Clinical Feasibility Study Of Omega-3 PUFA Therapy For The Reduction Of Post-cardiac Surgery Atrial Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$442,092.00
Summary
The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be li ....The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be linked to low incidence of AF. The main aim is to provide a cheap and safe preventative therapy against post-operative atrial fibrillation (AF), a key heart rhythm disorder that occurs in at least 1 in 4 patients after heart surgery and increases post-operative complications, limits recovery and increases hospital stay and cost. Biochemical study elements are important to gain valuable insight into the molecular mechanisms (directly in human heart) that underlie post-operative heart rhythm disorder and may delineate new more precise molecular targets for therapy. No previous clinical study has ever examined whether omega-3 PUFA therapy prevents post-operative heart rhythm disorder. Use of 3g-day omega-3 PUFA pre-treatment in the surgical setting has been shown to be safe in a number of small studies, including our own. Our preliminary data indicates that therapy increases heart and blood content of omega-3 PUFA ~2-fold, and reduces the incidence of AF. Post-operative AF is an expensive resource burden in all cardiothoracic surgery units of Australian hospitals and targets key health priorities. Due to the non-patentable nature of omega-3 PUFA, significant industry based support for clinical research is limited. A positive outcome would rapidly pave the way for widespread use in elective surgery. Reduced length of hospital stay, cost-savings, and the increase in productivity as healthy individuals return to their communities would nationally repay the investment many fold.Read moreRead less
Alternative Insufflation Gases For Laparoscopic Surgery
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
It is now recognised that laparoscopic (keyhole) surgery for cancer can be associated with the spread of tumour to surgical wounds, i.e. port sites. However, whether this is more likely following laparoscopy than conventional open surgery is controversial. Isolated case reports and the recent results of experimental studies suggest that the problem is important. Previous studies suggest that carbon dioxide gas used to inflate the abdomen during laparoscopy may be the specific cause of this probl ....It is now recognised that laparoscopic (keyhole) surgery for cancer can be associated with the spread of tumour to surgical wounds, i.e. port sites. However, whether this is more likely following laparoscopy than conventional open surgery is controversial. Isolated case reports and the recent results of experimental studies suggest that the problem is important. Previous studies suggest that carbon dioxide gas used to inflate the abdomen during laparoscopy may be the specific cause of this problem. A four to fivefold increase in the rate of cancer spread has been shown in previous experiments, and this can be reduced by using an inert gas such as helium. We propose to further investigate this issue using a combination of small and large animal models, and will also commence clinical trials of helium during clinical surgery. These studies aim will determine the gas of choice during laparoscopic surgery. They will also clarify advantages demonstrated for the use of helium in previous animal studies, and better investigate the safety of helium use. If our preliminary findings are supported by these studies, helium (or other inert gases) should be considered for routine use during clinical laparoscopy.Read moreRead less
Optimizing Implanted Cell Survival Using A Tissue Engineering Model
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Cell therapy and tissue engineering involve the insertion of specific cells into damaged tissues or into a bioraector in a patient's body to generate new replacement tissues. This project seeks to improve two factors associated with inserting cells : 1. The innate survival characteristics of the cells being inserted, and 2. The blood vessel supply at the site of insertion. These techniques will greatly improve the survival of inserted cells.
Randomised Controlled Trials Of Laparoscopic Techniques For Antireflux Surgery
Funder
National Health and Medical Research Council
Funding Amount
$1,031,381.00
Summary
Gastro-oesophageal reflux is common, with approximately 10% of Australians now using medication to control symptoms. Many Australians will need this medication for life, unless they undergo surgery. The cost of treating reflux is growing. Since 1992 the annual growth rate of the Pharmaceutical Benefits Scheme expenditure on reflux medication has been 13%, and the annual cost for the treatment of reflux now exceeds $1 billion. Not all patients with reflux are satisfied with medication, as some co ....Gastro-oesophageal reflux is common, with approximately 10% of Australians now using medication to control symptoms. Many Australians will need this medication for life, unless they undergo surgery. The cost of treating reflux is growing. Since 1992 the annual growth rate of the Pharmaceutical Benefits Scheme expenditure on reflux medication has been 13%, and the annual cost for the treatment of reflux now exceeds $1 billion. Not all patients with reflux are satisfied with medication, as some continue to experience symptoms. Surgery is the only treatment which will cure reflux. It has a clear role in the treatment of patients with ongoing symptoms, those who don t want to take tablets, and patients with a large hiatus hernia in whom symptoms occur due to the relocation of the stomach from the abdomen into the chest. Approximately 5,000 Australians per year undergo surgery for reflux. The standard operation achieves a good outcome in approximately 90%, although some patients are troubled by side effects. To reduce the risk of this, the original procedure has been modified. However, the evidence supporting modifications has until recently been limited. The best way to compare different operations is in randomised trials. The majority of the largest and best trials addressing this area have been undertaken in Adelaide. We have already entered 504 patients into 5 randomised trials, 4 conducted entirely in Adelaide, and one across multiple sites with the cooperation of 15 Australasian surgeons. These trials have provided a more reliable evidence base for surgeons undertaking surgery for reflux. However, long term follow-up is required to ensure that conclusions drawn are valid at late follow-up. In addition we are establishing 2 new randomised trials, which will determine how best to perform surgery for reflux, and how best to repair a large hiatus hernia. These studies will be undertaken in collaboration with more than 25 other surgeons throughout Australia.Read moreRead less
Perioperative Beta-blockade To Prevent Cardiac Morbidity In High-risk Patients Undergoing Surgery (The POISE Study)
Funder
National Health and Medical Research Council
Funding Amount
$189,625.00
Summary
Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure). About 11% of the Australian population are currently taking medications for heart disease or high blood pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have general anaesthesia for non-cardiac surgery every year, a subst ....Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure). About 11% of the Australian population are currently taking medications for heart disease or high blood pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have general anaesthesia for non-cardiac surgery every year, a substantial group of patients are therefore at risk of an adverse outcome following surgery. Despite the magnitude of this problem, however, few studies have established treatments to decrease the risk of complications and death following surgery. Beta-blockers are a group of drugs which have been used for decades in the treatment of heart disease and high blood pressure. Beta-blockers are known to improve the way the heart copes with the stress of surgery. They decrease the heart rate, make the heart more efficient at using energy and reduce the likelihood of imbalance between oxygen supply and demand. Some previous studies showed that beta-blockers may reduce the risk of heart attack and death for up to 2 years after surgery. However, other studies have shown no effect of beta-blockers on outcome. These previous studies have involved small numbers of patients who may not represent the broader population having surgery. We therefore propose to undertake a large trial to definitively answer the question about whether beta-blockers improve the outcome after non-cardiac surgery in patients with, or at risk of, heart disease. Even if the effect of beta-blockers is relatively modest, because such large numbers of patients with heart disease have surgery, the overall effect on the rate of complications and death in the population could be very significant. The results of this study could have major implications for the success of, and cost of, surgery worldwide.Read moreRead less
Evaluation Of Aspirin And Tranexamic Acid In Coronary Artery Surgery: The ATACAS Trial
Funder
National Health and Medical Research Council
Funding Amount
$1,185,000.00
Summary
This large study will compare two types of drug treatment in 4600 patients undergoing heart surgery, to see whether either can reduce the risk of death or major complications. The complications after surgery we are measuring include heart attack, stroke, lung embolism, bleeding around the heart, breathing failure, kidney failure, major haemorrhage, serious wound infection, and death. The first drug being tested is low-dose aspirin. It is believed that aspirin can reduce the risk of a further hea ....This large study will compare two types of drug treatment in 4600 patients undergoing heart surgery, to see whether either can reduce the risk of death or major complications. The complications after surgery we are measuring include heart attack, stroke, lung embolism, bleeding around the heart, breathing failure, kidney failure, major haemorrhage, serious wound infection, and death. The first drug being tested is low-dose aspirin. It is believed that aspirin can reduce the risk of a further heart attack or stroke in patients with pre-existing heart disease. There is some evidence that aspirin may have similar effects in people undergoing heart surgery, but such use is constrained by a concern that there may be an increased risk of bleeding after surgery. For this reason, most patients having heart surgery are advised to stop their aspirin about one week before surgery. But patients could be missing out on aspirin's beneficial effects. At present, we do not know whether the benefits of aspirin could outweigh the risk of excesive bleeding. The second drug being tested is tranexamic acid. This drug prevents blood clot being broken down at the stitching sites of surgery, and probably reduces the amount of blood loss during and after heart surgery. It is known that use of this drug reduces the need for a blood transfusion. It is possible that this could avoid other more serious complications after surgery. Both of these drugs are being tested individually, but in addition we are testing whether they may have an extra beneficial effect when used together. The study is being done by a partnership of anaesthetitsts and surgeons at more than 20 hospitals around Australia.Read moreRead less
Engineering Tissues And Organs In Vivo From Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,480.00
Summary
Tissue engineering is an exciting new area of medical research. We have developed a unique animal model of tissue engineering where new tissue spontaneously sprouts from the surface of a vascular loop enclosed inside a plastic chamber. The tissue thus created has its own blood supply. By adding cultured cells or altering the environment of the chamber we have been able to grow new specific tissues such as fat and muscle. This technology potentially allows the generation of spare body parts to re ....Tissue engineering is an exciting new area of medical research. We have developed a unique animal model of tissue engineering where new tissue spontaneously sprouts from the surface of a vascular loop enclosed inside a plastic chamber. The tissue thus created has its own blood supply. By adding cultured cells or altering the environment of the chamber we have been able to grow new specific tissues such as fat and muscle. This technology potentially allows the generation of spare body parts to replace lost or worn out organs and tissues. We have recently reproduced this model in the mouse to be able to screen a range of mouse and human stem cells. These cells have the ability to change (i.e. differentiate) into many different types of cell depending on how they are stimulated. In Part 1 of this project we will determine in the mouse chamber the growth characteristics and survival rates of these stem cells. A chamber encapsulating a flowing blood vessel will be implanted subcutaneously in each groin. In one chamber we will inject fluorescently labelled stem cells in a growth medium and in the other growth medium alone. Tissue will be analysed at 1, 2 and 4 weeks. In Part 2 we will inject a variety of Rosa26 labelled mouse stem cells obtained from several different tissues. Through the aid of naturally occurring growth and differentiation factors they will differentiate into one of several different tissues including fat, cartilage, bone, neural tissue, blood vessels, liver, etc, which will be identified by histology and cell culture. In one experiment we will genetically alter cells injected into the chamber so that they produce only skeletal muscle. In Part 3 we will grow new human tissues by injecting human stem cells into the same tissue engineering chambers in mice which will tolerate cells from other mammals (these are known as SCID mice). Success in novel method would be the precursor for the production of new human tissues to repair specific defects.Read moreRead less
In Vivo Tissue Engineering Of Adipose Tissue For Reconstructive Surgery
Funder
National Health and Medical Research Council
Funding Amount
$713,545.00
Summary
We are able to grow vascularised tissue in implanted plastic chambers to a predetermined size and shape in the rat and mouse (NHMRC Project Grant 01-03; #145782; CIA Morrison). The basis of this growth is blood vessel sprouting from the surface of the vessel bundle or loop, followed by synthesis of structural molecules and the migration of surrounding cells into the vascularised network to form a stable tissue. Unlike other in vivo models of tissue engineering, the tissue grows spontaneously and ....We are able to grow vascularised tissue in implanted plastic chambers to a predetermined size and shape in the rat and mouse (NHMRC Project Grant 01-03; #145782; CIA Morrison). The basis of this growth is blood vessel sprouting from the surface of the vessel bundle or loop, followed by synthesis of structural molecules and the migration of surrounding cells into the vascularised network to form a stable tissue. Unlike other in vivo models of tissue engineering, the tissue grows spontaneously and is densely vascularised, enabling continuous growth and surgically transfer to another part of the body, or to another animal. In this renewal application of the above NHMRC grant, we propose to direct these findings towards the development of vascularised fat tissue which would be ideal for reconstructive surgery as a stable, inert tissue filler. Our efforts to grow fat tissue in vivo to date have identified 4 major requirements: a fat precursor cell source; an instructive basement membrane matrix (which may include growth-differentiation factors); space into which the tissue can grow; a stable blood supply. We will focus here on optimising the precursor cell source and instructive matrix to generate vascularised fat tissue around the blood supply we can engender in our tissue engineering chamber. We have found Matrigel, a mouse tumor-derived matrix rich in basement membrane components, to be instructive for growing fat, and will also build on preliminary observations that either muscle or fat tissue can provide the appropriate precursor cells for this process. Finally we propose to adapt and upsize the vascularised fat tissue chamber to the pig, in a step towards human use, and assess its transplantability and longevity. The clinical application of our work is to produce breast reconstruction tissue and lipo filling for contour deformities resulting from trauma, congenital deformity, ageing and cancer surgery, particularly breast reconstruction.Read moreRead less
Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less