Introduction (Elin Cave)



Transcript for videoContents TOC \o "1-3" \h \z \u Introduction (Elin Cave) PAGEREF _Toc56432105 \h 1Introduction (Chris Halsey) PAGEREF _Toc56432106 \h 1Infographic 1 PAGEREF _Toc56432107 \h 1Interview with Alex PAGEREF _Toc56432108 \h 3Interview with Ainy PAGEREF _Toc56432109 \h 5Infographic 2 PAGEREF _Toc56432110 \h 5Lab tour PAGEREF _Toc56432111 \h 5Outro PAGEREF _Toc56432112 \h 6Introduction (Elin Cave)Hi, I'm Elin, a fourth year biochemistry student at the University of Glasgow. Biochemistry is a mix of biology and chemistry. It is basically the study of all the chemical processes that go on in living things! So thats everything from plants and animals to tiny little bacteria and us!Last year, we learnt about cancer and the amazing research going on. So, for my final year project, I wanted to learn a bit more about some of the research in Glasgow. I've made a short video about what I've found! If you click the link below, theres also some stuff to support the videos like the transcript and some key words! I also need to get as much feedback from you guys as possible, so please fill in the survey at the end saying what you thought!I hope you enjoy it!Introduction (Chris Halsey)Hi everyone, my names Chris Halsey. I’m a clinical academic which means that I’m a medically qualified doctor whos also employed to carry out research. I lead a childhood leukaemia research group in the institute of cancer sciences in the university of glasgow behind me. Although as you’ll see later, our research building is a lot more modern than the main campus building behind me! I also help out at the Royal Hospital for children looking after children with blood cancers and other blood disorders. And a third, really enjoyable part of my work is that I work with lots of international colleagues across Europe and the rest of the world to try and design new trials and new research studies to try and continue to improve the outlook for children with leukaemia, not just increasing cure rate, but developing kinder and gentler treatments with less long term side effects. Elin has prepared this video to show you a little bit about what we do, shes going to start by showing you how research has helped us transform the outlook for children with leukaemia over the years but also some of the remaining challenges we have to work on. Shes then going to meet a couple of the researchers from my lab and find out about their projects and also take you on a tour of the lab so you can see what goes on inside!I’ll hand over to Elin now, thanks a lot!Impact of researchI wanted to look at what impact research has had on treatment of leukaemia over the years. There has been research all around the world for years now but for this project, I focused on UK based studies.UKALL trials have been running since 1960 but there was little improvement in the survival rate until the 8th trial in 1980. This is where we’ll start! We’ll look at the results from 5 trials: 1980, 1985, 1990, 1997 and 2003. The name refers to the year the trial was first designed- the results often take a while to come back: for the 2003 trial the results didn’t come out until 2013. The next trial was 2011 so we’re still waiting on these!We will look at the first year of treatment as most stuff happens here! After this, the same medication is prescribed each month for 2/3 years. So, lets start looking at some data!So we’ll start in 1980. Here, we’ve got 1 block of ‘intense’ treatment for the first 2 months. So we’ve got steroids, vincristine, methotrexate (both oral and intrathecal), mercaptopurine, asparginase and radiotherapy.So you can see we’ve got an ‘intense’ period for the first 2 months. I’ve labelled these periods with the darker border. This period gets rid of 99% of the leukaemia cells. This is why there’s so many types of medication. Then the amount of medication decreases to just 4 types: steroids, vincristine, oral methotrexate and mercaptopurine. This is known as maintenance therapy and is super important! The boxes are lighter blue. It is lower dosages of medication over 2-3 years. Maintenance therapy is done to definitely get rid of all the cancer cells. In the early trials it was thought that all the cancer had gone but then the patient would relapse. This therefore gets rid of the last few difficult cells and makes sure the patient stays in remission. This is very important. The survival rate at this time was 6/10 people this was a big jump forward but obviously we want to cure everyone ! so lots of room for imporvemnt. This trial went on for 4 years, so the next set of results are from the 1985 trial. You can see that for the next trial, we’ve got a lot more medicine being prescribed. There is even another intense period in month 7. This had a positive impact: now we’re curing 7/10 children. For the next trial in 1990, even more medication was prescribed. You can see a huge range of medicine here. A third intensification period was introduced based on other studies in Germany where it was found that this improved survival rates CITATION Vor02 \l 2057 (Vora, 2002). This was found to benefit all risk categories and the survival rate increased to nearly 8/10 children cured! However, you may have noticed something missing, there is no radiotherapy in this trial! This is because radiotherapy was found to affect the brain once the patients were older.It was really good at killing leukaemia cells but can have damaging effects on the rest of the body, especially later on when the patients are older! It was swapped out for intrathecal therapy. This is an injection into the spinal fluid which has a less side effects!The maintenance therapy also extended from 2 years to 3 years in this trial. This was found to improve the survival rates of boys especially. The 1990 trial probably had the most medication we’ll see. You can see here for the 1997 trial there is only 2 intense periods. This was a huge turning point: it’s the first trial in which we’re reducing therapy! The 1990 trial showed that we’d reached the limits: the medication was as intense as it could be, more intense treatment would cause damage in the body. The third block cured more people but led to bigger side effects later in life so the benefit balanced out. //From the 1997 trial, intrathecal therapy is then given every 3 months throughout the maintenance period: lower levels of drugs prescribed for longer. Into the last trial we’ll look at today, we’ve got a period of consolidation before the first intense period in month 5. The intrathecal therapy is intense now, apart from the second maintenance interim, it is administered most months as well as throughout the maintenance period. 9/10 children were now being cured. This is significantly higher even that the last trial. This was because, after the first intense block we were looking at the number of leukaemia cells and adapting therapy based on this. This is called risk adapted therapy. After the 1990 trial, it was realised that people need different amounts of treatment- that third intense block hadn’t benefit everyone!What will the 2020 trial bring? The aim now is to increase the survival rate to 100%!! However, we are also looking at personalising medicine to each patient. This means we can make sure they get just enough to get rid of the cancer and no more!!?For example, this third intensification period increased the survival rate from 70 to 77%. This improvement is obviously very exciting however, if 70% of patients would have survived without it, was it really needed??The cured patient will hopefully go on to live a long, healthy and happy life. Will this extra treatment have an affect then? Lots of studies have been done and found that some survivors suffer from side effects later in life such as hypertension and obesity. ?Our research now is looking to see how we can ensure people get the exact amount of treatment so that they a) have no cancer but b) don’t have as many side effects! ?Interview with Alex E: Hi so nice to meet you!A: Hi Elin hows it going?E: Good thanks! So, what is your background?A: So I’m originally from London but I did all my training in Scotland. I did a Biochemistry degree and then a master in cancer sciences and I’m now in the final year of my PhD at the University of Glasgow?E: Great! So what is your focus right now then?A: I am focussing on a way to personalise treatment for children with acute lymphoblastic leukaemia where their leukaemia has spread to the brain or the central nervous system. Most children do not have any symptoms of brain involvement when they are first diagnosed with leukaemia, but we know that without treating the leukaemia in the brain, it can potentially relapse in this area in the future.The brain is protected from any chemotherapy in the bloodstream by something called the blood brain barrier. This means that any chemotherapy we give by mouth or into the bloodstream doesn’t kill leukaemia cells in the brain so they can hide away there, escape treatment and carry on growing and multiplying.E: How can we stop this?A: To treat the leukaemia cells hiding in the brain, we can directly inject chemotherapy into the spinal fluid by doing a procedure called a lumbar puncture or spinal tap and this method of treatment is known as intrathecal therapy. When patients have this intrathecal therapy, the doctors also take a sample of the fluid around the brain called cerebrospinal fluid or CSF for short. They look at this fluid under the microscope to see if they can see any leukaemia cells and they count how many there are. Most of the time this test comes back negative, even when we know that there should be some cells there.We know this because we have evidence that the leukaemic cells stick to the walls of the brain so the method we currently use to see if there are any leukaemic cells in the brain (by looking under a microscope and counting) doesn’t accurately portray the actual amount of leukaemic cells in the brain.To compensate for this, doctors inject a lot of harsh chemotherapy directly into the spinal fluid and brain multiple times, somewhere between 10 and 20 injections during their treatment. This works pretty well in most cases but there are almost certainly some patients who have smaller amounts of leukaemia in the brain and therefore could benefit from having less treatment and therefore less exposure to these harsh chemotherapies and this comes back to the idea that we want to personalise this type of treatment based on the individual patient.It is important to try and give patients just the right amount of treatment as we want to make sure we kill all the leukaemia cells but also avoid side effects of treatment.E: Wow that sounds so interesting! How can this be done then?A: Seeing as we know that the leukaemia cells in the brain stick to the walls of the brain, my project is to try and come up with a more accurate way of measuring how many leukaemic cells are in the brain and try to move away from the very inaccurate method of just looking and counting under a microscope. So instead of looking for cells in the spinal fluid I am looking for different types of molecules that the leukaemic cells release into the spinal fluid. This includes tiny amounts of genetic material called cell-free DNA and a number of small molecules called metabolites and proteins. I am investigating whether we can detect these molecules, in the spinal fluid, and see if these new tests are likely to be much better at detecting sub-microscopic amounts of leukaemia that accurately reflect the overall amount of leukaemia in the brain.E: How will this affect patients then?A: Knowing how much leukaemia in the brain is present, how quickly it responds to therapy, and if we can use this information to predict potential future relapses, should allow us to determine exactly how much treatment each child needs to completely eradicate all the leukaemia in their brain. This means we can personalise the amount of chemotherapy to each patient’s specific risk of leukaemia recurring in the brain.E: Wow that sounds so exciting thanks so much! Good luck!Interview with AinyE: Hi! Nice to meet you!A: Hi!E: So, what is your background?A: I am a clinical Research Fellow. This means I am a medical doctor with haematology background and I’m now doing a PhD!E: Cool! What is your PhD on?A: So, as we saw in the infographic, childhood leukaemia treatment is now curing most patients. But, it can be very toxic. This can cause some nasty side effects for patients, at the time of treatment as well as later in life.E: What kind of side effects are there?A: It is very rare but some patients have side effects like fits and stroke-like episodes. This is known as neurotoxicity. Because they are so rare, little is known about why they occur or how to prevent them. To tackle this, we are working with study groups across the world to try and find what causes these stroke- like episodes and whether there are ways to predict or prevent them. This should lead to less side-effects for children with leukaemia in the future.E: Wow! That sounds so exciting! How many countries are you working with then?A: We are working with 14 leukaemia study groups treating children in 23 countries. They have all shared detailed clinical data and genetic information on children who have suffered stroke-like episodes. Hopefully, this will mean we can see what causes them!E: Wow that sounds super interesting good luck! Is there a treatment for it at the moment?A: It has shown to be able to be blocked in animal?experiments?by?a drug called Dextromethorphan,?which?is found in cough mixture such as?Benylin.E: Wow that sounds mad! What does this mean for treatment then?A: Yes it’s very exciting as it offers the?possibility?of a new treatment?option! The?mechanism of action for Methotrexate and Dextromethorphan involves?separate?biochemical?pathways- so these drugs?can?be administered to patients at the same time. This would mean that methotrexate would get rid of the leukaemia cells and dextromethorphan can get to work on reducing or even preventing possible neurotoxicity.E: Ok great thanks so much for talking to me today! Good luck with everything!Research is internationalI loved the sound of Ainys research! I wanted to look a bit more at the countries she was working with. I found they were all across the world as far as Taiwan and New Zealand as well as closer to home like Scandanvia and the Netherlands! They all send data back up to Ainy in Glasgow where she sorts and analyses it. She’s in the writing stage of her phd now so soon her findings will be out! This is so exciting as these will impact those with neurotoxicity symptoms and also other rare symptoms can be looked at using this method!I then looked more at cancer centres across the world. These ones now are just the ones funded by Cancer Research UK; they are in every single continent and most countries! There will be so many more, for example in the UK alone there are 21 cancer centres! This is so exciting! All this research is going on which will build on each others result and improve treatment and hopefully find a cure!Lab tourOnto our final bit of the video! I thought this would be a great opportunity to have a look at what all this research actually looks like! I went up to the Wolfson Wohl centre to have a look at the lab. I met with Alex, the phd student we met earlier, working on personalising medicine, and he showed me around! (hi its me again alex).These are the CSF samples neatly laid out! Then Alex showed me how they grow up the leukaemia cells so they’ve got lots to work with.This is a tissue culture cabinet. Even before covid, this had to be kept super clean so that no random bacteria started growing in the media!Media is a liquid with all the right nutrients to grow up the cancer cells. There will be lots of leukaemia cells growing in there!. (centrifuge bit) This is done to separate the cells from the media. He then took out all the old media (the orange stuff) where all the nutrients have been used up and then adds fresh new media. this will have all the nutrients for the cells to keep growing. Then the cells go into the incubators. These are at 37C.This is a microscope which can be used to look at the cells. We couldn’t get a good photo with my phone but this is what we would have seen!We then went to see the cold room. This is at -4C and is used to store reagents which are used for experiments!This is a PCR machine. It is used to amplify DNA. This means millions/ billions of copies can be made from 1 teeny tiny sample! I’d used PCR in my labs before but I had never seen this! This is a vacuum manifold. It is used to extract the cell free DNA. This is one of the biomarkers Alex is using in his study.And lastly, these are freezers at -80C! Patient samples such as cerebral spinal fluid (CSF) and DNA are stored here.Outro (Chris Halsey)So that’s what it looks like inside our research lab at the Wolfson Wohl. Of course, we’re not the only people doing research in Glasgow and theres some really excellent childhood cancer research going on. There’s a big AML research program led by Professor Brenda Gibson in conjunction with Dr Karen Keeshan at the Paul O’Gorman leukaemia research centre. Theres also lots of local research studies run by dietitians, physios, psychologists etc here in Glasgow. Our patients and families also take part in lots of national trials to improve childhood cancer outcomes and international studies as well. If you are a patient or a family member and you want to find out more about research going on in Glasgow, a good first stop is our really excellent research nurse team based in the royal hospital for children and associated with the Schiehallion unit. We’ve included their photos here for information.Outro (Elin Cave)Thats all from us, thanks so much for watching this! I hope you enjoyed it and feel like you know even a little bit more about the amazing research in your city! And please please make sure to fill out the survey as you'll be helping me so much!Thanks, bye! ................
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