tag:theconversation.com,2011:/us/topics/cancer-medicines-2741/articlesCancer medicines – The Conversation2015-06-09T11:02:49Ztag:theconversation.com,2011:article/422912015-06-09T11:02:49Z2015-06-09T11:02:49ZYour dog could hold the answer to cancer treatments of the future<figure><img src="https://images.theconversation.com/files/84146/original/image-20150605-8692-zwnmoz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Not so different?</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Doctors and vets both receive an expensive subsidised education. They both train for at least five years at an enormous cost to the taxpayer. In the UK, recent increases in tuition fees don’t appear to have had any effect on the demand for medical and veterinary education, with several <a href="http://www.independent.co.uk/student/news/first-uk-private-medical-school-to-open-the-cost-35000-8787400.html">new schools</a> <a href="http://www.bbc.co.uk/news/uk-england-surrey-29489355">being established</a> in both fields to meet growing demand.</p>
<p>But although doctors and vets are supposed to speak the same clinical language, the sad truth is that medicine and veterinary research have become separate disciplines. Members of two of the most intelligent and ambitious professions <a href="http://journal.frontiersin.org/article/10.3389/fvets.2015.00002/full">barely talk</a> to each other.</p>
<p>Situations where veterinarians and physicians might cooperate successfully and productively are exceptions rather than the norm. If they <a href="http://www.cdc.gov/mmwr/preview/mmwrhtml/su5502a4.htm">worked together</a> <a href="http://www.bostonglobe.com/ideas/2012/06/23/what-human-doctors-can-learn-from-vets/blxikDkBpd4YCG3OJq9k1N/story.html">more closely</a>, they could speed up the translation of new treatments from laboratory and companion animals to humans. </p>
<p>They would also have a greater chance of tackling the common health problems that humans and animals face today. After all, a problem shared is a problem halved. Men are not mice and many treatments that are developed in pre-clinical animal models do not translate well to humans. However, humans and companion animals are much closer and since many of our pets suffer from the same chronic diseases that reduce our longevity and quality of life a collaborative approach is likely to be more fruitful.</p>
<h2>Cancer collaboration</h2>
<p>Cancer is one area in particular where greater collaboration between doctors and vets could benefit both sides. The incidence of cancer is steadily growing across the world because of the expanding ageing population and the rise in obesity. Many forms of cancer are essentially the same in humans and dogs. By studying osteosarcoma (the most common form of bone cancer) in dogs we can learn about aggressive bone cancers in humans and develop safer, more specific and more effective treatments for both species.</p>
<p>Dogs have a shorter lifespan than humans. Therefore <a href="http://www.nature.com/nrc/journal/v8/n2/full/nrc2273.html">studying and testing</a> new cancer treatments in dogs across their lifetime would be far quicker than making the same studies over the decades of a human life. This kind of research would be done more cheaply and the data sharing will benefit both species. And while plenty of cancer research is done in mouse models, the data from mice often does not translate well to human patients. So shifting the focus on to dogs would bring closer benefits to humans.</p>
<p>Clearly, the benefits for human and animal treatments are not mutually exclusive. If the disciplines of human and veterinary oncology were brought closer together, some of the biological therapies being developed for human cancer could benefit our pets.</p>
<p>Where there has been greater communication between the two disciplines, new treatment approaches have emerged as a result. Limb-sparing surgery in dogs with osteosarcoma led to the same thing being done <a href="http://ilarjournal.oxfordjournals.org/content/51/3/208.full.pdf">in human adolescents</a> years later. This has had a huge impact on human cancer patients, giving children with osteosarcoma the chance to keep the limb in which the tumour was located.</p>
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<span class="caption">Shared experiences.</span>
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<p>Another example is the <a href="http://www.cancerresearchuk.org/about-cancer/type/melanoma/treatment/melanoma-vaccines">melanoma vaccine</a> that was initially developed for humans and animals in parallel. While it is still being trialled for humans, it has taken a life of its own in veterinary medicine and a version for dogs has become the <a href="http://www.nature.com/nbt/journal/v28/n3/full/nbt0310-189a.html">first therapeutic cancer vaccine</a> approved for human or animal use.</p>
<p>The only cancer drug approved specifically for dogs, toceranib (marketed as Palladia), started with testing in laboratory dogs with mast cell tumours. Subsequent work focused on human cancer and more toceranib drugs were developed, creating a multi-billion dollar industry.</p>
<p>Although many people may think that this area can progress in human oncology without any veterinary involvement, vets can still help because they can use dogs to study endpoints and biomarkers in a shorter timeframe. This is much more difficult to do with human patients. The US Food and Drug Administration has now approved several of these kinds of drugs that were originally developed for use in dogs.</p>
<h2>One Health</h2>
<p>Multidisciplinary collaboration is the only way to make sure that advances in basic science can be translated into new diagnostics, therapeutics and most important of all, preventive strategies for the most common diseases in the 21st century.</p>
<p>With this in mind, some scientists argue for the introduction of the “<a href="http://www.onehealthinitiative.com">One Health</a>” concept, which aims to unite human and animal medical practice as two branches of “One Medicine”, particularly through greater openness and communication.</p>
<p>So what can be done to bring the two sides together? In my opinion, funding agencies, charities and major foundations should put more funding into joint research initiatives. I would like to see the likes of the <a href="http://www.gatesfoundation.org">Gates Foundation</a> create new funding calls and collaborative initiatives that require equal partnership and collaboration between medical and veterinary colleges.</p>
<p>The One Health concept is <a href="http://veterinaryrecord.bmj.com/content/174/4/85.full">still evolving</a>. But doctors and vets still don’t communicate enough. Unless things change, both humans and animals will continue to suffer needlessly.</p><img src="https://counter.theconversation.com/content/42291/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ali Mobasheri receives funding from the European Union through the Seventh Framework Programme (FP7; HEALTH.2012.2.4.5-2, project number 305815, acronym: D-BOARD), the Marie Skłodowska-Curie Actions (MSCA; FP7-PEOPLE-2013-IEF; project number: 625746; acronym: CHONDRION) and the Innovative Medicines Initiative (IMI, Grant Agreement 115770).</span></em></p>Greater collaboration between medicine and veterinary science would give us a better chance of tackling common health problems.Ali Mobasheri, Professor of Musculoskeletal Physiology, School of Veterinary Medicine, University of SurreyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/422012015-05-22T14:11:48Z2015-05-22T14:11:48ZUltrasound-activated bubbles could help make cancer drugs more effective and less nasty<figure><img src="https://images.theconversation.com/files/82558/original/image-20150521-985-1gxrao3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nanoparticles: small but deadly... to cancer</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Despite extraordinary advances in new drugs and biotechnology, cancer is still one of the leading causes of death worldwide.</p>
<p>In many cases, the problem lies not with the drugs but rather the difficulty in successfully delivering them to the site of a tumour. In healthy tissue there is a regular structure of blood vessels supplying oxygen and nutrients to cells, which divide and grow at a steady rate. In cancerous tumours, however, cells divide and grow in an unregulated way, producing a <a href="http://www.ncbi.nlm.nih.gov/pubmed/2292138">chaotic vessel structure</a> and regions of tissue with little or no blood supply.</p>
<p>This means when drugs are ingested or injected into the blood stream, they don’t reach all parts of the tumour and there is a high risk of cancer recurring after treatment. On top of this, the <a href="http://www.ncbi.nlm.nih.gov/pubmed/9018236">pressure inside</a> many tumours prevents a drug from being absorbed from the blood, meaning only a very small fraction of it is actually delivered. The rest of the drug circulates around the body and is eventually absorbed by healthy tissue, often leading to intolerable side effects.</p>
<p>One of the major goals of the research being carried out in the <a href="http://www.ibme.ox.ac.uk">Oxford Institute of Biomedical Engineering</a> (IBME) is to develop new methods for delivering anti-cancer drugs that overcome these barriers. While engineers are perhaps more commonly thought of in the context of large construction projects, we are using precisely the same combination of applied science and problem solving.</p>
<h2>Building nanoparticles</h2>
<p>There is a formidable series of challenges to address to solve this problem. First, we need to encapsulate the drug to prevent it from interacting with healthy tissue and/or deactivating before reaching the tumour. Second, we need a way to deliver the drug to the tumour to maximise the concentration it receives.</p>
<p>Third, we need a mechanism for releasing the drug on demand once it has built up within the tumour. Fourth, we need to ensure the released drug is evenly spread throughout the tumour. And finally, we need to be able to monitor the treatment from outside the body.</p>
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<img alt="" src="https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/82570/original/image-20150521-995-s69931.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Taking the fight to cancer.</span>
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<p>Our team at the IBME has developed a range of new techniques for creating tiny particles into which we can insert drugs with a high degree of precision. And we have tried a <a href="http://www.ncbi.nlm.nih.gov/pubmed/18261822">variety of methods</a> to make the particles release the drug. These include using materials that are sensitive to the pH change within a tumour and materials that break down upon heating or undergo a phase change (from a solid to a liquid or liquid to a gas).</p>
<p>But one of the most versatile means of triggering drug release is by firing a beam of <a href="http://www.ncbi.nlm.nih.gov/pubmed/23121385">ultrasonic vibrations</a> at the particles. Widely used as an <a href="http://www.nhs.uk/conditions/ultrasound-scan/pages/introduction.aspx">imaging method</a>, ultrasound can be used from outside the body and, unlike light or heat, can be tightly focused to produce highly localised effects.</p>
<p>In order to produce particles that respond to ultrasound, we have to include in them a gas or a liquid that easily vaporises. When exposed to the ultrasound, the gas/liquid will undergo a rapid expansion and force the drug out of the particle.</p>
<h2>Ultrasound activated bubbles</h2>
<p>This process generates a pulsating gas or vapour bubble that has several other significant benefits for drug delivery. The motion of the bubble produced by the ultrasound field helps to drive the drug out of the blood vessels and deep into the surrounding tumour. We have shown that bubbles can push drugs <a href="http://www.ibme.ox.ac.uk/research/non-invasive-therapy-drug-delivery/enhanced-drug-delivery">up to four times deeper</a> into tissue than they would normally diffuse, sufficient to achieve a uniform spread throughout a tumour.</p>
<p>There is also a growing body of research that shows microbubbles and ultrasound make cancer cells more permeable to drugs, speeding up the rate at which they work and ultimately cell death. The microbubbles’ motion produces a secondary ultrasound signal that can be detected outside the body. This means the location and activity of the particles can be <a href="http://www.ncbi.nlm.nih.gov/pubmed/25564961">continuously monitored</a>, providing real-time feedback on the progress of the treatment.</p>
<p>Our aim over the next five years is to translate these developments into clinical use. The work will focus on improving the delivery of four classes of drug that have shown enormous potential but that currently struggle to get inside a tumour and/or have unacceptable side effects. By combining our expertise in encapsulation with the use of ultrasound and shockwaves, we hope to create more effective drugs that can be delivered straight to the location of a tumour and monitored with advanced imaging techniques.</p>
<p><em>This article is adapted from the 2015 IET A. F. Harvey Prize Lecture</em></p><img src="https://counter.theconversation.com/content/42201/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eleanor Stride is a non-executive director of AtoCap Ltd. She receives funding from the Engineering and Physical Sciences Research Council, Cancer Research UK, Multiple Scelerosis Society.</span></em></p>New research could into nanoparticles could help deliver drugs straight to the site of tumours and make them more effective when they get there.Eleanor Stride, Professor of Engineering Science, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/405582015-04-23T05:01:34Z2015-04-23T05:01:34ZExplainer: how does Keytruda treat melanoma and why is it so costly?<figure><img src="https://images.theconversation.com/files/79009/original/image-20150422-1858-1oszuku.jpg?ixlib=rb-1.1.0&rect=0%2C82%2C1000%2C519&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Keytruda® targets a protein on the surface of immune cells that stopped them from attacking the melanoma cells.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-159846560/stock-photo-melanoma-skin-cancer-mole-high-definition-image.html?src=SAJLwoBr03ptKZAAQYM3zw-1-3">Australis Photography/Shutterstock</a></span></figcaption></figure><p>Keytruda® (pembrolizumab) is the latest drug to be <a href="http://www.melanoma.org.au/news-events/news/anti-pd1-immunotherapy-pembrolizumab-keytruda-has-been-registered-by-the-tga/">registered</a> in Australia for the treatment of widespread melanoma. This is the third class of drugs that improves survival in widespread melanoma to be registered since July 2011. Prior to this no chemotherapy drug prolonged survival once melanoma had spread. </p>
<p>The first of the new drugs, Tafinlar® (dabrafenib), targets an alteration in the <a href="http://ghr.nlm.nih.gov/gene/BRAF">BRAF gene</a>, which signals the melanoma cells to divide more quickly. This altered gene was found in half of all melanomas. </p>
<p>The second drug, Yervoy® (ipilimumab), is an immune therapy. It is an antibody against a protein (<a href="http://www.nature.com/icb/journal/v77/n1/full/icb19991a.html">CTLA-4</a>) on immune T cells that stops that protein from preventing the T cells from attacking the melanoma.</p>
<p>Keytruda® also works by targeting a protein on the surface of immune cells that stops them from attacking the melanoma cells. The drug is an antibody which blocks the protein called <a href="http://www.ncbi.nlm.nih.gov/pubmed/21061197">PD-1</a> (programmed cell death 1) on the surface of the immune system T-cells. This prevents an activated PD-1 protein from stopping the immune response against the melanoma. </p>
<p>Initially, Keytruda® was <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315269/">found to</a> prolong survival and outperform older chemotherapy drugs for patients whose melanoma had progressed after the other drugs. </p>
<p>Most recently, Keytruda® has been <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1503093">directly compared</a> to Yervoy® in patients with advanced melanoma who had either not received previous drugs or had only previously received Tafinlar® because the altered BRAF gene was present. The 834 patients with widespread melanoma from 16 countries were randomly allocated to Keytruda®, given every two weeks or three weeks, or Yervoy®. </p>
<p>In one-third of those treated with Keytruda®, their melanomas shrank, compared with only 12% of those on Yervoy®. Up to 74% of those treated with Keytruda® survived to 12 months compared with 58% of those on Yervoy®. </p>
<p>Those treated with Keytruda® also reported fewer side effects. These commonly included fatigue, diarrhoea, rash and itch, and more serious thyroid problems and inflammation of the bowel and liver.</p>
<p>The results indicate that Keytruda® could be used as the first drug in the treatment of widespread melanoma.</p>
<p>The decision to register a drug in Australia, and thereby make it available, is based on whether the beneficial effects are sufficient to justify the side effects. </p>
<p>However, there is another hurdle for a new drug: whether it gets approved for subsidy by the Pharmaceutical Benefits Scheme (PBS). Evaluators assess cost-effectiveness and how it compares to other treatments. PBS subsidisation effectively makes a drug affordable for a wide population. </p>
<p>If Keytruda® is not subsidised, the estimated cost is A$150,000 per patient for each year of treatment. </p>
<p>Why so expensive? The pharmaceutical industry points to the costs of research and development, including the expense of the large clinical trials needed to confirm efficacy. Often effective patent protection may last for only 15 years before competitors are allowed into the marketplace. </p>
<p>However, more likely, the price is set internationally by what the market is prepared to pay and that is often the American market, which can afford to pay more than many other nations. Australia has little leverage here as it represents less than 1.5% of the world’s pharmaceutical market.</p>
<p>What needs to be done? </p>
<p>In cancer, Australia has one of the highest survival rates in the world, so until now the most important cancer drugs have been subsidised on the PBS. However, with the very high cost of each new targeted therapy, the PBS clearly cannot continue to subsidise every new drug. </p>
<p>The bar needs to be set so the most effective drugs will continue to be made available. Examples would include drugs for which no alternative treatments exist, or drugs that demonstrate a large increase in survival over those currently used. </p>
<p>As now, there should always be special funding streams for drugs for rare diseases, which would otherwise not be commercially viable. </p>
<p>Drugs for life-threatening diseases should be made available as quickly as possible after efficacy is established. Here it would be desirable to have a managed entry scheme so that a drug could be approved on earlier endpoints than overall survival. Response rates or disease-free survival are examples. </p>
<p>For such a scheme to be feasible, there would have to be agreement that the subsidy could be removed or reduced if the drug did not subsequently meet its survival targets. </p>
<p>We must wait to see if Keytruda® will meet the cost-effectiveness targets.</p><img src="https://counter.theconversation.com/content/40558/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Olver does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Keytruda® is the latest drug to be registered in Australia for the treatment of widespread melanoma. But we must wait to see if it meets the cost-effectiveness targets for PBS subsidisation.Ian Olver, Director, Sansom Institute for Health Research; Chair of Translational Cancer Research, University of South AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/401892015-04-14T20:19:28Z2015-04-14T20:19:28ZManifesto Check: on health, the Tories make vague promises and claims that don’t stand up<p><em>Welcome to The Conversation’s Manifesto Check, where academic experts scrutinise the party manifestos.</em></p>
<h2>Health</h2>
<p><strong>Andrew Street, Professor of Health Economics at University of York</strong></p>
<p>The Conservatives recognise that the electorate is suspicious about their guardianship of the National Health Service. Prior to the last election, they promised that there would be “no top-down reorganisation of the NHS”, only for Andrew Lansley to <a href="https://theconversation.com/state-of-the-nation-ten-things-weve-learned-about-the-nhs-under-the-coalition-39334">embark on a reorganisation</a> of such scale that the NHS chief executive of the time described it as “so big you can see it from space”.</p>
<p>In the <a href="https://s3-eu-west-1.amazonaws.com/manifesto2015/ConservativeManifesto2015.pdf">party manifesto</a>, the Conservatives seek to put this behind them, by pointing to their triumphs over the past five years. But not all of their claims about health policy match up with the evidence. </p>
<p>The party claims to have “cleared out bureaucracy” and, indeed, there are <a href="https://theconversation.com/fact-check-are-there-more-nhs-doctors-and-nurses-than-before-the-coalition-39607">20,000 fewer managers and support staff</a> now than in May 2010. NHS productivity has improved year-on-year, mainly due to <a href="http://www.hsj.co.uk/5084013.article#.VS0yvvnF9c9">slower recruitment of staff</a>. And the manifesto correctly claims that The Commonwealth Fund has ranked the UK as having <a href="http://www.commonwealthfund.org/%7E/media/files/publications/fund-report/2014/jun/1755_davis_mirror_mirror_2014.pdf">the best health system</a> among 11 countries. </p>
<p>But other statements don’t stand up to scrutiny. The <a href="http://www.england.nhs.uk/statistics/statistical-work-areas/rtt-waiting-times/">official statistics</a> contradict claims that fewer patients are waiting longer than target times. In <a href="http://www.england.nhs.uk/statistics/statistical-work-areas/rtt-waiting-times/rtt-data-2014-15/">February 2015</a>, although 194 fewer patients were waiting more than 52 weeks, 18,804 more patients were waiting longer than 18 weeks – and 6,019 more than 26 weeks – for hospital admission, compared with May 2010. And many more patients were also waiting longer for outpatient care. </p>
<p>I’ve been unable to verify the claim that those waiting over a year for cancer treatment has fallen from over 18,000 to under 500 is correct, but <a href="http://www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2014/11/Cancer-Waiting-Times-National-Time-Series-Q4-2008-09-to-Q3-2014-15-Provider-based-155kB.xlsx">the evidence shows</a> that achievement against all cancer waiting time standards has deteriorated over the parliamentary term. </p>
<p>And the statement that “patients are reporting the highest levels of satisfaction for years” is true if compared to 2011, when 58% reported being at least “quite satisfied” with the NHS, which has risen to 65% in the most recent survey. But satisfaction <a href="http://www.kingsfund.org.uk/projects/bsa-survey-2014/satisfaction-nhs-overall">remains below</a> the all-time high of 70% recorded in 2010, prior to the re-organisation. </p>
<p>If their past record is patchy and claims are questionable, what of the promises for the future? The manifesto offers five highlights. </p>
<p>First, the Conservatives promise to increase spending on the NHS, so that it remains free at the point of use, and continue to back <a href="http://www.england.nhs.uk/wp-content/uploads/2014/10/5yfv-web.pdf">Simon Steven’s action plan</a> for the NHS, much of which is reflected in the manifesto. </p>
<p>Second, the action plan calls for increased NHS spending to help close a funding gap that is <a href="http://www.england.nhs.uk/wp-content/uploads/2014/10/5yfv-web.pdf">otherwise projected to widen</a> to £30 billion by 2021. To fill this gap, they promise to spend “at least an additional £8 billion by 2020 over and above inflation”. It remains unclear how this will be funded, despite Andrew Marr’s <a href="https://www.youtube.com/watch?v=94hdq5iX9m8">best efforts to secure clarity</a> from George Osborne, but the manifesto pins its hopes on increased tax returns from a stronger economy. </p>
<p>Third, reiterating a similar promise from <a href="https://www.conservatives.com/%7E/media/files/activist%20centre/press%20and%20policy/manifestos/manifesto2010">the 2010 manifesto</a>, the Conservatives pledge that people will be able to see a GP and receive hospital care seven days a week by 2020, and all those older than 75 will get a same-day appointment if needed. The costs of this were not factored into the action plan, so even more money might be required above the promised additional £8 billion. </p>
<p>What’s more, the Conservatives will have to convince the medical profession of the necessity of a 24/7 NHS, as <a href="http://www.bmj.com/content/350/bmj.h12">the British Medical Association claims</a> that the proposals “lack credible evidence and risk wasting resources and endangering patient safety”.</p>
<p>Fourth, recognising that people are living longer with multiple long-term conditions, the Conservatives promise to strengthen integration of health and social care. These include initiatives such as the <a href="http://www.england.nhs.uk/wp-content/uploads/2013/08/itf-aug13.pdf">Better Care Fund</a>, the <a href="https://theconversation.com/devomanc-can-it-make-the-nhs-a-success-38133">pooling of health and social care</a> funding in Greater Manchester and the <a href="http://www.england.nhs.uk/ourwork/futurenhs/5yfv-ch3/new-care-models/">trialling of new approaches</a>. </p>
<p>It will be a bigger challenge, though, to address reductions in social care funding, with around 320,000 fewer people receiving local authority supported social care in 2012/13 than in 2005/06, despite <a href="http://www.pssru.ac.uk/pdf/dp2867.pdf">the number in need increasing</a>.</p>
<p>Fifth, the Conservatives plan “to lead the world in fighting cancer and finding a cure for dementia”. Like Labour, the Conservatives will maintain support for the controversial Cancer Drugs Fund, which gives priority to cancer patients <a href="http://www.york.ac.uk/che/news/2015/estimating-the-nice-costeffectiveness-threshold/">at the expense</a> of those with other conditions. Cameron has personally prioritised improving care for those with dementia, and the manifesto reminds the electorate of <a href="https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/414344/pm-dementia2020.pdf">this commitment</a>. </p>
<p>After reneging on their “no top-down re-organisation” promise after the last election, the Conservatives will need to reassure the electorate that they can be trusted with the NHS. It remains to be seen whether the 2015 manifesto will succeed in doing this. </p>
<h2>Mental health</h2>
<p><strong>Richard Slinger, Clinical Psychologist at Lancaster University</strong></p>
<p>The <a href="https://s3-eu-west-1.amazonaws.com/manifesto2015/ConservativeManifesto2015.pdf">Conservative manifesto</a>, as with the <a href="http://b.3cdn.net/labouruk/e1d45da42456423b8c_vwm6brbvb.pdf">Labour equivalent</a>, makes broad and positive recommendations about the future of mental health care. It continues to highlight the <a href="https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/281250/Closing_the_gap_V2_-_17_Feb_2014.pdf">aim for parity</a> of esteem for mental and physical health, promises to increase funding for mental health care, promises to tackle waiting times and access to therapeutic support. </p>
<p>These are positive intentions, and will be supported by most people accessing and working within mental health services. But the manifesto also suffers from a conspicuous lack of detailed and clear plans. There is little explanation of how its objectives will be met or what they will look like in practice for users of mental health services. And this is badly needed.</p>
<p>The last five years have seen considerable disinvestment in some areas of mental health such as <a href="http://www.publications.parliament.uk/pa/cm201415/cmselect/cmhealth/342/342.pdf">child and adolescent services</a> and many services are deemed to be at <a href="http://www.theguardian.com/society/2015/feb/01/mental-health-care-pushed-breaking-point-lack-beds-psychiatrists-nhs-hospitals">breaking point</a>. More money, or at least less disinvestment, is clearly needed – but so is a fresh look at how we address mental health difficulties and how we can achieve better wellbeing for everyone. </p>
<p>But there’s still no consensus on whether we should do more of the same, or try a whole new tack.</p>
<p>There are plenty of ideas out there, from <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2960315-4/fulltext">professional bodies</a>, <a href="http://www.mind.org.uk/media/1113989/a-manifesto-for-better-mental-health.pdf">the third sector</a> and <a href="https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/414024/Childrens_Mental_Health.pdf">from within the government itself</a> around what could be done. </p>
<p>It is a shame that given the chance to go beyond vague promises and stake out a radical or at least innovative new approach, the Conservatives did not take it.</p><img src="https://counter.theconversation.com/content/40189/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Street receives funding from the National Institute of Health Research and the Department of Health's Policy Research Programme.</span></em></p><p class="fine-print"><em><span>Richard Slinger does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The Conservatives’ statements on health do not stand up to scrutiny, while their promises on mental health are vagueAndrew Street, Professor, Centre for Health Economics, University of YorkRichard Slinger, Clinical Psychologist, Lancaster UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/352922015-01-20T06:18:35Z2015-01-20T06:18:35ZHow deadly cancer may actually be spread by survival mechanism<figure><img src="https://images.theconversation.com/files/68845/original/image-20150113-28455-zxfu0l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The actions of cells underpin new thinking about pancreatic cancer, which took the life of Apple's Steve Jobs. </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/jamesmitchell/2565317822/sizes/o/in/photolist-4UFVBC-PQryd-PR3Bk-atUU1b-atmFQG-njDWVF-N9vns-b2Cbsk-b2Cbgt-b2CbdH-fCyLS1-atTMKv-aX3Nvk-atgskP-atnkuR-atqeSe-atJjxP-7ouSZj-atEwVT-atHcSG-atjecF-atm5vZ-7N9gtP-c4TiBy-atjpuM-83QwWp-fmspcP-9uQfFD-atsvzj-att4Rf-5fnMQj-83TDFL-85tiYG-atLZvu-atJj8x-atgMz6-baSZsK-x9aCj-fEKA4t-aAKFAs-avHR5C-7M6Jvx-aPZCei-aPZCFt-cSzo3W-ec3ZF-oX54Xh-av9vEA-atXjhg-c3NbHb-avRq5s/">James Mitchell</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Pancreatic cancer is a devastating disease. With a <a href="http://www.cancerresearchuk.org/cancer-info/cancerstats">ten-year survival rate of just 1%</a>, it has the poorest prognosis of all solid tumours. The main reason for this is that tumours of the pancreas largely develop without symptoms. Therefore, by the time many patients are diagnosed, the disease has advanced to a metastatic and incurable stage.</p>
<p>Metastasis, which describes when cancer cells leave (or disseminate from) the primary tumour and spread (or invade) to other organs in the body to form secondary tumours, is the main cause of cancer-related death. Hope for improved prognoses for many cancer patients lie in the ability to detect and diagnose the disease before it reaches this deadly stage.</p>
<p>Currently, there are no programmes available anywhere in the world <a href="http://www.pancreaticcancer.org.uk">to screen for pancreatic cancer</a> in the general population. The main reason for this is that we lack the suitable screening and diagnostic tools to detect at-risk individuals. In order to develop new methods to detect and diagnose this disease earlier, we need basic research to increase our knowledge and understanding of how this disease starts.</p>
<p>In recent years our knowledge of the genetics and pathology of pancreatic cancer has improved considerably. Genetic profiling of human disease has allowed researchers to estimate the timing of the development of the various stages of the disease and revealed that, on average, a primary tumour expands and <a href="http://www.nature.com/nature/journal/v467/n7319/abs/nature09515.html">grows within the pancreas for a decade</a> before spreading to other organs.</p>
<p>This suggests that there is a broad window of opportunity to detect and diagnose the cancer early – providing we have the right tools. However, we still do not know enough about how this disease begins and develops at a cellular level.</p>
<h2>A clear progression</h2>
<p>Under normal, healthy conditions cells <a href="https://theconversation.com/how-self-destructing-cells-may-hold-key-to-cancer-cure-31707">undergo a programme of cell death</a>, which causes them to self-destruct when their use is over. Over a cell’s life span, mutations can occur in specific genes, which transform the cell to become abnormal. Transformation of a cell disrupts this vital process of self-destruction and the cell continues to grow and divide without control. Therefore, transformation of cells is the first step in cancer development.</p>
<p>Pancreatic ductal adenocarcinoma, or PDAC, is the most common form of pancreatic cancer, which begins with non-invasive precursor lesions. These microscopic lesions develop primarily from the epithelial cells that line the ducts in the exocrine pancreas that become transformed when a specific cancer-causing gene (or oncogene) called KRas becomes mutated. KRas mutations are detected <a>in around 90% of all human PDACs</a>) and are known as the founder mutation in PDAC.</p>
<h2>Genetic profiling</h2>
<p>It is generally considered that PDAC develops from grade I precursor lesions to grade III and then to metastatic disease. Researchers have generated genetic “maps” of a sample of human tumours, <a href="http://www.nature.com/nature/journal/v467/n7319/abs/nature09515.html">and found</a> that PDAC genetically evolves over time. Metastatic or secondary stage tumours are genetically similar to the initial pre-invasive tumour. This suggests that founder mutations such the KRas mutation, are required for all stages of the disease’s progression. However, cells within a primary tumour must acquire additional genetic mutations to become metastatic or invasive.</p>
<p>However, <a href="http://www.ncbi.nlm.nih.gov/pubmed/22265420">a more recent study</a> suggests that our understanding of how this disease starts requires a new perspective. Using cutting-edge genetic and imaging tools, researchers have tracked transformed pancreatic epithelial cells in real time. This revealed that transformed cells (expressing KRas mutations) were detected in the bloodstream and had spread to the liver before a primary tumour was detected in the pancreas. In fact, KRas-transformed cells escaped from early grade precursor lesions.</p>
<p>It is possible that although these mutant cells spread out of the pancreas at very early stages of the disease, once seeded in secondary sites they become dormant or grow at a slower rate and are not detected until years later. What remains unclear is the process by which KRas-transformed cells leave the pancreas to enter the bloodstream and metastasise to other organs.</p>
<h2>Out of the frying pan, into the fire</h2>
<p>At the <a href="http://www.cardiff.ac.uk/research/cancer-stem-cell">European Cancer Stem Cell Research Institute</a>(ECSCRI) at Cardiff University, the primary focus of our research is to gain a better understanding of early pancreatic cancer. In particular, how precursor lesions start and develop once a normal cell becomes transformed. To further our research into pancreatic cancer, we study epithelial cell biology; how epithelial cells interact and communicate with each other within a tissue.</p>
<p>Along with muscle, nervous and connective tissue, epithelium – made up of epithelial cells – is one of the four major tissue types in the human body. The main function of an epithelium is to act as a tight barrier that protects our organs from potential harm in the external environment. Under normal conditions, epithelial cells tightly bind to each other to form this protective barrier. In addition to providing a physical structure to the tissue, each epithelial cell receives and communicates multiple networks of signals through cell-to-cell connections and these give cells instructions on position within a tissue as well as function.</p>
<p>So what happens to this communication network when epithelial cells become transformed but remain in direct contact with their normal neighbours? Working as a postdoctoral researcher in Yasu Fujita’s lab, then at UCL, London, I showed that <a href="http://www.ncbi.nlm.nih.gov/pubmed/19287376">normal cells detect and eliminate Ras-transformed cells</a>, which may act as an anti-cancer strategy. On the other hand, the signal to remove a mutant cell may act as a trigger to escape and therefore may promote the early spread of the mutant cells to other tissues.</p>
<p>At ECSCRI, and with the support of our collaborator, Owen Sansom and his team at the Beatson Institute in Glasgow, we are exploring both of these scenarios in pancreatic cancer. A big question is how normal cells detect the mutant cells – and we are currently investigating a specific cell-to-cell communication signal that could trigger this process.</p>
<p>One of the major risk factors for PDAC is pancreatitis, an inflammatory disease of the pancreas usually caused by alcohol misuse, which can significantly damage the tissue. With Ole Petersen’s team at Cardiff University – experts in pancreatitis – we are exploring whether and how pancreatitis alters cell-to-cell communication between normal and KRas-transformed cells.</p>
<p>We hope that our research will add knowledge to our understanding of how pancreatic cancer starts and develops from the earliest stages. An increased understanding will bring about the development of new screening, detection and diagnostic tools sooner, and may help increase the number of people living longer with this deadly disease.</p><img src="https://counter.theconversation.com/content/35292/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Catherine Hogan receives funding from European Cancer Stem Cell Research Institute, Pancreatic Cancer UK, CRUK Development Fund, Royal Society Research grant, Medical Research Council, Amser Justin Time</span></em></p>Pancreatic cancer is a devastating disease. With a ten-year survival rate of just 1%, it has the poorest prognosis of all solid tumours. The main reason for this is that tumours of the pancreas largely…Catherine Hogan, Research Fellow, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/356582015-01-06T10:45:44Z2015-01-06T10:45:44ZWhat should a hospital do when critical drugs are in short supply?<figure><img src="https://images.theconversation.com/files/67963/original/image-20141222-31542-yl5s4h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">How can doctors manage drug shortages ethically?</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-91838105/stock-photo-little-girl-in-hospital.html?src=BCRmva_ANsud5gAQn1G3bg-8-90">IV via drpnncpptak/Shutterstock</a></span></figcaption></figure><p>Four years ago, just before Christmas, my hospital ran out of cytarabine, an essential drug used to treat and cure certain kinds of acute leukemia. This drug was suddenly in short supply across the nation. At Duke, we had enough for about 10 days based upon our historical usage, but after that we could no longer treat those already on therapy or begin treatment for newly diagnosed patients. And we couldn’t ask other hospitals in the region to “lend” us some since they were in the same boat. </p>
<p>To figure out how to manage the cytarabine shortage, we called emergency meeting of pharmacists, oncologists, hospital administration and clinical ethics (that’s me). First, we immediately put all of our stock in one central location to control the supply and distribution. </p>
<p>Second, we decided not to access the so-called “gray market” for drugs, because the provenance of medications cannot be assured. The gray market is composed of private brokers or dealers of drugs who generally surface only during a shortage. </p>
<p>Third, we asked our oncologists if they could switch things around a bit for their patients, and perhaps give a treatment course that didn’t involve cytarabine first to conserve the supply. </p>
<p>Fourth, we decided that – all things being equal – we would prioritize giving the drug to children with acute myeloid leukemia rather than adults. This is because the cure rates are much higher in kids and they need less of the drug. </p>
<p>And finally, we started to make our own cytarabine. Duke Hospital has a compounding pharmacy that was able to produce cytarabine from raw materials. Fortunately, this last move saved us from disaster. The FDA gave us special permission to import cytarabine precursor from England and we prepared sufficient quantities so that we never ran out. However, there was no guarantee we would be so lucky again.</p>
<p>Keep in mind, simply making a drug to solve a shortage is not an option that every hospital has. It’s not practical for a hospital to, in effect, become a drug manufacturer to avoid shortages. With the number of shortages, the astonishingly different types and kinds of medications affected and the varying quantities needed, it would simply overwhelm the staff and facilities of what is designed to be a small, specialized – almost boutique – kind of production facility.</p>
<h2>Dealing with shortages</h2>
<p>Unfortunately, in recent years unexpected drug shortages have become very common in the United States, Canada and Western Europe. And the problem shows no evidence of improving any time soon. Shortages primarily affect generic sterile injectables, but a surprisingly <a href="http://www.ashp.org/menu/DrugShortages">broad range of medicines</a> are also affected. </p>
<p>When a drug is scarce, sometimes a similar medicine can be substituted but that isn’t always possible. In fact, that was the case with cytarabine. It is a generic, sterile injectible with a relatively small market and, at the time, available from only one source in the US. And it was never clear (as is often the case) why it suddenly became scarce. When a drug has no substitution, doctors have to figure out how allocate a scarce drug. Who gets priority? How do you distribute a critical medication equally and fairly? </p>
<p>I used our experience this experience <a href="http://www.ncbi.nlm.nih.gov/pubmed/23007382">to think</a> about how hospitals should approach <a href="http://www.ncbi.nlm.nih.gov/pubmed/22220948">rationing drugs</a> when they are scarce, and to develop a policy to handle shortages in the future. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/67966/original/image-20141222-31542-bweel2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Deliberations and rules should be open to all.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-158329685/stock-photo-four-doctors-standing-talking-and-smiling-in-the-hospital.html?src=_NnKmk5MLuX0g1SuOoTHrQ-7-57">Doctors via bikeriderlondon/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Managing fairness</h2>
<p>With the assistance of my colleagues at Duke, I wrote a policy that we have been using for two years and that has served as a model for many other institutions around the country. We adopted an approach originally developed by Norman Daniels and James Sabin that they called “<a href="https://global.oup.com/academic/product/setting-limits-fairly-9780195325959?cc=us&lang=en&">accountability for reasonableness</a>”.</p>
<p>They created a framework to maximize the chances that the rules governing how limited good are distributed are fair. They described four conditions that should regulate the development of a rationing plan: transparency, relevance, appeals and enforcement. </p>
<p>These principles mean that the proceedings, deliberations and rules should be open to all: hospital staff, patients and the public. The rules must relevant and directly related to the good being rationed. There must be a mechanism for appealing any decisions that are made, and there must be a process for ensuring that the rules actually are implemented and enforced. </p>
<p>To these four we added a fifth: <em>fairness</em>. Clinically similar patients should be treated similarly. A patient should be no more or less important than any other. The sort of fairness we emphasized was one that spurned any attempt to distinguish patients on the basis of what are known as morally irrelevant facts about them, like their ability to pay or their insurance or who they know, all of which also had no relevance to their clinical situation.</p>
<p>We also we created a Scarce Drug Allocation task force with representatives from the hospital pharmacy, risk management, and clinical ethics, as well as doctors and nurses who had to deal with drug shortages. </p>
<p>We decided to allocate scarce drugs based on both clinical need and clinical evidence. We also decided to stop using drugs for investigational purposes, unless the drug in question was being administered in a clinical trial in a non-experimental manner. In general clinical practice the experimental use of drugs is quite rare, but the off-label use of medications with minimal-to-no evidence base is distressingly common. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/67965/original/image-20141222-31545-9q40wm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Fairness is key.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-116502208/stock-photo-close-up-view-of-pharmacist-taking-medicine-from-drawer.html?src=SQqsr6XQbCnaVDdx3ebq_A-1-26">Medication via Stokkete/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Dealing with constant shortages</h2>
<p>Before we developed the framework, our hospital had experienced more than 30 shortages affecting everything from intravenous immunoglobulin (often used to fight infections and automimmune disorders) to anesthetics. So there was remarkably strong acceptance of the new policies from the staff. </p>
<p>In the more than two years we have used this policy, we have had to manage another 30 severe drug shortages. Some were resolved by simply substituting a similar drug. Others were controlled by limiting use based on clinical evidence, thus automatically increasing the effective supply. Nevertheless, we did come very close to exposing some patients to delayed treatment. </p>
<p>Our framework for managing drug shortages has worked, but there are still unresolved issues. We have never been faced with a tragic choice, where we have to decide between two equally needy patients and only one can receive a drug. We have tentatively decided that we would use the equivalent of a coin toss to make the final determination as the most reasonable and fair. But, there other questions. </p>
<p>Even though Duke Hospital is a regional, national (and, indeed international) referral center, most of our patients still reside within a local geographic area. Do we have a greater allegiance to our close community than to those from elsewhere even if the latter have an equal medical need? What about those people who, because of their socioeconomic and educational advantages, can utilize these privileges to come to Duke to get in line for a drug they can’t obtain locally? Clearly these (and other) thorny challenges demand answers in the real world, and we continue to discuss them.</p><img src="https://counter.theconversation.com/content/35658/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Philip M Rosoff does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Four years ago, just before Christmas, my hospital ran out of cytarabine, an essential drug used to treat and cure certain kinds of acute leukemia. This drug was suddenly in short supply across the nation…Philip M Rosoff, Professor of Pediatrics and Medicine Director of Clinical Ethics, Duke University Hospital, Duke UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/342692014-11-16T09:25:25Z2014-11-16T09:25:25ZMissing data may hold the key to finding new cancer treatments<figure><img src="https://images.theconversation.com/files/64609/original/9r4zwn5x-1415986030.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The answer's in there somewhere ...</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/bunchesandbits/4106216129/in/photolist-7fRqZP-7NLjJ1-ektUTA-2j4nGc-5FXaDU-4hSsNV-84kmXT-4zPuta-4gfNhz-dMoKLk-6B6TBB-en62JV-hH54JL-98Nt9g-dHr1Ed-5Da371-68ASTh-6DobSF-agQKVV-9VATSc-98NsUX-4YqYBt-24Z39z-2NJxPz-5zRG1q-9VDTvQ-aPfT7t-aPfTfD-9VDNKh-fQ6CnH-adZmEd-2tGzTk-5Qjix-68C3ry-68xPxD-doYzvs-LYqeS-fdSzhc-3erG2C-aEnUMn-dDp1UY-dDp2a3-dDiCPz-rfYQd-aj5Mpb-6hndgR-76mFYr-9rW1ZD-Hko71-Hks5p">Bunches and bits</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Imagine trying to follow a complex novel many times longer than War and Peace with hundreds of characters and twists. With every cancer having a unique story hidden inside its genetic code, this is similar to the challenge facing modern researchers. </p>
<p>Now imagine trying to follow the plot when some of the pages are missing. </p>
<p>This week, <a href="http://www.ncbi.nlm.nih.gov/pubmed/25256751">our latest study published in the journal Cancer Research</a>, suggests that such a challenge faces scientists deciphering a cancer’s story. We’ve discovered that the technology we use to “read” cancer’s DNA can sometimes cause pieces of the story to be missed at potentially crucial moments in the plot. It’s as if your eReader or tablet kept inexplicably skipping paragraphs as you tap through a novel.</p>
<p>By identifying this missing data we hope to develop techniques to look more closely to see if these areas contain further clues about how to tackle cancer. </p>
<h2>Written in code</h2>
<p>Every tumour has its own unique story about how it descended from being a normal cell into an invasive cancer. These tales are hidden in the genetic code that serves as the blueprint for each job a cell carries out. And the plot twists that make up the individual cancer story are caused by mistakes, or mutations, in this genetic blueprint. </p>
<p>So finding these mutations is a major challenge, and pinpointing them could help scientists develop new treatments to stop the growth of the cancer cells. </p>
<p>Fortunately, modern gene-reading technology has greatly improved our ability to spot these mutations. In our lab we’ve been using a technique called “Next Generation Sequencing”. Using this technology we can now reveal most of the genetic story of a cancer (more than three billion letters of code) in a single experiment. </p>
<p>But when we were searching genetic data from cancer cells for new mutations to target, we spotted inconsistencies between the different versions of data being shared from research institutes around the world. The question was why.</p>
<p>We wanted to find out if this was a common problem that might be preventing us from finding new cancer-causing mutations. To test this we turned to cancer data from two major online databases – the <a href="http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/">Sanger Institute’s COSMIC database</a>, and the <a href="http://www.broadinstitute.org/software/cprg/?q=node/11">Broad Institute’s Cancer Cell Line Encyclopaedia</a>. </p>
<h2>Same cancer, different stories</h2>
<p>We looked through the databases for where the two institutes had collected genetic data from the same type of cancer cell. If the cancer cells are matched you would expect the results to be similar, but what we found was surprising.</p>
<p>The databases showed that the genetic stories produced by the two institutes only matched for around half of the mutations. And in some instances there was much less agreement. We wanted to know why.</p>
<h2>Missing pages</h2>
<p>We picked out some of the cancer samples and homed in on sections of the story, looking for clues to explain why one institute was detecting a mutation when another institute was not. We found that in many cases, the discrepancies were caused by some samples not being read as completely as others. </p>
<p>When we looked for a reason, we found these poorly read regions often landed in areas where the code was less complex. Paradoxically, simple regions of code were actually making it harder for the gene-reading technology to spot any changes. </p>
<p>Another way to look at it is that in some areas of the cancer story the pages were effectively sticking together. This meant that valuable information was missing and the correct version of events could not be established.</p>
<h2>Are these missing pages important?</h2>
<p>The question is: are these missing data just irrelevant filler or do they contain important information that might reveal the strengths and weaknesses of a cancer? To answer this we used different techniques to look at these hidden areas in lung cancer samples, and found a mutation in a gene called PAK4 that had been previously missed. </p>
<p>When we examined the effects of this mutation we found it had the potential to make cancer cells grow more quickly. This indicates that some of these missing pages might carry important information about how a cancer behaves.</p>
<p>As we move into an era where the genetic history of more and more cancer biopsies are read it is important to understand the limitations of the technology. </p>
<p>This is especially important when genetic information becomes more routinely used to help make decisions about the best treatment for a patient.</p>
<h2>Filling in the gaps</h2>
<p>The good news is that gene reading technology is improving and is beginning to fill in these missing areas. This will help us learn more about these “blind spots” and we can use this information to develop new treatments in the future. </p>
<p>In the meantime, we’ll take a closer look at these regions as we also found other explanations about why the data between institutes does not match up. </p>
<p>So far we’ve pinpointed the location of more than 400 areas of missing data. By homing in on these missing pages we hope to piece together cancer’s complex story and write important new chapters which could one day lead to the development of new treatments for patients.</p><img src="https://counter.theconversation.com/content/34269/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Hudson receives funding from Cancer Research UK.</span></em></p>Imagine trying to follow a complex novel many times longer than War and Peace with hundreds of characters and twists. With every cancer having a unique story hidden inside its genetic code, this is similar…Andrew Hudson, Clinical Fellow, Cancer Research UK Manchester Institute, University of ManchesterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/160932013-07-17T05:39:24Z2013-07-17T05:39:24ZHippos and bumblebee bats can teach us about cancer<figure><img src="https://images.theconversation.com/files/27482/original/m4kcj3d7-1373893010.jpg?ixlib=rb-1.1.0&rect=3%2C0%2C2498%2C1565&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">How does a hippo know it should be big?</span> <span class="attribution"><span class="source">PA/David Cheskin</span></span></figcaption></figure><p>Mammals display an incredible diversity in size. The largest mammal, the blue whale, can grow up to 30m long and weigh up to 200 tonnes. Now compare that to the Bumblebee bat, which is 3cm long and weighs in at only 2g. </p>
<p>To put these figures into perspective: 30m is as tall as the ten-story <a href="http://www.youtube.com/watch?v=2NXK8pkL8ec">Instacon building</a> that was recently built in India; 200 tonnes is the weight of a 747 airliner; and a banknote can weigh 1g.</p>
<h2>Size matters</h2>
<p>So how does a blue whale “know” to be that big? And why don’t we have <a href="http://www.youtube.com/watch?v=G9hJK4fCq4U">tiny hippos</a> or enormous mice? And what can size control in mammals tell us about cancer and regenerative medicine?</p>
<p>The organs of animals are proportional to body size. The blue whale’s heart weighs 600kg and is the size of a small car while our lungs fit perfectly within our chest. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=393&fit=crop&dpr=1 600w, https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=393&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=393&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=494&fit=crop&dpr=1 754w, https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=494&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/27556/original/d8vk34yr-1373992947.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=494&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">He’s having a whale of a time.</span>
<span class="attribution"><span class="source">PA/David Parry</span></span>
</figcaption>
</figure>
<p>But if you compare cells taken from a whale and a miniature bat, they are the same size. We know then that the size of an animal is controlled by the number of cells in each tissue. And it’s the balance between cell growth and cell death that controls when an organ stops growing. </p>
<p>As cancer is caused by uncontrolled growth of cells, a better understanding of how cells decide to grow or die has important ramifications for health and disease.</p>
<h2>The Hippo pathway</h2>
<p>It has only been in recent years that the molecular and cellular pathways that control organ size have been studied. It has been known for many years that when cells grow in a test tube, they stop dividing when they come in contact with other cells. </p>
<p>This “cell-contact” mechanism mediates growth and is defective in cancer cells, which continue to grow even when they are extremely crowded. </p>
<p>In many animals, including flies, mice and humans, tissue overgrowth is triggered by faulty signalling systems. One of these signalling systems was recently identified and called the <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124840/">Hippo pathway</a>, a tongue-in-cheek nod to the size of hippos. </p>
<p>Mutations in this pathway lead to a massive increase in organ size because of uncontrolled growth of cells. There is now an explosion of research into how the Hippo pathway is regulated in normal tissue, as well as during cancer. But our new study, published last week in <a href="http://bit.ly/18lFXD4">Developmental Cell</a>, identifies a novel mechanism that controls this pathway.</p>
<p>The Hippo pathway is activated by contact with cells. When that happens, chemical signals within the cell cause a protein called Yap - or Yes-associated protein - to be switched off. The Yap protein causes cells to recognise that it’s time to stop dividing but if the signalling system is faulty, Yap isn’t inactivated and tissue and organs continue to grow.</p>
<p>We’ve seen it in flies or mice that lack the ability to inactivate Yap - cells continue to grow, leading to larger organs and ultimately cancer.</p>
<h2>Using proteins to send messages</h2>
<p>Signalling pathways use several proteins in the body to pass along a message from outside the cell into the nucleus of the cell, which changes the way the cell behaves. How proteins pass along this signal varies depending on what the ultimate message is. </p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=821&fit=crop&dpr=1 600w, https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=821&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=821&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1032&fit=crop&dpr=1 754w, https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1032&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/27559/original/xx395y47-1373999915.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1032&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A Yes-Association protein gets the chemical treatment.</span>
<span class="attribution"><span class="source">Flickr/Nikki Pugh</span></span>
</figcaption>
</figure>
<p>A common way the body creates different messages is by using chemicals to modify proteins, which then affects their ability to interact with the next link in the chain. </p>
<p>For the Hippo pathway and inhibiting cell growth, it’s the addition of a phosphate group of chemicals on the Yap protein that inactivates it. Our results also identify that an additional chemical modification - methylation - controls how Yap works - and ultimately the way the Hippo pathway works.</p>
<p>When we began this project, our focus wasn’t turned towards this signalling system but on the role of an enzyme called Set7. But differences we saw in the structure of the gut in the mice we studied and the publication of the another study into the characteristics of mice that had a mutation in their Hippo pathway, led to a series of experiments also linking Set7 and a role in inhibiting Yap - and therefore cell growth.</p>
<h2>Cancer drugs</h2>
<p>The ramifications of our findings are diverse. Our findings suggest that drugs that can block Set7’s function could result in more cell growth, which could improve regenerative processes such as tissue repair in people who have suffered damage. </p>
<p>But activation of Set7 could potentially increase the inhibition of Yap and thereby slow cell growth, creating a potential new cancer therapy. </p>
<p>We have yet to work out whether manipulation of Set7 during foetal development would have any drastic effect on tissue size - allowing us to create giant bumblebee bats for example. Or whether Set7 works differently in small or large animals. And for now, we still have very little understanding of all of the intricacies of this exciting Hippo pathway. </p>
<p>So unfortunately it will still be a while until <a href="http://www.youtube.com/watch?v=G9hJK4fCq4U">house hippos</a> are a reality.</p><img src="https://counter.theconversation.com/content/16093/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Colby Zaph receives funding from the Canadian Institutes of Health Research.</span></em></p>Mammals display an incredible diversity in size. The largest mammal, the blue whale, can grow up to 30m long and weigh up to 200 tonnes. Now compare that to the Bumblebee bat, which is 3cm long and weighs…Colby Zaph, Assistant professor of Pathology and Laboratory Medicine , University of British ColumbiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/141092013-05-22T05:39:06Z2013-05-22T05:39:06ZPain-relief access crisis leaves millions suffering around globe<figure><img src="https://images.theconversation.com/files/23763/original/cpfjt46n-1368540950.jpg?ixlib=rb-1.1.0&rect=0%2C5%2C3377%2C2152&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Prescriptions for pain relief are easy to get in the UK but not if you live in certain countries.</span> <span class="attribution"><span class="source">PA/Julien Behal</span></span></figcaption></figure><p>Ten percent of the <a href="http://www.painpolicy.wisc.edu/opioid-consumption-data">world consumes 90% of the morphine</a>. At first glance that’s just another statistic about haves and have nots. But it’s more stark than that - particularly if you have cancer in a country where access to pain relief is limited.</p>
<p>Pharmaceutical companies have little interest in producing cheap oral morphine because profits are only marginal. In Ukraine, for example, that means only injectable morphine is available. So patients with chronic cancer pain need injections several times a day and may be left without relief for hours in between. </p>
<p>But there is another problem - <a href="http://www.whocancerpain.wisc.edu/?q=node/244">the way pain relieving drugs are seen</a> in many countries. Legislation that uses language such as “addictive drugs” to describe pain relief leads to the belief that these drugs, even in controlled circumstances, facilitate crime and corruption. Such medication can be the only way to avoid a horrific end to many lives: among them the <a href="http://www.cancerresearchuk.org/cancer-info/cancerstats/world/the-global-picture/cancer-overall-world">12 million people with cancer</a>; those with advanced heart, lung or kidney diseases; progressive neurological diseases; HIV/AIDS or tuberculosis.</p>
<p>The various legal and regulatory barriers mostly relate to the prescribing and dispensing of opioids (medications that relieve pain, such as morphine). </p>
<p>Attitudes among healthcare professionals vary from country to country. Often there is fear of the possibility of prosecution from prescribing analgesics such as paracetamol and ibuprofen and a desire to avoid taking any responsibility in a murky area. Even when a law might recognise that controlled medicines are necessary, healthcare staff can be wary of the potential of being investigated and disproportionate punishments that might await them.</p>
<p>The <a href="http://qjmed.oxfordjournals.org/content/early/2013/04/05/qjmed.hct080.full">under-treatment of cancer pain</a> is a major public health crisis in both developing economies and many parts of the less developed world. There have been isolated efforts by international organisations to address the problem, but the headline is that little headway has been made. </p>
<p>Research led by the European Association for Palliative Care looked at treatment of cancer pain across 76 countries between 2010 and 2012 showed <a href="http://www.eapcnet.eu/Themes/Policy/Opioidaccessibilitysurvey/Untreatedcancerpain.aspx">highly restrictive regulations on what patients receive</a> in Africa, Asia, the Middle East and Latin and Central America.</p>
<p>Very few countries provided all <a href="http://www.eapcnet.eu/Themes/Policy/Opioidaccessibilitysurvey/Untreatedcancerpain.aspx">seven of the medicines we consider essential</a> for the relief of cancer pain. In many countries, less than three of them were available and often unsubsidised by the government. Availability is usually limited. </p>
<p>Restrictions for cancer patients include regulations that limit their entitlement to prescriptions, how long their prescriptions last, and what drugs they can have. There is often a great deal of bureaucracy surrounding the whole prescribing and dispensing process.</p>
<p>Eastern Europe is a crisis area. Essential pain killing medicines are unavailable in Lithuania, Tajikistan, Belarus, Albania, Georgia and Ukraine. </p>
<p>There are problems elsewhere, including Russia, Montenegro, Macedonia and Bosnia-Herzegovina, where regulations limit doctors’ ability to prescribe opioids even for patients in severe pain and healthcare providers and pharmacists are intimidated by legal sanctions. All this contravenes <a href="http://www.who.int/medicines/technical_briefing/tbs/ACMP_BrNote_PainGLs_EN_Feb09.pdf">regulations from the World Health Organisation</a> which recommends doctors should be able to prescribe pain relief according to each person’s individual needs.</p>
<p>There is a lack of training for doctors and other healthcare staff on this matter. Often legislation fails to help. We need more debate and education for healthcare officials and decision makers if palliative care is to become a normal part of healthcare. Excessive legislation needs to be stripped away and more attention paid to providing safe and secure distribution systems that allow everyone access to pain killers, as a human right, no matter where they are.</p><img src="https://counter.theconversation.com/content/14109/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sheila Payne is Director of the International Observatory on End of Life Care, Director of the Cancer Experiences Collaborative and President of the European Association for Palliative Care. She is affiliated with the charity Help the Hospices, where she is chair in hospice studies.</span></em></p>Ten percent of the world consumes 90% of the morphine. At first glance that’s just another statistic about haves and have nots. But it’s more stark than that - particularly if you have cancer in a country…Sheila Payne, Professor in Health Psychology, Lancaster UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/55992012-04-05T22:36:02Z2012-04-05T22:36:02ZWhy data from published trials should be made public<figure><img src="https://images.theconversation.com/files/9400/original/zv8r9x76-1333604901.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption"></span> <span class="attribution"><span class="source">AAP/Tracey Nearmy</span></span></figcaption></figure><p><strong>TRANSPARENCY AND MEDICINE – A series examining issues from ethics to the evidence in evidence-based medicine, the influence of medical journals to the role of Big Pharma in our present and future health.</strong></p>
<p><strong>Here Ian Haines makes an argument for research data from published papers to be made public.</strong></p>
<p>It’s time for medical journals to mandate data release and independent audits for all clinical trials submitted for publication. And here’s why.</p>
<p>Over the past few years, editorials and commentaries in some high-profile medical journals and magazines have heralded the exciting revolution in personalised cancer therapy. They talk of treatments involving combinations of antibodies and enzyme inhibitors specifically designed and tailored for each individual’s cancer. </p>
<p>But most of these many new treatments cost between $40,000 and $120,000 per patient per year. And results of clinical trials so far show miniscule benefits that require extraordinary statistical gymnastics to achieve the magical “significance” level. </p>
<p>The problem is that these usually commercially-sponsored studies are designed by the sponsor and the statistical endpoints are no longer one or more of the traditional “gold standards”. </p>
<p>Those gold standards include:</p>
<ul>
<li><p>extending overall average survival;</p></li>
<li><p>improving “quality of life” measures;</p></li>
<li><p>reducing toxicity of treatment and;</p></li>
<li><p>reducing the cost of treatment. </p></li>
</ul>
<p>So many contemporary clinical trials have stopped measuring things that matter, such as quality of life and overall survival. Instead, they measure things that are easier to achieve positive results for, such as how long a patient’s X-ray stays stable in the very subjective opinion of an investigator. </p>
<p>These measures are clinically inconsequential, often unverifiable because of unavailability of the “raw data” and are far too subjective.</p>
<p>In addition, the raw data from these studies are protected – seen and analysed only by the sponsor’s data team. The results are then usually written by “medical writers” employed by the sponsor together with clinicians who often have significant financial conflicts of interest with the sponsor. </p>
<p>The final analyses may have little relation to the originally stated primary and secondary endpoints of the study and may emphasise other, often inconsequential, positives. And the abstract, which is a summary of the results, often emphasises positives that are not even supported by the data. </p>
<p>This is akin to a large public company producing its end-of-year financial results but keeping the primary data hidden, and then doing an audit on itself. </p>
<p>So despite hyperbole of medical “revolutions”, the <a href="http://www.fda.gov/">US Food and Drug Administration (FDA)</a> recently withdrew its previous approval of the world’s biggest selling multi-billion dollar breast cancer drug, bevacizumab. This step is almost unprecedented. </p>
<p>And the <a href="http://www.nice.org.uk/">National Institute for Health and Clinical Excellence (NICE)</a>, the equivalent body in the United Kingdom, issued the shock announcement that it didn’t consider the use of any of the three “blockbuster” new targeted therapies for bowel cancer – cetuximab, bevacizumab and panitumumab – to be a cost-effective use of National Health Service (NHS) funds.</p>
<p>In fact, when the FDA examined the raw data of the key trial that had produced the initial approval for bevacizumab, its independent reviewers had to reverse the initial assessment in 51% of the cases. </p>
<p>When I completed my medical training in 1978, the first cures of solid tumour cancers by chemotherapy (as distinct from acute blood cancers or acute leukaemias) had just been reported in the medical literature. Hodgkin’s disease, aggressive non-Hodgkins lymphomas and advanced testicular cancer,
which had hitherto usually been fatal, had disappeared in many patients with combinations of new and older drugs. </p>
<p>This was a watershed moment for cancer treatment in the twentieth century and generated great optimism for the future. </p>
<p>Clinical trials needed to prove the benefits of new treatments could easily be done by well-organised research groups. We didn’t need statisticians to dissect the p-values and hazard ratios of multiple opaque statistical analyses to tell us that these were significant advances in treatment.</p>
<p>And the drugs were affordable.</p>
<p>The breakthroughs of the time spawned the new speciality of medical oncology even though we still didn’t have effective treatments for the common and usually fatal advanced solid cancers such as bowel, lung, breast, melanoma or prostate. </p>
<p>And as we did our daily ward rounds, seeing the many referrals with these conditions, our most common note in the medical record was that “chemotherapy had nothing meaningful to offer”.</p>
<p>To prevent us returning to those days, it’s time to mandate data release and independent audits for all clinical trials. This will increase the chance of trials that are designed to measure relevant endpoints, of producing results that are verifiable, and of generating analyses and conclusions that match the original design endpoints.</p>
<p>To avoid mirages in our quest for cancer treatment oases, our ongoing need for innovation, hard work and entrepreneurship will need to be carefully balanced with more transparency and accountability to independent reviewers and assessors. </p>
<p><strong>This is the tenth part of Transparency and Medicine. You can read previous instalments by clicking the links below:</strong> </p>
<p><strong>Part One: <a href="https://theconversation.com/power-and-duty-is-the-social-contract-in-medicine-still-relevant-3941">Power and duty: is the social contract in medicine still relevant?</a></strong></p>
<p><strong>Part Two: <a href="https://theconversation.com/big-debts-in-small-packages-the-dangers-of-pens-and-post-it-notes-4949">Big debts in small packages – the dangers of pens and post-it notes</a></strong></p>
<p><strong>Part Three: <a href="https://theconversation.com/show-and-tell-conflicts-of-interest-undeclared-for-clinical-guidelines-3890">Show and tell: conflicts of interest undeclared for clinical guidelines</a></strong></p>
<p><strong>Part Four: <a href="https://theconversation.com/eminence-or-evidence-the-ethics-of-using-untested-treatments-4046">Eminence or evidence? The ethics of using untested treatments</a></strong></p>
<p><strong>Part Five: <a href="https://theconversation.com/dont-show-me-the-money-the-dangers-of-non-financial-conflicts-5013">Don’t show me the money: the dangers of non-financial conflicts</a></strong></p>
<p><strong>Part Six: <a href="https://theconversation.com/ghosts-in-the-machine-better-definition-of-author-may-stem-bias-4288">Ghosts in the machine: better definition of author may stem bias</a></strong></p>
<p><strong>Part Seven: <a href="https://theconversation.com/clearing-the-air-why-more-retractions-are-good-for-science-6008">Clearing the air: why more retractions are good for science</a></strong></p>
<p><strong>Part Eight: <a href="https://theconversation.com/pharmas-influence-over-published-clinical-evidence-5325">Pharma’s influence over published clinical evidence</a></strong></p>
<p><strong>Part Nine: <a href="https://theconversation.com/insight-into-how-pharma-manipulates-research-evidence-a-case-study-4071">Insight into how pharma manipulates research evidence: a case study</a></strong></p>
<p><strong>Part Eleven: <a href="https://theconversation.com/open-disclosure-why-doctors-should-be-honest-about-errors-4070">Open disclosure: why doctors should be honest about errors</a></strong></p>
<p><strong>Part Twelve: <a href="https://theconversation.com/reaching-full-and-open-disclosure-for-universities-medical-schools-and-doctors-6004">Reaching full and open disclosure for universities, medical schools and doctors</a></strong></p>
<p><strong>Part Thirteen: <a href="https://theconversation.com/ethics-of-accepting-suppliers-gifts-in-the-business-v-medical-world-3968">Ethics of accepting suppliers’ gifts in the business v medical world</a></strong></p>
<p><strong>Part Fourteen: <a href="https://theconversation.com/conflicts-of-interest-in-guideline-development-the-nhmrc-responds-6395">Conflicts of interest in guideline development: the NHMRC responds</a></strong></p>
<p><strong>Part Fifteen: <a href="https://theconversation.com/consumer-input-in-medicines-australias-code-of-conduct-review-6370">Consumer input in Medicines Australia’s code of conduct review</a></strong></p><img src="https://counter.theconversation.com/content/5599/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Haines does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>TRANSPARENCY AND MEDICINE – A series examining issues from ethics to the evidence in evidence-based medicine, the influence of medical journals to the role of Big Pharma in our present and future health…Ian Haines, Adjunct Clinical Associate Professor & Senior Medical Oncologist and Palliative Care Physician, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.