Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution.

Toll-like receptor-targeted anti-tumor therapies: Advances and challenges.

Toll-like receptors (TLRs) are pattern recognition receptors, originally discovered to stimulate innate immune reactions against microbial infection. TLRs also play essential roles in bridging the innate and adaptive immune system, playing multiple roles in inflammation, autoimmune diseases, and cancer. Thanks to the immune stimulatory potential of TLRs, TLR-targeted strategies in cancer treatment have proved to be able to regulate the tumor microenvironment towards tumoricidal phenotypes.

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer.

The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism.

Novel Models of Epithelial Ovarian Cancer: The Future of Biomarker and Therapeutic Research.

Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types.

Clinicopathological characteristics and survival outcomes of patients with large cell neuroendocrine carcinoma of the uterine cervix: A systematic review and meta-analysis.

Purpose: Large cell neuroendocrine carcinoma (LCNEC) of the cervix represents a rare tumour entity associated with poor prognosis. Knowledge about carcinogenesis and therapeutic options is scarce, while novel therapeutic targeted approaches are limited.

Methods: We performed a systematic review of four electronic databases from inception to June 2020.

Validation analysis of the novel imaging-based prognostic radiomic signature in patients undergoing primary surgery for advanced high-grade serous ovarian cancer (HGSOC).

Background: Predictive models based on radiomics features are novel, highly promising approaches for gynaecological oncology. Here, we wish to assess the prognostic value of the newly discovered Radiomic Prognostic Vector (RPV) in an independent cohort of high-grade serous ovarian cancer (HGSOC) patients, treated within a Centre of Excellence, thus avoiding any bias in treatment quality.

Methods: RPV was calculated using standardised algorithms following segmentation of routine preoperative imaging of patients (n = 323) who underwent upfront debulking surgery (01/2011-07/2018).

Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies.

Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches.

Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients.

This study aimed to assess the predictive value of tumor growth rate estimates based on serial cancer antigen-125 (CA-125) levels on therapy response and survival of patients with recurrent high-grade serous ovarian cancer (HGSOC). In total, 301 consecutive patients with advanced HGSOC (exploratory cohort: = 155, treated at the Medical University of Vienna; external validation cohort: = 146, from the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) consortium) were enrolled. Tumor growth estimates were obtained using a validated two-phase equation model involving serial CA-125 levels, and their predictive value with respect to treatment response to the next chemotherapy and the prognostic value with respect to disease-specific survival and overall survival were assessed.

Discovery of a biomarker candidate for surgical stratification in high-grade serous ovarian cancer.

Background: Maximal effort cytoreductive surgery is associated with improved outcomes in advanced high-grade serous ovarian cancer (HGSOC). However, despite complete gross resection (CGR), there is a percentage of patients who will relapse and die early. The aim of this study is to identify potential candidate biomarkers to help personalise surgical radicality.

The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers.

Purpose: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier.

Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples ( = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy.

Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK-directed activation of NF-κB.

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression.

Value of pre-existent bacterial colonization in patients with advanced/relapsed ovarian neoplasms undergoing cytoreductive surgery: a multicenter observational study (BONSAI).

Objective: As an increasing number of patients with advanced/relapsed ovarian cancer need extensive cytoreductive procedures, there is an increasing number of complex cases collected in accredited tertiary cancer centers. With nosocomial infections and bacterial colonizations being a significant challenge in these patient cohorts, we aimed to evaluate the risk such infections pose to surgical outcome.

Methods: Prospective assessment of pathological bacterial colonization (vaginal, umbilical/groin, intraperitoneal, urine, oral/nose cavity) in patients who underwent open cytoreductive surgery for advanced/relapsed ovarian cancer in two large European tertiary referral centers for gynecologic malignancies.

Inflammatory state of lymphatic vessels and miRNA profiles associated with relapse in ovarian cancer patients.

Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n = 10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery.

Ovarian cancer stem cells: ready for prime time?

Introduction: The role of cancer stem cells (CSC) remains controversial and increasingly subject of investigation as a potential oncogenetic platform with promising therapeutic implications. Understanding the role of CSCs in a highly heterogeneous disease like epithelial ovarian cancer (EOC) may potentially lead to the better understanding of the oncogenetic and metastatic pathways of the disease, but also to develop novel strategies against its progression and platinum resistance.

Methods: We have performed a review of all relevant literature that addresses the oncogenetic potential of stem cells in EOC, their mechanisms, and the associated therapeutic targets.

Maximal-Effort Cytoreductive Surgery for Ovarian Cancer Patients with a High Tumor Burden: Variations in Practice and Impact on Outcome.

Background: This study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC).

Methods: A retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied.

Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer.

High grade serous ovarian cancer (HGSOC) is the most frequent type of ovarian cancer. Most patients have primary response to platinum-based chemotherapy but frequently relapse, which leads to patient death. A lack of well documented and characterized patient-derived HGSOC cell lines is so far a major barrier to define tumor specific therapeutic targets and to study the molecular mechanisms underlying disease progression.

A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer.

The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV).

Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients.

Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis.

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer.

In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides.

The passive biomechanics of human pelvic collecting lymphatic vessels.

The lymphatic system has a major significance in the metastatic pathways in women's cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking.

Review article: Novel technologies in the treatment and monitoring of advanced and relapsed epithelial ovarian cancer.

Epithelial Ovarian cancer (EOC) is the fifth most common cause of cancer death in females in the UK. It has long been recognized to be a set of heterogeneous diseases, with high grade serous being the most common subtype. The majority of patients with EOC present at an advanced stage (FIGO III-IV), and have the largest risk for disease recurrence from which a high percentage will develop resistance to chemotherapy.

Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer.

DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood.

A method for voltage measurements of cancerous vs non-cancerous omentum.

This paper presents and elaborates upon the practicalities of a method which enables the recording of voltage measurements from omental tissue in patients with advanced ovarian cancer. The key components of the proposed low-cost experimental setup are a tungsten electrode, a Ag/AgCl reference electrode and an instrumentation amplifier. Intriguingly, potential difference recordings between cancerous omentum and tissue culture media and between non-cancerous omentum and media, differ for tissue samples coming from the same patient.

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.

Our 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.