ISG15 mediates the function of extracellular vesicles in promoting ovarian cancer progression and metastasis.

The interferon stimulated gene 15 (ISG15), a ubiquitin like protein and its conjugates have been implicated in various human malignancies. However, its role in ovarian cancer progression and metastasis is largely unknown. In high grade serous ovarian cancer (HGSOC), ascites is the major contributor to peritoneal metastasis. In this study, we identified significantly elevated ISG15 protein expression in HGSOC patient ascites, ascites derived primary ovarian cancer cells (POCCs), POCC small extracellular vesicles (sEVs) as well as metastatic tissue. Our results demonstrates that ISG15 increases exocytosis in ascites-derived POCCs by decreasing the endosome-lysosomal fusion, indicating a key role in sEV secretion. Further, knockdown (KD) of ISG15 resulted in a significant decrease in vesicles secretion from HGSOC cells and in vivo mouse models, leading to reduced HGSOC cell migration and invasion. Furthermore, our pre-clinical mouse model studies revealed the influence of vesicular ISG15 on disease progression and metastasis. In addition, knockdown of ISG15 or using the ISG15 inhibitor, DAP5, in combination therapy with carboplatin showed to improve the platinum sensitivity in-vitro and reduce tumour burden in-vivo. We also found that ISG15 expression within sEV represents a promising prognostic marker for HGSOC patients. Our findings suggest that ISG15 is a potential therapeutic target for inhibiting progression and metastasis in HGSOC and that vesicular ISG15 expression could be a promising biomarker in the clinical management of ovarian cancer. Significance: High-grade serous ovarian cancer (HGSOC) has high morbidity and mortality rates, but its progression and metastasis are still poorly understood, and there is an urgent need for early detection and targeted therapies. Our study presents novel findings that implicate ISG15-mediated vesicular proteins in the advancement and spread of HGSOC. These results offer pre-clinical evidence of potential new molecular targets, prognostic markers and therapeutic strategies for HGSOC that could ultimately enhance patient survival.

Tissue factor as a novel diagnostic target for early detection of ovarian cancer using ultrasound microbubbles.

INTRODUCTION: Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF). METHODS: TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models. RESULTS: While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model. CONCLUSION: Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.

Imaging of Bone Perfusion and Metabolism in Subjects Undergoing Total Ankle Arthroplasty Using 18F-Fluoride Positron Emission Tomography.

BACKGROUND: Total ankle arthroplasty (TAA) continues to exhibit a relatively high incidence of complications and need for revision surgery compared to knee and hip arthroplasty. One common mode of failure in TAA is talar component subsidence. This may be caused by disruption in the talar blood supply related to the operative technique. The purpose of this study was to quantify changes in talar bone perfusion and turnover before and after TAA with the INBONE II system using 18F-fluoride positron emission tomography / computed tomography (PET/CT). METHODS: Nine subjects (5 M/4 F) aged 68.9 ± 8.2 years were enrolled for 18F-fluoride PET/CT imaging before and 3 months after TAA. Regions of interest (ROI) were placed on the postoperative CT images in the body of the talus beneath the talar component and overlaid on the fused static PET images. Standard uptake values (SUVs) along with dynamic K1 (bone blood flow) and ki (bone metabolism or osteoblastic turnover) were calculated. RESULTS: The SUV underneath the talar component compared to that measured at baseline before surgery was 1.93 ± 0.29 preoperatively vs 2.47 ± 0.37 postoperatively (P > .05). K1 was 0.84 ± 0.16 mL/min/mL preoperatively vs 1.51 ± 0.23 mL/min/mL postoperatively (P = .026). ki was constant at 0.09 ± 0.03 mL/min/mL preoperatively vs 0.12 ± 0.03 mL/min/mL postoperatively (P > .05). CONCLUSION: Our study was the first to link 18F-fluoride PET/CT with pre-post evaluation of total ankle replacements. The study quantified perfusion within the talus beneath the TAA implant supporting the hypothesis that perfusion of the talus remained intact after surgery. LEVEL OF EVIDENCE: Level II, prospective cohort study with development of diagnostic criteria.

Establishing a general medical outpatient clinic for cancer survivors in a public city hospital setting.

INTRODUCTION: Many cancer centers and community hospitals are developing novel models of survivorship care. However, few are specifically focused on services for socio-economically disadvantaged cancer survivors. AIMS: To describe a new model of survivorship care serving culturally diverse, urban adult cancer patients and to present findings from a feasibility evaluation. SETTING: Adult cancer patients treated at a public city hospital cancer center. PROGRAM DESCRIPTION: The clinic provides comprehensive medical and psychosocial services for patients within a public hospital cancer center where they receive their oncology care. PROGRAM EVALUATION: Longitudinal data collected over a 3-year period were used to describe patient demographics, patient needs, and services delivered. Since inception, 410 cancer patients have been served. Demand for services has grown steadily. Hypertension was the most frequent comorbid condition treated. Pain, depression, cardiovascular disease, hyperlipidemia, and bowel dysfunction were the most common post-treatment problems experienced by the patients. Financial counseling was an important patient resource. DISCUSSION: This new clinical service has been well-integrated into its public urban hospital setting and constitutes an innovative model of health-care delivery for socio-economically challenged, culturally diverse adult cancer survivors.