Our laboratory research group has two broad areas of research activity.  Our group has an extensive cancer biobank of tissue, serum and plasma used to develop novel biomarkers for ovarian and other gynaecological cancers.  The group also investigates mechanisms of chemoresistance and recurrence in ovarian cancers. 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 research is funded by Health Research Board, Emer Casey Foundation, St James Hospital Foundation Gynae Cancer appeal, Royal City of Dublin Hospital Trust Fund. 

Our group has an extensive biobank [DISCOVARY bioresource] of serum, blood and plasma and tissue from malignant and benign tumours. This biobank underpins all of our translational research and provides important material for investigating tumour markers which can help in early diagnosis and in more targeted treatments.  The bioresource is a collaborative effort between St James’s and Trinity College Dublin. This biobank is linked to a dedicated database which provides full clinical information and follow-up data on each patient.  This allows us to do studies looking at determinants of survival and treatment response.  To date it has recruited over 2000 patients and recruitment is ongoing.  A recent epidemiological review of 583 cases from our bioresource reveals our figures are in line with the national averages so we are confident our sample population is representative of the gynaecological cancer cases that present in Ireland. 

Our group participates in a nationwide network internationally recognised ovarian cancer clinical and scientific experts.  Established in 2014, the aim of INNOVATION is to integrate patient clinical pathways with cutting edge research to improve diagnosis and treatment of ovarian cancer.  Further information can be found here  

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 program (KEDS). You can download the leaflet here(PDF 599 kB).

Gynaecological cancers have been associated with high rates of VTE which is exacerbated by pelvic surgery and chemotherapy. A recent study in our centre showed that one third of VTE in ovarian cancer patients occurs within 5 days of surgery despite heparin prophylaxis. Recently, clinical risk models have been developed to predict VTE in patients undergoing chemotherapy, these models have been shown to be more powerful when combined with haemostatic biomarkers. Global tests of hypercoagulability which capture these effects are therefore attractive as determinants of thrombotic risk. Calibrated automated thrombograpy (CAT) is a global test which measures thrombin generation in plasma. Increased thrombin generation is predictive of VTE in a variety of clinical settings. The overarching aim of this project is to develop and validate a specific risk scoring model for VTE risk in gynaecological cancer patients using a combination of easily available clinical and laboratory parameters and haemostatic biomarkers in n a large population of 1000 gynaecological cancer patients.

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We previously reported a venous thromboembolism (VTE) incidence of 9.7% in a large cohort of women with ovarian cancer from 2006 to 2010. Of these, 33% occurred in the first 28 days following surgery. In keeping with current international guidelines we introduced a policy of extended VTE prophylaxis with low molecular weight heparin (LMWH) for four post-operative weeks in January 2012.  The aim of this project is to determine the effect of the introduction of extended prophylaxis on the rate of post operative venous thrombosis in ovarian cancer since the introduction of these guidelines.

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 chemoresistant 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.

Large scale studies have shown a strong link between a history of endometriosis and an increased risk of invasive clear cell and endometrioid cancers.  Our previous studies showed that Tissue Factor (TF), the major trigger for the coagulation cascade, is overexpressed in clear cell cancers but not in papillary serous or mucinous carcinoma. ).    Ectopic synthesis of factor VII is known to activate ovarian cancer cell migration and invasion.  Increased expression of both PAR-2 and TF in the eutopic and ectopic endometrium  from women with endometriosis compared with normal women has been reported however it is unknown whether a further increase in expression is implicated in malignant transformation of endometrioma into clear cell cancer.   Our hypothesis is that expression and activation of the TF-VIIa-PAR-2 signalling pathway is further increased in clear cell cancers particularly those formed on a background of endometriosis and that this may provide a potential target for treatment of clear cell cancers. The aim of the study is to compare the expression of TF, VIIa and PAR-2  in clear cell cancers with endometrial tissue from patients with endometriosis.

Patients with cancer have a higher risk of developing venous thromboembolism (VTE) and VTE is a major contributor to morbidity and mortality risk in these patients. Ovarian cancer, pancreatic cancer and glioblastoma are the cancers associated with the highest risk of VTE. The treatment and prevention of VTE is particularly challenging in gynaecological cancer. A recent study reported a VTE incidence of 11% of patients with ovarian cancer undergoing chemotherapy. The presence of a gynaecological malignancy increases the rate of post operative VTE fourfold compared with patients with benign disease. Genital tract cancers are a diverse group of diseases. The incidence of VTE in clear cell type of ovarian cancer has been found to be as high as 27%.  Cancer patients with VTE have a higher risk of recurrent VTE than those without malignancy. Nine percent of cancer patients who presented with VTE had a recurrence despite LMWH prophylaxis and 17% with a vitamin K antagonist in a mixed population of cancers (17).  The risk of recurrence is highest within the first 12 months and is most pronounced with concurrent cancer related events (e.g. disease progression or relapse).  Although gynaecological cancers are associated with one of the highest rates of cancer associated VTE, few studies have investigated VTE recurrence in gynaecological cancers.  This study aims to investigate the rate of recurrence of VTE in the gynaecological cancer population and the factors which influence VTE recurrence.

From May 2012, all patients undergoing surgery for a gynaecological malignancy in our centre receive 28 days extended LMWH prophylaxis post surgery.  Studies in other centres have reported that translation of the guidelines for prophylaxis into clinical practice has been problematic.    Introduction of extended prophylaxis is an additional burden on the cancer patient as they are responsible for purchasing, and in many cases, self-injecting the medication.  Additional educational and support services are also required in the community for these patients.  In other patient groups, lack of education and a negative opinion toward injection has affected compliance.  The cancer patient may have additional difficulty as they are managing multiple symptoms and treatments.  Among gynaecological cancer patients, the patient experience of extended prophylaxis has not been documented and compliance is largely unknown.  The aim of this study is to determine patient experience of and adherence to extended LMWH prophylaxis following gynaecological cancer surgery

The development of biomarkers as a non-invasive method of diagnosing endometriosis has been described as one of the highest priorities in endometriosis related research. Serum markers would allow for diagnosis, to measure disease activity and to monitor for improvement. Many varied markers have been looked at over the years but most studies have not been able to correlate markers with disease activity or with symptomatology.  The aim of this study was to investigate the diagnostic potential of serum levels of cytokines (interlukin-6, IL-6, matrix metalloproteinases, MMP, MMP-2 and MMP-9) and miRNAs (miR-21, miR-103,miR-122, miR-199a, miR-223, let-7A) in patients with endometriosis. A secondary aim was to look at the effect of surgical treatment on the serum biomarkers to determine the role markers of treatment success.

The estimated prevalence of endometriosis is 10% of the general population and up to 50% of those women suffering from infertility (3, 4). A significant delay in the diagnosis of endometriosis is often reported. This delay can have a negative effect due to a longer period of uncertainty for the woman without any diagnosis, possibly worsening the prognosis for fertility and increasing the risk for repeated surgical procedures.  There is evidence to suggest that the longer the delay in diagnosis, the further advanced the stage at the time of laparoscopy. It has also been shown that a diagnosis allows the woman some reprieve from work and social obligations as well as a framework in which to discuss the problem.   This study aims to look at the length of time to reach a diagnosis of endometriosis in the Irish health service as well as the impact age at the first onset of symptoms and presentation has on this time interval. We will also assess the impact of presenting symptoms on the delay in diagnosis.

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 aides 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 chemotatic 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 has also shown utility in endometrial cancer and we are currently investigating this.

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 Debulking Surgery (IDS).  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 IDS 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 chemoresponse 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.

Currently there are no reliable biomarkers for the diagnosis of early ovarian cancer (OC). A lack of specific symptoms of the disease means only 20% of ovarian cancers are diagnosed at an early stage (Stage 1). Autoantibodies are an attractive biomarker entity as they are present in blood and can be adapted into current diagnostic platforms. It is accepted that the complexity of cancer means that a panel of biomarkers will be required as a diagnostic test rather than the more traditional approach of identifying a single biomarker. Autoantibodies associated with ovarian cancer were identified and pathway analysis was performed to determine if autoantibodies can be indicative of pathway dysregulation associated with malignancy. This project is focussed on refining and validating a panel of biomarkers which has the potential to diagnose early ovarian cancer.

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)

Outreach and dissemination events are held frequently and often with the associated charities. The clinicians and scientists speak at town hall and public forum events, TV and partake in annual events highlighting the various cancer types; e.g. world ovarian cancer day.

A Public Patient Involvement (PPI) group within the Irish Society of Gynaecological Oncology in 2016. Two workshops have taken place and the group has commenced its first research project. Members of the PPI group invited as patient representatives on the National Cancer Guidelines committee for diagnosis of ovarian cancer.

Some of the patient charities that work directly with the Trinity Cancer group include:

Ovacare was established in 2011 to improve diagnosis and education of ovarian cancer within Ireland, through sharing global research and best practice, and providing support and advocacy through OvaCare’s dedicated support network. Patient Days take place across the country which provide information and support for ovarian cancer patients and their families.  It provides the opportunity to hear from leading clinicians, therapists and researchers specialising in the disease, as well as being a chance to meet fellow patients. 

Supporting Ovarian Cancer Knowledge (SOCK) was the brainchild of the late Jane Keating. Following her diagnosis with ovarian cancer, Jane wanted to do something positive as there was limited information available to women about ovarian cancer. SOCK it is a non-profit organisation and is dedicated to raising funds for research into and awareness of ovarian cancer.

The Emer Casey Foundation was established in 2006 following the death of Emer Casey. Emer was the youngest of a family of five daughters and she had just recently qualified as a solicitor at Matheson Solicitors in Dublin when she became ill. She was diagnosed with ovarian/endometrial cancer in February 2006 and she died on June 10th 2006 aged only 28. Since then Emer’s family, friends and work colleagues at Matheson Solicitors have been working on behalf of the Foundation. To date the Foundation has raised in excess of €900,000 and has supported 3 PhD fellowships in Trinity College Dublin.

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 eletive 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