Incidence of lymph node metastases in clinical early-stage mucinous and seromucinous ovarian carcinoma: a retrospective cohort study.

OBJECTIVE: The use of lymph node sampling during staging procedures in clinical early-stage mucinous ovarian carcinoma (MOC) is an ongoing matter of debate. Furthermore, the incidence of lymph node metastases (LNM) in MOC in relation to tumour grade (G) is unknown. We aimed to determine the incidence of LNM in clinical early-stage MOC per tumour grade. DESIGN: Retrospective study with data from the Dutch Pathology Registry (PALGA). SETTING: The Netherlands, 2002-2012. POPULATION OR SAMPLE: Patients with MOC. METHODS: Histology reports on patients with MOC diagnosed in the Netherlands between 2002 and 2012 were obtained from PALGA. Reports were reviewed for diagnosis, tumour grade and presence of LNM. Clinical data, surgery reports and radiology reports of patients with LNM were retrieved from hospital files. MAIN OUTCOME MEASURES: Incidence of LNM, disease-free survival (DFS). RESULTS: Of 915 patients with MOC, 426 underwent lymph node sampling. Cytoreductive surgery was performed in 267 patients. The other 222 patients received staging without lymph node sampling. In eight of 426 patients, LNM were discovered by sampling. In four of 190 (2.1%) patients with G1 MOC, LNM were present, compared with one of 115 (0.9%) patients with G2 MOC and three of 22 (13.6%) patients with G3 MOC. Tumour grade was not specified in 99 patients. Patients with clinical early-stage MOC had no DFS benefit from lymph node sampling. CONCLUSIONS: LNM are rare in early-stage G1 and G2 MOC without clinical suspicion of LNM. Therefore, lymph node sampling can be omitted in these patients. TWEETABLE ABSTRACT: Lymph node sampling can be omitted in clinical early-stage G1 and G2 mucinous ovarian cancer.

Microfluidic technologies for immunotherapy studies on solid tumours.

Immunotherapy is a powerful and targeted cancer treatment that exploits the body's immune system to attack and eliminate cancerous cells. This form of therapy presents the possibility of long-term control and prevention of recurrence due to the memory capabilities of the immune system. Various immunotherapies are successful in treating haematological malignancies and have dramatically improved outcomes in melanoma. However, tackling other solid tumours is more challenging, mostly because of the immunosuppressive tumour microenvironment (TME). Current in vitro models based on traditional 2D cell monolayers and animal models, such as patient-derived xenografts, have limitations in their ability to mimic the complexity of the human TME. As a result, they have inadequate translational value and can be poorly predictive of clinical outcome. Thus, there is a need for robust in vitro preclinical tools that more faithfully recapitulate human solid tumours to test novel immunotherapies. Microfluidics and lab-on-a-chip technologies offer opportunities, especially when performing mechanistic studies, to understand the role of the TME in immunotherapy, and to expand the experimental throughput when using patient-derived tissue through its miniaturization capabilities. This review first introduces the basic concepts of immunotherapy, presents the current preclinical approaches used in immuno-oncology for solid tumours and then discusses the underlying challenges. We provide a rationale for using microfluidic-based approaches, highlighting the most recent microfluidic technologies and methodologies that have been used for studying cancer-immune cell interactions and testing the efficacy of immunotherapies in solid tumours. Ultimately, we discuss achievements and limitations of the technology, commenting on potential directions for incorporating microfluidic technologies in future immunotherapy studies.

OS006. Functional expression of endogenous ligands of Toll like receptor4 on monocytes and placentae from women during normal pregnancy andpre-eclampsia.

INTRODUCTION: Preeclampsia (PE) is characterized by an exaggerated systemic inflammatory response (ESIR). Several recent studies by our group and others have demonstrated up-regulation of Toll like receptor 4 (TLR4) in trophoblast, placenta and leukocytes in PE but the exact role of TLR4 in the pathogenesis of PE remains unclear. OBJECTIVES: We sought to determine the expression levels of endogenous ligands of TLR4 in plasma and placentas from women with PE vs normotensive pregnant women (NP), and to compare the inflammatory cytokine expression profiles of monocytes from women with PE to NP, in order to identify which of these endogenous ligands of TLR4 may play a functional role in the pathogenesis of PE for further study. METHODS: We recruited 16 PE (gestational age=33.6±3.0weeks), 10 normal pregnant (gestational age=31.6±3.8weeks) and 10 non-pregnant women. Plasma levels of endogenous TLR4 ligands-heparan sulfate, hyaluronan, fibronectin, fibrinogen and High mobility group box-1(HMGB1)-were measured by ELISA. Monocytes were isolated from peripheral blood, cultured and stimulated by lipopolysaccharide (LPS; TLR4 bacterial ligand) and endogenous TLR4 ligands, and inflammatory cytokines were measured in supernatant medium by cytometric array. Placental tissue from PE and NP were investigated for the different endogenous ligands by immunohistochemistry. RESULTS: Plasma levels of heparan sulfate and fibronectin did not differ between study groups, but HMGB1 was higher in PE (P<0.05) whilst fibrinogen was significantly lower in PE compared to NP (P<0.05). Stimulation of PE monocytes with LPS resulted in profound secretion of various cytokines: IL-6, IL-8, IL-1ß, TNFα and IL-10, in comparison with NP. Moreover, exposure to fibrinogen, but not to other endogenous TLR4 ligands, was also associated with significantly increased production of inflammatory cytokines in PE compared to NP. Also, we observed altered distribution levels of studied endogenous ligands in the placenta from PE vs NP. CONCLUSION: Our findings of increased inflammatory cytokine expression levels in PE in response to LPS are consistent with upregulation of TLR4 in PE. A similar response induced by fibrinogen suggests an important role for this endogenous ligand of TLR4 in the pathogenesis of PE. Whether our observation of decreased plasma levels of fibrinogen in PE is linked to this observation, or represents increased fibrinogenesis and fibrinolysis associated with the abnormal coagulopathy seen in this condition, is unclear.

The autophagic paradox in cancer therapy.

Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.