00:00:00: Hello, everyone.

00:00:01: My name is Aglia and I'm the host of UG Talks, educational and hopefully fun dive into GI world and beyond.

00:00:07: We're very happy to have you with us for another exciting episode.

00:00:11: So today we're having a really cool flashback to the summer European Pancreatic Club Conference in Düsseldorf.

00:00:18: There we had the fortune to catch the pancreas master extraordinaire, continent jumping Italian surgeon currently running surgical oncology division in Denver, Colorado.

00:00:29: And the Chief of the Highly Anticipated Bank Continental Guidelines on Pancreatic Cystic Neoplasms, Professor Marco Del Carro.

00:00:37: Enjoy the moments from the summer.

00:00:40: So, Marco, you're now leading this global massive effort into new guidelines for Pancreatic Cystic Neoplasms.

00:00:48: Why the hell do we need it?

00:00:50: Because the Kyoto Guidelines just were published on IPMN.

00:00:55: There are new American guidelines.

00:00:57: Okay, the Europeans are quite old, they need an update, but why do we need global ones?

00:01:02: Well, thank you.

00:01:04: first of all, this is a very interesting question.

00:01:06: Number one, the Kyoto Gate Lines include only APMNs.

00:01:10: Those Gate Lines try to give guidance for all kinds of assistive tumor dependence.

00:01:16: That's one difference.

00:01:18: Also, I think that one of the problems that we face in the past has been having so many different guidelines.

00:01:25: And it's even true that, I mean, several of those are not so different.

00:01:30: But we are talking here about an extremely complex group of diseases to treat, even for experts, and having around guidelines with sometimes more difference, sometimes bigger difference.

00:01:43: I think it creates a lot of confusion.

00:01:46: But at least let's say it doesn't facilitate so much the work of our colleagues, especially the one that maybe they are on dealing every day with two more patients.

00:01:54: So I think trying to have a common ground that say designing together the rules of the game is probably better than just continuing to write in different guidelines.

00:02:05: OK, so we need a global one.

00:02:08: But how does it translate into different people?

00:02:10: Because these are like three continents, right?

00:02:13: different populations, different traditions, different technology, different availability of tools diagnostic.

00:02:20: How does it combine all these aspects in utilizing those guidelines?

00:02:25: Yeah, you're completely right.

00:02:27: I think one of the major challenges, more than tradition, our goal is to create global guidelines that are trying to homogenize diagnosis, treatment management of those patients.

00:02:40: But I agree with you.

00:02:42: that probably there will be problem of applicability, based, for example, on availability of resources.

00:02:49: And that, of course, is a problem that needs to be addressed.

00:02:53: What I want to try to underline here is that what we want to offer is what is the best of the evidence, which probably is not extremely high.

00:03:01: We don't have perspective on the mice trial in this topic, but what is the best level of evidence to treat those patients?

00:03:09: Obviously, you know, the guideline are not the low.

00:03:13: And I would not be surprised or I would not be even disappointed if there are people that feel that sometimes they cannot be out there and completely to the guideline.

00:03:23: At the end of the decision remaining doctor decision, patient decision, but we want to try to offer the best we have on evidence on managing this patient.

00:03:33: And that's it.

00:03:34: And then, of course, clearly, if there are situations in which you cannot fulfill completely those criteria, you can't.

00:03:42: But I think trying to design the best of the evidence is a duty that we should try to complete.

00:03:49: Yeah, I think you touched on the point that every guideline has a disclaimer at the bottom that this does not substitute your thinking.

00:03:58: But it's true because, I mean, probably there are no guidelines that can take in consideration every single aspect of the patient care, the patient characteristics, or the cystic characteristic.

00:04:09: You know, it's very difficult to copy and paste a guideline in a person.

00:04:12: Definitely.

00:04:14: And so I think this is not just a legal statement.

00:04:16: I think it's the truth.

00:04:18: And I think that every doctor at the end has the full responsibility to discuss with the patient whatever is needed.

00:04:24: And the patient has the full right to say I agree, I disagree, I want to have a second opinion, third opinion.

00:04:30: So again, no one of us has the truth, especially in argument with low evidence, trying to offer the best we can to guide people, I think is a good initiative.

00:04:40: What do you think about the guidelines that include the second and third best options?

00:04:45: If A is not available, let's do B. It's of lower quality.

00:04:51: Yeah, so here you touch a point.

00:04:52: There are, I think, choices.

00:04:53: when you decide to... through a project.

00:04:56: And I think when you go through a quite rigorous evidence-based methodology, I think it's extremely important that you remain very aligned with this methodology.

00:05:08: You know, there are many guidelines that are more expert opinion, and I have to tell you, sometimes they're good because... So, I'm not undermining the value of any of those.

00:05:20: Once we decide to do this choice, we did because you mentioned before, and I agree with you that there are very different practices across the world, sometimes even in the same continent, that more related to the practice, they're really...

00:05:37: Practition?

00:05:38: And then it becomes really very difficult.

00:05:40: together, if you want to really do with people across the world, putting together people with different practice, different beliefs, right?

00:05:47: Unless you really have a common background, which is, I mean, methodology.

00:05:50: And that's, I think, is what we try to do here.

00:05:52: But if you're sticking to great, where does belief come?

00:05:56: And where is the dispute then?

00:05:59: If it's black and white, if it's great?

00:06:02: Well, first of all, yes.

00:06:03: Well, you're right.

00:06:04: But take in mind that many of the questions we'll probably have a relatively moderate or low level of evidence because we don't have prospective randomized trial.

00:06:15: So I mean, that's, I believe, and again, I don't have the final version of the guidelines.

00:06:21: So I'm just guessing, but I believe that it would be very difficult to find a super high level of evidence in many aspects.

00:06:28: And then the part of the process would be the expert vote on the agreement on the single point.

00:06:34: That's, I think, is an intriguing part, because then, I mean, it's adding probably what you are telling now.

00:06:40: So what is the opinion of people that are expert on the statement that the same group of people basically made, right?

00:06:46: And this, I think, is very, very important.

00:06:49: But it's so peculiar because the statement comes from the evidence, and evidence is graded, the risk of biases assessed, so...

00:06:56: It is very true.

00:06:58: But that's, I mean, telling you somehow what is the practice that maybe could be changed.

00:07:04: But once we have enough level of evidence to say, OK, that's something we need to go in another direction.

00:07:09: But the reality is that building evidence takes time.

00:07:14: You know, when we speak about now, let me speak about the more common cystic lesion, so the APMNs.

00:07:20: I mean, it's a relatively new disease.

00:07:22: Twenty years?

00:07:23: Correct.

00:07:24: So what I'm saying is that it is a very difficult disease to randomize because of the clinical history, right?

00:07:30: You have a rare number of events.

00:07:33: And you have a long progression time.

00:07:36: So whenever you want to do a prospective study around the mice trial, I mean, it's extremely difficult to have a statistical power to really demonstrate something.

00:07:45: That's why I'm not saying we will not do it.

00:07:47: I'm sure we will, but I'm not sure I will be in a podcast at the time when you have a strong evidence in this topic.

00:07:54: Who has the patience to see the development, the natural history?

00:07:58: Well, that's one problem.

00:08:00: I think we can have the patient, but we need the time.

00:08:03: And that's, I mean, we cannot buy.

00:08:05: We need to wait.

00:08:06: OK, we'll see you then.

00:08:07: Let's meet in ten years and see where this is at.

00:08:11: So you already touch upon one thing that there are not many randomized control trials.

00:08:16: I mean, surveillance, there are some.

00:08:18: what to do.

00:08:18: But at least the European, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of the year, in the year of Do you have the feeling that the guidelines will go into more liberal route?

00:08:52: I have the feeling that everything we added to our knowledge will be part of the guideline.

00:08:57: And actually, I have the feeling, I'm sure, because that's the methodology we use it.

00:09:01: So everything will be included and weighted in every kind of answer we give to the guideline.

00:09:07: I want to add you one thing.

00:09:08: This is part of the issue that we discussed before.

00:09:12: There are different kinds of bias that you can, you know, identify in different kind of study.

00:09:17: For sure, the surgical series as bias, you're right, is a selected population of patients.

00:09:23: They have also an advantage.

00:09:24: You have an installment.

00:09:25: So whenever you have a population, a quarter of people, you fall over time.

00:09:30: There are three major problems as well.

00:09:33: One problem, how many of those you think are IPMN are IPMN?

00:09:37: We have studies showing that the diagnostic error are twenty, thirty percent of patients we see with cystification.

00:09:42: Those studies are maybe a little bit dated.

00:09:44: Maybe today is a little bit lower, but still is significant.

00:09:46: I'm sure about that.

00:09:47: Number two, are you sure that, you know, one patient that you see for five years will not develop something in ten years?

00:09:57: I'm never sure.

00:09:59: Exactly.

00:09:59: So the follow-up of those studies, some of those studies.

00:10:03: quite short if you consider the clinical history of cystic lesion.

00:10:07: And I go to the last and third point that I want to discuss.

00:10:11: I think, you know, even in terms of sample population, which is the ideal number to check the number of events in a disease that apparently has an incredible prevalence.

00:10:22: And then you see study, maybe including a few hundreds of patients, which compared to the prevalence in the population.

00:10:28: If the prospective study if the prospective study from Germany is true, represents really an extremely small, simple size.

00:10:36: Now, saying that is clear, that if the prevalence is very high, and we have an instance of pancreas cancer quite low, we know that very minority of those patients will develop cancer, right?

00:10:46: So that's, I mean, I think it's probably one of the few things I personally think that is quite clear.

00:10:52: But what I'm saying is that I agree with you, having more of this observational study is extremely important, but that doesn't cut some of the important bias that we have in every study regarding pancreatic cysts and especially apiamin.

00:11:06: At least this is my personal opinion.

00:11:08: Okay, then what's your, now you touched about the increased risk after ten years.

00:11:13: There's accumulating evidence on discontinuation on small stable cysts, but we know that with time the risk increases.

00:11:21: It's time-based risk increase.

00:11:24: So how can we discontinue surveillance after five years?

00:11:29: We have an incredible team of some of the most expert in this field for the global guideline that is working on this topic.

00:11:36: I'm sure they will give us a very good answer.

00:11:39: Now that we know that the guidelines are based on the other instruments we have, also on what we extrapolate from it and what we think or we believe, not even the data, actually black or white.

00:11:53: Okay, we have a consensus, we agree.

00:11:56: But how does it translate into everyday practice?

00:11:59: I think the study from your run guidelines on musinocystineoplasm did a systematic review and found that the actual risk of malignancy is much smaller than it was previously detected and it's like sixteen percent.

00:12:15: But what do you do with those sixteen percent and the patient when the counterpart is a Whipple?

00:12:21: most probably with one third of people having severe complications.

00:12:27: So this is a very intriguing question.

00:12:29: And I think that this question is following, you know, he's actually explaining very well how I think creating a line, but creating even working group is so important for making the next guideline even better.

00:12:43: So I don't know if you know the full story and you know, I full statement, I speaking my best knowledge, maybe I'm wrong in that, but I think the first, the very first guideline in which we recommended to do not reject every MCN were the first European guideline of the year.

00:13:05: As per opinion guidelines, so basically it was not really an evidence-based process in which basically we told, well, let's treat them like IPMN, at that time, if you remember, dimension was one of the most important criteria.

00:13:20: Actually, we went to four instead of three, both for IPMN and MCN.

00:13:24: That has been probably the first recommendation, saying we don't need to reject all MCN.

00:13:30: Based on a few data in literature, well, some data in literature.

00:13:36: Since then, we continue to work together, creating more evidence in the year.

00:13:41: that has been again confirmed by the... in the European evidence base at this time, guideline on assistive tumor.

00:13:48: And again, some of us still continue to investigate the topic and trying to give more evidence.

00:13:55: Now, MCN we know is rare.

00:13:57: So clearly, I mean, they are already so spetty serious.

00:14:00: And even if we say large, probably are not large enough to say, really, we are sure under percent.

00:14:06: Complication-wise and cost-benefit, I think that, so first of all, majority of the MCN It's not that we're policy distal because I'm most normally female body until of the pancreas Normally today down minimally invasive in many cases, but I think That you know, even if probably for many people of my generation still remains sometimes strange to recommend surveillance because a man for many years you're being teaching to remove all of them.

00:14:35: We have now quite a lot of data again not with strong evidence, but supporting the fact, most of these patients, if you follow at least up to four centimeters without any radiological concern or feature, is quite safe.

00:14:48: So I think we are learning and we are moving our target accordingly with the new insight that we have.

00:14:54: You know, one of the things that I hope and I really think would be probably one of the best things we can do in a new guideline, we put together more than a hundred experts across the world, several scientific society.

00:15:08: I think at the end of the guideline, we should consider the end of the guideline at the beginning of making this group continuing collaborating together and trying to understand which are the points with less evidence and invest together and create higher evidence for the next guideline.

00:15:24: Okay, so you're foolproofing your future.

00:15:28: Do you have a plan for an update already?

00:15:31: No, and I think you need to update when it's time to update.

00:15:34: Okay.

00:15:35: That is not an aspiring date.

00:15:37: I think I'm moving fast.

00:15:39: There are many area of medicine that are changing and maybe in the next year will give us much more insight on what we are doing, much more precise.

00:15:48: So, you know, we need to keep eyes open and whatever we feel there is something that we need to improve, that will be the time.

00:15:55: Do you think there will be biomarkers coming in the, let's say, the future five years?

00:16:00: I think we are entering in... this era and we're trying to enter in this era, I think that the future hopefully will be more and more based on, you know, on something measurable to give us, stratify for us the risk.

00:16:14: You know, I think so far, speaking about practice, the large part of the practice is based on quite traditional imaging and sampling.

00:16:23: There are some new tests that are there.

00:16:26: Let's see how they will perform it.

00:16:29: But I'm pretty sure that in the near future, we'll have more and more and even simpler, right?

00:16:33: I mean, the best would be take a blood test and say, okay, that's your risk profile.

00:16:38: That's what you have.

00:16:40: But it's quite scary if you know your risk profile.

00:16:42: It's like knowing when you are going to die.

00:16:45: Or maybe if you need an operation to avoid to die or not.

00:16:49: True, true.

00:16:50: But if you know all the risks that you have, You might opt for pancreatectomy if you know that you have a

00:17:00: possibility.

00:17:01: Well, if you really have a very trustable test, then you can argue that you can really pre-treat something before you risk to be too late.

00:17:11: The problem is that today, we don't know.

00:17:15: I want to be provocative in this idea.

00:17:18: Today, ideally, when you do an operation for an APMN, let's say, you hope I mean, probably the best timing is getting a patient at the level of high-grade dysplasia.

00:17:30: We know it's very difficult because at that point, it's quite high risk that you get even the patient in cancer, which is completely different situation, right?

00:17:36: But whenever you have even a patient with low-grade dysplasia, some of those patients may remain low-grade dysplasia in life.

00:17:42: Some of those patients may become cancer.

00:17:45: You don't really know, right?

00:17:46: I mean,

00:17:48: I

00:17:49: still believe that when you see some concerning feature, that normally associated with the risk of cancer, probably even if the histology is not there yet, that there is a good risk that this patient probably will go there.

00:17:59: So I think even the way we try to measure our performance today is very primitive if you want to use this term in the sense that really no one of us knows, especially at the very beginning, what would be the destiny of this system.

00:18:12: We know that when it's cancer, It's

00:18:15: too late.

00:18:16: Yeah.

00:18:17: But all the rest remains still an area where we argue, but we don't really approve in which direction would be one or the other.

00:18:23: So I think there is where I think the future potentially could be very useful in saying, okay, you have a cyst and we know, ninety eight percent of this cyst, ten years from now, two years from now, five years from now.

00:18:34: I mean, that's probably we cannot really state completely, but you have a huge chance would become a cancer.

00:18:39: Then I mean, you don't have so many problems to say to the patient, okay.

00:18:43: I think probably it's better to remove.

00:18:44: But the patient can say, no, I want to wait until, I mean, I see a patient, patient choice.

00:18:49: But I think, I mean, you know, I think this is really would be nice to understand who need to go one way with con gonad.

00:18:57: Coming back to your previous question, that's probably would be the moment, even in which very safely, you can say, okay, this patient doesn't need any follow up, right?

00:19:04: Or this patient need a follow up.

00:19:06: No, this patient better to go directly to surgery.

00:19:08: That's probably would be really something based on something more concrete.

00:19:12: Today is a statistical risk that we are analyzing on some data.

00:19:17: An average person, but also here's where the belief comes in.

00:19:22: I mean, if you have a pancreas, you have the risk for cancer.

00:19:25: And then if you have a cystic neoplasm, the risk is diverse, but it's for average person.

00:19:32: And how can you deal with that risk?

00:19:34: You don't know.

00:19:36: I think we'll discuss about that for the next guideline.

00:19:38: Okay, okay.

00:19:40: I think then this is a good point to end and there's a promise for meeting in ten years?

00:19:46: Well, let's meet again when the guideline will be out so we can maybe discuss more about the detail.

00:19:51: Okay, because you're very sparse with information.

00:19:54: We really wanted a sneak peek, but okay, okay.

00:19:58: Well, when they are published, I will be more clear with the information.

00:20:02: Okay, thank you.

00:20:02: Thank you so much, Marco.

00:20:04: It was incredible.

00:20:05: Thank you for running this guideline that we are so keen to see the results of.

00:20:09: Thank you very much.

00:20:11: See you after the publishing then.

00:20:13: Absolutely.