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Objectives: Determine the association between frailty and immediate survival of cardiopulmonary resuscitation (CPR) in older Veterans. Secondary outcomes: compare in-hospital mortality, duration of resuscitation efforts, hospital and intensive care unit (ICU) length of stay, neurologic outcomes, and discharge disposition between frail and non-frail Veterans. Methods: Retrospective cohort study including Veterans 50 years and older, who were “Full Code” and had in-hospital cardiac arrest between 7/1/2017 and 6/30/2020, at the Miami VAMC. Frailty Index for the VA (VA-FI) was used to determine frailty status. Immediate Survival was determined by return of spontaneous circulation (ROSC) and in-hospital mortality was determined by all-cause mortality. We compared outcomes between frail and non-frail Veterans using chi-square test. After adjusting for age, gender, race, and previous hospitalizations, we used multivariate binomial logistic regression with 95% confidence intervals to analyze the relationship between immediate survival and frailty, and in-hospital mortality and frailty. Results: 91% Veterans were non-Hispanic, 49% Caucasian, 96% male, mean age 70.7 ± 8.5 years, 73% frail and 27% non-frail. Seventy-six (65.5%) Veterans had ROSC, without difference by frailty status ( P = .891). There was no difference based on frailty status of in-hospital mortality, discharge disposition, or neurologic outcomes. Frail and non-frail Veterans had resuscitation efforts lasting the same amount of time. Conclusions and Implications: CPR outcomes were not different depending on frailty status in our Veteran population. With these results, we cannot use frailty – as measured by the VA-FI - as a prognosticator of CPR outcomes in Veterans.

Triple negative breast cancer (TNBC) occurs in 10-15% of all breast cancer (BC) patients, yet it accounts for almost half of all BC deaths. Women of African ancestry (WAA) are twice as likely as women of European Ancestry (WEA) to be diagnosed with advanced TNBC with worse prognosis. Emerging data shows that insulin resistance and high circulating levels of insulin are more prevalent in WAA with invasive BCs than in WEA, and activation of the AKT/mTOR pathway by insulin may occur in aggressive TNBC. Reports show diabetic patients treated with metformin, a biguanide drug used to treat diabetes type 2, have reduced incidence of BC and improved survival. However, anticancer actions of metformin require use of high drug doses with limiting side effects in vivo. To address this challenge, we used a structure-activity strategy to develop biguanide analogues with more potent anticancer action and safety at lower doses in vivo. Using TNBC cell proliferation in vitro to screen analogues, promising candidates were identified that exerted dose-dependent inhibition of cell proliferation at significantly lower doses than that of parental metformin (P Citation Format: Diana C. Márquez-Garban, Gang Deng, Lorena P. Burton, Gaoyuan Ma, Vishaka Muhunthan, Begonya Comin-Anduix, Gabriela Llarena, Neda Moatamed, Jennifer Murphy, Nalo Hamilton, Daivd Shackelford, Michael E. Jung, Richard J. Pietras. Targeting metabolic vulnerabilities to reduce triple negative breast cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 510.

Pancreatic ductal adenocarcinoma (PDCA) is a leading cause of cancer death in the US. Patients diagnosed with PDCA generally present with advanced disease with poor prognosis and limited treatment options. African American patients have higher incidence and mortality of PDCA than Caucasian American or any other ethnic group. Different factors have been attributed to contribute to this health disparity, among them higher incidence of Diabetes Mellitus type 2. To address the need for new therapeutic approaches, we note epidemiologic reports that patients with diabetes mellitus-type 2 treated with the biguanide drug metformin, but not other antidiabetic drugs, have a reduced risk of PDCA and an increased survival rate among those with PDCA. The main physiologic effect of metformin is to lower blood glucose and reduce hyperinsulinemia associated with insulin resistance. In the cell, metformin stimulates AMP-activated protein kinase (AMPK) that in turn inhibits mTORC1 which integrates signals from an array of intracellular pathways to regulate cell growth. Recent clinical trials describe modest antiproliferative effects from use of neoadjuvant metformin, but no significant clinical benefit occurred when metformin was dosed at glycemic control levels in patients with advanced cancers. These findings suggest that development of more potent anticancer analogues of metformin may help to boost clinical benefit and patient survival. Hence, we have designed new biguanide analogues of metformin, and screening of these compounds in preclinical PDCA models show that selected analogues are more efficacious in blocking tumor progression than parental metformin at lower doses. Using proliferation assays in vitro, PDCA cells (Panc 1, MIA Paca-2) were treated 72-hrs with metformin or analogues, and greater dose-dependent inhibition of PDCA cell proliferation was found with analogues as compared to metformin (P

The tumor microenvironment (TME) is a complex infrastructure composed of stromal, epithelial, and immune cells embedded in a vasculature ECM. The microenvironment surrounding mammary epithelium plays a critical role during the development and differentiation of the mammary gland, enabling the coordination of the complex multihormones and growth factor signaling processes. Progesterone/progesterone receptor paracrine signaling interactions in the microenvironment play vital roles in stem/progenitor cell function during normal breast development. In breast cancer, the female sex hormones, estrogen and progesterone, and growth factor signals are altered in the TME. Progesterone signaling modulates not only breast tumors but also the breast TME, leading to the activation of a series of cross-communications that are implicated in the genesis of breast cancers. This chapter reviews the evidence that progesterone and PR signaling modulates not only breast epitheliums but also the breast TME. Furthermore, crosstalk between estrogen and progesterone signaling affecting different cell types within the TME is discussed. A better understanding of how PR and progesterone affect the TME of breast cancer may lead to novel drugs or a therapeutic approach for the treatment of breast cancer shortly.

Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC are urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs and mediates its proliferative effects via two hormone receptors, insulin-like growth factor -1 receptor (IGF1R) and insulin receptor (IR). Using a TNBC tissue microarray (TMA) consisting of 159 archival clinical samples, we confirm that IGF2 is highly expressed in tumor tissue as compared to nearby normal tissue (P Citation Format: Nalo M. Hamilton, Diana Marquez-Garban, David Austin, Neda Moatamed, Lorena P. Burton, David Elashoff, Begonya Comin-Anduix, Tristan Grogan, Madhuri Wadehra, Helena Chang, Adrienne Martinez, Mary-Lynn Brecht, Isabel Jabara, Richard Pietras, Yahya Elshimali, Jaydutt Vadgama, Michael Jung. Insulin-like growth factor-2 a potential target for screening and treatment in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 943.

Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC is urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs in African-American and Latina patients. Since hormone receptors, like insulin-like growth factor-1/insulin (IGF1R/IR, are known to be enriched and to cross-communicate in subtypes of TNBC, we assessed effects of IGF1R/IR antagonists on proliferation of human and murine TNBC cells in vitro. Combination treatment of BMS-754807 (IGF1R/IR) with NVP-AEW541 (IGF1R inhibitor) reduced proliferation of human MDA-MB-231, BT549, HCC1937 and murine 4T1 TNBC cells in vitro (P Citation Format: Nalo M. Hamilton, Diana C. Marquez-Garban, Lorena P. Burton, Begonya Comin-Anduix, Alejandro J. Garcia, Jaydutt V. Vadgama. Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) antagonist with anti-PD-L1 antibody blocks triple-negative breast cancer (TNBC) progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-391.