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Purpose: We aimed to study the potential influence of tumour blood flow –obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)- in the metabolomic profiles of endometrial tumours. Methods: Liquid chromatography coupled to mass spectrometry established the metabolomic profile of endometrial cancer lesions exhibiting high (n=12) or low (n=14) tumour blood flow at DCE-MRI. Univariate and multivariate statistics (ortho-PLS-DA, a random forest (RF) classifier and hierarchical clustering) and receiver operating characteristic (ROC) curves were used to establish a panel for potentially discriminating tumours with high versus low blood flow. Results: Tumour blood flow is associated with specific metabolomic signatures. Ortho-PLS-DA and RF classifier resulted in well-defined clusters with an out-of-bag error lower than 8%. We found 28 statistically significant molecules (False Discovery Rate corrected p

// Anna Berg 1, 2 , Ankush Gulati 3 , Sigmund Ytre-Hauge 3, 4 , Kristine E. Fasmer 3 , Karen K. Mauland 1, 2 , Erling A. Hoivik 1, 2 , Jenny A. Husby 3, 4 , Ingvild L. Tangen 1, 2 , Jone Trovik 1, 2 , Mari K. Halle 1, 2 , Ingunn Stefansson 5, 6 , Lars A. Akslen 5, 6 , Kathrine Woie 2 , Line Bjorge 1, 2 , Helga B. Salvesen 1, 2 , Oyvind O. Salvesen 7 , Henrica M.J. Werner 1, 2 , Ingfrid S. Haldorsen 3, 4, * and Camilla Krakstad 1, 2, * 1 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway 2 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway 3 Department of Radiology, Haukeland University Hospital, Bergen, Norway 4 Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway 5 Department of Pathology, Haukeland University Hospital, Bergen, Norway 6 Department of Clinical Medicine, Centre for Cancer Biomarkers, Bergen, Norway 7 Unit for Applied Clinical Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway * These authors have contributed equally to this work Correspondence to: Camilla Krakstad, email: camilla.krakstad@uib.no Keywords: endometrial carcinoma, endometrial hyperplasia, PBK, MRI, FDG-PET/CT Received: April 27, 2017 Accepted: June 19, 2017 Published: July 31, 2017 ABSTRACT Purpose: Distinguishing complex atypical hyperplasia (CAH) from grade 1 endometrioid endometrial cancer (EECG1) preoperatively may be valuable in order to prevent surgical overtreatment, particularly in patients wishing preserved fertility or in patients carrying increased risk of perioperative complications. Material and methods: Preoperative histological diagnosis and radiological findings were compared to final histological diagnosis in patients diagnosed with CAH and EECG1. Imaging characteristics at preoperative magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computer tomography (FDG-PET/CT) were compared with tumor DNA oligonucleotide microarray data, immunohistochemistry findings and clinicopathological annotations. Results: MRI assessed tumor volume was higher in EECG1 than in CAH (p=0.004) whereas tumor apparent diffusion coefficient value was lower in EECG1 (p=0.005). EECG1 exhibited increased metabolism with higher maximum and mean standard uptake values (SUV) than CAH (p≤0.002). Unsupervised clustering of EECG1 and CAH revealed differentially expressed genes within the clusters, and identified PDZ-binding kinase (PBK) as a potential marker for selecting endometrial lesions with less aggressive biological behavior. Conclusion: Both PBK expression and preoperative imaging yield promising biomarkers that may aid in the differentiation between EECG1 and CAH preoperatively, and these markers should be further explored in larger patient series.

Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients. publishedVersion