Citations

Striking cardiovascular health disparities exist among African-Americans in Minnesota compared to Whites; however, community-based interventions to address cardiovascular disease risk are lacking. This study explored participant perceptions of a culturally tailored, cardiovascular disease prevention program developed using a community-based participatory research process. Research participation perceptions, program benefits, and program satisfaction/acceptability were analyzed using a mixed-methods approach. Overall, acceptability was high. Findings highlight the favorable inclusion of African-Americans (research perception), knowledge gained about healthy lifestyle practices (benefits), and quality of the curriculum/speakers (satisfaction). Community-based participatory research may be useful in fostering the acceptability of behavior change interventions among marginalized African-American communities.

Objective: To summarize the epidemiology and outcomes of children with multiple organ dysfunction syndrome as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26–27, 2015). Data Sources: Literature review, research data, and expert opinion. Study Selection: Not applicable. Data Extraction: Moderated by an experienced expert from the field, issues relevant to the epidemiology and outcomes of children with multiple organ dysfunction syndrome were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis: Summary of presentations and discussion supported and supplemented by the relevant literature. Conclusions: A full understanding the epidemiology and outcome of multiple organ dysfunction syndrome in children is limited by inconsistent definitions and populations studied. Nonetheless, pediatric multiple organ dysfunction syndrome is common among PICU patients, occurring in up to 57% depending on the population studied; sepsis remains its leading cause. Pediatric multiple organ dysfunction syndrome leads to considerable short-term morbidity and mortality. Long-term outcomes of multiple organ dysfunction syndrome in children have not been well studied; however, studies of adults and children with other critical illnesses suggest that the risk of long-term adverse sequelae is high. Characterization of the long-term outcomes of pediatric multiple organ dysfunction syndrome is crucial to identify opportunities for improved treatment and recovery strategies that will improve the quality of life of critically ill children and their families. The workshop identified important knowledge gaps and research priorities intended to promote the development of standard definitions and the identification of modifiable factors related to its occurrence and outcome.

Abstract The extracellular matrix (ECM) is increasingly recognized as having a key role in cancer development. Advances in biomaterials design and preparation have led to highly defined sophisticated platforms that can recapitulate key features of the complex tumor microenvironment. We have developed a biomaterial tumor mimic that recapitulates systematically the main characteristics and heterogeneities of glioblastoma ECM. With the use of these 3D in vitro platforms we seek to understand the key features that make this cancer so challenging to treat. We are using this device in three different ways: (1) to further understand how particularities of brain tumor ECM affect cancer cells and assist in the diagnostic of different GBM tumor types, (2) provide new models for drug screening to afford more personalized therapies and (3) study the mechanisms of resistance to current therapies in order to identify more effective combinatorial treatments and new therapeutic targets. Glioblastoma (GBM) tumors are highly heterogeneous, both cell composition and ECM biophysical properties are key factors in cancer cell malignancy and treatment outcomes. Hyaluronic acid (HA), is the main component of the brain extracellular matrix and GBM is associated with aberrant HA secretion and overexpression of receptors associated with HA, such as CD44 and EGFR. We use a microfluidic system to culture GBM patient-derived cells within gelatin based hydrogels that contained gradually increasing concentrations of HA, in order to recreate the heterogeneity of the tumor mass. Cell proliferation and gene expression analyses demonstrate that biomimetic hydrogels support xenograft culture; cells remain viable, active, and upregulate matrix remodeling genes and others related to tumor growth. More importantly, we found that GBM cells respond to changes in the ECM composition presenting different gene expression profiles (VEGF, IL6, MMP2, MMP9, HAS3, CD44) depending on the particularities of every tumor, such as EGFR overexpression or PTEN suppression. These findings pave the way for new clinical tools that allow a more precise cataloging of GBM tumor types and tailoring treatments to individual patients. We have also used these platforms to evaluate potential therapeutic strategies for different GBM xenograft cells and to study the mechanisms of cell resistance. For this purpose, we first focused on the epidermal growth factor receptor (EGFR), which has been identified as a molecular target and associated with worse clinical outcomes. Amplification, overexpression and mutation of the EGFR tyrosine kinase has been identified in 50% of GBM patients. The genetic aberration of EGFR (EGFR+) often comes with the overexpression of the mutant EGFR variant III (EGFRvIII). We characterized the 3D in vitro behavior of 3 patient-derived xenografts that represent these EGFR variants: GBM10 (EGFR, wild type), GBM12 (EGFR+) and GBM6 (EGFRvIII). We studied the relationship between the HA contained in the surrounding matrix and response of GBM cells to a tyrosine kinase inhibitor (TKI), erlotinib. We demonstrate that an interaction exists between CD44 and EGF receptors. Results indicate that while EGFR+ cells are sensitive to TKI in HA hydrogels, HA seems to collaborate with EGFRvIII signaling to stir cell activity. Our results indicate that a combination of both bound and cell secreted soluble HA may influence GBM sensitivity and resistance to erlotinib. Moreover, immunoblots that analyze PI3K pathway support the hypothesis that matrix-bound HA is a key factor in the negative response of vIII tumors to EGFR inhibitors, and that the benefits of EGFR inhibition in GBMs may be found in combination to other inhibitors of ECM signaling. In summary, we demonstrate that engineered tumor avatar biomaterials can be used to reproduce some of the main characteristics of brain tumor microenvironment and become a valuable tool in the mechanistic studies of tumor development and treatment efficacy. Citation Format: Sara Pedron, Amanda M. Pritchard, Jann N. Sarkaria, Mark A. Schroeder, Brendan A. Harley. Engineered biomaterials as essential tools to determine the mechanisms of resistance to tyrosine kinase inhibitors in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B05.

Abstract Clinical data indicate that certain regions within glioblastoma (GBM) have a relatively intact blood-brain barrier (BBB), but controversy surrounds whether associated heterogeneous delivery may limit efficacy for otherwise highly active drugs with poor brain distribution. In this study, the efficacy of molecularly targeted therapies was compared in relevant GBM patient-derived xenograft (PDX) models grown either as heterotopic or orthotopic tumors. The impact of further disrupting BBB integrity in non-responsive orthotopic tumors was evaluated by over-expressing vascular endothelial growth factor (VEGF) and measuring drug distribution by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The brain:plasma ratio for five targeted agents was determined by LC-MSMS and treatment efficacy was evaluated in target-relevant GBM PDX lines: erlotinib (brain:plasma = 0.02 ± 0.02; efficacy tested in GBM6), palbociclib (brain:plasma = 0.06; efficacy tested in GBM22), AZD1775 (brain:plasma = 0.05; efficacy tested in GBM22), SAR405838 (brain:plasma = 0.01 ± 0.003; efficacy tested in GBM108), and AZD4547 (brain:plasma = 0.045 ± 0.02; efficacy tested in GBM150). Each of these drugs was effective in relevant GBM PDX flank tumor models with a 27% to 218% prolongation in the median time to exceed their pre-specified endpoint compared to placebo treatment (p≤0.02 for each drug). In contrast, none of these drugs were effective in prolonging survival in the same target-relevant orthotopic tumor models (-6% to 8% extension in median survival; p>0.05 for each drug). Consistent with partial and heterogeneous disruption of the BBB, MALDI-MSI of erlotinib, AZD1775 or SAR405838 distribution within orthotopic tumors demonstrated highly heterogeneous drug levels with large regions within each tumor approaching the low drug levels observed within surrounding normal brain. To further evaluate whether heterogenous drug distribution in orthotopic tumors could account for poor treatment efficacy, GBM108 was transduced with lentiviral constructs encoding for VEGF or empty vector (EV). While both GBM108-sublines were readily detectable with gadolinium-enhanced magnetic resonance imaging (MRI), the GBM108-VEGF tumors had a significantly more disrupted BBB, as evidenced by a more uniform and intense distribution of a brain-impenetrant TexasRed-dextran vascular marker. Similarly, the distribution of SAR405838, measured by MALDI-MSI, was markedly higher and more uniform in the GBM108-VEGF tumors when compared to the GBM108-EV tumors. Enhanced delivery of SAR405838 into orthotopic GBM108-VEGF models translated into a marked enhancement in treatment efficacy in comparison to GBM108-EV with a median survival prolongation of 37 vs. 4 days, respectively (p=0.0055). Collectively, these data highlight the importance of testing novel therapeutic agents in orthotopic tumor models and suggest that limited brain penetration for many molecules may significantly limit their efficacy in brain tumors that have a partially intact BBB. In the face of continued failure to develop effective targeted agents for GBM, these in vivo results highlight the importance of re-evaluating the dogma in neuro-oncology that the BBB is fully disrupted in GBM and, therefore, drug delivery across the BBB is not a major factor limiting treatment efficacy. Citation Format: Jann N. Sarkaria, David Calligaris, Daniel Ma, Karen Parrish, Ann C. Mladek, Janice Laramy, Minjee Kim, Shuangling Zhang, Mark Schroeder, Brett L. Carlson, Katrina Bakken, Aaron Johnson, Nathalie Agar, William Elmquist. The critical importance of the blood-brain barrier in modulating the response to otherwise highly effective targeted therapies in patient-derived orthotopic glioblastoma xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B25.

Abstract Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal translocation event in a patient presenting with aggressive, endocrine therapy resistant estrogen receptor (ER) positive disease, producing an in-frame fusion gene consisting of N-terminal ESR1 and the C-terminus of the Hippo pathway coactivator YAP1 (ESR1-YAP1). We recently identified another ESR1 fusion through RNA sequencing (RNA-seq) in advanced stage ER+ disease from a chest wall recurrence in a male patient that was refractory to multiple lines of treatment. Two examples of fusions discovered in primary breast cancer samples include ESR1 fused in-frame to C-terminal sequences from NOP2 (ESR1-NOP2), identified in a resistant cohort from a RNA-seq screen focused on 81 primary breast cancers from aromatase inhibitor clinical trials, and a second ESR1 fusion, fused in-frame to the entire coding sequence of POLH (ESR1-POLH), that was identified from RNA-seq analysis of 728 Cancer Genome Atlas breast samples. This current study extends our previous characterization of ESR1-YAP1 by comparing functional and pharmacological properties of these three additional ESR1 gene fusion events of both early stage and advanced breast cancers. Methods. In vitro and in vivo experiments were conducted to test ESR1 fusions to induce therapeutic resistance, and metastasis. The transcriptional and binding properties of each fusion was also examined. Pharmacological inhibition with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was utilized to assess drug sensitivity in ESR1 fusion containing breast cancer cells and in a patient derived xenograft (PDX) model expressing ESR1-YAP1 (WHIM18). Results. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth. Immunohistochemistry revealed significantly higher numbers of ER+ cells in lungs of mice xenografted with T47D cells expressing the YAP1 and PCDH11x fusions compared to YFP control, NOP2 and POLH fusions. Results from ChIP-seq and microarray studies suggest that these two fusions promote proliferation and metastasis through genomic action by binding estrogen response elements (ERE) and subsequent gene activation. We thereby define these fusions as “canonical” fusions compared to “non-canonical” NOP2 and POLH fusions, which demonstrated dramatically decreased genomic binding ability. The non-canonical fusions induced genes associated with basal-like breast cancer and promoted HER2, EGFR, and MAPK gene expression signatures in contrast to genes associated with cell cycle/proliferation induced by canonical fusions. The proliferative ability of canonical fusion-containing ER+ cells was inhibited by Palbociclib in a dose-dependent manner. In vivo WHIM18 tumors in mice fed with Palbociclib-containing chow demonstrated significantly reduced tumor volume, growth rate, and weight compared to tumors in mice on control chow. Conclusions. In-frame ERE activating canonical fusions occur in end-stage drug resistant advanced breast cancer and can be added to ESR1 point mutations as a class of recurrent somatic mutation that may cause acquired resistance. Growth induced by these fusions can be antagonized by Palbociclib and is potentially clinically helpful. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Cao J, Chan DW, He X, Kosaka Y, Schmidt C, Matsunuma R, Haricharan S, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Chen X, Perou CM, Creighton CJ, Maher C, Ellis MJ. Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-03.

On‐board magnetic resonance (MR) image guidance during radiation therapy offers the potential for more accurate treatment delivery. To utilize the real‐time image information, a crucial prerequisite is the ability to successfully segment and track regions of interest (ROI). The purpose of this work is to evaluate the performance of different segmentation algorithms using motion images (4 frames per second) acquired using a MR image‐guided radiotherapy (MR‐IGRT) system. Manual contours of the kidney, bladder, duodenum, and a liver tumor by an experienced radiation oncologist were used as the ground truth for performance evaluation. Besides the manual segmentation, images were automatically segmented using thresholding, fuzzy k‐means (FKM), k‐harmonic means (KHM), and reaction‐diffusion level set evolution (RD‐LSE) algorithms, as well as the tissue tracking algorithm provided by the ViewRay treatment planning and delivery system (VR‐TPDS). The performance of the five algorithms was evaluated quantitatively by comparing with the manual segmentation using the Dice coefficient and target registration error (TRE) measured as the distance between the centroid of the manual ROI and the centroid of the automatically segmented ROI. All methods were able to successfully segment the bladder and the kidney, but only FKM, KHM, and VR‐TPDS were able to segment the liver tumor and the duodenum. The performance of the thresholding, FKM, KHM, and RD‐LSE algorithms degraded as the local image contrast decreased, whereas the performance of the VP‐TPDS method was nearly independent of local image contrast due to the reference registration algorithm. For segmenting high‐contrast images (i.e., kidney), the thresholding method provided the best speed ( ) with a satisfying accuracy ( ). When the image contrast was low, the VR‐TPDS method had the best automatic contour. Results suggest an image quality determination procedure before segmentation and a combination of different methods for optimal segmentation with the on‐board MR‐IGRT system. PACS number(s): 87.57.nm, 87.57.N‐, 87.61.Tg

LBA1000 Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR=1.1; p=0.27) and 80.1 % (HR=0.97; p=0.71) in TAC group. 5-year OS was 90.8% in DD AC→PG group as compared with 89.1% (HR=.89; p=0.25) in DD AC→P group and 89.6 % (HR=0.90; p=0.32) in TAC group. HR for DFS and OS of DD AC→P vs. TAC were 0.89 (p=0.14) and 1.01 (p=0.92) respectively. Toxicities for TAC, DD AC→P, DD AC→PG, respectively: febrile neutropenia (Gr 3/4: 9%, 4%, 4% [p<0.001]), sensory neuropathy (Gr 3/4: <1%, 7%, 6% [p<0.001]), diarrhea (Gr 3/4: 8 %, 2%, 2% [p<0.001]). Hgb was <10 in 12%, 26%, 33% with ESA use in 35.2%, 47%, 51.6% and transfusions in 3.7%, 6.3%, 9.4%. Deaths on treatment: N=13, 5, 7 (p=0.2). AML/MDS: N=5, 8, 11. All cycles completed in 91% for TAC and 88% for DD regimens. Conclusions: Addition of G to DD AC→P did not improve outcomes. No significant differences in efficacy endpoints were identified between DD AC→P and TAC, though toxicity profiles differed. Funding: NCI PHS U10-CA-37377, -69974, -12027, -69651 and NCCTG U10-CA25224, with additional funding from Eli Lilly & Company, and Amgen, Inc.

CRA1002 Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) naïve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P. Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease. Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P. Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.

134 Background: Brain metastasis (BM) is an uncommon site of failure in patients (pts) with esophageal cancer (EC) with reported rates between 1-6%. EC pts are living longer with the wider adoption of trimodality therapy and, as with other malignancies, this may change the patterns of failure. We evaluated the incidence and outcomes of BM in EC at Mayo Clinic in Arizona. Methods: A retrospective review identified pts who developed BM from cancer of the esophagus or gastroesophageal junction. A total of 321 patients treated for stage I-IV EC (adenocarcinoma, n = 273; squamous, n = 46; small cell, n = 2) were identified between 1997 and 2012. Fisher’s exact test was used for comparisons. Actuarial survival was calculated using Kaplan-Meier analysis. Results: BM developed in 13 pts (4%), all of whom had adenocarcinoma. Nine pts initially presented with T3 and/or node-positive disease. Four pts presented with metastatic disease to other sites, but only 1 of this group was diagnosed with BM at initial presentation. The median time from initial diagnosis to BM detection was 12 months (range 0-40). All pts were symptomatic at diagnosis. BM was solitary in 6 pts, multiple in 6 pts, and unknown in 1 pt. The posterior fossa was involved in 9 pts. The brain represented the first site of failure in 9 pts. Treatment included surgical resection (n = 5), stereotactic radiosurgery (n = 4), and whole brain radiotherapy (n = 9). Median overall survival was 24 months from initial diagnosis and 5 months from BM detection. Among pts with adenocarcinoma, 3/119 (2.5%) were diagnosed between 1997-2006 compared to 10/154 (6.5%) between 2007-2012 (P = 0.1). Conclusions: The brain remains an uncommon site of failure among pts with EC. A recent series reported an incidence of BM in 13% of pts, raising the possibility of a changing failure pattern. In our series, BM was detected in only 4% of pts. Our study is suggestive of a trend towards increased incidence of BM in more recent years, although it did not reach statistical significance and could be a consequence of the retrospective nature of the study. Both series found BM limited only to pts with adenocarcinoma, and a possible association has been reported between HER-2 overexpression and BM in EC. Therefore, BM in EC may be an interesting area for future study.