"Pancreatic Cancer Early Detection and Prevention -The sweet promise of family and pancreatic cysts” and "Alcohol and Cancer"

May 17, 2022

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Yale Cancer Center Grand Rounds | May 17, 2022

Presentations by: Dr. James Farrell and Dr. Vasili Vasiliou

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00:00Good afternoon everyone. Welcome to
00:02the Yale Cancer Center grand rounds.
00:06Today we have two fantastic speakers both
00:08who are in the developmental therapeutics
00:11program of the Yale Cancer Center.
00:15And why don't we get started?
00:16I'm delighted to introduce
00:18Doctor James Farrell,
00:19who is a professor of medicine in
00:22the director of the Yale Center
00:24for Pancreatic Diseases.
00:25He's an internationally recognized,
00:27expert and pancreatic disease
00:29treatment and research,
00:30and is known for his development of
00:33personalized therapy approaches for
00:35pancreatic cancer and early detection
00:37biomarkers for pancreatic cancer.
00:39He received his medical medical
00:41degree from University College
00:43Dublin and completed internal
00:44medicine training at Johns Hopkins.
00:46And a gastroenterology fellowship
00:48at MGH and Harvard Medical School.
00:51He then completed advanced Therapeutic
00:54Endoscopy fellowship training at
00:56mass General and Brigham and Women's,
00:58in addition to his clinical
01:00practice and pancreatic disease
01:01and interventional endoscopy.
01:03His clinical research has focused on
01:05early detection of pancreatic cancer,
01:07including studying pancreatitis,
01:09high risk individuals and pancreatic cysts.
01:12His translational research includes the
01:15development of personalized therapy.
01:16Approaches for pancreatic cancer
01:18and the evaluation of biomarkers
01:20and pancreatic disease.
01:22Delighted to turn it over to you
01:24Doctor Farrell and look forward
01:26to hearing what you have to say.
01:28Thank you.
01:29Thanks everyone and good afternoon.
01:33Thanks for the invitation.
01:34So we're going to talk
01:35about pancreatic cancer,
01:36early detection prevention this morning.
01:39It really is going to be an overview
01:41in the time allotted and kind
01:43of emphasizing some of the work
01:44that we've been involved with.
01:46Disclosures.
01:48So when you think about pancreatic
01:50cancer in terms of overall incidence,
01:51it's actually low down in the list,
01:53and maybe sometimes doesn't get as
01:55much prominence as other cancers
01:57such as prostate or lung or colon.
01:59But when you look at cancer related deaths,
02:01it jumps up the list,
02:02and it's probably around the
02:04third or fourth most common
02:06cause of cancer related death.
02:08So in 2022,
02:09it's estimated there'll be about
02:1162,000 cases and just under 50,000
02:14deaths related to it and has long been
02:17predicted and certainly on its way by 2030,
02:20it's expected to be the second most
02:22common cause for cancer related death.
02:25It also needs to be emphasized.
02:27The fact that yes,
02:28there have been improvements
02:29in the management and treatment
02:31of pancreatic cancer,
02:32but really,
02:33they have fallen short,
02:34although progress still continues
02:35to be made and just emphasizing the
02:38need for a better and improved early
02:40detection for this particular disease.
02:42If we're hoping to improve
02:44the overall survival.
02:45Now,
02:46there has been tremendous progress in
02:48the world of understanding cancer,
02:50biology of pancreatic cancer.
02:52Along the bottom,
02:53here is a normal progression through
02:55low grade and high grade dysplasia
02:57or so called pen and lesions to
03:00invasive pancreatic ductal adenocarcinoma.
03:03It always typically starts with
03:05the activation of an oncogene,
03:07and then it's been several
03:09well known characterized tumor
03:11suppressor gene mutations,
03:12including P53 and SMAD 4.
03:16It's also worth noticing that related
03:18to this is another entity of the
03:20pancreas called Ipmn or introductive
03:23papillary mucinous neoplasm.
03:24It also goes through a similar sequence,
03:27resulting in an invasive neoplasm
03:29with similar mutations, such as in K.
03:31Ras, but also some unique ones.
03:33Which is Gina Genas uncle
03:36Gene observation activation,
03:38but it's very hard to talk about.
03:43Carcinoma without without talking
03:45about the other disease of ipmn.
03:49It's also worth making the
03:50point that this progression,
03:51we think from the initial K.
03:53Ras mutation to the time of
03:55let's say metastatic cancer,
03:57is probably of the region
03:59of of about 11 years or so.
04:02And so this number is debatable.
04:03But basically it's a long time for us
04:05to try and intervene and understand
04:07what's going on during this sequence.
04:10However, it's also worth noting
04:12that in its early stages and pre
04:15invasive stages with pannin,
04:16it typically can't be seen.
04:18Radiologically,
04:18when an early stage cancer does arise,
04:21this can be seen by radiologic imaging,
04:25but in the time required to go
04:27from an early stage, resectable,
04:29surgically manageable pancreatic cancer
04:31to an advanced metastatic stage can
04:34be as short as one to 1 1/2 years, and so.
04:37At that point,
04:38the clock does start ticking.
04:40And it brings up the issue of missed cancers,
04:43interval cancers,
04:44cancers that may be seen on imaging
04:47with more advanced uses of of imaging.
04:50Now there's no shortage of biomarker
04:53signatures for early pancreatic cancer.
04:55This is just a selection of of some of these,
04:58and they all have very promising
05:00operating characteristics or AUC.
05:04So in the top left is a salivary
05:06based 4 gene panel of RNA that we
05:08worked with again comparing non
05:10cancers to patients with cancers
05:12with a very respectable AUC of .97.
05:17Below is a work of Anoop Sharma.
05:20He said who Jim looking at?
05:22DNA methylation markers?
05:23And this is a particular 4 gene
05:26cell free DNA methylation panel,
05:28again with very respectable AU C curves.
05:32We've kind of come to the age in
05:332022 where we now have the beginning
05:36of commercially available panels,
05:38not just for cancer in general,
05:41so you have heard of GRAIL and
05:42you've heard of cancer seek,
05:43but now Innovia has an imray pan candy,
05:46which is an antibody panel
05:49specifically for pancreatic cancer,
05:51and in the studies to date at
05:53least shows very promising AUC's
05:56for the differentiation between
05:57early stage cancer and control.
05:59And in fact,
06:00this is being currently tested
06:01in a high risk.
06:02Population the Pantheon One study
06:04in which we're involved with
06:07results of which will be out soon.
06:09But the problem is yes,
06:10there are all these great
06:12biomarker signatures,
06:12but they're not being applied or can't
06:14be applied to the general population.
06:16And this has to do with an issue of
06:19mathematics and the 1.6 lifetime risk,
06:21and the low,
06:22relatively low prevalence
06:23of pancreatic cancer.
06:25What that means is that even with a
06:27very good sensitivity and specificity,
06:29whereas you have a very high
06:31negative predictive value,
06:32you have a very low
06:34positive predictive value.
06:36And even as you increase the
06:38sensitivity and specificity of these
06:40tests in the general population,
06:42the positive predictive value
06:43only gets as good as about 20%.
06:46And what that means is that most of
06:48the positive tests that you're going
06:50to see in the general population
06:51will turn out to be false positive tests,
06:54and this is one of the major
06:55reasons why we haven't.
06:57Unraveled general population
06:59screening currently.
07:00So as a result of that,
07:01we tend to focus on high risk groups
07:03and the three big high risk groups
07:05which are these enriched groups
07:07that increase the prevalence of the
07:09chances of developing pancreatic
07:10cancer include new onset diabetes.
07:13And I'm not going to go spend
07:14too much time on this today.
07:16Shiraz Shari,
07:16who's kind of a leader in this area, spoke.
07:18Very passionate about this subject.
07:20Here at Yale several weeks back,
07:22but diabetes interplays with everything
07:24that we talk about with pancreatic system,
07:26family history.
07:27The other two high risk groups.
07:30So what about
07:31pancreatic cysts?
07:32So pancreatic cysts, and specifically
07:34a type of cyst called an ipmn,
07:36are incredibly common findings,
07:38incidentally, found typically on
07:40CT scans or Mris of the abdomen.
07:44We use a variety of imaging
07:47features of these incidental cysts,
07:49such as high risk stigmata,
07:51are they associated with jaundice or amass.
07:53Is the pancreatic duct,
07:55for example dilated,
07:56are worrisome features?
07:57Is there a nodule?
07:58Is there an intermediate ductal
08:00dilation of the main pancreatic duct is
08:02assessed greater than 3 centimeters?
08:04Is there a change in caliber?
08:05Is a cyst getting rapidly bigger over time?
08:09So we use these imaging features to try
08:12and better understand what's the risk of?
08:14This particular IP man having cancer,
08:18and so we think that overall
08:20there's a 1% chance per year of
08:23these IP amends developing cancer,
08:25and when we look at the imaging,
08:27one of the first questions that we
08:29end up trying to sort out is should
08:31these patients undergo surgery and so
08:33we use a combination of the imaging.
08:35But even with our best imaging in 2022,
08:38it's likely that anywhere in the
08:40region of about 60% of patients are
08:43undergoing unnecessary surgery,
08:44meaning that we are resecting
08:46low grade dysplastic lesions,
08:48not the high grade dysplastic,
08:50not the invasive cancer patients
08:52that we're really trying to find.
08:54And so this kind of begs for an
08:56improvement in this particular area
08:58and one particular area has been in
09:00looking at the role of cyst fluid,
09:02and so we have the ability with
09:05endoscopic ultrasound to pass a
09:07camera down into the stomach and
09:09sample the fluid in these cysts.
09:11And this can be very helpful for
09:12making the diagnosis of the cyst.
09:14Like is it an ipmn or some other
09:16type of precancerous?
09:18But it also has the ability for
09:19us to look at, for example,
09:21methylation markers,
09:22and this is very promising 2 panel
09:24marker that has a very good high
09:27operating characteristics for separating
09:28out low grade dysplastic system
09:30which we don't want to operate on
09:33and high grade dysplastic and cancer cells.
09:35So expect to hear more in time about
09:37these particular markers and SIS fluid
09:39as well as other even protein based
09:41markers in this particular field.
09:45The other issue with pancreatic
09:47cysts relates to surveillance,
09:49and so as we get better at deciding which
09:52patients shouldn't undergo surgery,
09:54it'll become obvious to people that the
09:56vast majority of these patients with I PMN
09:59nothing really happens them dramatically.
10:01Over time, they might get
10:03a little bit bigger.
10:04They're duct might get a little bit bigger,
10:06but their chances of developing cancer
10:09requiring surgery is incredibly low,
10:11but we're obliged to follow them,
10:13especially younger patients,
10:14because we're telling them your cyst.
10:16As a risk of developing cancer.
10:18And in that, the field of surveillance
10:20has really become a very complex issue,
10:22primarily because there's a lot
10:24of cysts involved,
10:25so it's estimated at about 6 million
10:27people in the United States.
10:28At least have some form of pancreatic cyst,
10:31and it's brought up questions of
10:32when should we stop surveying
10:34patients that have pancreatic cysts?
10:36Is there an age?
10:37Are there Co morbidities that we
10:39should say outweigh the risk of cancer?
10:41Is there any way of tailoring or
10:43having kind of a frank discussion with
10:45patients to kind of educate them on
10:47who needs surveillance and who doesn't?
10:48And is there any progress we could
10:50make in the realm of understanding
10:53the biology of progression?
10:54So we know for a fact that says do
10:57change at some says do change over
10:59time and some cysts will change
11:02even after periods of stability.
11:04On the flip side,
11:05we also know that stability,
11:06especially for small cyst,
11:08is a good hallmark, or it's not great,
11:11but it's a good hallmark.
11:12Nonetheless,
11:13in a variety of guidelines that are
11:14out there to help us understand who
11:16we should be following who we should be,
11:18stopping surveillance on the American
11:21Gastroenterology Association has
11:23made the recommendation that after
11:25five years of CIS stability that
11:28you should stop surveillance and
11:29this actually has been quite a
11:31controversial recommendation.
11:34I could choda one of the physicians
11:36in our research group had the
11:38ability to look at about 18 studies
11:41with over 10,000 patients followed
11:43for almost 60,000 patient years.
11:45And I could look at in these studies
11:47that have now long term follow up for
11:49patients with otherwise low risk IP men.
11:51So patients that we would typically
11:53just be following and he was
11:55able to notice that yeah,
11:56after five years or so,
11:59the risks of them developing progression
12:02is probably around 3% per year and the
12:05risk of them developing a cancer or an
12:08advanced lesion is about 1% per year.
12:11And when he looked at the
12:13subgroup of patients,
12:14so patients who were stable for five years,
12:17so this would be the group that we
12:18would typically talk about stopping.
12:20There's still a .2% risk per year
12:23of developing cancer long-term out,
12:25so we don't think that there's enough
12:27evidence right now to really be
12:30talking about stopping surveillance.
12:31What we do know is that there are
12:33subgroups of patients who we should
12:35be probably having a more intelligent
12:37conversation with,
12:38and particularly patients who
12:40have significant comorbidities.
12:42We had the ability to look at.
12:47440 patients that we were
12:49actively surveying at Yale over a
12:51period of about 56 months or so,
12:53and in that group of patients,
12:5644 patients died,
12:57but the vast majority of deaths
13:00on follow-up were not related to
13:03pancreatic disease, and in fact,
13:05when we took a cut off of a
13:07comorbidity index of four.
13:09So an index that takes in
13:11cardiac renal pulmonary issues to
13:13determine long term comorbidity,
13:15a cutoff of four.
13:17It's very good at predicting
13:18long term comorbidities,
13:20not related to pancreatic cancer,
13:22and so now we're beginning to have
13:25these discussions with patients
13:26based on their overall prognosis,
13:28not just focusing specifically on
13:30the issue related to their pancreas.
13:34This very useful tool that's now available.
13:36We actually have it on our high risk website.
13:39The PCD website is a validated
13:43tool that was initiated and
13:46validated in both Dutch,
13:48Italian and several US sites for
13:50looking at both the five year and
13:52the three year and five year risk
13:54of developing worrisome features.
13:56A high risk of matter if you
13:58have a a low risk branch.
13:59Strict IP men so you you as a patient
14:01are able to go on to the website.
14:03You're able to put in.
14:04The size of your cyst,
14:05for example.
14:06There's some other parameters like
14:08smoking is your SIS multifocal,
14:10and it's able to give you a pictorial
14:12representation of your risk of the
14:14cyst developing into worrisome
14:15features and high risk matters,
14:16so this is very helpful in
14:19discussions with patients overall
14:20and ultimately we would like to
14:22get greater numbers to to be able
14:24to calculate individual risk of
14:26developing an advanced neoplasia.
14:30But I think a key issue is also
14:32trying to understand at a molecular
14:34level what makes some sense
14:35stable for periods of time.
14:37What makes certain IP amends
14:39decide that they want to take
14:41off after five years and develop
14:43into an invasive malignancy?
14:45And to this end there was a need to
14:47understand IP mensys progression more.
14:50To date,
14:50there have been some limited data
14:52and the use of organoids derive
14:54some surgical resection specimens
14:56so patients who have gone to
14:58the operating room and people
14:59have been able to develop ipmn
15:02organoids for additional study.
15:03We've taken a slightly different approach.
15:05We were actually interested in the
15:07groups of patients that were surveying,
15:08so patients who do not go for surgery
15:11and using again endoscopic ultrasound.
15:13We've been sampling the fluid
15:15from these pancreatic cysts and
15:17generating organoid structures.
15:18This is very preliminary data,
15:20and these are some of the images
15:22that we are identifying similar
15:24to what we would see in organoids.
15:27To date we have studied 9
15:30patients with presumed ipms.
15:31They're all growing,
15:33they're all growing exceptionally slow,
15:35but we've been able to
15:36passage some of them as well,
15:37so this is a an interesting
15:39development to allow us to study.
15:41I PM and progression to maybe
15:43tailor approaches for individuals,
15:45and maybe offer interventions such
15:47as chemoprevention, so stay tuned.
15:51Now the other large area within the risk
15:55or the high risk of pancreatic cancer
15:57is your hereditary susceptibility,
15:59or your inherited risk of developing
16:01cancer pancreatic cancer raw,
16:02but we think that maybe about 10% of
16:04all pancreatic cancers are at risk for
16:07developing cancer based on a family history,
16:10and there's a variety of guidelines that
16:12we've been involved with specifically
16:13the CAPS guidelines to help us
16:15understand who we should be surveying
16:17and who we shouldn't be surveying.
16:18And very Simply put,
16:20there's a high risk group that
16:22carries a very high lifetime risk
16:25of developing pancreatic cancer.
16:27It includes individuals with
16:29mutations and P-16 puts YAGERS,
16:31but also individuals who have
16:33a family history with three or
16:35four first degree relatives.
16:36So these people are at a higher risk
16:39without a known genetic abnormality.
16:41There's also a low to moderate risk that
16:43includes genes that you're familiar with,
16:44such as Braca one bracket,
16:46two other DNA repair genes
16:47like Paul V2 and ATM,
16:49but also again in there is a family
16:52risk of two first degree relatives
16:54and that carries a significant,
16:57albeit low risk than those that have
16:59three first three relatives with no
17:00abnormality identifiable in the germline.
17:04To take care of these
17:06individuals several years back,
17:07we set up a pancreatic cancer early
17:08detection clinic at Yale through smile
17:10through the general support of Smile and
17:12Javier Loras group and in this group.
17:14Currently we're following about 185 patients,
17:16most of them in protocol who are at high
17:19risk of developing pancreatic cancer,
17:21and again, you can see this from this group.
17:23The the majority of patients are actually
17:25individuals who have a strong family history
17:28but do not have any genetic abnormality.
17:30One of the original studies that was done
17:33in this area was that what's called the
17:35Caps three study and these patients are
17:37typically imaged with a variety of CT scans.
17:40Mris and endoscopic ultrasounds,
17:42and a small percentage of them will have an
17:45abnormality that requires surgical resection.
17:47So in Caps 3, for example,
17:50225 patients were enrolled.
17:52Umm?
17:54A total of 216 were ultimately
17:56studied and the majority of these
17:58are the time were familial patients.
18:00This is a multicenter study.
18:03For the majority of patients,
18:04no abnormality was identified,
18:05but you can see that for some of these
18:09patients had a dilated pancreatic duct.
18:11For example, a cyst, probably an ipmn,
18:14and a small percentage ended
18:16up having a solid lesion.
18:17In total,
18:18five of these patients
18:20underwent surgical resection,
18:212 of them had high grade dysplasia,
18:23and three of them had low
18:25grade dysplasia IP and then,
18:27although all five of them ended up
18:29with having either an intermediate
18:30or high grade dysplastic completion.
18:32In the form of a panel lesion.
18:35Very interesting data from these CAP studies.
18:37In fact has been the ability to
18:40collect pancreatic juice and what's
18:42been noticed in individuals who
18:45subsequently developed established
18:46pancreatic Dr Latner carcinoma is
18:48that investigators were able to go
18:50back and look at the pancreatic juice
18:52of these individuals at a time when
18:54they had no radiologic abnormality.
18:56And they were able to identify
18:59either combinations of P53 mutations
19:01or P60 mutations long before a
19:04radiologic abnormality was identified.
19:06So this is another direction to go in
19:09in terms of surveying these patients.
19:12The initial results of the Caps five study,
19:15which is a much larger multicenter study,
19:17which Yale was part have just been
19:20accepted for publication in in JCO in
19:23Caps 5 almost 1500 patients were studied.
19:28A total of nine screen detected
19:31pancreatic cancers were identified,
19:32of which eight were resectable
19:34and seven at a stage 1A,
19:37and when you put that together with some
19:39of the high grade dysplastic lesions,
19:41well over 50% of the patients
19:43enrolled in these studies had an
19:45achievement of what's called a
19:47successful goals surveillance.
19:48So we identified either an early stage
19:51cancer or a high grade dysplastic lesion.
19:54When all the patients from the
19:56caps one through five study
19:58were amalgamated together,
19:59what we were able to demonstrate was
20:02that those patients who were diagnosed
20:04during a surveillance protocol with
20:06pancreatic cancer had a much higher
20:09median survival than those that were
20:11diagnosed outside of surveillance protocol,
20:13showing some form of survival benefit
20:16within this within this initiative.
20:20Anca Chotto you know.
20:21Again, being very productive went and
20:23looked at some of these surveillance
20:25studies that were done more
20:27concerned about what was happening.
20:29Not so much when patients were
20:30initially enrolled, but as they
20:32were followed over a period of time.
20:34He took 13 of the most recent studies
20:37and what he noted was that in 53
20:39patients that were identified with
20:42pancreatic ductal adenocarcinoma.
20:43In these 13 odd studies or so.
20:46Whereas 22 patients or 41% had goals of
20:50surveillance achieved so in early cancer,
20:52a high grade dysplastic,
20:54a very worrisome,
20:55almost 60% of patients had an advanced Lee.
20:58A more advanced lesion including
21:01metastatic lesions.
21:02He tried to look at some of the
21:04factors that might be associated
21:05with these late stage presentations.
21:07It had nothing to do with
21:09surveillance modality,
21:10a baseline imaging abnormality,
21:11even the presence or absence of
21:13a germline mutation.
21:14A lot of the patients who presented
21:16were actually asymptomatic.
21:17We were able to look at the timing of
21:20preceding imaging and most patients
21:22had a normal preceding image.
21:24There was some questions about
21:26diagnostic errors in the in the limited
21:28data that was available and there was
21:29some issue of surveillance adherence.
21:31In some of this data.
21:34And what this leads into is kind
21:36of a growing conversation about
21:37how we can do better.
21:39You're going to see more and more
21:40of these types of studies in
21:42the next couple of years or so.
21:44This is the initial study that
21:45proved this point.
21:46These are patients who had a diagnosis
21:49of pancreatic ductil adenocarcinoma made,
21:52and when we when they went back
21:54over a year or so,
21:55it was said that the pancreatic
21:57cancer could be identified.
21:59So a variety of of methods were
22:03looked at in these individuals.
22:05But issue is with to do with issues
22:08relating to abnormalities that were
22:10identified on imaging that could
22:12be seen and maybe radiomics or some
22:15other feature could help figure that out.
22:17I think it's important to say,
22:18just to summarize,
22:20I'm sorry.
22:30That the the stage of pancreatic
22:32cancer at an early stage is improving,
22:35especially in younger populations,
22:37and the overall survival related
22:39to early stage pancreatic cancer is
22:42increased from about 44% in 2004.
22:45And now getting closer
22:47to about just over 80%.
22:49This is unclear why this is happening,
22:52but may be related to increased
22:54use of abdominal imaging,
22:55and perhaps some of the
22:56surveillance programs.
22:56So we're beginning to gather some
22:59information about the benefit of both
23:02the surveillance programs as well as.
23:04As well as.
23:06Are the outcomes related to
23:09those surveillance programs?
23:10And I'll leave you with this.
23:11Notice something to kind of
23:13look forward within the CAPS
23:14cohort of patients at Hopkins.
23:16Currently there is now open a mutant
23:19Karas targeted vaccine for patients at
23:21risk of developing pancreatic cancer.
23:23This is a phase one study that
23:26requires multiple intramuscular
23:27injections over a period of time.
23:29The initial outcome is for
23:31safety and tolerability,
23:33but they are going to look at changes in
23:36K Ras specific CD8 and CD4T cells at 2.
23:40And that four years.
23:42I'm also interested to know that modern
23:44it does have an M RNA based KRAS target.
23:46These are typically being
23:48used in in oncology trials,
23:50but may actually have a role
23:52in the high risk population to
23:54ultimately prevent and the the
23:57development of pancreatic cancer.
23:59So in summary,
24:00therefore just looking at the time.
24:03We currently are not performing
24:05screening in the general population.
24:07We are focusing on high risk groups,
24:09such as pancreatic cysts.
24:10Although we're trying to get
24:12better at surgical selection,
24:14but also get better at tailoring
24:16individuals who should be surveyed
24:17and those that should not be
24:19with respect to the familial
24:21pancreatic cancer cohort patients,
24:23we're getting better at documenting some of
24:25the outcomes associated with these studies.
24:27Really,
24:28with the view to improving
24:30those outcomes long term.
24:32And I think you'll hear more about nuance.
24:34Set diabetes.
24:35It certainly plays a role.
24:36And it it.
24:37It helps us stratify our
24:39patients with pancreatic cysts
24:40and familial pancreatic cancer.
24:42And I would use this talk just to say
24:44that there are plenty of opportunities
24:46within our group for collaboration,
24:48for additional biomarker developed
24:50development and validation,
24:51but also in the realm of imaging.
24:54And just to say that really it
24:56takes a group of people to try
24:57and keep these studies going.
24:58This is a picture of Ankit who's been
25:01incredibly productive and helpful.
25:02Getting our group up and running by there.
25:04Several other individuals such as
25:06Scott and disease and Ling helping
25:08on the the steady side as well as
25:10our really close and productive
25:12collaboration with Doctor,
25:14Hutch, and Doctor Sharma's lab.
25:15Thank you.
25:18Wonderful doctor Farrell.
25:19Thank you so much for
25:22that really nice overview.
25:24I don't see any questions in the chat,
25:26but if if there are those watching
25:27who have a question, please type it
25:30in and I'll make sure to ask it.
25:33I have a question for you,
25:34so it I'm thinking about the sort
25:36of the root cause of the increased
25:38incidence in pancreatic cancer.
25:40Because we we're seeing an
25:42increase incidence nationally,
25:43but also in the state of Connecticut,
25:45correct?
25:45And so it's either I can't remember
25:49what you said the the number of
25:52pancreatic says of the population
25:54that have pancreatic cysts.
25:55It was.
25:55It seemed like a quite large
25:57number, typically 6,000,000,
25:58is a number that's quoted.
25:59Yeah, if you would do extrapolation
26:01from imaging studies and extrapolate.
26:03Up to to the general population,
26:06so are we seeing an increase in the
26:09instance of cysts or is it diabetes and
26:13therefore with diabetes? Is it obesity?
26:15So what do you think is the root cause
26:18driving this increased incidence?
26:21There's different explanations given for
26:23the different increases specifically
26:25for pancreatic ductil adenocarcinoma.
26:28It's felt that it's also
26:29related to an aging population,
26:31so as the population ages,
26:32that's driving up the overall incidence
26:34of it, so that's one explanation,
26:36but for sure there are other issues
26:38with it and so issues related to.
26:43Like you know, metabolic explanations
26:44and obesity would be one one explanation.
26:47Trying to link that then to pancreatic cysts.
26:49The reason for the large volume of cysts
26:52are perception that there are more.
26:53This is really to just do
26:54with the use of imaging.
26:55So the prevalent use of MRI scans
26:58CT scans has really been driving
27:00why we see more assists.
27:02Also, imaging scans are getting
27:04better so we can see 3 millimeter,
27:05says 2 millimeter cysts on
27:07MRI scans done routinely.
27:09Now the question is.
27:10Can finding those cysts be converted
27:13to a better early detection strategy
27:15for ipms the OR for pancreatic cancer?
27:19The issue is that maybe those cysts
27:22account for 1015% of the total volume
27:25of pancreatic ductal adenocarcinoma.
27:29OK, thank you David.
27:30RIM had a question.
27:32Stage ones went from 40,
27:33some to 80 some percent.
27:35Survival is that due to greater
27:38diagnosis in stage one and have
27:40high stage diagnosis decreased.
27:44So this this phenomenon is from is from
27:47SEER data and all the positive glowing
27:50phenomena has been related to stage one a.
27:53So it has been the increase in incidence,
27:55the increase in survival associated
27:57with stage one as the decrease in age of
28:01diagnosis and it's not seen in the other.
28:04The other stages it's not even seen
28:06in stage twos and for sure it's not
28:09being seen and advanced stages.
28:10So there's something going on
28:12and so it's pure speculation.
28:14Whether it's related to the fact that people
28:16are more worried about pancreatic cysts,
28:18you know our surveillance programs
28:19in high risk individuals that
28:21count for certain population,
28:22but I'm not sure they account for
28:23all that population to switch it,
28:25so there's something going
28:26on that's changing,
28:27but it's it's a unique facet of stage one,
28:30as rather than the global
28:32numbers in in pancreatic cancer,
28:35and then with that year period of
28:38stage one progressing to metastatic,
28:40that's probably explaining in 2030 being the.
28:44Second, cancer mortality related
28:46to pancreatic cancer, correct?
28:49I think that's true,
28:50and I think also because there
28:51have been some significant
28:53improvements in other cancers, right?
28:54So you're seeing you know they're
28:56being slow improvements and having
28:57some improvements in the therapeutic
28:59side for pancreatic cancer.
29:00But you know, we really need to
29:02make a real dent for the early
29:04detection to really kind of begin
29:05to move that needle a bit better.
29:07And then the last question from
29:09Rosa is there also an increase of
29:11incidence in patients with young onset?
29:13And I believe you just.
29:15They said that in answering David's
29:17question, the age of the age of the
29:20diagnosis for the stage 1A's is going down,
29:23not for the other councils but for
29:25the other stages, but the stage one
29:27age of diagnosis has gone down.
29:29There are data about the overall decrease in
29:32the age of diagnosis of pancreatic cancer,
29:34and it may in fact be associated
29:36with slightly different types of
29:37genotypes and molecular profiling and
29:39some of that data has been kind of
29:41presented here at Yale in the past,
29:42so certainly focusing in
29:44on the younger population,
29:45hearing about a younger population.
29:47With pancreatic cancer,
29:48which is certainly very concerning.
29:50Well, thank you so much.
29:52It'd be great to to continue our
29:54our work here with the focus
29:56on Connecticut and how we can
29:58really improve upon the lower
30:00the incidence and or mortality.
30:02So thank you so much.
30:04Thanks very much.
30:06OK, if you can stop sharing and
30:08I'm now I'm delighted to introduce
30:11Doctor Bacillus Vessella who
30:13is chair of our Department of
30:15Environmental Health Sciences in
30:17the Yale School of Public Health.
30:19He's also the Susan Dwight Bliss
30:21professor of epidemiology and
30:22of ophthalmology and visual
30:24science and of the environment.
30:26He received his bachelors in Chemistry
30:28and PhD in biochemical pharmacology
30:30from the University of Ioannina
30:32in Greece and then he trained in
30:35gene environment interactions,
30:37molecular toxicology and pharmacogenetics
30:39at the Department of Environmental
30:42Health in the College of Medicine
30:44at University of Cincinnati.
30:46He's established an internationally
30:48recognized research program
30:50that's been continuously funded by
30:52NIH since 1997 and his research
30:55interests include the etiology.
30:57The molecular mechanisms of
30:58environmentally induced human
31:00disease such as liver disease,
31:02obesity and diabetes,
31:04cancer and neurogenic
31:05neurodegenerative diseases.
31:06His laboratory uses state of the
31:09art integrated approaches that
31:10include metabolomics, lipidomics,
31:12expoza, omics tissue imaging,
31:14mass spec,
31:15deep learning as well as human
31:17cohorts and genetically engineered
31:18mouse models and we are delighted
31:21to have him here today to talk
31:24specifically about alcohol and cancer.
31:27Thank you Vasilis.
31:28Thank you many days my microphone.
31:30Yes, my microphone is on.
31:32Thank you very much for your nice work
31:34and thanks also James for pointing
31:37out our T 32 who has helped on the
31:41studies before before I start mine I
31:44also want to address a little bit of
31:47the question of Melinda your question
31:49regarding the increasing density of
31:52cancer lately one of the things that
31:54I would like to point out is we have.
31:57Some increases in environmental exposures,
32:00especially for the perfluorinated compounds,
32:03namely PFAS, which may have
32:06contributed in all all kind of tumors.
32:09I wish we should have a round table another
32:12time to discuss about all these factors.
32:14So today what I'm going to talk to you
32:17about it is molecular mechanisms of
32:20alcohol and cancer, and so we have.
32:24We have edited 3 books on alcohol.
32:27You cancer and one special issue on
32:30chemical biological interactions which
32:33was based on my third international
32:37conference on alcohol and cancer,
32:39which we held it here in Newport.
32:42A couple of just before the COVID
32:46As a matter of fact,
32:47we just received a note from
32:51from Springer that our books doing so
32:54good and alcohol and cancer and they want
32:57us to write another one very much.
33:00But we will see. So I have all there
33:05is this association between alcohol
33:07and cancer and it's actually, you know,
33:11there is epidemiological evidence that
33:13is kind or is convincing that alcohol.
33:16Is associated with several
33:18cancers listed in here.
33:19Mouth fighting, slurring, esophagus,
33:22colon and breast for women and you
33:27know there is some more breast and
33:29liver based on IRC and there is a
33:32probable liver and colorectal for women.
33:35One of the things that I have not
33:37included in this presentation though
33:39and I have to say that as well they
33:42have been epidemiological studies which
33:44indicates that alcohol in sometimes.
33:47Is a positive factor in preventing alcohol,
33:51so I I don't have time to go with that.
33:56I'm gonna stick with the mechanisms today.
33:58Molecular mechanisms of the
34:00alcohol induced cancer.
34:02So let me before we go to that.
34:05And since we're talking about epidemiology
34:08is I want to tell you the categories of
34:12association between alcohol consumption and
34:14cancer and there is first case is sufficient.
34:17Evidence of a causal association,
34:19which is the case for every every study.
34:23There is sufficient
34:25evidence of an association.
34:27There is limited and suggestive
34:30evidence of unappreciation.
34:32Inadequate or insufficient to determine
34:35whether an association exists.
34:38Limited and suggestive.
34:40Evidence to of no association.
34:43This has been described very well in a
34:46paper by our junior faculty just walach.
34:51It was in in 2020 in the International
34:55Journal of Epidemiology,
34:57and this is worth reading it.
34:59One of the problems with alcohol.
35:02Based.
35:04Epidemiological studies is most of the
35:08studies are based on a questionnaire
35:10and rather than having clinical data
35:12in terms of the alcohol consumption
35:15and we know there are certain
35:17biases that could really interfere
35:19with the outcome of the studies,
35:21and this is most of the time
35:23people really are.
35:24You know, don't tell the truth.
35:26So answering the question,
35:27how many drinks you have there per week?
35:30Well maybe 1,
35:31maybe you know and could be just a bottle.
35:34Of of of of Hard Liquor per week.
35:38So this may create some problems,
35:40and this is what I'm trying to introduce.
35:43A new term which called the ALCOM,
35:45which is a panel of markets that could
35:48indicate what is your alcohol consumption
35:51throughout the years of your life.
35:53So in December 2020 I I was involved
35:59in an NCI workshop that we presented.
36:03You know the existing.
36:05Knowledge and everything.
36:06Evidence and gaps across the cancer
36:09continuum regarding the alcohol and cancer.
36:12So we have looked at from epidemiology to
36:16and biology of the alcohol and cancer risk.
36:20What needs to be addressed and how
36:23we can really work in preventing
36:26you know this alcohol consumption
36:29that could lead to cancer.
36:31Again,
36:32this is a readily available to everybody.
36:36And I'm going to go directly
36:38to the mechanism,
36:39so I've been working with alcohol metabolism
36:42since day one of my graduate studies,
36:45and that was the metabolism of alcohol,
36:48which actually is involved is been.
36:54Consider it as the mechanism of inducing
36:57cancer so your alcohol, your ethanol,
37:00is metabolized by alcohol dehydrogenases
37:02to an aldehyde which is a powerful.
37:05You know it's an aldehydes
37:07and an electrophile,
37:07which is capable of interacting with
37:10DNA and protein and forming adducts and,
37:14and this is a very important molecule in
37:18here, so ethanol can also be metabolized
37:21by catalase and also by cytochrome P.
37:24The 50s, mostly cytochrome P452 you
37:26want and to a lesser extent by 182.
37:30What happens during the ethanol metabolism.
37:33P4, fifties.
37:33You have generation of reactive
37:36oxygen species.
37:37You have glutathione depletion which
37:39leads to oxidative stress and as
37:41you will see later on we have the
37:44formation of further aldehydes namely
37:464 hydroxy nonenal and malondialdehyde
37:48which are further capable of
37:50causing DNA and protein adducts so.
37:54Ald H2 is the major enzyme
37:57which metabolizes acetaldehyde.
37:59The major product of ethanol,
38:01and it is converted to acetate and then
38:04from the acetate can go to kettle coenzyme,
38:07which can be used as a building
38:10biomolecule for a lot of.
38:13Cells, including the cancer cell,
38:16that's another story.
38:16We don't have the time to go over that today,
38:19so as you can see, the other heads and the
38:22reactive oxygen species are very important.
38:24My lab is focusing in all aldehyde metabolism
38:27and I'll show you a little bit more.
38:29But we also looking at the LDH
38:312 and a LDH 1V1 and a LDH 1A1.
38:35This is aldehyde dehydrogenase enzymes
38:37which they take us at aldehyde and
38:40convert it to acetate.
38:41So again you can see for the risk.
38:44Factors in terms of alcohol drinking
38:47as mentioned earlier there is aids,
38:50the personal history,
38:51family history, race and also diet,
38:54physical activity, obesity,
38:56smoking and alcohol use.
38:58As Melinda and James were mentioning above.
39:01So what Mike what we're doing in my lab
39:04is and I have a center funded by the NAA
39:06as we have all you can see here is this.
39:09The ethanol metabolism and
39:11also glutathione metabolism.
39:12They the synthesis of your major.
39:15Antioxidant of your system here and
39:18what you can see on those red letters.
39:21Are the enzymes involved in these
39:24pathways and we have single and
39:26double knockouts of all these enzymes
39:28which are involved in the eye in
39:31the ethanol metabolism and the
39:32interplay and essentially trying to
39:34clear up the reactive oxygen species
39:37generated and protecting yourselves.
39:39So we just published a review in cancers
39:43on molecular mechanisms of alcohol.
39:45And yours.
39:47Colorectal cancer so this is one
39:49of the area that my lab has been
39:52focusing for a number of years.
39:53We had EU one which I'm planning
39:56to go for the renewal as well and
39:59essentially again you can see that
40:02ethanol metabolism is involved in
40:04here and we have what I described
40:07you before the pathways here.
40:09But one of the things I want to tell
40:11you is the ethanol per se is not only
40:15metabolized by cytochrome P452 one,
40:18but.
40:18Constantly induces increases the
40:21levels of cytochrome P452E1 why?
40:24This is important?
40:25Because 2 E one it can metabolize
40:28the processing loggens into the
40:31carcinogens and that is very important
40:34and other area of the cytochrome P.
40:37For the two one it can increase
40:39the cell proliferation and also
40:41as we discussed it can create
40:43reactive boxes and species.
40:44The other is the important
40:46roles of both sides.
40:48From P452 you are and also you
40:50know the aldehyde dehydrogenases
40:52in retinoic acid homeostasis,
40:55which they been also involved
40:57in the the whole process.
40:59Another important issue here is
41:01the ratio between NADH and NAD
41:04which is completely changed based
41:07on the ethanol metabolism.
41:09Another area which ethanol could
41:11affect is the one carbon metabolism
41:14and that has effects on the DNA
41:17methylation which can really.
41:19Umm?
41:20Give a lot of.
41:24Changes in DNA methylation associated
41:26with cancer, as I told you before,
41:28I get there may can be used as macromolecule
41:32biosynthesis including including
41:34in the cancer cells we have a lot.
41:37I don't have the time to go,
41:39I just want to give you a brief
41:41overview of what's going on.
41:42So one of the major thing.
41:43So here if we can focus is you
41:46have the the adduct formation,
41:49the DNA and the proteins.
41:51I'm just going to show you
41:52some examples of the DNA.
41:53And we're gonna talk about
41:55some the inflammation as well,
41:58and we're gonna go from there.
42:00So what happened with the
42:02acetaldehyde and also the other
42:04aldehyde generating the DNA attacks?
42:06So these aldehydes are both in electrophiles,
42:09they can interact with
42:10bases of the DNA, and
42:11they can form others. And
42:13these adducts then they they are
42:15responsible for causing mutations
42:17into your into your transcripts.
42:20And I said aldehyde by.
42:23Also interact with various amounts.
42:25Can give a crotonaldehyde and
42:28this also conform further.
42:30Adducts in here at the same
42:32time as I mentioned before,
42:34you also have an increased lipid
42:37peroxidation from acetaldehyde,
42:38which is due to the glutathione depletion
42:41which generates further aldehydes for
42:44hydroxyzine on and all, and so on.
42:46So you have another type of the
42:48ethanol the the shock should
42:50go on Guana sitting here.
42:52Another type of attack.
42:53So it is very well documented that
42:56both acetaldehyde per se or the
42:59byproduct atheists that can interact
43:01with DNA that can cause addicts,
43:03and these others can lead to mutations
43:05and they can cause the cancer.
43:06This is a causative effect,
43:08and this is what helped to establish and put.
43:13That the goodbyes,
43:15as ethanol as a cancer agent.
43:19Another area I am not going to go
43:21on this aspects in here what I want
43:24to tell you is that ethanol also
43:26can induce inflammation and changes
43:28in the cytokines and chemokines
43:31and then they can have a various
43:33effects into all the signaling which
43:35essentially they can affect the DNA
43:37repair mechanisms into the system.
43:39So the importance this is less
43:42studied but this is an area that.
43:44We should emphasize and as a matter of fact,
43:48you know, this is what I'm going to tell you.
43:50What we're planning to do in here,
43:51but you know, again,
43:53it is a pathway that ethanol could
43:57affect all these pathways in here,
43:59including the DNA damage,
44:01and you know,
44:02and essentially having the more
44:04further mutations.
44:06So one of the
44:07areas that I am planning to expand
44:10is the immuno metabolism and
44:12this is the interplay between the
44:15monological and metabolic processes.
44:16And as a matter of fact we have
44:19published several papers on the role
44:22of glutathione in the control of
44:24the T cell and macrophage fashions.
44:26But essentially again you can see the
44:30mitochondrial metabolism here and how
44:32the ethanol metabolism can interfere
44:34with that in terms of the cancer.
44:37Incidents. As I told you before,
44:41the ethanol can also.
44:42I mean, alcohol can also affect the
44:45one carbon metabolism and ethanol
44:47can block the absorption of the
44:49folic acid and can interfere with
44:51all the the folate and cycle,
44:54and the methionine cycle which
44:56eventually and as you can see here
44:59in very stages through the either
45:02interacting with proteins and you
45:05know forming adducts or interacting
45:07with pathways or absorption or stuff.
45:10Essentially,
45:10we have a DNA hypermethylation which
45:12can be associated with cancer.
45:15And of course,
45:16you know that's the other pathway
45:18that you know by interfering
45:20with the one carbon metabolism,
45:22you can have decreased through the thione,
45:24which really you know gives
45:27rise to oxidative stress,
45:29which is a result of reactive
45:31oxygen species generated by the
45:34cytochrome P-450 metabolism of
45:36the P42 and taking a break here.
45:40What I wanted to tell you is,
45:42in the slide before here
45:44is the broker synonyms.
45:46We have a lot of Procter
45:48synonyms exposed in our lives,
45:50so if alcohol induces the
45:52site from P452 you want,
45:54then we have increased levels
45:55of the two you want.
45:57So I've been exposed to dimethyl nitrosamine,
46:00for example the nitrosamines or the P.
46:02Fashion everything.
46:03Then you can have a further activation
46:06of this carcinogens and you can
46:08have this generation of reactive.
46:10Which is in species and further mutation.
46:13I'm gonna end up very quick.
46:15I'm gonna talk. I'm not gonna spend
46:18my time you all know the incidence of
46:20the colon cancer and what is going on.
46:23But my lab has been focusing on the colon
46:26cancer and alcohol metabolism we have.
46:30We were the first to clone the
46:32secondary enzyme. If you remember,
46:34said aldehyde is metabolized
46:36to acetate by the aldehyde.
46:39Progenesis Ald. Stew is
46:41the major enzyme, but we did
46:43found we cloned this enzyme and
46:46mitochondrial enzyme which is very
46:49similar to a LH2 and we cloned it.
46:52We expressed it throughout the
46:54years we made beautiful antibodies.
46:56We made the cover pages of several
46:59journals and we found that
47:02first of all that metabolizes
47:03acetaldehyde with very high affinity,
47:05which is makes it as equal as a LD.
47:08It's too in terms of clearing.
47:11The acetaldehyde but also what we found
47:14out is this enzyme is also involved
47:17into the retinoic acid metabolism,
47:19which is very important.
47:21So one of the things in early
47:24we found out that aldh 1B1 is a
47:28potential biomarker for colon cancer,
47:30so we have screened several
47:32several panels of humors,
47:35and we found that especially
47:37for colon cancer,
47:38every single column cancer sample.
47:41But we have tested.
47:43It really expresses AL H1B1
47:46at the very high level, very
47:48high level and which we didn't see it
47:50in long breast on ovary or anything.
47:53And it was especially this it
47:55was not a LH1A1, it was a L
47:58H1B1 and this has to do also.
48:00You know with the colony
48:02formation and everything else.
48:03So we also in addition to colon cancer.
48:06We have also found out that
48:10ADH 1B1 plays a really big.
48:11Call in pancreatic cancer.
48:13Trying to make a connection
48:14with James talk earlier on,
48:17so this is the AL H1B1 and then you can
48:22series really high expression of this
48:24in the pancreatic Andrew carcinoma.
48:26So one of the things that actually
48:30you can use that as a prognostic
48:32market is you can take the tumor
48:34and then you can really isolate aldh
48:37positive and aldh negative sales,
48:40and then you can put them in culture.
48:42As you can see,
48:43if aldehyde hydrogenase is not present,
48:45you have very small formation
48:47of the colonies,
48:48but if they LDH positive you have
48:50really have seen the tumor formation.
48:53So for somehow this a LDH is involved
48:57in the tumor proliferation initiation.
48:59I don't know we're still looking at the
49:03role of this throughout either through the.
49:05DNA repair mechanisms,
49:07or through retinoic acid.
49:09It's an active area,
49:09so we have several papers on the
49:13how the Ald H1B1 could be that,
49:15and we found out that can be
49:18modulating the wind better.
49:20Catherine Pathway and the the also
49:24P1K they get signaling pathway,
49:27but the most important thing,
49:28and this is a work that we have
49:30done and we have identified that it
49:34is immunohistochemical market for.
49:36Further,
49:36for colorectal cancers and we look
49:39at that and several several samples
49:42and including some comparisons
49:44that we have done here at Yale.
49:47So it's a very strong market for that.
49:50And whereas as I said,
49:52we're still looking on what is going on.
49:55So one of the ways that we have trying
49:57to address the role of this is we
50:00have generated specific knockouts,
50:02so it's a tissue specific inducible knockout.
50:06The triple knockout mice show
50:07the APC mean mice.
50:09We know that the they are forming,
50:13they're
50:14forming many cancers.
50:15So anyway to make time is running
50:18we have generated a triple knockout
50:20of this with a PC and everything.
50:23So this mice we have found out that
50:26this is the ASPCA knockout and this
50:28is the well typed knockout mice
50:31and this is the experiment.
50:33This is how we generate it.
50:34It was a painful process.
50:36Triple knockout is not an easy way to do it,
50:39but the way that you're doing that
50:40is you have an industrial model,
50:42you you treat them with tamoxifen,
50:44you delete the gene and then you can
50:47further figure out of what's going on.
50:49So we did not find anything
50:52any difference in the.
50:54Vehicle treated mice and also in
50:57the tamoxifen treated groups at
50:59the numbers were not evident in
51:01jejunum or ileum in these mice.
51:03However, we did find the
51:06carcinoma colorectal adenomas,
51:08which in the knockout developed significant
51:11loan numbers of the macro and enormous.
51:15And there was a significant reduction in
51:18the total macroadenomas in the knockout.
51:20So, when we knockout the gene
51:22in a model that.
51:24Induces
51:27colorectal and the normas, uh it is the gene.
51:32If you knock out the aldehyde progenesis
51:34you reduce you can see that you reduce.
51:36So this confirms our initial studies
51:40that the ALDH 1B1 it is involved in the
51:44development of under cellular carcinomas.
51:48And we have been trying to to dissect
51:51more more involvement of this gene and we
51:54didn't see any difference at the P53 level.
51:58But we did see a decreased expression of
52:01the beta catenin in the knockout, a LH now
52:06beta catenin knockout for beta catenin.
52:11Expression which you know that Becca
52:13took Catenin is plays an important
52:15role in the development.
52:16All colon carcinoma.
52:19So the expression of of 191 could be used as
52:25a novel biomarker in identified colorectal
52:28cancers and also in pancreatic cancers.
52:31The Althe knocked down because
52:33the dramatic reduction of humor,
52:35growth, and loss of function of APC,
52:38and options of.
52:39Maybe it's trying to be 1 reduces the
52:42column adenoma and in turn delays
52:44that emerged in the progression
52:46of cancer in that to that effect.
52:49I have collaborated with.
52:53And cuts and we have developed
52:56special specific inhibitors of the
52:58aldehyde dehydrogenases that could
53:00be used for delaying the expression,
53:04delaying the progression of the
53:06tumor once it's been detected so.
53:11It looks like the Ald H1B1 is a
53:13key player in this carcinogenesis,
53:16so if I can go back a little bit on
53:19the molecular mechanisms to conclude my
53:22studies in here and the the directions
53:24is the alcohol metabolism is a key
53:27player through the cytochrome P-450,
53:29or through the aldehydes
53:31generated in here and then.
53:33You have also the changes in the
53:36NADH NADH ratio, which we can have
53:39also have epigenetic modifications.
53:41Remember reactive oxygen species.
53:43They can cause the inflammation
53:45that can lead to cancer.
53:46In addition to that,
53:47you also, as mentioned,
53:49this is very important here.
53:51This is especially with increased
53:53exposure to environmental casino egens
53:56the high levels of the two one they
53:59can lead to DNA damage segmentation.
54:01Then they can cause cancer.
54:03And of course you know the DNA repair
54:06can be also be affected by both the
54:08two U one and also the alcohol.
54:11Double so a very important process in here,
54:14and this is where we're focusing as well.
54:16Is how ethanol metabolism could the could.
54:21Have a defect in the day DNA
54:24repair as well and as I mentioned,
54:26also you know we have the one carbon
54:29metabolism and DNA methylation.
54:31I didn't have time to go on your micro
54:34RNA in here but also I did mention
54:37the crosstalk between these pathways.
54:39The alcohol and the immune system
54:41which eventually they can end up in
54:43causing epigenetic modifications
54:44that they can cause the cancer.
54:47This is a slide that the best
54:49slide that I've seen in terms of.
54:51Mark concluding all the effects of
54:55the alcohol in terms of the cancer,
54:57and this was from the former director
55:00of the metabolism of the NAIA SAMSARIC,
55:02who is a very good friend and
55:04colleague of mine,
55:05and I want to tell you this slide is I'm,
55:09you know, a little bit sad,
55:11but my next fifth international
55:13conference on alcohol and cancer
55:15was going to be in in Greece 2021.
55:18Unfortunately with the COVID we
55:20have to move it ahead and probably.
55:23It's not gonna be 2022.
55:25It's gonna be probably
55:272023 and I expect to see quite a few of our
55:31Yale colleagues here. Thank you,
55:34Melinda. I'm going to stop and
55:35get some time for questions. Thank
55:37you vicellous.
55:38Count me in on a trip to Greece.
55:41I know you just returned
55:43and I wasn't invited.
55:44Anyway to the topic at hand.
55:47I was intrigued at the beginning of
55:49your talk when you were talking about
55:51measurement error and the fact that often.
55:54We measure alcohol intake through
55:56questionnaire and we know there's
55:58a lot of misclassification with
56:00that underreporting, perhaps,
56:02and then that misclassification
56:06really attenuates the, say,
56:08the hazard ratio to the null.
56:10So in reality the impact of
56:12alcohol on cancer is probably
56:15even higher than noted in studies,
56:18but you then mentioned what
56:20do you call an alcohol zone
56:22or something of a channel of.
56:24Can you can you discuss that briefly?
56:26A little bit more So what
56:28we you see. Also show me this term
56:31similar to the Exposome and I'm
56:33trying to pattern actually this word,
56:36so I'm trying to figure out
56:38through animal studies and human
56:41studies how I can define a.
56:45Motif of changes that you can utilize
56:50by looking at the blood and finally
56:53modeling it to how much alcohol the one
56:57person has consumed during lifetime.
57:00This is not an easy task.
57:02OK, so because one of The thing is
57:05remember you can drink alcohol and then
57:08even if you measure a few of the enzymes,
57:11you're a pathic enzymes if you have.
57:13If you have abstinence of alcohol.
57:15Delivery cover so you don't know to
57:18how much alcohol you have drunk,
57:20So what we're trying to do is we're
57:23trying to have a a more educated.
57:28Measurement of determining how
57:30much alcohol a person have done
57:33throughout life and the same
57:36thing as the explosion concept.
57:38As I said, it's not easy,
57:39but we're trying to do that and
57:41we're trying to do with animal
57:42studies and also with human studies.
57:44This is one of the of the
57:46ways that it can help.
57:48Really, the epidemiology to assess you
57:51know the causal effects of alcohol because
57:53they this is another area of big debate.
57:56Melinda, as you know, you know,
57:57there was a couple of years ago
57:59there was one paper from New Zealand
58:01and it's saying all the women,
58:02even if they have one one drink.
58:05Per year they can develop colon,
58:08I mean breast cancer and if you look
58:10at really of these studies they were,
58:12you know,
58:13based everything on on on,
58:15on just the questioners.
58:17And as I said,
58:18this is not the accurate measure to do this.
58:23Yeah, yes, I agree.
58:24So much work to be done. Well.
58:27Thank you so much to both of
58:29our speakers today and if others
58:32who tuned in have questions,
58:34I'm sure you can reach out to both
58:37our speakers via email and hopefully
58:39there will be some collaborations.
58:41Initiated from today's talk. Thank you.
58:44Both have a great rest of the day.
58:46Thank you.