Prof Ruth Clifford MD PhD

Consultant Haematologist, University Hospital Limerick

Paul Murray

Professor of Molecular Pathology in the Health Research Institute, University of Limerick

The Limerick region is increasing its research profile through ground-breaking advances in blood cancers.

A rich portfolio of cancer clinical trials has been developed over the last decade at University Hospital Limerick (UHL) under the leadership of Professor Linda Coate and Maureen O’Grady. This has already led to more effective and safer treatments for patients.

The current director of the Trials Unit, Professor Ruth Clifford, is working closely with a team of internationally leading cancer researchers delivering new treatments within clinical trials. Professor Clifford highlights: “We are opening important trials across blood cancers including lymphoma, chronic lymphocytic leukaemia and acute leukaemia. International evidence confirms that higher quality services are delivered by academic centres that run clinical trials. This is a cornerstone of our vision for cancer patient treatment in the mid-west region.”

A strong focus on patient-centred research

The research profile of the Limerick region is broadening through collaborative networks. Groups working in cancer research have come together to form the UL Cancer Network (ULCaN), directed by Professor Patrick Kiely. Through ULCaN, platforms to enable the public and patients to direct research are under development. As Professor Clifford states: “It is important that people living in this region have the opportunity to contribute to the development of research. A recent survey revealed that many patients were unaware that clinical trials were undertaken in UHL.”

We hope that our patients and the public will join us in progressing cancer research for this region aiming for higher standards of care for our cancer patients.

Looking to the future – personalised cancer care

Research within the newly established Limerick Digital Cancer Research Centre, in partnership with Dell Technologies and UHL, is working towards personalised treatments for all blood cancer patients. As Professor Paul Murray confirms: “Until now, we have lacked the tools that can identify the key features of a patient’s tumour that can predict treatment response. However, this is now possible using a new technology known as ‘spatial profiling’ in which we can identify how different cells in the cancer interact with each other.”

Working with artificial intelligence experts, Professor Pepijn van de Ven and Professor Conor Ryan, the UL research team plan to design a new generation of diagnostic tests based on these features. As Dr Eanna Fennell, a post-doctoral fellow at University of Limerick (UL), says: “These new tests will ensure that only patients who will respond to a given therapy will be treated. This will improve their chance of cure and reduce the unnecessary toxicity and costs associated with the use of ineffective treatments.”

“This is a very exciting time for the team in Limerick” states Professor Clifford, “we hope that our patients and the public will join us in progressing cancer research for this region aiming for higher standards of care for our cancer patients.”

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Von Willebrand Disorder (VWD) is the most common inherited bleeding disorder with approximately 1 in 1,000 people being affected.

VWD results from the von Willebrand factor (VWF) protein in the blood being lower than normal or poor quality VWF being produced. Normal VWF levels are greater than 50% whereas in VWD, levels are less than 30%. Those with levels between 30% and 50% are said to have low VWF levels but are not categorised as having VWD although they may have some bleeding problems such as easy bruising or heavy menstrual bleeding.  

Understanding signs and symptoms

It is a complex disorder with several subtypes and with severity ranging from mild to severe. VWD affects both men and women. In men or children, easy bruising or frequent, heavy nosebleeds may be the first sign of a bleeding disorder.

The most common warning sign for women are heavy periods or excessive bleeding after childbirth. One in five of those with heavy periods will have an underlying bleeding disorder, which is often undiagnosed. It can be difficult to tell if menstrual bleeding is heavy. Comparing yourself to other women in the family can be misleading as they, too, may also have low VWF levels or VWD without knowing it.

The following symptoms should alert a woman to a potential problem:

• Bleeding which lasts longer than seven days, requires you to change pads or menstrual cup every two hours or passing clots larger than a €1 coin.
  
• Unpredictable bleeding.
  
• Menstrual bleeding which affects daily activity (needing time off work or school).
  

Both men and women with VWD can experience prolonged or heavy bleeding after dental procedures, surgery or trauma. Bleeding into joints can also occur.  

It is a complex disorder with several subtypes and with severity ranging from mild to severe. VWD affects both men and women.

Increasing awareness and diagnosis

Von Willebrand Disorder is massively underdiagnosed in many countries, including Ireland. There are currently 1,643 people in Ireland diagnosed with VWD of whom 618 are male and 1,025 are female.We would expect to have 4,900 diagnosed if all those with VWD were identified.

Treatment options for VWD include desmopressin (a synthetic hormone),tranexamic acid (an anti-fibrinolytic), fibrin glue or factor replacement therapy. For women, options can also include hormonal contraceptives or intrauterine devices.

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The COVID-19 pandemic has presented the global healthcare community with unprecedented challenges. One such challenge has been the dramatically increased risk of blood clots observed among infected patients.

Venous thromboembolism (VTE) is the term used to describe the formation of harmful blood clots within the circulation. These occur most commonly in the limb veins or lungs. Thrombosis occasionally occurs within the brain and abdomen.

Preventing VTE-related mortality

VTE has long been recognised as being a major cause of cardiovascular mortality. Fortunately, the appropriate use of anti-clotting medicines has been shown to reduce the risk of death associated with blood clots among high-risk individuals (including hospitalised patients). 

Increased VTE risk in COVID-19

Worryingly, an early trend which was observed in this pandemic was that VTE appeared to be occurring at very high rates among infected patients, despite the use of these anti-clotting medicines.

Moreover, a link between the severity of the COVID-19 illness and activation of blood clotting has been reported (based on laboratory findings), with high levels of clotting activation markers in the blood appearing to be predictive of poor outcomes and death.

Clinical trials of VTE treatment

These observations have sparked massive efforts to better understand the link between this infection and clotting as well as to improve our ability to prevent and treat these blood clots. A number of large, global studies are currently underway aiming to investigate whether intensified anti-clotting treatment may be required in COVID-19.

The Mater Hospital in Dublin has been the sole European recruitment site for one such study (The RAPID COVID COAG Trial). Results of these studies are expected this year, however preliminary results reported from similar clinical trials in recent months suggest that this treatment option may be of significant benefit to certain groups of patients with COVID-19 – not only in preventing VTE, but also in reducing risk of death and requirement for intensive care.

Given the limited treatments for this infection, these trials may provide significant hope for new options to improve outcomes, and the final results are eagerly awaited.

COVID-19 vaccines and thrombosis

The risk of thrombosis associated with certain COVID-19 vaccines has gained significant attention in recent months. In particular, unusual cases of cerebral thrombosis have been reported, although are extremely rare.  Our understanding of this rare complication of vaccination is evolving but in the face of the significant risk of blood clotting and death due to a COVID-19 illness, it remains the firm recommendation of the healthcare community that individuals should accept the offer of a vaccine.

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A lack of new treatment options has led to a plateau in survival rates for childhood AML patients. Systems biology is uncovering new treatment strategies for this deadly disease.

Acute myeloid leukaemia (AML) is the leading cause of blood cancer-related mortality in children. While outcomes for patients have certainly improved in recent decades, survival rates have reached a plateau at approximately 60%. Efforts to improve survival rates have been hampered by a lack of knowledge about the nature of paediatric AML and limited development of new treatments.

In fact, treatments for childhood AML have remained essentially unchanged for nearly 50 years, comprising highly toxic drugs which carry significant short- and long-term side effects. It is therefore a priority to identify safer, more effective treatments for these patients.

Uncontrolled growth

Many blood cancers, including AML, are aggressive because mutations (alterations in a cells’ DNA) cause overactivity in proteins called kinases. Kinases are enzymes that act like traffic lights within a cell, dynamically switching from ‘go’ to ‘stop’ to allow cells to make decisions, such as whether to grow or divide. When a kinase is mutated, it often results in a constant ‘green light’, causing the cells to grow uncontrolled.

Treatments for childhood AML have remained essentially unchanged for nearly 50 years, comprising highly toxic drugs which carry significant short- and long-term side effects.

Kinase inhibitors act as ‘stop signs’   

Recent decades have seen the development of drugs called kinase inhibitors, with many already used clinically across a range of cancers. These drugs interact with overactive kinases to halt the uncontrolled growth of cancer cells. Unfortunately, these drugs are commonly ineffective when used on their own as they are unable to completely shut down kinase activity.

In keeping with the traffic analogy, cancer cells can divert traffic away from the targeted kinase and use an alternate route. These drugs are more effective when used in combination, however the challenge lies in identifying which combinations will work best for which patient.

Predicting effective combinations

An approach called systems biology, which combines in vitro experimental data with computer modelling, can be used to predict kinase inhibitor combinations able to shut down overactive kinases.

Thanks to funding from the Irish Cancer Society, we are currently applying this approach to kinase mutations frequently observed in childhood AML patients. These predicted combinations will require rigorous lab testing before reaching patients, however this approach has significant potential to allow rapid identification of kinase inhibitor combinations that will provide safe and effective treatment strategies for childhood AML patients.

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Haemophilia is an inherited bleeding disorder caused by deficiency in one of the clotting factors – either FVIII or FIX. Research is currently underway to assess the use of gene therapy to help treat the disorder.

Current licensed therapies for haemophilia involve regular intravenous injections of the missing clotting factor to prevent or treat bleeding episodes. A subcutaneous clotting factor mimetic is also available now in Ireland as a treatment for Haemophilia A.

Haemophilia is an ideal disease for treatment with gene therapy as it is a single gene disorder, requiring the replacement of only one clotting factor and normal levels of factor are not needed to significantly improve health related quality of life. The missing clotting factor protein can be provided by delivering the gene in a suitable carrier (usually an adeno associated viral vector) to the liver as a “one-off” infusion.

Future research into haemophilia

There are currently more than 30 clinical trials underway in haemophilia gene therapy with several in advanced phase 3 trials. The most recent published results in a FVIII phase 3 trial in 134 men reported data one year post infusion of the vector. They reported a mean FVIII expression of 43.6% with a median of 24.2%. Eighty per cent of participants had no bleeding episodes from five weeks post vector dosing to the end of year one.

There are currently more than 30 clinical trials underway in haemophilia gene therapy with several in advanced phase 3 trials.

Data was recently reported also on a phase 3 FIX clinical trial using a modified enhanced FIX gene. Six months post vector infusion, the 54 participants had a mean FIX expression of 37%. This trial includes three Irish participants all of whom have achieved very good factor expression to date.

There remain unanswered questions in relation to predictability of factor expression, duration of response, the proportion who will not respond and long-term safety. The economics of gene therapy will also require new and imaginative thinking in relation to payment models, perhaps with a pay for performance type model being considered. We have travelled from the theoretical to the point where now we have people with haemophilia in Ireland already treated with gene therapy as part of a clinical trial. The work progresses and the future awaits.

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In many people, systolic blood pressure increases as we age, rising exponentially after the age of 55. Whilst this is true on a population level, we can see very different relationships (changes in blood pressure across age) on an individual level.

The variability in blood pressure changes associated with ageing is predominantly due to an individual’s biological age or stiffness of their arteries. We regularly see people in their 80s with an artery stiffness of a 50-year-old and normal blood pressure.

In contrast, we also see a 50-year-old presenting with the artery stiffness of an 80-year-old with high blood pressure. Therefore, it is the individual’s biological age or their artery stiffness (health) that increases their risk of high blood pressure.

The arterial system deteriorates and becomes stiffer as we age. Whilst we cannot stop time, we can influence our lifestyle through things like increased physical activity to help maintain a healthy arterial system. 

Maintaining healthy and elastic arteries has been shown to delay the rate and development of increased systolic blood pressure as people get older.

Whilst we cannot stop time, we can influence our lifestyle through things like increased physical activity to help maintain a healthy arterial system.

Impact of the aorta

We know that artery stiffness increases more rapidly after 55-60 years because the aorta (the largest and most elastic artery in our body) can no longer expand and buffer the blood ejected from the heart. This inability of the aorta to stretch repeatedly and buffer the blood flow leaving the heart increases the resistance experienced by the cardiac muscle. This excessive strain on the heart leads to the heart muscle increasing its size to deal with the increased resistance, resulting in a greater risk of future heart disease.

Furthermore, the increased aortic pressure is also transmitted as excessive pulsatile pressure downstream into delicate end organs, causing irreversible microvascular damage including stroke, dementia and kidney failure.

Thankfully, Croí, the heart and stroke charity, is currently undertaking a pilot cardiovascular prevention programme in County Mayo to address such health issues. The Croí Third Age Mayo programme message is ‘Own it’, ‘Check it’, ‘Sort it’ – targeting those over 55 years of age to be proactive with their heart health.

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Patients in Ireland with blood cancers have seen a marked improvement in their prognosis primarily due to enhanced access to targeted treatments. This improvement in mainly due to our increasing participation in crucial new clinical trials.

Clinical trials are about improving access for our patients to the newest most effective treatments as early as we can. It is well recognised that patients who participate in trials or are treated in a unit that participate in trials have better outcomes.

Since the first COVID-19 patients were identified in Ireland in early 2020, the provision of care to patients with blood cancers faced unprecedented difficulties, including how to continue to conduct clinical trials without compromising patient care. It also highlighted to the patient and their physician the importance of ensuring we have access to the safest targeted and least toxic therapy available.

Increased awareness of clinical trials

One of the few benefits of the pandemic is the increased awareness of the public to the importance of the application of science to drug development and the integral part clinical trials have in bringing new treatments to those who need them in a safe and timely manner.  

In late 2020, a study by Cancer Trials Ireland revealed an increased public understanding of clinical trials, with one in two people willing to participate in a trial themselves. Despite this, we have seen a fall in the number of cancer patients recruited to clinical trials in Ireland since the start of the pandemic and this is a trend we wish to reverse in 2021.

We have seen a fall in the number of cancer patients recruited to clinical trials in Ireland since the start of the pandemic and this is a trend we wish to reverse in 2021.

Greater participation in trials

Since 2017, Cancer Trials Ireland have rolled out an annual campaign “Just Ask” to promote public awareness of clinical trials. I am delighted to say that for blood cancer patients we are now in a position to offer trials to increasing numbers of patients.

This year, we are opening important trials for AML, Myeloma, CLL, myeloproliferative disorders and low and high grade lymphomas. This is made possible by important collaborations that we have fostered with international collaborative groups such as the HOVON group and the German CLL Group, national collaborations with BCNI and important partnerships with the pharmaceutical industry.

We are constantly striving to encourage the opening of important trials across the full range of blood cancers, aiming to put Ireland at the forefront of clinical trials internationally, providing the state of the art treatment for our patients.

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The European Society of Cardiology (ESC) branded CVD “the biggest epidemic in human history”. It has affected the greatest numbers; it has had the greatest cost and it is not over yet.¹

Cardiovascular disease (CVD) is Europe’s biggest killer.¹ Each year it accounts for 3.9 million deaths in Europe² and has an economic burden in the European Union of €210 billion.¹

With research showing a clear link between COVID-19 and CVD, Europe’s silent pandemic is being further amplified.

In Ireland, chronic heart disease is one of the top three conditions associated with an increased risk of COVID-19 related ICU admissions, while CVD is also amongst the top three most common underlying health conditions of fatal COVID-19 cases.³ This is supported by analysis from the British Medical Journal and the British Heart Foundation, who found CVD patients are more likely to die as a result of COVID-19⁴ or suffer serious complications.⁵

Adding to this, the reprioritisation of clinical resources during the current pandemic has led CVD patients to delay much needed medical help or diagnosis, worsening their cardiac conditions.⁶

The growing scale of the crisis has resulted in increasing calls among industry experts to tackle CVD differently. The ESC and European Heart Network have recently called for urgent Government action across the EU to improve the care of CVD patients to prevent an even greater future crisis.⁷

The reprioritisation of clinical resources during the current pandemic has led CVD patients to delay much needed medical help or diagnosis, worsening their cardiac conditions.⁶

The hidden risk

As part of the ongoing debate over Government intervention and therapy options, it is important to acknowledge that the current treatment options do not fully address cardiovascular risk.

Lowering low-density lipoprotein (LDL) levels has been the major focus of treatment for the past 30 years and statins have been the first line of treatment to achieve this.^8,9 While statins have an important role to play, they are not the panacea many people seem to think.

LDL-cholesterol is not the whole story; patients are still dying of heart attacks and strokes and the residual risk remains unresolved. Various primary and secondary prevention trials have shown a significant reduction of 25% to 35% in the risk of cardiovascular events with statin therapy, leaving a residual risk beyond LDL-cholesterol control of 65% to 75%.^9-12

To tackle this growing crisis, preventative care, alongside LDL-cholesterol management, must be prioritised for at-risk CVD patients.¹³ There is a clear need for pragmatic new options, proven to treat high-risk patients on statins. We need to think beyond LDL reduction to tackle the problem and take a closer look at elevated triglycerides as a marker of residual cardiovascular risk.

Rethinking cardiovascular risk

Recent breakthroughs in clinical research have shown that there are new treatment solutions available. The landmark REDUCE-IT study showed icosapent ethyl could significantly reduce the incidence of cardiovascular death, strokes and heart attacks for statin-treated patients with untreated residual CV risk, identified by elevated triglycerides.¹⁴ High triglyceride levels are a common warning sign of cardiovascular risk, despite statin therapy and controlled LDL-cholesterol.^15,16

The REDUCE-IT study found that icosapent ethyl achieved a 25% relative risk reduction for serious cardiovascular events for high-risk statin-treated patients with elevated triglycerides, corresponding to an absolute risk reduction of 4.8%.¹⁴

Two major European medical societies, the ESC and European Atherosclerosis Society (EAS) recommend the usage of icosapent ethyl in appropriate patients, in addition to 15 other medical societies across the globe.^13,17

This new treatment has the potential to benefit patients across Europe and Ireland who are at high risk of a potentially fatal cardiovascular event. As the COVID-19 vaccine programme continues to rollout and something resembling normality starts to emerge, now is the time to rethink cardiovascular care in Europe, using new scientifically proven insights and treatment strategies, to ultimately save patients’ lives and provide a sense of relief from the burden of living with CVD.

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In the past year, Irish haematologists have been at the forefront of investigations into the causes of life-threatening clotting problems associated with COVID-19 infection, whilst Irish scientists continue cutting edge research in many other areas of haematology.

Irish haematologists are currently reporting outcomes of haematology patients who have contracted COVID-19 to an anonymised international registry.

At the recent meeting of the American Association for Cancer Research, a meta-analysis reported that, whilst the overall risk of death for patients with cancer and COVID-19 was 25% compared to a risk of 1-2% in the general population, the risk of death was 47% greater in haematological cancers compared to solid tumours. Therefore, Irish haematologists remain extremely vigilant about reducing the risk of this infection in their patients.

Investigating COVID-19 associated thrombosis

Researchers at the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland (RCSI), under the leadership of Professor James O’Donnell, have extensively researched the causes of clotting complications commonly seen in the more severe forms of COVID-19 infection. In particular, they have shown that viral induced damage to endothelial cells lining the blood vessels in the lungs leads to micro-clots and poorer outcomes.

Patients with myeloma are also at increased risk of thrombotic complications, especially if they are taking immunomodulatory drugs (IMIDs), a common anti-myeloma therapy.

Personalised therapies for myeloma

Myeloma is a cancer of cells in the bone marrow which often cause severe bone disease and/or renal failure. Professor Siobhan Glavey is Consultant Haematologist at Beaumont Hospital and RCSI Professor of Pathology. Her laboratory is now able to measure if a myeloma patient is completely free of disease following therapy, using state of the art molecular techniques. This will lead to personalised therapy for patients and improvement in their quality of life.

Patients with myeloma are also at increased risk of thrombotic complications, especially if they are taking immunomodulatory drugs (IMIDs), a common anti-myeloma therapy. Researchers at Beaumont Hospital and the Irish Centre for Vascular Biology at RCSI are thus currently researching the role of the pro-thrombotic molecule, von Willebrand factor, in the pathogenesis of myeloma.

New research pipeline

This year, Blood Cancer Network Ireland (BCNI) in collaboration with Cancer Trials Ireland, is starting an important phase Ib trial for patients with recurrence of their myeloma. Led by Dr Janusz Krawczyk, patients will be treated with a novel combination of standard anti-myeloma therapy plus an antibody directly targeting the myeloma cells.

Currently, BCNI is using patient reported outcome measurements (PROMs) in common haematological cancers, such as leukaemia and myeloma, to better understand patient quality of life and adverse effects of treatment.

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Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting one in four people over 50 years old. With AF the heart rate becomes completely irregular.

Although some people complain of palpitations, dizziness, breathlessness or chest tightness, 70% of AF is asymptomatic or ‘silent’. This means the actual true prevalence in the community is unknown and probably underestimated.

Data collected from pacemakers, loop recorders and Holter monitors show that even short episodes of AF (less than one hour) convey an increased risk of stroke. The difficulty in diagnosing such cases can be improved by screening with regular pulse checks, more prolonged monitoring, or loop recorder insertion.

Risk factors for atrial fibrillation

The risk of developing atrial fibrillation increases with age. Prevalence is also increasing due to better survival post myocardial infarction (MI), congenital and valvular heart disease, and increasing hypertension and obesity. Other recognised risks are viral infections, pneumonia, heart failure, lung disease, diabetes, sleep apnoea, thyroid disease and lifestyle factors such as excess alcohol, coffee and cigarettes.

The difficulty in diagnosing such cases can be improved by screening with regular pulse checks, more prolonged monitoring, or loop recorder insertion.

Overweight populations have a higher AF incidence and progression of AF compared with normal weight counterparts. Obese patients with atrial fibrillation who lose at least 10% of their body weight are six times more likely to achieve long-term freedom from AF compared to those who don’t lose weight.

Finding the right treatment

Treatment includes ensuring there are no potentially reversible causes such as thyroid disease and excess alcohol. Good blood pressure control and weight loss in obese patients reduces the risk of recurrent AF. In some studies, statin therapy appears to reduce AF and in other studies beta-blocker use in heart failure also reduces the risk of AF.

AF significantly increases the risk of stroke so prevention of stroke with anticoagulants (blood thinners), if appropriate, is crucial. In some patients we would consider restoration of sinus rhythm with medication, ablation or cardioversion. In others it’s important to ensure adequate rate control with a variety of medications. The treatment options will vary depending on patient factors and symptoms.

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