Episode Transcript
[00:00:09] Speaker A: Welcome to the BSG From Top to Bottom podcast series. I am your host, Dr. Shahid Addin, a consultant gastroenterologist in Edinburgh with a specialist expertise in inflammatory bowel disease and the current chair of the IBD section of the British Society of Gastroenterology. And I've led subgroups in surveillance and main guidelines. Today I'm really delighted that we'll be joined by Professor James east, who led the IBD surveillance guidelines with Professor Morris Gord. And in this podcast we will discussing cancer risk and stratification. And this will be followed by a second podcast focusing on the technical endoscopic options MDT management, being led by Professor Pradeep Pandari, who's the Vice president and current chair of the BSG IBD Endoscopy Committee.
So I would like to extend a very warm welcome to Professor James East, a consultant gastroenterologist and endoscopist and director of the Bowel Cancer Screening Program in Oxford with an academic interest in GI cancer prevention and co author on a number of guidelines and consensus. So welcome, Professor East.
[00:01:04] Speaker B: Jahida, thank you for that kind introduction.
[00:01:06] Speaker A: So I think I'd really like to ask you to start off and tell us the evolution of IBD surveillance and guidelines and how that started and where we have come to here today.
[00:01:16] Speaker B: So I think IBD guidelines actually go back perhaps rather further than we think.
And although the BSG, the current guidelines are described as the BSG 2025 guidelines, strictly they are an update. And in fact, the first BSG guidance came out in 2022, again with Matt Rutter's guidance in 2000, 2010, further guidance in 2019 that folded in scenic. So all of the major societies have at some point issued guidelines for inflammatory bowel disease surveillance, both from ECHO and the AGA and the acg.
And we've seen an evolution over time and you can see that there is a direction of travel. So if we look at say around 2000, we were doing standard definition white light colonoscopies and relying heavily on on random biopsies. But by the time we reached 2010, we'd gone risk adapted. We were doing chromo endoscopy and targeted biopsies. And then as we come through 2019 into the 2000s, much more personalized risk stratification and even the use of risk calculators. And similarly on the timing of surveillance intervals. Again, if you look at sort of late 1990s, 2000s, if you had longstanding disease, you are on annual surveillance.
As we got to 2010 we were sort of one to three or one to five years if we're outside the United States.
And then in the most recent guidelines, we're certainly one to five years or possibly slightly controversially, even no surveillance for patients who are at very low risk.
I think part of that we can see is driven by changes in IBD cancer risk and IBD cancer risk of death.
And we can, you know, looking back that there's the very well known Olin Scandinavian population, population based data. If you were in the 1990s, your risk of dying of colorectal cancer was about four times that of the general population. But that has clearly reduced over time. And now it's maybe only, you know, 1.5, 1.6 times. And you know, there are lots of good reasons for that. So patients are stopping smoking. Hopefully surveillance is a bit more effective. We're a bit better at timing colectomy, but I think we really know that the driver here has been better disease control. And particularly as we've entered the biologics era, we really, you know, patients have, you know, often have normal looking colonoscopies.
[00:03:42] Speaker A: I think that's really comprehensive analysis of where we have started and where we are now. And I think the reason it's special to me is that when I joined the BSG IBD committee in 2019, it was with that sole intention of asking, so if we can review the IBD surveillance guidelines. Because in my own practice I realized that I was doing a number of surveillance colonoscopies and actually wasn't finding inflammation or dysplasia or cancer. And that initial work stream, when we thought about it, was destroyed, disrupted by the pandemic. And then Dr. Ian Pemmin handed it over to Dr. John Morris and it landed beautifully with you as you know, to lead that guidelines with Professor Morris Gordon. So I guess what we might do is just structure the podcast and think about sort of why do we do surveillance, when do we do it and how do we do it, and we might even touch on who should be doing it. So maybe just to ask you to help us understand why do we actually do surveillance? And you've already explained a little bit about the population risk or the IBD specific risk here that helps influence that program for us.
[00:04:41] Speaker B: So I think historically we've always felt that we were going to prevent IBD related colorectal cancer and that's a good aim. But I think there are challenges to that.
And certainly the data suggests while surveillance and that this is thinking about three yearly surveillance, there is some data that it reduces risk of developing colorectal cancer by about a third, it reduces death from colorectal cancer by about 2/3. And when you look at the data, the patients who are on surveillance are patients are developing early curable colorectal cancers, and the patients who are not on surveillance are developing advanced colorectal cancers and dying. Therefore, if a cancer develops on surveillance that's still early and curable, this is not a surveillance failure. But the corollary of that is that potentially we can't prevent all of the cancers that are developing. The biology of IBD associated colorectal cancer is clearly different in molecular genetic terms to sporadic cancer, and it is probably substantially faster. Equally, we're trying to detect subtle dysplastic lesions, which are the ones that are IBD driven colorectal cancers that there is a risk of missing and therefore cancer developing in between. And we can see that a little bit in the post colonoscopy colorectal cancer data, where patients with inflammatory bowel disease have a post colonoscopy colorectal cancer risk that is six times that of the sporadic population.
And while there are methodological reasons, because we scope them quite frequently, why that might be the case, nevertheless that probably does reflect that we can't beat the biology.
[00:06:29] Speaker A: And I think that's an interesting point to think about as opposed to cancer prevention and detection and how that actually aligns. And I think one of the things that maybe we need to focus on as a community is actually we're trying to detect cancer early because the biology is different. And for us to actually change that biology, we'd have to work a number of years backwards to work at what time point we can actually intervene with the way we actually treat disease optimally to actually stop cancer from developing in the first place. So I think that's nicely summarised why we actually do surveillance and the purpose of surveillance, I can maybe just push it a little bit and say, when should we start surveillance?
[00:07:10] Speaker B: So this is difficult. I mean, historically we had the Eden et al meta analysis where we saw a sort of inflection point at about 10 years.
But when you look at the data in that meta analysis, the sort of midpoint of it is sort of the 1950s and 60s, so that very, very different to our current practice.
So I think the key thing is we should choose that the start point is the start of symptom, not from where you get diagnosis. So if you've had symptoms for eight years, you're already ready for surveillance.
Now, why we chose eight years.
Other guidelines have chosen somewhere between six and 10. And we think that you need sufficient inflammation to drive your cancer risk and therefore to some extent it's a slightly arbitrary number. Again, if you look in the for instance, Team Jess population based work, the cancer risk only starts to become significantly above population population risk out to maybe 12 or 15 years.
But equally there are some patients perhaps who've had kind of slow burn disease, where we might not really have known and they seem to develop cancer early.
Equally, patients with psc, clearly the risk and that kind of curve divergence of cancer risk starts quite early. So they're on surveillance from their disease inception.
[00:08:35] Speaker A: And I think that's really a neat way to think about it. It's been very clear in the guidelines this time that we start at eight years from the onset of symptoms, taking into account that burden of disease people have before they get diagnosed. But for psc, we do it at diagnosis and that's because we believe that PSC in itself is an independent risk factor for colorectal cancer.
What about stopping surveillance or suspending surveillance? Because that is something I think we have to consider firstly, because as you've done rightly demonstrated that cancer risk is not the same in everybody, it's dynamic. We've also got a huge number of patients now who will have had disease for a number of years. And if you estimate that from a population perspective, I suspect about half of the population in the UK, which there's about half a million that have IBD, I suspect, you know, 250,000 patients might be in need of surveillance.
And you've also then got to think about someone's frailty index and whether they actually receive any benefit from going through regular colonoscopies and the burden that gives to patients and services.
So I guess the new thing in this guidelines is we've started to think a little bit about how we risk stratify better. And part of that we've kind of started to discuss when to stop surveillance. So I wonder if you could maybe elaborate that on a little bit.
[00:09:50] Speaker B: So I think absolutely. So fundamentally, surveillance is about trying to improve patients quality and length of life, as are practically all medical interventions. And so if patients are are frail and they have well controlled disease, they've got a low risk of developing cancer, they've got an increased or low risk of developing cancer in their lifetime.
But I think we substantially underestimate the burden of surveillance colonoscopy. It's not the patients don't like surveillance colonoscopy. Patients hate surveillance colonoscopy putting elderly patients through relatively high risk procedures with bowel prep and sedation, if it's not absolutely clear that it's going to offer them benefit in their lifetime, is not good medicine.
And so we need to think about, you know, or we need to move away from kind of sort of rote following of surveillance guidelines. See the patient in front of you. There's strong emphasis in the guidelines that this should be. These are decisions to be made with patients and that we take into account what is their realistic life expectancy, what are the risks for that particular patient if they have renal failure or significant cardiorespirit disease, what are the risks of them having repeated colonoscopies and what are the benefits? And we know that for patients with well controlled disease who haven't got dysplasia or other significant risk factors, actually their risk is very low if they have population based risk. If you are in the population, you get 75.
Actually, we don't really recommend further surveillance for you. And so equally in our IBD cohort we should apply the same logic.
[00:11:40] Speaker A: And I think that's a really good way to think about it, applying that same logic. I suppose whilst we don't have direct evidence from randomised controlled trials, we do have evidence from the work that's come from St. Mark's and from other. I think the Danish team have produced some information that allows us to think about risk. Could you maybe elaborate on that a little bit?
[00:12:01] Speaker B: So I think you're alluding to Matt Rush's recent work on the thinking about the risk of polypectomy in patients with limited life expectancy. And I think this has been a super helpful piece of work that essentially matches up your risk of dysplasia becoming cancer versus your risk of having a severe adverse event.
And that means a kind of readmission to hospital type event for patients who come for colonoscopy and therapy. And it's with and without anticoagulation.
And you know what that shows is for certainly for many older patients who are carrying comorbidities, measured by the Charleston Comorbidity Index, that actually risk of intervention rapidly starts to exceed the benefits in terms of their risk of colorectal cancer. And while that's not directly applicable to IBD dysplasia, I think conceptually it's a very helpful way to see it because I think doctors underestimate the risk of intervention and they overestimate how long people are going to live with good quality of life.
[00:13:07] Speaker A: Yeah, and I think that's beautifully coined about how we maybe need to start thinking about the surveillance programs in inflammatory bowel disease, because I think there's going to be a mismatch between demand and our capacity and the perceived benefit of this.
So thank you for summarizing that. And I think aspirationally I would love us to have that kind of framework in that paper, thinking about someone's frailty index and the benefits or the risk of cancer over time.
So I guess what I might ask you to then maybe talk about a little bit is about how our cancer risk estimation is different this time compared to what we did in the previous guidelines.
[00:13:46] Speaker B: So historically we've mainly had data on single risk factors. And Matt Rutter beautifully kind of corralled those into a series of low, moderate and high risk groups.
And then from that it flowed how frequently you would get surveillance with lower risk groups having five years, then moderate at three years and high risk at one year. And at that time there was almost no multivariate analysis available. Although it's clear just from first principles that those risk factors must interact.
Inflammation, previous dysplasia, age, sex, other things post inflammatory problems and strictures.
And so in the current guidance we've looked again at those single risk factors, tried to use more modern data because again, some of that data goes back well into before the 1990s, which doesn't reflect modern practice and where possible use multivariate models. But that still is problematic that you're broadly getting a single risk factor. It's the top trumps thing.
What's your best card? And that's what defines your surveillance interval.
And so it was very exciting, just as the guideline development group was gathering that a Dutch group led by Baz Oltenburg produced a multivariate risk score that included eight different risk factors and used them all together.
And rather than that feeding into a surveillance interval, it just gives you a percentage risk. So in the paper they enabled you to calculate your 5 year or your 10 year risk and you can adjust the variables so as patients, diseases progresses over time, maybe they get worse inflammation or they develop dysplasia. You can include those things so that their risk level changes and potentially their, their surveillance interval. What the paper didn't do was make that clinically, you know, didn't enable us to operationalize it clinically. And therefore part of the task of the guideline committee was to say at what levels do we consider risk to be high enough that we should trigger three yearly surveillance, one yearly surveillance, or even high enough that actually, you know, surveillance is inappropriate and we should consider colectomy.
And so there was a risk thresholding exercise that's actually quite challenging because you have to do it before you see the data to try and reach risk thresholds for advanced colorectal neoplasia that trigger certain surveillance intervals. So that was one challenge. The other part is that essentially the model that the Dutch group produced is on an Excel spreadsheet and that's not usable in clinic. And therefore we built an online risk calculator that essentially gives you an access to a cut down version of the model. It only allows you to look at the five year advanced colorectal neoplasia risk and in areas where the data set was quite thin.
So for extremes of age, we didn't have many 90 year olds with inflammatory bowel disease. Equally beyond 30 years, we don't have much data for more than 30 years surveillance. So in areas where the data set was thin and confident intervals would get wide.
We've restricted it, but it does otherwise.
It will allow you essentially to use that model by entering the risk factors with little radio buttons and then it will output a five year advanced colorectal neoplasia risk. What it doesn't do is output a surveillance interval and deliberately so because there are other factors to consider. You'll see on the flowchart, there are special circumstances and equally the risk model doesn't include the risk of first degree relative with colorectal cancer.
So you need with the patient to sit down and say this is your five year risk. These are the other factors we would consider and we think this would then lead to, we could consider a three year or a one year surveillance interval. Critically, it is quite likely that this will not be the same as the top trumps interval. So it's a different methodology and by combining risk factors, actually you get a much more precise estimate that is personalized to the patient. And we think probably the guideline committee supported this as our preferred strategy, but it's a big change. And so both options are available and that we hope with time, as people get used to multivariate risk calculation and there is further validation that we move strongly towards that as our future strategy.
[00:18:42] Speaker A: For somebody who likes data, I actually like the fact that we can actually translate our clinical experience and skills into that risk thresholding exercise where we came out with percentages about either odds ratio or hazard ratio or the actual absolute risk that somebody has for cancer. And then I think it's very unique that the work that you actually and Gaurav had led from Oxford, to be fair, has transformed that information into an online calculator because it becomes immediately, immediately clinically useful for everybody. I guess what you're saying is that whilst we prefer that model because it integrates a number of different risk factors, it is, you know, a difference of what we were doing before. And so it was always important for us to try and provide the two different approaches. So our high top trumps model goes for the odds ratio or the hazard ratio over population based risk that we understand from patients in ibd. Whereas the multivariate risk category is much more personalised to the patient and gives you, I guess, an, an absolute type risk for that patient. Would that be a fair summary?
[00:19:42] Speaker B: Summary, that's the kind of dichotomy that you get.
And certainly quite a lot of experience with patients suggests that this idea that it is precise and personalized is quite appealing and particularly that it also uses present day data. So the idea that for the multivariate risk model, the data is actually relatively modern, whereas for a lot of the single risk factors it goes back quite a long way. And even though we've tried to update it, some of the data still perhaps reflects practice from a different era.
[00:20:19] Speaker A: Yeah. And I think the feedback that we've had from the community so far, both in the UK and far afield, is that they do actually like using the calculator. We've planned a webinar to go through some of the more detailed information about how it's built, the limitations as you've discussed some of them, and where we might go in the future with this. But I think it's certainly the direction of travel, certainly for a complicated disease like ibd, that is dynamic and changes over time. And so this is something that actually I think is very welcomed by many in the community.
If I maybe go on and then just ask you a little bit more technical aspects of some of the different things that we've talked about. So we've talked about, I guess, who should get surveillance, why we actually do it, the purpose, the cancer risk, stratification, how should we actually do it? But this won't necessarily include any of the endoscopic procedures. But how should we actually do surveillance? What would be the two or three sort of key messages that you would want the audience to be aware of and use to actually implement in the clinical practice.
[00:21:14] Speaker B: So I think that there have been a few changes kind of around endoscopy. Certainly thinking about bowel preparation, it turns out, you know, patients don't like having surveillance colonoscopy, they really, really don't like it.
And one of the things that they find most distressing is the bowel preparation.
And so the guideline contains a new meta analysis that looks at bowel preparation. And I think that there are a couple of key messages that come away from that. That low volume pegs, so 2 liters or less equivalent cleansing to 4 liters, but much better acceptability.
And then there are some new bowel preps out. So pica sulfate or oral sulfate based, which interestingly so this is data that post date the ESG 2019 bowel prep guidance and in those studies so comparing 2 liter PEG versus oral sulfate versus or picosulfate, again equivalent cleansing, but maybe a bit more tolerable, so easier to finish the prep. And so this is not, you know, we're not trying to choose one prep or the other, but to give patients a range of choices, volumes, flavors for something where they can find an acceptable prep for their procedure.
And you know, fundamentally without good prep, surveillance is impossible and futile.
So we want them to have good prep first time, get surveillance done, hopefully forget about it for a few years.
[00:22:42] Speaker A: That's great. That's a very key message for us to focus on and try and improve overall. What, are there any other key aspects that you'd like people to take away?
[00:22:50] Speaker B: So I think perhaps one of the controversial bits of the guidelines is about taking in quadrantic biopsies. And I know many people have, I think, felt beyond quite sad that this seems to have reappeared.
And you know, part of the reason it's reappeared is because it is clear that even with chromo endoscopy and targeted biopsies, there are still some patients, they tend to be high risk patients who benefit in terms of displays detection from additional quadrantic targeted biopsies. And the two key groups here are patients with PSC and patients with previous dysplasia where yield is increased. Part of that may reflect the pathologist slightly changing the goalposts on what counts as dysplasia. So this idea of non conventional dysplasia that can be very subtle and is often endoscopically invisible, if we're going to detect that, particularly for PSC patients, taking biopsies is critical.
And so many people have felt that's a retrograde step. But I think the data, there are a number of studies that support that fairly consistently.
And in fact that's not a huge proportion of your IBD patients. So the combination of patients with PSC and patients with previous dysplasia is probably only 10% of the surveillance population. So we're not saying you have to take quadrantic biopsies every time.
Still, probably chromal endoscopy with high definition white light is our optimal detection technique with targeted biopsies. But in this small group, it looks like there is additional value in quadrantic biopsies.
[00:24:35] Speaker A: Yeah, I think that's a very good point. I guess the other sound bite is just to say that we still want people to take biopsies for disease activity assessment, because I think that's something that's often just forgotten when you're doing a surveillance procedure. There's no targeted lesion that you need to biopsy, but you still need to remember to take some biopsies from the right, left and rectum for disease activity, because that will help us inform the future of what the next surveillance would be. Especially if we're going to use histological inflammation grading to actually inform that.
You're going to have another podcast with Professor Bhandari talking about the endoscopic modalities and sort of how you manage dysplasia.
If I can maybe just ask you, who do you think should be doing surveillance?
And I think the other new thing about these guidelines is that we did actually consider service provision and we did this time round think about or just introduce that topic, that we need to have some training or teaching in this aspect. So who do you think from your experience and who's someone who's done lots of endoscopy, both in IBD patients and non IBD patients, and that experience you bring, who do you actually think should be doing these procedures?
[00:25:43] Speaker B: So I think, as you allude to, we should be thinking about an IBD surveillance service. It's not about individual endoscopists, although they're important. So it's how you run your service and whether everybody should be delivering colonoscopy as part of an IBD surveillance service, or whether it should be restricted to a smaller group of individuals? And I think, I think certainly the guideline development group felt that possibly a degree of restriction probably is appropriate. You do need to have appropriate training.
Even if you can technically do dye spray in the sense that you can apply the dye to the colon in a consistent manner, you then have to have the experience to interpret those images and turn that into either biopsies or a section or a strategic management plan.
Historically, I think it's fair to say training in IBD surveillance, to say there's not much of it. It's been very ad hoc and you're lucky if your mentor happened to do it for you. But in terms of structural training, there is none. The only real piece of training, Marietta Ikichi has produced an optical diagnosis web tool that certainly is evidence based in terms of improving performance and can be recommended. But I think it might be something for JAG and the BSG to look at whether we actually need training and not necessarily accreditation, but appropriate experience.
And again, one of the things that patients want, they want pain control, they want good communication, and they want to be confident in the technical skills of the endoscopist doing their procedure. So to deliver what patients want, we need to be appropriately trained to deliver that service as probably a smaller group of endoscopists. And just on that, and I know this is a point, Matt Rutter feels very strongly that not only is this, it's actually quite one of the most challenging diagnostic exercises, a badly scarred post inflammatory colonial that you've got to examine and find the one bit of dysplasia and feel the post inflammatory polyps.
It's hard work. It's tiring whether we should have a Full list of 4 IBD surveillance colonoscopies on a list, because you do need a bit of extra time.
But equally, the people who are doing IBD surveillance colonoscopy, a bit like doing family cancer surveillance, you need to understand it's not about this colonoscopy be, it's about their lifetime of disease. And therefore it is critical that you don't rough the patient up and give them a bad experience.
And so that means doing a technically good endoscopy with perhaps underwater intubation and position changes.
But critically, you just need to give a lot of sedation.
So I start in titrated doses now for pretty much everybody with ulcerative colitis or Crohn's disease. When I'm doing IBD surveillance, I start with 5 and 100. And if there's any indication that the patient's not enjoying it, I give more sedation. And I think I'm reasonably technically good colonoscopist. But the patients have had significant bowel inflammation. If they have visceral hypersensitivity, being technically good is not enough that they actually need proper amounts of sedation.
And we should consider Propofol if patients can't have a comfortable examination, because they're going to have to have this again and again and again if you have PSC or annual surveillance. So you've got 40 colonoscopies to have.
But I think there is very clear data that patients find the whole process Distressing, they blame themselves, they feel loss of control, but critically, they're very worried about pain.
And I think we seriously underestimate this and I think the data supports that.
And so you just, you know, if you think you're giving enough sedation, just give a bit more and have a very low threshold to go further, even beyond 5 and 100, assuming, you know, the other physiological parameters are okay. And equally think about, for patients who are still finding it difficult, think about propofol and critically ask your patients what their experience is. So this idea, which is quite strong in the guidelines, in fact very strong and in fact is the idea that we should collect patient reported experience measures. So that essentially means, you know, ask giving them a questionnaire to do once they've, once they're back at home, you can use a validated questionnaire like the Newcastle IBD endoprem, which is quite long but covers a lot of ground. It doesn't have to be every patient, so it's not going to destroy your service by having to do this, but once in a while for all of your IBD endoscopists and therefore individually and as a service, to have feedback on what the patient experiences and then to take action on what the feedback is. So if patients are still saying, it's still hurting me, and pain is a big problem, even if that's in a reason, you know, if it was 20%, but if you have to have a colonoscopy every year and 20% of the time it's going to really hurt, I don't think that's not really acceptable. It's going to be very hard to get people to come back. And if people don't come back, that's how they get cancer.
[00:31:15] Speaker A: And I think that's a very well made point, is that we need to make sure that the patient experience actually from their perspective, is a good one that we can offer. And just to be clear, I guess when you say 5 in 100, you mean 5 milligrams of methazelam and 100 of fentanyl.
[00:31:29] Speaker B: Yeah.
Or equivalent.
[00:31:32] Speaker A: Or equivalent. And I think just for readers or sorry, listeners who may not be aware when we talk about Professor Matt Rutter, he is the clinical chair of jag. JAG is a joint advisory group in the UK who are the organisation that sets standards and quality for endoscopic procedures. And as you've shared with us, we don't have one specifically for inflammatory bowel disease at the minute.
[00:31:58] Speaker B: If any listeners are looking for a little project, this would be A great one to get started.
[00:32:03] Speaker A: Done. Absolutely. So I guess that's been a really comprehensive discussion about our guidelines. I'm sure there's lots else that we've not been able to cover.
Just some final thoughts from you. What would be your final take home message from all of this that we've discussed?
[00:32:17] Speaker B: I think one of the things that came out amazingly strongly in the guidelines is this idea of concordance.
So it's not about telling patients to attend, it's helping patients be concordant with their surveillance interval. And if you look across international data, patients only turn up the appropriate surveillance time, about half the time.
So we need the entire IBD team. So that means you as the clinician, your IBD nurses, your medical secretary and the endoscopy booking team, all to help patients attend on time because we know that there is no cancer prevention if the patient doesn't attend.
[00:32:53] Speaker A: Yeah. And I think that's a fundamental point, isn't it? Is that we need to restructure our services, our expectations, patients expectations, to actually deliver an IBD surveillance program that's actually fit for purpose.
So we also asked ChatGPT what they thought about our new guidelines. And James, do you want to tell them?
[00:33:11] Speaker B: I thought they're very complimentary. They said overall improvement, more personalised evidence, rich endoscopy, focused and patient centered. And certainly that last bit I think is critical and actually that's not a bad summary.
[00:33:24] Speaker A: Okay, yeah, and I agree with that too. So thank you for joining us and hope that you've enjoyed that podcast. As I said, there will be a second episode that will be more focused on the endoscopic and technical aspects of my managing dysplasia and shared decision making.
Just again, a plug. We do have a cancer estimation webinar that's planned and I hope you'll be able to join us. If you're not able to join us live, then please do watch it on demand. So, Professor Rees, thank you for coming to speak with me today. I've really enjoyed that conversation and hope the listeners enjoy it too.
[00:33:50] Speaker B: Jahida, thank you, it's been a great pleasure.
