Ovarian cancer cells direct monocyte differentiation through a non-canonical pathway.

BACKGROUND: Alternatively-activated macrophages (AAMs), an anti-inflammatory macrophage subpopulation, have been implicated in the progression of high grade serous ovarian carcinoma (HGSOC). Increased levels of AAMs are correlated with poor HGSOC survival rates, and AAMs increase the attachment and spread of HGSOC cells in vitro. However, the mechanism by which monocytes in the HGSOC tumor microenvironment are differentiated and polarized to AAMs remains unknown. METHODS: Using an in vitro co-culture device, we cultured naïve, primary human monocytes with a panel of five HGSOC cell lines over the course of 7 days. An empirical Bayesian statistical method, EBSeq, was used to couple RNA-seq with observed monocyte-derived cell phenotype to explore which HGSOC-derived soluble factors supported differentiation to CD68+ macrophages and subsequent polarization towards CD163+ AAMs. Pathways of interest were interrogated using small molecule inhibitors, neutralizing antibodies, and CRISPR knockout cell lines. RESULTS: HGSOC cell lines displayed a wide range of abilities to generate AAMs from naïve monocytes. Much of this variation appeared to result from differential ability to generate CD68+ macrophages, as most CD68+ cells were also CD163+. Differences in tumor cell potential to generate macrophages was not due to a MCSF-dependent mechanism, nor variance in established pro-AAM factors. TGFα was implicated as a potential signaling molecule produced by tumor cells that could induce macrophage differentiation, which was validated using a CRISPR knockout of TGFA in the OVCAR5 cell line. CONCLUSIONS: HGSOC production of TGFα drives monocytes to differentiate into macrophages, representing a central arm of the mechanism by which AAMs are generated in the tumor microenvironment.

Neoadjuvant chemotherapy is associated with more anemia and perioperative blood transfusions than primary debulking surgery in women with advanced stage ovarian cancer.

OBJECTIVE: The purpose of this case-controlled study was to determine the prevalence of anemia and incidence of perioperative blood transfusions in patients undergoing treatment for advanced ovarian cancer with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS). METHODS: We performed a single institution review of patients diagnosed with stage IIIB-IVB epithelial ovarian cancer between 2010 and 2013 undergoing either NACT or PDS. Anemia was defined as a hemoglobin (Hgb) concentration of ≤11.5 g/dL. Continuous variables were compared by student t-test and binary variables compared via chi square analysis. RESULTS: One hundred thirty-one women were included, 66 treated with NACT and 65 treated with PDS. Average Hgb prior to surgery was lower in women who received NACT (10.7 g/dL vs 12.8 g/dL, p < 0.0001). Women treated with NACT had a decrease in mean Hgb during chemotherapy treatment (11.8 g/dL at diagnosis to 10.7 g/dL preoperatively). Seventy-seven percent of NACT patients were anemic prior to surgery compared to 15% of patients prior to PDS (p < 0.001). Mean EBL at debulking was higher in patients selected for PDS (871 mL) than NACT (544 mL); however, the perioperative transfusion rate was higher during interval debulking surgeries (NACT 77% vs PDS 56%, p = 0.01). CONCLUSION: Women selected for NACT were more likely to be anemic at diagnosis and became progressively anemic during NACT. Despite less blood loss during debulking surgery, NACT patients receive more blood transfusions perioperatively than patients undergoing PDS. This represents a potential opportunity for therapeutic intervention during NACT to correct anemia prior to interval debulking surgery.

Peri-operative allogeneic blood transfusion is associated with poor overall survival in advanced epithelial ovarian Cancer; potential impact of patient blood management on Cancer outcomes.

BACKGROUND: Transfusion related immune modulation associated with red blood cell (RBC) transfusion is thought to result in decreased cancer survival. Results in epithelial ovarian cancer (EOC) have been mixed however most suggest worse oncologic outcomes in patients who were transfused at the time of debulking surgery. The impact of restrictive transfusion strategies on this patient population is currently not known. METHODS: We conducted a retrospective study of women with EOC. The study population was divided into two groups based on whether they were transfused RBCs during the peri-operative period or not. Clinical characteristics and prognosticators were compared between groups. Overall survival was compared between groups based on transfusion status and other known prognostic factors. Cox proportional hazard modeling was used to examine the association between the prognostic factors and the study endpoint. RESULTS: Sixty-six percent of women were transfused. Transfusion was associated with CA125, the use of neoadjuvant chemotherapy (NACT), surgical blood loss, and anemia. The mean pre-transfusion Hgb was 7.8 + 0.6 g/dL and 94% had a hemoglobin level greater than the transfusion threshold of 7 g/dL. RBC transfusion, suboptimal debulking, anemia, and NACT were associated with decreased survival. Only RBC transfusion and suboptimal debulking status remained significant in a multivariate model. CONCLUSIONS: Peri-operative RBC transfusion compromises survival in ovarian cancer supporting the need to minimize the use of transfusion at the time of debulking surgery. Adherence to evidence-based transfusion guidelines offers an opportunity to reduce transfusion rates in this population with a resulting positive influence on survival.

Retaining early career registered nurses: a case study.

BACKGROUND: A core objective of the Australian health system is to provide high quality, safe health care that meets the needs of all Australians. To achieve this, an adequate and effective workforce must support the delivery of care. With rapidly changing health care systems and consumer demographics, demand for care is increasing and retention of sufficient numbers of skilled staff is now a critical priority to meet current and future health care demands. Nurses are the largest cohort of professionals within the health workforce. Reducing the rates at which nurses leave the profession and supporting nurses to practice in their profession longer will have beneficial implications for the sustainability of a nursing workforce and, ultimately, to patient outcomes. The aim of the study was to describe and explain early career registered nurses' (ECRNs) experiences and support requirements during the first five years of practice for the purposes of identifying strategies that would support greater retention of ECRNs. METHODS: A single case study design focused on early career registered nurses (ECRNs) working in a hospital and health service in northern Australia. The research team adopted Djukic et al's definition of ECRNs as "RNs who have practiced for less than 5 years". Data was collected via three individual interviews and two focus groups. Thirty-five ECRNs participated in the study. RESULTS: Qualitative analysis of data generated during interviews and focus groups, identified the key themes of receiving career advice and choice or no choice. Analysis of study data in the context of the broader literature resulted in the researchers identifying six areas of focus for ECRN retention: 1) well-planned, supported and structured transition periods; 2) consideration of rotation through different areas with a six month minimum for skills development; 3) empowering decision making; 4) placement opportunities and choice in decisions of where to work; 5) career advice and support that considers ECRNs' personalities and skills; and 6) encouragement to reflect on career choices. CONCLUSIONS: Reducing turnover and improving retention relies on understanding the factors that influence nurses' decisions to leave or remain within an organisation and the profession. Ensuring nurses in the current workforce remain engaged and productive, rather than leave the profession, is reliant on addressing factors that cause attrition and implementing strategies that strengthen retention rates and workforce sustainability.

Clinical Staging of Ovarian Cancer.

Ovarian cancer may arise from any of the histologic portions of the ovary including the epithelium, stroma, or germ cells. Of these, high-grade serous carcinoma arising from the epithelium of the ovary is the most common type. The clinical management and prognosis of ovarian cancer depend upon the stage of the cancer. Cancer stage is the extent to which the cancer has spread from its site of origin. For ovarian cancer, staging guidelines are determined by FIGO, the Fédération Internationale de Gynécologie et d'Obstétrique. The stage of ovarian cancer is determined by performing surgery to remove the ovaries and other gynecologic organs as well as lymph nodes and other tissues where the cancer may have spread. The histologic specimens from this surgery provide information from which the stage can be determined. In more advanced cases, this surgery may also include procedures to remove other areas of cancer. The stage of ovarian cancer guides treatment and is also the most important factor in ovarian cancer prognosis. Most epithelial ovarian cancers are diagnosed in advanced stages and are treated with surgery and chemotherapy. Despite aggressive treatment, the survival of patients with advanced stage epithelial ovarian cancer remains low, and more effective diagnostic and therapeutic approaches are needed.

Ovarian Cells Have Increased Proliferation in Response to Heparin-Binding Epidermal Growth Factor as Collagen Density Increases.

It is well known that during ovarian cancer progression, the omentum transforms from a thin lacy organ to a thick tougher tissue. However, the mechanisms regulating this transformation and the implications of the altered microenvironment on ovarian cancer progression remain unclear. To address these questions, the global and local concentrations of collagen I were determined for normal and metastatic human omentum. Collagen I was increased 5.3-fold in omenta from ovarian cancer patients and localized to areas of activated fibroblasts rather than regions with a high density of cancer cells. Transforming growth factor beta 1 (TGFß1) was detected in ascites from ovarian cancer patients (4 ng/mL), suggesting a potential role for TGFß1 in the observed increase in collagen. Treatment with TGFß1 induced fibroblast activation, proliferation, and collagen deposition in mouse omental explants and an in vitro model with human omental fibroblasts. Finally, the impact of increased collagen I on ovarian cancer cells was determined by examining proliferation on collagen I gels formulated to mimic normal and cancerous omenta. While collagen density alone had no impact on proliferation, a synergistic effect was observed with collagen density and heparin-binding epidermal growth factor treatment. These results suggest that TGFß1 induces collagen deposition from the resident fibroblasts in the omentum and that this altered microenvironment impacts cancer cell response to growth factors found in ascites. Impact statement Using quantitative analysis of patient samples, in vitro models of the metastatic ovarian cancer microenvironment were designed with pathologically relevant collagen densities and growth factor concentrations. Studies in these models support a mechanism where transforming growth factor ß1 in the ascites fluid induces omental fibroblast proliferation, activation, and deposition of collagen I, which then impacts tumor cell proliferation in response to additional ascites growth factors such as heparin-binding epidermal growth factor. This approach can be used to dissect mechanisms involved in microenvironmental modeling in multiple disease applications.