.This work is partially supported by the CPRIT (Cancer Prevention Research Institute of Texas) grant RP110732.

SU‐E‐J‐169: Process for QA of Normal Tissue Delineation and Reported Doses in Clinical Trials

Purpose:To create and evaluate a process of using auto‐segmentation for quality assurance of doses reported to normal structures in clinical trials.Methods:Multiple atlases for normal tissue segmentation were created for the esophagus, trachea/large bronchus, and brachial plexus. These atlases were used to independently delineate 21 patients who were enrolled in a phase III study of accelerated hypofractionated IGRT for patients with stage II‐III NSCLC. The results of the multi‐atlas segmentation were visually evaluated for acceptability. The dose volume limits and the maximum point doses specified by the protocol were compared for the originally delineated and auto‐segmented contours. It was noted whether these differences affected whether plans met or failed the protocol constraints.Results:On visual inspection, the auto‐segmented contour was acceptable with the exception of 8 cases (38%) of the esophagus. In these cases, the anatomy of the esophagus was notably different from that of atlases so that the autosegmentation failed. On the other hand, the process using auto‐segmentation identified two cases where not all contours of the structure had been delineated in the original plan (one trachea/large bronchus case and one brachial plexus case). The average difference in maximum dose to the esophagus, trachea, and brachial plexus were 0.2±4.4Gy (range: – 13.6:4.7Gy), 0.2±1.1Gy (−3.9:0.8Gy), and 3.6±10.7Gy (−1.2:34.1Gy), respectively. In one esophagus case and one trachea case, the plan became unacceptable when calculated using the auto‐segmented contour, but in both cases the dosimetric difference was very small.Conclusion:Two cases (10%) of contouring with insufficient coverage (trachea/large bronchus and brachial plexus) in the original plan were identified using the proposed process. However, patient‐to‐patient variations in the position of the esophagus meant that our current auto‐segmentation is inadequate to evaluate this organ, and more work is needed to optimize the process.Work funded by Cancer Prevention Research Institute of Texas (CPRIT)

MO‐C‐17A‐09: Deformation Image Registration Using a Spatial‐Context Regularization Filter

Purpose:Intensity‐based deformable registration with spatial‐invariant regularization will generally fail when distinct motion exists across the interface of different type of tissues. The purpose of this work was to develop a new regularization scheme for deformable registration that is adaptive to motion discontinuities along different types of tissue.Methods:Our approach was built upon a multi‐resolution Demons‐type framework, and used the prior knowledge defined in the image context as an additional constraint to regularize deformation vector fields, which leads to a spatialcontext vector smoothing filter. This filter is spatial‐variant and anisotropic, and can be reduced to the product of a Gaussian function of spatial locations and an additional Gaussian function of image intensity difference. This additional regularization favors the motion vectors within the same tissue type, but penalized the motions vectors from different tissues. Five lung patient cases from a benchmark data set, each with 300 landmark pairs delineated by a physician, were adopted for the validation of our algorithm. Our approach was also compared against a state‐of‐the‐art implementation of dual‐force Demons algorithm. We also included one difficult lung case with large sliding motion and one head‐neck cases with large motion in air cavity into our validatioResults:For five lung cases, the mean and standard deviation of the landmark displacements were 1.3±0.8(mm) using our approach, but this number went up to 2.3±2.9(mm) using Demons algorithm. Particularly for a case with largest initial displacement of 15± 9(mm), our approach reduced the mean displacement to 1.3±1.1(mm), but Demons can only achieve 3.6±5.9(mm). We also found that, for the two difficult cases in which the original intensity‐based registration failed the registration accuracy was drastically improved using the proposed algorithm.Conclusion:We have demonstrated the effectiveness of an algorithm using adaptive regularization in addressing large distinct motion across different types of tissue.This work is partially supported by the CPRIT (Cancer Prevention Research Institute of Texas) grant RP110732