Hello and welcome to Episode one of Gut Instinct Research Updates, bringing you the latest research in gastroenterology and Hepatology.
I'm Tamzin Cogill.
I'm a gastro registrar, MBA student in Oxford, and I'm interested in hepatology, particularly viral hepatitis and vaccine development.
And I'm Michael Fitzpatrick, known as Fitz. Pretty much everyone, and as well as Tamzin Podcast's Sidekick.
I'm a clinical lecturer in gastroenterology at Oxford with a research interest in G.I. immunology, coeliac disease and nutrition.
Now, we've started this podcast to bring you some of the most interesting G.I. related papers that have come out recently.
Hopefully saving you time and assuaging that terrible guilt of not reading enough journals.
Now, each episode, we're going to talk you through to cracking primary research papers in some detail.
One clinical and one translational. And we will give you our take on the research and what we think of it.
Clearly, there are loads of great papers coming out every month.
So in addition, we're going to give you a rapid fire rundown of what else there is out there in the gastro world.
In our five and five section, where we will try and give you the key points of five papers in five minutes, we're aiming to give you some context,
a bit of critical a play appraisal of the papers that we talk about and try not to take ourselves too seriously in the process.
We both love gastro and and research fits is more interest in IBD.
Small bowel disease and nutrition. Well, I'm more interested in liver disease.
So we hope this podcast will have something for everyone. Now, obligatory disclaimer alert.
Clearly nothing in this podcast constitutes medical advice. If you're a patient, you should consult your medical medical practitioner.
For doctors, I'm sure you wouldn't base your medical management solely on what a couple of people told you on a podcast.
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All one word at Gmail dot com. So, Thomson, shall we get started with the first paper?
Let's go for it. Excellent, so I'm. I've got the clinical paper for this episode, and I think this is a really topical and important paper.
But I am afraid that it involves the C word. And I know we had talks about not talking about Kofod during this podcast, but I think I think we got it.
We're gonna have to mention it. I'm sorry. OK. You're forgiven this time.
Thank you for forgiving me. So this paper is from Lancet's Gastroenterology and Hepatology from a couple of weeks ago,
and it's entitled The Impacts of the Kovik 19 Pandemic on the Detection and Management of Colorectal Cancer in England, a population based study.
Deep breath long title. So this is from a collaboration of several groups within Oxford,
from the Department of Population Health and the Big Data Institute, as well as a variety of researchers from around the UK.
So clearly during the Kofod pandemic, health surfaces have really had to adapt and change in order to deal with that
sort of an influx of patients on the acute side and particularly critical care.
And that's had a range of impacts on other services.
And there's been real concern in the media, particularly about the impacts on cancer pathways in cancer care.
And there's particular reasons we should be worried about colorectal cancer pathways.
So first, bowel cancer is common. Colorectal cancer is the fourth most common cancer in the UK, with over 40000 diagnoses each year.
Second, while colorectal cancer has a really excellent prognosis if diagnosed early stage one disease has a five year survival of over 90 percent.
If diagnosed late, it's got a really poor prognosis with only a 10 percent five year survival.
If diagnosed, stage four, so early diagnosis and early treatment really matters.
And third, diagnosis relies on colonoscopy, a procedure that was severely affected during the pandemic.
So health care leaders both regionally and nationally want to address the challenges that the Kovar have placed on on cancer pathways.
But they need data. And something that I hadn't appreciated was that the usual related cancer data is collected for the official statistics.
Takes a lot of time. So often it's 18 months to two years after.
After the year in question, the data comes out. And clearly, we can't be discussing the impact of coated in twenty twenty two or twenty two.
Twenty three. So how did this group solve that problem?
Yes. I think this this group have been quite inventive by using some administrative datasets which have more kind
of real time data or at least a much shorter lag in the data being released to compare referrals for cancer,
as well as investigations, diagnoses and treatments for colorectal cancer in 2020 with the previous year.
So they've extracted information from four NHS England datasets.
So I will avoid using their long acronyms.
But they include datasets that look at cancer waiting times on the two week weight referral pathways to diagnostic tests like colonoscopy,
diagnoses of colorectal cancer, and then admitted patient care.
So things like operations. What is radiotherapy databases?
So the result was really tell us the tale of the initial pandemic impact and the peak.
But I think more importantly, what happened afterwards. So if you remember, lockdown hit in about the last week of March 10, 20, 20.
And so what we see is that in April, the number of of urgent cancer referrals from primary care.
So the two week wait referrals for suspected colorectal cancer dropped by 63 percent in April 2020.
And those referrals remain low in May. They started to pick up in June, which was when lockdown started to be relaxed.
But it took until September until levels returned to to those seen in twenty nineteen.
And the impact on Colon ASCAP was even more striking. So in 2019, colonoscopy numbers averaged around 46000 procedures a month in England.
And that went down to just three and a half thousand in April 2020.
So in 92 percent drop in colonoscopy procedures.
And again, although numbers slowly rose over the following months, it took until October to get back to expected capacity.
Most of the kind of Skippy's we do even on two week wait pathway, they're negative for cancer.
So did this temporary drop in referrals and procedures lead to a reduction in diagnoses?
Yeah, so a great question. And yes, so they looked at the number of new colorectal cancer diagnoses per month in 2020 and in
the period of April to October where there was that big drop in referrals and colonoscopy.
There were 22 percent fewer diagnoses of colorectal cancer than would be expected if we compare to last year's data.
And that corresponds to about three and a half thousand fewer cases of colorectal cancer diagnose than would be expected.
Now, consequently, there were fewer operations for Škoda rectal cancer during that period,
and there were also some changes in the types of surgery performed and other and other treatments given.
So during that that time, there were concerns about laparoscopic laparoscopic approaches.
So they were more open operations that corresponded to a greater proportion of patients having a stoma formed at surgery.
And there were also changes in radiotherapy treatments. So an increase in short course radiotherapy, particularly for rectal cancers.
And is there any sign that we're sort of catching up and starting to diagnose any of the missing cases?
No. Yeah, so from a clinical perspective,
I agree that's that's definitely the biggest concern is where are those missing three and a half thousand
diagnoses of cancer in that period in 2020 and up until the end of their data collection period,
which was, I think, till the end of October 2020. There was no evidence of a compensatory increase in referrals.
Scopes were diagnoses.
So things have gone back to preprint pandemic levels that they haven't gone gone higher to catch up that those of those missing cases.
So it raises the question of where are those patients that we would have expected
to diagnose and which services would we have expected to pick up those cancers?
Would they have been picked up on the two week wait pathway, symptomatic referrals, all bowel cancer screening programme?
And what are the consequences for those salade diagnoses? So second, I think it really shows the enormous impact of the.
The entirely necessary changes to the NHS during kov it so the fewer fewer consultations, referrals and scope's led to this reduction in diagnoses.
And it shows how difficult it was to to get services back to normal once the lockdown and so on was was was eased in June.
Now, for those for those who are listening from abroad,
the UK has has had a very serious second wave of Kovik cases in the autumn and winter of this year.
And we've gone into a second lock down from from the end of December onwards.
But endoscopy services nationally have been much more protected than in the first wave.
And it will be really important to see if we're maintaining enough capacity in the system in terms of procedures and and most importantly,
diagnoses during during the second wave.
And the researchers are laudably continuing to produce these data analysis each month on their website.
And the data for November shows that procedures are remaining at at 2090 levels,
but will be interesting to see what happens in December and January figures because that's when things have have have really hit the hospitals.
So we'll have to wait a couple of months to see the full impact on that.
I think finally, this this paper shows just how powerful real world big data analysis is to kind of guide health care policy and resource use.
And I think the researchers have really done a cracking job in that.
I think the main deficits of this paper can't really be blamed, the researchers themselves.
But the limitations of the data sets that they're looking at.
So for me, there's two questions that remain unanswered. The first is,
how do those changes in diagnoses or potential delays to diagnoses correspond to
the stage of disease at diagnosis or to surrogate endpoints of curative surgery?
So resection margins or lymph node involvement and so on.
So we can kind of see what the impact is going to be on on on patients prognosis.
And the second is that these data sets cannot be linked to individual level factors like age or ethnicity or socio economic status status.
And that means that those researchers can't look at things like potential health inequalities, which I think is really important,
as we know that this pandemic has had a disproportionate effect on certain groups in society.
Thanks, fits. That was a really, really interesting and topical paper. We're going to re summarise the key points at the end of the podcast.
So times in what have you got for me from the the translational side of things?
So this week I've got a hepatology flavoured translational paper looking at the immune system in acute on chronic liver failure.
It was published last month in January 2021 and Guts by Coche, which stands for the Chinese group on the study of severe hepatitis B, fantastic times.
And you're going to have to remind me, I've been thinking about T cells, I think, for far too long.
Can you remind me what Accutron chronic liver failure is, how it's defined and why it's important?
Yes, all very good questions. So ACL F stands for Acute on chronic liver failure.
And it basically describes a syndrome in which a patient with an acute decompensation of chronic liver disease
develops organ failure associated with a very high short term mortality rate and diagnostic criteria,
and score calculators to predict mortality have been developed and links to these will be on the show notes.
So obviously understanding the pathogenesis of ACL life is really important so that we can identify novel targets
for therapy in these patients and that might modify the disease process and improve the mortality at the moment.
We know that ACL is initiated by a pesticide damage and that its development is associated with systemic inflammation.
So within the scoring system to diagnose ACL F, for example,
the white cell count being high school's points and some other research has shown
that in patients with ACL F as opposed to decompensated chronic liver disease alone,
they have raised pro inflammatory cytokines. And there's also been some analysis at the transcriptase MC level.
So the transcription of proteins in immune cells,
in the blood from people who have acute and chronic liver failure, and that's been compared to healthy people.
And there are some differences have been found.
But what we don't understand is what some of those differences might be in their mean cells between persons with compensated cirrhosis,
decompensated cirrhosis and ACL F and what makes ACL F different and causes that really high mortality.
So the aim of this study was to describe the transcription profile of what the paper calls PDM sees.
And these are peripheral blood, one of nuclear cells. So the immune cells in the blood across different stages of liver disease,
right from healthy people through to ACL F in order to try and identify the molecular pathways that might then serve as norful, therapeutic targets.
So how did they do this?
They already had a large cohort study underway, which is the Coche study and their studies, the Chinese group on the study of severe hepatitis B.
So all patients in the study have had. It's got over a thousand people in it overall.
They selected 340 patients from that and also recruited an additional 60 people who were healthy, making a total cohort of 400.
And then they evaluated cross sectionally individuals at different stages of hepatitis B.
So from healthy controls without infection to people with chronic hepatitis B infection.
But no cirrhosis. Those with cirrhosis. But compensated stable cirrhosis.
Decompensated cirrhosis and HCF. So these 400 participants were then randomised into a sequence in group.
So. Sixty five of them in that group versus a validation group.
And in the sequencing group, they took immune cells from these 65 individuals and they underwent a process called
RNA Seke or RNA sequencing to identify what these immune cells were transcribing.
And then they validated some of the things they found. Using PCR in the validation cohort.
Okay, so they've got their cohort of patients. And then they're looking for difference in the gene expression between between the different groups.
So individuals healthy with chronic liver disease, but not with ACL.
And then those with ACL. That's correct. Yes.
Okay. So for those who might be less familiar with molecular biology, what is already a Sikh,
and how does that compare to other techniques like Q PCR that you've mentioned as well?
So already seek is basically a technique that identifies genes that are being transcribed
at a particular time by either a particular group of cells or within individual cells.
And for the purposes of this study, the authors collected Devean cells in the blood from the participants and they extracted
the MRN a being beat by each of the cells from each donor and pulled that together.
So it was pooled RNA from all the cells from one donor and then pooled RNA from all the cells of donor two and so on,
because the signal of the MRSA from those cells is quite weak to start with in order to be able to find out what TISM read it.
As such, that signal needs to be amplified.
So that step sort of uses polymerase chain reaction and amplifies all the M RNA that's been extracted from these cells.
And then the results of that are sequenced, usually using a kind of technique where nucleotides are attached to fluorescent markers.
And then the sequence of the first markers can be read and decoded into the nucleotide sequence.
So, for example, it might be, I don't know, blue, red, green, yellow.
And that might mean a. T. C. G.
And that can be then mapped back onto the genome to understand which proteins are being transcribed from that set of cells.
And then once you've got that,
the expression or levels of the different M RNA molecules can be assessed and compared between different groups of cells from different donors.
So it allows you to compare the gene expression of all of the of all of the genes in a kind of an unbiased way.
Exactly. So you don't go in with a hypothesis and say, right, I want to try and detect this particular MRN.
And and just amplify that particular one that you're interested in by PCR.
You actually amplify and detect everything that that cell is making.
And that means that it's a sort of unbiased way of finding out what's going on at the molecular level within cells.
OK, great, thanks. So what did they find that was different between these different groups?
They found firstly that in ACL F there is a particular transcriptional signature of Amien cells.
And they they look different to cells from people that have other liver disease phenotypes.
And a particular thing that they noticed that they found interesting was that there was an increase in differentially express
genes that were associated with metabolism and that progressively increased it in a spectrum from healthy to A.S.A. left.
So in ACL left, there were more genes that were differentially expressed to do with metabolism.
And what else did they find? How else are they different?
Well, there were also differential expression of genes that were associated with viral activation.
So an example might be genes that regulate viral replication, immune processes such as in a to be activated cell surface receptors,
inflammatory processes, in particular, inflammatory cytokines.
And as I've mentioned, metabolism, genes associated with dysregulation of glycogen, metabolism, cholesterol,
a flux and HDL metabolism were all found to be differentially expressed in immune
cells from individuals with ACL F as opposed to other liver disease phenotypes.
So these sort of broad classifications that they had discovered,
they then went on to pick out the genes that were differentially expressed the most and
that they thought would therefore be the most important potentially in the pathogenesis.
So for that, they looked at in more detail and again, I had to look up what some of the functions of these genes were.
So something called Thrummed responded one, which is a protein that is involved in.
Sell, sell, sell, matrix interactions so binds to collagen, fibrinogen, laminin, that kind of thing.
Militarising kinase, which is involved in extracellular matrix, cytoplasm signalling and also phagocytes acis of apoptotic cells.
Semaphore Inbee. And these are proteins that are involved in immune regulation and PPA or gamma.
And this was the only one I've actually heard of. So in relation to insulin metabolism that but it also has roles in lipid metabolism as well.
So they took these four genes that they had found to be expressed more highly in immune cells from individuals with ACL.
And they specifically looked for them in the immune cells from the validation cohort.
So the three hundred and thirty five patients that they hadn't sequenced,
they took their immune cells probe to them for these particular proteins and amplified
them by PCR to see if they were there at the transcript payment level again.
So detecting the MRSA and they found that by PCR in the validation cohort, these four genes were also speculated.
They also looked to see whether they were expressed at the protein level.
So to do this, they took liver biopsies from persons with ACL left,
but also at the different stages of liver disease in the cohort and stained them with immunohistochemistry for these four proteins.
And again, this confirmed the findings that they were up regulated in AC Alef and therefore might have an important role in the pathogenesis.
While say I mean, this this paper, as there's so much data in this, it's just an enormous amount of work.
As is often the case in these these big kind of translational papers.
It's kind of it's almost quite overwhelming and tinkly figure three and better figure
for it makes me feel like Neoh looking at the code in The Matrix for the first time.
Well, I feel for the person who isn't gater to pore over figure three.
What do you think of the key take home findings in particular?
What might be the findings for kind of clinical practise down the line? Yeah.
Excellent points.
So I think, number one, the authors have identified that immune cells in AC alef express different proteins than in less severe liver disease.
To a lot of these genes are associated with immuno metabolism.
Three, they've identified four of these proteins that could potentially be used as either biomarkers of ACL F or as targets for therapy.
And they've sort of proposed a model of pathogenesis using their findings.
Where there is some kind of exacerbation of the hepatitis B virus itself.
And that was detected through the genes that were up regulated to do with viral replication and processing, for example.
And then there is an excessive innate immune response to the virus and inflammation,
which leads to a metabolic order within the immune cells and then ultimately leads to Voltio organ failure.
Now, there's a lot of questions that remain from this paper.
And I mean, I could just list a few of them. The technique they've used doesn't actually tell us which immune cell types are most district related.
So which ones are expressing those genes that they found to be up regulated?
How does the dysregulated, Amien, resort response result in this metabolic disorder?
And how does that in turn lead to multi organ failure and death? This paper doesn't explain that.
And is this a common vinyl pathway in ACL or from other causes?
Because, of course, all the individuals enrolled in this study had chronic hepatitis B virus.
But as we know, especially in Europe and North America, a lot of patients will have alcoholic related liver disease, for example.
So on that point times, and do they speculate about whether it could be a common pathway or whether they think this is actually HPV specific?
Because some of the genes that were up circulated are to do with the virus itself.
Those ones in particular won't be relevant for liver disease if other aetiology.
But because this is the first piece of work that has really looked in this much detail,
they don't really know whether this is going to be a common pathway and in liver disease of other aetiologies.
I think that's what these kind of papers can do, is generate new hypotheses that need to be tested in other ways using other methods.
So, for example, this paper can't tell us which cells are over or under producing the proteins that they found that might be important.
And what they're actually doing, because often they have several functions, whether they're expressed on the surface of cells.
So therefore, are they accessible to drugs and other studies need to be done.
And to answer these questions. And the other thing that I think is important to mention that is probably quite obvious,
especially to a clinical audience, is that these kind of investigations cannot prove causality.
They can only find associations. And that's why we need to build on them.
And in order to understand what they really do mean.
Yeah, I think that's a really good point. I mean, I really like this paper.
I think the bit that I really like is the fact that they've got this huge cohort of patients.
You know, they really take a lot of time to get a really clinically relevant large cohort in patients,
because we know that in these sequencing studies,
you know, there's often a lot of variation between patients, humans, unlike mice or annoyingly heterogeneous.
And so they've got such a big cohort. They've really tried to validate some of their biomarkers and things like that.
And, you know, full credit to them for that. But as you say, in a way, it it's poses more questions than it gives answers.
But, yeah, it's great to see. It's great to see a study like that's being done in actually a really, really sick and unwell greif with patients.
So now we get to move on to the bit that I think is putting the most ambitious of our podcast, which is to is the five in five section,
where we are going to try and summarise five other interesting recent publications in five minutes.
As with the main page papers, we'll put the titles and the links to all the papers in the show notes.
And so here goes. If we if we get this in five minutes, I would be absolutely stunned.
So I've got three for you, Tamsin, and I think you've got you've got two as well.
So the first I'm going to mention is this paper just out in gastroenterology by teams in Cambridge and Imperial.
The first authors are Gas, Breteau and Pain, and it's entitled Transcription and DNA Methylation.
Patterns of blood derived CDH t cells are associated with age and inflammatory bowel disease, but do not predict prognosis.
Another very long title, the background to this paper is really important.
So back in 2011, Li McKinnie and Lyons had a paper in JCI which showed a transcription of signature of circulating seeds.
Eight T cells predicted prognosis in patients with IBD.
And clearly this was huge because if we can have an accurate biomarker of severe inflammatory bowel disease,
this would be enormously helpful in identifying patients for aggressive escalation of therapy.
And that work has led to further research.
A spin out company has been formed and they are developing a commercial biomarker based on this gene signature.
Unfortunately, this paper put someone somewhat of a dampener on that work.
So this group have looked at that, have looked at the transcriptional signatures,
so the gene expression signatures and then the methi relation profiles.
So these are epigenetic changes on the DNA of cells which control what can and can't be expressed.
Of of CDH cells in the blood of two cohorts of IBD patients, one paediatric and one adult.
And they found differences in the gene expression and methylation profiles which were associated with age and with sex,
and also whether the individuals had disease or not. But they were unable to validate this previously described gene signature with disease prognosis.
And this finding has led to a pretty frosty series of letters in the journal between the authors of the 2011 paper and the authors of this one.
I think the key take home is that, I mean, clearly this is disappointing for clinicians and for patients who'd hoped that this might be a
great biomarker for prognosis to not IBD and could be something really useful in the clinic.
But I think it also offers a sort of salutary lesson about biomarker development and validation.
And that's discussed quite nicely in the accompanying editorial. So that's number one.
And I think I'm way over time already. So we'll go on for the second. This one is about microscopic colitis, something a bit different.
Specifically about the risks of cancer associated with it.
This was published in JCC a couple of a few weeks ago by David Bergman and Yona Slewed fixin' from the Karolinska Institute.
And they've used a Swedish pathology register, which is then linked to patient data to compare a huge Kobold 11000 patients with
microscopic colitis with 50000 unaffected comparative subjects over a 25 year period.
They've got quite decent follow up for these patients, just under seven years on average.
And once they've adjusted for a variety of other variables,
microscopic colitis was associated with a small increased risk of cancer with a hazard ratio of one point zero eight.
But I think the interesting devil's in the detail here.
So first, that increased risk was almost entirely confined to the first year of the after diagnosis,
which suggests that this association is due to an association with either microscopic colitis,
with some malignancies or a surveillance bias where patients who are being
investigated for microscopic colitis and an Okkult cancer is diagnosed in parallel.
Second, microscopic colitis was in so associated with an increased risk of lung cancer and lymphoma.
And surprisingly to me, a decreased risk of colorectal cancer,
which suggests that the mucosal information in microscopic colitis does not lead to colorectal cancer.
And indeed, you know, the number suggests that it may even be protective. So they're very different from IBD and IBD related malignancies.
On a practical level, I think it will prompt me to think about the possibility of synchronous non GI malignancy at the time of diagnosis.
But at the same time,
I think I will be less worried about about the any kind of colorectal cancer risk from ongoing inflammation in microscopic colitis.
And the third one is hopefully a quick one. This is a paper about real world outcomes of Vitalis, about treatment in IBD,
which is from Marcus Neurath and Sebastian Zoeller, who are based in Langan in Germany.
So this is a single cohort of one hundred eighty one patients treated with Pheto at a single specialist centre.
And really just encouraging results that it's at about a third of patients achieved clinical remission after four months of treatment.
And those benefits were maintained for the best part of three years of follow up.
And this is really reassuring because this cohort of patients looks very much like
those that get treated in in kind of in real life rather than in clinical trials.
So the patients had been had had a diagnosis of of IBD for many years.
So eight years or 13 years for UC and Corden's respectively.
And almost all of them had received at least one a TANF before, had required courses of steroids.
So in a kind of a real world, patients setting vido shows, you know, really solid results for patients with IBD.
Nice. Nice three. I liked those are all very, very good.
I'll try and through my two. So they're both hepatology papers.
So the first is another hepatitis B paper and asking whether we should treat
patients who have a minimal minimally raised altie and a high and happy viral load.
And this is these are the results from the Torch B trial, which is a really important multicenter randomised trial from Prof.
Jiao Tao Lin in Taiwan. And that's been published within the last couple of weeks in The Lancet infectious diseases.
So the background to this. So so easel guidelines currently recommend treatment for people who have chronic
happy with raised viral load and an alti that is above the upper limit of normal.
But the American guidelines and the Asian Pacific guidelines recommend treatment only when heavy DNA is raised.
And the Alti is two times above the upper limit of normal.
So there's this kind of question about whether people with an alty of between one and two times the upper limit of normal should be treated or not,
whether it actually benefits them in terms of Hep B outcomes down the line.
So in this trial, individuals are randomised to having to not avail once a day or placebo for three years.
And the cohort of patients had chronic hep be with a raised HPV, DNA and a raised alti of between one and two times the upper limit of normal.
So the primary outcomes are interesting. And for this trial, because they were actually histological.
So the primary outcomes were a change in liver neck inflammation by measure by the nodal school,
which Fitz thought was a delicious Austrian snack blood.
That's Kinnaird, apparently. But but in this context, it's actually a score of netcode.
Inflammation in the liver and or a change in the Firebrace is great for the Ishaq's go on pedal of a biopsy.
And the important finding from this trial really is that they found that to not reduce the risk of fibrosis progression.
It didn't change Niekro inflammation. But overall, this supports its use in those with a minimally raised alti and a raised happy DNA.
So this is a great trial and I was really glad to see that out.
There's still obviously lots of questions about other populations of people with chronic hepi, for example, those who have raised happy DNA,
viral load, but a normal loyalty and whether treatment with Niks could actually reduce their risk of fibrosis and therefore cirrhosis.
And actually see long term. And finally, final paper is a paper looking at budesonide treatment in primary Bellary cholangitis.
So this was recently published in the Journal of Hepatology, led by Gideon Hirshfield.
And this trial enrolled 62 individuals at PPC across multiple centres in North America or Europe who had raised ILP.
So above one point five times the upper limit of normal and either inflammation or fibrosis liver biopsy.
And despite being treated with as a toxic Kotick acid for at least six months.
So participants remain Donoso, but were randomised to receive nine milligrams a day of budesonide or placebo for 36 months.
So quite high dose budesonide for quite a long time. And the primary outcome, again, was histological.
So improvement in inflammation and no progression of fibrosis, a liver biopsy was the primary outcome.
Unfortunately, this wasn't achieved. And although some of the secretary outcomes, so by chemical improvements,
a reduction in ILP and a normalisation of a reburn was significantly higher in the budesonide group compared to the placebo group.
Now, this trial, I thought, was really interesting,
partly because of the results and partly because I just think it exposes some of the real difficulties in conducting trials in rare diseases like PPC.
And actually, the trial in the end was underpowered for the primary outcome firstly.
So really, in a way, the jury's still out as to whether he doesn't what could be helpful.
And secondly, they actually had to open up their inclusion criteria.
Halfway through the trial, because the inclusion criteria at the beginning was so strict that they weren't able to recruit enough patients.
So is food for thought. And I think the jury's still out.
And but it really highlights the need and the difficulties of conducting trials in these kind of rare diseases.
So shall we. Shall we recap what we have learnt? Just a quick bullet point of each of the papers that we have.
The way that we've presented. So. So the first paper that I talked about.
So the Kofod 19 pandemic has had a major impact on colorectal cancer.
Pathway's in the U.K. with huge reductions in referrals and colonoscopy procedures in the first wave.
And that led to a 22 percent reduction in diagnosed diagnoses corresponding to about three and
a half thousand fewer patients diagnosed with colorectal cancer than we would have expected.
Acute on chronic liver failure is associated with changes in gene expression and immune cell populations,
particularly in immuno metabolism, which might help us to develop new biomarkers and potentially new treatments in the future.
And then on to the five and five. Well, talking about biomarkers, disappointingly,
a previously reported gene expression biomarker of of IBD progression could not be validated in two further cohorts by an independent group.
And I think it highlights that we need to be cautious and I would argue probably pretty sceptical about novel
transcriptional biomarkers for disease and prognosis until we've seen multiple independent validation studies.
Then we have the paper on microscopic colitis, which is associated with a small overall risk of cancer,
which mainly seems to be lung cancer and lymphoma at the time of diagnosis.
But interestingly, a lower risk of colorectal cancer over time.
And finally, I presented a paper about some real world real world data about vitalism abuse in inflammatory bowel disease,
which shows decent proportions in terms of clinical remission,
even in patients who've who are several years post diagnosis, have had previous M.S., TANF agents and required steroids.
And my final two treatment of patients with minimally raised altie and high viral leading
chronic hepatitis B with turn-off of their reduces the risk of fibrosis progression.
Treatment of individuals of PPC, resistance to URSO, adding budesonide does not improve liver histology.
Fantastic. I think we've got to the end of our first episode of G.I. Instinct.
Your G.I. research update. We're got to put all of the details of the papers that we've discussed in the show notes.
Please let us know what you think of the format. Any ideas you've got, any coup papers you've seen that you think we should be talking about?
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