Abstract PD5-6: Sustained hyperactivated mTOR & JAK2/STAT3 pathways in inflammatory breast cancer (IBC): Evidence for mTOR plus JAK2 therapeutic targeting

Abstract Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality therapy results in a 5 year OS of 30%, underscoring the unmet need for targeted therapy. Our preclinical research in cell lines &amp; xenograft tumor models has identified a role for hyper-activated PI3K/mTOR signaling in IBC. IBC cells express IL-6 and IL-8, which recruit tumor activated macrophages (TAMs) that further induce inflammatory cytokines and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC patient tissues. Methods: Archived tissue specimens of 42 IBC patients (dx 1999-2009) and 27 non-IBC patients (dx 2001-2005) with invasive ductal carcinoma (IDC) were obtained. Surrounding non-tumor normal tissue from IBC (companion controls) was also utilized. All specimens were analyzed using immunohistochemistry (IHC) and scored by 3 independent pathologists. Results were defined as 0 = negative; 1+,2+ = positive for activated mTOR (P-S6); activated JAK2/STAT3 (P-JAK2; P-STAT3); cytokine (IL-6); macrophage infiltration (CD68) and TAM (CD163). Proportions of IBC cases with positive expression were compared with non-IBC cases (Fisher's exact test) &amp; companion controls (McNemar's test). Clinical &amp; survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early stage IBC [EIBC] (n = 37) &amp; 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n = 5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) &amp; 3/4 were HER2+ (1 unk). 88% were rx with neoadjuvant &amp;/or adjuvant anthracycline &amp; taxane w/o adjuvant trastuzumab. There were 24 pt deaths (5/5 MIBC). Median f/u for EIBC: 6.3 yrs and for MIBC: 3.4 yrs. Median OS: 81.4 mo (95% CI lower 48 mo) for EIBC &amp; 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). The non-IBC patients were all stage 2-3 with median age at diagnosis: 58 yrs (39-94). 19/27: ER+; 7/25 HER2+ (2 unk); 15/25 ER+/HER2-; 3/25 ER-/HER2-. 78% were rx with adjuvant anthracycline &amp; taxane, 4% were rx with FEC and 18% did not receive adjuvant chemotherapy. 18% received adjuvant trastuzumab. Median f/u: 8.0 yrs. Median OS: not yet reached and median RFS: 111.3 mo (95% CI lower 34.5 mo). EIBC cases were compared with non-IBC cases &amp; companion controls (Table 1). PS6, pJAK2 and pSTAT3 expression was significantly increased in IBC compared to non-IBC. Of the 29 EIBC patients with complete biomarker data who were PS6+, 28/29 (97%) were JAK2+, 15/29 (52%) were STAT3+, 26/29 (90%) were CD68+, 20/29 (69%) were CD163+ and 28/29 (97%) were IL6+. Conclusion: This is the first study to validate preclinical findings &amp; show a strong co-association between hyper-activation of mTOR &amp; JAK/STAT pathways in most IBC patient tumors when compared to surrounding non-tumor tissue and non-IBC (IDC) tumors and tissues. These findings suggest a key role for dual blockade of mTOR &amp; JAK/STAT pathways for IBC in phase I trials. BiomarkerMcNemars p-value: Early Stage IBC vs companion controls (N = 37)Fishers p-value: Early stage IBC (N = 37)vs non-IBC (N = 27)PS6&amp;lt;0.00010.0315pJAK2&amp;lt;0.0001&amp;lt;0.0001pSTAT30.0003&amp;lt;0.0001CD163&amp;lt;0.00010.0908CD68&amp;lt;0.00010.0582IL60.00030.3882 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-6.</jats:p

Predictors of the number of under-five malnourished children in Bangladesh: application of the generalized poisson regression model

Islam MM, Alam M, Tariquzaman M, et al. Predictors of the number of under-five malnourished children in Bangladesh: application of the generalized poisson regression model. BMC Public Health. 2013;13(1): 11.BACKGROUND: Malnutrition is one of the principal causes of child mortality in developing countries including Bangladesh. According to our knowledge, most of the available studies, that addressed the issue of malnutrition among under-five children, considered the categorical (dichotomous/polychotomous) outcome variables and applied logistic regression (binary/multinomial) to find their predictors. In this study malnutrition variable (i.e. outcome) is defined as the number of under-five malnourished children in a family, which is a non-negative count variable. The purposes of the study are (i) to demonstrate the applicability of the generalized Poisson regression (GPR) model as an alternative of other statistical methods and (ii) to find some predictors of this outcome variable. METHODS: The data is extracted from the Bangladesh Demographic and Health Survey (BDHS) 2007. Briefly, this survey employs a nationally representative sample which is based on a two-stage stratified sample of households. A total of 4,460 under-five children is analysed using various statistical techniques namely Chi-square test and GPR model. RESULTS: The GPR model (as compared to the standard Poisson regression and negative Binomial regression) is found to be justified to study the above-mentioned outcome variable because of its under-dispersion (variance < mean) property. Our study also identify several significant predictors of the outcome variable namely mother's education, father's education, wealth index, sanitation status, source of drinking water, and total number of children ever born to a woman. CONCLUSIONS: Consistencies of our findings in light of many other studies suggest that the GPR model is an ideal alternative of other statistical models to analyse the number of under-five malnourished children in a family. Strategies based on significant predictors may improve the nutritional status of children in Bangladesh

Determinants of breast-feeding within the first 6 months post-partum in rural Vietnam

Objective: This study explored the determinants of breast-feeding practices within the first 6 months post-partum among women residing in rural Vietnam.Methods: The study was conducted in Quang Xuong district, in the Thanh Hoa Province of Vietnam. In the first phase, 463 women were prospectively studied at weeks 1, 16 and 24 post-partum. During the second phase, 16 focus group discussions were undertaken to obtain complementary information.Results: Exclusive breast-feeding dropped from 83.6% at week 1 to 43.6% at week 16 and by week 24, no infant was exclusively breast-fed. A logistic regression analysis found 'mother's education level', 'mother's decision-making on breast-feeding', 'mother's comfort to breast-feed in public places', 'father's occupation', 'feeding preference of father' and 'having sufficient food for the family' significantly influenced the exclusive breast-feeding practice. Qualitative data provided in-depth information on factors relating to mother, infant, close relatives and providers.Conclusion: Providing appropriate training and supportive supervision on breast-feeding counselling to health workers and supporting working mothers to exclusively breast-feed their infants through community mobilization were recommended to improve breast-feeding in rural Vietnam