Peritoneal Surface Malignancies: Novel therapeutics and insights

April 04, 2023

Yale Cancer Center Grand Rounds | April 4, 2023

Presentation by: Dr. Kiran Turaga

Information

ID: 9802
To Cite: DCA Citation Guide

Download Transcript

00:00It is. My name is Pam Koons.
00:03I'm a GI medical oncologist and the
00:05director of the Center for GI Cancers.
00:07It's my great pleasure to get to
00:11introduce Doctor Kiran Taraga as
00:13today's speaker and welcome to those
00:15in person and everybody online.
00:18So Doctor Traga is a professor of
00:20surgery and the division Chief of
00:21Surgical Oncology in the Department
00:23of Surgery and the Assistant medical
00:25director for the Clinical Trials Office.
00:28At Yale Cancer Center,
00:29he joined Yale in fall of 22,
00:33and I'm from the University of Chicago,
00:35where he was vice chief of the
00:37section of General Surgery and
00:39Surgical Oncology and director of
00:41the surgical GI Cancer program.
00:43He is considered a national,
00:46international thought leader in the
00:49management of Oligometastatic disease
00:50and is an expert in regional perfusion,
00:53including hyperthermic intraperitoneal
00:55chemotherapy or hypec.
00:58This is a technique that delivers
01:01chemotherapy intraparate mealy
01:03following resection of visible
01:05tumors and his research focuses in
01:08this space specifically on clinical
01:11trials exploring the interface of
01:13immunotherapy and liquid biopsy and
01:15the surgical management of cancers.
01:17I can say personally it's been really
01:19just wonderful to have you here,
01:21Karen and is he is a fantastic
01:23collaborator for the scientists
01:24in the room and in the zoom room
01:26I'm putting in a plug that he is
01:29looking for potential partners.
01:30So I'm.
01:31So Karen,
01:31thank you for joining us today,
01:39but thank you Doctor Koons and
01:41thank you everyone for coming today.
01:44I, I, I took the liberty to of sharing some,
01:47some slides which have some
01:49of our research interests.
01:50And so forgive me if it seems like
01:53there's just so many topics we're
01:55covering it just we'll hopefully share
01:56with you how excited I am about this
01:58field and how much I would love to get
02:00all of you excited about it as well.
02:04Renee, do you know if I can
02:05turn some of the lights
02:07down around this space here?
02:08Because I think I have some
02:09videos I was running here.
02:13So I am a surgeon and it is
02:14lunchtime and I do apologize.
02:16I'm going to show some pictures.
02:17I tried to kind of reduce the
02:20number of pictures I have.
02:22I do consult for I've I've just
02:24done some consulting for Mark,
02:26but it's not anything I'm
02:27going to speak about today.
02:29So in 2016 there was this this
02:31news frenzy that I'm sure most
02:33of you probably didn't even see,
02:36but it said a new organ has been discovered.
02:38And this is a based on a paper
02:41published in Lancet gastroenterology,
02:42hepatology and the new organ was the
02:45the peritoneum and the mesentery.
02:48And so for all of us surgeons in
02:49the room we laughed because you
02:51know this is something people have
02:52known for thousands of years.
02:54But I think what you're seeing
02:55in this schematic over here is
02:57you're seeing the the colon.
02:58So you can see in in the the panel C here
03:06I guess. So in the panel C here,
03:09maybe I'll just move my mouth
03:10so everyone can see it.
03:11So in the panel C,
03:11you can sort of see how the mesentery
03:13kind of wraps around the colon.
03:15And I tell patients the peritoneum
03:17is just sort of like a membrane,
03:19which is essentially like Saran wrap.
03:21It's essentially as thin as Saran wrap,
03:23but it has some remarkable functions.
03:25It it has, you know,
03:27it clears a lot of endotoxins,
03:29bacteria, there's macrophages,
03:30there's some T cells in that.
03:33It has very important roles
03:35in cellular adhesions.
03:37And so it's a very interesting thing.
03:38And as surgeons we notice
03:40this because cancers when they
03:41spread to the peritoneal lining,
03:43they rarely cross the peritoneal barrier.
03:45So it's a very interesting phenomenon
03:47that such a thin membrane can actually
03:50restrict tumors within this membrane.
03:52And so it's a very exciting
03:54sort of space to think about.
03:56And you know the biggest question
03:58is always you know,
03:59where do peritoneal surface
04:00malignancy stand and should we
04:02club all of them together like.
04:04Is the phenotypic expression of
04:06metastasis as the peritoneal metastases,
04:08is that more important or do we think
04:11of cancer is more like gastric cancer,
04:13pancreatic cancer,
04:14liver cancer?
04:14And so is it more Histology
04:17specific in terms of where they
04:19start or the phenotypic expression?
04:21And I would argue that it is
04:22a combination of both.
04:23So I think clearly you have to
04:26recognize Histology specific,
04:27you have to think about the
04:28somatic mutations,
04:29you have to think about
04:30what the primary tumor is.
04:32The tumors that spread to the
04:34peritoneum are somewhat bound by
04:36some some general common principles,
04:38which is that they tend to spread
04:40in a very different way than
04:42hematogenous or lymphatic spread.
04:44So they rarely spread,
04:45you know,
04:46beyond sort of these spaces and
04:48they spread by almost contact.
04:50It's a very bizarre phenomenon when
04:52we open the abdomen and we look.
04:54It's always in spaces which are
04:56sort of sequestered where the flow
04:57of peritoneal fluid gets stopped.
04:59So the right diaphragm for instance
05:01or by the ligament of trite,
05:02so just a very mechanical sort
05:04of a problem that we see.
05:06And in this talk when we're talking
05:08about peritoneal metastasis,
05:09you know generally we're thinking
05:11of secondary peritoneal tumors,
05:13so tumors that have started at
05:14another site and then spread to
05:16the peritoneum even though there
05:17are primary peritoneal malignancies
05:19like mesothelioma or decimal
05:20plastic small round cell tumors.
05:22That occur in in the peritoneum itself.
05:26Now the the question is how do we
05:28estimate the incidence of this?
05:30Is this a big problem or is
05:31this a very small problem?
05:33And the answer is we don't exactly
05:35know how big the problem is.
05:37But I would contend and we've done
05:38the math on this and we've kind
05:41of looked at this annually there's
05:43probably about 100 to 150,000
05:44patients with peritoneal metastases
05:46that are diagnosed every year.
05:49If you add up everyone that's a lot,
05:51that's about three times the number of
05:53new pancreas cancer diagnosis every year.
05:55So it it is something phenotypically is a
05:58very large but heterogeneous population
06:01and I I've shown this slide many times.
06:03So those of you that have heard this talk,
06:04you know or heard some version of my
06:06talk have seen this slide, but I don't,
06:08I won't apologize for it because I
06:11do think this was a very important
06:13part in my life in deciding how and
06:15why to do paranew metastasis.
06:17And this was a young patient who had
06:20colon cancer and had clean scans and
06:22presented with a bowel obstruction.
06:24And I explored his abdomen over
06:25here and and for you know,
06:27those of you in the room,
06:29what we're seeing here,
06:30you know, this is the liver,
06:31this is the head of the patient.
06:33You can see the graphic there,
06:34the liver right
06:35there, the transfer of stolen
06:36is right here. And the
06:38sheet of Elmer's glue,
06:40that was his peripheral metastasis and.
06:43And it was very unfortunate that
06:45despite our best treatments and the
06:47best surveillance and the best scans,
06:48we just could not help this young
06:50patient who then succumbed to this
06:52cancer in a few months after this.
06:54So. So it's a,
06:55it was a very thought provoking problem
06:58that I have dedicated my career to.
07:02And so First off,
07:03I would just say that peritoneum metastases
07:05are much more common than we think they are.
07:07And and why is that?
07:09Well, think about it this way if you cannot.
07:11Detected on CT scans or PET scans or Mri's,
07:14you cannot actually measure it.
07:16So in this, in this graphic that one
07:18of our residents made many years ago,
07:21we just looked at all the
07:23different sort of sources of
07:25incidence of peritoneal metastases.
07:26And if you look at the NCCN text,
07:28which comes from randomized trials
07:30which require resist measurable tumor,
07:32which means you should be
07:33able to measure the tumor,
07:35the incidence only seems 2% or 3%.
07:37But if you actually look at autopsy series,
07:39which are dominated by patients
07:41probably who die of different reasons,
07:44but when you look in that,
07:45the incidence of metastasis
07:46is as much as 20%.
07:47And this is only for colon cancer.
07:49So I imagine 135,000 new
07:51colon cancers a year,
07:52140 and you have 20% of them
07:55with peritoneal metastasis.
07:56And if they're mucinous tumors, it's 40%.
07:58So it's a much higher incidence.
08:00But the problem is we don't
08:02know where the reality is.
08:04Because we don't know how to
08:05measure pertinal metastasis.
08:06So that's one of the big problems
08:08and challenges that are there.
08:10I think the second is that these patients
08:12don't have clinical trials for them often.
08:15Why?
08:15Because we can't measure it.
08:16If you can't measure it,
08:17there's no drug company that's willing
08:18to give you a drug to put these
08:21patients on clinical trials because
08:22you don't have measurable disease.
08:23So how do you know if your
08:25drug is working or not?
08:25And that's the biggest challenge we all face.
08:28And in fact,
08:28this is one of the papers that one of our
08:30fellows had looked at many years ago.
08:32In which we saw that for colon cancer,
08:34there were 46,000 patients at that
08:35time point who had been enrolled
08:37in clinical trials of which only
08:39600 had some version of peritoneal
08:41disease and there was no outcomes
08:42reported for these folks.
08:44So a very excluded population of patients,
08:47a very big population of patients,
08:49but excluded from clinical trials and
08:51excluded from from a lot of treatments.
08:54And the problem then becomes those
08:56that do get enrolled on clinical
08:57trials or those that have widespread
08:59disease or very measurable disease,
09:01they have big tumors, lumpy tumors.
09:03And so we look at these graphs
09:05and we're very nihilistic.
09:06We're like, ah, pertinent metastases.
09:08It's,
09:08you know,
09:08not something that we would
09:09take care of and these patients
09:11should just go to Hospice.
09:12And I think palliative care is very important
09:14in the management of these patients,
09:16but but just being very nihilistic about this
09:18disease is not fair to these patients either.
09:21And in fact, so much so that almost
09:23five or six years ago, in fact,
09:24when I started and when I had that graphic,
09:26none of the surgical textbooks had a
09:28chapter about peritoneal metastasis.
09:30It's remarkable.
09:30Now we do have many chapters because
09:33of our constant advocacy work.
09:36And then finally, you know,
09:37when you think about sort of this
09:38nihilism around peritoneal metastasis,
09:40the question is why?
09:41Why are these patients dying?
09:42Are they dying of cancer, cataxia?
09:44Do they die because these patients have
09:46this sort of overwhelming interleukin
09:47response that they can't eat or
09:49drink and they kind of waste away?
09:51Is this a catabolic phenomena like
09:53that or the are they just dying
09:55because they have bowel obstructions?
09:57It's like if someone had renal failure and
09:59you don't put them on dialysis and they die,
10:01you wouldn't say,
10:02Oh my God, you know,
10:03renal failure is such a horrible problem
10:05it it is a horrible problem because
10:06you don't have treatment for it,
10:08but if someone has a bowel obstruction
10:10and and you are unable to fix it.
10:13You know is that is that truly
10:15more the nature of the disease or
10:16is it the biology of these tumors.
10:19And so one of my colleagues at
10:21the University of Chicago,
10:22Ralph Wexselbaum,
10:23who's one of the the world leaders in in
10:25the thought process of oligo metastasis
10:27actually coined the term oligo metastasis.
10:29And when you look at sort of
10:32colorectal and this is colorectal
10:34metastasis with liver tumors,
10:35there's a completely differential
10:37expression of micro RNAs.
10:38There's very different profiles and.
10:40And they published a lot of subsequent
10:42work looking at immune rich profiles
10:43which seem to do really well.
10:45These patients.
10:45If you look at the X axis on
10:47the survival curve over here,
10:48it's 10 plus years,
10:50almost 15 years and you have about
10:5240-40 to 60% of patients actually living
10:55that long when you have this sort of
10:58appropriate expression of of your tumor.
11:01And and and this is one of those
11:03experiments where you know in this
11:04specific case they looked at micro
11:06RNA200C and you basically have vial
11:08type versus those that express it.
11:10And of course you can see an oligo
11:12metastatic phenotype which is
11:14eligible for surgical therapies,
11:15radiation or ablation,
11:17ablative therapies versus those patients
11:19that have Poly metastatic phenotypes.
11:22And and similarly when you when you
11:25essentially reduce the expression of
11:26these micro RNAs you can actually
11:28these are these are rat livers and so
11:31they kind of look funky but you can
11:32see sort of some of these will have
11:34oligometastatic disease some of these
11:36will have polymetastatic disease.
11:37So clearly there is a differential
11:39phenotype of patients that can be cured.
11:42So not all stage 4 cancer is the same
11:44is is sort of where I I I would try to
11:46say these three slides or
11:47what what I wanted to convey.
11:50And so you know, how do we as surgeons
11:52approach a problem like this?
11:53You know, very often we would see
11:55patients with peritoneal metastasis.
11:56So you can see the livers down here,
11:58it's a large amount of peritoneal
12:00metastasis is the phals form ligament.
12:02And very often surgeons would come
12:03out of these cases saying, oh gosh,
12:05we cannot do anything for these patients.
12:07But we've subsequently developed
12:08techniques called peritonectomies.
12:10I tell patients it's like peeling
12:11the wallpaper off the walls.
12:13So essentially you're not
12:14destroying the walls,
12:14but you're actually taking disease out.
12:17And so here you can sort
12:18of see what it looks like,
12:19it's that Saran wrap which is
12:21underneath our our instruments
12:22right here and the same patient
12:24you can actually strip or clean
12:26out that entire peritoneal layer
12:28by keeping an intact peritoneal
12:29SAC so that you can actually remove
12:31all of this in its entirety.
12:33So it is something that that is
12:35interesting and surgically would
12:37become more more aggressive at it.
12:39But right now this is a very,
12:42you know it is an aggressive approach.
12:43You know you can see this is
12:45a big laparotomy incision.
12:46The head of the patient is on one side,
12:47the feeder on the other.
12:49And after we remove all this cancer,
12:51we put heated intrapartinial
12:52chemotherapy and the concept is why
12:54heated intrapartinial chemotherapy.
12:56The the concept is that you know you
12:58have application of chemotherapy at
13:00high doses which has low toxicity
13:02to systemic absorption is very low,
13:04you can actually enhance the
13:06penetration of the drug.
13:08You know these tumors are very hypovascular,
13:10so you can kind of enhance the
13:12vascularity during that period
13:13of the application.
13:14But again it's,
13:15it's it's a little bit also
13:17controversial because you know
13:18how does one application of
13:20chemotherapy work so effectively
13:21versus multiple applications that
13:23we do in the systemic setting.
13:26And clearly you know now we do these
13:28laparoscopically as well in selected
13:30patients when we find disease early,
13:32so we can deliver heated
13:34chemotherapy that way.
13:35And then also now what is what
13:37is very hot in Europe and Asia
13:39is intrapertinal aerosolized
13:40chemotherapy where you can actually
13:42distribute the drug a lot better
13:44across the entire pertinal cavity.
13:46This is called pipec and over 10,000
13:49procedures have already been done
13:50in the world for these technologies.
13:54And as you would imagine a lot
13:56of these patients require very
13:58close management as as a team,
14:00the team that consists of physicians.
14:02Which consists of nurses and dietitians
14:04and program and only when you do
14:06that you're able to achieve you know,
14:08good outcomes.
14:09And so this is sort of where you know,
14:11we were before I left the
14:13University of Chicago,
14:14we did about 180 procedures a year.
14:17We were able to reduce the length of stay
14:18for patients from 10 days to six days,
14:20the benchmark programs being
14:22MD Anderson and Wake Forest and
14:24readmission rates of 8%.
14:26So it it took a lot of effort for
14:27us to bring this program together.
14:30For patients that that
14:31had pertinum metastases,
14:33but the biggest question is well,
14:34is it, is it helping these patients,
14:36are they living longer?
14:37Is it worthwhile to do these aggressive
14:39approaches for these folks and this
14:41is what happens when patients get
14:43selected patients with good performance
14:45status get systemic chemotherapy,
14:47that's the reference
14:48survival data right here.
14:49And then of course those that
14:51had cytoreductive surgery,
14:51this was our own data for
14:53how these patients did.
14:54Only about 20% of our high grade
14:56patients live 10 years or longer.
14:58So if you look and remember the graph
15:00that I showed earlier for those that
15:01enrolled in NCT and clinical trials
15:03that were good performance status,
15:05patients got systemic chemotherapy.
15:06No one lived more than five years.
15:08So you do have the select population
15:10of patients that you can help.
15:11But the question is where do we go from here?
15:13How do we make this better?
15:15And this is really where I think it's
15:17important for all of us to think about it.
15:19So the first question we
15:20want to ask ourselves is,
15:21can you actually prevent
15:23peritoneal metastasis?
15:24And I'll show you some science behind this,
15:26but something that is very
15:28interesting is that a recent
15:29trial that was just looking at
15:31patients that had T4 colon cancers,
15:34nothing has spread outside and.
15:59On that patients actually have
16:00better local regional control.
16:02If you apply intrapertinal chemotherapy
16:03at the time of a primary cancer
16:05resection without pertinal metastasis,
16:07can you actually,
16:09can you actually reduce that?
16:11And so if you think about it
16:12and this is something I will,
16:14I will tell you is is
16:15very interesting science.
16:16And so this is science that was
16:17done by one of my colleagues
16:19at the University of Chicago.
16:20Where we're thinking about
16:21the intestinal microbiome,
16:22I think many of you might might
16:24have heard about the important
16:25role of the microbiome and thinking
16:27about carcinogenesis as well
16:28as development of metastases.
16:30And clearly in a Peri operative event
16:32we change the microbiome of the intestines.
16:35And so the hypothesis for their
16:37experiments were to look at what
16:38happened if you took a Western diet.
16:40So essentially the experiments
16:41were in in in mice you basically.
16:45Resected the colon,
16:46put colon cancer cells inside it,
16:49and the mice were either fed a vestrin diet,
16:50they were fed chow,
16:52or they were given antibiotics.
16:53And then you gave them a collagenolytic
16:56bacteria called ephycallus,
16:58with the hypothesis that collagenolytic
17:00bacteria cause increase in astomatic leaks.
17:02So this is their work.
17:03This has been their life's work
17:05on this and it's remarkable and
17:06there's lots of experiment that
17:08support that it causes this.
17:09But what was interesting to me.
17:11Is when you actually look at this,
17:13these anastomosis.
17:14So once you've cut the mice,
17:16you put them back together and you
17:18inject collagenolytic bacteria and
17:20then you put colon cancer cells in there.
17:22All the all the tumors that developed
17:24were on the serosal surface and
17:26not on the mucosal surface.
17:28So all of them came on the serosal surface.
17:30A lot of these mice ended up
17:32dying of peritoneal metastasis.
17:33It's a very interesting credence to
17:35the theory that perhaps there may
17:37be a microbial alteration that is
17:39occurring in these in these primary
17:41cancer resections that is leading to
17:43these patients getting peritoneal metastases.
17:45And what is very funny is that one
17:47of our colleagues in Belgium said
17:49maybe the reason mitomycin which is
17:51our intraperitoneal chemotherapy
17:53works is that it is also an antibiotic.
17:55And again it's not been proven,
17:56but it's just a very thought
17:58provoking way of thinking about.
18:00Where the microbiome lies as we think
18:02about why patients get hurt in metastasis,
18:05but if we can find these tumors
18:06and we can actually detect them
18:07early and we can treat them,
18:09these patients beat the survival curves.
18:11So this is the survival of patients that
18:13if they were found early and had surgery,
18:15you can look at the X axis is five
18:17years and you can see that 90% of
18:19these patients are alive at five years.
18:21So really a,
18:22can you prevent them and B,
18:24can you find them if they're
18:26very early and then treat them.
18:27That is sort of really where we
18:29need to move the needle and that's
18:31really where I would love for
18:33us to think about it, about it together.
18:36And so the problem is conventional
18:38cross-sectional imaging.
18:39So this is a CT scan on a coronal view of a
18:42patient and on a cross-sectional imaging,
18:43the peritoneum is incredibly
18:45difficult to image.
18:46So the imaging of the peritoneum,
18:47if you can see my cursor,
18:50which you cannot, is actually this
18:53line that kind of goes along the colon.
18:56It's this sort of little little fun time
18:58stuff here. This stuff right there,
19:00that's the first name right there.
19:02And so it is, it is very difficult for
19:04us to believe that our radiologists
19:06are going to be able to tell us that
19:09a patient has peritoneal metastasis.
19:10It is just not feasible.
19:12You can certainly tell if someone
19:13has liver metastasis or not,
19:14but it's very difficult to tell
19:16if they have peritoneal meds.
19:18And so we've played with this
19:19along with many,
19:19many other groups and there's a lot of
19:22radiomics work that folks have done.
19:23We've done our own radiomics work.
19:25We did some work with our physics
19:27group at the University of Chicago
19:28and try to kind of pick up better
19:30ways of looking at the pertinum.
19:32You can look at panel B,
19:33you can sort of see how you can
19:35actually enhance the pertinum better by
19:36kind of playing around with contrast
19:38agents and how do you give it later?
19:39How do you give it earlier and how
19:41does that kind of make a difference?
19:43I think the other thing that
19:44we've very been very,
19:45very interested in is
19:47study of circulating DNA,
19:49whether it's cell free or whether
19:51it's circulating tumor DNA.
19:52And clearly we know as surgeons
19:54that it's very prognostic.
19:56What do we do with that information
19:58is still something we're all
19:59trying to figure out.
19:59But we know that if they're,
20:01if they don't have cell free DNA
20:02prior to surgery and you operate or
20:04at least vary in cell free DNA before
20:06surgery you operate and they stay negative.
20:08These patients will do really well,
20:09whether it's GI cancers of different
20:11types or other types of cancers.
20:14And so this is some of our work
20:15that just got published as well and
20:17was one of the plenary sessions.
20:19Some of you have heard this before.
20:21But really what we did was we took
20:22patients who had peritoneum metastases.
20:24We did surgery for these folks and
20:26then we studied them and followed
20:28them at CTDNA.
20:29We said can we actually figure out
20:31a better way of identifying these
20:33tumors early and the answer was yes,
20:35CTDNA did work for us.
20:36This is a small sample size with
20:38with numerous assessments.
20:39It's not 100% sensitive.
20:40It was only about 90% sensitive in in this,
20:43in this cohort and it it did have
20:46a false negative rate.
20:47So patients who did have undetectable CTDNA,
20:501/5 of them still had peritoneal metastasis.
20:51And in fact if you look at cohorts
20:53of different technologies,
20:55many times you have florid peritoneal
20:57disease and they shed almost no CTDNA.
21:00In fact one of our research fellows
21:01were run in the back has has just
21:03submitted an abstract where if
21:05you have a single solitary liver
21:07metastasis your CTDNA is super high.
21:09But if you have a full abdomen
21:11full of peritoneal metastases,
21:13you have almost no CTDNA in the
21:15range of like point some MTM per ML.
21:17So it's a it's a remarkable phenomenon
21:19that the burden of tumors this
21:21is almost the same or even many
21:23fold more, but it doesn't shed it.
21:24It gives credence to the belief that maybe
21:27local regional treatments like surgery,
21:29intravertinal chemotherapy may have
21:30a role in in these sort of metastatic
21:33settings and then as expected
21:35if they shed DNA they do worse.
21:38If they don't shed DNA,
21:39they do a lot better and that's
21:40sort of what we saw in this.
21:42And the biggest question was we saw
21:44these patients you know three months
21:46before they showed up on scans and
21:48you know ceas and things like that.
21:49But really the bigger question is
21:51what are we going to do with that
21:53information and how do we make
21:55it practical for our patients.
21:56And so you know some of our research
21:58has been focused a lot on looking at
22:01epigenetic modifications and why this
22:03is important is because right now.
22:05We need a large amount of DNA
22:07to actually do CT DNA,
22:08to do other types of cfdna.
22:10And so the question is,
22:11can we actually extract DNA at very
22:12low levels without the bisulphite
22:14conversion so that it doesn't
22:15destroy a lot of the DNA in the
22:17blood and then look at alterations
22:19in a cheap sort of reproducible way?
22:21And so this is where we work with
22:23one of our chemists, Schwan hey,
22:25who actually came and gave chemistry
22:27grand rounds not long ago at Yale.
22:29And a phenomenal colleague and collaborator,
22:31but you know basically looking at
22:325 HMC and now we're looking at 5
22:35MC modifications.
22:36So we have different sorts of
22:38modification profiles and and his
22:40lab has already shown and this is I
22:42think published in cellular science.
22:43But looking at sort of the five
22:46HMC distributions of patients and
22:47you know essentially with with
22:49this you can identify patients who
22:51have cancer versus controls,
22:52you can look at adenomas versus controls.
22:55Adenomas versus cancer and then
22:56what we found was peritoneal disease
22:58versus no peritoneal disease.
22:59We also had understanding of the
23:02mechanistic underpinnings of peritoneal
23:03metastasis and you know I've identified
23:05some epithelial meas and camel
23:07transition markers that potentially
23:08could be part of our signature to
23:11identify peritoneal disease better.
23:13So switching gears a little bit,
23:15you know So what I what I hope I've
23:18emphasized in this first few minutes of
23:20my talk is that peritoneal metastases.
23:22Maybe a heterogeneous group of things.
23:24There may be population of patients that
23:26are treatable with local regional therapies.
23:29We struggle to figure out how
23:31to identify these patients,
23:32whether it's with cross-sectional imaging,
23:34radio omics,
23:34that type of work or whether
23:36it's with cell free DNA work,
23:38although there's promising
23:39avenues in both of these.
23:41So the question comes to how can you actually
23:43think about treating these patients?
23:44Are there things we can do differently?
23:46In clinic,
23:46we often see patients coming and
23:48saying I stopped having sugar
23:49because I was told I have cancer,
23:51I've told sugar feeds these cancers and
23:53really what happens to these tumors.
23:54We believe that these tumors are hypoxic.
23:57We believe that the peritoneum has very
24:00little vasculature as compared to say
24:02the liver and other sort of solid organs
24:04like the lungs and we all know that.
24:08You know tumors as they
24:10develop metastatic potential,
24:11they rely more on anaerobic pathways,
24:15but they also still have location
24:17specific metabolic needs specifically
24:19around oxidated phosphorylation.
24:21And so the question is,
24:22is where are these tumors
24:24getting their their fuel from?
24:26So again can you interrupt this field?
24:28And so we did a couple of trials
24:29with one of my colleagues,
24:30Ernst Langel over there where
24:32we gave patients sort of tracer
24:34labeled glucose and kind of studied
24:36these tumors and and clearly they
24:38go along more anaerobic pathways.
24:40You see a lot more lactate in these
24:43in these tumors and they kind of
24:45use different metabolic substrates
24:47as they're kind of getting it.
24:48But what was very interesting is the omentum,
24:51which is the commonest site
24:53of peritoneum metastases.
24:55And we don't know why it does
24:57have a very rich source of fuel
24:59with it which is adipocytes.
25:00And and in these experiments what
25:03what basically Ernst Group showed
25:05was that when you actually control
25:07for Fab BP4 which is which is
25:12associated integrally with adipocytes,
25:14you can actually reduce the amount
25:17of in vivo metastasis in in mice
25:20and so essentially it is somehow.
25:22You know,
25:23lending critics to the theory that
25:24the momentum and the adipocytes that
25:26are in the momentum are providing
25:28fuel as opposed to a lot of the
25:30vasculature which provides fuel
25:31to these pertinent metastases.
25:33Very interesting preliminary work.
25:34It's again not meant for you know like
25:37inpatient in in patient care right away,
25:40but I think very interesting for us
25:42to think about how do we take care of
25:44these patients and perhaps how do we
25:46think about alteration of adipocytes.
25:48And and the other thing we've
25:49been very interested in is how do
25:51we actually enhance the effect
25:52of intrapertinal chemotherapy,
25:53how do we leverage this to,
25:55to enhance the care of these patients.
25:56So these are patient panels where we had
25:59patients with high grade unresectable tumors,
26:01where we did multiple applications
26:03of intrapertinal chemotherapy only,
26:05no surgery and we actually almost
26:08developed complete pathological
26:09responses as you can see in panel
26:12C for these patients that had very
26:14high grade disease that we would not
26:16have routinely offered surgery for.
26:17And they lived exactly the same
26:19as those that we did open big
26:21cytoreductive surgeries and hypex for.
26:23But what was more interesting was that a
26:25lot of these tumors actually developed
26:26and I don't have that data here,
26:28but they all had alterations in their P,
26:32DL1 expression, their C,
26:33PS:,
26:33scores to the to the factor where we
26:35have now a clinical trial for adding
26:38an intravertinal chemotherapy plus
26:40immunotherapy for these patients
26:42that are otherwise cold tumors.
26:44These are incredibly cold tumors.
26:46If you look at the TCGA Atlas,
26:47a lot of these GI tumors actually
26:49have a lot
26:50of you know sort of hot immune signatures.
26:53But when you actually go to giving these
26:55folks checkpoint inhibition or do any
26:57sort of conventional immunotherapy,
26:59they don't respond as well unless they're MSI
27:01high or they have specific characteristics.
27:03And so with intrapartinal chemotherapy we
27:06believe that you can actually change some of
27:08the the the immune profile of these tumors.
27:12And so I think in the last,
27:13you know maybe 5 or 10
27:15minutes of this of my talk.
27:17You know I just wanted to tell you that
27:19there are numerous unanswered questions in
27:21the management of peritoneal metastasis.
27:23Numerous I will tell you that we
27:25don't even know the basics of the
27:27immune environment of the peritoneum.
27:29It's fascinating.
27:29I was talking to Steve Rosenberg
27:31once and I asked him,
27:32I said do you understand the immune
27:33environment of the peritoneum and
27:34and the bottom line is for for some
27:36you know many of the labs many,
27:37many animal models look at
27:39intrapertinal tumors.
27:40But we actually don't understand what the
27:42native immune environment of the pertinum is.
27:44How is T cell trafficking
27:46happening over there?
27:47What is the repertoire of T cells
27:48that are present in the pertinum.
27:50We understand what happens
27:51when there's peritonitis.
27:52We certainly know that when
27:53someone has inflammation,
27:54what happens to these tumors and how do they,
27:57what happens to the the diseases
27:59and the inflammatory processes.
28:00But we don't actually understand
28:01what happens to these clinically.
28:03How we see this is many times
28:05our patients are dying because
28:07of the inflammatory response.
28:08They die of bowel obstructions
28:09because the tumors create the
28:11significant inflammatory response,
28:12it causes medenteric fibrosis and
28:14then we're unable to fix these bowel
28:16obstructions that these patients have.
28:18And so we don't understand this.
28:20The other work that is very
28:21interesting is that we all know that
28:23the vent beta ketenin pathways are
28:25activated in a lot of these GI tumors
28:26that cause peritoneum metastasis.
28:27But what we have also seen is
28:30the conventional bad actors,
28:31the B RAF mutant tumors.
28:33They don't do as poorly when
28:35they have peritoneal metastasis.
28:36They actually do almost exactly the same.
28:38And indeed it's the big three CA
28:40pathways that are mutated that
28:42seem to predict differently.
28:43So they do differently based on sort
28:45of what they're signaling pathways.
28:47And we don't understand that.
28:48We don't know why that is the case.
28:50And then finally,
28:51there's a lot of science about
28:53pharmacokinetics of drugs and
28:55novel drug delivery.
28:55We know that if you give someone
28:58systemic chemotherapy by the time it
29:00crosses the plasma peritoneal barrier.
29:02The concentration of the drug
29:04depending on the molecular size
29:06of it is one by two to the 10th,
29:07so 1 by 1000 and 24th of the serum
29:10concentration of this chemotherapeutic
29:12and and that is a remarkably low
29:14dose of systemic chemotherapy
29:15when it comes to the peritoneum.
29:18The question is how do you
29:19alter that pharmacokinetics?
29:20How do you actually change
29:21that such that your drug
29:22substrate substrates are able to
29:24actually enter the peritoneum?
29:25And how do you think about
29:27the pharmacokinetics?
29:28I'm just, I just have two like sort of
29:30quick slides for for folks to look at.
29:33And this is the work that was actually
29:34done by one of our medical students.
29:35All the work that I've shown today,
29:37most of it has been done by either our
29:39lab or one of our collaborator labs.
29:40And and it's all been driven
29:42by medical students, residents,
29:43undergraduate research students, fellows.
29:46And so I, I,
29:48we truly have been very hungry for for young,
29:50you know smart minds to come work
29:52with us to help figure out how do we
29:54actually make a difference in this.
29:56And this is just the work looking at
29:58the number of pathways that are altered
30:00for patient with pertinum metastases.
30:01And you know of course the APC pathways
30:03are always affected in a lot of these
30:05GI tumors here as about half of the time.
30:07But the big three kind is which we
30:09thought was the most important pathways
30:11in particular metastasis only about
30:1217% and of course mad for 11% and
30:15then this sort of you know and again
30:17done by one of our medical students.
30:19So,
30:19so remarkable sort of work and then
30:21this is something where we've been
30:23looking at microparticles and how do you
30:25actually deliver microparticle based.
30:27Packlet axle,
30:272 tumors and what we discovered is that
30:29these microparticles are just bound by mucin.
30:32So mucin just kind of binds it
30:33and doesn't let it distribute
30:35within the peritoneal cavity.
30:36And so this is just sort of some
30:38of the other work that's coming out
30:39right now when we've been working with
30:41one of our pharmacologists to try to
30:43figure this out and really finding that,
30:46you know,
30:47it really binds our nanoparticles
30:49and microparticles that we're
30:50introducing in the peritoneal cavity.
30:52So just kind of a very tough space.
30:56But that exactly that is why
30:58it makes it exciting.
30:59That's why we're Yale because,
31:02you know, we don't,
31:02we don't address simple problems.
31:04We want to take on the tough problems.
31:05And I think that's where having
31:06all of you smart folks here is,
31:08is so important and exciting to me.
31:10And so my pitch for all of you would
31:13be that it's a poorly studied field,
31:15but it has a large impact.
31:16There's a huge population of patients
31:19that would benefit tremendously.
31:20From from improvements in the
31:22management of peritoneal metastasis.
31:24So,
31:24so I welcome all of you if you're interested.
31:27There's lots of tissue.
31:28We do laparoscopies for these patients.
31:30We take out tons of tissue.
31:32Sometimes my tissue specimens
31:33go across the alphabet,
31:34which means I have more than
31:3626 specimens per case.
31:38So lots of tissue to be to be drawn.
31:40Most of these patients are very generous.
31:42It is not infrequently once a month
31:44or once twice a month I get an e-mail
31:46of someone who wants to donate
31:47their body to science research.
31:49And that is probably the most generous gift
31:51that any any human being can ever make.
31:53But we don't know what to do with that.
31:55Like what do we do with that.
31:55We don't even have a mechanism of of actually
31:58studying that or or making use of it.
32:00It's a nice window of
32:02opportunities environment.
32:02We're able to give chemotherapeutics.
32:04We're able to give Immunotherapeutics
32:06to patients. We do laparoscopies,
32:08we get biopsies, we go do surgery.
32:102 weeks later, we can actually show
32:12you and get you tissue for how these
32:14patients will do afterwards as well.
32:16I think these patients have
32:18a significantly tough time,
32:19not only with the disease,
32:21the lack of knowledge of the disease.
32:2390% of patients who would come to
32:25my clinic were told they were going
32:26to live less than three months,
32:2790% we actually,
32:28we actually did a survey and we
32:29asked people in our waiting room
32:31and they had been told by some
32:32healthcare provider who did this.
32:34We did a lot of education around this.
32:36We have lots of processes
32:37of working together.
32:39Jen Capital is here and we
32:40were just chatting about this.
32:41But how do we cointegrate palliative
32:42care into our into our clinics
32:44so that we make sure that we're,
32:46we're taking care of the human being
32:48as a whole and not just you know
32:50pertinent metastases or not just GI cancer,
32:51but we're taking care of our,
32:53our patients and appropriately
32:55transitioning when we're not able to
32:57provide them with therapeutic options.
32:59And how do we build clinical trials
33:01in this space you know how do you
33:04advocate for pharma companies.
33:05To to get allow these patients
33:06to get onto clinical trials,
33:08because right now we cannot put
33:09these patients on clinical trials.
33:10Many times you have ascites
33:12that's not enough.
33:13Or if you have tumors which are very small,
33:15don't even fit the 1 centimeter category,
33:17you can't put them on a clinical trial.
33:18So there's a big,
33:20big initiative at the Coke Institute
33:21at MIT where we're trying to get
33:23together to try to figure out how do we,
33:25how do we fix this.
33:26But I think it's a great space
33:28to build a career.
33:28That is what I will tell you when I
33:31started as a surgical oncologist.
33:33You know, every surgical oncologist,
33:34for those of you that may not
33:35know what we do,
33:36we want to do the big
33:38liver pancreas operations.
33:39That is sort of the sexy thing
33:40for us to want to do.
33:41And that's what I wanted to do.
33:42I wanted to do robotic whipples.
33:44That's what I went and trained
33:45and I became an expert in that.
33:47And I said I published the first
33:48series of how to do robotic
33:49whipples and I said this is what
33:51I'm going to make my career on.
33:52And I got a job offer from Milwaukee,
33:55which which changed my life
33:56forever and and I had a job offer
33:59from Mount Sinai and Milwaukee.
34:00And I chose the job offer in Milwaukee,
34:02even though it paid less, just because
34:04I had the right people to work with.
34:05I had good mentors and and that
34:09was the best decision of my life.
34:10But they said, oh, you know,
34:11you can do sort of liver and pancreas,
34:12but why don't you do this stuff?
34:14And I said, oh,
34:15OK and and I started doing it.
34:17And I love my patient population
34:19and I love what I did.
34:20It was a tough problem.
34:21No one else wanted to do it.
34:23And so I got to write the book chapters,
34:24I got to write be at the podiums, I got
34:26to be coming and doing all of this stuff.
34:28And here look at me, I'm,
34:29I'm division chief of surgical oncology,
34:30one of the best divisions in the world.
34:32So it is a remarkable space
34:34and not much has changed.
34:36Yes, some has changed,
34:37but I think it's a great opportunity
34:39for those of you that are excited
34:41to build your careers on this
34:43because there's not those many
34:44people that want to do this stuff
34:45or can do this stuff really well.
34:47So I would say we were looking
34:48for collaborations,
34:49lots of partnerships and
34:51and feel free to reach out.
34:53I do have to acknowledge this is
34:55obviously not a comprehensive group,
34:56but this is some of my group
34:57that we've worked really,
34:58really closely on for understanding
35:00a lot of our chemistry work.
35:02A lot of our fellows and residents that I,
35:05I have not acknowledged,
35:07but I have some of their work in the
35:09in the slides that have really been
35:11very helpful and a lot of funding that
35:13we've had over the years that have
35:15that have supported our research.
35:16So with that I'm going to stop.
35:17I know it's a little early but but
35:19I'd welcome any questions or comments
35:21and and love a good discussion on
35:23this and and of course this is
35:25this is my cell phone and e-mail.
35:26So thank you again for your attention today.
35:28Go ahead
35:30Laura. So
35:44I think this talk
35:48kind of group
35:53together the context of like a
35:57legal mess that you need for.
36:00A lot of life, and normally we obviously
36:04haven't used either reduction a lot
36:06without a care of intent in MGI center.
36:09And I'm hoping you could weigh in on
36:12your perspective on the difference
36:14of what your new goals are when
36:16you're working in this space,
36:18whether you're considering it,
36:21no matter whether you're considering
36:23it like a rapid process or if
36:25that matters and try to discuss
36:27that with people as well.
36:29Yeah. No, great question.
36:30And I I I would say that one of
36:32the things that we've tried to
36:34do quite deliberately is we've,
36:35we've separated the term cycle
36:38reduction from say debulking.
36:39So I think when we use the word
36:42debulking we're talking about
36:43enhancing quality of life.
36:45So those, those are not
36:46very frequent settings,
36:48but we would do debulking procedures if
36:50patients have large amounts of mucinous
36:51societies or large amount of mucin
36:53that is debilitating or large ovarian
36:55metastasis that is making it difficult.
36:57Those are the bulking but non
36:59curative intent procedures.
37:01For the curative intent procedures,
37:03we call them site reduction and we have very
37:05specific goals of what we want to achieve,
37:07which is a CC0 site reduction,
37:09which means there's no visible cancer
37:11with oncological principles of surgery.
37:13So no longer are we satisfied with,
37:16we just go pluck a little something out
37:18and feel like we've done a great job.
37:19We have to be oncologically precise in the
37:21way we're doing our surgical techniques,
37:23just like we are when we're
37:24doing liver resections,
37:25pancreas resections or things like that.
37:27The drawback is we can't image it.
37:29So we don't know what a good,
37:30you know, good or bad job we've done.
37:32And so one of the big things
37:33we've been doing is making sure
37:35our laparoscopy pictures,
37:36our surgical pictures are actually
37:37in the chart and we can review,
37:39review it with the patients because many
37:41times they don't even know what's going on,
37:42right.
37:42They look at the scan and they're like,
37:44oh,
37:44the doctor said I don't have much
37:46cancer and you look inside and
37:47there's just cancer everywhere.
37:49And so, so we're very specific in our intent.
37:52I think, you know,
37:53usually I try to have three
37:55visits with every patient prior.
37:57And in my ideal world with our palliative
38:00care physicians for the three visits,
38:02but really the first visit is where
38:03I kind of give people hope because
38:05most of them have already been told,
38:07you know,
38:07three months they're going to
38:08live and die and whatever.
38:09And I tell them, hey, listen,
38:10this may not be quite the same.
38:11Let's assess it and evaluate it.
38:13The second visit is where we really
38:15just go through the numbers and again,
38:17you know,
38:17you know that very nice essay by
38:19the evolutionary biologist of like
38:20how median is not the mean and,
38:22you know, it's not the message and.
38:24And you know,
38:24it's very hard for patients
38:25to wrap their heads around it,
38:26but I do think it's important
38:28for them or their caregivers to
38:29at least understand what the
38:31reasonable expectations are.
38:32What is our survival data that we have?
38:35What is sort of best case scenario,
38:36what is worst case scenario?
38:38And are we using the hitchhiker model,
38:40like are we trying to keep people
38:41alive like a diabetes chronic
38:42disease type model and saying,
38:44hey,
38:44we'll look for this next
38:45disease site or are
38:46we saying we're going to
38:47go for a cure or not.
38:49And that's where we really have a lot
38:50of conversations about goal matching
38:52and how are we doing the right thing.
38:53And then the third visit is just
38:55much more specific around the
38:56surgical procedure and what does
38:57that involve and everything else.
38:58So, so you know we've tried to
38:59take a very deliberate approach,
39:01but I will tell you that having another
39:04physician or another team member in this
39:08conversation that may not be a surgeon,
39:11you know, very often obviously our
39:13medical oncologist we were Co, you know,
39:15seeing patients or palliative care
39:16physicians was really helpful for patients.
39:19Because, you know, I'm an optimist and I
39:20can sell things different ways, right.
39:21I mean I could say, oh,
39:22you know, surgery is no problem.
39:24I can take care of it.
39:25It's a big no, it'll be fine versus,
39:27you know, Oh my God,
39:28it's a tough surgery and you're
39:29going to do poorly.
39:30So as surgeons,
39:30we have a lot of power in how
39:32we can actually navigate this
39:34conversation and having a sounding
39:36board for the patients to talk to
39:38someone who is perhaps not quite,
39:41you know,
39:42as narrow minded or or as focused
39:44I should say.
39:45Has helped I think generally our
39:47patients make the right decisions
39:49and I think for all of us to also
39:51internalize the fact that you know
39:52to make sure that we're not pushing
39:55therapies on our patients and especially
39:57you know when we're not seeing a
40:00good sort of outcome on the end.
40:01So I think it's a very complex thing.
40:03I mean I think and I'm sure all of us
40:05face it in our clinics every day and
40:08and what I'm saying is probably not unique,
40:10but I think what has helped me.
40:13Is being deliberate about it and
40:14and also it has helped our team.
40:16You know, I will tell you,
40:17we go through cycles of despair even as,
40:20you know, physical teams like our,
40:22our nurses, physicians,
40:23everyone who takes care of these patients.
40:25Because you see people that look
40:26like you could be your friends,
40:28neighbors, colleagues who are
40:29dying a very miserable death.
40:31And you know,
40:32we took care of all these patients
40:34all the way through Hospice.
40:35So it is,
40:36it is a very difficult thing to
40:37to kind of be part of the process.
40:39And so I think it rejuvenates
40:41to have other physicians,
40:42providers and then of course
40:44having a clinic that's balanced
40:45because you have 20 people that are
40:47doing great and you have you know
40:48maybe three or four that are not.
40:50So
40:52we're so thrilled you're here.
40:53I think you've heard me say that
40:55many times and I'll repeat it again.
40:58So I'm going to build on the
40:59conversation that you were more
41:01we're just having and as curious.
41:03Just on into patients that come
41:05to desiring this therapy aren't
41:06a yearly candidates that or maybe
41:09it wants to decide not to pursue
41:11the decide on productive therapy.
41:13And then the other related to that is he
41:15talked about the recovery from that surgery.
41:17So what what does it look like?
41:21Yeah, so I think what when we've
41:23looked at our own data I would say
41:25about 67% of our patients had.
41:28You know, at least a diagnostic
41:30laparoscopy and about 50% of our
41:32patients who came through our doors
41:33ended up having cytoreductive surgery.
41:34So 50% didn't have it.
41:36So as you can tell, we are selective,
41:37but we track our whole cohort.
41:39So we're not just saying, oh,
41:40we're going to just look at those
41:42that we've done surgery and say
41:43this is how well we're doing it.
41:44The second comment is it,
41:46it really dependent on the surgery itself.
41:48So it's a, it's a whole gamut of things.
41:50When we do a laparoscopic hypec,
41:51they go home the same day.
41:52I tell them they can do their normal
41:54physical activities like the next week.
41:56So that's what when we just
41:57do a laparoscopic one,
41:58when we do these big monster
42:00open side reductions, hypex 812,
42:01you know,
42:0214 hour cases right now our median
42:05hospital stays about 5 to 6 days.
42:07But I tell them they feel about
42:0880% of normal in six weeks and they
42:11feel 110% of normal at three months
42:13because now the cancer is better,
42:14so they feel better.
42:15But this is all generally sort
42:17of what things are.
42:18I think the biggest comment we have
42:20during discussion of surgery is not so
42:22much mortality because our mortality rates,
42:24as you saw,
42:25are very low.
42:26It's more about loss of autonomy
42:27and functional independence.
42:28So you know there's an 8% risk
42:31of having failure to thrive.
42:33Which is a difficult problem.
42:34You know then you are on TPN,
42:35you're getting drains,
42:36you have this and that and I think that
42:39is the the the most stressful part of these.
42:42But we've tried to integrate sort
42:43of quality of life initiatives,
42:45you know fertility management,
42:46young patient care,
42:48obviously palliative care and advanced
42:50direct advanced care planning.
42:51So you know the goal is to have
42:52a more comprehensive way that
42:54patients get the most information.
43:00I know that this is a slowly evolving
43:02deal with what we discussed,
43:04but has it been evaluated from a racial,
43:07ethnic standpoint as far as incidents
43:10of care communities along with
43:12outcomes? Yeah.
43:13So I mean, I think we have, you know,
43:15obviously our own cohorts and our
43:17own data that we've looked at.
43:18And in Chicago about 17% of our patients
43:20were African American and I think about,
43:23you know, maybe another 15% were other
43:25ethnicities and everyone else was white.
43:28I think the we, we found that our
43:31African American patients were less
43:33likely to do advanced care planning,
43:35they were less likely to
43:37look in clinical trials.
43:38They were usually presented
43:41with a higher PCI score,
43:44so higher pertinal index,
43:46but actually recovered remarkably the same
43:50from cytoreductive surgery procedures.
43:52In fact you know at some level I would
43:54say that are at least in Chicago
43:56or African American population had
43:58better social structures than some of
44:00our white populations of patients.
44:01And I think it's a very selective
44:03cohort because I think the the
44:04African American patients who were
44:06didn't have the means or lived in
44:07food deserts or things like that,
44:08they probably never made it to our clinics.
44:10So I think you know I'm very
44:12cognizant of that.
44:12But those that did make it to our clinics
44:14actually had remarkable social support,
44:16so much less rates of post
44:18operative depression or you know
44:19so they did pretty well.
44:21From a survival standpoint,
44:22I don't know.
44:23Vrun probably left,
44:23but I don't think we've seen
44:25a significant difference.
44:26But I don't think our cohort is big
44:28enough to make that conclusive.
44:33There are a couple of questions in
44:34the Q&amp;A and the chat. Ask for Nas feeding
44:38those questions. OK, I actually got it.
44:40So Nick, Nick says.
44:43Is there any consistency in localization
44:45in terms of where the metastasis
44:46form in the peritonema momentum?
44:48I'm wondering if it's random or if
44:50it's in proximity to lymphoid tissues.
44:51Nick, you know this is,
44:52this is a phenomenal question and I will
44:54tell you that in our minds as surgeons
44:56there is very remarkable consistency
44:58like we see it on the right diaphragm.
45:00We think it's because there's Milky
45:02spots on the diaphragm, big channels.
45:04We always see it in the momentum.
45:06So those are very common sites.
45:07Mechanistically,
45:07we see it by the ligament of
45:09triads as a very common site.
45:11And then in the pelvic peritoneum,
45:12especially on the left side,
45:13in fact,
45:14you'll see many of these peritoneal
45:15patients will have bowel obstructions
45:17and they obstructed the pelvis as
45:18the sigmoid colon is turning down.
45:20And in those cases,
45:21stents don't work very well.
45:23And so that's usually the thing.
45:24I don't think it's particularly
45:26close to lymphoid tissues,
45:28but I think that's where hopefully
45:30we'll send you some specimens and
45:32you can help us figure it out.
45:34And then I think Guillermo,
45:35Hi Guillermo it's good to see you
45:37as one of our my colleagues from
45:39Mexico who says what are your
45:40thoughts on the debate for drug
45:42combinations on hyper protocols.
45:43I think we just need to do better.
45:46I think you know mitomycin is like
45:47a 60 year old drug and you know
45:49we've we've just got to figure
45:50out better ways of doing it.
45:51So people are looking at
45:53intrapartinal immunotherapy now on
45:54different versions of cytotoxics.
45:56Do
45:58you ever analyzed CTD and A
46:02and? We don't but we we there are
46:05other groups that have looked
46:07at it and certainly it is more
46:09sensitive than serum CT DNA.
46:11But on the flip side it's
46:13logistically impractical.
46:13So you know you have to leave a catheter
46:15in there and measure it and stuff.
46:16So I think that's the the headache with that.
46:22Great, ohh, very good. Thank you so much.
46:24Thank you all for your attention.