Peritoneal Surface Malignancies: Novel therapeutics and insights

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&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.