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Journal articleNasser S, Lazaridis A, Evangelou M, et al., 2016,
Correlation of pre-operative CT findings with surgical & histological tumor dissemination patterns at cytoreduction for primary advanced and relapsed epithelial ovarian cancer: A retrospective evaluation
, Gynecologic Oncology, Vol: 143, Pages: 264-269, ISSN: 1095-6859ObjectivesComputed tomography (CT) is an essential part of preoperative planning prior to cytoreductive surgery for primary and relapsed epithelial ovarian cancer (EOC). Our aim is to correlate pre-operative CT results with intraoperative surgical and histopathological findings at debulking surgery.MethodsWe performed a systematic comparison of intraoperative tumor dissemination patterns and surgical resections with preoperative CT assessments of infiltrative disease at key resection sites, in women who underwent multivisceral debulking surgery due to EOC between January 2013 and December 2014 at a tertiary referral center. The key sites were defined as follows: diaphragmatic involvement(DI), splenic disease (SI), large (LBI) and small (SBI) bowel involvement, rectal involvement (RI), porta hepatis involvement (PHI), mesenteric disease (MI) and lymph node involvement (LNI).ResultsA total of 155 patients, mostly with FIGO stage IIIC disease (65%) were evaluated (primary = 105, relapsed = 50). Total macroscopic cytoreduction rates were: 89%. Pre-operative CT findings displayed high specificity across all tumor sites apart from the retroperitoneal lymph node status, with a specificity of 65%.The ability however of the CT to accurately identify sites affected by invasive disease was relatively low with the following sensitivities as relating to final histology:32% (DI), 26% (SI), 46% (LBI), 44% (SBI), 39% (RI), 57% (PHI), 31% (MI), 63% (LNI).ConclusionPre-operative CT imaging shows high specificity but low sensitivity in detecting tumor involvement at key sites in ovarian cancer surgery. CT findings alone should not be used for surgical decision making.
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Conference paperWahba J, Natoli M, Whilding L, et al., 2016,
PD-1 blockade enhances synergistic killing of ovarian tumour cells by combination chemotherapy and T cell immunotherapy
, 24th Biennial Congress of the European Association for Cancer Research, Publisher: Elsevier, Pages: S218-S218, ISSN: 0014-2964 -
Journal articleFrench JD, Johnatty SE, Lu Y, et al., 2016,
Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer
, Oncotarget, Vol: 7, Pages: 6353-6368, ISSN: 1949-2553 -
Journal articleBonito NA, Borley J, Wilhelm-Benartzi CS, et al., 2016,
Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.
, Clinical Cancer Research, Vol: 22, Pages: 3097-3104, ISSN: 1557-3265PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. EXPERIMENTAL DESIGN: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. RESULTS: CpG sites at contiguous genomic locations within theMSX1gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P< 0.05,q< 0.05,n= 78), have poor RECIST response (P< 0.05,q< 0.05,n= 61), and are associated with PFS in an independent cohort (n= 146). A decrease in methylation at these CpG sites correlates with decreasedMSX1gene expression.MSX1expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99;P= 0.029;n= 309). Cisplatin-resistant ovarian cancer cell lines have reducedMSX1expression, andMSX1overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. CONCLUSIONS: Hypomethylation of CpG sites within theMSX1gene is associated with resistant HGSOC disease at presentation and identifies expression ofMSX1as conferring platinum drug sensitivity.Clin Cancer Res; 1-8. ©2016 AACR.
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Journal articleKyriakides M, Rama N, Sidhu J, et al., 2016,
Metabonomic analysis of ovarian tumour cyst fluid by proton nuclear magnetic resonance spectroscopy
, Oncotarget, Vol: 7, Pages: 7216-7226, ISSN: 1949-2553The majority of ovarian tumours are of the epithelial type, which can be sub classified as benign, borderline or malignant. Epithelial tumours usually have cystic spaces filled with cyst fluid, the metabolic profile of which reflects the metabolic activity of the tumour cells, due to their close proximity. The approach of metabonomics using 1H-NMR spectroscopy was employed to characterize the metabolic profiles of ovarian cyst fluid samples (n = 23) from benign, borderline and malignant ovarian tumours in order to shed more light into ovarian tumour and cancer development. The analysis revealed that citrate was elevated in benign versus malignant tumours, while the amino acid lysine was elevated in malignant versus non-malignant tumours, both at a 5% significance level. Choline and lactate also had progressively increasing levels from benign to borderline to malignant samples. Finally, hypoxanthine was detected exclusively in a sub-cohort of the malignant tumours. This metabonomic study demonstrates that ovarian cyst fluid samples have potential to be used to distinguish between the different types of ovarian epithelial tumours. Furthermore, the respective metabolic profiles contain mechanistic information which could help identify biomarkers and therapeutic targets for ovarian tumours.
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Journal articleBolton KL, Tyrer J, Song H, et al., 2015,
Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer.
, Nature Genetics, Vol: 48, ISSN: 1546-1718 -
Journal articleNevedomskaya E, Perryman R, Solanki S, et al., 2015,
A systems oncology approach identifies NT5E as a key metabolic regulator in tumor cells and modulator of platinum sensitivity
, Journal of Proteome Research, Vol: 15, Pages: 280-290, ISSN: 1535-3893Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5′-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.
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Conference paperMenezes KA, Cunnea P, Lawton P, et al., 2015,
Targeting genomic instability to identify molecular drivers of poor prognosis in cancer
, AACR Special Conference on Translation of the Cancer Genome, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472 -
Journal articleBowtell DD, Boehm S, Ahmed AA, et al., 2015,
Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer
, Nature Reviews Cancer, Vol: 15, Pages: 668-679, ISSN: 1474-175XHigh-grade serous ovarian cancer (HGSOC) accounts for 70–80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.
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Journal articleCheraghchi-Bashi A, Parker CA, Curry E, et al., 2015,
A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway
, Oncotarget, Vol: 6, Pages: 41736-41749, ISSN: 1949-2553Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.
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