Hello and welcome to episode six of Gut Instinct. Research Updates Bringing you the latest research in Gastroenterology and Hepatology.
I'm Tamsin Cargill. Lecturer in gastroenterology at Oxford.
Interested in hepatology. Follow hepatitis vaccine.
And I'm Michael Fitzpatrick, known as Fitz to pretty much everyone.
And as well as Thomson's podcast sidekick, clinical lecturer in Gastroenterology at Oxford.
My research interests in coeliac disease, clinical nutrition.
So we started this podcast to bring you some of the most interesting GI related papers that have come out recently, and we're already on episode six.
Each episode we'll talk you through normally a couple of primary research papers in a bit of detail, one clinical and one translational.
Although today we've got two cracking clinical endoscopy papers for you.
So it'll give we'll 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'll give you a slightly more Rapidfire rundown of what else is out there in the gastro world.
In our five in 15 section, we're aiming to give you some context and critical appraisal of the papers we talk about.
And and while we both love gastro, I'm more interested in liver disease, whereas Fitz is more interested in IBD small bowel and nutrition.
So hopefully this podcast will have something for everyone.
Now, as we say, each episode, no podcast should constitute medical advice.
If you are a patient, go and consult your medical practitioner for advice about your medical management and for doctors, please.
I'm sure you would not base your medical management solely on what some people told you on the Internet,
and you will verify this with your own reading and research to let us know what you think of the podcast.
We're on Twitter. You can rise. Write us a lovely review on Apple Podcasts, Spotify or whatever streaming platform you use,
and we'd really love to hear from you with any suggestions or thoughts.
Now. Tamsin, do you want me to start today?
Yeah. Go for it. Okay, cool. So I'm.
I read too many papers. It's not often a problem. But I realised I had.
I had. I had five that I wanted to talk about today. And there were two too I think really interesting endoscopy papers.
I don't think we spent enough time talking about endoscopy, so they're nice clinical trial papers in endoscopy.
And interestingly, I was reading one of them this afternoon while an endoscopy and the consultant I was scoping with,
he's one of the authors on the paper. You go multitasking.
I interviewed them about the paper while while chatting over a light kaleidoscope.
And this is about colonoscopy. And this paper was in gastroenterology just a few days ago,
and it is entitled The Impact of Artificial Intelligence on Ms. Rate in Colorectal Neoplasia.
And this is from a group of authors from Florida, from Italy, a few other centres, and also from Oxford, where we are based and so on.
The author is James East, Rebecca Palmer and and Beth Burt Lieberman, amongst others from the Oxford Endoscopy Group,
said the background to this is that we know that there is a significant Ms. rate in colorectal rectal neoplasia.
So say polyps after an index surveillance colonoscopy.
And it's one of the key drivers for you know, that the real problem in colorectal cancer screening, which is post colonoscopy, colorectal cancer.
So that's a that's a cancer occurring after a screening colonoscopy that wasn't picked up.
And the the incidence for that is around 1% at ten years.
So quite significant. And studies have suggested that around half of that is due to the fact effectively we've missed smaller polyps at that index
colonoscopy and that that's progressed along that adenoma carcinoma pathway and developed into a kind of rectal cancer.
So in studies that have Yeah. Have looked at the missed rate of co-direct neoplasia.
So if you for instance do back to back colonoscopy,
the Ms. rate is surprisingly high in the range of 25% missed polyps at these these screenings since
effectively they can either be due to the fact that the mucosa is been inadequately visualised,
we've not been able to see around a certain fold or particular areas like in the caecum or the hepatic
or splenic lecture that which are harder to visualise are just not seen or we've visualised it.
But the endoscopy has not recognised that there's pathology there and there are a variety of factors that can drive that.
So inexperienced operators, lack of training, distraction, tiredness,
all of these reasons why a polyp may flash up on screen, but the colonoscopy doesn't see this.
So it would be great if there was a way we could augment our detection of polyps during colonoscopy.
And certainly there's been a lot of research over that over the last decade or so using artificial intelligence platform.
So sort of deep learning platforms to analyse the the data from the colonoscopy and try and highlight areas that may contain a pull out.
And studies of these technologies have been pretty successful in that they are in the range of sort
of 95% sensitive and 88% specific for finding colorectal neoplasia finding polyps on colonoscopy.
But what we're really interested in is how they affect either adenoma detection rates.
So the percentage of surveillance, colonoscopy is where and that's oedema is detected, but also adenoma.
Ms. Right. So how many astronomers are missed?
And now there are quite a lot.
There are a number of trials using AI technologies and in particular AI technology called GI Genius, which is made by Medtronic.
And they've looked at adenoma detection rates. So that's the number of surveillance.
Colonoscopy is where you find it out today.
And and studies have shown that the RET that there's a relative increase in your added no mat detection rate of about 44%.
So it increases your adenoma detection rate,
which is great but and post colonoscopy colorectal cancers will be also driven by your missed your your adenoma Ms. rates and they're.
Really different things because your adenoma detection rate is per patients.
So like we've either found a polyp in this patient or we happens.
But your adenoma, Miss Rate, is per polyp.
So let's say the patient has three polyps, but you only found two.
You've missed one polyp. So you might you might have detected one polyp in that patient, but actually missed the other two.
So they are both important metrics when we consider trying to prevent post polyp back to me and colorectal cancers and this is
what this trial was trying to trying to test was whether using this I can increase or sorry can decrease the adenoma miss rate.
Okay. So the study design, this was performed in three countries and in eight centres.
And in each centre there were at least three endoscopies.
So I really like this sort of trial design.
So we're controlling for we're controlling for, for sort of Europe, UK and United States in terms of location, but also different endoscopies.
And actually they controlled to some extent of further kind of, I guess, the quality and experience of these endoscopy.
So they were all pretty experienced.
They'd all done at least 2000 colonoscopy and they all had adenoma detection rates in the range of between 20 to 40%.
So yeah, pretty good. They're, they're pretty good endoscopies.
But it's not like some trial just, you know, just with with to, you know, to incredible endoscopies or indeed just with novel.
And so I think this is kind of representative of, you know, kind of high quality, high quality endoscopy.
But but in the kind of more real world setting, all of these the patients were in the trial were patients over 45 years old
who were having a screening or surveillance procedure for colorectal cancer.
So these had previous polyps or they met whatever the criteria was for screening in that country.
And they excluded people with polyposis syndromes.
So they were sort of standard, sort of and, you know, adenoma risks as opposed to specific polyposis syndromes.
And they randomised the patients to undergo one of two arms of a back to back design.
So these lucky patients got one colonoscopy turns into two to back to back.
Of course, you know, you just you to pull out. That's the end of the procedure, sir.
And then and now we're going to do it again. We're going to do it all over again or roll over and let's start.
So let's all go. Wow.
I'm I'm surprised anyone consented to that, but that's great.
Yeah, well, you'd be delighted to know. 230 patients,
200 230 subjects are included in the analysis and they were split in either have standard
white light endoscopy followed by a II augmented white light endoscopy or vice versa.
I kind of effectively they were they were kind of measuring is how many polyps were found on the second endoscopy and the the
operator for both endoscopy was was the same the same I presume on the first endoscopy they didn't remove any polyps they saw.
No, I think they locked them off if they if they were okay to be to be removed.
So it was about okay anymore. Okay, fine.
And they they clearly randomise patients.
They the randomisation was very sensibly stratified by by age, by indication for endoscopy, by study site in country and so on.
So it was all all very it's all very sensible in terms of design and.
I am not an expert, Tamsin, but I will basically just read this paragraph from the paper.
I'm not either. So guy genius by Medtronic has has been evaluated in a number of different trials before.
But it's a technology on a convolutional neural network that was trained on a series of 2684 histologically confirmed polyps in a previous
high quality randomised trial and the idea of the GI genius is that it can recognise these polyps and also classify what it thinks they are.
So whether it thinks they're adenomas or hyperplastic or serrated or things like that, so basically whether you should remove them or not.
And the output is quite nice because some of the early AI tools had a whole separate screen.
So you were trying to look at two screens at once. So that's that's not great.
But all this does is effectively it puts a little, little red box around the it puts a little box around the what it thinks is the lesion.
And so it just attracts your eye and then you can evaluate it as you as you usually would.
And it's currently approved for use in both the US and Europe.
Okay, um, that sounds really very good. I think the, I mean, the only limitations of the colonoscopy procedure was that they,
the endoscopes were not allowed to use MBI or display narrowband imaging or display for the detection of the polyps.
They could use NPI to characterise a lesion further if they wanted to once they spotted it, but not not for anything thing.
So this was not using any of those other and those other tools.
Okay. So they screen 253 patients, randomise 249 and 230 were included in the main analysis.
And, you know, there were a few people who didn't complete their that that colonoscopy,
a few patients who dropped out for technical reasons or withdrawal or adverse events.
But the vast majority were included in the analysis, and they did a sensible power calculation.
So the results. So the key one was the adenoma miss rate,
which was calculated by how many polyps were found on the second colonoscopy in the back to back
colonoscopy as a percentage of the total number of polyps found in both procedures together.
So the total number of polyps that's I guess as a as a sort of a ground truth for how many polyps we think there actually were.
Um, and the adenoma miss rate was significantly lower in the air compared to the standard white light endoscopy arm.
So it was 16.6% in the eye versus 34.6% in the white light.
Endoscopy. Um, so that sounds like quite a big absolute difference.
So that's, that's a reduction. Yeah, about about half the rate of of misstated.
I was using the AI technology. Um, so that's the headline used that this technology works effectively and in a slightly more real world setting.
Um. What's interesting is when you start to look at the kind of the size and what kind of lesions they were.
So the way this was driven. In the main by small polyps.
So the detection of polyps less than five millimetres in in diameter.
So that was significantly difference.
But actually polyps between six and ten millimetres or polyps greater than ten millimetres were not significantly difference between the two arms.
Now, the trial wasn't powered to detect those subgroup differences,
but it does seem that the major effect seems to be with smaller polyps, and these were mainly little sessile lesions.
It seemed to augment the detection in all parts of the colon, the right colon and and the left colon.
Which is which is encouraging.
And that then affects how those patients have managed, because for a number of those patients, they had a more more polyps detected.
And that then puts them into a shorter surveillance interval.
Yes. So actually, it's not just that when lopping of those polyps and preventing them progressing potentially to colorectal cancer,
but actually it changes their surveillance interval as well.
And of course, that would have a different that would have a different impact depending on which country
you're in with the different surveillance guidelines in different areas of the world.
Yeah, definitely.
And potentially in the UK with less and less frequent surveillance compared to, for example, the US, that could potentially have a bigger impact.
Yeah, it could put someone from not having follow up endoscopes to having them.
So actually, you know, for those patients could make a big difference.
I think the other thing that's helpful is there's a nice forest plot on Figure two.
And although a lot of the these differences in larger polyps and so on were not significance,
all of them were trending in some some towards A.I. being superior.
And I suppose if the if the study isn't powered to detect those subgroup analysis, then, you know, you'd expect that.
But maybe they don't find a significant difference when in the real world there might well be.
So overall, I think this is a really interesting technology.
And and I guess when the costs come down, when it gets just integrated within systems rather than being an expensive add on,
I think I can't imagine anybody doing surveillance endoscopy and not wanting to just turn on the extra button and and having this and it sounds great.
Has it ever been compared directly to other methods like in the I?
They haven't mentioned it in this paper. I'm not sure I know the literature well enough to say for certain, but it doesn't, it doesn't look like it's,
um, I guess, I guess most people don't use MBI as a kind of routine to all the way round.
No, no. Whereas this would just literally sort of highlight when you're there,
it's like you don't have to do anything differently really as the yeah, the operator definitely.
And, and in terms of display, I think everybody would love to find evidence that display isn't needed because it's,
you know, it's it's a pain in the proverbial. Yes.
So it would be great to be able to, you know, have have something that was as good as display and didn't involve all the fuss.
So that's really that's really encouraging, I guess my.
My caveat is that.
The polyps that it seem to detect most often, the the ones that really drive this difference in miss rate are these really kind of diminutive polyps,
which are the least likely to progress to invasive colorectal cancer over a short period of time.
And certainly in countries that have a bowel cancer screening programme or a colonoscopy programme.
And I guess there is a question of how in, in, in real world data,
what's finding a few more of these tiny polyps would actually would actually do to missed colorectal cancers.
And so I think I think if I were, you know, having to pay a huge amount of money to implement this technology,
I can imagine maybe being a bit sceptical.
Having said that, I think it's always a patient being scoped or if I was the endoscope doing surveillance,
I can't, you know, I can't really see any great downsides what they had once clipped in.
And I think it's very cool and I think it really shows one kind of where the future of aspects of endoscopy are going.
And I think these sort of focussed, focussed uses of sort of A.I. technology to help us with certain sets and tasks.
But also, I think just a really, really nice study which is being done in a kind of a rigorous manner to evaluate these technologies,
where I think sometimes the hype can maybe exceed the reality.
Yeah, no, I think it's great paper. Thank you for presenting that one.
It's a good one. Shall I do a sciencey paper?
Yeah, I do sciencey one and then I'll do an endoscopy sandwich and industry sandwich with that second second.
So my sciencey paper is entitled Next Generation Sequencing of file cell free
DNA for the early detection of patients with malignant biliary strictures.
And this was published last month in gut.
And the lead author, I hope I pronounce this correctly, is Archer Deira and it's Al, and the group is from Spain.
So the background for this paper is that, as we all know,
the diagnostic accuracy of the current methods for diagnosing a malignant
biliary stricture as opposed to a benign biliary stricture is relatively poor.
So sort of looking at studies,
overall sensitivity using cytology with biliary Russians plus SCA 99 plus maybe fish analysis on a pathology specimen ranges from between 14 to 60%.
So not fabulous. So that means that we see a stricture that we think might be latent.
And the the diagnosis is either a it's a benign stricture when actually it's malignant
or it's unclear whether it's benign or malignant when it's actually malignant.
And this sort of problems with that is that that feeds into some of the poor prognosis of patients
with malignant biliary strictures because it contributes to late diagnosis of malignancy,
and therefore the treatment options for them are more limited.
And so we know that there are molecular changes in both pancreatic ductal adenocarcinoma and cholangiocarcinoma,
which can both lead to malignant biliary strictures.
And and they've been identified using either whole genome sequencing or targeted platforms,
looking at particular cancer associated genes in tumour DNA.
And whether you've actually taken either a proper and histological sample of tumour or a biopsy and sequenced the tumour itself.
And there are some recurrent ulcerations in oncogene and tumour suppressor genes and they can be associated with the anatomical site of the tumour.
So for example, intrahepatic mangos are associated with a mutations in something called IDR,
one in 13% of patients and FGF or two in 20% of mutations and extrahepatic palanga and
gallbladder cancer are associated with KRAS or EOB two mutations in up to 20% of patients.
There are also differences between tumours with a different background aetiology.
For example, patients that have PSC related biliary cancer or liver fluke related BEN-ARI cancer are associated with particular mutations.
And but and the importance of this overall is that some of these mutations are
now molecular targets for oncology drugs that are now approved for treatment.
So for example, with that idea, one mutation in intrahepatic cholangiocarcinoma is there's a drug called either cediranib,
which is a small molecule inhibitor of IDR one, and that's been shown to improve progression free survival in addition to the usual treatment
for non surgically respectable and Billary cancers that have that mutation in them.
But in order to have that drug, you need to have had a biopsy that shows you have that mutation.
So previous pilot studies have shown that you can identify cancer, meet these cancer mutations using next generation sequencing technologies,
and that this can improve the diagnostic accuracy of diagnosing a malignant as opposed to a benign biliary stricture.
And these previous sequencing methods, have they been looking at Bille or have they been looking at circulating various different things?
So there's been about four different studies.
So two of them have looked at circulating tumour DNA in the blood, and these were published 2015, one of them in 2019 another.
And basically they take blood from patients with biliary strictures and they both use it used different but targeted panels genetic
panels that use next generation sequencing to identify between 15 and 54 different cancer mutations or common cancer mutations.
And often these studies paired that with analysis of mutations detected in tumour biopsies as well as the blood.
And they've basically shown that the sequencing of cell free DNA in the blood is feasible, is accurate, and it's sensitive.
So the concordance between mutations found in the blood and in the tumour itself was pretty good in those studies.
They haven't actually tested or investigated their diagnostic accuracy in the clinical sense of diagnosing a malignant versus a binary stricture.
These were all proven malignant strictures. And now a more recent paper that was published in Gut two years ago has sequenced use next generation
sequencing of biliary bushings or biopsies in the diagnostic algorithm alongside usual imaging pathology.
And see a 99. And this study basically showed that using a 28 gene targeted next generation sequencing panel in a lot of patients actually.
So over 250 patients this improved malignant stricture detection when they used the sequencing versus looking at the biopsy or cytology alone.
And that increased the sensitivity. To about 73% and versus pathology alone being about 48%, both with high specificity of nearly 100%.
And the other thing it can do in a small majority of patients was identify and some of them for targeted therapy.
Like I was saying before, there are certain new drugs that are approved for the treatment.
If they can, the patient can be shown to have that mutation in the tumour.
So these methods also allow that allow tailored treatment for specific patients looking for cell free tumour.
DNA and bile has also been done but a long time ago and not using next generation sequencing methods.
So we know that there is cell free tumour DNA in bile in patients with biliary strictures, malignant killer restrictions.
And in the early 2000s, there were several papers that looked at cell free DNA,
and they looked at two two common mutations or two common genes that are mutated in
biliary cancer K and TP53 And because they didn't use next generation sequencing,
you know, it took a long time and they only focussed on a few codons only and that all of
those lacked sensitivity so didn't improve the diagnostic algorithm at all.
And that was all kind of left and left a bit at that at that time.
And have any of these previous methods progressed towards any kind of diagnostic test,
or have they really stayed as a sort of a translational as a translational study?
So none of them are used in any diagnostic algorithm that I know of in clinical practise.
And that's really what this study set to address.
So the panels that were available commercially and sort of the the targeted the targeted panels, a variety of different ones,
and they're made by science, technology companies, you know, essentially that one of us could buy and use in a lab for research purposes only.
So what the study set out to do was to evaluate two commercially available assays of
of two different targeted next generation sequencing platforms to identify cancer.
So genetic mutations in cell free DNA from bile samples in patients with biliary strictures undergoing LCP.
So it's a pilot study to see whether this is feasible and also see whether
clinically this improves diagnostic accuracy in the usual diagnostic algorithm.
We know from that 2020 study that using these kind of things can improve the diagnostic
accuracy when you've got cytology and brushing and you use this technology on them.
But can this improve things even more if you just look at the cell free DNA in bile samples and which could potentially open it up to more patients?
Because, of course, often you have an insufficient cytology or pathological sample for analysis.
I thought it might be good just very briefly to talk about what next generation sequencing is and what it means as a little scientific aside.
Do you think that would be helpful? Interesting. I think a couple of minutes on it is a is a good one because I'll be honest,
it was it was a couple of years into my Ph.D. really only when I was about to run some NGS experiments that I actually bothered to learn how it works.
Same. And actually the history. History is quite interesting, I think.
So basically if you go back through the history of how we have learnt as a scientific community to sequence genes and then whole genomes,
there was a big kind of leap forward as such in the seventies with the development of Sanger sequencing,
which uses something called the chain termination method.
And and basically what this does is it takes a primer which targets a specific start code, one of interest within a genome.
So you have to know what you're looking for.
You have to know where you want to start. That primer, you add in some DNA polymerase, you add in some new nucleic acids, and you also add in some.
Actually some special nucleic acids, I guess.
And so the terminal nucleic acids with a fluorescent detached and initially it was actually radial labels and then it uses PCR to amplify.
So you start with start with a DNA sample, you add all this stuff,
the primer and then and the DNA polymerase then leads to the addition of these nucleic acids.
And then finally you'll get this terminal nucleic acid, which you can detect either by radio labour or later with a fluorescent dye.
And because that labelled one is a terminal nucleic acid from this one primer,
you will get gene reads of different lengths and or DNA strands of different lengths, and you can then work out if you order them all by length.
And what's each nucleic acid at that terminal point is because the first dye or the radial
label is different for the four different nucleic acids and nucleic acid possibilities.
And then you can build up what you think the genetic code of that sequence is.
The basic method is still used now in next generation sequencing.
The main difference with next generation sequencing is you can do it much quicker or much more sample in a massively parallel way.
So rather than you just targeting one specific start coding and just looking at, you know,
one gene that you're interested in, you can sequence an entire genome pretty quickly.
So in order to do that, the setup is a little bit different.
But but essentially it's the same.
It's a very, very similar process.
But you're not restricted to a particular you can be restricted to a particular gene of interest, but you can just sequence everything.
So that's a quick overview of next generation sequencing.
And you know, and as as you said, like the scale and power of these technologies has just, you know, absolutely, absolutely.
You know, lapse over the last 25, 30 years is transformed so much.
And it has so many different applications.
And and in the context that we're talking about now with these sort of gene panels, the known cancer mutations.
This wouldn't have been possible really without next generation sequencing to bring to a clinical content context or to have basically
a kit you can buy from a bioscience company that you can use on on patient samples in a lab because it would have taken too long.
And so these panels, I'm sure you probably want to go into this, but all the panels looking for just detection of a particular gene in the vial,
or are they detecting mutations in those genes within the body?
So I think they are detecting specific mutations.
Okay. They looked at two different commercially available ones, both produced by some official of the same company.
Both were not designed specifically to look for biliary malignancy.
They are just panels of genes. And so one of them is a 52 gene panel and one of them's 161 gene panel.
One of the assays was called the Oncogene Pan Cancer Cell Free Assay.
They called it in this paper, the bile nuit assay. This looks at 52 genes.
And the panel was developed to detect sort of cell free DNA fragments and in blood.
And the cell free DNA fragments that are found in blood in general do tend to be small.
So it's a bit more sensitive. And they also used something called the oncoming comprehensive assay,
which looks for more genes or gene mutations 161 But this is has been developed to detect larger
DNA fragments from histological specimen specimens that are sort of paraffin embedded or,
you know, in slides or frozen sections.
So the initial part of this paper,
they took bile and plasma ran these two different commercially available panels on them and found that the first one,
so the bone meat assay detected a higher number of mutations than the other one in the bile and it was more sensitive.
So that's the one they decided to test more extensively in their patient sample.
What they then set out to do was really a pilot study of diagnostic accuracy of this ball metre assay and the the cohort
they tested it in was prospective and in 68 patients with below restrictions that clinicians were suspicious for,
you know, they could be malignant, they could be benign in a single centre in Spain.
That was the inclusion criteria then they had to be undergoing in the LCP and they had to have an undiagnosed biliary stricture.
There weren't any specific exclusion criteria, there wasn't a detailed consort diagram,
and it wasn't how it but I think this was just because it was a pilot study
trying to understand whether these methods were feasible in in this context.
So the the reference standard they used was the usual care diagnostic pathway, which as we know,
includes imaging LCP, if the patient is appropriate for that plus if possible, cytology.
So from biliary brushing or histology from biopsies,
if again that's technically possible and actually the reference standard really was using that
diagnostic pathway and what their final diagnosis was at a year after their initial LCP.
And we'll talk about why a year not immediately later.
And the index tests they compared that to was this ball meet assay.
So the cell free DNA mutation detection in file and and the usual diagnostic pathway.
But the initial diagnosis so that diagnosis after their initial LCP imaging and cytology, the primary outcome wasn't specified,
but they reported the sensitivity and specificity of each diagnostic test calculated for the initial fine diagnosis.
So I presume that was what the main outcome was.
Looking at the 68 patients with the biliary strictures all underwent an LCP and their initial diagnosis after the LCP.
With cytology or histology.
Histology 26 are benign, nine with an indeterminate and 33 were malignant.
And of those 33 that were diagnosed as being malignant.
And their final diagnosis at year was they were all malignant.
So if you're labelled as having a malignant stricture and that initial diagnosis with the current diagnostic pathway,
we know it's probably pretty much cancer. But the final diagnosis for the 26 benign strictures at a year.
Actually 14 of them turned out to be malignant.
And of the nine indeterminate strictures. Eight of them turned out to be malignant, just using a two year just using the normal diagnostic pathways.
And what happened between the initial and the final diagnosis in these patients?
A Completely ignoring the bomb me to say this is just using normal clinical practise is patients had more imaging, more A.L.S. pains,
maybe more more histology, etc., etc. and clinically they progressed clinically or ideologically they progressed or died or whatever.
And the diagnosis was made clear. So the crux of this is actually does the bottle meat assay improve the diagnostic accuracy of the initial diagnosis?
So for the index test being usual care initial diagnosis that it turns out a year there were 13 benign strictures and 55 malignant strictures,
of which 24 worse linggo and nine were pancreatic.
And the sensitivity of that usual care initial diagnosis was 60% not great.
The specificity, as we said before, was 100%.
When they looked at the follow meat assay and they classified a positive result as any positive detected mutation on that value.
To say the initial point of diagnosis, of the benign of the strictures that turned out to be actually benign at a year.
Nine of them didn't have any mutations in the bomb to say, but four of them were false positives, so they had mutations.
So they would have been classified as malignant by that allowed me to say.
But in fact, at that year they did not have malignant stricture.
But for the detection of malignant, malignant strictures,
the bell meat assay identified 53 of 55 truly malignant strictures, and there were two false negatives.
Now that working out the numbers, that means that the sensitivity using the ball meat assay increases to 96.4%,
but the specificity does drop to about 70%.
But this is not in combination.
And the other thing to say for those four false positives, one of them actually on longer follow up turned out to have pancreatic cancer,
which is interesting because it had essentially probably picked up a mutation that was the very,
very early of a cancer that probably wasn't already there.
But of course, that can't be present. Now, that's really interesting.
So this assay most frequently identified KRAS and TP53 mutations.
And it's these these mutations are not molecular therapeutic targets currently.
And there are also mutations that occur in lots of different types of cancers, not just malignant biliary cancers.
And it did identify Ida H one and FGFR two in a well in two in one patient.
And these are molecular targets and this was a small sample.
But for these particular patients that would that would change their management because it meant they were eligible for different drugs.
And those targets they've detected in the bio, did they have match tissue and did they show that?
The mutations in the vial correspond to the mutations in the tumour.
Yeah. So this was in a supplementary figure and they did have tissue samples for all of the bile samples.
In total, 68 mutations were identified and 50% of them were nearly 50%.
And they were common to both the tissue and the bile. But 35% of them were found in the bottle and not the tissue.
So it's not the concordance is not as high as, for example,
it was in previous studies of these type of assays looking at cell free DNA in the blood versus a tumour sample, which is interesting, but I guess.
The point of the paper is not to look at that so much because it does overall probably improve the sensitivity of diagnosis earlier,
which might increase diagnostic accuracy in these patients.
Just in terms of diagnostic accuracy, I mean, clearly, they've evaluated it compared to standard,
which is it's great for a pilot study, but in reality, we're not going to ignore other things like,
you know, radiological features or or the brushing those or other other aspects that push you towards,
you know, labelling to me as a benign or malignant thing.
Do they do any kind of exploratory analyses about how how it might be integrated into the is the care pathway?
So there is a figure where they suggest how it could be integrated.
But what they don't do specifically is an integrated analysis, you know, in adding it to usual care.
But I mean, that's how they envision it being used, obviously,
because you wouldn't want to drop that specificity that's already good in there from the usual diagnostic pathway.
You just want to improve the sensitivity so it makes sense that you add it rather than use it instead of a plus.
We'd still do the imaging, plus we'd still do the you have to do the ACP for this,
but you'd still do the brushing or the spyglass biopsy or whatever it was.
And I guess, I mean, what,
what seems to be really attractive about this is whether it can deal with that half of patients where we either get a benign in inverted commas label,
half of which will go on and develop malignancy at a year, or that indeterminate label, which is almost certainly cancer.
But we probably don't have enough to necessarily go straight to surgery.
So like, if you can if you can augment the diagnosis for those and either have like a,
you know, a more rapid follow up test or repeat or whatever it is that's actually,
you know, that's massive for those patients because that period of uncertainty and often that delay for surgery is,
you know, is really clinically important. Yeah. Yeah, absolutely.
So I think I think it's really promising and a really useful pilot.
But obviously, as you said, it requires validation and together with the other tests,
but also in prospective studies with larger patient numbers, the needs, the population they look.
I mean, this wasn't a controlled study and they hadn't powered it for a primary outcome.
And they assessed sensitivity and specificity, but they didn't look at, you know,
the positive or negative predictive values or number, the numbers needed to treat and numbers needed to test in this case.
And and in terms of the generalisability of the population they looked at.
So it was a single centre in Spain. Most of these patients had a distal stricture.
Okay. And, and this actually matters basically because the distal strictures,
especially if this have a broadly different mutational profile to intrahepatic ones and also the treatment options are often slightly different.
Like it's easier to operate on a on a distal stricture than is on an intra partic stricture.
Plus, they mentioned that there wasn't a high proportion of patients in the cohort.
For example, I couldn't tell from the table that they provided.
They didn't say who had PSC and who didn't, but that also changes the mutational profile.
So there's there's a few different things in that sense that could change the accuracy of this.
And then the there were obviously some practical things to address, like is the technology scalable?
Like ultimately at the moment these tests are validated in a lab only, not in a clinical setting.
And we would want it to be performed in a hospital lab in a sort of automated way.
Would this actually impact on treatment? Because, yes, it is been shown in a minority of patients that it picks up certain mutations.
But um, you know, these cancers because it requires a C LCP and because this LCP is being prompted by clinical stuff plus imaging,
you know, they're not, these patients aren't just rocking up for surveillance.
The OCP will actually diagnose it that much earlier enough to make a difference.
That's the key. Yeah. Will it diagnose it early enough?
Early enough that they could have surgery. But that's the key.
And I and I don't know the answer to that. And you do have to get you do still have to have the LCP.
And some patients cannot have any LCP for various reasons who probably wouldn't be
suitable for the surgery anyway if they're not suitable for any LCP for whatever reason.
But nevertheless, it doesn't help those that particular group of patients.
But certainly it's, it's promising. Yeah, it's, it's, it's very much so and interesting.
So, yeah. Has anyone just tried sampling like small bowel contents?
Because, you know, my, my anatomy is not great,
but even I am aware that the bile goes into the small bowel and it is a relatively straightforward plumbing.
But that's you know, you can you could do an OCD, you know, and, you know,
weighing down a tube and aspirate aspirate some small bowel contents as long as your distal to the distal to the,
um, puller and there'll be a bit of bit of bile around.
Yeah, yeah, that's possible I assume. But it's a total assumption that you can't detect things in stool.
Otherwise people would have looked just because presumably the DNA is degraded by the time you've choked through the rest of the GI tract.
I guess the other thing about doing both of these techniques is that.
And. Well, it's the same with plasma, isn't it? You will pick up all sorts of mutations that might be due to a different tumour somewhere else.
Any kind, colon, stomach, whatever. You need some A.I. to pick it up on your colonoscopy first before you do the stool test.
Cool. That's it's really interesting. And it's sometimes sometimes you see these sequencing papers and and you go, that is absolutely lovely.
And that super interesting. That is of no use to man or beast for for a while.
But actually but I like this because it's it's tried it's trying to make it relevant to clinical practise.
And and I think there's enough evidence from this to go on to potentially do bigger trials or develop of the assay itself.
Yeah. There's maybe a bit more targeted for biliary tree malignancy.
Yeah. So that someone. So we've done colonoscopy.
We've now done LCP, albeit for stretches.
So I've got I've got two more endoscopy papers. Okay, cool.
Okay. So I've got. We're now getting on to uppers now offers for GI bleeding.
So this was a paper in guts that I think is really interesting and I think it's quite cool technology.
I have to say I'm slightly sceptical about this study, I think.
And if any of the authors are amongst our, you know, our small coterie of listlessness, I'd love to I'd love to hear from you.
And this is a trial that was in got just a few weeks ago.
This first author is Benjamin Meyer. This is a German group,
and the title of the paper is Over the scope clips versus standard treatment for high risk patients with acute non-venomous heel upper GI bleeding.
A randomised controlled trial. The Sting two trial.
It's good name and it's good name. Non-Racial upper GI bleeding is really common.
So it's around 100 cases per 100,000 population in Europe, in the US,
and it's still associated with a pretty high mortality somewhere in the region of 7 to 10%, depending on what studies you look at.
Most of that is actually not driven by the bleeding itself,
but the fact that the people who bleed are generally old, frail, co-morbid and on anticoagulants.
And now the the major treatment for for vast upper GI bleeding is endoscopic therapies,
a diagnostic endoscopies diagnostic endoscopy and then endoscopic therapy for haemostasia and standard therapy for that is based
on based on previous trials pretty successful with rates of haemostasia considerably greater than 90% in previous trials.
And usually, as you know, we use dual therapy,
so we inject in diluted adrenaline and then we either we the use mechanical haemostasia we clip it or we use coagulation,
thermal therapy, we burn it, say, inject it, clip it.
And burnet butts and.
We know that if you have insufficient haemostasia or ongoing bleeding, then a repeat endoscopy is often unlikely to be successful.
And then you need to have various types of salvage therapy so you can either have an angiographic therapy,
so interventional radiology treatments or in some cases surgical treatments.
And I think the key thing is, is that those those salvage therapies are associated with a greater mortality,
whether that's because of the procedure itself, because of the cohort of patients it is, or because the ongoing bleeding is is not entirely clear.
But the mortality is, you know, is higher sort of 10 to 30%.
Now, there was a sort of a new clip on the block, which is the over the scope clip.
And I have to say, I've only actually ever seen one deployed once, so I've never seen them.
They kind of look like a bear trap, one of those kind of comedy bear traps that you see in a cartoon with two big kind of jaws with claws on them,
that snapshots, that sort of that kind of sprung load.
And they snapshots. And what you do is you put put effectively a cap which has the over scope clip loaded in the open position on the top.
A little bit like a speaker band.
Yeah, exactly. Yeah. And very much like the band. And there's a little,
little thread or something that goes up the working channel of the scope and effectively you find whatever
you want to what want to bear a bear trap and suck it up into your cap and then deploy this massive clamp.
The thing that that grabs grabs hold of it. So over over the scope clips were developed by a company called Invesco, which are a German company,
and they were originally developed for the closure of G.I fistulas and GI perforation.
So the idea is you made a whacking great hole in the bowel and then effectively you just close it trying to reduce the,
the, the, the need for, for surgery for those kind of situations.
But they have been increasingly used in case series in clinical trials for haemostasia in certain situations because their,
their physical kind of reach, their bite is, is bigger than most standard clips.
And also the sheer kind of strength of them and the fact that they've got these ruddy great teeth that really kind of dig in means that,
you know, in a kind of more sort of fibrotic setting,
you can kind of oppose the edges of an ulcer and gets that kind of that mechanical pressure on the vessel to allow it to coagulate and stop bleeding.
So there have been some retrospective studies that have shown that they are in case controlled series
highly effective for the management of severe arpeggio bleeding in certain patient populations.
However, it's unclear whether of scope these over the scope clips are a useful treatment as first
line for high risk non partial API bleeds and that's what this trial is trying to do.
Okay. So. And is this still used with dual therapy?
So if you use about it. Oh, not necessarily.
Okay. But I think I think most of these patients.
Yeah. So they injected adrenaline for most of these patients.
Okay. And that's all. And so this trial, the sting two trial, that was a sting one.
I have some. I forgot what Sting one was. Presumably the same thing, but in a different cohort.
So Sting two was in 13 academic referral centres in Germany.
So this is all in Germany. And each centre there was only one or two endoscopies.
So this is a little bit different from the previous trial.
So we've got effectively a whole clinical trial and you can probably get them around a small table,
all of the documents who were doing these procedures and they were all highly experienced in the management of the GI bleeding.
And there's an interesting line.
They are all highly experienced in the application of over the scope clips greater than 20 over the scope clips per year.
So that means they use them normally, they are using them normally.
And I would say that they are converts force.
And it is interesting to look at the competing interests statement because although this was not funded by the company,
several authors are either consultants for of ASCO have received fees for INVESCO anything like that
to say that these these people are converts to the technology which comes into relevance later.
So these are all participants who were hospitalised for acute non-volatile upper GI bleeding.
They had the endoscopy,
they were consented for the trial before they had the endoscopy and then they were included in the trial and basically during the endoscopy.
So what they did is they did the endoscopy and then they did the complete rock score.
So including the endoscopic elements of the recalled score.
And if they had a recall score, a complete recall score of seven or greater,
then they met the criteria and then the little envelope was opened and they were randomised to one of two arms standard therapy or a vesco.
Okay. Yeah. So that was the plan. I mean, you wouldn't do that in real life, would you?
But. Okay, well, you know, a little envelope halfway through, and then I might do that.
Just got some letters. I just need to see what's in my correspondence.
Please help escape that. Yeah. No, no, no.
Calculate the ruffle. But no, you know, but it's.
It's a trial note and they need to do that. But effectively, they, you know, they're assessing the forest score.
These people have got a forest one or one or two way.
So effectively they've either got her actively bleeding, actively bleeding ulcer, or they have got a visible vessel in the presence of clot.
Okay. So these are sort of high, high risk bleeds that we need to intervene in.
And they've got a circle of seven or more. There are a couple of things that are worth noting.
They were not allowed to use a couple of other potential treatments.
So in particular, they were not allowed to to use chemo.
Pray he might spray topical therapies that we've discussed.
You can't call it that anymore. We can't call it because it was a great trial, wasn't it?
Because it was great. Yeah. But again, it comes up into, into relevance here.
Um, so they weren't allowed to use topical therapies like chemo spray.
Um, and they said that for ethical reasons people were allowed to crossover between the arms if they, if haemostasia was not achieved.
And I'm not sure I desperately agree with that. But that's interesting.
That's what the trial says. You know, I presume they mean crossover to having a basically if the rest hasn't worked.
Yeah, yeah, yeah. You're seeing where this is going.
Tamsin Cool. So there were some, there were some,
some power calculations in which they've ended up with a made up made up number of people that they're going to put in that trial.
So assessed 246 patients.
Um, and 100 of those were randomised.
So most of them didn't meet the criteria for it because either they couldn't,
they couldn't get consent or when they did the procedure they didn't have severe enough bleeding and didn't meet the criteria.
So that's fine. So they randomise them roughly once,
once a standard group 52 and over the scope clip 48 and then they and all of the ones who are randomised are included in the analysis which is good.
The primary end point of this study was clinical success.
So clinical haemostasia from the as decided by the managing endoscopic.
So endoscopy opens,
the envelope goes either standard therapy or back in and then they apply the therapy and then they decide whether that was clinical success or not.
So and and the outcome was that in the standard therapy arm, 38 of the patients had clinical success, which is only 73%, only 73%, which is low.
That is a low number compared to previous studies of standard dual therapy.
And in the over the scope, it was 44 patients with a clinical success rate of 91.7% in 92%.
So it sounds like quite a big difference, 73% compared to 92% big difference in that.
But first, the 73% is quite low. And second, actually, that only corresponds to six patients, six patients difference between the two arms.
And in those six patients, the endoscopies, having applied a couple of clips of that,
that standard therapy has decided that the therapy is not working and has switched to the Skype, which in all six of them.
I provided him instant haemostasia. So.
I'm trying to put this in a very diplomatic way. There is an element of subjectivity by the endoscope test to decide that they've done enough standard
therapy and that there is now not haemostasia and then they've switched over to the other other therapy.
That is the key. Significant results in this in terms of re bleeding rates.
There was a there was a nonsignificant trend for increased recurrent bleeding within the first seven days in the standard of therapy group.
So eight patients replied compared to four patients, so 15% compared to eight patients 8%.
But that was not significant. However, there were two delayed bleeds in the over the scope clip on.
And it gets slightly convoluted about re bleeding and different interventions.
But I think that the only person who actually ended up going for surgery for ongoing bleeding was in the over the Skype clip creep in terms of like,
you know, big headline, you know, the things that people really care about like dying.
And there was no difference in overall 30 day mortality between the two arms.
It was around 7%. So that's to me, half saying they picked the wrong.
Have they picked the wrong primary outcome? Um.
I don't know. It is a plexi. I'm thinking.
I'm just thinking out loud. Yeah. No, I think you're.
I think you're spot on. So I agree with you that I think that this is a proxy and point that makes a certain amount of sense.
But one isn't actually what patients care about.
They care about whether they keep on bleeding over the following days.
And then that leads to them either requiring something else or them having some kind of bad outcome.
But also it is an outcome that is a subjective measure, very subjective.
And it's not like that was a sort of essential reader or somebody who who decided and made an independent person who knew decided that.
So there's a bit of judgement there and these people are proponents of this treatment.
Otherwise they wouldn't be doing this study and they wouldn't be doing to over the scope, perhaps a year each.
So these are people who think that it works well and therefore are probably likely to lean towards it in certain circumstances.
I think there are a couple of other things here. Um, I am concerned that the clinical success rate in the standard arm was only 73% because first,
that doesn't tally with other trials of chil therapy, which suggest it's well over 90%.
What's interesting is that, um, they pretty much only used clips.
So this pretty much, I think there was one patient who ended up getting a little bit of Bernie with the, with the heater probe.
Pretty much everybody had had clips rather than adrenaline.
And that includes what's a single therapy? Not dual therapy.
No. Sorry. No. So they had adrenaline plus clips.
Yeah, but but very few people had thermal therapy.
And that interested me because there were 16 or 17 ulcers that were over 20 millimetres wide.
And my experience is that big old 20 or 30 millimetre ulcers are nigh on impossible to close with standard standard clips.
You either need to get those giant ultra clips or you need to or you need to burn.
So I wonder about those those those cases.
I think the other one is is that they weren't allowed any haemostatic powders.
And actually, as a if we're thinking about somebody who may have some ongoing issues after you've applied partial standard therapy,
actually, you might well convert to a Hema spray and and add that on and get Haemostasia.
Yeah. So and I guess that would be part of standard of care at the moment,
although that's not sort of guideline based, but it would be an alternative that people would use.
So are there any adverse ALK adverse outcomes or reasons not to use a backflip in in those cases rather than he was very apart from lack of evidence.
So not in this trial. So I think I think it's fair to say that these are actually pretty safe things.
However, I have seen some case reports and I've also seen some presentations where people have talked about complications from them,
most obviously perforation. So you've got like a thinned duodenal ulcer and you put on this whacking great thing
over your your fibrotic ulcer and you just just go through and you've perforated them.
And so there are potential complications about it.
I think it's a really interesting trial. And I think they've I think they've tried to answer a question about whether this should be standard of care,
whether it is an alternate, a suitable alternative is standard of care.
And I think I think you could argue that it is an alternative to standard of care.
Like in this trial, it seems to work.
I am not convinced, however, with the statement that it is superior to standard of care because of the caveat, all the caveats raised and from people.
I don't know many people who've used it, but from hearing presentations where people.
And speaking to a couple of people who have used them mean there are certain situations where they could be really useful for bleeding.
So particularly if you've got a large ulcer that you can't just physically get any kind of clip around,
and particularly if it's got a bigger vessel that you're not,
you're a bit worried about, you know, touching with the heater probe and actually getting a big old clip over.
It sounds a lot of sense. And also, if you re scoping someone and standard therapy has failed, particularly for one of those bigger ulcers,
then that's maybe a nice alternative to prevent people go to angiography and then,
you know, maybe in very safe areas in terms of putting on a whacking great clip.
So like a stomach, a stomach bleed,
particularly if you can't accurately localise exactly where it's coming from like a OD due to for a lesion or something like that.
Maybe just grabbing it with one of these massive things might work well.
So I think this is an interesting trial and I don't think it's answered my question, which is where is Invesco?
Where do these oversight clips fit into to the therapeutic sort of armamentarium?
I think you could argue that they're an alternative, and but I think it's probably a bit more complex than that.
And I'm not sure in this trial they'd be any better than standard therapy plus hemo spray if initial statement doesn't work.
Yeah. Thank you. That was another really interesting trial. So thank you for bringing that one as well.
Brilliant. Let's do one more endoscopy. One, because it's quite quick.
Yeah. Okay. Focus on it. Okay. And now for something completely different.
This is also in goats. Oh. So Billy goat focussed on three in a row.
So this is a bit off piste.
Estimating the environmental impact of disposable endoscopic equipment and endoscopic is good that we're thinking about this now.
Really good. I do. And there's a there's a awesome movement in that in the UK and there's a gastroenterologist in at King's he's
Hussain Bely who has been involved in setting up this sort of green endoscopy group as part of the BSG,
which I think is brilliant, to start to think about how we can make positive environmental changes in health.
Yeah, I think it's because health care is, according to this paper,
at least responsible for 4.4% of total greenhouse gas emissions and 8% within the EU.
The US said we all we have terrible.
And call that a disposable stuff. Things all the plastic, the heat is a lot of rubbish that we do.
Yeah, there's a lot of rubbish we generate and in the USA we also probably do far too many procedures.
In the US, 18 million endoscopies performed each year and a lot of the kit we use is single use and disposable.
Yeah. Now you may well remember that there were a of people who got really horrible
cholangitis with resistant organisms from contaminated duodenoscopes a few years ago.
I don't. Thanks anyway. Yes.
So there was this run of like people who got horrible, like carbapenems producing, you know, enterococcus, horrible, horrible bugs.
And they were being transmitted because of inadequate cleaning of the bridge of the Duodenoscope.
And because of that and concerns about infection, transmission and things like CJD and things like that.
And uh, companies have started manufacturing single use endoscopes and the FDA has recently approved old endoscopes for,
for gastrostomy, colonoscopy, duodenoscope.
I've seen adverts for sister scopes. This is a bit of a movement.
And from the joke and from the story, from the manufacturers, it's a win win moneywise.
So it's a good line of business to encourage so and so despite the absolute risks of of endoscope
acquired infection being like tiny in the one per million this there is a bit of a move towards.
I mean I do feel the NHS will never be able to afford that.
So from all you say that the nice thing about it is you buy a whole lot of
single use stuff and then what you do is you sack all your staff who are clean.
Yeah, yeah. So, you know, it's for some departments there is a financial thing you can ask,
argue about the the ethics about this and about the shortsightedness about sacking staff.
But that's often how I think it's sold to departments that, hey,
we've all single use and then you don't have to have any of your your processing deacons staff.
You can just get rid of that unit because, hey, you're just chucking it away afterwards.
So what this study did actually, this was just a really nice basically an audit and they published it in gut.
So well done then. I love this.
And basically they audited two centres, a high volume endoscopy centre and a low volume endoscopy centre for a week in 2020, just before the pandemic.
And they then used their audit data and measuring all of the rubbish that was generated from those from the procedure.
Then they study hospitals to work out how much trash does endoscopy make.
And so there's a whole lot of methods about how they calculated the the amount of rubbish that's all generated.
And so they've they've calculated this the base of 278 endoscopies performed in this five day period at these two hospitals.
And those 278 and the scoping procedures filled 190 20 gallon waste bins and generated 619 kilos of rubbish.
Of which two thirds of which was destined for the landfill.
Another 17% of it was biohazard waste that was headed for incineration.
Um. And it's not good, is it?
The vast majority of it was not. Yeah, I was going to say nothing was recycled.
Yeah, that sounds so. The average scope produced 2.1 kilos of waste and filled half a waste bin.
And these are standard. These are standard scopes. No, no serving single use scopes.
So basically we make a lot of rubbish. So they then calculated based on the 18 million endoscopic procedures performed in the US each year,
that the US fills 11 million waste bins and generates approximately 38,000 metric tonnes of rubbish each year,
which would cover 117 soccer fields in a metre of rubbish and is equivalent to the weight of around 25,000 cars.
So that's always depressing we generate.
So we already, we already generate an inordinate amount of rubbish from doing it.
Yeah. They've then estimated what would happen if we switched to single use endoscopes.
And if you did it for. All single use and escape.
So Cullen escapes, gastro escapes and duodenoscopes you increase the amount of rubbish by 40%.
If you just did it for kaleidoscopes and duodenoscopes you would increase by 25%.
So we're going to make a whole load more rubbish.
So if you calculate it, you will do this. So that's an extra kilo of rubbish for every endoscope.
It's a big difference.
And that's not including the costs of making it the costs of the raw materials, some of which are not not recyclable and and and all of that.
And that's, you know, and that's calculated and and factored in the kind of decon and reprocessing things.
So, I mean, I, I feel pretty strongly that, you know, we should push, push back against single use and discuss.
Yeah, it sounds like that's not from an environmental engineer.
Yeah. Except in situations where there is clearly an infection control risk.
You know, this seems to be a a no brainer.
And I think we need to push back against companies that are, I think,
trying to exploit a a line of arguments about patient safety, which I think is not really justified.
And we need to really consider on a wider level, not just in endoscopy, but in clinical practise in general,
about moving towards using less waste, moving towards recycling things.
And you know, yeah, because there's so much waste generated that we could do better.
And the other thing that they mentioned right off the bat, which actually I think is much more important,
is that I think we should start to factor in not just kind of clinical harm in
terms of when we when we arrange telescopes and thinking about the patient,
the risk benefit, environmental loss of the patient is the fact that we're spending a whole load of, you know,
the Government's money in an NHS system and we're also using some of Earth's valuable resources for that procedure.
And there is no doubt that we do a whole load of scopes that if we're honest with ourselves and we were honest with the patients,
have pretty, pretty borderline indications. Yeah, absolutely.
You know, so do less do less tests is the best way to make your tests more environmentally friendly.
And the second one is, don't use it to use a single use endoscope.
If at all possible.
Yes, we do need to think about all of these things and just the fact that it's starting to come into our consciousness as clinicians now,
I think is a really good thing. So I've got two more.
But I know you've got a couple of paper papers that I am going to try and be really, really quick with.
So I'll let you do your ones and then I'll wait through these two.
A while ago I discussed a modelling paper about minimum unit pricing and how that might impact on various different health,
but also broader social outcomes if it were applied in England.
So this is sort of going back to this little bit and this paper or report anyway is from commissioned by the Public Health Scotland
and it's entitled Evaluating the impact of minimum unit pricing in Scotland on people who are drinking at harmful levels.
And this was published on the 7th of June this year.
So it's not in a peer review paper and it's it's 210 pages long.
I didn't read all of it, but I did read quite a bit of it actually, and it was really interesting and definitely changed my view.
About minimum unit pricing and perhaps what the evidence says about it,
because obviously as a sort of lefty hepatologist, I'm like, yeah, minimum unit pricing, great.
We need to get people to drink less. But is it impacting on the people we want it to impact the most?
So quick background, I think most people know this minimum unit price for a unit of alcohol in Scotland was introduced on the 1st of May 2018.
So the minimum price for a unit of alcohol in Scotland is 50 p.
And one unit of alcohol is ten mils or eight grams of pure ethanol.
This policy does have a sunset clause, so that means that six years after it started, say,
2024, this policy will expire unless the Scottish Parliament votes for it to continue.
Hence why Public Health Scotland has commissioned quite a few different studies to evaluate its impact.
And so this piece of work was specifically targeted at the population of people that
drink at harmful levels and including people with alcohol dependence in Scotland.
And this is a specific group of people.
So the definition in the UK of somebody that drinks at a harmful level is a person that drinks more than 35 units a week.
If you're a woman or more than 50 units a week. If you're a man.
And within that group, one in five of them will be classified as being alcohol dependent.
So they have a physical and or and or psychological dependence on alcohol.
And these this particular group, are most at risk of poor health outcomes from alcohol consumption,
high alcohol consumption, and also some of the other social and.
Negative outcomes that go hand in hand with it. So the intervention was obviously the introduction of the price and and I'll talk about the,
the different outcomes they looked at that some of the outcomes they looked at when there was no control
group just because of the nature of the methods used and where there was quantitative work done.
They did use control populations in northern England as a as a control.
So there were four work packages. So these are the outcomes they looked at.
One was to look at the impact of the minimum unit pricing on people who use
alcohol treatment services specifically with harmful and with healthy drinking.
So they had to be in touch with those services work package to looked at the impact of it in the community and
that included on speaking to families and carers of people that lived with those that drinker harmful levels.
And both of these work packages used same qualitative better methods.
They were package one used qualitative interviews with service users that use the alcohol treatment services,
but also some quantitative surveys and work package to use interviews and focus
groups with people with alcohol dependence and their families and carers.
Then what? Package three, which I'll focus on a bit more,
it's a probably more interesting one is looked at the impact of the minimum price on harmful drinking in the general population.
So that's looking at just the prevalence of harmful drinking change after minimum pricing is introduced.
And does the the consumption patterns of alcohol change often in pricing in this particular group work package for wasn't completed,
but it aimed to look at the impact on within primary care.
I aim to analyse the data set of linked electronic GP hospital death records,
but as with previous IT projects in the NHS, it sounds like that linkage didn't work out.
And so that hasn't it hasn't been completed yet. And so the headline findings really are from I'll start with the work package three.
So. The consumption patterns.
So after minimum unit pricing was introduced, there is evidence that people with alcohol dependence are paying more for alcohol.
So the cost for them has gone up from about 49 P to about 59 per unit and that's in line with other
studies that have looked at the population levels and not just people with alcohol dependence,
but the population level. People are paying more for their alcohol as you would imagine.
However, the prevalence of drinking at harmful levels did not change significantly after the minimum unit pricing was introduced.
And. That was a key,
a key kind of a wish of the Scottish Government by introducing this policy is
that actually by introducing a minimum unit pricing that it should impact and
reduce the number of people drinking harmful levels because they're the people
that are often paying and buying cheap alcohol with the is high percentage.
So it should impact them more than people that drink at lower levels.
Now the dataset they used to evaluate this was a a market survey and this market
survey used individual level data on alcohol consumption over a ten year period,
and they used an interrupted time series design. And the control in this case was the same data that from individuals from northern England.
It's a commercial market research survey. It's continuously collected.
It's cross-sectional it's adults that a resident in Great Britain and the survey
about 30,000 individuals a year and they have a weekly quota sample based on age,
sex, social status and where they live in the UK. And the nature of the data they collect is that the participants first answer
questions on the typical alcohol related behaviours and alcohol related attitudes,
and then they complete a one week retrospective drinking diary.
And so you get an idea of how often they're drinking, what they're drinking, how much they're drinking, and this has been collected for a long time.
And so they used diary data that from the 1st of May 2018, anything after that was post and the placement and pricing data and before that.
Was pre and the number of individuals was this was massive.
So 38,000 plus individuals in Scotland.
So that's an average of 267 people a month filling in this survey over the time.
And in northern England, 71,000 people average 494 a month and.
And and so they looked at using these diaries.
They looked at how much people were consuming to define whether they were drinking a harmful level or not, i.e. over 35 or over 50 units per week.
And that's how they worked out.
The prevalence of drinking harmful levels in the last week based on the survey didn't change significantly after the introduction of minimum pricing.
They did look at some other groups that don't fall into that harmful level.
So there's another definition of people that drink hazardous levels, and these are people that drink about 14 units a week, but below 35 or 50.
And the proportion of people drinking at that level did fall significantly between 2017 and 2018, superimposed by a 3.5%.
And the people drinking at moderate levels. Didn't didn't change significantly, but increased a bit.
So suggests that people drinking at hazardous levels fell and they just started drinking a bit less,
maybe as an impact, maybe impacted by the minimum price.
There's some evidence of a switch from high percentage lager in or cider to spirits,
but it wasn't significant and there was no significant impact on the variation in prevalence or consumption patterns between urban and rural areas.
Now, this is different. These findings are very different to what I.
Thought they would find and also what some other studies have found.
So I looked into this a bit more to understand perhaps why.
So the previous studies that have been published looking at the minimum unit price of
alcohol in Scotland have used similar time series analysis data to what these authors used.
But they've used a different type of.
Dataset. So they've looked at household level data on household purchasing rather than individual level data.
Okay. And that's really the difference.
So there's been several different studies since the introduction of minimum unit pricing
that have all looked at household level data and found that alcohol purchasing.
Has decreased at the population level in Scotland since the introduction of minimum
unit pricing and the households that are in the top of sort of fifth so to
the top 20% of households that buy the most alcohol have been most affected have
have reduced their alcohol spend or the amount of alcohol they buy the most.
But it doesn't tell you within that household how much someone's drinking.
Doesn't say how many people are drinking at hazardous level, a moderate level or a harmful level who are alcohol dependence.
And in that household, you know, is it one person in that household that drinks like that?
Is it all of the adults in that house that drink like that?
So this data set is different, quite different and quite it's important because it's looking at slightly different data.
And and I think all of it needs to be looked at together in context with the other work packages.
The outcomes that they looked at, I thought were really interesting and important as well.
So and they were more mixed methods studies qualitative.
And looking at how individuals for example how in a minute pricing had impacted on the daily lives of people who drink at a harmful level.
So they found there was evidence of increased financial strain in in many and the coping mechanisms that people used to account for these
the increased prices were that they used the for intensified say they bought less food they spent less money on gas and electricity.
They borrowed money from friends and family and pawnbrokers and things like that.
They relied on food banks.
And but there were there were obviously unrelated factors that were occurring during this period that may have also impacted that.
So, I mean, right now we've got lots of inflation and things in the economy,
but there was a reduction in universal credit and that might have also contributed.
There was no substantial evidence of the people within this group.
Substituted alcohol for illicit drugs or that there was increased stealing or
violence or alcohol related crimes and no increase in acute alcohol withdrawal.
But there was some evidence in from from the carers and the family members that some of the some of the people with
alcohol dependence or harmful use actually switched to spirits and they were more fearful of violence towards terrorism.
Family members. But there wasn't any. Quantitative evidence of that.
And then, of course, the health side of things wasn't really analysed. I'm in this particular study.
So I thought this was really interesting because it looked at a specific population of people
that we're really interested in what their outcomes are to minimum unit pricing in Scotland,
because actually they're where the money is, the higher risk of negative impacts of alcohol dependence or harmful drinking.
And and there are obviously some limitations and there are several explanations
as to why their findings might be a little bit different to previous studies.
So the methodological limitations obviously include non-random sampling and survey data, which is notoriously and often not not very accurate.
And some of the work packages looked at particular populations within that group of alcohol dependence.
So they had to be in touch with, you know, alcohol services, for example.
So they're missing lots of people and. And it also required it also has heavily relied on data from people drinking at
harmful levels that only participated in that online market research panel.
So I bet there's a whole load of people that do not do that and therefore weren't captured in this.
And so the way they interpreted the sort of main, main findings.
Well, the first thing is they might have the findings might have underestimated the effect
of minimum unit pricing on the consumption of alcohol in this particular population.
It differs from other published data, as I've already talked about, the household data and modelling studies is the other thing to talk about.
They consistently and I know they're modelling not real world studies,
but they consistently model that there will be a positive impact of minimum unit pricing on alcohol consumption,
particularly in these groups that drink the most harmful levels.
But equally, another argument is that people with alcohol dependence might be less responsive
and probably are less responsive to price changes than lighter drinkers,
particularly if they're dependent not just harmful drinkers,
because they've got a physiological, psychological, physical addiction essentially to alcohol.
So they will put alcohol consumption above eating and buying fuel and all of those things.
And it might be that the minimum unit price is too low, therefore,
to have a have the impact we want it to have on the people that are drinking at that high level.
And they also commented on, you know,
these management strategies that people seem to be using to offset that increased price in alcohol might not be very sustainable,
and especially in the current economic climate, you know, how long can you know?
They're all they're all short term solutions and that might not.
And actually, longer term, it might be that people do change their behaviour and it also might be that it might encourage people who
are younger that would have become hazardous or sort of harmful drinkers to not drink to that level.
So it hasn't looked at that particular group. And also the other important thing,
and I guess the most interesting thing for us is it hasn't it's only this
particular report hasn't really evaluated the health effects and a few of the.
Reports have touched on it, but in terms of admissions, so.
Yeah, exactly. Tendencies without. Yeah. Related problems or injuries or alcoholic hepatitis.
Exactly. Right. I mean, the the Public Health Scotland plan to undertake health outcome analysis.
So that should come and there will be a final over overarching report next June about all the different things that they've reported.
And the other thing that will muddy the water obviously here is COVID, because that did change things that at times in I go through a whole episode.
I know. I'm sorry. But so so I just I just thought it was really interesting mean to look at because I kind of thought oh yeah.
Minimum unit pricing, right? Yeah. I mean, that is very new.
Sold as a bit of a panacea because it's I think the the modelling data that it was a really it's a bit of a silver silver bullet.
Yes. You know, and it's it's, you know, the Royal College of Physicians, you know, health inequalities and policy,
you know, include support for minimum unit pricing and as as do as do many others.
And. It will be interesting to see the kind of the real world effects hopefully trying to control,
try and treat, trying to control for COVID and other other parallel effects.
But yeah, actually, this is a slightly, slightly depressing outcome actually, though I was rather hoping that this is going to happen.
Yeah, I know it wasn't. It wasn't what I was expecting, but yeah, really, really interesting.
And I'll definitely look out for the further reports that are going to be published in the next year or so.
Progress. Yeah. Yeah. So I've got a short, mildly depressing one, and then I've got a positive one to end on.
Right. Okay. Well, it's good. As long as we end on a positive.
That's fine. Yeah. Say something.
Negative one. Is a commentary a commentary in gastroenterology by Lauren and Danielle Rabinovich.
They are from Harvard. Beth Israel Deaconess Medical Centre and the Boston Children's Hospital.
This is a paper about the disparities in inclusion of female, pregnant, lactating and older individuals in IBD clinical trials.
And this is a nice and nice little read and I like the way they did the study.
And so inclusion is really important.
It is a priority for the National Institutes of Health Health,
the niche in the US who have specifically said that they want health, you know, medical,
medical trials and health research to include groups that have historically been excluded from that,
including women, children, older adults and members of racial and ethnic minority groups.
And it's really important in the context of clinical trials,
because we want to know that the results of those clinical trials are generalisable to the populations that we serve and Crohn's.
Quincy's is an interesting one because it's not it's a heterogeneous population,
which includes some of those some of those harder to reach populations.
So there is a female preponderance in IBD overall and more so in crimes than you see.
But you know, overall, overall, 55% of people with IBD are female and IBD affects a whole range of ages.
So this this this commentary isn't about paediatric space.
Clearly, there's a considerable number of kids with IBD who are often excluded from from trials that focus just on adults.
But we also have that bimodal age distribution, and we are increasingly diagnosing people later in life with de novo IBD,
as well as having patients who've had IBD for a long time and are now entering their latter years.
But 10 to 15% of new diagnoses of IBD are in the over sixties.
So this study was looking at the effects of the how representative clinical trials were,
and the other group that importantly are often excluded are pregnant women and women who are breastfeeding.
And we know that this this, this group is quite large, quite important.
And we have lots of our IBD patients who are either pregnant or are interested in becoming pregnant.
Indeed. And so this study, they looked just they looked at clinical trials,
dot gov and all IBD trials registered in a 20 year period up to June the 30th, 2020.
And they found 146 trials that met their criteria.
And then they went through the demographic data and compared it to the US population data.
So basically, do U.S. IBD trials match the US population?
And spoiler alert, they don't say.
So 146 trials, 50,000 participants, paediatric and adults.
Most of these are industry funded because most of these are therapeutic drug trials, although there were few other like fam t trials or device trials.
80% industry funded and 75% are phase two or phase three trials.
So these are the key registration trials upon which, you know, the key data upon which we then decide how we use these, these, these drugs.
Yeah. So then we use them in all sorts of different populations.
Yeah. But these are, you know, these are, these are the key results.
So women and total trial participants and this is include all the paediatric trials as well.
51.6 were female, so quite similar.
But when we look at adult studies, female patients comprise 54.6% of Crohn's disease trials, but only 44% of U.S. trials.
They slightly underestimate representing women compared to kind of, you know, the known IBD frequency in the U.S.
Pregnant or lactating women were excluded from over 60% of the trials, you know, off the bat.
And but what's also of relevance there is that even when they were allowed to be included, they often don't they weren't.
Um, well, they either weren't. But also it's not possible to tell.
So there's no subgroup analysis for those patients.
So it's often, even if they don't seem to be a formal exclusion criteria, you then don't have the data that you kind of pull out to say,
ah, there were, you know, three breastfeeding women in this group and, and, you know, with that this was the outcomes.
Um, so when we start thinking we've got 10 to 15% of IBD patients diagnosed with IBD over 60 buts of the 105 trials in adults,
the mean age is relatively low, which is, I guess what you would expect, say, in Crohn's disease, the median age was 37 and you see it was, it was 42.
Um, only 39% of trials included patients over 65 years old.
So all they did was just exclude them off the bars.
But even where they were included, they often made up a small minority of of the the patients in the trial.
And so overall, if we look at all Crohn's disease trials in this cohort, less than 1% of patients were over 65.
And in the U.S. trials, less than 4%.
And this is so important, actually, because, you know, we we don't have the data for these patients, these older patients.
And yet a lot of our clinical decision making is, especially for biologics and things like that,
is based on, oh, you know, they're over a certain age or have lots of co-morbidities.
Let's not give them let's give them V do. Yeah.
So, so we infer risk. Yeah.
But it's not actually I but it's actually not. Yeah, it's not from, it's not from a great deal of clinical trial data is like, oh,
they're at higher risk of, for instance, cancer or heart failure related to anti-TNF, let's say.
But actually a lot of these trials are excluding these patients off the bat because of those risks.
So self-fulfilling prophecy. So you don't include them because you haven't got the data about them.
But the reason you have the data about them is because you didn't include them. So, yes, yeah, this is a problem.
And then we come on to race and ethnicity.
And in these trials this is a US population.
So big difference in the UK. Um, US trials overall we've got nearly somewhere between 85 and 90% of trial participants are white, um, uh,
depending on how you stratify it into Crohn's or you see, but only 76% of the US population is, is white the populations that are underrepresented.
In particular are those of black and African American nationality, which make up more like 13% of the U.S. and they make up about 3%.
In these trials, Hispanic communities are also lower, and I don't even think they were able to delineate populations like,
you know, South Asian descent or First Peoples and, you know, Pacific Islanders.
And and so this is poor. This is so.
Yeah. So isn't it. And not surprising. Sadly, it's not.
It's it's not it's cool. And, you know, they haven't actually gone on to to look at this,
but I don't think they've scratched the surface in terms of thinking then about socio economic status.
And I have, you know, no doubt that there is disparities along along those lines there.
Yeah. So it's it's a little bit of a depressing kind of outcome.
You know, I think if we were grading grading IBD clinical trials in the US,
I think we would say, you know, in terms of inclusion, four out of ten could do better.
We really need to make an effort to include these groups and if there are reasons not to include them,
I think, you know, that needs to be looked at quite carefully and the default should not be,
oh, let's just exclude all old people and let's exclude women because they might get pregnant and mock up our stance like those.
Those are not good reasons to exclude people from trials.
Yeah. And it perpetuates. And I suspect this is true of not just the IBD field, but.
Much the wider medical field and it reflects wider society.
Indeed, indeed. I suppose gastroenterology is a microcosm of society.
Right. Happy news. Only take a few minutes. And also a positive paper.
Positive, positive paper. Yeah, exactly. Yeah. New England Journal of Medicine.
This paper is called to zap her tide once weekly for the treatment of obesity.
So it has appetite is a drugs that I find incredibly difficult to say.
But this is the main thing. Say obesity is bad.
And unfortunately, most of the US and and Europe are overweight or obese.
But we've had a couple of really exciting trials.
We've spoken about one that came out a few months ago on this podcast before of Semaglutide, which is a GLP one receptor agonist.
And that demonstrated some really nice efficacy for the full weight loss,
I think in the region of sort of 12 to 14% body weight lost after a bit over a year on the drug,
which was pretty amazing and is much better than previous drugs.
It comes with some problems, particularly things like gall bladder related complications and and pancreatitis
as well as a variety of GI side effects to cause appetite is it's quite cool.
It's a peptide, it's a sort of it's engineered from the native GI GI sequence and it's an agonist both for GIP receptors but also GLP one receptor.
So it's targeting both the GLP one pathway, but also the GP sort of gut hormone pathway.
And it is licenced for the treatment of type two diabetes, I think.
Well, it's certainly been used in trials for type two diabetes. I am not a diver ologist.
Anyway, this is a phase three multi-center double blind randomised controlled trial in 119 sites.
Nine countries in adults who have a BMI of 30 or more or 27 if they've got complications.
So this is including people who are very overweight and obese,
but also people who are sort of on the kind of borderline overweight or obese, but with some dyslipidemia or cardiovascular disease.
Okay. This was not a trial, including people with diabetes.
They were excluded and they were randomised 1 to 1 to 1 to 1 to either placebo or three different doses of this drug that I cannot say.
And as an adjunct as an adjunct to the drug therapy, they were given lifestyle intervention.
So they had regular lifestyle counselling sessions. They saw a dietician.
They were helped with a healthy, balanced diet with a calorie deficit of 500 kilocalories a day.
And they were also incentivised to exercise for 150 minutes of physical activity a week.
So we did all of the right things and then we either gave them the drug or not for 72 weeks.
Okay. So quite a long time as well. You say the Co-Primary endpoints were the percentage in body weight change from baseline
to week 72 and also the proportion of people who had lost a certain increment of weight.
And the key one that's become one of the key metrics in these trials is losing more than 5% of your body weight.
Mm hmm. There's two reasons for that.
One is that basically all trials of any kind of kind of conventional lifestyle therapy has have deltas of less than that.
People lose less than 5% over a year on average.
And two, that seems to be associated with tangible benefits in terms of blood pressure,
cardiovascular risk, fatty liver disease, blah, blah, blah, blah, blah.
So overall, this is a really well powered study.
They had 2539 participants, 86% adherence to the therapy.
And the demographics were much as they planned. These people have a meet mean BMI of 38.
That's sort of 105 kilos. And they have, you know, some 40% had prediabetes at baseline.
The results are stonking.
Absolutely stonking. So in the placebo arm, after a year, the percentage body weights, the mean percentage, body weight is -3%.
So people lost 3% of their body weight. Mm hmm. In the.
To his appetite arms, particularly in the ten and 15 mg arms of the two higher doses, they lost 19.5 and 20.9.
Wow. That's massive. That's just me.
That's the mean. So that's when we start looking at the people who've lost 5%, 10%, 15%, 20% within that time.
So basically, in the two top doses, the ten or 15 milligram doses, 90% of people are losing 5% body weight.
Well, that's pretty good, losing 10% body weight and two thirds losing 15%.
And, you know, as you would expect, half are losing 20% of their body weight by the end of the trial.
So what's the drawback? Well, honestly, this is this is pretty pretty amazing.
Yeah. The trial was really nicely designed.
And actually it's a good follow on from the previous one because 71% of the participants was white, which is exactly the proportion of people.
Yeah. It states they also have 7% black participants, a slightly less than the US average, but a bit better than the average.
And they've also quoted for people of Asian origin and also people who are American-Indian or Alaska Natives and also Hawaiian and Pacific Islander.
So that's stratified properly. That was good.
Or ethnic group, which is great. The downsides are actually not too bad.
So interesting. There really wasn't any kind of cholesterol.
Sorry, a cola. Stacy's gallbladder gallstone on the signal or a pancreatitis signal, which were the ones from things like Semaglutide and Liraglutide.
And is there a kind of. I don't know much about these drugs.
Is there a biological reason as to why that might be? I don't know.
It's a great question. I have no answer for you, Tamsin. The main thing is that loads of people get GI side effects.
They get GI side effects, say like, you know, in compared to the placebo arm, like 25 to 30% of people are getting nausea.
20% of people are getting diarrhoea. But did it stop them?
It didn't stop them taking so. So it looks like a lot of people have adverse events.
Most of them seem to be mild to moderate in terms of stopping their overall in the higher dose terms.
His appetite arms 6 to 7% are stopping because of adverse events within a year compared to 2.6% in the placebo arm.
So maybe four or 5% extra leaving the trial because of the side effects.
But they do have some quality of life data and some of that health related quality of life is improving.
So clearly this is balancing out. There's a bit of a signal for alopecia, which isn't great, but in terms of ones that are sort of,
you know, serious adverse events or death, there was no signal of harm in for for this treatment.
Well, overall, that's very, very positive indeed. Extremely positive.
And basically, we should put this in the water.
Yes. You know, honestly, this is absolutely brilliant. I think would be great to see more quality of life data.
They've got plexi outcomes for long term health benefits like blood pressure and you know, lipids and insulin levels and stuff like that.
But you know,
clearly we want to follow up with these cohorts to see why if they keep their weight off and to to they have less progression to diabetes,
heart attacks, strokes. But overall, I think this is really exciting.
And if you look back, you know, even two or three years ago,
you'd say there's a couple of really rubbish drugs and surgery as good treatments for obesity.
And now I think you can actually say that we've got multiple medical alternatives.
Yeah. Suitable for patients with obesity. That's actually really good for this.
Yes. Yes. Well, that's that's really great.
A great one to end on. Super. I think this is a world record for the longest podcast with FDA, which is very interesting types of reading really.
I'm going to say thanks for listening. We'll see you next time.