Citations

Abstract Eosinophils are multifunctional cells of the innate immune system linked to allergic inflammation. Asthmatics were more likely to be hospitalized but less likely to suffer severe morbidity and mortality during the 2009 influenza pandemic. These epidemiologic findings were recapitulated in a mouse model of fungal asthma wherein infection during heightened allergic inflammation was protective against influenza A virus (IAV) infection and disease. Our goal was to delineate a mechanism(s) by which allergic asthma may alleviate influenza disease outcome, focused on the hypothesis that pulmonary eosinophilia linked with allergic respiratory disease is able to promote antiviral host defenses against the influenza virus. The transfer of eosinophils from the lungs of allergen-sensitized and challenged mice into influenza virus–infected mice resulted in reduced morbidity and viral burden, improved lung compliance, and increased CD8+ T cell numbers in the airways. In vitro assays with primary or bone marrow–derived eosinophils were used to determine eosinophil responses to the virus using the laboratory strain (A/PR/08/1934) or the pandemic strain (A/CA/04/2009) of IAV. Eosinophils were susceptible to IAV infection and responded by activation, piecemeal degranulation, and upregulation of Ag presentation markers. Virus- or viral peptide–exposed eosinophils induced CD8+ T cell proliferation, activation, and effector functions. Our data suggest that eosinophils promote host cellular immunity to reduce influenza virus replication in lungs, thereby providing a novel mechanism by which hosts with allergic asthma may be protected from influenza morbidity.

Abstract Introduction: Small studies have indicated a possible correlation between a HER2 gene polymorphism at codon 655 and trastuzumab-associated cardiotoxicity. Association between a synonymous coding variant rs7853758 within the SLC28A3 gene and anthracycline induced cardiotoxicity has also been reported. This study aimed to validate these correlations and assess for any relationship with prognosis. Methods: Genomic DNA was isolated from 666 patients enrolled in a large trial of adjuvant chemotherapy in HER2 amplified early breast cancer (BCIRG 006). Genotyping was conducted using Sequenom MassARRAY System for HER2 G->A polymorphism at amino acid codon 655 (rs1136201) and variant rs7853758 (L461L) within the SLC28A3 gene. Results: Of the 666 patients analyzed, 216 patients were treated with anthracycline based therapy, 226 with trastuzumab based therapy, and 224 with regimens containing both an anthracycline and trastuzumab. Compared with the overall results of the BCIRG006 study (N=3,222), in the subset of patients genotyped in this analysis, a less robust improvement in disease free survival (DFS) was observed for the trastuzumab arms than control arm (HR, 0.821). When stratified for prognostic features, the hazard ratio in favor of trastuzumab was consistent with that of the overall study (HR, 0.674). Samples from 662 patients were successfully genotyped for rs1136201. Of these, 424 (64%) were AA, 30 (4.5%) were GG, 208 (31%) were AG genotype. Samples from 665 patients were successfully genotyped for rs7853758. Of these, 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. There was no correlation seen between mean left ventricular ejection fraction (LVEF) and HER2 genotype at codon 655 in patients treated with trastuzumab. Of patients tested for the HER2 polymorphism, cardiac dysfunction [defined as > 10% decline in LVEF or clinical congestive heart failure (CHF)] developed in 16% of patients with AA, 17% of patients with GG and 20% of patients with AG. There was also no correlation between mean LVEF and variant rs7853758 in patients treated with anthracyclines. The percentage of patients who developed cardiac dysfunction was 13%, 17% and 21% in AA, GG, and AG genotypes respectively. No correlation between disease free survival and any of the genotypes was seen. Conclusion: In the largest analysis to date to evaluate for relationship between cardiac toxicity and HER2 polymorphism, we did not find a correlation with rs1136201 HER2 polymorphism and trastuzumab induced cardiac toxicity. Our study also did not show a correlation between variant rs7853758 (L461L) and anthracycline induced cardiotoxicity. Neither polymorphism correlated with prognosis. Citation Format: Peddi PF, Hurvitz SA, Fasching PA, Wang L, Cunningham J, Weinshilboum RM, Liu D, Quinaux E, Fourmanoir H, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Slamon DJ. Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-09.

Abstract Background: I-SPY2 is a multicenter phase 2 trial in high risk stage II/III breast cancer (BC) using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard neoadjuvant chemotherapy. The first regimen to graduate based on the predicted probability of a higher pCR rate within predefined subsets was veliparib/carboplatin + paclitaxel (VC+T→AC vs T→AC) in triple negative BC (TNBC). In TNBC the residual cancer burden (RCB) is prognostic, whether as a continuous index or grouped into classes, with pCR (RCB-0) and RCB-I classes having identical survival. Therefore, we evaluated the use of RCB to further discriminate between investigational and control arms. Methods: Site pathologists reported RCB for 99% of subjects in the primary efficacy analysis based on pCR (n=114/115). We compared the distribution of RCB reported as a continuous index in each treatment-subset combination to matched concurrently randomized controls using the Wilcoxon rank sum test for RCB index, and Fisher's Exact test for RCB classes (RCB-0/I vs RCB-II/III). The statistics are descriptive rather than inferential, and given the small sample size have no claim on generalizability. We modified the Bayesian model used to compute the estimated probability of success in a future, randomized, phase 3 trial of 300 subjects, if response were defined by either pCR or RCB-I (RCB0/I), or separately if it were defined by pCR alone. Results: VC+T→AC led to a significantly lower RCB index than T→AC in TNBC (p=0.0021), with a near-significant trend when those with pCR were excluded (p=0.06). There was no significant difference in RCB distributions in the other breast cancer subtypes treated. In TNBC, the odds ratio (OR) for achieving RCB-0/I in the VC+T→AC arm vs control was 8.2 (95% confidence interval (CI): 2.1–35), whereas the OR for achieving pCR was 4.56 (95% CI: 1.25–19.53). The simulations using response information from I-SPY2 to predict the probability of success for VC+T→AC for TNBC in a future phase 3 trial estimated this probability to be 0.99 if modeled using RCB-0/I as the response endpoint, and 0.90 if modeled using pCR as the response endpoint. Conclusions: Use of RCB index and classes provided additional insight into the effect of adding VC to T, appearing to magnify the improved treatment response that had been observed with pCR rates in TNBC. It will be important to test in randomized trials whether a decrease in the RCB index relative to controls, and/or increased rates of RCB-0/I class, are predictive of survival benefit in TNBC. Citation Format: Liu MC, Symmans WF, Yau C, Chen Y-Y, Rugo HS, Olopade OF, Datnow B, Chen B, Feldman M, Kallakury B, Hasteh F, Tickman R, Ritter J, Troxel M, Mhawech-Fauceglia P, Duan X, Berry D, Esserman L, DeMichele A. Residual cancer burden (RCB) with veliparib/carboplatin in the I-SPY2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-49.

AbstractPremature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity‐related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region‐specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n =65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed‐effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (P <0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high‐risk patients.Hum Brain Mapp 37:678–688, 2016. ©2015 Wiley Periodicals, Inc.

Abstract Rationale Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. Objectives To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. Methods We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. Measurements and Main Results A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P &lt; 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. Conclusions CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.