Our laboratory research group has two broad areas of research activity. The first centres around diagnostic and prognostic biomarkers across gynaecological cancers, with a strong emphasis on the liquid biopsy and  cancer metastasis. The second area of research activity involves the pathogenesis of thrombotic complications in obstetrics and gynaecology.  These include the development of risk models for prediction of venous thrombosis in gynaecological cancers, and determining the role of tumour expression of coagulation proteases in the aetiology of gynaecological cancers. Our gynaecological cancer biobank underpins the research programme. Our research is funded by the Health Research Board, Higher Education Authority, Royal City of Dublin Hospital Trust Fund, Emer Casey Foundation, SOCK and the St James Hospital Foundation Gynae Cancer appeal.

The Gynaecological Biobank was set up in 2004 to support research between Trinity College Dublin and St James’s Hospital. This biobank underpins all of our translational research and provides important material for investigating tumour markers which can help develop new tests and better treatments for gynaecological cancer.

Patients attending the gynaecology service who are scheduled for surgery and/or chemotherapy may be invited by their doctor to sign a consent form to donate samples and healthcare data to the biobank. The biobank collects samples from all the gynaecological cancers and from non-cancer patients; these include ovarian cancer and benign ovarian disease, endometrial cancer and benign endometrial disease, cervical cancer, vulva cancer and vaginal cancer. The biobank stores bloods, excess tissue from surgery, urine and ascites fluid (fluid produced by some ovarian cancers).

The biobank is extremely grateful to all the participants who donate to the biobank. The importance of biobanks is outlined in this leaflet. More information on the biobank can be found on the Trinity St James’s Biobank Network page.

All cancers are associated with an increased risk of clots to the legs and lungs; however, gynaecological cancers have a particularly high risk. A recent survey of patients who suffered a clot during their cancer journey showed that, generally, patients are not warned about the risk of clots during cancer and are not told what to look out for. Our group have produced a patient information leaflet explaining the risk of thrombosis in gynaecological cancer patients. The leaflet was launched at the OvaCare patient information day held in Cork. OvaCare is a patient support group for women with ovarian cancer (www.OvaCare.ie). The leaflet has been distributed to all centres treating gynaecological cancer patients in Ireland and is available in all Irish Cancer Society Daffodil Centres. This initiative was funded by the Health Research Board under its knowledge exchange programme (KEDS). You can download the leaflet here.

Ovarian cancers carry a high risk of thrombosis, but coagulation activation and thrombin formation are also thought to play a role in tumorigenesis and metastasis. Preliminary data from our group has shown that the activated protein C pathway (aPC), is dysregulated in ovarian tumours. Type 1 ovarian cancers are predominantly chemo-resistant and associated with a poor prognosis; a novel therapeutic approach is urgently required. Reduced expression of key proteins in the aPC pathway (Thrombomodulin (TM), EPCR, protein S) combined with enhanced expression factor V were observed in tumour extracts; these changes were associated with reduced survival. Using our biobank, we aim: (1) to determine the role of EPCR, Factor V and TM as prognostic markers and to determine their role in survival (2) using cell models, to determine the potential role of recombinant EPCR and TM as novel therapeutics in ovarian cancer.

The association between malignancy and venous thromboembolism (VTE) is well documented with up to 20% of all cancer patients experiencing a VTE during their cancer journey. Prevention and treatment of cancer-associated VTE(CAT) represents an important medical challenge, since oncology patients concomitantly display higher rates of both bleeding and VTE recurrence than the non-cancer population. Recent guidelines recommend that in ambulatory cancer patients receiving systemic therapy, at intermediate/high risk for VTE, thromboprophylaxis with Direct Oral Anti-Coagulants (DOACs) should be considered.

Several biomarkers have been shown to predict VTE in cancer; however, prediction is based on one sample and does not account for the dynamic nature of thrombogenesis particularly during chemotherapy. This suggests that serial risk assessment may be more effective in capturing ongoing effects during therapy.  Data from our group and others indicates that three biomarkers may be suitable as dynamic predictors of VTE during chemotherapy: (1) the thrombin generation assay modified by adding thrombomodulin( TGA-TM), (2) soluble thrombomodulin (sTM) levels and (3) Factor VIIIc activity (FVIIIc). The aim of the study is to serially measure TGA-TM, sTM, and FVIIIc levels in lung, ovarian, pancreatic, and gastric cancer patients during chemotherapy and compare their ability to predict CAT with the Khorana score.

Recent reports from a global study of cancer patients revealed that almost in 70% of cases, the possibility of receiving primary prophylaxis for VTE during chemotherapy was not discussed with patients [8]. Most patients only became aware of the risk when they were diagnosed with VTE and required treatment, and in these patients, the majority were not informed of the risk of bleeding. All guidelines for VTE prophylaxis during chemotherapy agree that a shared decision making approach with consideration given to patient values and quality of life should be implemented; [3,4] however, how this can be best achieved is not clear. Bridging this knowledge gap is important in informed decision-making and can improve outcomes associated with cancer-associated VTE. 

The aim of the study is to identify patient priorities and preferences for shared decision-making with regard to VTE prevention during chemotherapy.

Chemotherapy alters key pathways leading to thrombus formation, although the precise mechanisms are unknown. We and others have shown that dysregulation of a key inhibitory pathway, (the aPC pathway) is implicated in thrombus formation during chemotherapy. In addition, Factor VIIIc activity has also been shown to be increased in cancer-associated VTE across a number of cancer types. Our pilot in vitro work shows a reduced expression of TM on the endothelial surface following treatment with carb/paclitaxel which could be implicated in the augmented protein C activation observed in vivo.  Chemotherapy stimulates release of extracellular histones, cytokines and the generation of NETs which may be implicated in increasing Factor VIIIc and/or impairing TM dependent protein C activation. Pilot data from our group (Figure 4) shows that the protein S100A12 is increased in plasma of serous ovarian cancer patients who received neoadjuvant chemotherapy compared to treatment of naïve patients. The aim of this project is to investigate using in vitro and in vivo studies the mechanism by which chemotherapy alters the prothrombotic phenotype in patients who develop VTE during chemotherapy.

Gynaecological cancer is associated with an increased incidence of venous thromboembolism (VTE) even with appropriate thromboprophylaxis. The risk is greatest following surgery and can persist for up to 6-12 months post-surgery. Lymph node dissection (LND) is a common procedure in gynaecological cancer surgery and increases the complications and complexity of the surgery. In prostate cancer, lymph node dissection during radical prostatectomy increased the incidence of deep venous thrombosis and pulmonary embolism (7). In addition, the Vienna in Cancer group has shown that lymph node metastasis is a strong risk factor for VTE and that early metastasis is associated with an activation of the haemostatic system. Gynaecological cancers are poorly represented in this study and there is a paucity of data in this group.  The aim of our study is to investigate the role of lymph node dissection and lymph node metastasis in VTE following both open and laparoscopic surgery for gynaecological cancer. 

Rates of VTE are significant in patients with gynaecological cancer, occurring on average in 10% of patients. Despite extended anti-coagulant prophylaxis, VTE still occurs in 6-7% of patients post-gynaecologic oncology surgery.  Our group have developed the Thrombogyn score, a risk model for prediction of VTE post surgery. Using this score, patients at low and high risk for VTE can be identified and the data used to guide prophylaxis post surgery. The score requires only 3 pieces of data (haemoglobin, chemotherapy treatment and BMI).  The aim of the study was to prospectively validate the thrombogyne score and compare it to existing models including the Khorana and Caprini risk score. We welcome external validation of the score by other groups; please contact lnorris@tcd.ie.

Aromatherapy is practiced within international clinical settings and has been the subject of a growing number of clinical studies examining its impact and benefit on patient care. Its use in oncology and palliative care has become a beneficial support to patients who experience distressing side-effects associated with treatment such as anxiety, pain, insomnia and nausea.

Complementary therapy units are well-established within the leading cancer hospitals in the UK and USA providing this support which is considered a safe, non-invasive, cost effective and therapeutic therapy. In Ireland, aromatherapy massage is one of the complementary therapies offered to palliative care patients in the Irish Hospice. Research into the use of inhalation aromatherapy for the relief of stress and anxiety experienced by patients undergoing medical interventions has grown exponentially in the last 20 years. Most of the studies report a positive impact from the intervention but in some cases, evidence is limited by the quality of study design, lack of blinding, uniformity in dosage and low sample size. There is a need for more convincing evidence. To date, no pilot studies have been conducted in Ireland to investigate the potential benefit of aromatherapy within an Irish clinical setting. The proposed research will be the first of its kind in Ireland.  

The aim of the study is to determine the effects of inhalation aromatherapy on stress and anxiety in patients following treatment for gynaecological cancer.

CLuB is an exciting collaboration building on internationally-recognised leadership in cancer research at Trinity College Dublin, Queen’s University Belfast, and the University of Galway.

CLuB’s ambition and focus is on identifying and developing minimally-invasive, cost effective, blood tests to complement or, where possible, replace surgical biopsies for cancer diagnosis and optimal treatment selection. CLuB also uses excised tumours as “avatars” to better understand the specific origin of important components of the liquid biopsy and to test the optimal drug treatment regime for a given patient. For more information, please see the CLuB webpage.

Ovarian cancer (OC) is the seventh most common female cancer and one of the most devastating diseases affecting the life of many women worldwide. It has become increasingly clear that the effectiveness of the available platinum-based chemotherapies is profoundly inadequate, largely due to the development of acquired resistance in patients with OC. In this study, nanomedicine-based therapeutic approaches are being used to enhance the treatment efficacy with minimal doses of chemotherapeutic drugs against cancers. Nano Diamonds are being coated with drugs and targets such as HE4 used to direct the treatment to the correct cells. The models being used include cell line models and ex vivo explant models.

Tumour metastasis is the pivotal contributory factor in determining prognosis for cancer patients. Haematogenous dissemination of circulating tumour cells [CTCs] from the primary tumour is essential for establishment of metastases at secondary sites. A key goal in cancer research is to understand the mechanism centrally underlying metastasis. Given that CTCs are essentially the ‘liquid phase’ of the cancer metastatic cascade, an understanding of their biology, survival characteristics and dynamic interaction with components of the blood and vascular system are essential to increasing the knowledge base of metastasis. However, many issues still remain in relation to detection, characterisation, biological activity and disease forming activity of these cells. CTCs can exist in many forms including singlets, doublets and clusters; clusters are thought to represent more aggressive disease. This is currently being interrogated using a novel CTCID capture mechanism.

CTCs are tumour cells shed from a primary tumour and carried through the bloodstream, which is a necessary step for the establishment of metastases at secondary sites. To unlock the full clinical potential of CTCs what is needed is a means to identifying diagnostically /prognostically relevant forms, i.e. those cells with the highest propensity to form metastatic tumours. To achieve this, we must understand the molecular mechanisms driving the establishment, the survival and the invasive capabilities of CTCs. Initial work focused on the interaction with ovarian cancer cells; however, they have demonstrated that there is universal, potent and dynamic interaction between platelets and cancer cells, which aids survival and drives a pro-metastatic phenotype in cancer cells. This work has lead to the identification of gene panel that are hypothesised to be potential significant effector molecules of the platelet’s pro-metastatic drive; including Plasminogen activator inhibitor type 1 (PAI1) and Monocyte chemotactic protein 1 (MCP1) and this is being investigated as part of this project. In addition to examining the effect of platelets on cancer cells, the research group has extended this work to study how this interaction influences immune surveillance. Understanding how CTCs survive in the vasculature by evading natural immune responses is central to establishing which CTCs are biologically/clinically relevant to metastasis.

HE4 is a serum biomarker which has both diagnostic and prognostic roles in ovarian cancer. We are currently working with industry to evaluate this biomarker in our centre and assessing the clinical scenarios where it may have potential. HE4 may have utility in endometrial cancer also so this is under investigation. 

There is still considerable controversy over the sequencing of treatment in advanced ovarian cancer. With Primary Debulking Surgery (PDS) forming the cornerstone of treatment for decades, there has now been debate over the possible increasing role of neoadjuvant chemotherapy (NACT) followed by Interval Cytoreduction Surgery (ICS). Optimal cytoreduction at surgery regardless of sequence remains key in optimising overall survival. Recent development of a validated histological chemotherapy response score following IDS for high grade serous ovarian cancer has provided another method of prognostic scoring along with debulking status. We are reviewing our cohort of neoadjuvant chemotherapy and ICS patients and will perform a further independent validation of the Chemotherapy Response Score with assessment of its correlation to clinical outcome.

The group has focussed a lot of work on identification of novel prognostic biomarkers and chemo response biomarkers for ovarian cancer. Many biomarkers have been validated and mechanistic functional work is currently in progress. Such markers include TLR4, MyD88, MAD2 and MMP-9.

Early diagnosis of gynaecological cancers such as ovarian and endometrial cancer can result in improved outcomes for patients because of earlier treatment. Current methods for ovarian cancer rely on the biomarker cancer antigen 125 (CA 125) and transvaginal ultrasound, both of which have limitations. Endometrial cancer diagnosis involves an invasive procedure to obtain tissue from the lining of the womb and currently there are no non-invasive biomarkers for endometrial cancer. Thus, there is a clinical need to develop new minimally invasive tests to detect ovarian and endometrial cancer at early stage. This project will access the unique DISCOVARY bioresource of blood samples from ovarian and endometrial cancer patients. Raman and FTIR spectroscopy will be used to profile the biochemical content of patient blood plasma/serum. Advanced multivariate and machine learning methodologies will be used to develop a classification model for early diagnosis using spectral data and clinical data.

Ovarian cancer is a common gynaecological cancer. Most women are diagnosed when the disease has already spread and at some point, most women stop responding to their anti-cancer drugs. Previous work in UCD found a gene (called NKAPL) that changes when tumours become “resistant”. NKAPL looked different in patients compared to healthy women and it changed after chemotherapy. This suggests that NKAPL could be one of the reasons why the anti-cancer drugs stop working and this project will investigate that and examine patient blood and tissue samples for NKAPL.

According to the radiomics principles, images are more than pictures, they are data, and as such they contain a huge amount of information that cannot be analysed visually but need a deep level of analysis. Radiomic features can be used to obtain information about heterogeneity and have the potential to uncover disease characteristics. Tumoral heterogeneity has been one of the first parameters to be correlated with treatment response. Radiogenomic uses another approach with advanced computational techniques that are used to extract and analyze innumerable quantitative descriptors of tumor heterogeneity and phenotype (e.g., shape, intensity, texture) from radiologic images and to correlate them with clinical reports, laboratory test results, and transcriptomic or proteomic data.

Radiomics has applications across gynaecological cancers and may assist in addressing some of the clinical challenges faced with these cancers.

In this project, we plan to evaluate radiomics in ovarian, endometrial, cervical, vagina and vulva cancers. Patients are consented to access their imaging as part of recruitment into the biobank. The region of interest will be selected for cancer types and this project will then use a dedicated software to extract radiomic features.

The clinical challenges varies with disease but overall it is hoped that prognostic ability will be derived from radiomic features which may ultimately assist in patient management.  

The clinical challenges to be addressed in the gynaecological cancers are detailed below;

Ovarian cancer: we will integrate clinicopathological features and radiological features in order to categorise prognostically women with ovarian cancer. This will be performed on a retrospective cohort of patients recruited into the gynaecological cancer biobank. A review of the literature will be performed before the final list of features are extracted to ensure any updates from a fast evolving field are incorporated. The Imaging biomarker initiative and the recent omental prognostic features will be incorporated into this list of features

Endometrial cancer: we propose to use radiomics to assess if it can aid in predicting the molecular subtypes of endometrial cancer and whether it can aid in the clinical decision for lymphadectomy in patients. We will attempt to integrate clinicopathological features and radiological features in order to categorise prognostically women with endometrial cancer. A retrospective and prospective analysis will be performed. The retrospective cohort of patients have been recruited into the gynaecological cancer biobank (up to 300 patients depending on imaging availability). Many open access software packages exist such as Py Radiomics, which will be evaluated.

Vulva cancer: the cornerstone treatment of vulval cancer is surgery, which carries significant morbidities mainly lower limb lymphoedema secondary to lymphadenectomy. The International Federation of Gynecology and Obstetrics  (FIGO) staging requires a histopathological dissection of the primary tumour and the inguinofemoral lymph nodes (IFLN). Metastasis to IFLN constitutes a stage 3 cancer. However, radiological methods of IFLN assessment often lack accuracy. It is proposed to evaluate the accuracy of radiomics in this setting.

Cervical cancer: the accuracy of radiomics to predict lymph node involvement in cervical cancer will be assessed in a retrospective cohort.

Vaginal cancer: the accuracy of radiomics to predict lymph node involvement in vaginal cancer will be assessed in a retrospective cohort.

The purpose of this clinical study is to investigate whether markers of serous tubal intraepithelial carcinoma (STIC) pre-cancer cells could be detected in washings from the cavity of the womb. If this is possible, it could lead to prevention or earlier detection of ovarian cancer. For the purposes of this study, women at high risk of ovarian cancer who have decided to have their tubes and ovaries removed surgically will be invited to have an irrigation of the cavity of the womb following their anaesthetic. https://clinicaltrials.gov/ct2/show/NCT02039388

(A multi-centre European study in conjunction with Institut Curie, Paris, France).

The aim of this study is to assess dominant mutations and activation pathways in cervical cancers predictive to standard treatment response. Rational molecular Assessments and Innovative Drug Selection | RAIDS | Project | Fact sheet | FP7 | CORDIS | European Commission (europa.eu)

A randomised controlled trial of oxytocin (Syntocinon®) 5iu versus oxytocin 5iu and 40iu infusion for the control of blood loss at elective caesarean section.

ECSSIT is a large multi-centre randomised controlled trial comparing two different approaches to reduce blood loss at elective caesarean section.  It compares bolus and oxytocin infusion with oxytocin bolus and placebo infusion. The trial commenced in February 2008 in the three Dublin Maternity Hospitals (Coombe Women and Infants University Hospital, National Maternity Hospital and Rotunda Hospital) with the aim of recruiting 2000 women.  Two further centres (Our Lady of Lourdes Hospital, Drogheda and Mount Carmel Hospital) have since been included in the trial.

Principal Investigator:

Professor Deirdre J. Murphy
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: murphyd4@tcd.ie
Telephone: (01) 4085200

Senior Research Fellow and Trial Co-ordinator:

Dr. Sharon Sheehan
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: sharon.sheehan@tcd.ie
Telephone: (01) 4085200

Research Midwives:

Ms. Michelle D'Arcy
Rotunda Hospital 
Email: ecssit@rotunda.ie
Telephone: (01) 8730700

Ms Claire Dunney
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: claredunney@hotmail.com
Telephone: (01) 4085200

Ms Eleanor Woods
National Maternity Hospital 
Email: elle56woods@hotmail.com
Telephone: (01) 6609925

Ms Ann-Marie Connor
Our Lady of Lourdes Hospital, Drogheda
Email: annemarie.connor@hse.ie
Telephone: (041) 9837601

Ms Ruth O'Connor
Mount Carmel Hospital 
Email: roconnor@mcm.ie
Telephone:(01) 4063400

Funded by HRB Project Grant
Dr Sharon Sheehan registered for PhD

Publication:

Study protocol.  ECSSIT- Elective Caesarean Section Syntocinon Infusion Trial.  A multi-centre randomised controlled trial of oxytocin (Syntocinon) 5IU bolus and placebo infusion versus oxytocin 5IU bolus and 40IU infusion for the control of blood loss at elective caesarean section.
Murphy DJ, Carey M, Montgomery AA, Sheehan SR; ECSSIT Study Group.
BMC pregnancy and childbirth. 2009 August 24;9:36.

This research project explored medication use during pregnancy. In particular, the focus was on the prevalence and determinants of early pregnancy medication use using electronic hospital records from The Coombe Women & Infant’s University Hospital.

Principal Investigator:

Professor Deirdre J. Murphy
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: murphyd4@tcd.ie
Telephone: (01) 4085200

Senior Research Fellow and Trial Co-ordinator:

Brian Cleary MSc (Clin Pharm) BSc (Pharm) 
Coombe Women & Infant’s Hospital
Dublin 8.
Email: bcleary@coombe.ie
Phone:(01) 4085527

Co-Supervisor:

Prof. Tom Fahey 
HRB Centre for Primary Care Research 
Department of Family Medicine and General Practice
Royal College of Surgeons in Ireland.
Email: tomfahey@rcsi.ie

Publication

Cleary BJ, Butt H, Strawbridge JD, Gallagher PJ, Fahey T, Murphy DJ. Medication use in early pregnancy-prevalence and determinants of use in a prospective cohort of women. Pharmacoepidemiology and Drug Safety; 2010 Jan 22. [Epub ahead of print]

McGuire M, Cleary B, Sahm L, Murphy DJ.  Prevalence and predictors of periconceptional folic acid uptake - prospective cohort study in an Irish urban obstetric population.
Human Reproduction. 2010 Feb;25(2): 535-543.

The impact of maternal methadone use during pregnancy is being examined in a series of interlinked studies. A systematic review, retrospective cohort study and prospective cohort study are in progress. These complementary studies examine the effect of methadone on a range of adverse perinatal outcomes including neonatal abstinence syndrome.

Principal Investigator:

Professor Deirdre J. Murphy
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: murphyd4@tcd.ie
Telephone: (01) 4085200

Senior Research Fellow and Study Coordinator:

Mr Brian Cleary MSc (Clin Pharm) BSc (Pharm) 
Coombe Women & Infant’s Hospital
Dublin 8.
Email: bcleary@coombe.ie
Phone:(01) 4085527

Collaborators:

Prof. Tom Fahey
HRB Centre for Primary Care Research
Royal College of Surgeons in Ireland

Prof. Bengt Källén
Tornblad Institute
University of Lund
Sweden

Judith Strawbridge
School of Pharmacy
Royal College of Surgeons in Ireland

Dr. Paul Gallagher
School of Pharmacy
Royal College of Surgeons in Ireland

Mairead McGuire
Pharmacy Dept.
Coombe Women and Infants University Hospital

Dr. Laura Sahm
School of Pharmacy
University College Cork

Dr. Maeve Eogan
Consultant Obstetrician & Gynaecologist
The Rotunda Hospital.

Justin Gleeson
Drug Liaison Midwife
The Rotunda Hospital.

Prof. Tom Clarke
Consultant Paediatrician
The Rotunda Hospital

Dr. Michael O' Connell
Consultant Obstetrician & Gynaecologist
Coombe Women and Infants University Hospital

Deirdre Carmody
Drug Liaison Midwife
Coombe Women and Infants University Hospital

Dr. Martin White
Consultant Paediatrician
Coombe Women and Infants University Hospital.

Alcohol Use During Pregnancy, Perinatal Outcomes and Fetal Alcohol Syndrome-a Prospective Cohort Study and Longitudinal Observational Study.

This prospective cohort study aims to investigate the association between alcohol consumption in pregnancy and perinatal outcomes in a cohort of women giving birth in The Coombe Women's and Infants University Hospital. The cohort will include all women booking for antenatal care in the hospital during a 1-year period. An observational study will also be carried out on a subset of the above cohort. Infants of the mothers in this group will be followed and examined for signs of alcohol-related effects. The trial commenced in December 2009.

Principal Investigator:

Professor Deirdre J. Murphy
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: murphyd4@tcd.ie
Telephone: (01) 4085200

Senior Research Fellow and Study Coordinator:

Dr. Aoife Mullally 
Department of Obstetrics & Gynaecology
Trinity College Dublin and Coombe Women and Infants University Hospital
Email: amullall@tcd.ie
Telephone: (01) 4085200

Collaborators:

Prof. Tom Fahey 
HRB Centre for Primary Care Research. 
Department of Family Medicine and General Practice.
Royal College of Surgeons in Ireland.
Email: tomfahey@rcsi.ie

Prof Joe Barry 
Department of Public Health and Primary Care
Trinity College Dublin
Email: joebarry@tcd.ie

Dr Bob McDonnell
EUROCAT Ireland
Email: bob.mcdonnell@hse.ie

Dr. Martin White
Consultant Paediatrician
Coombe Women and Infants University Hospital