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Clinical pharmacology studies conducted at Newcastle have led to optimisation of the administration of the chemotherapy drug carboplatin in children with neuroblastoma and other cancers. The research provided the rationale for carboplatin dosing based on patient renal function, with individualised dosing resulting in increased drug efficacy and reduced toxicity. This approach is now in widespread use in national and European treatment protocols, benefitting over 2,500 children. Similar drug monitoring approaches are being implemented for an increasing number of important drugs. Following a recent Newcastle-led national clinical trial, new dosing guidelines for the drug 13-cis retinoic acid have been adopted for high-risk neuroblastoma patients across Europe.
Malignant pleural mesothelioma (MPM) is a treatable but incurable cancer that originates in the cells lining the lungs. Over 14,000 people worldwide are diagnosed annually with MPM. Antifolates are often used in cancer therapy, but side effects are a major issue. A retrospective analysis of cancer trials and phase 1 trial of MPM patients, carried out by Newcastle in collaboration with Eli Lilly Pharmaceuticals, determined that plasma homocysteine levels were a good predictor of drug toxicity in cancer patients treated with the antifolate pemetrexed, and that this drug was well tolerated by patients with low homocysteine levels. It was also determined that pemetrexed treatment should be supplemented with vitamin B12 as well as folic acid, to reduce drug toxicity. Ultimately, this permitted the continued development of pemetrexed, which otherwise would have been too toxic for clinical use. It is now the only licensed drug for MPM treatment in combination with platinum-based chemotherapy.
As a result of University of Sheffield research in 1995-2002, a new gold standard treatment for major bleeding on warfarin has been established, ensuring the more effective treatment of tens of thousands of patients requiring emergency anticoagulation reversal each year in the UK alone. The treatment, using prothrombin complex concentrate (PCC) was demonstrated to be superior to fresh frozen plasma (FFP), the standard alternative at the time, and two PCCs have now been licensed for this indication in the UK.
UK and international guidelines now recommend PCC over FFP.
Research at UCL firmly established tacrolimus as the optimal calcineurin inhibitor to use in immunosuppressive regimens following liver transplantation. Compared to ciclosporin its use improved graft survival by 6% and patient survival by 7%. Assuming 550 liver transplants per year in the UK since 2008, we can estimate that, with 90% of patients treated with tacrolimus and 10% ciclosporin, tacrolimus-based immunosuppression has resulted in 165 grafts and 192 lives being saved during the period 2008-13.
Neuroblastoma is a paediatric cancer that arises from the sympathetic nervous system. The average age at diagnosis is 18 months and the disease accounts for approximately 15% of all childhood cancer-related deaths. Determining optimal treatment for individual patients is crucial for increasing chances of survival and for reducing side effects of chemotherapy and radiotherapy. Newcastle-led research identified unbalanced 17q gain as the most common segmental chromosomal abnormality (SCA) in patients with neuroblastoma; this was present in more than 50% of patients. Gain of 17q is now one of the key SCAs used to determine treatment for patients in a European neuroblastoma trial and in UK treatment centres. Newcastle research also led to the development of a simple diagnostic test for the detection of the main SCAs in neuroblastoma.
Every year in the UK, 150,000 heart attacks are caused by coronary artery occlusion (blockage); worldwide, the figure is 17 million, according to the World Health Organization (WHO). Since 1993, the Leicester Interventional Cardiology group has been at the forefront of research to determine how best to manage such patients. Its findings have been incorporated into official UK (2008), European (2008, 2012) and US (2008) guidelines and have helped to change the way coronary heart disease and heart attacks are treated, with the number of patients treated with primary angioplasty doubling between 2008 and 2011. By guiding service provision, supporting industrial innovation and informing clinical practice, the Unit has contributed to improved healthcare and outcomes for thousands of heart patients. Overall, one-month mortality according to European figures has fallen from 15% to 4% between 2008 and 2013.
Congenital myasthenic syndromes (CMS) are inherited neuromuscular disorders caused by defects at neuromuscular junctions, which are often a result of acetylcholine receptor gene mutations. A subset of CMS patients (around 14% in the US and Europe) have limb-girdle myasthenia (LGM). This disease can be highly disabling with symptoms including increasing weakness of skeletal muscles. As a result of collaborative work between Newcastle and Oxford, it was determined that many LGM patients have a mutation of the Dok-7 gene (unrelated to the acetylholine receptor), and do not, therefore, respond to standard CMS treatments. Since then, a number of additional mutations have been discovered, and genetic testing is now available for the majority of known LGM-causative genes. Crucially, Dok-7 patients, and those with other non-receptor related mutations, can now be diagnosed accurately and treated effectively, with ephedrine and salbutamol (in the US, albuterol). This significantly improves these patients' quality of life by enabling them to walk and breathe unassisted.
Research conducted by Professor Tim Goodship and co-workers at Newcastle has had a profound effect on the prognosis for patients with atypical haemolytic uraemic syndrome (aHUS). By engaging in research on the genetic factors underlying the disease they developed an understanding of the molecular mechanisms responsible. Identifying that the majority of patients with aHUS have either acquired or inherited abnormalities of the regulation of complement (part of the immune system) led to the establishment of a UK national service for genetic screening and treatment with the complement inhibitor eculizumab. As eculizumab is now available to patients in England, the progression to end-stage renal failure can be prevented and patients already on dialysis will soon be successfully transplanted.
Impact: Health and welfare; public health studies in Sri Lanka and clinical trials in a cohort of 35,000 pesticide self-poisoning patients have led to the withdrawal of high-dose pralidoxime as a WHO-recommended treatment and bans of three toxic pesticides in Sri Lanka.
Significance: Resultant changes in clinical practice and pesticide regulation have saved 3000 lives in the last four years in Sri Lanka alone; in the rest of Asia many times this as local guidelines and practice have changed.
Beneficiaries: Patients and communities, healthcare providers, policy-makers.
Attribution: Studies designed and led, with international collaborators, by Michael Eddleston, UoE.
Reach: International, particularly Asia, changes in WHO and international guidelines on pesticide use.
This case study summarises the research undertaken by Professor Sewell at Plymouth University in defining and developing the understanding of dose banding, a method for pre-defining standard dose ranges for Chemotherapy. The introduction of dose banding has improved care for patients by reducing the time patients wait for their chemotherapy infusions, enabling prospective quality control of infusions, optimising the infusion preparation process, and reducing wastage resulting in a more efficient, patient focused service for patients. Dose banding is now part of the professional guidelines produced by regional cancer Networks, and is being used in UK hospitals and increasingly across Europe.