Cancer stem cells (CSC) present a formidable clinical challenge by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe small subpopulations of pancreatic cancer cells with high intrinsic Wnt activity (Wnt high ) that possess properties indicative of CSCs, including drug resistance and tumor-initiating capacity, whereas cell populations with negligible Wnt activity (Wnt low ) preferentially express markers of differentiation. Spontaneous response to extrinsic Wnt signals induces signaling networks comprising ERK1/2 and epithelial-mesenchymal transition that subsequently confer cancer stemness traits to susceptible cells. Wnt enhancer R-Spondin 2 (RSPO2) seems to play a prominent upstream role in regulating this interplay. In this context, Wnt high cells were more likely to give rise to Wnt high progeny, tended to be more metastatic, and revealed higher levels of RSPO2 expression. Our studies reveal adaptive aspects of pancreatic cancer stemness arising from driver populations of CSCs that misappropriate functional and responsive elements of archetypical self-renewal pathways. Blocking such stemness-promoting pathways in conjunction with established chemotherapy could provide means to disrupt dynamic CSC process and present novel therapeutic targets and strategies. Cancer Res; 75(9); 1883-96. Ó2015 AACR.

Multipotent stromal cells (MSCs) derived from bone marrow, adipose tissue, cord blood, and other origins have recently received much attention as potential therapeutic agents with beneficial immunomodulatory and regenerative properties. In their native tissue environment, however, such cells also appear to have essential functions in building and supporting tumor microenvironments, providing metastatic niches, and maintaining cancer hallmarks. Here, we consider the varied roles of these tissue-resident stroma-associated cells, synthesize recent and emerging discoveries, and discuss the role, potential, and clinical applications of MSCs in cancer and regenerative medicine.-Ilmer, M., Vykoukal, J., Recio Boiles, A., Coleman, M., Alt, E. Two sides of the same coin: stem cells in cancer and regenerative medicine.

505 Background: Two major trials and meta-analysis of patients (pts) with active cancer and VTE suggests that apixaban (A) and rivaroxaban (R) showed similar efficacy to enoxaparin and warfarin while having less associated major bleeding. GICA is associated with a higher incidence of VTE compared to other tumors. Moreover, bleeding complications of DOACs are not well defined in GICA pts. We compared the efficacy and safety of DOACs in pts with active GICA and VTE at the University of Arizona Cancer Center (UACC). Methods: A retrospective chart review of pts receiving DOACs with GICA and VTE treated at UACC was performed (11/2013-02/2017). GICA subgroup extracted from clinical trial delineations followed: active cancer, defined as cancer diagnosed at any stage +/- 6 months of VTE diagnosis. Efficacy outcomes were recurrent DVT, nonfatal pulmonary embolism (PE), or fatal PE. Safety outcomes for major bleeding were Hg drop of ≥2 g/dL, transfusion of ≥2 units of PRBC, bleeding in a critical site, or bleeding contributing to death. Fisher exact test is used for testing the difference in categorical variables for p-value < 0.05. Results: Our review included pts on A (n = 28) and R (n = 34). Pts had similar baseline characteristics compared to AMPLIFY (n = 81) and pooled-EINSTEIN (n = 71). Recurrent VTE at 6 months were 7.1% and 2.9% for pts on A and R, respectively. VTE historical comparison to AMPLIFY (3.7%) and EINSTEIN (2.8%) showed no significant difference. Major bleeding at 6 months were 7.1% and 14.7% for A and R, respectively, compared to 2.3% AMPLIFY / 2.8% EINSTEIN. R had the one recurrent non-fatal PE event and a significantly worse safety profile with 2 fatal bleeds (hemopericardium and upper GI bleed) and 2 critical bleeding sites (subarachnoid hemorrhage and retroperitoneal) [p = 0.0348], whereas A had non-significant of the before stated. Conclusions: To our knowledge, this is the first retrospective analysis to present long-term outcome data of DOACs in pts with GICA and VTE, which showed a similar risk of recurrent VTE and worse safety profile with R versus A. This data warrants further prospective clinical analysis of the efficacy and safety of DOACs in pts with GICA and VTE.

Metastatic castration-resistant prostate cancer (mCRPC) is universally incurable and represents an area of substantial unmet medical need. Novel targets and therapeutic strategies have emerged based on an improved understanding of the crosstalk between prostate cancer cells and the bone microenvironment. A wide variety of signaling systems including the RANKL/RANK/OPG, IGF-I, FGF and Wnt:DKK-1 pathways can be targeted to suppress tumor growth and treatment resistance. Antisurvival factor therapy can increase the efficacy of standard antineoplastic regimens by targeting biologic molecules acting as "survival factors" within the bone microenvironment. Novel agents can also be used to mobilize the host immune system to attack prostate cancer cells. Clinical testing of these therapeutic approaches has produced encouraging objective clinical responses in subsets of patients with mCRPC. The present review summarizes data regarding the emerging strategies used to target the bone microenvironment in mCRPC.

Purpose To characterize and compare both the outcome and cost of treatment of outpatient (OP) and inpatient (IP) ifosfamide therapy. Methods A single-center retrospective chart review of patients 18 years and older receiving ifosfamide therapy. The primary endpoint compares and evaluates the side effect profiles of ifosfamide-treated patients in the OP/IP settings. The adverse event grading system was characterized using the CTCAE Version 5.0. The highest grade was documented per cycle. The secondary endpoint of this study compares the costs of OP/IP therapy. It was assumed that the cost of medication was equivalent for IP/ OP treatments. The cost saved with OP administration was determined by the average cost of hospital stay for IP admission. Results Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were doxorobucinifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB) occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. Conclusions Transitioning ifosfamide to the OP setting is feasible for academic and community infusion centers with the OP administration being safe, well-tolerated, and associated with decreased total cost of care. The current processes allow for safe transition of chemotherapy of chemotherapy under times of COVID.