Search

PDF file - 1147KB, 2 x 106 MDA-MB-231 or MDA-MB-435 cells were injected into 6- to 7-week-old female NOD/SCID or nu/nu mice via mammary fat pad. The control cohort (n=4) received weekly saline subcutaneous injections, while three other cohorts (n=4 per group) received rHuEPO doses of 300U/kg, 600U/kg or 1200U/kg. (A-D) Data from MDA-MB-231 breast cancer cells in NOD/SCID mice. (E-H) Results from MDA-MB-435 breast cancer cells injected into nude (nu/nu) mice. (A,E) Primary tumor growth of human breast cancer cells injected into mice over time. EPO treatment was initiated at 3 weeks post injection (black arrow). Data are presented as mean � SEM. (B,F) Incidence of lung metastasis (% of mice in each treatment group that developed metastases). (C,G) Size (diameter) of lung metastases scored. Data are presented as mean � SEM. (D,H) Number of lung metastases observed. Data are presented as the mean � SEM. For all panels, # denotes a statistically significant difference relative to the untreated control cohort (p

PDF file - 119KB, Supplemental Table 1- Cell lines used. Supplemental Table 2 - PCR primers and cycling conditions. Supplemental Table 3 - Anti Human EPOR antibodies used. Supplemental Table 4 - In Vivo hemoglobin measurements.

Purpose: Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.Experimental Design: Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.Results: A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05).Conclusions: The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy. Clin Cancer Res; 17(19); 6151–62. ©2011 AACR.

PDF file - 145KB, EPOR and JAK2 amplification was normalized to GAPDH intensity for mBM, UT7/EPO, 3T3, H838, MDA-MB-435, MDA-MB-231, MDA-MB-468 and 4T1 samples, with (*) or without rHuEPO treatment and subjected to densitometric analysis.

Introduction: Unplanned visits (UPV) — re-admissions and emergency room (ER) visits — are markers of healthcare system quality. Radical prostatectomy (RP) is a commonly performed cancer procedure, where variation in UPV represents a gap in care for prostate cancer patients. Here, we systematically synthesize the rates, reasons, predictors, and interventions for UPV after RP, to inform evidence-based quality improvement (QI) initiatives. Methods: A systematic review was performed for studies from 2000–2020 using keywords: “re-admission,” “emergency room/department,” “unplanned visit,” and “prostatectomy.” Studies that focused on UPV following RP and that reported rates, reasons, predictors, or interventions, were included. Data was extracted via a standardized form. Meta-analysis was completed. Results: Sixty studies, with 406 107 RP patients, were eligible; 16 028 UPV events (~5%) were analyzed from 317 050 RP patients. UPV rates after RP varied between studies (ER visit range 6–24%; re-admissions range 0–56%). The 30-day and 90-day ER visit rates were 12% and 14%, respectively; the 30-day and 90-day re-admission rates were 4% and 9%, respectively. A total of 55% of all re-admissions after RP are directly due to postoperative genitourinary (GU)-related complications such as strictures, obstructions, fistula, bladder-related, incontinence, urine leak, renal problems, and other unspecified urinary complications. The next most common re-admission reasons were anastomosis-related, infection-related, cardiovascular/pulmonary events, and wound-related issues. Thirty-four percent of all ER visits after RP are directly due to urine-related issues such as retention, urinoma, obstruction, leak, and catheter problems. The next most common ER visit reasons were abdominal/gastrointestinal issues, infection-related, venous thromboembolic events, and wound-related issues. Predictors for increased re-admission included: open RP, lymph node dissection, Charlson comorbidity index≥2, low surgeon/hospital case volume, and socioeconomic determinants of health. Of the 10 interventions evaluated, a 3.4% average reduction in UPV rate was observed, highlighting an approximate two-fold decrease. Meta-analysis demonstrated a significant benefit of interventions over controls with odds ratio 0.62 (95% confidence interval 0.46–0.84). Interventions that used multidisciplinary, nurse-centered, programs, with patient self-care/empowerment were more beneficial than algorithmic patient care pathways and preoperative patient education. Conclusions: Twenty years of international, retrospective, experience suggests UPV after RP are often related to GU complications, infection- or wound-related factors. QI interventions to reduce UPV should target these factors. While many re-admissions after RP appear to be unavoidable, ER visits have more opportunity for volume reduction by QI. The interventions evaluated herein have potential to reduce UPV after RP.

Purpose: Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study. Experimental Design: Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents. Results: A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05). Conclusions: The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy. Clin Cancer Res; 17(19); 6151–62. ©2011 AACR.

Abstract 3345 Background: Erythropoietin (EPO) is a key regulator of erythropoiesis, and has been shown to stimulate growth, maintain viability, and promote differentiation of red blood cell precursors. The EPO receptor (EPO-R) is expressed by erythroid cells and by several non-hematopoietic cell types including various neoplastic cells. Erythropoiesis-stimulating agents (ESAs) are used clinically for the treatment of chemotherapy-induced anemia. The results of some recent randomized clinical trials have reported an increased incidence in adverse events and reduced survival in ESA-treated metastatic breast cancer patients receiving chemotherapy, potentially related to EPO-induced cancer progression. These results have raised concerns over ESA treatment in metastatic cancer patients. However, very little pre-clinical data is available regarding the impact of EPO on breast cancer metastasis. The goal of the current study was therefore to determine if EPO can influence the malignant behavior of breast cancer cells and/or influence the metastatic process. Methods: MDA-MB-468, MDA-MB-231, MDA-MB-435, and 4T-1 breast cancer cell lines were treated with recombinant human EPO (rHuEPO; 10 U/ml) or control media and screened for EPO-R mRNA expression levels by RT-PCR, and for EPO-R protein expression by Western blot and flow cytometry. MDA-MB-231 (231) and MDA-MB-435 (435) cell lines were used for functional assays in vitro and in vivo. Untreated or rHuEPO treated cells were grown in 2D and 3D in vitro systems (standard tissue culture plates and 0.6% soft agar, respectively) to determine if rHuEPO influenced growth. In vitro cell survival was also assessed in response to treatment with rHuEPO in the presence or absence of paclitaxel chemotherapy (10mg/ml), radiation (10G), or hypoxic conditions (1% O2). Following mammary fat pad injection, in vivo effects of rHuEPO (300U/kg) alone or in combination with paclitaxel treatment (10mg/kg) were assessed in mouse models of tumorigenicity and spontaneous metastasis. Results: Expression analysis of EPO-R mRNA and protein revealed a large variation in levels across different cell lines. The majority of cell lines did not express cell surface EPO-R by flow cytometry, although two cell lines (231 and 435) did show weak expression of EPO-R mRNA, with only the 231 cell line showing EPO-R expression by Western blot. In vitro, a small protective effect from rHuEPO on radiation-treated 435 cells was seen (p Conclusions: The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. Our novel findings demonstrate that rHuEPO can reduce the efficacy of chemotherapy in the metastatic setting in vivo, and in some cases enhance the inherent metastatic growth potential of human breast cancer cells. This work was supported by funding from the London Regional Cancer Program and Janssen Ortho Canada Disclosures: Xenocostas: Janssen Ortho: Consultancy, Honoraria, Research Funding. Allan:Janssen Ortho: Research Funding.