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And now, so now back to the UK to welcome another true English gentleman, Mr Tom Cadoux Hudson who uh trained in French a for a couple of years became a consultant at Oxford and he's now doing research. I had the pleasure of working with Tom as an S are um he like Mr Torrance, he had a, a cerebral hemisphere which is much bigger than mine. And um it was a great pleasure working with him. So Tom Tom is going to talk about the early 19 nineties uh French, a neurosurgery, enduring influence. Well, thank you for the introduction, Ian. Um I've got to grapple this machine now. Um it's done it. Um So this is a personal reflection of my time at French A and there's a large element inevitably of hindsight here. Um And how my time at uh French has influenced what I've done over the next 30 or so years. I was appointed as a senior registrar and the Advil it at the time was one job and at the end of the interview and the name Ian Poeple was wrung out and Ian got up and I thought that's it. It's time to pack the bags. I'm getting back to Oxford, but I was told to sit down and I think it was Hugh Griffith. It could have been Hugh who came into the room and said, could you come in and have a chat? And so I went in and they said the first question I think was, can you work with the in? And I thought, well, that's a loaded question because if I say no, I clearly don't have the job. And if I say yes, I might get the job, but I'm gonna have to work with the in. But, but actually, it worked out incredibly well. Ian's an amazingly supportive senior red really, really took me under his wing in the early days and weeks. The culture shock of hitting French A from Oxford was breathtaking the first weekend I think I remember with David was started off with a Cesarean section at eight o'clock in the morning, followed by an acoustic neuroma. We continue to do three or four. Craniotomy is for various urgent tumors. During the day, the operations went on during the night. David was still there having been on call all the entire week and I have to say he was looking a bit weak on the knees on Sunday, mercifully, we had a three hour break and then the operating started again and I thought that's it. That's a years neurosurgery Oxford experience in one weekend at French and it didn't stop so many thanks to Ian, the consultants. You, we've all heard about this extraordinary crew of people and I could spend hours talking on as it's already been said on each one of them. But I'm not going to, I'm going to talk about. Uh the first part was the house of Evan Coid. So this is Evan Coid and Annie and Brian had bought a house in bath and they said, do you want to rent our house? Once again, a loaded question, it was going to be very difficult to say no to that one. But in fact, we did stay there with my wife Helen and the three boys uh at that stage and Brian kept access to his study. So we did meet from time to time uh to talk mainly about mountains, trees and occasionally head injury and the mechanisms there in and particularly the acute mountains. Uh sickness was was a topic of interest. One day he arrived and the boys had basically converted the bath which was a large Victorian bath into a swimming pool and water was pouring through the hall. Uh I noted there was no plaster on the ceiling. Brian walked in and basically said, I'm pleased this house has come back to life because clearly his boys have done exactly the same thing. Um So this is a very fit young uh Brian, no, not so young but a fit Brian who's obviously lost a lot of the baggage at the front doing press ups with an I see people in his head and this was a paper this work was done in 1985 but it was written up in two papers that both came out in 2008. I think one appropriately in the alpine journal and the other one in the neurosurgery journal. And I thought this was an extraordinary study. It's clearly as comments saying the papers, this isn't gonna get repeated. Um And I think the driver behind it was that one of the climbers had a VP shunt um insight you. And I think Brian was extremely concerned about how to manage this person at, at 16,000 ft. And I can understand that, but I think that lead onto Brian having a an ICP bolt put in as well as Mike with one of the climbers in the group village. Um And um the story goes that Brian had the bolt put in by Hugh uh Griffith before doing an outpatient in the afternoon. And he was sitting there with a sticky plaster on his forehead and some fluid coming down his head. And the patient said Mr Cummins, are you sweating? So, yes, of course, I'm sweating when in fact, it was CSF leaking out, but he recovered from that. So this is um the research and altitude, the only three bolts were put in. Um But basically the evidence was that the tight brain argument which had been around for some time. Um probably held true that the less CSF space you had, the less reserve you had for your brain swelling. Um uh More likely you were to develop a MS. And this influenced some ideas about Hidden Dri which followed at Oxford. We're, we're not. Nope, we jumped. I said to stand a if Katie can't get this right. I'm stuffed and I think I'm stuffed. So this was the head injury research. Uh There should be a list of, so this was um I think this is a wonderful portrait of Brian. It's got that slight angle to his head, which is always questioning. Do you really know what you're talking about? And he's got that look in his eyes, which implies, have you really thought about this? Um But there we are, I think that's a wonderful portrait. Um So we set up a research program in Oxford, uh sponsored by the Medical Research Council. We were interested in the relationship between injury and outcome, particularly the moderate injury group, severe head injury was one thing and mild hendry one another. But the government were interested in basically people going back and paying tax. And uh these were the uh research workers who were with us Matthew Garnets now a consultant that Cambridge Robin cortical sensibly went off to do neurology, Public Goats and Tim Laurence more recently. Um Is it come through here? We are that it? That's good. So these are some of the papers that were published from that group. And um this is Pablo Goats who sensibly went off to work in Cardiff. He has a love of paragliding. Um, and sadly died from clonic cancer a few years back. Um, but there was a whole string of papers and the most recent is from, uh Tim Laurence. So these were a group of people who I think benefited from that influence from Brian, uh from my time at French, eh I'm going to come on to Hugh now and Hughes published a lot of extremely important papers. But what I find fascinating about papers that have a commentary and this is Hugh making a commentary on a paper. Um This is Triple A's work and it's these two comments caught my eye and, and he's a a short paragraph on how tumor's evade attack. Um And I distinctly remember a patient with carcinomas meningitis from breast cancer coming in and we were very busy, there were no beds. And I think on the Monday morning, I took in aside and said, Ian, what on earth is going on? We're expected to take on uh carcinoma as meningitis as a neurosurgery unit. And he said, yes, you have to admit this patient, it'll make you happy. And to my astonishment, she was subjected to this immunotherapy. Uh put with a burr hole. I think we did a burr hole. She was put in a lead lined room uh where there was limited access. This is quite a sick patient with intense cranial nerve pain, nerve root pain. And to my astonishment, all those symptoms settled over the next few weeks, the intracranial pressure settled, the pain settled and she was left with a bit of a nerve palsy. And so clearly, this stuff worked. There was no doubt about that. On the other hand, when we re operated on a few patient's who've had intra cavity treatment for their glioblastomas, you often found this eggshell of dead tissue and then this rim of growing stuff around the edge of it. And one of the conclusions is that the radioactive side of this treatment wasn't working. The other conclusion was that these tumors were actually rather good at defending themselves against a lot of stuff including uh immune attack. And I think that's a lesson that still applies. There are lots of people who are doing checkpoint blockades. There, there is a vaccine um being trial being run in Germany, I think, aimed at the IDH mutation. So how did that affect my top those? So, yes, the um the the that's the highly effective kill rate. Um And uh eventually the I CRF unit was closed and that was quite a painful experience for everybody I think. Um So what is the biochemical basis of resistance? And this is some work um that I initially started off with Vincenzo Sirin Dolo, who was a professor at the uh weather or Institute in Oxford. And he had a lot of interest in tryptophan and the secretion of uh I'd eo into the extracellular space by tumor's to protect them from t lymphocyte attack. And um at about that time, we're talking somewhere around 2008, 9 Parsons sl published on IDH mutation. And then Lenny Dang did extraordinary work to identify uh two HG as being too hydroxycut rate as being the quote on come metabolite produced by Idh and Vincenzo looked at this structure and said, I think that's an immunosuppressive agent and it's tumor evasion that we're dealing with here. Sadly, he died from a heart attack. And so the immune side of the research came to a halt. But we continued the work with Chris Scofield and we were interested in trying to develop a Covalin tely binding IGH inhibitor. One of the problems with solid tumors are that the allosteric inhibitors which we can use today and work very well in the acute myeloid leukemia aren't so effective in solid tumors. Um And so that was, has been a period of work that, that we have carried out. Um And in fact, a paper has been published by the Heidelberg Group in cancer uh nature cancer, identifying the roles of two HG uh in inhibiting immune attack. So we carried out this was just the uh I was called into a room to say, how could we measure to HG in cancer? And I said, well, you're going to need a very powerful magnet and we're going to have to invent a new way of um running the pulse sequence to identify to HG. And in fact, with the help of Irene Tracy's nullifies Chancellor of Oxford University, we got a seven tesla magnet, a young lad called, who's a mere, who was born in East Turkey and fought his way up through NIH in America, came over to write the program, a semi laser technique and it produced an extremely accurate way of measuring two hydroxid glue to rating tumor's. Um And a lot of other peaks were identified, which we, which we couldn't actually put chemical structure too. And that's been our subsequent research we've done following on from that, we've done tissue cultural work on a number of glioblastoma cell lines. We've been developed a number of inhibitors uh which are co violence and are currently under scrutiny by the pharmaceutical industries. And we've also got ways of accelerating IDH as an enzyme as well as a potential treatment avenue. And we're hoping that we'll be able to reverse this immune evasion effect in some of these tumor's oops. Um So I think that's where we're probably headed. There's always going to be a multiple approach to treating climbers. I think there will be treatment to deal with the immune side and then an attack system. And that could be obviously using chemotherapy and the external beam treatments that we have today. So many thanks to the consultants differentiate at that time, an amazing experience. As Hugh said, as Ian said, it was only a two year experience for me just over two years, but it's highly influential. So thank you. Thank you very much. Um Great deal.
