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National and international guidelines recommend the use of 1 dose of intravesical chemotherapy immediately following surgery for nonmuscle invasive bladder cancer, which is performed infrequently on a population level. We sought to understand the importance of potential environmental and clinical dimensions involved in the decision to offer this therapy.Urologists from the Michigan Urological Surgery Improvement Collaborative (MUSIC) rated 8 distinct clinical vignettes involving patients with nonmuscle invasive bladder cancer. A ratings-based conjoint analysis method was used to evaluate the clinical vignette responses. Each vignette included 4 clinical dimensions and 2 environmental dimensions, with each dimension consisting of 2 possible attributes. The relative importance of each attribute was derived from the regression model and ranked in order.A total of 58 urologists answered the clinical vignettes which represents75% of MUSIC sites. The median age of urologists was 53, most were male, and median years in practice was 20 years post residency. An environmental attribute, having a recovery room protocol for instilling and disposing of the chemotherapy, ranked as the most influential attribute for giving postoperative chemotherapy (utility=8.6). The clinical attribute yielding the strongest preference for giving chemotherapy was tumor grade (utility=4.9). These preferences varied by different subgroups of urologists, particularly regarding the type of practice a urologist was in.This study demonstrates that urologists have clear preferences for when they offer postoperative immediate chemotherapy. Factors beyond just clinical variables play a role in this decision making process such as the structure of the recovery room.

Topic Significance & Study Purpose/Background/Rationale High dose chemotherapy followed by hematopoietic cell transplantation (HCT) is an intensive cancer treatment associated with devastating complications. Persistent physical inactivity after HCT is sufficient to cause muscle mass loss, decreased strength, physical deconditioning, and potential progression to disability. Sustainable physical activity incorporated into activities of daily living may break this negative cycle. This pilot, randomized controlled trial tested the feasibility and preliminary effects of a free-living physical activity intervention (STEPS) compared to usual care on fatigue (primary outcome), functional ability, muscle strength, physical activity, and quality of life (secondary outcomes) in people with multiple myeloma treated with autologous HCT. Methods, Intervention, & Analysis This study used a two-group, randomized block, repeated measures design (n = 32). The six-week STEPS intervention aimed to increase physical activity by 10% weekly through education, goal-setting, daily step tracking using wearable technology, and guided integration of physical activity into daily routines. Data were collected using self-report questionnaires, physical performance tests, and wrist actigraphy prior to HCT and seven weeks following hospital discharge. Split-plot 2 × 2 ANOVAs were used to analyze the preliminary group (STEPS versus usual care), time (prior to HCT versus seven weeks after hospital discharge), and group x time interactions effects. Findings & Interpretation The STEPS group achieved their daily physical activity goal 53% of the time. Compared to usual care, the STEPS group experienced greater appetite loss (p = .05), more diarrhea (p = .05), and slept more (p = .03). Both groups reported improvements in mental fatigue (p = .02), emotional functioning (p = .01), pain (p = .009), sleep disturbance (p = .001), anger (p = .003), anxiety (p = .001), and depression (p = .02) seven weeks after HCT discharge compared to baseline. Conversely, both groups climbed the stairs slower (p = .003) and had weaker hand-grips (p Discussion & Implications The STEPS intervention is feasible for people with multiple myeloma treated with HCT. Although preliminary, differential improvement in the STEPS group's patient outcomes did not occur (no significant group x time interactions). Both groups reported improved symptoms and experienced some declines in physical function seven weeks after HCT hospital discharge.

Few studies have assessed the long-term functional outcomes of traumatic brain injury (TBI) in large, well-characterized samples. Using the Traumatic Brain Injury Model Systems cohort, this study assessed the maintenance of independence between years 5 and 15 post-injury and risk factors for decline. The study sample included 1381 persons with TBI who received inpatient rehabilitation, survived to 15 years post-injury, and were available for data collection at 5 or 10 years and 15 years post-injury. The Functional Independence Measure (FIM) and Disability Rating Scale (DRS) were used to measure functional outcomes. The majority of participants had no changes during the 10-year time frame. For FIM, only 4.4% showed decline in Self-Care, 4.9% declined in Mobility, and 5.9% declined in Cognition. Overall, 10.4% showed decline in one or more FIM subscales. Decline was detected by DRS Level of Function (24% with >1-point change) and Employability (6% with >1-point change). Predictors of decline factors across all measures were age >25 years and, across most measures, having less than or equal to a high school education. Additional predictors of FIM decline included male sex (FIM Mobility and Self-Care) and longer rehabilitation length of stay (FIM Mobility and Cognition). In contrast to studies reporting change in the first 5 years post-TBI inpatient rehabilitation, a majority of those who survive to 15 years do not experience functional decline. Aging and cognitive reserve appear to be more important drivers of loss of function than original severity of the injury. Interventions to identify those at risk for decline may be needed to maintain or enhance functional status as persons age with a TBI.

Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD. Methods This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function. Results Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio. Conclusions In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Context Most children with cancer die in hospital settings, without hospice, and many suffer from high-intensity medical interventions and pain at end of life (EOL). Objectives To examine the effects of COMPLETE: a communication plan early through EOL to increase hospice enrollment in children with cancer at EOL. Methods This is a two-phase, single-arm, two-center, and prospective pilot study of hospice enrollment in children with cancer whose parents received COMPLETE. COMPLETE is a series of medical doctor (MD)/registered nurse (RN)-guided discussions of goals of care using visual aids that begin at diagnosis. COMPLETE training for MD/RNs in Phase II was revised to increase their use of empathy. Preintervention/postintervention measurements for child include: time of hospice enrollment, pain, high-intensity medical interventions at EOL, and location of death; and for parent the following: uncertainty and hope. Results Twenty-one parents of 18 children enrolled in the study, and 13 children were followed through EOL. At EOL, 11 (84.6%) died on home hospice or inpatient hospice, and only two (15%) received high-intensity medical interventions. Similar to published findings in the initial 13 parents enrolled in Phase I, parents in Phase II (n = 7) had improvement in hope and uncertainty, and child pain was decreased. Revised training resulted in significant improvement in MD/RN (N = 6) use of empathy (11% in Phase I vs. 100% in Phase II; P = 0.001). Conclusion COMPLETE resulted in increased hospice enrollment in children with cancer at EOL compared with historical controls. In preanalysis/postanalysis, COMPLETE decreased child pain while supporting hope and reducing uncertainty in their parents.

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

BackgroundCD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody-drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT.Patients and Methods This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown.Results18 patients were enrolled. Median age 34.7 (range, 23-56). All patients had non-seminoma. Median AFP 4.9 (range, 1-219,345) and hCG 282 (range, 0.6-172,064). Five patients had late relapse (>2years). Median number of previous chemotherapy regimens was 3 (range, 2-7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9-14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient >50% decline in baseline AFP/hCG: 4 had CD30 -ve and 2 had CD30 +ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response.ConclusionBrentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT. Trial Registration Number: NCT02689219Date of registration: February 12, 2016

Background Human Fatty Acid Synthase (FASN) is the sole cytosolic enzyme responsible for de novo synthesis of long chain fatty acids. Unlike normal tissues, cancer cells require FASN dependent fatty acid synthesis for survival. FASN is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and associated with significantly shorter disease free and overall survival. In vitro, FASN overexpression induces resistance to multiple DNA damaging agents including doxorubicin and cisplatin. Proton pump inhibitors (PPI), particularly omeprazole can selectively inhibit FASN enzyme activity at a Ki of 3.4umol. Inhibition of FASN activity with PPIs induces apoptosis selectively in cancer cells with minimal effect on non-malignant breast cell lines. PPIs are well tolerated and are FDA approved for a variety of gastro-intestinal disorders. We hypothesize that PPIs will effectively inhibit FASN activity and improve clinical efficacy of neoadjuvant chemotherapy with minimal added toxicity in operable TNBC. Materials and Methods This is a single arm multi -center phase II study of omeprazole 80mg PO BID in combination with standard neoadjuvant anthracycline-weekly taxane chemotherapy (AC-T; Adriamycin 60mg/m2 Cyclophosphamide 600mg/m2 given every q2w with G-CSF or q 3wk x 4 followed by weekly paclitaxel 80mg/m2 x 12) in patients with newly diagnosed clinically stage II or greater TNBC (NCT02595372). Neoadjuvant carboplatin may be offered with weekly paclitaxel at treating physician’s discretion. Patients with prior over the counter or prescription PPI use within 12 months are excluded. An initial core biopsy is performed at baseline, after which patients begin omeprazole monotherapy for a brief period (4-7 days). This is followed by a second research core biopsy and initiation of standard AC-T. PPI is continued until night before definitive surgery. Study follow up ends with definitive surgery and after resolution of known adverse events ( Citation Format: Sagar Sardesai, Alexandra Thomas, Christopher Gallagher, Filipa Lynce, Yvonne Ottaviano, Tarah Ballinger, Brian P Schneider, Anna Maria Storniolo, Susan Perkins, Jian Tian Zhang, Kathy D Miller. Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-01.

Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

Purpose: Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. Patients and Methods: Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4–7 days prior to neoadjuvant anthracycline–taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics. Results: Forty-two patients were recruited with a median age of 51 years (28–72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% [95% confidence interval (CI), 52.8–87.3] in FASN+ patients and 74.4% (95% CI, 57.9–87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC50 for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); P = 0.02]. Omeprazole was well tolerated with no grade ≥ 3 toxicities. Conclusions: FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia, however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of &gt, 5% cancer weight loss (FC &ge, 1.5|, p &le, 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1, Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r &ge, 0.50|, p &le, 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

High-grade serous ovarian cancer (HGSOC) harbours aberrant epigenetic features, including DNA methylation. In this study we delineate pathways and networks altered by DNA methylation and associated with HGSOC initiation and progression to a platinum-resistant state. By including tumours from patients who had been treated with the hypomethylating agent (HMA) guadecitabine, we also addressed the role of HMAs in treatment of HGSOC. Tumours from patients with primary (platinum-naïve) HGSOC (n = 20) were compared to patients with recurrent platinum-resistant HGSOC and enrolled in a recently completed clinical trial (NCT01696032). Human ovarian surface epithelial cells (HOSE; n = 5 samples) served as normal controls. Genome-wide methylation profiles were determined. DNA methyltransferase (DNMT) expression levels were examined by immunohistochemistry and correlated with clinical outcomes. Cancer-related and tumorigenesis networks were enriched among differentially methylated genes (DMGs) in primary OC vs. HOSE. When comparing platinum-resistant and primary tumours, 452 CpG island (CGI)-containing gene promoters acquired DNA methylation; of those loci, decreased (P

Purpose Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next‐generation HMA guadecitabine (SGI‐110) with cisplatin in recurrent, cisplatin‐resistant GCT patients. Methods Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28‐day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD). Results The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer., A phase I trial demonstrates tolerable toxicity and clinical activity for combining the hypomethylating agent guadecitabine with cisplatin for testicular cancer patients that have failed prior chemotherapy. This strategy has the potential to be the first targeted treatment for chemotherapy refractory testicular cancer.

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

Introduction Although African Americans have the highest colorectal cancer (CRC) incidence and mortality rates of any racial group, their screening rates remain low. Study design/purpose This randomized controlled trial compared efficacy of two clinic-based interventions for increasing CRC screening among African American primary care patients. Methods African American patients from 11 clinics who were not current with CRC screening were randomized to receive a computer-tailored intervention (n = 335) or a non-tailored brochure (n = 358) designed to promote adherence to CRC screening. Interventions were delivered in clinic immediately prior to a provider visit. Univariate and multivariable logistic regression models analyzed predictors of screening test completion. Moderators and mediators were determined using multivariable linear and logistic regression analyses. Results Significant effects of the computer-tailored intervention were observed for completion of a stool blood test (SBT) and completion of any CRC screening test (SBT or colonoscopy). The colonoscopy screening rate was higher among those receiving the computer-tailored intervention group compared to the nontailored brochure but the difference was not significant. Predictors of SBT completion were: receipt of the computer-tailored intervention; being seen at a Veterans Affairs Medical Center clinic; baseline stage of adoption; and reason for visit. Mediators of intervention effects were changes in perceived SBT barriers, changes in perceived colonoscopy benefits, changes in CRC knowledge, and patient-provider discussion. Moderators of intervention effects were age, employment, and family/friend recommendation of screening. Conclusion This one-time computer-tailored intervention significantly improved CRC screening rates among low-income African American patients. This finding was largely driven by increasing SBT but the impact of the intervention on colonoscopy screening was strong. Implementation of a CRC screening quality improvement program in the VA site that included provision of stool blood test kits and follow-up likely contributed to the strong intervention effect observed at that site. The trial is registered at ClinicalTrials.gov as NCT00672828 .

Objective In participants with traumatic brain injury (TBI) and peer controls, examine (1) differences in negative attributions (interpret ambiguous behaviors negatively); (2) cognitive and emotional factors associated with negative attributions; and (3) negative attribution associations with anger responses, life satisfaction, and participation. Setting Two TBI outpatient rehabilitation centers. Participants Participants with complicated mild to severe TBI (n = 105) and peer controls (n = 105). Design Cross-sectional survey study. Main measures Hypothetical scenarios describing ambiguous behaviors were used to assess situational anger and attributions of intent, hostility, and blame. Executive functioning, perspective taking, emotion perception and social inference, alexithymia, aggression, anxiety, depression, participation, and life satisfaction were also assessed. Results Compared with peer controls, participants with TBI rated behaviors significantly more intentional, hostile, and blameworthy. Regression models explained a significant amount of attribution variance (25%-43%). Aggression was a significant predictor in all models; social inference was also a significant predictor of intent and hostility attributions. Negative attributions were associated with anger responses and lower life satisfaction. Conclusion People with TBI who have higher trait aggression and poor social inferencing skills may be prone to negative interpretations of people's ambiguous actions. Negative attributions and social inferencing skills should be considered when treating anger problems after TBI.

SummaryIntroduction: Dual healthcare system use can create gaps and fragments of information for patient care. The Department of Veteran Affairs is implementing a health information exchange (HIE) program called the Virtual Lifetime Electronic Record (VLER), which allows providers to access and share information across healthcare systems. HIE has the potential to improve the safety of medication use. However, data regarding the pattern of outpatient medication use across systems of care is largely unknown. Therefore, the objective of this study is to describe the prevalence of medication dispensing across VA and non-VA health care systems among a cohort Veteran population Methods: This study included all Veterans who had two outpatient visits or one inpatient visit at the Indianapolis VA during a 1-year period prior to VLER enrollment. Source of medication data was assessed at the subject level, and categorized as VA, INPC (non-VA), or both. The primary target was identification of sources for medication data. Then, we compared the mean number of prescriptions, as well as overall and pairwise differences in medication dispensing.Results: Out of 52,444 Veterans, 17.4% of subjects had medication data available in a regional HIE. On average, 40 prescriptions per year were prescribed for Veterans who used both sources compared to 29 prescriptions per year from VA only and 25 prescriptions per year from INPC only sources. The annualized prescription rate of Veterans in the dual use group was 36% higher than those who had only VA data available and 61% higher than those who had only INPC data available.Conclusions: Our data demonstrated that 17.4% of subjects had medication use identified from non-VA sources, including prescriptions for antibiotics, antineoplastics, and anticoagulants. These data support the need for HIE programs to improve coordination of information, with the potential to reduce adverse medication interactions and improve medication safety.

OBJECTIVE We tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.

Objective Parent variables (stigma, mood, unmet needs for information and support, and worry) are associated with behavioral difficulties in children with seizures; however, it is not known how this relationship is influenced by additional seizures. This study followed children (ages 4–14 years) and their parents over a 24-month period (with data collected at baseline and 6, 12, and 24 months) and investigated the effect of an additional seizure on the relationship between parenting variables and child behavior difficulties. Methods The sample was parents of 196 children (104 girls and 92 boys) with a first seizure within the past 6 weeks. Child mean age at baseline was 8 years, 3 months (SD 3 years). Data were analyzed using t-tests, chi-square tests, and repeated measures analyses of covariance. Results Relationships between parent variables, additional seizures, and child behavior problems were consistent across time. Several associations between parent variables and child behavior problems were stronger in the additional seizure group than in the no additional seizure group. Conclusions Findings suggest that interventions that assist families to respond constructively to the reactions of others regarding their child's seizure condition and to address their needs for information and support could help families of children with continuing seizures to have an improved quality of life.

Luminal subtype of breast cancers that express the estrogen receptor alpha (ERα) represents approximately two-thirds of all breast cancer cases. ER+ tumors tend to have the most favorable prognoses when treated with endocrine therapy. However, a relapse or endocrine therapy resistance is often seen in ER+ breast tumors. UNC5A belongs to the dependence receptor family which can mediate two different intracellular signals: cell survival, differentiation or migration when engaged with its ligand (such as Netrin-1; NTN1) or cell death/apoptosis in the absence of the ligand. Here we demonstrate that, depending upon the cell type, UNC5A and NTN1 are estradiol (E2)-inducible genes. Using shRNA or CRISPR knockdown strategies, we show that the disruption of the NTN1-UNC5A signaling axis in ER+ (MCF7 and T-47D) cells generates a mixed basal-like/luminal phenotype with stem cell-like characteristics. RNA-seq of UNC5A knockdown cells showed deregulated expression of several E2-target genes in both cell lines. Moreover, knockdown of UNC5A resulted in increased cell proliferation, and elevated expression of the E2-inducible anti-apoptotic, BCL2. Furthermore, the expression of ΔNp63 was enhanced in UNC5A knockdown cells. ΔNp63 is a TP53 family transcription factor that promotes breast epithelial stem cell maintenance and basal-like breast cancer. Accordingly, UNC5A knockdown cells displayed cancer stem cell phenotype as evident from ~3-fold increase in the number of CD44+/CD24+, CD44+/EPCAM+ and ITGA6+/EPCAM+ subpopulation compared with control cells. In addition, the expression of NTN4, a pro-angiogenic and lymphangiogenic factor, was increased upon UNC5A knockdown. In vivo, UNC5A knockdown cells implanted in nude mice were able to form tumors in the mammary fat pad independent of E2 supplementation and were able to colonize and develop into overt metastasis in multiple organs such as lungs, ovaries and adrenal glands. Consequently, analysis of mammary fat pad tumors from animals that received UNC5A knockdown cells revealed an increased expression of PECAM1 (CD31), a marker for endothelial cells used to evaluate tumor angiogenesis. In contrast to UNC5A, knocking down NTN1, decreased the expression of BCL2 and TP63 in both cell lines. Thus, knockdown of UNC5A resulted in deregulated expression of E2-regulated genes, E2-independent and anti-estrogen-resistant growth in vitro, and E2-independent tumor formation in xenograft models. Consistent with results of in vitro studies, analysis of tissue samples from breast cancer patients (n=196) revealed that lower expression of UNC5A is associated with lower overall survival (P < 0.05). Thus, loss or mutational inactivation of UNC5A could lead to unrestricted E2:ERα signaling and anti-estrogen resistant growth while simultaneously enabling ERα-positive luminal breast cancer cells to acquire basal-like and cancer stem cell-like features. Citation Format: Padua MB, Bhat-Nakshatri P, Anjanappa M, Hao Y, Liu Y, McElyea K, Sandusky G, Althouse S, Perkins S, Nakshatri H. Disruption of the estradiol-regulated NTN1-UNC5A dependence receptor signaling axis causes a hybrid basal/luminal molecular phenotype in estrogen receptor-positive breast cancer cells [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 P6-08-02.

4572 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulates PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of PD-L1 inhibitor durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who had residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: Initially 24 pts were enrolled, study was expanded to enroll additional 13 pts. Median age: 61yrs (range, 43-73). 31 received carbo/paclitaxel and 6 received cis/5-FU concurrently with RT. 24(64.9%) pts had positive lymph nodes(LN) at the time of surgery following CRT: N3(n = 3,8.1%), N2(n = 10, 27%), N1(n = 11,29.7%).17 pts relapsed: 11 on tx, 6 had late relapses. 3/5 late relapses were locoregional and were re-treated with chemo-RT. Remaining relapses were systemic with lung and LN being the most common sites. 2 of 3 pts who developed grade 3 irAEs are alive and disease free at 17 and 23 mo. RFS/OS:1 yr- 79.2%/95.5%, 2yr-55.5%/67.4%. 20/37 pts have HER-2 status available: 5/6 HER2 positive pts had disease relapse, 1 is undergoing tx. Molecular profiling is available on 8 relapsed pts: all were microsatellite stable with low TMB and PD-L1 < 10% CPS. Mutations in DNA repair genes ( ARID1A, ATM, ATR, CHEK2), and PIK3CA E542K were more prevalent among late relapsing pts. Circulating tumor cells (CTCs) analysis is available for 10/37 pts. 4/5 pts where CTCs increased from C1 to C4 had disease relapse. Molecular profiling of the remaining pts and correlation of PD-L1 expression, TMB, specific genes mutations, CTCs, and Immunoscore with outcomes with durva is being evaluated will be presented at the meeting. Conclusions: Adjuvant durva following trimodality therapy for LA-EAC and GEJ adenocarcinoma improved 1-yr RFS to 79.2% compared to historical rate of 50%.2-yr RFS and OS data are encouraging in this high risk pt population. HER-2 positivity may be associated with lack of benefit from durva. Mutations in DNA repair genes are prevalent in pts with delayed relapse. Rise in CTCs during durva tx may be an early marker of disease relapse. Clinical trial information: NCT02639065 .

TPS472 Background: Adenocarcinoma of esophagus (EAC) and GEJ is the fastest rising cancer in the US. The outcomes are extremely poor with median overall survival (OS) being 12 mo in patients (pts) with metastatic disease. The standard first line treatment for metastatic EAC is platinum-based regimen with median progression free survival (PFS) of 6 mo. Second line options are associated with limited efficacy. An analysis of TCGA has shown 40% of EAC harboring abnormalities in HR genes, most likely resulting from chronic acid reflux induced DNA damage. HR dysregulation is commonly associated with high LOH. Sensitivity to PARP inhibition has been shown to be a surrogate for HR defects or BRCAness phenotype. Clinically PARP inhibitors have shown activity in HR defective prostate and ovarian cancers. These findings provide the basis for this study. Methods: Pts with metastatic esophageal/GEJ/proximal gastric adenocarcinoma, previously treated with 1 line of platinum containing chemotherapy, and harboring high LOH and/or deleterious alteration(s) in HR genes ( BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A, GEN1) are eligible for this study. Pts can be prescreened at the time of diagnosis of locally advanced or metastatic disease by genomic analysis of the most recent available tumor tissue. Pts will receive oral niraparib until disease progression or unacceptable toxicity. Primary objective is response rate (RR). Secondary objectives are safety and tolerability, progression free survival (PFS), and disease control rate (DCR). Exploratory objectives include correlation between high LOH and response to niraparib, mechanisms of resistance to PARP inhibition, EZH2 expression and its correlation with response and resistance to PARP inhibition, and analysis of germline HR gene mutations and correlation with response to niraparib. Estimated sample size is 43. The study has recently opened to accrual at Indiana University with intended collaboration with 2 additional sites. Clinical trial information: NCT03840967.

404 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulate PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who have residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018(median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0(n = 3, 12.5%), T2N2(n = 3, 12.5%),T3N0(n = 6, 25%), T3N1(n = 6, 25%), T3N2(n = 4, 17%), T3N3(n = 1, 4%), T3Nx(n = 1, 4%).19 pts(79%) had positive lymph nodes(LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx because of relapse(6), AEs(5), and consent withdrawal(1). Most common AEs were fatigue(n = 8, 33.3%) and nausea(n = 6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis(1), hepatitis(1), colitis(1). At median follow up of 21.9mo(range, 1.7-23.9mo), 11 pts have relapsed: 9 distant and 2 locoregional. Two of 3 pts with grade 3 irAEs are alive and disease free at 17 and 23 mo respectively. 1-yr RFS and OS were 79.2% and 95.5%, respectively. RFS at 26 mo was 20.6%. Overall mOS and mOS after relapse were 28.1mo(range, 22.9-28.1) and 11.1 mo(range, 0.1-11.3mo) respectively. The study was expanded to enroll 14 additional pts who are currently undergoing tx. Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma is safe with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. RFS was 20.6% at 26 months. Evaluation of predictive biomarkers of RFS with durva is underway. Clinical trial information: NCT02639065.

Background and Aims Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. Methods In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naive LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. Results Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm3 (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. Conclusion EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132 .)

BackgroundOver 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis.MethodsSerum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r≥ 0.5 and pResultsOverall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction.ConclusionTaken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

Objective: Guidelines recommend that decision aids provide quantitative information about risks and benefits of available options. Impact of providing this information is unknown. Methods: Randomized trial comparing two decision aids about colorectal cancer (CRC) screening with colonoscopy or fecal immunochemical test (FIT). 688 primary care patients due for CRC screening viewed a decision aid that uses words only (Verbal arm) vs. one that provides quantitative information (Quantitative arm). Main outcomes included perceived CRC risk, intent to be screened, and test preference, measured before and after viewing decision aid, and screening uptake at six months. Analyses were performed with ANCOVA and logistic regression. Results: Compared to the Verbal arm, those in the Quantitative arm had a larger increase in intent to undergo FIT (p = 0.011) and were more likely to switch their preferred test from non-FIT to FIT (28% vs. 19%, p = .010). There were decreases in perceived risk in the Verbal Arm but not the Quantitative Arm (p = 0.004). There was no difference in screening uptake. Numeracy did not moderate any effects. Conclusions: Quantitative information had relatively minor impact and no clearly negative effects, such as reducing uptake. Practice implications: Quantitative information may be useful but not essential for patients viewing decision aids.

Early detection of lung cancer offers an important opportunity to decrease mortality while it is still treatable and curable. Thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells, and alveolar myeloid cells of the CCSP-rtTA/(tetO)7-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. Further analyses showed that TTR treatment enhanced the reactive oxygen species production in myeloid cells and enabled them to become functional myeloid-derived suppressive cells. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, these 13 Stat3 downstream inducible secretory protein biomarkers potentially can be used for lung cancer diagnosis, classification, and as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood.

Background The majority of estrogen receptor-positive (ERα+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown. Methods We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses. Results Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα+/PR+/HER2− tumors, was associated with poor outcome. Conclusion These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα+ breast cancers. Electronic supplementary material The online version of this article (10.1186/s13058-018-0963-5) contains supplementary material, which is available to authorized users.

Objectives Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy. Materials and methods Patients with unresectable thymic malignancy were treated with saracatinib 175 mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%. Results 21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated. Conclusion Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population ( NCT00718809 ).

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R–dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. Cancer Res; 74(23); 7069–78. ©2014 AACR.

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients. Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631–44. ©2017 AACR.

The prevalence, effect on health outcomes, and economic impact of chronic kidney disease (CKD) have created interest in self-management interventions to help slow disease progression to kidney failure. Seven studies were reviewed to identify knowledge gaps and future directions for research. All studies were published between 2010 and 2013; no investigations were conducted in the United States. Knowledge gaps included the focus on medical self-management tasks with no attention to role or emotional tasks, lack of family involvement during intervention delivery, and an inability to form conclusions about the efficacy of interventions because methodological rigor was insufficient. Educational content varied across studies. Strategies to improve self-management skills and enhance self-efficacy varied and were limited in scope. Further development and testing of theory-based interventions are warranted. There is a critical need for future research using well-designed trials with appropriately powered sample sizes, well-tested instruments, and clear and consistent reporting of results.

Background Communication problems between family surrogates and intensive care unit (ICU) clinicians have been documented, but few interventions are effective. Nurses have the potential to play an expanded role in ICU communication and decision making. Objectives To conduct a pilot randomized controlled trial of the family navigator (FN), a distinct nursing role to address family members' unmet communication needs early in an ICU stay. Methods An interprofessional team developed the FN protocol. A randomized controlled pilot intervention trial of the FN was performed in a tertiary referral hospital's ICU to test the feasibility and acceptability of the intervention. The intervention addressed informational and emotional communication needs through daily contact by using structured clinical updates, emotional and informational support modules, family meeting support, and follow-up phone calls. Results Twenty-six surrogate/patient pairs (13 per study arm) were enrolled. Surrogates randomized to the intervention had contact with the FN on 90% or more of eligible patient days. All surrogates agreed that they would recom mend the FN to other families. Open-ended comments from both surrogates and clinicians were uniformly positive. Conclusions Having a fully integrated nurse empowered to facilitate decision making is a feasible intervention in an ICU and is well-received by ICU families and staff. A larger randomized controlled trial is needed to demonstrate impact on important outcomes, such as surrogates' well-being and decision quality.

5 Background: The standard of care for locally advanced esophageal adenocarcinoma(LA-EAC) is concurrent chemoradiation (CRT) followed by esophagectomy. Approximately 30% of patients (pts) achieve complete pathologic response (pCR) with this approach. The risk of relapse in the remaining 70% of pts is high, with 1-yr relapse free survival (RFS) of 50%. No adjuvant therapies have been shown to improve survival. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1 pathway with radiation +/- chemotherapy. Methods: We conducted a phase II study evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GE junction (GEJ) adenocarcinoma who do not achieve pCR after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1 yr after surgery. Primary objective was 1-yr RFS. Secondary objectives were incidence and severity of treatment related adverse events (AEs). Results: Twenty-four pts were enrolled from Apr 2016 to Jan 2018 (median age: 60yrs (range, 43-74)). Fourteen pts had GEJ adenocarcinoma and 10 had distal EAC. Eighteen received carboplatin/paclitaxel and six received cisplatin/5-FU concurrently with 50-50.4Gy radiation. Nineteen pts (79%) had positive lymph nodes at the time of surgery after neoadjuvant CRT, including three (12.5%) with N3, nine (37.5%) with N2, and seven (29%) with N1 disease. Among N0 pts, two had T3N0, one had T2N0, and two had T1N0 disease. At median follow-up of 11.7 mo (range 1.7-23.9 mo), seven pts (29%) have relapsed (five alive, two died); 17(67%) are disease free (six on treatment, seven completed treatment, three off-treatment); 1-yr and projected 26 mo RFS are 78.6% and 62.9%, respectively. Five pts (20.8%) developed grade 3 AEs: diarrhea (n = 1), hepatitis (n = 1), encephalopathy (n = 1), hyperglycemia (n = 1), hypoglycemia (n = 1). Most common grade 1 and 2 AEs were fatigue (33.3%), nausea (25.0%), and cough (20.8%). Conclusions: Adjuvant durva in pts with residual disease following trimodality therapy for EAC and GEJ adenocarcinoma is safe and feasible with 1-yr RFS of 78.6% compared to historical rate of 50%. Clinical trial information: NCT02639065.

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.

Background Provider recommendation is a predictor of colorectal cancer (CRC) screening. Purpose To compare the effects of two clinic-based interventions on patient–provider discussions about CRC screening. Design Two-group RCT with data collected at baseline and 1 week post-intervention. Setting/participants African-American patients that were non-adherent to CRC screening recommendations ( n =693) with a primary care visit between 2008 and 2010 in one of 11 urban primary care clinics. Intervention Participants received either a computer-delivered tailored CRC screening intervention or a nontailored informational brochure about CRC screening immediately prior to their primary care visit. Main outcome measures Between-group differences in odds of having had a CRC screening discussion about a colon test, with and without adjusting for demographic, clinic, health literacy, health belief, and social support variables, were examined as predictors of a CRC screening discussion using logistic regression. Intervention effects on CRC screening test order by PCPs were examined using logistic regression. Analyses were conducted in 2011 and 2012. Results Compared to the brochure group, greater proportions of those in the computer-delivered tailored intervention group reported having had a discussion with their provider about CRC screening (63% vs 48%, OR=1.81, p p -values Conclusions The computer-delivered tailored intervention was more effective than a nontailored brochure at stimulating patient–provider discussions about CRC screening. Those who received the computer-delivered intervention also were more likely to have a CRC screening test (fecal occult blood test or colonoscopy) ordered by their PCP. Trial registration This study is registered at www.clinicaltrials.gov NCT00672828.

Objective: To characterize patients who voluntarily enrolled in an electronic health information exchange (HIE) program designed to share data between Veterans Health Administration (VHA) and non-VHA institutions.Materials and Methods: Patients who agreed to participate in the HIE program were compared to those who did not. Patient characteristics associated with HIE enrollment were examined using a multivariable logistic regression model. Variables selected for inclusion were guided by a health care utilization model adapted to explain HIE enrollment. Data about patients’ sociodemographics (age, gender), comorbidity (Charlson index score), utilization (primary and specialty care visits), and access (distance to VHA medical center, insurance, VHA benefits) were obtained from VHA and HIE electronic health records.Results: Among 57 072 patients, 6627 (12%) enrolled in the HIE program during its first year. The likelihood of HIE enrollment increased among patients ages 50–64, of female gender, with higher comorbidity, and with increasing utilization. Living in a rural area and being unmarried were associated with decreased likelihood of enrollment.Discussion and Conclusion: Enrollment in HIE is complex, with several factors involved in a patient’s decision to enroll. To broaden HIE participation, populations less likely to enroll should be targeted with tailored recruitment and educational strategies. Moreover, inclusion of special populations, such as patients with higher comorbidity or high utilizers, may help refine the definition of success with respect to HIE implementation.

// James Haley 1 , Sunil Tomar 1 , Nicholas Pulliam 1 , Sen Xiong 1 , Susan M. Perkins 2 , Adam R. Karpf 3 , Sumegha Mitra 1, 4 , Kenneth P. Nephew 1, 5, 6 , Anirban K. Mitra 1, 5, 7 1 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA 2 Department of Biostatistics, Indiana University, Indianapolis, IN 46202, USA 3 Eppley Institute and Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA 6 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 7 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA Correspondence to: Anirban K. Mitra, email: anmitra@indiana.edu Keywords: ovarian cancer, migration, invasion, proliferation, clonogenicity Received: January 27, 2016 Accepted: April 10, 2016 Published: April 27, 2016 ABSTRACT Genomic analysis of ovarian cancer cell lines has revealed a panel that best represents the most common ovarian cancer subtype, high-grade serous ovarian cancer (HGSOC). However, these HGSOC-like cell lines have not been extensively applied by ovarian cancer researchers to date, and the most commonly used cell lines in the ovarian cancer field do not genetically resemble the major clinical type of the disease. For the HGSOC-like lines to serve as suitable models, they need to be characterized for common functional assays. To achieve that objective, we systematically studied a panel of HGSOC cells CAOV3, COV362, Kuramochi, OVCAR4, OVCAR5, OVCAR8, OVSAHO and SNU119 for migration, invasion, proliferation, clonogenicity, EMT phenotype and cisplatin resistance. They exhibited a range of efficacies and OVCAR5, OVCAR8 and Kuramochi were the most aggressive. SNU119 and OVSAHO cells demonstrated the lowest functional activities. Wide differences in expression of EMT markers were observed between cell lines. SNU119 were the most epithelial and OVCAR8 had the most mesenchymal phenotype. COV362 was the most resistant to cisplatin while CAOV3 was the most sensitive. Taken together, our systematic characterization represents a valuable resource to help guide the application of HGSOC cells by the cancer research community.

The Virtual Lifetime Electronic Record (VLER) Health program provides the Veterans Health Administration (VHA) a framework whereby VHA providers can access the veterans’ electronic health record information to coordinate healthcare across multiple sites of care. As an early adopter of VLER, the Indianapolis VHA and Regenstrief Institute implemented a regional demonstration program involving bi-directional health information exchange (HIE) between VHA and non-VHA providers. The aim of the study is to determine whether implementation of VLER HIE reduces 1 year VHA medical costs. A cohort evaluation with a concurrent control group compared VHA healthcare costs using propensity score adjustment. A CHEERs compliant checklist was used to conduct the cost evaluation. Patients were enrolled in the VLER program onsite at the Indianapolis VHA in outpatient clinics or through the release-of-information office. VHA cost data (in 2014 dollars) were obtained for both enrolled and nonenrolled (control) patients for 1 year prior to, and 1 year after, the index date of patient enrollment. There were 6104 patients enrolled in VLER and 45,700 patients in the control group. The annual adjusted total cost difference per patient was associated with a higher cost for VLER enrollees $1152 (95% CI: $807–1433) (P

In the study we describe adaptive functioning in children with epilepsy whose primary caregivers identified them as having learning problems. This was a cross-sectional study of 50 children with epilepsy and learning problems. Caregivers supplied information regarding the child’s adaptive functioning and behavior problems. Children rated their self-concept and completed a battery of neuropsychological tests. Mean estimated IQ (PPVT-III) in the participant children was 72.8 (SD = 18.3). On average, children scored 2 standard deviations below the norm on the Vineland Adaptive Behavior Scale–II and this was true even for children with epilepsy who had estimated IQ in the normal range. In conclusion, children with epilepsy and learning problems had relatively low adaptive functioning scores and substantial neuropsychological and mental health problems. In epilepsy, adaptive behavior screening can be very informative and guide further evaluation and intervention, even in those children whose IQ is in the normal range.

PURPOSE The aim of this study was to describe strategies for recruiting participants into an intervention study that focused on improving problem-solving skills in caregivers of children with mental health problems. BACKGROUND Caregivers of children with mental health problems report feeling physically and psychologically overwhelmed and have high rates of depression because of the demands of caregiving. Research on the needs of these caregivers and interventions to ameliorate their stress is needed. However, recruiting this population can be particularly difficult because of the stigma of mental illness. Available literature on recruitment of caregivers of persons with physical illness cannot be transferred to caregivers of children with mental health problems because of the different caregiving situations. There is a need to identify effective recruitment strategies to reduce cost and answer research questions. Clinical nurse specialists have the skills to facilitate the recruitment of research participants. We revised and expanded health system referrals, community outreach, and recruiting advertisement (ads). When these strategies did not increase recruitment, radio ads were used. The Andersen's Behavioral Model of Health Services Utilization was selected as a guiding framework. OUTCOME Radio ads were the most effective strategy for recruiting caregivers of children with mental health problems for this study. CONCLUSION Recruitment was ultimately successful because we were flexible and made decisions consistent with the Andersen's Behavioral Model of Health Services Utilization. IMPLICATIONS Clinical nurse specialists who study this population of caregivers should really consider the use of radio ads and systematically track which recruitment strategies lead to the greatest number of participants screened, eligible, and enrolled into studies.

Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence due to hepatitis C. Stereotactic body radiotherapy (SBRT) is a noninvasive, effective therapy in the management of liver malignancies. The authors evaluated radiological response in 26 patients with HCC treated with SBRT at Indiana University. METHODS: Between March 2005 and June 2008, 26 patients with HCC who were not surgical candidates were enrolled in a phase 1 to 2 trial. Eligibility criteria included solitary tumors ≤ 6 cm or up to 3 lesions with sum diameters ≤ 6 cm, and well-compensated cirrhosis. All patients had imaging before, at 1 to 3 months, and every 3 to 6 months after SBRT. RESULTS: Patients received 3 to 5 fractions of SBRT. Median SBRT dose was 42 Gray (Gy) (range: 24-48 Gy). Median follow-up was 13 months. Per Response Evaluation Criteria in Solid Tumors (RECIST), 4 patients had a complete response (CR), 15 had a partial response (PR), and 7 achieved stable disease (SD) at 12 months. One patient with SD experienced progression marginal to the treated area. The overall best response rate (CR + PR) was 73%. In comparison, by European Association for the Study of the Liver (EASL) criteria, 18 of 26 patients had ≥ 50% nonenhancement at 12 months. Thirteen of 18 demonstrated 100% nonenhancement, being > 50% in 5 patients. Kaplan-Meier 1- and 2-year survival estimates were 77% and 60%, respectively. CONCLUSIONS: SBRT is effective therapy for patients with HCC with an overall best response rate (CR + PR) of 73%. Nonenhancement on imaging, a surrogate for ablation, may be a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months, supporting EASL criteria. Cancer 2012;118: 3191–98. © 2011 American Cancer Society.

Objectives The purposes of this 36-month study of children with first recognized seizures were: (1) to describe baseline differences in behavior problems between children with and without prior unrecognized seizures; (2) to identify differences over time in behavior problems between children with seizures and their healthy siblings; (3) to identify the proportions of children with seizures and healthy siblings who were consistently at risk for behavior problems for 36 months; and (4) to identify risk factors for behavior problems 36 months following the first recognized seizure. Risk factors explored included demographic (child age and gender, caregiver education), neuropsychological (IQ, processing speed), seizure (epileptic syndrome, use of antiepileptic drug, seizure recurrence), and family (family mastery, satisfaction with family relationships, parent response) variables. Methods Participants were 300 children aged 6 through 14 years with a first recognized seizure and 196 healthy siblings. Data were collected from medical records, structured interviews, self-report questionnaires, and neuropsychological testing. Behavior problems were measured using the Child Behavior Checklist and the Teacher's Report Form. Data analyses included descriptive statistics and linear mixed models. Results Children with prior unrecognized seizures were at higher risk for behavior problems at baseline. As a group, children with seizures showed a steady reduction in behavior problems over time. Children with seizures were found to have significantly more behavior problems than their siblings over time, and significantly more children with seizures (11.3%) than siblings (4.6%) had consistent behavior problems over time. Key risk factors for child behavior problems based on both caregivers and teachers were: less caregiver education, slower initial processing speed, slowing of processing speed over the first 36 months, and a number of family variables including lower levels of family mastery or child satisfaction with family relationships, lower parent support of the child's autonomy, and lower parent confidence in their ability to discipline their child. Conclusions Children with new-onset seizures who are otherwise developing normally have higher rates of behavior problems than their healthy siblings; however, behavior problems are not consistently in the at-risk range in most children during the first 3 years after seizure onset. When children show behavior problems, family variables that might be targeted include family mastery, parent support of child autonomy, and parents’ confidence in their ability to handle their children's behavior.

Advances in breast cancer treatment have resulted in improved survival rates and concomitant reports of chemotherapy-related cognitive dysfunction. Music cognition, a form of general cognition, also may be negatively affected by chemotherapy. Moreover, chemotherapy may have general ototoxic effects. The goal of this study was to explore whether breast cancer survivors (BCS) had similar hearing thresholds and music cognition abilities compared with age-matched healthy controls (HC). A total of 56 women (28 BCS and 28 HC) completed the audiometric tests and the Montreal Battery Evaluation of Amusia (MBEA). Results indicate the 2 groups have similar hearing thresholds. A comparison of music cognition variables suggests possible differences in some music cognition tasks, with HC scoring slightly, but not significantly, better in melodic perception. The BCS scored slightly better, though not significantly, on melodic memory. An adequately powered study including cognitive variables is needed for verification of findings and to establish clinical meaningfulness.

Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer. VEGF has a major impact on vascular permeability and lymphangiogenesis. In a prior case control study, we found a significant increase in serum VEGF-C (median 6895 vs. 5349 pg/mL, p=0.0016) in women with lymphedema compared to women without lymphedema suggesting inhibition of VEGF-C as a potential therapeutic strategy. Methods: Pts with significant unilateral lymphedema were treated with pazopanib 800 mg/day continuously. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C,-D, and R3. IFP was measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed every 4 weeks. Results: Ten pts were enrolled. Median duration of lymphedema was 3.5 years (0.7-8.2) Median time since surgery was 5.1 years (1.0-14.2); median time since radiation (n=9) was 4.7 years (0.4-8.8). Complete IFP data are available in 7 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (mean 5.73 vs. -1.78 mmHg; p=0.0005). Mean IFP in the affected arm decreased an average of 76% 24 hours after initiation of pazopanib (5.73 vs. 1.56 mmHg; p=0.0061). Toxicity was greater than anticipated with grade 3 fatigue (n=3), arthralgia (n=2), and anorexia (n=1); three pts discontinued therapy prior to the first post-treatment assessment. Five pts met the definition of response with a ≥25% reduction in excess arm volume four weeks after initiating treatment. ECF significantly (p=0.014) decreased as well though the mean difference in excess arm volume did not significantly change (p=0.06). Conclusions: Preliminary data supports the hypothesis that VEGF plays a role in the development and/or persistence of lymphedema after local therapy for breast cancer. Pazopanib acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume but results in significant toxicity at the dose used on this study. Subsequent studies will explore a lower dose of pazopanib in this population. This study was supported by the Breast Cancer Research Foundation with pazopanib supplied by GSK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-02.

Objectives Children with long-standing epilepsy have a significantly increased risk of academic underachievement compared with healthy controls. We prospectively followed children from seizure onset to assess the relationship between change in neuropsychological functioning and change in academic achievement and to explore the risk and protective moderating effects of demographic, seizure, and family variables. Methods As part of a larger study, neuropsychological and academic data were collected at both baseline and 36 months for 219 children 6–14 years of age with seizures. Prior factor analysis of results from a battery of well-standardized neuropsychological tests yielded four factors: language, processing speed, attention/executive/construction, and verbal memory/learning. Academic achievement was measured with the Woodcock–Johnson Revised Achievement Test Battery. Correlation coefficients and linear mixed models were used for analysis. Results The reading and math scores of children with seizures and siblings did not differ at baseline, but children with seizures had lower scores than siblings at 36 months. Writing scores were significantly lower for affected children than siblings at both times. Among children with seizures, there were positive correlations between neuropsychological functioning and academic achievement at baseline and 36 months. Changes in language and in verbal memory/learning were positively correlated with change in reading achievement ( r = 0.25 and r = 0.17, respectively). Age at onset moderated the association between change in neuropsychological functioning and change in reading and writing achievement ( P ≤ 0.006), with stronger relationships among younger children (β = 0.25–0.44). The association between change in language and change in writing achievement was moderated by caregiver anxiety ( P = 0.04; stronger for more anxious parents, β = 0.40), and the association between change in processing speed and change in math achievement was moderated by etiology ( P = 0.02; stronger for symptomatic/cryptogenic vs idiopathic, β = 0.29). Gender and other family variables did not have significant moderating effects. Conclusions Changes in neuropsychological function were associated with changes in academic achievement following onset of seizures, with risk factors being younger age at onset, lower caregiver education, high parental anxiety, and symptomatic/cryptogenic etiology. Academic performance should be closely monitored in children with early-onset seizures.

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.

e16545Background: Preclinical data suggests platinum resistant embryonal carcinoma (EC) cell lines are sensitive to hypomethylating agents. Guadecitabine (G), a novel hypomethylating dinucleotide o...